CZ20002455A3 - 2,3-Substituted indoles, pharmaceutical compositions based thereon, a method of treatment and methods of manufacture - Google Patents

Abstract

2,3-Substituted indoles of the general formula I, wherein Z represents a hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a -NR2R3 group or a heterocycle; Q represents (a) an optionally substituted phenyl group, (b) an optionally substituted 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms, (c) an optionally substituted 5-membered monocyclic aromatic group containing one heteroatom selected from oxygen, sulfur and nitrogen, which in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms, (d) an optionally substituted cycloalkyl group with 3 to 7 carbon atoms and (e) an optionally substituted benzo-annelated heterocycle; R* 1 represents hydrogen, an alkyl group with 1 to 4 carbon atoms or halogen; R2 and R3 are each independently hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, or CN; X is independently at each occurrence hydrogen, halogen, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkylthio, NO2, NH2, di(alkyl)amino with 1-4 carbon atoms in each alkyl moiety, or CN; and n represents the number 0, 1, 2, 3 or 4. Pharmaceutical compositions useful for treating medical conditions in which prostaglandins are considered to be pathogens, and a method of treating such conditions.

Description

2,3-Substituted indoles, pharmaceutical composition based thereon, method of treatment and methods of production

The invention relates to novel 2,3-substituted indoles as pharmaceutical agents. The invention further relates to pharmaceutical compositions based on these agents and methods for treating or alleviating pain and inflammation and other disorders associated with inflammation, such as arthritis.

State of the art

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and signs and symptoms of arthritis due to their analgesic and anti-inflammatory effects. It is generally believed that the action of NSAIDs is to block the activity of cyclooxygenase (COX), also known as prostaglandin G/H synthase (PGHS), the enzyme that converts arachidonic acid to prostanoids. Prostaglandins, particularly prostaglandin E ₂ (PGE ₂ ), which is the predominant eicosanoid detected in inflammatory conditions, are mediators of pain, fever, and other symptoms associated with inflammation. Inhibition of prostaglandin biosynthesis represents a therapeutic target for the development of anti-inflammatory drugs. However, the therapeutic use of conventional NSAIDs is limited by their associated side effects, such as life-threatening peptic ulcer disease and renal toxicity. An alternative to NSAIDs is the use of corticosteroids. However, long-term therapy using these compounds can also lead to serious side effects.

Recently, two forms of COX have been identified: a constitutive isoform (COX-1) and an inducible isoform (COX-2), the expression of which is increased at sites of inflammation (Vane, J. R, • ·

Mitchell, J. A., Appleton, I, Tomlinson, A., Bishop-Bailey D., Croxtoll, J. , Willoughby, D. A., Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). 0 COX-1 is thought to have a physiological role and is responsible for protecting the gastrointestinal tract and kidneys. In contrast, COX-2 appears to play a pathological role and is the predominant isoform present under conditions of inflammation. The pathological involvement of prostaglandins has been demonstrated in a number of human disease states, such as rheumatoid arthritis and osteoarthritis, pyrexia, asthma, bone resorption, cardiovascular disease, nephrotoxicity, atherosclerosis, hypotension, shock, pain, cancer and Alzheimer's disease. NSAIDs currently on the market inhibit both COX isoforms with small differences in selectivity, which explains their beneficial (COX-2 inhibition) and detrimental (COX-1 inhibition) effects. It is believed that compounds that selectively inhibit prostaglandin biosynthesis by affecting the induction phase of the inducible enzyme cyclooxygenase-2 and/or by affecting the activity of the cyclooxygenase-2 enzyme on arachidonic acid would provide an alternative therapy to the use of NSAIDs or corticosteroids, in which these compounds would exert anti-inflammatory effects without the undesirable side effects associated with COX-1 inhibition.

Various indole compounds are known and are described in several patent applications. International application WO 96/32379 describes N-substituted indole compounds as cGMP-PDE inhibitors. International patent applications WO 96/37467, WO 96/37469, patent publication GB 2283745 A and US patent publication 5,510,368 describe 2-methyl-N-substituted indole compounds as cyclooxygenase-2 inhibitors. Various indole compounds are also described in European patent publication 0 556 949 A2 (Konya, Kazumi et al.) as agents for controlling aquatic polluting organisms. International publication WO97/09308 describes indole compounds as neuropeptide receptor antagonists. In addition, a method for preparing 2-ester-substituted indolines is described in Sci. Pharm. 64, 577, 1996.

The essence of the invention

The subject of the invention are compounds of general formula I

2,3-substituted indoles where

(AND)

Z represents a hydroxy group, an alkoxy group with 1 to carbon atoms, a group -NR ² R ³ or a group of the general formula II or III (CH ₂ ) _r -(CH,) _r _κι γ NJ ^N \__/ VJi-W (II) (ΠΙ) where r represents the number 1, 2, 3 or 4; Y represents a direct bond, oxygen, sulfur or NR ⁴ ; and W represents a hydroxy group or -NR ² R ³ ;

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkyl-4..thio of 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino of 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino of 1 to 4 carbon atoms, CN, HO-alkyl of 1 to 4 carbon atoms, alkoxyalkyl of 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl of 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , ·· titititi

- 5’

• titi (b) (c) (d) (e) dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group listed above in (a-1)

R ¹ represents hydrogen, alkyl of 1 to 4 carbon atoms or halogen;

R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN;

R 1 represents hydrogen or an alkyl group having 1 to 4 carbon atoms;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

and pharmaceutically acceptable salts thereof.

The indole compounds of the invention exhibit inhibitory activity on COX activity. Preferably, the compounds of the invention exhibit inhibitory activity against COX-2, with compounds with COX-2 selectivity being more preferred.

The invention further provides a pharmaceutical composition for the treatment of medical conditions in which prostaglandins are considered to be pathogens, the essence of which consists in containing a compound of general formula I or a pharmaceutically acceptable salt thereof.

The invention also provides a method of treating a condition in which prostaglandins are implicated as pathogens in a mammal, comprising administering to such mammal a therapeutically effective amount of a pharmaceutical composition as described above.

Examples of medical conditions in which prostaglandins are implicated as pathogens include the relief of pain, fever and inflammation in various conditions such as rheumatic fever, symptoms of influenza and other viral infections, the common cold, lower back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis such as rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout, ankylosing spondylitis, systemic lupus erythematosus and juvenile arthritis, bursitis, burns and surgical and dental injuries.

The compounds and pharmaceutical compositions of the present invention can inhibit cellular neoplastic transformation and the growth of tumor metastases, and can therefore be used in the treatment and/or prevention of colon, breast, skin, esophageal, gastric, bladder, lung and liver cancers. The compounds and pharmaceutical compositions of the present invention can inhibit cellular neoplastic transformation and the growth of tumor metastases, and can therefore be used in the treatment and/or prevention of colon, breast, skin, esophageal, gastric, bladder, lung and liver cancers.

The therapeutic compositions of the invention are used in the treatment and/or prevention of cyclooxygenase-mediated proliferative diseases, such as those found in diabetic retinopathy and tumor angiogenesis.

The compounds and pharmaceutical compositions of the present invention can inhibit prostanoid-induced smooth muscle contraction by inhibiting the synthesis of contractile prostanoids. Accordingly, the compounds and pharmaceutical compositions can be used in the treatment of dysmenorrhea, premature labor, asthma, and eosinophil-related disorders, as well as in the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, in the treatment of bone loss (osteoarthritis), stroke, convulsions, migraine, multiple sclerosis, AIDS, and encephalopathy.

Based on their activity on COX-2 and/or specificity for COX-2, as opposed to COX-1, the compounds of the invention are useful as an alternative to conventional NSAIDs, particularly in cases where NSAIDs are contraindicated, such as in patients with ulcers (such as peptic and gastric ulcers), gastritis, regional enterosis, ulcerative colitis, diverticulitis or recurrent gastrointestinal lesions, gastrointestinal bleeding, coagulation disorders such as anemia, such as hypoprothrombinemia, hemophilia and other bleeding disorders; renal disease; and in cases where anticoagulants are administered prior to surgery.

The invention also relates to compounds of general formula 7-VI

B • · where

B represents a suitable protecting group;

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group containing one heteroatom selected from oxygen, sulfur and

nitrogen and in addition to this heteroatom optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(0) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part • · · · · · · ·

Γ2

• ·

moieties, an alkylsulfonylamino group with 1 to 4 carbon atoms and a cycloalkyl group with 3 to 7 carbon atoms;

R ⁵ represents an alkyl group with 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4.

general

The invention further relates to compounds

protecting group;

represents a suitable

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O» · · ·

- ΙΟ -alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms of each of the alkyl parts, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN;

• · ··· · • · · • · · *- ι’5 ·«· ··

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms;

R represents an alkyl group of 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4.

A more detailed description of the invention follows.

The term halogen as used herein means fluorine, chlorine, bromine or iodine.

The term alkyl group with 1 to 4 carbon atoms refers to straight or branched saturated radicals with 1 to 4 carbon atoms. Non-limiting examples thereof include methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

The term propyl group refers to n-propyl or isopropyl group.

·· ····

The term butyl group refers to n-butyl, isobutyl, sec-butyl and tert-butyl groups.

The term alkoxy group means, for example, methoxy, ethoxy, η-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy, tert.butoxy, etc.

The term alkylthio group refers, for example, to methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec.butylthio, tert.butylthio, etc.

The term dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts means, for example, dimethylamino, diethylamino, dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-butylamino, N-ethyl-N-propylamino, etc.

The term alkylamino group with 1 to 4 carbon atoms means, for example, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec.butylamino, tert.butylamino, etc.

The term HO-alkyl with 1 to 4 carbon atoms means, for example, hydroxymethyl-, hydroxyethyl- (for example 1-hydroxyethyl and 2-hydroxyethyl-) and hydroxypropyl- (for example 1-hydroxypropyl-, 2-hydroxypropyl- and 3-hydroxypropyl-) groups.

The term alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part means, for example, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, etc.

The term "halogen-substituted alkyl" refers to an alkyl group as defined above which is substituted with one or more halogen atoms. Non-limiting examples of such groups include chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl,

2.2.2- trichloroethyl group, etc.

The term halogen-substituted alkoxy group means, for example, chloromethoxy, dichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trichloroethoxy, and the like.

The term "cycloalkyl" means a carbocyclic radical having 3 to 7 carbon atoms. Non-limiting examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term aryl group means, for example, phenyl and naphthyl.

A 5-membered monocyclic aromatic group usually contains one heteroatom selected from oxygen, sulfur and nitrogen in the ring and in addition to these heteroatoms, it may optionally contain 1, 2 or 3 nitrogen atoms in the ring. Examples of such 5-membered monocyclic aromatic groups include thienyl, furyl, thiazolyl (for example 1,3-thiazolyl and 1,2-thiazolyl), imidazolyl, pyrrolyl, oxazolyl (for example 1,3-oxazolyl, 1,2-oxazolyl and isoxazolyl), pyrazolyl, tetrazolyl, triazolyl (for example 1,2,3-triazolyl and 1,2,4-triazolyl), oxadiazolyl (for example

1,2,3-oxadiazolyl-), thiadiazolyl (for example 1,3,4-thiadiazolyl- and 1,2,3-thiadiazolyl).

—· .18 **

Examples of 6-membered monocyclic aromatic groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl (e.g. 1,3,5-triazinyl), tetrazinyl, and the like.

Examples of benzo-annelated heterocycles include quinolyl-, isoquinolyl-, cinnolinyl-, quinoxalinyl-, benzoimidazolyl-, benzothiazolyl-, benzoxazolyl-, benzofuryl-, benzothienyl-, indolyl-, isoindolyl-,

ΙΗ-indazolyl-, quinazolinyl-, phthalazinyl group, etc.

For example, the scope of the (ethyl)(ethoxy)pyridyl group includes 3-ethoxy-4-ethyl-2-pyridyl group, 4-ethoxy-3-ethyl-2-pyridyl group, and the like.

The scope of the (chloro)(ethyl)pyridyl group includes, for example, 3-chloro-4-ethyl-2-pyridyl group, 4-chloro-3-ethyl-2-pyridyl group, and the like.

For example, the scope of (fluoro)(ethyl)phenyl includes 3-fluoro-4-ethyl-2-pyridyl, 4-fluoro-3-ethyl-2-pyridyl, and the like.

Preference is given to compounds according to the invention of the general formula I, where Z represents a hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a dimethylamino group, a methylamino group, an amino group, an N-methoxy-N-methylamino group, a 2-cyanoethylamino group, a 2-hydroxyethylamino group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a N-methylpiperazinyl group, a morpholino group, a methoxyamino group, a piperazinyl group, an aminopyrrolidinyl group or an aminoethylamino group.

Furthermore, compounds according to the invention of general formula I are preferred, where • · ·

Z represents a hydroxy group or an alkoxy group having 1 to 2 carbon atoms;

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n ~aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkyl2.0 · · amino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains

- *21*

1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group having 3 to 7 carbon atoms selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which is optionally substituted with one substituent selected from the group consisting of hydroxy, methyl, ethyl, propyl, fluorine, chlorine and trifluoromethyl; and (e) a benzo-fused heterocycle selected from the group consisting of quinolyl, cinnolinyl, quinoxalinyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzofuryl, benzothienyl and indolyl, which is optionally substituted with one, two or three substituents independently selected from the group set forth in (a-1) above.

Further preferred are compounds according to the invention of general formula I, wherein

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino of 1 to 4 carbon atoms in • · ···· · 4 carbon atoms in the alkyl moiety, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and groups -O-(CH ₂ ) _n ~aryl, wherein the aryl group and the aryl moiety are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms

(b) (c) (d) (e) each of alkyl moieties, alkylamino groups of 1 to 4 carbon atoms, and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

cyclopropyl, cyclobutyl or cyclohexyl; and a quinolyl or isoquinolyl group, wherein said quinolyl or isoquinolyl group is optionally substituted with one substituent selected from the group consisting of halogen, alkyl with 1 to 4 carbon atoms, NH ₂ , hydroxy, alkoxy with 1 to 4 carbon atoms, and

- 24 -halogen-substituted alkyl groups with 1 to 4 carbon atoms.

Further preferred are compounds according to the invention of general formula I, wherein

Z represents a hydroxy group or an alkoxy group having 1 to 6 carbon atoms;

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, ·· *·0· *· 9 ·« 0 < « 0 t * · · ««·· • · · ··· · 0 · • 0 · < » · a 0 · « ·

0 _O _0 0 Φ · a « ac · — it® “·· ·* ··· ·· ·«· alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to said heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); and (e) an isoquinolyl group;

R ¹ represents hydrogen or an alkyl group having 1 to 4 carbon atoms;

About

R and R each independently represent hydrogen or methyl;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ Nr2nr3, acetyl, -COOR^, alkylsulfonylamino with 1 to 4 carbon atoms or cycloalkyl with 3 to 7 carbon atoms; and

represents the number 0, 1, 2, or 3.

·· ···· · · • · · · · · · · · · · · · · · · · · ·

Further preferred are compounds according to the invention of general formula I, wherein

Z represents a hydroxy group, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group;

Q represents (a) phenyl optionally substituted with one or two substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl portion and 1 to 4 carbon atoms in the alkyl portion, -COOH, alkylsulfonylamino with 1 to 4 carbon atoms, nitro, alkylsulfonyl with 1 to 4 carbon atoms, and cyano;

(a-2) phenyl or benzyloxy, wherein the phenyl and the phenyl portion of the benzyloxy are optionally substituted with one substituent selected from alkyl having 1 to 4 carbon atoms, halogen-substituted alkyl having 1 to 4 carbon atoms, halogen, hydroxy, alkoxy having 1 to 4 carbon atoms, halogen-substituted alkoxy having 1 to 4 carbon atoms, and NH ₂ ;

(a-3) 5-membered monocyclic aromatic groups selected from imidazolyl-, thiazolyl-, furyl-,

- 2δ· thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl groups, wherein the 5-membered monocyclic aromatic group is optionally substituted with one substituent selected from alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, halogen, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms and NH ₂ ;

(a-4) a 6-membered monocyclic aromatic group selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein the 6-membered monocyclic aromatic group is optionally substituted with one substituent selected from alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, halogen, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms and NH ₂ ;

(b) a 6-membered monocyclic aromatic group selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, said monocyclic aromatic group being optionally substituted with one or two substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group selected from the group consisting of imidazolyl, thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyloxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, said monocyclic aromatic group being optionally substituted with one or

29' by two substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

R ¹ represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl part and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms or aminosulfonyl; and n represents the number 0, 1, 2 or 3.

Further preferred are compounds according to the invention of general formula I, wherein

Z represents a hydroxy group, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group;

Q represents (a) a phenyl group optionally substituted with one or two substituents independently selected from the group consisting of

30· - ··

(a-1) fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, butyl, CH ₂ F, CHF ₂ , CF ₃ , methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, CH ₂ FO-, CHF ₂ ~O-, CF ₃ -O-, methylthio, ethylthio, hydroxymethyl, methoxymethyl, methoxyethyl, ethoxymethyl, hydroxy, nitro, methylsulfonyl, cyano, (HO)(H ₃ C) ₂ C-, acetyl and methylsulfonylamino;

(a-2) phenyl or benzyloxy, wherein the phenyl and the phenyl portion of the benzyloxy are optionally substituted with one substituent selected from methyl, ethyl, propyl, CF ₃ , F, Cl, OH, methoxy, ethoxy and NH ₂ ;

(a-3) a 5-membered monocyclic aromatic group selected from furyl, thienyl and pyrrolyl, wherein the 5-membered monocyclic aromatic group is optionally substituted with one substituent selected from methyl, ethyl, propyl, CF ₃ , F, Cl, OH, methoxy, ethoxy and NH ₂ ;

(a-4) pyridyl, which is optionally substituted with one substituent selected from methyl, ethyl, propyl, CF ₃ , F, Cl, OH, methoxy, ethoxy and NH ₂ ;

(b) a pyridyl group which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) an imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl, 1,2,3-thiadiazolyl or pyrrolyl group, wherein said imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl, 1,2,3-thiadiazolyl or pyrrolyl group is optionally substituted with one or two substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

η

R represents hydrogen, methyl, ethyl, n-propyl or isopropyl;

X is independently, at each occurrence, fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, _CH2F , _CHF2 , _CF3 , methoxy, _CF3O , or ethoxy; and n is 0, 1, or 2.

Further preferred are compounds according to the invention of general formula I, wherein

Z represents a hydroxy group, an ethoxy group or a methoxy group;

Q represents a phenyl group, a chlorophenyl group, a fluorophenyl group, a bromophenyl group, a methylphenyl group, a methoxyphenyl group, a (furyl)phenyl group, a trifluoromethylphenyl group, a trifluoromethoxyphenyl group, a pyridyl group, a methylpyridyl group, an ethylpyridyl group, a propylpyridyl group, a dimethylpyridyl group, a chloropyridyl group, a fluoropyridyl group, a trifluoromethylpyridyl group, a methoxypyridyl group, a (ethyl)(ethoxy)pyridyl group, a (chloro)(ethyl)pyridyl group, a thiazolyl group, a methylthiazolyl group, a furyl group, a methoxymethylfuryl group, an isoquinolyl group, a cyclohexyl group, a methoxy·· ··*· · · • · · · · ·

- 3Ϊ2··phenyl, (fluoro)(ethyl)pyridyl, diethylpyridyl or (ethoxy)(ethyl)pyridyl;

R ¹ represents hydrogen;

X represents fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, CF ₃ or methoxy; and n represents the number 1 or 2.

Further preferred are compounds according to the invention of general formula I, wherein

Z represents a hydroxy group, an ethoxy group or a methoxy group;

Q represents a phenyl group, a chlorophenyl group, a pyridyl group, a methylpyridyl group, an ethylpyridyl group, a propylpyridyl group or a chloropyridyl group;

*1

R represents hydrogen;

X represents fluorine, chlorine, methyl or CF ₃ ; and n represents the number 1 or 2.

Preference is given to particular compounds of the invention selected from the group consisting of ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

• ·

- 3*3 sodium salt of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-7-chloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate;

·· ···· · · · · · « · · · · · · · · · ·

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N,N-dimethylacetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-methylacetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-methoxy-N-methylacetamide;

2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone;

- 36··«· ·

2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-(4-methyl-1-piperazinyl)-1-ethanone;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-cyanoethyl)acetamide;

(2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-hydroxyethyl)acetamide;

2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-morpholino-1-ethanone;

[2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

• · «··· ·· * ·· «· · ··«· ·

- 37,.

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [2-(4-tert.butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate;

[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;

methyl-[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate;

[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

8, · · t [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

• · [5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-[4-(hydroxymethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl-[5-chloro-2-[4-(hydroxymethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate;

[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

• · methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5,6-dichloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl] acetate;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridin-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl [5-tert.butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1-hindol-3-yl]acetate;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

methyl-[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-ΙΗ-indol-3-yl]acetic acid;

methyl [6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl-(2-benzoyl-1H-indol-3-yl)acetate;

(2-benzoyl-1H-indol-3-yl)acetic acid;

methyl-[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

methyl [6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate;

• · · · · · • · · [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-benzoyloxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-benzoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

4 4··· 4«

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate;

[6-Chloro-2-[4-methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate;

^J

methyl [6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate;

methyl [6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-Chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate;

[6-Chloro-2-[14-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl] acetate;

[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate;

methyl [6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl dl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate;

dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid;

methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(isoquinolin-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(5-methylisoxazol-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indole-3-yl]acetate;

[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate;

• ti ti··· ti· ti titi • » ti ti ti · ti tr ti • titi · ti » titi • ti ·· titi tititi ti* tititi [6-chloro-2-(4-methyl-1,2,3-thiadiazol-5-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl-3-acetate;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-thienyl)carbonylindol-3-ylacetic acid;

methyl [6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate;

• · methyl-[5-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(1-methylimidazole-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-chloro-2-[3-(ethoxycarbonyl)isoxazol-5-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate;

[6-Chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate;

[6-Chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid;

methyl-[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N,N-dimethylacetamide;

[6-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-methylacetamide;

- α5 [5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)acetamide;

[5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-methoxyacetamide;

2-[5-chloro-2-(4-methylpyridin-2-carbonyl-1H-indol-3-yl]-1-piperazinyl-1-ethanone;

[5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide;

2-[5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone;

[6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

methyl [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl] acetate;

[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-difluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;

methyl [6-fluoro-2-(4-methylpyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid; and [2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid;

and their salts.

···«·· * * · *· · • · * * · · ♦ ···· ··· ·»· ··· ·

- 55 Further preferred are specific compounds of the invention selected from the group consisting of ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

sodium salts of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid;

16-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

16-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

·· 0* · ·· » · · » · · · 9 · 0 • · · · ·· · ·0 · »0 *» ·· 00· 0· 00·

- 56 [6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-7-chloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

• · [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

16-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[2-(4-Chlorobenzoyl)-1H-indol-3-yl-3-acetic acid

• · · ·

- 58 [6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-tert.Butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-ylacetic acid;

[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

• · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

« ·

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-ΙΗ-indol-3-yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

(2-benzoyl-1H-indol-3-yl)acetic acid;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl-3-acetic acid;

[6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl-3-acetic acid;

[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid;

[2-(4-Chlorobenzoyl)-5-methoxy-1H-indol-3-yl-3-acetic acid;

[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-Chloro-2-[4-methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate;

methyl [6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-Chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid;

[6-Chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(2-thienyl)carbonylindol-3-yl]acetic acid;

[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate;

• «« · ·· • · · «

- 66 ·· · · [5-chloro-2-(1-methylimidazole-2-carbonyl-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-ylacetic acid;

[5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid;

[6-Chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid;

[6-Chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid;

[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

«··· ·» · f ** · »··· «·· [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate;

[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-difluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid and [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

and their salts.

Further preferred are specific compounds of the invention selected from the group consisting of ethyl (2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

• · ·· ···· « * ·

- 68 • · · · ·

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

• · • · · · • ·

- 69 • · · [2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

[6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

• ·

- 70 methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

15-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-ylacetic acid;

[6-Chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-Chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-ylacetic acid;

methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

16-chloro-2-(4-methoxybenzoyl)-1H-indol-3-ylacetic acid;

methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

• · · · • ·

- 71 [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [2-(4-tert.butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate;

[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

ti ti ti · · • tititi • ti [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate;

• · · ♦ « ·

• · [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-chloro-2-[4-(hydroxymethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate;

[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

• 4 *«·» • 4 ·4

- 74 [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5,6-dichloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl] acetate;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridin-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl [5-tert.butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1-hindol-3-yl]acetate;

• · ·

ΊΊ [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-ΙΗ-indol-3-yl]acetic acid;

methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid;

methyl [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1-indol-3-yl] acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-Chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(isoquinolin-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-ylacetic acid;

methyl [6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl acetate;

[6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-ylacetic acid;

methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

C 6-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-ylacetic acid;

methyl [5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl] acetate;

[5-Chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

-··

methyl [5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate;

[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;

and their salts.

Further preferred are specific compounds of the invention selected from the group consisting of ethyl (2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

(2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

— · · · · • · and [6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

(2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid;

[6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

• · [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-Chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

-·· [6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

- ·· t 5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

15-Chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

•titi· titi ti ·· • ···· ···

-·· • ti titi ti·· titi tititi [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]-1H-acetic acid;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

• « « · · « e · · ' • 9 ···« · · ·

-·· • · * · · ·· · · ·· [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate;

[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

2-{6-chloro-2-[(4-ethyl-3-fluoro-2-pyridinyl)carbonyl]-1H-indol-3-yl}acetic acid; and ·· 000* 0« 0 0« < * 9 * 0 00 *0« « · 0 0 0 · φ φ

0· * 0 « 0 «000

0» »0 ·Ο 000 ·· ·ΐ· methyl-[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;

and their salts.

Further preferred are specific compounds of the invention selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate;

······ ·· · «· • · · · · · · ··« [5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl (2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

• · ·· · · · · • · · · · ·

methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5,6-dichloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridin-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl-[5-tert-butyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethoxy-1-hindol-3-yl]acetate;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

• · • · · · · · • « · « · «

methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid;

methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid;

methyl-[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(isoquinolin-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

· methyl-[5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl] acetate;

[5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-ylacetic acid;

methyl [5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;

and their salts.

Further preferred are specific compounds of the invention selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid;

• ·

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

12-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

100 [6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate;

[5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate;

[6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

• · • · · · · « • · · · ·

methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

······ ·· · «· ·· · · · · · · · · · · • · · · · · · ·

102 • · · · · · · · · · · · · · [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

103 [5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid;

[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid;

·· Jtititi ti· ti titi · » ti * · ti · - « · · • · ti·· ti · 9

104 _· ······ ··· *» ·· ·« ·«· «.· ·«· [5-chloro-2-(isoquinolin-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl] acetate;

[6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate;

[6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

- ^: aK~ methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; and [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

and their salts.

Further preferred are specific compounds of the invention selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-ylacetic acid;

[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid;

[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-ylacetic acid;

[2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-ylacetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

-·Λ08 • · · · · · • · · · · ·· ··· Methyl-[6-chloro-2-(isoquinolin-3-carbonyl)-1H-indol-3-yl]acetate;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-ylacetic acid;

E 6-Chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-ylacetic acid;

methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate;

[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

E 6-chloro-2-(5-chloropyridin-2-carbonyl)-1H-indol-3-ylacetic acid;

methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate;

E 6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-ylacetic acid;

methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate

E 5-Chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

-•.IDU.*· [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid (cj-020 099); and methyl [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate;

and their salts.

More preferred are specific compounds selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; and [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

and their salts.

Preferred pharmaceutical compositions according to the present invention comprise compounds of general formula I as defined above.

As compounds to be included in pharmaceutical compositions, highly preferred are compounds selected from the group consisting of: · · · · · · · · (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid;

[6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid;

[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

(2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid;

[6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

·· ···· · · • · · · · ·

[6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid;

[6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-chloropyridin-2-carbonyl)-1H-indol-3-ylacetic acid;

[6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-ylacetic acid;

[6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid;

- iik. • · · · [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid;

[5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; and [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid;

and their salts.

The invention also provides a method for producing compounds of general formula 7-IV

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms • · · · · · » *· ·· · ·«·· · · · · • ·

each of the alkyl moieties, alkylamino groups of 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino of 1 to 4 carbon atoms each of the alkyl moieties, alkylamino of 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

• 4 • 4 4 «

- ·1Γ7\γ·

R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

NO ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

the essence of which is that it includes the following stages:

i) reaction of the compound of general formula 7-II

•j^co ₂ r ⁵ (7-II)

NHB

wherein B represents a suitable protecting group; R ⁵ represents an alkyl group having 1 to 6 carbon atoms; and X and n are as defined above;

with a compound of the general formula wherein E represents halogen and Q has the meaning as defined above; using a first base and a suitable solvent;

ii) reacting the product of step i) with a second base; and iii) reacting the product of step ii) with an acid.

In a preferred embodiment of the above-described method, the first base is potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate.

The process described above is preferred in which the first base is potassium carbonate.

In a preferred embodiment of the above-described method, aqueous sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium pentoxide (with subsequent addition of water), sodium methoxide (with subsequent addition of water) or potassium tert-butoxide (with subsequent addition of water) is used as the second base.

Preference is given to the process described above in which the second base is sodium hydroxide.

• » · ··· 9« » · · · · ·

- w.r

In a preferred embodiment of the above-described method, aqueous hydrochloric acid, hydrobromic acid, sulfuric acid or ammonium chloride are used as acids.

Preference is given to the process described above in which the acid is aqueous hydrochloric acid.

In a preferred embodiment of the above-described method, N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran are used as solvents.

The process described above is preferred in which the solvent is N,N-dimethylacetamide.

The invention further provides a method for producing compounds of general formula 7-IV

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino of 1 to 4 carbon atoms in »· »··· ·· « ·· • r * · * · e · ·

each of alkyl moieties, alkylamino groups with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxy and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(0) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl moiety are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group • · • · · · (b) (c) (d) (e) with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to this heteroatom optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group listed above in (a-1);

• ·

- 12¾

R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN;

X represents, at each occurrence, independently halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms,

N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

the essence of which is that it involves the reaction of a compound

wherein R ⁵ represents an alkyl group with 1 to 6 carbon atoms; and Q,

X and n have the meanings given above; with a base in a suitable solvent.

• · · ·

123·

In a preferred embodiment of the above-described method, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-pentoxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide.

The process described above is preferred in which the base is sodium hydroxide.

In a preferred embodiment of the above-described method, aqueous mixtures of methanol, ethanol, isopropyl alcohol or tetrahydrofuran are used as solvents.

The process described above is preferred in which the solvent is methanol containing water.

The invention further provides a method for producing compounds of the general formula 7-VII ™ ₂ r ⁵ □

H

(7-VII) wherein (a) represents a phenyl group optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in • ·

- 124

each of alkyl moieties, alkylamino groups with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxy and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl moiety are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms

12¾ each of alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

126

R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms;

R ⁵ represents an alkyl group having 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

the essence of which is that it involves the reaction of a compound of general formula 7-VI

127 where B, Q, X, and R ⁵ are as defined above; with a base in a suitable solvent.

In a preferred embodiment of the above-described method, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,1,3,3-tetramethylguanidine, sodium tert-pentoxide, sodium methoxide or potassium tert-butoxide.

Preference is given to the process described above, in which the base is 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium tert-butoxide.

In a preferred embodiment of the above-described method, N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran are used as solvents.

The process described above is preferred in which the solvent is N,N-dimethylacetamide.

nine

The invention relates to a method for producing compounds of general formula 7-VI.

B represents a suitable protecting group;

Q represents (a) a phenyl group optionally substituted with one, two or three substituents independently selected from the group consisting of

126.

• · · · · ·· (a-1) halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino groups with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n ~aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl parts, alkylamino groups with 1 up to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group having 1 to 4 carbon atoms•· ··«»

- 129.

ku, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 7 carbon atoms,

- 13ϋ to 4 carbon atoms, halogen and halogen-substituted alkyl groups having 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms;

R ⁵ represents an alkyl group with 1 to 6 carbon atoms; and

represents the number 0, 1, 2, 3 or 4;

·44· • » · 4 4 ·

- 131 - · « ♦ 4 4 4 whose essence lies in the fact that it involves the reaction of the compound

wherein B, Q, X, and R ⁵ have the meanings given above; with a base in a suitable solvent.

In a preferred embodiment of the above-described method, the base is potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate.

The process described above is preferred in which the base is potassium carbonate.

In a preferred embodiment of the above-described method, N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran are used as solvents.

The process described above is preferred in which the solvent is N,N-dimethylacetamide.

The invention further provides a method for producing compounds of general formula 7-V

Q (7-V)

- 132· • · · · · · ·

where

B represents a suitable protecting group;

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups... ........

· ·· ·· · pins with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group containing one heteroatom selected from oxygen, sulfur and

- 134. .nitrogen and in addition to this heteroatom optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

R ² and R ³ each independently represent hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, or alkyl of 1 to 4 carbon atoms substituted with halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, NH ₂ or CN;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(0) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part • · ·

135· moieties, an alkylsulfonylamino group with 1 to 4 carbon atoms and a cycloalkyl group with 3 to 7 carbon atoms;

R ⁵ represents an alkyl group having 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

the essence of which is that it involves the reaction of a compound of general formula 7-II

NHB

CO,R ⁵ (7-II) where Β, X, and R ⁵ have the meanings given above; with a compound of the general formula

O

where E represents halogen and Q has the meaning given above; and a base in the presence of a solvent.

In a preferred embodiment of the above-described method, the base is potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate.

The process described above is preferred in which the base is potassium carbonate.

In a preferred embodiment of the above-described method, N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran are used as solvents.

13β

The process described above is preferred in which the solvent is N,N-dimethylacetamide.

The invention further relates to a method for producing compounds of general formula XII

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(0) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n ~aryl groups, wherein the aryl group and the aryl part are optionally

13?

substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

·« 9 9 9 • 9 9 « 9 9 ·· · · 9 9 « (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

R ¹ represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or halogen;

about about

R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN;

R ⁵ represents an alkyl group having 1 to 6 carbon atoms;

X, at each occurrence, is independently halogen, alkyl of 1 to 4 carbon atoms, halogen·· ·««· * · ·

- 139· . ₇ ·

-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms,

NC>2, NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

the essence of which is that it involves the reaction of a compound

wherein R ¹ , R ⁵ , X, Q and n are as defined above; and B represents a suitable protecting group, in the presence of a suitable base to form a compound of formula XII.

The invention further relates to a method for producing compounds of general formula XII

CO ₂ R ⁵ (X)n-£ (XII) • ·

- 140 where

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each

- 141 • · · · alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted» · · · · ·

142 on one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

R ¹ represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or halogen;

R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN;

C

R represents an alkyl group having 1 to 6 carbon atoms;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

NO ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsul·· ·*·· ·· • * · «

- 143· ·· ·· «·« · · · · · phenyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms; an represents the number 0, 1, 2, 3 or 4;

the essence of which is that it involves the reaction of a compound of general formula IX

wherein R ¹ , R ⁵ , X and n are as defined above; and B represents a suitable protecting group;

with a compound of general formula XI (XI) wherein E represents halogen and Q has the meaning as defined above; in the presence of a suitable base at a temperature of from -40 to 200°C to form a compound of general formula XII.

In a preferred embodiment, the reaction in the above-described process is carried out at a temperature of from 0 to 100°C.

In this process, potassium carbonate, cesium carbonate, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide are preferably used as suitable bases.

- 144; : ·: : :

• · «φ · φ φφφ ·Φ Φ·· ny, sodium hydride, potassium hydride or potassium fluoride.

Preferably, in this method, the reaction with a base is first carried out for a period of 2 minutes to one day, after which another base is added to the reaction mixture.

In the above-described method, the reaction is first carried out for a period of 30 minutes to 8 hours.

Suitable protecting groups, which are preferred in the above-described process, include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl.

More preferred protecting groups for the above-described process include phenylsulfonyl, ρ-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl.

In a preferred embodiment of the above method, the first base is selected from the group consisting of sodium tert.butoxide, potassium tert.butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine and diethylisopropylamine; and the second base is selected from the group consisting of sodium tert.butoxide, tert. potassium butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabi145

cyclo[4,3,Ο]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine and diethylisopropylamine.

In a preferred embodiment of the above method, the first base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium hydride and potassium fluoride; and the second base is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate, pyrrolidine, diisopropylamine, triethylamine, diethylisopropylamine and diisopropylethylamine.

In a more preferred embodiment of the above method, the first base is potassium carbonate, cesium carbonate or potassium fluoride and the second base is 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide or cesium carbonate.

The combination of the first base and the second base (first base/second base) is preferably selected from the group consisting of the combinations potassium carbonate/1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate/cesium carbonate, cesium carbonate//potassium tert.butoxide, cesium carbonate/1,8-diazabicyclo[5.4.0]undec-7-ene, potassium fluoride/1,8-diazabicyclo[5.4.0]undec-7-ene and potassium fluoride/cesium carbonate.

The combination of the first base and the second base (first base/second base) is more preferably selected from the group consisting of the combinations potassium carbonate/1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate/cesium carbonate and cesium carbonate/potassium tert-butoxide.

The invention further relates to a method for producing compounds of general formula VIII

146 ······ ·· · ·· • · · · ··· ··· • ·

(VIII) where

Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(0) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms

147 •· ·· ·· ·· ·· ·· ·· carbon, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents;

- 148 ·· ·· · ·· ·· ·«« tuents independently selected from the set set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to this heteroatom optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

*1 ,

R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or halogen;

R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms

149

in each of the alkyl moieties, an alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, an alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxy and 1 to 4 carbon atoms in the alkyl moiety, an alkylsulfonyl group with 1 to 4 carbon atoms, an aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , an acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl moiety, an alkylsulfonylamino group with 1 to 4 carbon atoms and a cycloalkyl group with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

the essence of which is that it involves the reaction of a compound of general formula X

wherein R ¹ , R ⁵ , X, Q and n are as defined above; with a suitable base under hydrolysis conditions to form a compound of general formula VIII.

The invention further relates to a method for producing compounds of general formula VIII where

(VIII)

Q represents (a) a phenyl group optionally substituted with one, two or three substituents independently selected from the group consisting of

150

(a-1) halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino groups with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n ~aryl groups, wherein the aryl group and the aryl moiety are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl having 1 to 4 carbon atoms-

151 ku, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN;

(a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN;

(b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4);

(d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 7 carbon atoms,

152 to 4 carbon atoms, halogen and halogen-substituted alkyl groups having 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1);

R represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or halogen;

oh _oh

R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN;

X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio,

N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4;

153 the essence of which is that it involves the hydrolysis of a compound of general formula XII

(XII) wherein R ⁵ represents an alkyl group having 1 to 6 carbon atoms; and R ¹ , X, Q and n are as defined above.

A general description of the synthesis follows.

Compounds of formula I can be prepared by any synthetic procedure that can be applied to structurally related compounds known to those skilled in the art. The following description should be understood as providing representative examples that serve to illustrate and in no way limit the scope of the invention. Unless otherwise indicated, the general symbols Q, X, Z, R ¹ and n have the meanings given above.

For example, in one embodiment, compounds of formula VI can be prepared by the reaction sequence shown in Scheme 1. Compounds of formula VI correspond to compounds of formula I, wherein R ¹ is hydrogen and Z is hydroxy.

154 (X) ·· · · ·· · · · tt • · · · · · · · · · ·· ·· · · ··· · · · (lil)

C(R ⁴ )H(CQR ⁵ ) ₂

Mn(OAcb.2H2O

AcOH

C(Bi)H(CO2R ⁵ )2

Et ₃ B/O2 or

CH ₂ (CO ₂ R ⁵ ) ₂ Ce(IV) r

[R ⁴ = H or halogen] [R ⁵ = alkyl with 1 to 6 carbon atoms]

The procedure according to Scheme 1 can be briefly described as follows: the compound of general formula III is subjected to oxidative homolytic malonylation (see in particular J. M. Muchowski et al., Can.

J. Chem., 70, 1838, 1992 and E. Baciocchi et al., J. Org. Chem., 58, 7610, 1993). In one example, a compound of formula III is reacted with a suitable malonyl radical formed from a compound of formula C(R ⁴ )H(CO2R ⁵ )2, where R ⁴ is hydrogen or halogen, preferably chlorine, and R ⁵ is an alkyl group having 1 to 6 carbon atoms, and a manganese reagent, preferably manganese acetate. The manganese reagent is usually used in stoichiometric amounts, or it may be combined as a catalyst using a suitable reoxidizing agent, such as sodium persulfate, usually in the presence of a cocatalyst, such as a silver salt, such as a nitriding agent• · · · · · · • · ·

155 silver nan. The preferred reaction solvent is acetic acid; however, mixtures of acetic acid and acetic anhydride or other protic solvents such as propionic acid may be used. The reaction is preferably carried out in the presence of sodium acetate or potassium acetate, but it may be carried out in the solvent itself. The reaction temperature is usually in the range from room temperature (for example 25°C) to the reflux temperature of the solvent, preferably 60 to 100°C; however, lower or higher temperatures may be used if necessary. The reaction is usually carried out for a period of 1 hour to one day, preferably 4 to 16 hours; however, shorter or longer reaction times may be used if necessary. In the case described immediately above, the α-acetoxy compound of the general formula IV is usually obtained as the main product. Compounds of formula IV can be readily converted to compounds of formula V by reduction with a suitable reducing agent, for example trialkylsilane, sodium-α-(dimethylamino)naphthalenide, lithium in liquid ammonia, sodium naphthalenide, preferably triethylsilane in a suitable protic solvent, especially trifluoroacetic acid. Alternatively, the reaction can be carried out in a reaction-inert cosolvent, such as dichloromethane or 1,2-dichloroethane. Reaction temperatures are usually in the range from room temperature to the reflux temperature of the solvent, preferably from 15 to 100°C. Higher or lower temperatures can be used if necessary. The reaction is usually carried out for a period of several minutes to one day, preferably for a period of 20 minutes to 5 hours; if necessary for a shorter or longer period. Alternatively, the compound of formula V can be obtained directly from the compound of formula III and a malonyl radical formed from (i) a suitable monohalomalonate, preferably bromomalonate, which is mediated by air oxidation of a trialkylborane, such as triethylborane (see B. Giese, Radicals in organic synthesis: formation of carbon-carbon bonds, Pergamon Press, Oxford, pp. 86-89, 1986 and P. G. Allies and P. B. Brindley, J. Chem. Soc. (B),

156

1126, 1960); or (ii) a malonic acid ester in the presence of a cerium salt such as cerium ammonium nitrate (see, for example, E. Baciocchi et al., Tetrahedron Lett., 2763, 1986). Compounds of formula V can be readily converted to compounds of formula VI by subjecting them to standard saponification/decarboxylation conditions.

Scheme 2

Alternatively, as shown in Scheme 2, a compound of general formula VIII [i.e., a compound of general η

of formula I, wherein Z is hydroxy], wherein R is C1-4 alkyl, can be prepared in a similar manner to the compound of formula VI using suitable reaction conditions for illustration described above from a suitable monoalkyl malonate, wherein R is ^C1-4 alkyl, W is hydrogen or halogen, preferably bromine, and ^R is C1-6 alkyl, from a compound of formula III.

CíRbWfCOjR ⁵ ^ oxidizing agent

(i) hydrolysis/decarboxylation [R [R

halogen] (H) H ⁺ does not represent hydrogen] = alkyl with 1 to 6 carbon atoms]

4444 44 4 ·· ·· 4 * W 4 4 ”44

157 > < 44 4 4 444 4« 444

In the process according to Scheme 2, for example, a manganese reagent, such as manganese acetate, or a cerium reagent, such as ceric ammonium nitrate and cerium sulfate, is used as the oxidizing agent.

Scheme 3

In another embodiment, the compound of formula VIII can be readily obtained from a suitable 2-aminocinnamic acid ester of formula IX, where B represents a suitable protecting group, for example methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, methanesulfonyl or trifluoromethanesulfonyl (preferably phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl).

• ·

- 158

(X) base or oxidizing agent at room temperature / hydrolysis

hydrolysis ->.

IN

[ ^R5 = alkyl with 1 to 6 carbon atoms [B = suitable protecting group]] [E = halogen]

In the process of Scheme 3, a suitable 2-aminocinnamic acid ester of the general formula IX is reacted with a compound of the general formula XI, where Q is as defined above and E is halogen, preferably iodine, bromine or chlorine, in the presence of a suitable base. Examples of suitable bases include alkali metal or alkaline earth metal alkoxides, carbonates, fluorides or hydrides, such as sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium fluoride or potassium hydride. Non-limiting examples include

- 159 • · · · · · · • · » · · « ·· ··· · ··· Preferred solvents inert to the reaction include acetone, methyl ethyl ketone, acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dioxane or tetrahydrofuran (THF). The reaction temperature is preferably in the range of -40°C to the reflux temperature of the solvent (for example 200°C), usually in the range of 0 to 100°C; however, higher or lower temperatures can be used if necessary. The reaction time is usually from 2 minutes to 1 day, preferably from 30 minutes to 8 hours; however, shorter or longer reaction times can be used if necessary. If the reaction is carried out, for example, at room temperature (for example at 25°C), the intermediate indoline of the general formula X can be isolated. Reaction at higher temperatures (for example, in the range of 40 to 100°C) may lead to the formation of indole of general formula XII. The intermediate indoline of formula X is usually not isolated, but is either (i) hydrolyzed under standard conditions known to those skilled in the art to form the indole ring directly to the compound of formula VIII, or (ii) converted to the compound of formula XII using a suitable base, for example an alkali or alkaline earth metal carbonate, such as sodium carbonate, potassium carbonate or cesium carbonate, or an organic base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine, diethylisopropylamine, Hunig's base, potassium tert-butoxide, sodium tert-butoxide etc., or a suitable oxidizing agent, such as ceric ammonium nitrate (CAN), manganese dioxide, manganese acetate, copper acetate/air, chloranil, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), N-methylmorpholine-N-oxide, etc. (see, for example, H. Dumoulin et al., J. Heterocycl. Chem., 32, 1703, 1995; H. Rapoport et al., Tetrahedron Lett., 5053, 1991; P. Martin et al., Helv. Chim. Acta, 77, 111, 1994; Y. Kikugawa et al., J. Chem. Soc.

160

Perkins. Trans. 1, 7, 1401, 1984; A. Goti et al., Tetrahedron Lett., 6567, 1996; L. S. Liebeskind et al., J. Org. Chem., 61, 2594, 1996). Non-limiting examples of preferred solvents inert to the reaction include acetone, methyl ethyl ketone, acetonitrile, dioxane or tetrahydrofuran. The reaction temperature is preferably in the range of 0°C to the reflux temperature of the solvent, usually in the range of 15 to 60°C; however, higher or lower temperatures can be used if necessary. The reaction time is usually a few minutes to a day, preferably from 30 minutes to 8 hours; however, shorter or longer reaction times can be used if necessary. Compounds of general formula XII can be readily hydrolyzed to compounds of general formula VIII under standard conditions.

Scheme 4

According to another embodiment, the compound of general

X of formula VIII, where Q, X, R and n are as defined above, can be prepared as shown in Scheme 4.

161 • ·

carbon atoms] hydrolysis

For example, the intramolecular radical cyclization described in J. Am. Chem. Soc. 116, 3127, 1994; T. Fukuyama et al., by reacting a compound of formula XIII, where R ¹ , R ⁵ , X and n are as defined above, with a trialkyltin hydride, for example tributyltin hydride, usually in the presence of a radical initiator, such as 2,2'-azobisisobutyronitrile (AIBN), yields the intermediate 2-stannylindole of formula XIV. The in situ formed intermediate of formula XIV is subsequently reacted with an acyl halide, where Q and E are as defined above, in the presence of a suitable palladium catalyst, using the Stille procedure (see, for example, J. K. Stille et al., J. Am. Chem. Soc., 109, 813, 5478,

1987 and J. Am. Chem. Soc., 106, 4833, 1984), yielding • · ··» · » · ·· • · · · · · · · · · · · · · · · · * • · · · · · · · · · ·

- 162 indole of general formula XII, which can be hydrolyzed in the usual manner to a compound of general formula VIII.

Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), bis(dibenzylideneacetone)palladium(0), benzyl(chloro)bis(triphenylphosphine)palladium(II) and bis(acetonitrile)dichloropalladium(II).

Scheme 5

According to another embodiment, compounds of general formula VIII, wherein Q, X, R ¹ and n are as defined above, can be prepared by the method illustrated in Scheme 5.

For example, the reaction of a compound of the general formula *1

XV, where R, X and n have the meanings given above, with a compound of the general formula Q-C(O)-A gives a compound of the general formula VIII or a compound of the general formula XVI (see for example U. Pindur et al., Liebigs Ann. Chem., 601, 1991 and C. J. Moody et al., J. Chem. Soc. Perkin Trans. I, 3249, 1988), which can be hydrolyzed to a compound of the general formula VIII under

163 ·· ···· · ·

• · · using conventional procedures (see, for example, E. B. Fray et al., Tetrahedron, 49, 439, 1993 and U. Pindur et al., J. Heterocycl. Chem., 29, 145, 1992). In the compound of the general formula A-C(O)-Q, the value of A is defined such that the compound of the general formula A-C(O)-Q represents, for example, an acyl halide, a carboxylic acid, a carboxylic acid anhydride, a mixed carboxylic and sulfonic acid anhydride, etc. The reaction can optionally be carried out using a catalyst, preferably using a catalyst such as boron trifluoride-diethyl ether, tin tetrachloride, aluminum chloride, ferric chloride, zinc chloride, iodine, iron, etc. Non-limiting examples of solvents inert to the reaction include diethyl ether, dichloromethane, 1,2-dichloroethane, carbon disulfide, nitrobenzene or nitromethane. The reaction temperature is preferably in the range of -78 to 210°C, usually from -10°C to the reflux temperature of the solvent; however, higher or lower temperatures can be used if necessary. The reaction time is usually several minutes to one day, preferably 30 minutes to 8 hours; if necessary, the reaction time may be longer or shorter.

Scheme 6

The acetic acid compounds of formula VI and VIII, depicted in the preceding schemes, can be readily converted to the corresponding amides, compounds of formula XVII and XVIII, or the ester, compound of formula XII, by any conventional procedure known to those skilled in the art.

• · ·

164

or hnr ² r ³

>>

(XVIII) year ⁵ oh

[R ⁵ = alkyl with up to 6 carbon atoms]

By the method shown in Scheme 6, compounds of general formulas XVII and XVIII can be readily prepared by reacting the corresponding acetic acid compounds of general formulas VI and VIII with a suitable amine, where R ² , o _x

R, Y and r are as defined above, in the presence of a suitable coupling agent. Non-limiting examples of suitable coupling agents include 1-(dimethylaminopropyl)-3-ethylcarbodiimide (WSC), N,N'-dicyclohexylcarbodiimidazole (DCC), carbonyldiimidazole, diethylphosphorocyanide (DEPC) • ·

- 165 etc. Non-limiting examples of solvents inert to the reaction include acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), dioxane, tetrahydrofuran (THF) or pyridine. The reaction temperature is preferably in the range of -40 to 150°C, usually in the range of 15°C to the reflux temperature of the solvent. However, it is possible to operate at higher or lower temperatures if necessary. The reaction is usually carried out for a period of several minutes to one day, preferably for a period of 30 minutes to 8 hours, although the reaction time may be shorter or longer if necessary. The compounds of general formula VI and VIII can also be easily converted into the corresponding esters using conventional procedures.

wherein B represents a suitable protecting group, R ⁵ represents an alkyl group having 1 to 6 carbon atoms, E represents halogen and X, Q and n are as defined above.

166

The compound of formula 7-1 used in the process of Scheme 7 can be prepared by methods well known to those skilled in the art. Such methods include one or more of the methods described in R. W. Carling, P. D. Leeson, K. Moore, J. D. Smith, C. R. Moyes, J. Med. Chem., 1993, pp. 3397-3408.

Compounds of formula 7-II are prepared from compounds of formula 7-1 by reaction with a base and an electrophilic agent in a suitable solvent. Examples of suitable bases include triethylamine, diisopropylethylamine or pyridine optionally substituted with 1 to 3 alkyl groups having 1 to 4 carbon atoms, preferably pyridine. Suitable electrophilic agents include methanesulfonyl chloride or anhydride or phenylsulfonyl chloride, the phenyl portion of which optionally contains 1 or 2 substituents selected from halogen, nitro and alkyl groups having 1 to 4 carbon atoms. Suitable solvents include, for example, dichloromethane, dichloroethane, methyl tert.butyl ether, diisopropyl ether or toluene, preferably dichloromethane. The above-described reaction can be carried out at a temperature ranging from about 0 to about 50°C, preferably at about room temperature (20 to 25°C) for a period of about 1 hour to about 30 hours, preferably for about 18 hours.

Compounds of formula 7-IV are prepared from compounds of formula 7-II by reacting the compound of formula 7-II with a first base and an alkylating agent of formula 7-III in the presence of a solvent, followed by reaction with a second base and subsequent reaction with an acid. Examples of the first base include potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate. Suitable solvents include, for example, N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran, preferably N,N-dimethylacetamide. The above reaction is carried out at a temperature in the range of about 0°C to about 100°C, preferably at room temperature (20 to 25°C) for a period of about 10 minutes to 5 hours, usually for 15 minutes. An example of a suitable second base is an aqueous solution of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium tert-pentoxide, sodium methoxide or potassium tert-butoxide, preferably sodium hydroxide. The reaction with the second base is carried out at a temperature in the range of about 20 to about 120°C, preferably at 100°C, for a period of about 1 to about 24 hours, usually for a period of about 8 hours. Examples of suitable acids include aqueous hydrochloric acid, hydrobromic acid, sulfuric acid or ammonium chloride, preferably hydrochloric acid. The reaction with the acid is carried out at a temperature in the range of about 0 to about 50°C, preferably from 20 to about 25°C, for a period of about 0.5 hours to about 6 hours, usually for a period of about 1 hour.

Alternatively, the conversion of the compound of formula 7-II to the compound of formula 7-IV can be carried out stepwise. The compound of formula 7-V can be prepared from the compound of formula 7-II by reaction with a base and an alkylating agent of formula 7-III in the presence of a solvent. Suitable bases include potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate. Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran, preferably N,N-dimethylacetamide. The above-described reaction can be carried out at temperatures ranging from about 0°C to about 50°C, preferably at room temperature (20 to 25°C) for about 10 to 40 minutes, usually for 30 minutes.

The compound of general formula 7-VI is prepared from the compound of general formula 7-V by reaction with a base in the presence of

168 solvent. Suitable bases include potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate, preferably potassium carbonate. Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran, preferably N,N-dimethylacetamide. The above-described reaction can be carried out at temperatures ranging from about 0°C to about 50°C, preferably at room temperature (20 to 25°C), for a period of about 1 hour to about 6 hours, preferably for a period of 4 hours.

The compound of formula 7-VII is prepared from the compound of formula 7-VI by reaction with a base in a suitable solvent. Examples of suitable bases include 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,1,3,3-tetramethylguanidine, sodium tert-pentoxide, sodium methoxide or potassium tert-butoxide, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium methoxide or potassium tert-butoxide. Suitable solvents include N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran, preferably N,N-dimethylacetamide. The above-described reaction can be carried out at temperatures ranging from about 0°C to 100°C, preferably at room temperature (20 to 25°C), for a period of 30 minutes to 5 hours, preferably for 1 hour.

The compound of formula 7-IV is prepared from the compound of formula 7-VII by reaction with a base in a suitable solvent. Suitable bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium dihydrogen carbonate, sodium tert-pentoxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide, preferably sodium hydroxide. Suitable solvents include, for example, an aqueous mixture of methanol, ethanol, isopropyl alcohol or tetrahydrofuran, preferably methanol

169 containing water. The above reaction can be carried out at temperatures ranging from about 10°C to 100°C, preferably at room temperature (20 to 25°C) for 12 to 48 hours, preferably 24 hours, to form a carboxylate salt of the compound of formula 7-IV, which can be reacted with an acid to give the compound of formula 7-IV.

Compounds of formula 7-VI contain asymmetric atoms and therefore exist in different enantiomeric and diastereomeric forms. Diastereomeric mixtures can be separated into individual diastereomers based on their physicochemical differences using techniques known to those skilled in the art, such as chromatography or fractional crystallization. The use of all such isomers, including diastereomeric mixtures and pure enantiomers, is within the scope of the present invention.

The starting materials used in the above-described synthetic processes can be obtained by conventional methods known to those skilled in the art. The preparation of such starting materials is described in the following examples, which are illustrative and do not limit the invention in any way. Alternatively, the required starting materials can be obtained by methods analogous to or modifications of the methods described below.

The products shown in the synthetic procedures described above and illustrated in the examples below can be isolated using standard procedures, and their purification can be carried out by conventional methods known to those skilled in the art, such as distillation, crystallization or chromatography techniques.

Some of the compounds described herein contain one or more centers of asymmetry and may therefore be

170

may occur in various stereoisomeric forms. All possible stereoisomers, as well as their racemic and optically resolved, enantiomerically pure forms and their pharmaceutically acceptable salts, are within the scope of the present invention.

Certain compounds of the present invention are capable of forming addition salts with inorganic or organic acids. For the preparation of pharmaceutically acceptable acid addition salts of compounds of formula I, those acids are used which form non-toxic addition salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, sulfates or hydrogen sulfates, acetates, benzoates, benzene sulfonates, citrates, fumarates, glucuronates, hippurates, lactates, tartrates, saccharates, succinates, maleates, methane sulfonates, p-toluene sulfonates, phosphates and pamoates (i.e. 4,4'-methylenebis(3-hydroxy-2-naphthoates). These pharmaceutically acceptable acid salts are prepared using conventional procedures.

Some of the compounds of the invention are capable of forming salts containing pharmaceutically acceptable non-toxic cations. Salts of compounds of formula I containing pharmaceutically acceptable non-toxic cations can be prepared by conventional methods, for example by contacting the compound with a stoichiometric amount of a suitable alkali metal or alkaline earth metal hydroxide or alkoxide (sodium, potassium, calcium or magnesium) in water or a suitable organic solvent such as ethanol, isopropyl alcohol, or mixtures thereof, and the like.

The invention also includes bioprecursors (also called prodrugs) of compounds of general formula I. Bioprecursors of compounds of general formula I are their chemical derivatives that can be readily converted back to the parent compound of general formula I in a biological system. Specifically

171 thus, the bioprecursor of the compound of general formula I, after administration and absorption in a mammalian, e.g. human, organism, converts back to the parent compound of general formula I. If the compounds of general formula I according to the present invention can form solvates, such as hydrates, then these forms also fall within the scope of the present invention.

Examples of prodrugs of compounds of general formula I include compounds of general formula I whose indole ring is substituted in position 1 with a group selected from the group consisting of a hydroxymethyl group, a -C(O)-alkyl group with 1 to 4 carbon atoms in the alkyl moiety, -C(O)-(NH ₂ )CH-alkyl with 1 to 4 carbon atoms in the alkyl moiety, -C(O)-phenyl, -CH ₂ NHC(O)-aryl, -CH ₂ -alkyl-OC(O)-alkyl with 1 to 4 carbon atoms in each of the alkyl moieties, -alkylpyridyl with 1 to 4 carbon atoms in the alkyl moiety, -C(O)CH ₂ NR ₂ and -CH ₂ N(alkyl) ₂ with 1 to 4 carbon atoms in each of the alkyl moieties.

Another example of prodrugs of compounds of general formula I are compounds of general formula I in which the carboxy group is substituted with a group selected from the group consisting of an alkyl group with 1 to 4 carbon atoms, a -CH ₂ -alkyl-OC(O)-alkyl group with 1 to 4 carbon atoms in each of the alkyl moieties, a -CH ₂ -alkyl-OC(O)-N(alkyl) ₂ with 1 to 4 carbon atoms in each of the alkyl moieties, a -CH ₂ C(O)-N(alkyl) ₂ with 1 to 4 carbon atoms in each of the alkyl moieties, a -CH ₂ -alkyl-OC(O)-O-alkyl with 1 to 4 carbon atoms in each of the alkyl moieties, ethyl-OH and -CH ₂ CO ₂ H.

The compounds of formula I according to the invention can be administered orally, parenterally or topically. In humans, these compounds are usually most conveniently administered in doses ranging from about 0.01 mg to about 100 mg per day, although there will of course be variations in these dosages.

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doses depending on the weight, sex and condition of the patient being treated, the stage of the disease being treated and the particular route of administration chosen. However, in the treatment of the above diseases in humans, it is most appropriate to use a daily dose level in the range of 0.01 mg to 10 mg/kg of body weight, whether in the form of a single dose or several divided doses.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the above routes, and may be administered in one or more doses. The therapeutically useful compounds of the invention may be administered in a variety of dosage forms, in which they are mixed with various pharmaceutically acceptable inert carriers and formulated into tablets, capsules, lozenges, pills, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents, etc. Pharmaceutical compositions for oral administration may additionally contain sweetening and/or flavoring agents. The therapeutically active compounds of the invention are typically present in such dosage forms at a concentration ranging from about 5 to 70% by weight, preferably from 10 to 50% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be used, together with various disintegrants such as starch (preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, and granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. For tabletting purposes, lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc may additionally be present. Solid preparations of a similar type may also be present as gelatin capsule fillings. In this case, the preparations used preferably also contain lactose or high molecular weight polyethylene glycols. In the manufacture of aqueous suspensions and/or elixirs suitable for oral administration, the active ingredient may be mixed with various sweetening or flavouring agents. substances, coloring additives or dyes and - if necessary - emulsifiers and/or suspending agents and also such diluents as water, ethanol, propylene glycol, glycerol and various combinations thereof.

For parenteral administration, solutions of the therapeutically useful compounds of the invention in either sesame or peanut oil or in aqueous propylene glycol may be used. Aqueous solutions should, if necessary, be suitably buffered (preferably to pH > 8) and the liquid diluent should first be isotonized. Such aqueous solutions are suitable for intravenous injection. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection. The preparation of all such solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. The compounds of the invention may also be administered topically in the treatment of inflammatory skin diseases and this may preferably be accomplished using creams, jellies, gels, pastes, ointments and the like, which are manufactured by standard pharmaceutical techniques.

The compounds of formula I may also be administered in the form of suppositories for rectal or vaginal administration of the active ingredient. These compositions may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature (e.g. 10 to 32°C) but liquid at rectal temperature and will therefore be present in the rectum.

174

4« 44·· ·· · ··

4· · «·»· ·«· ·· ·· · « · ··· or vagina to melt, releasing the active ingredient. Such substances are polyethylene glycols, cocoa butter and wax.

For buccal administration, the compositions may be formulated into tablets or lozenges by conventional methods.

Combination with other drugs

Compounds of formula I may be useful for the treatment of inflammation and other disorders associated with inflammation (but not limited to these conditions), for example as analgesics in the treatment of pain and headache, or as antipyretics in the treatment of fever. The combinations of the invention may be useful, for example, in the treatment of arthritis, such as rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, etc. Such combinations may further be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis and skin diseases and disorders, such as psoriasis, eczema, burns and dermatitis. The combinations of the invention may also be useful in the treatment of gastrointestinal conditions, such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis, and for the prevention of colorectal cancer. Furthermore, the combinations of the invention may be useful in the treatment of inflammation in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, post-traumatic edema, myocardial ischemia, etc. The combinations of the invention may also be useful in the treatment of certain central nervous system disorders such as Alzheimer's disease and dementia.

Further, these combinations may be useful as anti-inflammatory agents, for example for the treatment of arthritis, with the added advantage of having significantly fewer harmful side effects. These combinations may also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, and central nervous system damage caused by stroke, ischemia, or trauma.

The compounds of formula I will be useful as partial or complete replacements for conventional NSAIDs in formulations in which they are co-administered with other agents or additives. The invention therefore provides pharmaceutical compositions for the treatment of the above-mentioned COX-2 mediated diseases, which comprise non-toxic therapeutically effective amounts of a compound of formula I and at least one additive, such as an analgesic such as acetaminophen or phenacetin; a potentiator such as caffeine; an _H2 antagonist, aluminum or magnesium hydroxide, simethicone; a decongestant such as phenylephrine, phenylproanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine or levodesoxyephedrine; an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane or dextramethorphan; a prostaglandin such as misoprostol, enprostil, rioprostil, ornoprotol or rosaprostol; a diuretic; a sedative or non-sedating antihistamine; an anticancer agent, such as angiostatin and endostatin; anti-Alzheimer's drugs, such as donepezil and tacrine hydrochloride; and TNFα inhibitors, such as etanercept.

These cyclooxygenase inhibitors can further be used in combination with the nitric oxide inhibitors described in WO 96/28145.

176 N

The invention also provides pharmaceutical compositions for the treatment of the above-mentioned COX-2 mediated diseases, the essence of which lies in the fact that they contain a non-toxic therapeutically effective amount of a compound of general formula I and at least one of the antiulcer agents and/or prostaglandins described in WO 97/11701.

Useful prostaglandins include misoprostol, plus-minus methyl-11a,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate, enisoprost, and methyl 7-[2B-[6-(1-cyclopenten-1-yl)-4-hydroxy-4-methyl-1E,5E-hexadienyl]-3a-hydroxy-5-oxo-1R,1α-cyclopentyl]-4Z-heptenoate. Prostaglandins that fall within the scope of the present invention include arbaprostil, enprostil, rioprostol, nocloprost, mexiprostil, ornoprostol, dimoxaprost, tiprostanide, and rosaprostol.

The compounds of the invention can also be used in combination therapy, as a partial or complete replacement for other conventional anti-inflammatory agents, such as together with steroids, 5-lipoxygenase inhibitors, LTB ₄ antagonists and LTA ₄ hydrolase inhibitors.

Examples of LTB ₄ are described in WO 97/29774. Suitable LTB ₄ inhibitors include compounds such as ebselen, Bay-x-1005 (Bayer), compound CGS-25019C (Ciba Geigy), compound ETH-615 (Leo Denmark), compound LY-293111 (Lilly), compound ONO-4057 (Ono), compound TMK-688 (Terumo), compounds LY-213024, 264086 and 292728 (Lilly), compound ONO-LB457 (Ono), compound SC-S3228 (Searle), calcitrol, compounds LY-210073, LY-223982, LY-233469 and LY-255283 (Lilly), compound ONO-LB-448 (Ono), compounds SC-41930, SC-50605 and SC-51146 (Searle) and the compound SKF-104493 (SK&F). The LTB ₄ inhibitors are preferably selected from the group consisting of ebselen,

177 -»

Bay-x-1005 (Bayer), CGS-25019C compounds (Ciba Geigy), ETH-61S compounds (Leo Denmark), LY-293111 compounds (Lilly), ONO-4057 compound (Ono) and TMK-688 compounds (Terumo).

5-LO inhibitors are described, for example, in WO97/29776. Suitable 5-LO inhibitors include, for example, masoprocol, tenidap, zileuton, pranlukast, tepoxalin, riloperox, flezelastine hydrochloride, enazaderm phosphate and bunaprolast.

LTA ₄ hydrolase inhibitors are described, for example, in WO 97/29774. Suitable LTA ₄ hydrolase inhibitors include RP-64966 (Rhone-Poulenc Rorer).

The compounds of the invention can be administered for treatment or prevention. The methods and compositions of the invention can be used alone or in conjunction with other preventive or curative therapies for angiogenesis known to those skilled in the art. Alternatively, the methods and compositions of the invention can be used as adjunctive therapy. For example, a cyclooxygenase-2 inhibitor can be administered alone or in conjunction with another antineoplastic agent or other growth inhibitory agent or other drugs or nutrients.

There are a large number of antineoplastic agents that are commercially available or in clinical trials or preclinical development that can be used to treat angiogenesis with combination chemotherapy. Such antineoplastic agents fall into several major categories, including antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, and miscellaneous agent categories. Matrix metalloprotease (MMP) inhibitors, such as • ·

- 178 MMP-13 inhibitors such as batiastat, marimastat, AG-3340 (Agouron Pharmaceuticals) and RO-32-3555 (Roche) or α,β-inhibitors.

The first group of antineoplastic agents that can be used in combination with selective cyclooxygenase-2 inhibitors are antimetabolite-type antineoplastic agents. Suitable antimetabolite antineoplastic agents can be selected from the group consisting of 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, CGP-30694 (Ciba-Geigy), cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates, DATHF (Lilly), DDFC (Merrel Dow), desaguanine, dideoxycytidine, dideoxyguanosine, didox, DMDC (Yoshitomi), doxifluridine, EHNA (Wellcome), EX-015 (Merck&Co.), fasarabine, fluoxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, FO-152 (Daiichi Seiyaku), isopropylpyrrolizine, LY-188011 (Lilly), LY-264618 (Lilly), methobenzaprim, methotrexate, MZPES (Wellcome), norspermidine, NSC-127716 (NCI), NSC-264880 (NCI), NSC-39661 (NCI), NCS-612567 (NCI), PALA (Warner-Lambert), pentostatin, piritrexim, plicamycin, PL-AC (Asahi Chemical), TAC-788 (Takeda), thioguanine, tiazofurin, TIF (Erbamont), trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, UFT (Taiho) and uricytin.

The second group of antineoplastic agents that can be used in combination with selective cyclooxygenase-2 inhibitors are alkylating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents can be selected from the group consisting of cytostatics 254-S (Shionogi), aldo-phosphamide analogues, altretamine, anaxiron, BBR-2207 (Boehringer Mannheim), bestrabucil, budotitan, CA-102 (Wakunaga), carboplatin, carmustine, Quinoin-139, Quinoin-153, chlorambucil, cisplatin, cyclophosphamide, • · · · • ·

CL286558 (American Cyanamid), CY-233 (Sanofi), cyplatate, D-19-384 (Degussa), DACHP(Myr)2 (Sumitomo), diphenylspiromustine, and diplatin; and further from derivatives of distamycin (Erba), DWA-2114R (Chugai), E09 (ITI), elmustine, FCE-24517 (Erbamont), sodium salt of estramustine phosphate, fotemustine, G-6-M (Unimed), GYKI-17230 (Chinoin), hepsul-fam, ifosfamide, iproplatin, iomunistin, mafosfamide, mitolactol, NK-121 (Nippon Kayaku), NSC-264395 (NCI), NSC-342215 (NCI), oxaliplatin, PCNU (Upjohn), prednimustine, PTT-119 (Proter), ranimustine, semustine, SK&F-101772 (SmithKline), SN-22 (Yakult Honsha), spiromustine, TA-077 (Tanabe Seiyaku), tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.

A third group of antineoplastic agents that can be used in combination with selective cyclooxygenase-2 inhibitors are antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents can be selected from the group consisting of 4181-A (Taiho), aclarubicin, actinomycin D, actinoplanon, ADR-456 (Erbamont), aeroplysinin derivative, AN-201-II (Ajinomoto), AN-3 (Ajinomoto), anisomycins (Nippon Soda), anthracycline, azinomycin-A, bisucaberine, BL-6859 (Bristol-Myers), BMY-25067 (Bristol-Myers), BMY-2551 (Bristol-Myers), BMY 26605 (Bristol-Myers), BMY-27557 (Bristol Myers), BMY-28438 (Bristol-Myers), bleomycin sulfate, bryostatin-1, C-1027 (Taiho), calichemycin, chromoximycin, dactinomycin, daunorubicin, DC-102 (Kyowa Hakko), DC-79 (Kyowa Hakko), DC-88A (Kyowa Hakko), DC89-A1 (Kyowa Hakko), DC92-B (Kyowa-Hakko), ditrisarubicin B, DOB-41 (Shionogi), doxorubicin doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamycin-Al, esperamycin-Alb, FCE-21954 (Erbamont), FK-973 (Fujisawa), fostriecin, FR900482 (Fujisawa), glidobactin, gregatin-A, grinkamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins,

180 ^J

KM-5539 (Kyowa Hakko), KRN-8602 (Kirin Brewery), KT-5432 (Kyowa Hakko), KT-5594 (Kyowa Hakko), KT-6149 (Kyowa Hakko), LL-D49194 (American Cyanamid), ME 2303 (Meiji Seika), menogaryl, mitomycin, mitoxantrone, M-TAG (SmithKline), neoenactin, NK-313 (Nippon Kayaku), NKT-01 (Nippon Kayaku), NSC-357704 (SRI International), oxalysin, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, RA-I (Tobishi), rapamycin, rhizoxin, rhodorubicin, sibanomycin, siwenmycin, SM-5887 (Sumitomo), SN-706 (Snow Brand), SN-07 (Snow Brand), sorangicin-A, sparsomycin, SS-21020 (SS Pharmaceutical), SS-313B (SS Pharmaceutical), SS-9816B (SS Pharmaceutical), steffimycin B, 4181-2 (Taiho), talisomycin, TAN-868A (Takeda), turpentine, thrazine, tricrosarin A, U-73975 (Upjohn), UCN-10028A (Kyowa Hakko), WF-3405 (Fujisawa), Y-2SO24 (Yoshitomi) and zorubicin.

A fourth group of antineoplastic agents that can be used in combination with selective cyclooxygenase-2 inhibitors are various antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethylarginine, acitretin, AD-5 (Biotec), AHC-52 (Kyorin), alstonine, amonafide, amfethinil, amsacrine, angiostat, ankinomycin, anti-neoplaston AIO, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, APD (Henkel), aphidicolin glycinate, asparaginase, avarol, baccharin, batracyline, benflurone, benzotript, BIM-23015 (Ipsen-Beaufour), bisantrene, BMY-40481 (Bristol-Myers), boron-10 (Vestar), bromophosphamide, BW-502 (Wellcome), BW-773 (Wellcome), caracemid, carmethizole hydrochloride, CDAF (Ajinomoto), chlorsulfaquinoxalone, CHX-2053 (Chemex), CHX100 (Chemex), CI-921 (Warner-Lambert), CI-937 (Warner-Lambert), CI-941 (Warner-Lambert), CI-958 (Warner-Lambert), clanfenur, claviridenone, compound 1259 (ICN), compound 4711 (ICN), contracan, CPT-11 • · · ·

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(Yakult Honsha), krysnatol, kuraderm, cytochalasin B, cytarabine, cytocytin, D-609 (Merz), DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihematoporphyrin ether, dihydrolenperone, dynalin, distamycin, DM-341 (Toyo Pharmar), DM-75 (Toyo Pharmar), DN-9693 (Daiichi Seiyaku), elliprabine, elliptinium acetate, EPMTC (Tsumura), ergotamine, etoposide, etretinate, fenretinide, FR-57704 (Fujisawa), gallium nitrate, genkwadafnine, GLA-43 (Chugai), GR-63178 (Glaxo), grifolan NMF-5N, hexadecylphosphocholine, HO-221 (Green Cross), homoharringtonine, hydroxyurea, ICRF-187 (BTG), ilmofosine, isoglutamine, isotretinoin,

JI-36 (Otsuka), K-477 (Ramot), K-76COONa (Otsuak), K-AM (Kureha Chemical), KI-8110 (MECT Corp.), L-623 (American Cyanamid), leukoregulin, ionidamine, LU-23-112 (Lundbeck), LY-186641 (Lilly), MAP (NCI, US), marycine, MDL-27048 (Merrel Dow), MEDR-340 (Médeo), merbarone, merocyanine derivatives, methylanilinoacridine, MGI-136 (Molecular Genetics), minactivin, mitonafide, mitochidone, mopidamol, motretinide, MST-16 (Zenyaku Kogyo), N-(retinoyl)amino acids, N-021 (Nisshin Flour Milling), N-acylated dehydroalanines, naphazatrom, NCU-190 (Taisho), derivative nocodazole, normosang, NSC-145813 (NCI), NSC-361456 (NCI), NSC-604782 (NCI), NSC-95580 (NCI), octreotide, 0N0-112 (Ono), ochizanocin, Org-10172 (Akzo), pancratistatin, pazelliptin, PD-111707 (Warner-Lambert), PD-115934 (Warner Lambert), PD-131141 (Warner-Lambert), PE-1001 (Pierre Fabre), D peptides (ICRT), piroxantrone, polyhematoporphyrin, polypreic acid, porphyrin (Efamol), probimane, procarbazine, proglurnide, protease nexin I (Invitron), RA-700 (Tobishi), razoxane, RBS (Sapporo Breweries RBS), restrictin-P, retelliptin, retinoic acid, RP-49532 (Rhone Pouleno), RP-56976 (Rhone-Poulenc), SK&F-104864 (SmithKline), SM-108 (Sumitomo),

SMANCS (Kuraray), SP10094 (SeaPharm), spatol, spirocyclopropane derivatives, spirogermanium (Unimed), SS-554 (SS Pharmaceutical), strypoldinone, stypoldione, SUN 0237

182 (Suntory), SUN 2071 (Suntory), superoxide dismutase, T-506 (Toyama), T-680 (Toyama), taxol, TEI-0303 (Teijin), teniposide, thaliblastin, TJB-29 (Eastman Kodak), tocotrienol, topostin, TT-82 (Teijin), UCN-01 (Kyowa Hakko), UCN-1028 (Kyowa Hakko), Ukraine, USB-006 (Eastman Kodak), vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidin, withanolide, and YM-534 (Yamanouchi).

Examples of radioprotective agents that can be used in the combination chemotherapy of the present invention include AD-5, adchnon, amifosphine analogs, detox, dimesna, 1-102, MN-159, N-acylated dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, ketoprofen transdermal, naburneton, superoxide dismutase (Chiron), and superoxide dismutase (Enzon).

Methods for the preparation of the antineoplastic agents described above can be found in the literature. Methods for the preparation of doxorubicin are described, for example, in U.S. Patent Nos. 3,590,028 and 4,012,448. Methods for the preparation of matrix metalloprotease inhibitors are described in EP 780,386, WO 97/20824 and WO 96/15096. Methods for the preparation of SOD mimetics are described in EP 524,101. Methods for the preparation of α,β-inhibitors are described in WO 97/08174.

In addition, selective COX-2 inhibitors can be administered with other anti-inflammatory agents, such as NSAIDs, selective COX-1 inhibitors, and leukotriene pathway inhibitors, such as 5-lipoxygenase inhibitors, to maximize safety and efficacy. Examples of NSAIDs include indomethacin, naproxen, ibuprofen, salicylic acid derivatives such as aspirin, diclofenac, ketorolac, piroxicam, meloxicam, mefenamic acid, sulindac, tolmetin sodium, zomepirac, fenoprofen, phenylbutazone, oxyphenbutazone, nimesulide, zaltoprofen, and letodolac.

183 • · ··0· • * *

Methods for determining biological efficacy

The efficacy of the compounds of general formula I according to the invention can be demonstrated using the following tests:

In vitro tests

COX-1 assay on human cells

Human peripheral blood obtained from healthy volunteers is diluted to 1/10 volume with 3.8% sodium citrate solution. The immediately obtained platelet-rich plasma is washed with 0.14M sodium chloride containing 12mM Tris HCl (pH 7.4) and 1.2mM EDTA. The platelets are then washed with platelet buffer (Hanks buffer, calcium-free, containing 0.2% BSA and 20mM Hepes). Finally, the washed human platelets (HWP) are suspended in platelet buffer at a concentration of 2.85 x 10 ⁸ cells/ml and stored at room temperature until use. The HWP suspensions (70μl aliquots, 2.0 x 10 ⁷ cells/ml) are sampled into a 96-well round-bottom plate and 10μl aliquots of 12.6mM calcium chloride are added. Plates are incubated with A23187 (final concentration 10μM, Sigma) and test compound (0.1 to 100μM) dissolved in DMSO (final concentration less than 0.01%) for 15 minutes at 37°C.

The reaction is stopped by the addition of EDTA (final concentration 7.7 mM) and TxB ₂ in the supernatant is quantified using a radioimmunoassay kit (Amersham) according to the manufacturer's instructions.

COX-2 assay on human cells

Inhibition of COX-2 activity after COX-2 induction using hIL-Ιβ

The COX-2 assay in human cells is performed as previously described (Moore et al., Inflam. Res., 45, 54,

1996). Confluent human umbilical vein endothelial cells

184 (HUVEC, Morinaga) in 96-well round-bottom plates were washed with 100 μl of RMPI1640 containing 2% FCS and incubated with hIL-Ιβ (final concentration 300 U/ml, R&D Systems) for 24 hours at 37°C. After washing, activated HUVEC cells were stimulated with A23187 (final concentration 30 μΜ) in Hanks' buffer containing 0.2% BSA, 20 mM Hepes and test compound (0.1 mM to 100 μΜ) dissolved in DMSO (final concentration less than 0.01%) for 15 minutes at 37°C. After appropriate dilution, 6-keto-PGFα, a stable metabolite of PGI ₂ , was quantified in the supernatant using a radioimmunoassay kit (Amersham) according to the manufacturer's instructions.

COX-2 inhibition during the induction phase

Confluent human umbilical vein endothelial cells (HUVEC, Morinaga) in 96-well round-bottom plates are washed with 100 μΐ RMPI1640 containing 2% FCS and test compound (0.1 nM to 100 μΜ) dissolved in DMSO (final concentration less than 0.01%). The cells are then incubated with hIL-Ιβ (final concentration 300 U/ml,

R&D Systems). After washing, HUVEC cells are stimulated with A23187 (final concentration 30μΜ) in Hanks buffer containing 0.2% BSA and 20mM Hepes for 15 minutes at 37°C. After appropriate dilution, 6-keto-PGFα, a stable metabolite of PGI ₂ , is quantified in the supernatant using a radioimmunoassay kit (Amersham) according to the manufacturer's instructions.

In vivo tests

Carrageenan-induced edema in rats

Male Sprague-Dawley rats (5 weeks old, Charles River Japan) are fasted overnight. A line is drawn with a marker above the ankle of their right hind paw, and the volume of water displaced is measured using a plethysmometer.

185

9999 99 9 ·· • · · « « « · 9 9*

9« ««· « · ·· 9 9 9 C 999«

9 9 «. 9« 9 · b ~·* 99 99 999 »9 9 (Muromachi) paw volume (VO) is measured. Animals are orally administered either vehicle (0.1% methylcellulose or 5% Tween 80) or test compound (2.5 ml/100 g body weight). After 1 hour, animals are administered lambda-carrageenan (0.1 ml of a 1% (w/v) suspension in saline, Zushikagaku) by intradermal injection into the right hind paw (Winter et al.,

Proc. Soc., Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim. Forsch., 25, 1629, 1975). After 3 hours, the cuff volume (V3) is measured and the volume increase (V3-V0) is calculated. Since the maximum inhibition achievable with classical NSAIDs is 60 to 70%, ED ₃₀ values are calculated.

Gastric ulcers in rats

The gastric ulcerogenicity test of the test compound is carried out using a modified conventional method (Ezer et al., J. Pharm. Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29, 330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles River Japan) that have been fasted overnight are orally administered either vehicle (0.1% methylcellulose or 5% Tween 80) or test compound (1 ml/100 mg body weight).

After 6 hours, the animals are sacrificed by cervical dislocation. The stomachs are removed, filled with 1% formalin solution (10 ml) and opened by an incision along the greater curvature. The incidence of ulceration is calculated from the number of rats showing at least one gastric ulcer or hemorrhagic erosion (including ecchymosis). The animals are deprived of access to food and water during the test.

Data analysis

The statistical software packages SYSTAT (SYSTAT, Inc.) and StatView (Abacus Concepts, Inc.) for Macintosh are used. Differences between the group of animals treated with test compounds and the control group are determined by

186 using ANOVA. IC ₅₀ (ED ₃₀ ) values are calculated from the equation for a log-linear regression line of concentration (dose) versus percent inhibition.

Some of the compounds, the preparation of which is described in the Examples, showed IC ₅₀ values of 0.001 μM to 10 μM for COX-2 inhibition in the tests described above.

The most preferred compounds listed above were also tested using these methods. These compounds showed IC ₅₀ values ranging from 0.001μM to 0.5μM for COX-2 inhibition.

COX-2 selectivity can be determined as the ratio of the _IC50 value of COX-1 inhibition to that of COX-2 inhibition. In general, it can be said that compounds that show a COX-1/COX-2 inhibition ratio higher than 2 have good selectivity towards COX-2.

Some of the compounds shown in the Examples exhibit a COX-1/COX-2 inhibition ratio of more than 10.

The following examples of the invention contain a detailed description of methods for preparing compounds of general formula I. These examples are purely illustrative in nature and do not limit the scope of the invention in any way.

In the following non-limiting examples, unless otherwise stated: All operations are carried out at room or ambient temperature, i.e. at 18 to 25°C. Evaporation of the solvent is carried out using a rotary evaporator under reduced pressure and a bath temperature of up to 60°C. The progress of the reaction is monitored by thin layer chromatography (TLC). Reaction times are given as illustrative examples only. The melting points given are uncorrected (polymorphism can lead to different melting points). The structure and purity of all

187

The identity of the isolated compounds was verified by at least one of the following methods: thin layer chromatography (plates precoated with Merck silica gel 60F-254), mass spectrometry, nuclear magnetic resonance (NMR) or microanalysis. Yields are given for illustration only. Flash column chromatography was performed using Merck silica gel 60 (38 to 63 μπι). Low resolution mass spectra (EI) were measured on an Automass 120 mass spectrometer (JEOL). Low resolution mass spectra (ESI) were measured on a Quattro II mass spectrometer (Micromass). NMR spectra were determined at 270 MHz (JEOL JNM-LA 270 spectrometer) using deuterochloroform (99.8% D) or dimethyl sulfoxide (99.9% D) as solvent, unless otherwise stated, with tetramethylsilane (TMS) as internal standard, and are reported in parts per million (ppm). Peak shapes are expressed using the usual abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad.

Examples of embodiments of the invention

Example 1

Ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate

Stage 1: Ethyl trans-4-chloro-2-nitrocinnamate

To a suspension of sodium hydride [60% (w/w) dispersion in mineral oil, 4.4 g, 0.11 mol) in tetrahydrofuran (150 ml) was added dropwise a solution of triethylphosphonoacetate (25.0 g, 0.11 mol) in tetrahydrofuran (50 ml) at room temperature.

The resulting mixture was stirred for 1 hour and a solution of 4-chloro-2-nitrobenzaldehyde (19.0 g, 0.10 mol) in tetrahydrofuran (50 ml) was added. The resulting mixture was stirred for another 1 hour and at 188

Saturated aqueous ammonium chloride (50 ml) was added thereto. The reaction mixture was extracted with ethyl acetate (300 ml x 2). The combined organic extracts were dried over magnesium sulfate and concentrated to give 27 g (quant.) of the title compound as a brown solid.

¹ H NMR (CDCl ₃ ): δ 8.04 (1H,d , J = 15.8 Hz), 8.03 (1H, d, J = 1.8 Hz), 7.64 - 7.58 (2H, m), 6.36 (1H, d, J = 15.8 Hz), 4.30 (2H, q, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz)

Stage 2: Ethyl trans-2-amino-4-chlorocinnamate

A mixture of ethyl trans-4-chloro-2-nitrocinnamate (from step 1, 27.0 g, 0.11 mol) and sodium bisulfite (92 g,

0.53 mol) in a 1:1 mixture of tetrahydrofuran and water (500 ml) was stirred at room temperature for 1 hour, and then saturated aqueous sodium bicarbonate solution (300 ml) was added thereto. The reaction mixture was extracted with ethyl acetate (300 ml x 2). The combined organic extracts were dried over magnesium sulfate and concentrated. 16.7 g (67%) of the title compound was obtained as a yellow solid.

¹ H NMR (CDCl ₃ ): δ 7.72 (1H, d, J = 15.8 Hz), 7.27 (1H, d, J = 8.4 Hz), 6.78 - 6.68 (2H, m), 6.31 (1H, d, J = 15.8 Hz), 4.27 (2H, q, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz)

Step 3: Ethyl trans-4-chloro-2-formamidocinnamate

A mixture of acetic anhydride (20 mL) and formic acid (10 mL) was heated at 60°C for 2 hours, cooled to 0°C, and ethyl trans-2-amino-4-chlorocinnamate (from step 2, 15.5 g, 0.069 mol) in tetrahydrofuran (80 mL) was carefully added. The reaction mixture was allowed to warm to room temperature, stirred overnight, and concentrated. The precipitate that separated was collected by filtration. The solid that separated was washed with hexane. 9.6 g (55%) of the title compound was obtained.

^. _​ 15.8 Hz), 4.25 (2H, q, J = 7.3 Hz),

1.34 (3H, t, J = 7.3 Hz)

Step 4: Ethyl trans-4-chloro-2-isocyanocinnamate

To a solution of triphenylphosphine (5.3 g, 20 mmol) in dichloromethane (80 ml) cooled to 0°C was added dropwise a solution of triphosgene (2.0 g, 6.7 mmol) in dichloromethane (20 ml).

The ice bath is removed, the resulting mixture is stirred for 10 minutes at room temperature, cooled to 0°C and a solution of ethyl trans-4-chloro-2-formamidocinnamate (from step 3,

5.2 g, 0.020 mol) in dichloromethane (80 ml). The reaction mixture was allowed to warm to room temperature overnight and then concentrated. The residue was partitioned between water (80 ml) and ethyl acetate (100 ml). The aqueous layer was separated and extracted with ethyl acetate (100 ml). The combined organic extracts were dried over magnesium sulfate and the solvent was evaporated. The crude product was purified by flash chromatography using ethyl acetate:hexane 1:6 as eluent to give 3.9 g (83%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 7.89 (1H, d, J = 16.1 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.45 (1H, d , J = 1.8 Hz), 7.42 (1H, d, J = 1.8, 8.8 Hz), 6.52 (1H, d, J = 16.1 Hz), 4.30 (2H, q, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz)

Step 5: Ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate

A mixture of ethyl trans-4-chloro-2-isocyanocinnamate (from step 4, 1.2 g, 5.1 mmol), tributyltin hydride (1.6 g, 5.6 mmol) and AIBN (43 mg, 0.26 mmol) in acetonitrile (30 mL) was heated to 100°C. After 1 hour, tetrakis(triphenylphosphine)palladium(0) (580 mg, 0.50 mmol) was added to the resulting mixture and

190

benzoyl chloride (0.65 ml, 5.6 mmol). The reaction mixture was heated for a further 17 hours, then cooled and poured into 2M aqueous hydrochloric acid (50 ml). The resulting mixture was extracted with diethyl ether (80 ml x 2). The combined organic extracts were washed with saturated aqueous potassium fluoride (50 ml), dried over magnesium sulphate and the solvent was evaporated. The crude product was purified by flash chromatography using ethyl acetate:hexane 1:5 as eluent to give 0.43 g (25%) of the title compound as a white solid, mp 160-163°C.

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, br s), 7.82 - 7.75 (2H, m), 7.67 - 7.47 (4H, m), 7.37 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.4 Hz), 4.11 (2H, q, J = 7.3 Hz), 3.78 (2H, s), 1.22 (3H, t, J = 7.3 Hz)

Example 2 (2-Benzoyl-6-chloro-1H-indol-3-yl)acetic acid

Method A

To a solution of ethyl (2-benzoyl-6-chloro-1H-indol-3-yl)acetate (from Example 1, 380 mg, 0.11 mmol) in ethanol (15 mL) was added 2M aqueous potassium hydroxide (5 mL). The resulting mixture was heated at 80°C for 1 hour, then cooled and concentrated. To the residue was carefully added 2M aqueous hydrochloric acid (15 mL). The resulting mixture was extracted with diethyl ether (50 mL x 2). The combined organic extracts were dried over magnesium sulfate and concentrated. The solid residue was recrystallized from ethyl acetate-hexane to give 60 mg (17%) of the title compound as a pale yellow solid, mp 183-186°C.

IR (KBr) at: 1700, 1610, 1520, 1425, 1330, 1000 cm ^-1

191

¹ H NMR (DMSO-dg): δ 12.26 (1H, br s), 11.76 (1H, s), 7.77 7.66 (4H, m), 7.62 - 7.54 (2H, m), 7.48 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 3.80 (2H, s)

Method B

Step 1: 6-chloro-1-(phenylsulfonyl)indole

A mixture of 6-chloroindole (Y. Watanabe et al., J. Org. Chem., 1990, 55, 580, 36.2 g, 0.24 mol), tetrabutylammonium hydrogen sulfate (8.1 g, 0.024 mol) and 50% aqueous potassium hydroxide (160 ml) in benzene (500 ml) was stirred at room temperature for 10 minutes, then cooled to 0°C and a solution of benzenesulfonyl chloride in benzene (20 ml) was added.

The reaction mixture was stirred at room temperature for 3 hours and then poured into water (200 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (200 mL x 2). The combined organic extracts were washed with brine (200 mL), dried over magnesium sulfate and concentrated. The solid residue was washed with ethanol (100 mL x 3). 58 g (83%) of the title compound was obtained as an off-white solid.

¹ H NMR (CDCl ₃ ): δ 8.02 (1H, s), 7.92 - 7.85 (2H, m), 7.60 7.40 (5H, m), 7.21 (1H, dd, J = 1.8, 8.4 Hz), 6.62 (1H, d, J = 3.6 Hz)

Step 2: 6-chloro-2-benzoyl-1-(phenylsulfonyl)indole

To a stirred solution of 6-chloro-1-(phenylsulfonyl)indole (from step 1, 12.58 g, 43.0 mmol) in tetrahydrofuran (270 mL) cooled to -78°C was added dropwise tert-butyllithium (32 mL, 52.0 mmol, 1.64M in n-pentane). The internal temperature was maintained below -65°C during the addition. After stirring at -78°C for 30 min, the resulting solution was added dropwise via cannula to a solution of benzoyl chloride (6.0 mL, 52.0 mmol) in tetrahydrofuran (30

192 ml) cooled to -78°C. The resulting mixture was stirred for 1.5 hours and then quenched with saturated ammonium chloride (200 ml) at -78°C and allowed to warm to room temperature. The aqueous layer was separated, neutralized with aqueous sodium carbonate and extracted with ethyl acetate (50 ml x 2). The combined organic extracts were washed with aqueous sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated. The residue was crystallized from a 1:3 mixture of diethyl ether and hexane to give the title compound as a white solid (14.4 g, 85%).

¹ H NMR (CDC1 ₃ ): δ 8.20 - 8.16 (IH, m), 8.14 - 8.06 (2H, m), 8.01 - 7.93 (2H, m), 7.66 - 7.47 (7H, m), 7.29 (IH, dd, J = 1.7, 8.5 Hz), 6.89 (IH, J = 0.7 Hz)

Step 3: 3-benzoyl-6-chloroindole

A mixture of 2-benzoyl-6-chloro-1-(phenylsulfonyl)indole (from step 2, 48 g, 0.12 mol) and potassium carbonate (80 g, 0.58 mol) in a 4:2:1 mixture of tetrahydrofuran, methanol and water (1100 ml) was heated to reflux overnight and the solvent was removed. The residue was extracted with diethyl ether (300 ml x 2). The extract was dried over magnesium sulfate and the solvent was removed. The crude product as a light brown solid was recrystallized from ethyl acetate to give 20 g (65%) of the title compound as a white solid, mp 206-207°C.

¹ H NMR (CDCl ₃ ): δ 9.31 (1H, brs), 8.01-7.95 (2H, m), 7.68-7.47 (5H, m), 7.17-7.12 (2H, m)

Step 4: Diethyl-α-acetoxy-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate

A mixture of 2-benzoyl-6-chloroindole (from step 3, 4.0 g, 16 mmol), manganese(III) acetate dihydrate (13 g, 48 mmol), diethyl malonate (14 g, 80 mmol), and sodium acetate (6.6 g, 80

193 ·· ··4 · * · • « · · · mmol) in acetic acid (150 ml) was heated at 80°C with stirring for 2 hours. Manganese acetate dihydrate (3 g, 11 mmol) was added to the resulting mixture and heating was continued for another 2 hours. The reaction mixture was cooled and aqueous sodium chloride solution (200 ml) was added. The resulting mixture was extracted with diethyl ether (200 ml x 2). The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using ethyl acetate:hexane (1:3) as eluent to give 5.2 g (69%) of the title compound as a yellow solid, mp 141-144°C.

¹ H NMR (CDCl ₃ ): δ 8.84 (1H, brs), 7.90 - 7.81 (3H, m), 7.66

- 7.58 (1H, m), 7.51 - 7.42 (2H, m), 7.38 (1H, d, J = 1.3 Hz), 7.15 (1H, dd, J = 2.0, 8.7 Hz), 4.30 - 4.06 (4H, m), 1.70 (3H, s), 1.30 - 1.58 (6H, m)

Step 5: Diethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate

A mixture of diethyl α-acetoxy-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate (from Step 4, 5.0 g, 11 mmol), trifluoroacetic acid (3.3 mL, 44 mmol), and triethylsilane (2.1 mL, 13 mmol) in dichloromethane (80 mL) was heated to reflux for 12 h, then cooled and concentrated. The residue was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (80 mL). The aqueous layer was separated and extracted with dichloromethane (80 mL). The combined organic extracts were dried over magnesium sulfate and the solvent was removed. The crude product was purified by flash column chromatography using ethyl acetate:hexane (1:4) as eluent to give 4.0 g (87%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, brs), 7.81 - 7.70 (3H, m), 7.68

- 7.60 (1H, m), 7.55 - 7.48 (2H, m), 7.32 (1H, S ), 7.12 (1H, dd, J = 1.8, 8.8 Hz), 5.29 (1H, s), 4.26 - 4.09 (4H, m),

1.21 (6H, t, J = 7.1 Hz)

194

Step 6: (2-Benzoyl-6-chloro-1H-indol-3-yl)acetic acid

Diethyl (2-benzoyl-6-chloro-1H-indol-3-yl)malonate (from Step 5, 4.4 g, 11 mmol) in a mixture of ethanol (120 mL) and 2M aqueous sodium hydroxide (15 mL) was heated to reflux for 1 h, cooled, and concentrated. The residue was carefully acidified with 2M aqueous hydrochloric acid (30 mL). The resulting mixture was extracted with diethyl ether (150 mL x 3). The combined organic extracts were dried over magnesium sulfate and concentrated. The solid residue was recrystallized from ethyl acetate-hexane to give 1.1 g (30%) of the title compound as a pale yellow solid, mp 183-186°C.

IR (KBr) at: 1700, 1610, 1520, 1425, 1330, 1000 cm' ^{1 1} H NMR (DMSO-dg): δ 12.26 (1H, brs), 11.76 (1H, s), 7.77 7.66 (4H, m), 7.62 - 7.54 (2H, m), 7.48 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 3.80 (2H, s)

Example 3

Sodium salt of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (2-Benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2, 480 mg, 1.5 mmol) in ethanol (10 mL) was treated with 2M aqueous sodium hydroxide (0.7 mL, 1.4 mmol) at room temperature for 30 minutes. The resulting mixture was concentrated, the residue was dissolved in water (10 mL) and washed with diethyl ether (15 mL x 2). The aqueous layer was concentrated to give 350 mg (68%) of the title compound as a light brown solid, mp 185-189°C.

IR (KBr) Vi 1523, 1380, 1230, 1060, 1004, 918 cm ^{-1 1} H NMR (DMSO-dg): δ 11.46 (1H, brs), 7.88 - 7.84 (2H, m),

7.66 (1H, d, J = 8.4 Hz), 7.64 - 7.46 (3H, m), 7.39 (1H, d,

J = 1.8 Hz), 7.00 (1H, dd, J = 1.8, 8.4 Hz), 3.32 (2H, s)

- 19¾

Example 4 [6-Chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(2-methylbenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared as described in Step 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 1 - Method B) and o-toluoyl chloride.

tle: Rf = 0.3 (ethyl acetate/hexane, 1 : 10)

Step 2: 6-Chloro-2-(2-methylbenzoyl)indole

The title compound was prepared according to the method described in Step 3 of Example 2 (Method B) from 6-chloro-2-(2-methylbenzoyl)-1-(phenylsulfonyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 9.37 (1H, br s), 7.58 (2H, d, J = 8.91Hz), 7.48 (1H, s), 7.42 (1H, dd, J = 1.49, 7.75 Hz), 7.34 - 7.27 (2H, m), 7.12 (2H, dd, J = 1.81, 8.56 Hz), 2.44 (3H, s)

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 4 of Example 2 (Method B) from 6-chloro-2-(2-methylbenzoyl)indole (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.52, (1H, brs), 7.78 (1H, d, J = 8.88 Hz), 7.48 - 7.13 (6H, m), 4.31 - 4.16 (4H, m), 2.52 (3H, s), 1.96 (3H, s), 1.22 (6H, t, J = 7.26Hz)

Step 4: Diethyl-[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]malonate • ·

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 9.0 (1H, brs), 7.73 (1H, d, J = 8.88 Hz), 7.73 - 7.09 (5H, m), 7.11 (1H, dd, J = 1.97, 8.75 Hz), 4.89 (1H, s), 4.20 - 4.08 (4H, m), 2.35 (3H, s), 1.19 (6H, t, J 7.1 Hz)

Step 5: [6-Chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl] malonate (from Step 4). The product obtained had a melting point of 150-152°C.

IR (KBr) v: 3321, 1717, 1624, 1602, 1568, 1531, 1431, 1319, 1249, 1230 cm ^{1 1} H NMR (DMSO-dg): δ 11.70 (1H, s), 7.69 (2H, d, 8.72 Hz), 7.51 - 7.31 (3H, m), 7.10 (2H, dd, J = 1.97, 8.56 Η), 3.57 (2H, s), 2.24 (3H, s)

Example 5 [6-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(3-methylbenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared as described in Step 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 1 - Method B) and o-toluoyl chloride.

tle: Rf = 0.3 (ethyl acetate/hexane, 1 : 10)

197·.7'

Step 2: 6-Chloro-2-(3-methylbenzoyl)indole

The title compound was prepared according to the method described in Step 3 of Example 2 (Method B) from 6-chloro-2-(3-methylbenzoyl)-1-(phenylsulfonyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 9.37 (1H, s), 7.77 (2H, brs), 7.64 (1H, d, J = 8.56 Hz), 7.47 - 7.12 (5H, m), 2.47 (3H, s)

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(3-methylbenzoyl)indole (from Step 2).

^X H NMR (CDCl ₃ ): δ 8.80 (1H, brs), 7.83 (1H, d, J = 8.88 Hz),

7.67 - 7.32 (5H, m), 7.16 (1H, dd, J = 1.81, 8.88 Hz), 4.27 - 4.15 (4H, m), 2.39 (3H, s), 1.72 (3H, s), 1.29 (6H, t, J = 7.26 Hz)

Step 4: Diethyl-[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (from Step 3).

^Χ Η NMR (CDC1 ₃ ): δ 9.21 (1H, brs), 7.71 (1H, d, J = 8.51 Hz), 7.59 - 7.28 (5H, m), 7.10 (1H, dd, J = 1.97, 8.72 Hz), 5.27 (1H, s), 4.23 - 4.07 (4H, m), 2.40 (3H, s), 1.21 (6H, t, J = 7.1 Hz)

Step 5: [6-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (from Step 4). The product obtained had a melting point of 182-184°C.

IR (KBr) v: 3313, 1699, 1616, 1568, 1533, 1408, 1325, 1265, 1203 cm ^{1 1} H NMR (DMSO-d ₆ ): δ 11.75 (1H, s), 7.70 (1H, d, J = 8.75), 7.55 - 7.46 (5H, m), 7.12 (1H, dd, J = 1.97, 8.72 Hz), 3.75 (2H, S), 2.39 (3H, s)

Example 6 [6-Chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(4-methylbenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared as described in Step 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 1 - Method B) and o-toluoyl chloride.

tle: Rf - 0.3 (ethyl acetate/hexane, 1 : 10)

Step 2: 6-Chloro-2-(4-methylbenzoyl)indole

The title compound was prepared according to the method described in Step 3 of Example 2 (Method B) from 6-chloro-2-(4-methylbenzoyl)-1-(phenylsulfonyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 9.37 (1H, br s), 7.90 (2H, d, J = 8.6 Hz), 7.63 (1H, d, J = 8.9 Hz), 7.48 (1H, s), 7.34 (2H, d, J = 8.6 Hz), 7.16 - 7.10 (2H, m), 2.47 (3H, s)

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate • ·

- 199..The title compound was prepared according to the method described in step 4 of Example 2 (method B) from 6-chloro-2-(4-methylbenzoyl)indole (from step 2).

¹ H NMR (CDCl ₃ ): δ 8.65 (1H, brs), 7.84 (1H, d, J = 8.9 Hz), 7.76 (2H, d, J = 8.2 Hz), 7.39 - 7.37 (1H, m), 7.27 (2H, d,

J = 8.2 Hz), 7.16 (1H, dd, J = 1.8, 8.2 Hz), 4.36 - 4.16 (4H, m), 2.44 (3H, s), 1.72 (3H, s), 1.34 - 1.22 (6H, m)

Step 4: Diethyl [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.83 (1H, brs), 7.76 (1H, d, J = 8.7 Hz), 7.71 (2H, d, J = 8.2 Hz), 7.39 - 7.36 (1H, m), 7.32 (2H, d,

J = 8.2 Hz), 7.14 (1H, dd, J = 2.0, 8.7 Hz), 5.30 (1H, s), 4.26 - 4.14 (4H, m), 2.47 (3H, s), 1.22 (6H, t, J = 7.1 Hz)

Step 5: [6-Chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]malonate (from Step 4). The product obtained had a melting point of 182-184°C.

IR (KBr) v: 3321, 1705, 1616, 1602, 1566, 1529, 1431, 1323, 1257, 1230 cm' ^{1 1} H NMR (DMSO-dg): δ 11.72 (1H, s), 7.74 - 7.64 (3H, m), 7.49 - 7.45 (1H, m), 7.39 (2H, d, J = 8.1 Hz), 7.16 - 7.09 (1H, m), 3.81 (2H, s), 2.43 (3H, s)

- 200.Example 7 [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole

To a stirred suspension of 6-chloroindole-2-carboxylic acid (Η. N. Rydon and J. C. Tweddle, J. Chem. Soc., 1955. 3499, 7.0 g, 36 mmol) in thionyl chloride (30 ml) was added dropwise dimethylformamide (1 ml). The resulting mixture was stirred for 30 minutes and then concentrated. The residue was dissolved in dichloromethane (100 ml), the resulting solution was cooled to 0°C and N,O-dimethylhydroxylamine hydrochloride (7.0 g, 72 mmol) and pyridine (15 ml) were added. The resulting mixture was stirred for 2 hours and then quenched with water (100 ml). The aqueous mixture was extracted with dichloromethane (150 ml x 2). The combined organic extracts were washed with 2M aqueous hydrochloric acid (100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL), dried over magnesium sulfate, and the solvent was removed to give 8.2 g (96%) of the title compound as a yellow solid.

¹ H NMR (CDCl ₃ ): δ 9.48 (1H, brs), 7.60 (1H, d, J = 8.6 Hz), 7.46 - 7.41 (1H, m), 7.22 - 7.18 (1H, m), 7.11 (1H, dd, J = 8.6, 1.8 Hz), 3.85 (3H, s), 3.44 (3H, s)

Step 2: 6-Chloro-2-(3-chlorobenzoyl)indole

To a stirred solution of 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from step 1, 610 mg, 2.56 mmol) and 3-bromochlorobenzene (1.47 g, 7.67 mmol) in tetrahydrofuran (20 mL) at -78°C was added dropwise n-butyllithium (1.54M in hexane,

4.90 mL, 7.67 mmol). The resulting mixture was stirred for 1 hour and then quenched with saturated ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with 2M aqueous hydrochloric acid (50

201· ml), saturated sodium bicarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate and the solvent removed. The crude product was purified by flash column chromatography using a 1:10 mixture of ethyl acetate and hexane as eluent.

565 mg (76%) of the title compound are obtained as a light brown solid.

¹ H NMR (CDCl ₃ ): δ 9.31 (1H, brs), 7.94 (1H, t, J = 1.9 Hz), 7.85 (1H, dt, J = 1.9, 7.6 Hz), 7.65 (1H, d, J = 8.4 Hz),

7.63 - 7.58 (1H, m), 7.52 - 7.45 (2H, m), 7.18 - 7.12 (2H, m)

Step 3: Diethyl α-acetoxy-[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(3-chlorobenzoyl)indole (from Step 2).

^X H NMR (CDCl ₃ ) : δ 8, 88 (1H, brs ) ), 7.87 - 7.74 (3H, Germany), 7.6 - 7.56 (1H, m), 7.43 (lH,d, J = 7.6 Hz), 7.41 7, 38 (1H, m), 7.20 - 7.14 (1H, m) , 4, 30 - 4.14 (4H, m), 1.74 (3H, s), 1.20 (6H, t, J : = 8.2 Hz)

Step 4: Diethyl [6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.87 (1H, brs), 7.79 - 7.74 (2H, m), 7.70 - 7.58 (2H, m), 7.47 (1H, t, J = 8.1 Hz), 7.39 - 7.37 (1H, m), 7.15 (1H, dd, J = 1.8, 8.7 Hz), 5.19 (1H, s), 4.27 4.10 (4H, m), 1.22 (TH,t, J = 7.1 Hz) • ·9 ·

- 202*.v*

Step 5: [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl] malonate (from Step 4). The product obtained had a melting point of 199-201°C.

^Χ Η NMR (DMSO-dg): δ 12.25 (1H, brs), 11.81 (1H, s), 7.79 7.57 (5H, m), 7.48 (1H, d, J = 1.8 Hz), 7.14 (1H, dd, J = 1.8, 8.7 Hz), 3.81 (2H, s)

Example 8

Methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

Method A

Step 1: Methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate

To a solution of methyl trans-2-amino-4-chlorocinnamate (R. W. Carling et al., J. Med. Chem., 1993, 36, 3397, 30.7 g, 0.15 mol) and pyridine (36 ml, 0.45 mol) in dichloromethane (500 ml) was added benzenesulfonyl chloride (20 ml, 0.16 mol).

The reaction mixture was stirred for 20 hours, then methanol (50 mL) was added. The resulting mixture was concentrated and the solid residue was dissolved in dichloromethane (700 mL). The methanolic solution was washed with 2M aqueous hydrochloric acid (150 mL) and brine (150 mL), dried over magnesium sulfate, and the solvent was removed. The solid residue was recrystallized from ethanol to give 40 g (76%) of the title compound as a pale yellow solid.

^H NMR (CDCl ₃ ): δ 7.77 - 7.71 (2H, m), 7.59 - 7.52 (1H, m), 7.48 - 7.35 (5H, m), 7.20 (1H, dd, J = 2.0, 8.4 Hz), 6.85 (1H, bsr), 6.15 (1H, d, J = 15.8 Hz), 3.78 (3H, s) • · ··· · • · ·

203'

Step 2: Methyl-[6-chloro-2-(4-chlorobenzoyl)-1-(phenylsulfonyl)indolin-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1, 1.1 g, 3.1 mmol), 4-chlorophenacyl bromide (1.1 g, 4.6 mmol) and potassium carbonate (2.1 g, 15.4 mmol) in acetone (10 mL) was stirred at room temperature for 1.5 h and then filtered. The filtrate was concentrated and the solid residue was recrystallized from ethyl acetate-hexane to give 0.91 g (59%) of the title compound as a pale yellow solid.

¹ H NMR (CDCl ₃ ): δ 7.97 - 7.94 (2H, m), 7.86 - 7.81 (2H, m),

7.65 - 7.58 (1H, m), 7.55 - 7.46 (5H, m) 1, 7, 02 (1H, dd, J = 2.0, 8.2 Hz) / 6, 90 (1H, d, J = 8.2 Hz), 5.99 (1H, d, J = 9.7 Hz) , 4.00 - 3.87 (1H, m), 3.41 (3H, s), 2.63 (1H, dd, J = 6,: 3, 17.6 HZ) , 2.51 (1H, dd, J = 6.3, 17.6 Hz)

Step 3: Methyl-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

To a stirred solution of methyl [6-chloro-2-(4-chlorobenzoyl)-1-(phenylsulfonyl)indolin-3-yl]acetate (from step 2, 50 mg,

0.10 mmol) in tetrahydrofuran was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 30 μΐ, 0.20 mmol). The resulting mixture was stirred for 15 h and then quenched with water (30 mL). The aqueous mixture was extracted with ethyl acetate (50 mL). The extract was washed with 2M aqueous hydrochloric acid (30 mL), saturated sodium bicarbonate (30 mL), and brine (30 mL), dried over magnesium sulfate, and the solvent was removed. 34 mg (93%) of the title compound was obtained as a yellow solid.

MS (E1) m/z: 361 (M ⁺ ) ¹ H NMR (CDCl ₃ ): δ 8.90 (1H, brs), 7.74 (2H, d, J = 8.6 Hz),

7.56 (1H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.36 (1H, d, J = 1.6 Hz), 7.16 (1H, dd, J = 1.6, 8.6 Hz), 3.81 (2H, s), 3.66 (3H, s)

204. -:.

• · <

Method B

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Method A, 0.70 g, 2.0 mmol), 4-chlorophenacyl bromide (0.51 g, 2.2 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in acetone (20 mL) was stirred at room temperature for 2 h, then cesium carbonate (2.0 g, 6.0 mmol) was added. Stirring was continued for another 4 h. The mixture was then concentrated and the residue was diluted with water (100 mL). The aqueous mixture was extracted with ethyl acetate (100 mL x 2). The combined organic extracts were washed with 2M aqueous hydrochloric acid (100 mL), saturated sodium bicarbonate (100 mL) and brine, dried over magnesium sulfate and the solvent was removed. The solid residue was recrystallized from ethanol to give 0.44 g (61%) of the title compound. The MS and NMR spectra were identical to those of the compound prepared in step 3.

Example 9 [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

Method A

Step 1: 6-Chloro-2-(4-chlorobenzoyl)indole

The title compound was prepared according to the method described in Step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 7, Step 1) and 4-bromochlorobenzene.

*Ή NMR (DMSO-d ₆ ): δ 12.14 (IH, brs), 7.97 (2H, d, J = 8.4 Hz), 7.76 (IH, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.4 Hz), 7.54 - 7.50 (IH, m), 7.20 (IH, s), 7.14 (IH, dd, J = 2.0, 8.6 Hz)

- 2Ů5

Step 2: Diethyl-α-acetoxy-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(4-chlorobenzoyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 8.83 (1H, brs), 7.87 - 7.77 (3H, m), 7.48 - 7.36 (3H, m), 7.17 (1H, dd, J = 2.0, 8.9 Hz), 4.28 - 4.14 (4H, m), 1.73 (3H, s), 1.20 (6H, t, J = 7.1 Hz)

Step 3: Diethyl-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, brs), 7.75 (2H, d, J = 8.6 Hz), 7.75 - 7.69 (1H, m), 7.50 (2H, d, J = 8.6 Hz), 7.29 (1H, d,

J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 5.23 (1H, s), 4.28 - 4.07 (4H, m), 1.23 (6H, t, J = 7.2 Hz)

Step 4: [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl] malonate (from Step 3). The product obtained had a melting point of 189-190°C.

IR (KBr) v: 3309, 1699, 1616, 1525, 1431, 1325, 1255, 1226, 1091 cm ^{1 1} H NMR (DMSO-dg): δ 11.78 (1H, s), 7.80 - 7.72 (3H, m), 7.65 (2H, d, J = 8.6 Hz), 7.47 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 3.83 (2H, s)

206 ·· ··· ·· · ·· • ·

Method B [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

A mixture of methyl-[6-chloro-2-(4-chlorobenzoyl)-1-indol-3-yl]acetate (from Example 8, 1.80 g) and 2M aqueous sodium hydroxide (7.5 ml) in a mixture of methanol and tetrahydrofuran (10 ml - 10 ml) was stirred at 80°C for 1 hour, then cooled and concentrated. The residue was dissolved in water (150 ml) and washed with diethyl ether (50 ml). The aqueous layer was acidified with 2M aqueous hydrochloric acid (10 ml) and extracted with ethyl acetate (100 ml x 2). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and concentrated. The solid residue was recrystallized from toluene to give 1.58 g (91%) of the title compound.

The IR and NMR spectra are identical to those of the product prepared by method A.

Example 10 [6-Chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(3-fluorobenzoyl)indole

The title compound was prepared according to the method described in Step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 7, Step 1) and 3-bromofluorobenzene.

^Χ Η NMR (CDC1 ₃ ): δ 9.28 (1H, brs), 7.79 - 7.75 (1H, m), 7.68 - 7.63 (2H, m), 7.56 - 7.48 (2H, m), 7.36 - 7.30 (1H, m), 7.17 - 7.14 (2H, m)

Step 2: Diethyl α-acetoxy-[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate

- 207 The title compound was prepared according to the method described in step 4 of Example 2 (method B) from 6-chloro-2-(3-fluorobenzoyl)indole (from step 1).

¹ H NMR (CDCl ₃ ): δ 9.15 (1H, brs), 8.83 (1H, d, J = 8.72 Hz), 7.66 -7.27 (5H, m), 7.17 (1H, dd, J = 2.00, 8.72 Hz), 4.25 4.13 (4H, m), 1.75 (3H, s), 1.19 (6H, t, J = 7.07 Hz)

Step 3: Diethyl-[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, brs), 7.77 - 7.12 (7H, m), 5.21 (1H, s), 4.25 - 4.11 (4H, m), 1.22 (6H, t, J = 7.07 Hz)

Step 4: [6-Chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]malonate (from Step 3). The product obtained had a melting point of 278-281°C.

IR (KBr) at: 3385, 1697, 1638, 1583, 1541, 1508, 1420, 1400, 1315, 1261, 1236 cm" ^{1 1} H NMR (DMSO-dg): δ 11.79 (1H, s), 7.76 - 7.48 (7H, m),

7.13 (1H, dd, J = 1.97, 8.56 Hz), 3.80 (2H, s)

Example 11 [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(4-fluorobenzoyl)indole

208

The title compound was prepared according to the method described in Step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 7, Step 1) and 4-bromofluorobenzene.

¹ H NMR (CDCl ₃ ): δ 9.29 (1H, brs), 8.05 - 8.00 (2H, m), 7.64 (1H, d, J = 8.72 Hz), 7.48 - 7.11 (5H, m)

Step 2: Diethyl-α-acetoxy-[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(4-fluorobenzoyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 9.20 (1H, brs), 7.92 - 7.11 (7H, m), 4.25 - 4.14 (4H, m), 1.73 (3H, s), 1.20 (6H, t, J = 7.10 Hz)

Step 3: Diethyl [6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 9.01 (1H, brs), 7.87 - 7.69 (2H, m), 7.71 (2H, d, J = 8.91 Hz), 7.27 - 7.10 (4H, m), 5.25 (1H, s), 4.26 - 4.11 (4H, m), 1.22 (6H, t, J = 7.07 Hz)

Step 4: [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl] malonate (from Step 3). The product obtained had a melting point of 181-183°C.

209

IR (KBr) v: 3309, 1701, 1616, 1601, 1566, 1527, 1508, 1419, 1323, 1257, 1229 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 11.75 (1H, s), 7.87 - 7.82 (2H, m) , 7.73 (1H, d, J = 8.72), 7.47 - 7.36 (3H, m), 7.12 (1H, dd, J = 1.84, 8.72 Hz), 3.78 (2H, s)

Example 12 [2-(3-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid

Step 1: 2-(3-Bromobenzoyl)-6-chloroindole

The title compound was prepared as described in Step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 7, Step 1) and 3-bromoiodobenzene.

¹ H NMR (CDCl ₃ ): δ 9.28 (1H, brs), 8.11 - 8.08 (1H, m), 7.93 - 7.87 (1H, m), 7.79 - 7.73 (1H, m), 7.65 (1H, d, J = 8.6 Hz), 7.50 - 7.38 (2H, m), 7.19 - 7.01 (2H, m)

Step 2: Diethyl α-acetoxy-[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-(3-bromobenzoyl)-6-chloroindole (from Step 1).

^Τ Η NMR (CDC1 ₃ ): δ 8.73 (1H, brs) , 7.93 (1H, t, J = 1.8 Hz) , 7.85 (1H, d, J = 8.6 Hz), 7.82 - 7.72 (2H, m), 7.42 - 7.32 (2H, m), 7.18 (1H, dd, J = 2.0, 8.6 Hz), 4.32 - 4.16 (4H, m), 1.75 (3H, s), 1.20 (6H, t, J = 7.1 Hz)

Step 3: Diethyl-[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate • ·

- 210

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.88 (1H, brs), 7.92 - 7.90 (1H, m), 7.80

- 7.68 (3H, m), 7.45 - 7.36 (2H, m), 7.15 (1H, dd, J = 1.8, 8.7 Hz), 5.20 (1H, s), 4.30 - 4.10 (4H, m), 1.23 (6H, t, J = 7.2 Hz)

Step 4: [2-(3-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (from Step 3). The product obtained had a melting point of 215-218°C.

IR (KBr) v: 3369, 1710, 1604, 1558, 1533, 1423, 1319, 1253, 1228 cm" ^{1 1} H NMR (DMSO-dg): δ 11.81 (1H, s), 7.92 - 7.83 (2H, m), 7.78

- 7.70 (2H, m), 7.54 (1H, t, J = 7.8 Hz), 7.48 (1H, d, J = 2.0 Hz), 7.13 (1H, dd, J = 2.0, 8.7 Hz), 3.80 (2H, s)

Example 13 [2-(4-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid

Step 1: 2-(4-Bromobenzoyl)-6-chloroindole

The title compound was prepared as described in Step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 7, Step 1) and 4-bromoiodobenzene.

¹ H NMR (DMSO-dg): δ 12.28 (1H, brs), 7.88 (2H, d, J = 8.7 HZ), 7.80 (2H, d, J = 8.7 Hz), 7.76 (1H, d, J = 8.7 Hz), 7.53 - 7.50 (1H, m), 7.22 - 7.19 (1H, m), 7.13 (1H, dd, J = 2.0, 8.7 Hz)

211

Step 2: Diethyl α-acetoxy-[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-(4-bromobenzoyl)-6-chloroindole (from Step 1).

¹ H NMR (CDC1 ₃ ): δ 8.72 (1H, brs), 7.84 (1H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.4 Hz), 7.62 (2H, d, J = 8.4 Hz), 7.38 (1H, d, J = 1.8 Hz), 7.18 (1H, dd, J = 8.4 Hz). 1.8, 8.7 Hz), 4.28 4.14 (4H, m), 1.73 (3H, s), 1.20 (6H, g, J = 7.1 Hz)

Step 3: Diethyl-[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (from Step 2).

^Χ Η NMR (CDC1 ₃ ): δ 8.86 (1H, brs), 7.75 (1H, d, J = 8.4 Hz), 7.67 (4H, s), 7.37 - 7.32 (1H, m), 7.18 - 7.12 (1H, m), 5.22 (1H, s), 4.26 - 4.10 (4H, m), 1.23 (6H, t, J = 7.1 Hz)

Step 4: [2-(4-Bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]malonate (from Step 3). The product obtained had a melting point of 199-201°C.

IR (KBr) v: 3300, 1699, 1618, 1587, 1525, 1433, 1406, 1325, 1255, 1226 cm ^{1 1} H NMR (DMSO-dg): δ 11.78 (1H, s), 7.80 (2H, d, J = 8.4 Hz), 7.75 (1H, d, J = 8.6 Hz), 7.69 (2H, d, J = 8.4 Hz), 7.47 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.6 Hz), 3.84 (2H, s)

212

Example 14 [6-Chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(3-trifluoromethylbenzoyl)indole

The title compound was prepared according to the method described in Step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 7, Step 1) and 3-bromobenzotrifluoride.

NMR (CDCl ₃ ): δ 12.23 (1H, brs), 8.28 - 8.04 (3H, m), 7.89

- 7.75 (2H, m), 7.55 - 7.51 (1H, m), 7.22 - 7.12 (2H, m)

Step 2: Diethyl-α-acetoxy-[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(3-trifluoromethylbenzoyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 8.82 (1H, brs), 8.25 - 7.80 (4H, m), 7.68

- 7.57 (1H, m), 7.43 - 7.41 (1H, m), 7.22 - 7.16 (1H, m), 4.36 - 4.20 (4H, m), 1.67 (3H, s), 1.20 (6H, t, J = 7.1 Hz)

Step 3: Diethyl-[6-chloro-2-(3-trifluoromethylbenzoyl)-1Hindol-3-yl]malonate

The title compound was prepared according to the method described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, brs), 8.08 - 8.03 (1H, m), 8.02

- 7.87 (2H, m), 7.76 (1H, d, J = 9.0 Hz), 7.73 - 7.64 (1H, m), 7.39 - 7.36 (1H, m), 7.15 (1H, dd, J = 1.8, 9.0 Hz),

5.15 (1H, s), 4.26 - 4.10 (4H, m), 1.22 (6H, t, J = 7.2 Hz)

- 213 • ·

Step 4: [6-Chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate (from Step 3). The product obtained had a melting point of 194-196°C. IR (KBr) at: 3371, 1705, 1631, 1421, 1307, 1228, 1168, 1122, 1072 cm- ^{1 1} H NMR (DMSO-d ₆ ): δ 11.86 (1H, s), 8.10-7.98 (3H, m), 7.83 (1H, t, J = 7.7 Hz), 7.75 (1H, d, J = 8.6 Hz), 7.49 (1H, d,

J = 2.0 Hz), 7.15 (1H, dd, J = 2.0, 8.6 Hz), 3.80 (2H, s)

Example 15 [6-Chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-1-(phenylsulfonyl)-2-(4-trifluoromethylbenzoyl)indole

The title compound was prepared as described in Step 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 2, Method B) and 4-trifluoromethylbenzoyl chloride.

tle: Rf = 0.2 (ethyl acetate/hexane, 1:4)

Step 2: 6-Chloro-2-(4-trifluoromethylbenzoyl)indole

The title compound was prepared as described in Step 3 of Example 2 (Method B) from 6-chloro-1-phenylsulfonyl-2-(4-trifluoromethylbenzoyl)indole (from Step 1). ¹ H NMR (CDCl ₃ ): δ 9.53 (1H, brs), 7.94 (4H, dd, J = 8.24, 69.1 Hz), 7.63 (1H, d, J = 8.56 Hz), 7.49 - 7.11 (3H, m) • 4 · · · · · · · ·

214 • 4 44 • 4 44· ·· ···

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(4-trifluoromethylbenzoyl)indole (from Step 2).

¹ H NMR (CDC1 ₃ ): δ 8.66 (IH, brs), 7.98 (2H, d, J = 8.24 Hz), 7.87 (IH, d, J = 8.91 Hz), 7.75 (2H, d, J = 8.07 Hz), 7.39 (IH, d, J = 1.81 Hz), 7.19 (IH, dd, J = 1.81 Hz). 1.81, 7.10 Hz), 4.36 - 4.16 (4H, m), 1.70 (3H, s), 1.34 - 1.22 (6H, m)

Step 4: Diethyl-[6-chloro-2-(4-trifluoromethylbenzoyl)-1Hindol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 9.24 (IH, brs), 7.84 (4H, dd, J = 7.91, 25.7 Hz), 7.69 - 7.09 (3H, m), 5.24 (IH, s), 4.21 - 4.06 (4H, m), 1.21 (6H, t , J = 7.07 Hz)

Step 5: [6-Chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl] malonate (from Step 4).

^H NMR (DMSO-dg): δ 11.78 (1H, s), 7.94 (4H, s), 7.76 (IH, d, J = 8.72 Hz), 7.47 (IH, m), 7.14 (IH, d, J = 1.81, 8.72), 3.81 (2H, s)

215 ·· ·«*· ·« η ·· * · · ···· ··· »· ·· 00 ··· >· 00 0

Example 16 [6-Chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(3,4-dichlorobenzoyl)indole

The title compound was prepared as described in Step 2 of Example 7 from 6-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Step 1 of Example 7) and 1-bromo-3,4-dichlorobenzene.

tle: Rf = 0.7 (ethyl acetate : hexane, 1:3)

Step 2: Diethyl α-acetocy-[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in step 4 of Example 2 (method B) from 6-chloro-2-(3,4-dichlorobenzoyl)indole (from step 1) ¹ H NMR (CDCl ₃ ): δ 8.80 (1H, brs), 7.90 - 7.79 (2H, m), 7.71 (1H, dd, J = 2.0, 8.4 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.40 7.35 (1H, m), 7.18 (1H, dd, J = 1.8, 8.8 Hz), 4.30 - 4.14 (4H, m), 1.77 (3H, s), 1.20 (6H, t, J = 7.1 Hz)

Step 3: Diethyl-[6-chloro-2-(3,4-dichlorobenzoyl)-1-hindol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDC1 ₃ ): δ 8.95 (1H, brs), 7.88 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 8.7 Hz), 7.68 - 7.58 (2H, m), 7.28 (1H, d, J = 1.6 Hz), 7.14 (1H, dd, J = 1.6 Hz). 8.7 Hz), 5.18 (1H, s), 4.28 - 4.10 (4H, m), 1.23 (6H, t, J = 7.1 Hz)

216

444· • 4 · • »*

4« ·· 4 4 44 4 · < ·4·

Step 4: [6-Chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl] malonate (from Step 3) and had a melting point of 206-209°C.

IR (KBr) Vi 3435, 1708, 1620, 1583, 1525, 1423, 1384, 1301, 1263, 1228 cm" ^{1 1} H NMR (DMSO-d ₆ ): δ 11.62 (1H, brs), 7.95 - 7.75 (3H, m),

7.68 (1H, d, J = 8.7 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.02 (1H, dd, J = 2.8, 8.7 Hz), 3.50 (2H, s)

Example 17 (2-Benzoyl-4-chloro-1H-indol-3-yl)acetic acid

Step 1: 4-Chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared as described in Example 7 using 4-chloroindole-2-carboxylic acid (F. C. Uhle, J. Amer. Chem. Soc., 1949, 71, 761).

¹ H NMR (CDCl ₃ ): δ 9.56 (1H, brs), 7.36 - 7.29 (2H, m), 7.24 - 7.12 (2H, m), 3.88 (3H, s), 3.45 (3H, s)

Step 2: 2-Benzoyl-4-chloroindole

To a solution of 4-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from step 1, 3.4 g, 0.014 mol) in tetrahydrofuran (60 ml) cooled to -78°C was added dropwise phenyllithium (1.8M in cyclohexane:ether 7:3, 30 ml, 0.070 mol). The resulting mixture was stirred for 1 hour and then poured into water (80 ml). The aqueous mixture was extracted with ethyl acetate (80 ml x 2), the extract was dried over magnesium sulfate, and the solvent was removed. The crude product was purified by flash column chromatography using ethyl acetate:hexanes 1:10 as eluent to give 3.6 g (100%) of the title compound as a white solid.

³ H NMR (CDCl ₃ ): δ 9.46 (1H, brs), 8.05 - 8.00 (2H, m), 7.73

- 7.51 (3H, m), 7.40 (1H, dd, J = 1.0, 8.3 Hz), 7.33 - 7.24 (2H, m), 7.18 (1H, d, J = 7.6 Hz)

Step 3: Diethyl-α-acetoxy-(2-benzoyl-4-chloro-1H-indol-3-yl)malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-benzoyl-4-chloroindole (from Step 2).

¹ H NMR (CDCl ₃ ): δ 9.49 (1H, brs) , 7.98 - 7.92 (2H, m) , 7.66

- 7.57 (1H, m), 7.53 - 7.44 (2H, m), 7.34 (1H, dd, J = 2.0, 7.1 Hz), 7.21 - 7.15 (2H, m), 4.30 - 3.90 (4H, m), 2.08 (3H, s), 1.15 (6H, g, J = 7.3 Hz)

Step 4: Diethyl-(2-benzoyl-4-chloro-1H-indol-3-yl)malonate

The title compound was prepared as described in Step 5 of Example 2 from diethyl α-acetoxy-(2-benzoyl-4-chloro-1H-indol-3-yl)malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.88 (1H, brs), 7.83 - 7.77 (2H, m), 7.64

- 7.58 (1H, m), 7.55 - 7.46 (2H, m), 7.25 - 7.05 (3H, m), 5.86 (1H, s), 4.25 - 4.08 (4H, m), 1.23 (6H, t, J = 7.3 Hz)

Step 5: (2-Benzoyl-4-chloro-1H-indol-3-yl)acetic acid

The title compound was prepared as described in step 6 of Example 2 (method B) from diethyl (2-benzoyl-4-chloro-1H-indol-3-yl)malonate. The product obtained had a melting point of 206-209°C after recrystallization from ethyl acetate/hexane.

IR (KBr) at: 1700, 1575, 1245 cm ^-1

218

¹ H NMR (DMSO-d 6 ): δ 12.20 (1H, brs), 11.98 (1H, s), 7.85 - 7.67 (3H, m) , 7.63 - 7.55 (2H, m), 7.45 (1H, d, J = 8.2 Hz), 7.25 (1H, t, J = 8.2 Hz), 7.12 (1H, d, J = 7.6 Hz), 4.02 (2H, s)

Example 18 [5-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 5-Chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared as described in step 1 of Example 7 from 5-chloroindole-2-carboxylic acid.

¹ H NMR (CDCl ₃ ): δ 9.68 (1H, brs), 7.68 - 7.65 (1H, m), 7.37 (1H, d, J = 8.7 Hz), 7.23 (1H, d , J = 1.6 Hz), 7.18 - 7.15 (1H, m), 3.85 (3H, s), 2.05 (3H, s)

Step 2: 5-Chloro-2-(3-benzylbenzoyl)indole

The title compound was prepared as described in Step 2 of Example 17 from 5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Step 1) and 3-methylphenyllithium. The product obtained had a melting point of 197.5-198°C after recrystallization from ethyl acetate/hexane.

IR (KBr) V'. 3310, 1626, 1603, 1583, 1516, 1404, 1377, 1337, 1269, 1178, 1134 cm' ^{1 1} H NMR (CDCl ₃ ): δ 9.39 (1H, brs), 7.28 - 7.76 (2H, m), 7.71 - 7.68 (1H, m), 7.46 - 7.38 (3H, m), 7.32 (1H, dd, J = 8.7, 2.0 Hz), 7.08 (1H, dd, J = 2.0, 0.8 Hz), 2.47 (3H, s)

Step 3: Diethyl-α-acetoxy-[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

- 219

The title compound was prepared as described in Step 4 of Example 2 (Method B) from 5-chloro-2-(3-methylbenzoyl)indole (from Step 2) and after recrystallization from ethyl acetate/hexane had a melting point of 173-174°C.

^Τ Η NMR (CDC1 ₃ ): δ 8.64 (1H, brs) , 7.91 (1H, brs) , 7.69 7.61 (2H, m), 7.46 - 7.22 (4H, m), 4.30 - 4.16 (4H, m), 2.39 (3H, s), 1.72 (3H, s), 1.23 (3H, t, J = 7.2 Hz)

Step 4: Diethyl-[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (from Step 3) and after recrystallization from ethyl acetate/hexane had a melting point of 143-144°C.

¹ H NMR (CDCl ₃ ): δ 8.88 (1H, brs), 7.84 - 7.80 (1H, m), 7.62 - 7.55 (2H, m), 7.48 - 7.36 (2H, m), 7.32 - 7.28 (2H, m), 5.27 (1H, s), 4.30 - 4.10 (4H, m), 2.42 (3H, s), 1.24 (3H, t, J = 7.1 Hz)

Step 5: [5-Chloro-2-(3-methylbenzoyl)-1H-indol-3-ylacetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl] malonate (from Step 4) and after recrystallization from ethyl acetate/hexane had a melting point of 241-242°C.

IR (KBr) Vi 3321, 1703, 1618, 1535, 1431, 1335, 1232, 1016, 808, 758 cm ^{1 1} H NMR (DMSO-dg): δ 11.7 (1H, brs), 7.62 (1H, d, J = 1.8 Hz), 7.45 - 7.30 (6H, m), 7.19 (1H, dd, J = 8.6, 1.8 Hz), 3.63 (2H, s), 2.27 (3H, s)

220 • ·

Example 19 [5-Chloro-2-(4-Chlorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 5-Chloro-2-(4-chlorobenzoyl)indole

The title compound was prepared according to the method described in Step 2 of Example 7 from 5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 18 Step 1) and 4-bromochlorobenzene.

¹ H NMR (CDCl ₃ ): δ 9.32 (1H, brs), 7.94 (2H, d, J = 8.4 Hz), 7.70 (1H, s), 7.53 (2H, d, J = 8.4 Hz), 7.42 (1H, d, J = 8.9 Hz), 7.34 (1H, dd, J = 2.0, 8.9 Hz), 7.07 (1H, s)

Step 2: Diethyl α-acetoxy-[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 5-chloro-2-(4-chlorobenzoyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 9.11 (1H, brs), 7.87 (1H, s), 7.76 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.27 (1H, d, J = 8.7 Hz), 7.22 (1H, dd, J = 1.8, 8.7 Hz), 4.25 - 4.14 (4H, m), 1.72 (3H, s), 1.24 - 1.19 (6H, m)

Step 3: Diethyl-[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDC1 ₃ ): δ 9.13 (1H, brs), 7.73 (2H, d, J = 8.4 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.48 (2H, d, J = 8.4 Hz), 7.11 • · • · ··· · (1H, dd, J = 2.0, 8.9 Hz), 7.02 (1H, d, J = 8.9 Hz), 5.28 (1H, s), 4.24 - 4.03 (4H, m), 1.27 - 1.21 (6H, m)

Step 4: [5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl] malonate and after recrystallization from ethyl acetate/hexane had a melting point of 220-224°C.

IR (KBr) v: 3321, 1618, 1535, 1379, 1339, 1263, 1130, 1090, 1057, 1007 cm' ^{1 1} H NMR (DMSO-dg): δ 11.83 (1H, s), 7.80 - 7.75 (3H, m), 7.67 - 7.62 (2H, m), 7.48 (1H, d, J = 8.7 Hz), 7.31 (1H, dd, J = 2.0, 8.7 Hz), 3.84 (2H, s)

Example 20 [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 5-Chloro-2-(3-chlorobenzoyl)indole

The title compound was prepared as described in Step 2 of Example 7 from 5-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Example 18 Step 1) and 3-bromochlorobenzene.

^Χ Η NMR (CDC1 ₃ ): δ 9.28 (1H, brs) , 7.95 (1H, t, J = 1.7 Hz) , 7.88 - 7.84 (1H, m), 7.71 (1H, d, J = 2.0 Hz), 7.36 - 7.59 (1H, m), 7.49 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.34 (1H, dd, J = 2.0, 8.7 Hz), 7.10 - 7.09 (1H, m)

Step 2: Diethyl-α-acetoxy-[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate ·· ··«·

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 5-chloro-2-(3-chlorobenzoyl)indole (from Step 1).

^Χ Η NMR (CDC1 ₃ ): δ 8.94 (1H, brs), 7.91 (1H, d, J = 1.8 Hz), 7.79 - 7.76 (1H, m), 7.74 (1H, d, J = 7.7 Hz), 7.60 - 7.56 (1H, m), 7.42 (1H, t, J = 7.7 Hz), 7.33 (1H, d, J = 8.7 Hz), 7.27 (1H, dd, J = 1.8, 8.7 Hz), 4.37 - 4.19 (4H, m), 1.75 (3H, s), 1.26 - 1.20 (6H, m)

Step 3: Diethyl [5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl] malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 9.04 (1H, brs), 7.77 - 7.75 (2H, m), 7.68

- 7.58 (2H,m ), 7.46 (1H, t, J = 7.7 Hz), 7.24 - 7.20 (2H, m), 5.23 (1H, s), 4.27 - 4.14 (4H, m), 1.27 - 1.22 (6H, m)

Step 4: [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-ylacetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl] malonate and after recrystallization from ethyl acetate/hexane had a melting point of 243-247°C.

IR (KBr) v: 3329, 1707, 1618, 1535, 1431, 1406, 1375, 1333, 1279, 1232, 1053 cm ^{-1 1} H NMR (DMSO-dg): δ 11.87 (1H, s), 7.81 - 7.68 (4H, m), 7.64

- 7.58 (1H, m), 7.49 (1H, d, J = 8.9 Hz), 7.32 (1H, dd, J = 2.0, 8.9 Hz), 3.82 (2H, s) ·· ··· · • ·

Example 21 [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid

Step 1: 5-Fluoro-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared as described in Step 1 of Example 7 from 5-fluoroindole-2-carboxylic acid.

¹ H NMR (CDCl ₃ ): δ 10.15 (1H, brs), 7.41 - 7.36 (1H, m), 7.32 (1H, dd, J = 2.5, 9.1 Hz), 7.20 - 7.19 (1H, m), 7.09 - 7.01 (1H, m), 3.84 (3H, s), 3.47 (3H, s)

Step 2: 2-(4-Chlorobenzoyl)-5-fluoroindole

The title compound was prepared according to the method described in Step 2 of Example 7 from 5-fluoro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Step 1) and 4-bromochlorobenzene.

¹ H NMR (CDCl ₃ ): δ 9.27 (1H, brs), 7.94 (2H, d, J = 8.4 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.45 - 7.40 (1H, m), 7.37 - 7.33 (1H, m), 7.21 - 7.12 (1H, m), 7.10 - 7.09 (1H, m)

Step 3: Diethyl α-acetoxy-[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-(4-chlorobenzoyl)-5-fluoroindole (from Step 2).

¹ H NMR (CDCl ₃ ): δ 9.01 (1H, brs), 7.80 - 7.77 (2H, m), 7.58

- 7.54 (1H, m), 7.45 - 7.41 (2H, m), 7.36 - 7.27 (1H, m), 7.12 - 7.01 (1H, m), 4.29 - 4.15 (4H, m), 1.74 (3H, s), 1.28

- 1.17 (6H, m) ·· ···· ·· • · · ·

-•2.24..-»

Step 4: Diethyl-[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl acetoxy-[2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (from Step 3).

η NMR (CDCl ₃ ): δ 8.98 (1H, brs), 7.77 - 7.72 (2H, m), 7.51 - 7.46 (2H, m), 7.40 (1H, dd, J = 2.5, 9.7 Hz), 7.18 - 7.13 (1H, m), 7.04 - 6.96 (1H, m), 5.28 (1H, s), 4.26 - 4.07 (4H, m), 1.30 - 1.18 (6H, m)

Step 5: [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (from Step 4) and after recrystallization from ethyl acetate/hexane had a melting point of 233-238°C.

IR (KBr) v: 3317, 1707, 1624, 1609, 1587, 1526, 1458, 1408, 1344, 1263, 1242 cm' ^{1 1} H NMR (DMSO-d ₆ ): δ 11.73 (1H, s), 7.77 (2H, d, J = 8.6 Hz), 7.65 (2H, d, J = 8.6 Hz), 7.52 - 7.44 (2H, m), 7.22 - 7.15 (1H, m), 3.84 (2H, s)

Example 22 [2-(3-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid

Step 1: 2-(3-Chlorobenzoyl)-5-fluoroindole

The title compound was prepared as described in step 2 of Example 7 from 5-fluoro-2-[(N-methoxy-N• ·

- 325·-methylamino)carbonyl]indole (from step 1 of example 21) and 3-bromochlorobenzene.

¹ H NMR (CDCl ₃ ): δ 9.29 (1H, m), 7.96 - 7.94 (1H, m), 7.88 7.84 (1H, m), 7.63 - 7.59 (1H, m), 7.48 (1H, t, J = 8.0 Hz), 7.45 - 7.40 (1H, m), 7.36 (1H, dd, J = 2.6, 8.6 Hz), 7.20 7.11 (2H, m)

Step 2: Diethyl α-acetoxy-[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-(3-chlorobenzoyl)-5-fluoroindole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 8.73 (1H, brs), 7.79 - 7.74 (2H, m), 7.61

- 7.56 (2H, m), 7.43 (1H, t, J = 7.6 Hz), 7.37 - 7.32 (1H, m), 7.13 - 7.06 (1H, m), 4.34 - 4.20 (4H, m), 1.76 (3H, s), 1.33 - 1.20 (6H, m)

Step 3: Diethyl-[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl acetoxy-[2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 9.05 (1H, brs), 7.76 - 7.75 (1H, m), 7.687.64 (1H, m), 7.61 - 7.56 (1H, m), 7.48 - 7.40 (2H, m), 7.24

- 7.19 (1H, m), 7.08 - 7.00 (1H, m), 5.25 (1H, s), 4.28 4.07 (4H, m), 1.33 - 1.21 (6H, m)

Step 4: [2-(3-Chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid

The title compound was prepared as described in step 6 of Example 2 (method B) from diethyl-[2• ·

- '226./

-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]malonate (from step 3) and after recrystallization from a mixture of ethyl acetate and hexane has a melting point of 208-212°C.

IR (KBr) v: 3337, 1709, 1618, 1560, 1529, 1477, 1458, 1427, 1407, 1335, 1304 cm" ^{1 1} H NMR (DMSO-dg): δ 11.78 (1H, s), 7.77 - 7.58 (4H, m), 7.52 - 7.46 (2H, m), 7.24 - 7.16 (1H, m), 3.82 (2H, s)

Example 23 [5-Methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 5-Methoxy-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared as described in step 1 of Example 7 from 5-methoxyindole-2-carboxylic acid.

¹ H NMR (CDCl ₃ ): δ 9.29 - 9.13 (1Hk, bs), 7.33 (1H, d, J =

8.9 Hz), 7.19 - 7.14 (1H, m), 7.10 (1H, d, J = 2.3 Hz), 6.98 (1H, dd, J = 8.9, 2.3 Hz), 3.86 (3H, s), 3.84 (3H, s), 3.42 (3H, s)

Step 2: 5-Methoxy-2-(3-benzylbenzoyl)indole

The title compound was prepared according to the method described in Step 2 of Example 17 from 5-methoxy-2-[(N-methyl-N-methylamino)carbonyl]indole (from Step 1) and 3-methylphenyllithium.

¹ H NMR (CDCl ₃ ): δ 9.65 - 9.45 (1H, bs), 7.84 - 7.75 (2H, m), 7.46 - 7.35 (3H, m), 7.12 - 7.01 (3H, m), 3.85 (3H, s), 2.46 (3H, s)

Step 3: Diethyl-α-acetoxy-[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 5-methoxy-2-(3-methylbenzoyl)indole (from Step 2).

tle: Rf = 0.45 (ethyl acetate/hexane, 1:3)

Step 4: Diethyl-[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 9.52 - 9.13 (0.5H, m), 8.81 - 8.71 (0.5H,

m), 7.80 - 7.72 (1H, m), 7.63 - 7.55 (1H, m), 7.47 - 7.00 (5H, m), 5.41 (0.5H, s), 5.37 (0.5H, s), 4.27 - 4.15 (4H,

m), 3.89 (1.5H, s), 3.84 (1.5H, s), 2.45 (1.5H, s), 2.43 (1.5H, S), 1.29 - 1.19 (6H, m)

Step 5: [5-Methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl] malonate (from Step 4) and after recrystallization from ethyl acetate mixture had a melting point of 230.4-232.0°C (dec.).

IR (KBr) v: 3310, 1705, 1614, 1583 cm ^{1 Χ} Η NMR (DMSO-d ₆ ): δ 11.47 (1H, brs) , 7.60 - 7.34 (5H, m) ,

7.16 -7.09 (1H, m), 6.98 (1H, dd, J = 9.0, 2.4 Hz), 3.78 (5H, s), 2.40 (3H, s) ¹³ C NMR (DMSO-dg): δ 188.1, 172.1, 153.8, 138.9, 137.9

132.7, 132.3, 132.0, 129.2, 128.5, 128.0, 125.8, 117.0,

115.6, 113.6, 100.7, 55.3, 30.6, 20.8

Example 24 (2-Benzoyl-7-chloro-1H-indol-3-yl)acetic acid

Step 1: 7-Chloro-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared by the method described in Step 1 of Example 7 from 7-chloroindole-2-carboxylic acid (H. N. Rydon and J. C. Tweedle, J. Chem. Soc., 1955, 3499).

¹ H NMR (CDCl ₃ ): δ 9.40 (1H, brs), 7.59 (1H, d, J = 8.1 Hz), 7.32 - 7.25 (2H, m), 7.08 (1H, t, J = 8.1 Hz), 3.85 (3H, s), 3.43 (3H, s)

Step 2: 2-Benzoyl-7-chloroindole

The title compound was prepared according to the method described in step 2 of Example 17 from 7-chloro-[(N-methoxy-N-methylamino)carbonyl]indole and phenyllithium.

¹ H NMR (CDCl ₃ ): δ 9.40 (1H, brs), 8.01 - 7.96 (2H, m), 7.70

- 7.50 (4H, m), 7.38 (1H, d, J = 7.6 Hz), 7.18 (1H, d, J = 2.0 Hz), 7.11 (1H, t, J = 7.6 Hz)

Step 3: Diethyl-α-acetoxy-(2-benzoyl-7-chloro-1H-indol-3-yl)malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-benzoyl-7-chloroindole (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.76 (1H, brs), 7.92 - 7.81 (3H, m), 7.68

- 7.60 (1H, m), 7.53 - 7.45 (2H, m), 7.33 (1H, d, J = 7.6 Hz), 7.15 (1H, t, J = 8.2 Hz), 4.60 - 4.20 (4H, m), 1.71 (3H, s), 1.98 (6H, t, J = 7.1 Hz)

Step 4: Diethyl-(2-benzoyl-7-chloro-1H-indol-3-yl)malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-(2-benzoyl-7-chloro-1H-indol-3-yl)malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.94 (1H, brs), 7.86 - 7.80 (2H, m), 7.75 (1H, d, J = 8.1 Hz), 7.70 - 7.62 (1H, m), 7.55 - 7.50 (2H, m), 7.36 (1H, d, J = 7.6 Hz), 7.13 (1H, t, J = 7.6 Hz), 5.29 (1H, s), 4.25 - 4.11 (4H, m), 1.22 (6H, t, J = 7.3 Hz)

Step 5: (2-Benzoyl-7-chloro-1H-indol-3-yl)acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl (2-benzoyl-7-chloro-1H-indol-3-yl) malonate (from Step 4) and after recrystallization from ethyl acetate/hexane had a melting point of 190-193°C.

IR (KBr) Vi 1691, 1627, 1598, 1323, 1260, 1199, 1010 cm ^{1 1} H NMR (DMSO-d ₆ ): δ 11.90 (1H, brs), 7.82 (2H, m), 7.74 7.65 (2H, m), 7.62 - 7.38 (2H, m), 7.40 (1H, d, J = 7.6 Hz), 7.13 (1H, t, J = 7.6 Hz), 3.75 (2H, s)

Example 25 (2-Benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid

Step 1: 4,5-Dichloroindolyl-2-carboxylic acid

To a suspension of ethyl 4,5-dichloroindole-2-carboxylate (Ishii et al., Chem. Pharm. Bull., 1974, 22, 1981, 1.8 g,

7.0 mmol) in ethanol (40 mL) was added 2M aqueous sodium hydroxide (10 mL). The resulting mixture was heated to reflux for 2 h, cooled to room temperature and concentrated. The solid residue was acidified with 2M aqueous hydrochloric acid (30 mL) and extracted with diethyl ether (80 mL x 2). The organic extracts were dried over magnesium sulfate and concentrated. The product was obtained.

with 1.5 (94%) of the title compound as a yellow solid.

³ H NMR (DMSO-dg): δ 12.34 (1H, brs), 7.47 - 7.39 (2H, m), 7.08 (1H, d, J = 1.8 Hz)

Step 2: 4,5-Dichloro-2-[(N-methoxy-N-methylamino)carbonyl]indole

The title compound was prepared as described in Step 1 of Example 7 from 4,5-dichloroindole-2-carboxylic acid (from Step 1).

^•H NMR (CDCl ₃ ): δ 9.62 (1H, brs), 7.40 - 7.05 (3H, m), 3.88 (3H, s), 3.45 (3H, s)

Step 3: 2-Benzoyl-4,5-dichloroindole

The title compound was prepared as described in Step 2 of Example 17 from 4,5-dichloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Step 2) and phenyllithium and after recrystallization from ethyl acetate/hexane had a melting point of 206-210°C.

³ H NMR (CDCl ₃ ): δ 9.58 (1H, brs), 8.05 - 7.98 (2H, m), 7.71

- 7.53 (3H, m), 7.42 (1H, d, J = 8.9 Hz), 7.35 (1H, d, J =

8.9 Hz), 7.22 (1H, s)

Step 4: Diethyl-α-acetoxy-(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-benzoyl-4,5-dichloroindole (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.85 (1H, brs), 7.91 - 7.86 (2H, m), 7.66

- 7.58 (1H, m), 7.52 - 7.44 (2H, m), 7.36 (1H, d, J = 8.7 Hz), 7.21 (lH, d, J = 8.7 Hz), 4.20 - 3.98 (4H, m), 2.07 (3H, S), 1.15 (6H, t, J = 7.3 Hz)

Step 5: Diethyl-(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-(2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate (from Step 4).

¹ H NMR (CDCl ₃ ): δ 9.24 (1H, brs), 7.82 - 7.76 (2H, m), 7.65

- 7.58 (IH, m), 7.55 -7.44 (2H, m), 7.20 (IH, d, J = 8.7 Hz), 7.03 (IH, d, J = 8.7 Hz), 7.03 (IH, d, J = 8.7 Hz),

5.89 (IH, s), 4.16 - 4.02 (4H, m), 1.20 (6H, t, J= 7.3 Hz)

Step 6: (2-Benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl (2-benzoyl-4,5-dichloro-1H-indol-3-yl)malonate (from Step 5) and after recrystallization from ethyl acetate/hexane had a melting point of 249-252°C.

IR (KBr) at: 1701, 1625, 1523, 1450, 1330, 1257, 1012 cm ^{1 1} H NMR (CDCl ₃ ): δ 9.92 (1H, brs), 7.85 - 7.81 (2H, m), 7.66

- 7.42 (3H, m), 7.36 (IH, d, J = 8.8 Hz), 7.29 (IH, d, J =

8.8 Hz), 4.09 (2H, s)

Example 26 (2-Benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid

Step 1: 4,6-Dichloro-2-[(N-methoxy-N-methylamino)carbonyl] indole

The title compound was prepared according to the method described in step 1 of Example 7 from 4,6-dichloroindole-2-carboxylic acid (Slituro, Francesco G. et al., J. Med. Chem. 1990, 33, 2944).

^T H NMR (DMSO-άθ): δ 12.09 (1H, brs), 7.48 (1H, dd, J = 1.0,

1.6 Hz), 7.25 (1H, d, J = 1.6 Hz), 7.11 (1H, s), 3.82 (3H, s), 3.63 (3H, Ξ)

Step 2: 2-Benzoyl-4,6-dichloroindole

The title compound was prepared as described in Step 2 of Example 17 from 4,6-dichloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Step 1) and phenyllithium and had a melting point of 214-218°C.

•'-Η NMR (CDCl ₃ ): δ 9.45 (1H, brs), 8.02 - 7.95 (2H, m), 7.70

- 7.52 (3H, m), 7.40 (1H, d, J = 1.6 Hz), 7.25 (1H, s), 7.20 (1H, d, J = 1.6 Hz)

Step 3: Diethyl α-acetoxy-(2-benzoyl-4,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-benzoyl-4,6-dichloroindole (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.92 (1H, brs), 7.95 - 7.86 (2H, m), 7.68

- 7.43 (3H, m), 7.29 (1H, d, J = 1.8 Hz), 7.23 (1H, d, J =

1.8 Hz), 4.60 - 4.00 (4H, m), 2.04 (3H, s), 1.30 - 1.10 (6H, m)

Step 4: Diethyl-(2-benzoyl-4,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-(2-benzoyl-4,6-dichloro-1H-indol-3-yl)malonate (from Step 3) and had a melting point of 170-172°C.

¹ H NMR (CDCl ₃ ): δ 9.15 (1H, brs), 7.84 - 7.75 (2H, m), 7.66

- 7.45 (3H, m), 7.26 (1H, s), 7.12 (1H, s), 5.79 (1H, s),

4.20 - 4.00 (4H, m), 1.20 (6H, g, J = 7.3 Hz)

Step 5: (2-Benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl (2-benzoyl-4,6-dichloro-1H-indol-3-yl)malonate (from Step 4) and after recrystallization from ethyl acetate/hexane had a melting point of 239-243°C.

IR (KBr) at: 1725, 1555, 1525, 1330, 1287, 1250, 1005 cm ^{-1 1} H NMR (DMSO-dg): δ 12.40 (1H, brs), 12.12 (1H, brs), 7.80 7.67 (3H, m), 7.64 - 7.54 (2H, m), 7.48 (1H, d, J = 1.8 Hz), 7.23 (1H, d, J = 1.8 Hz), 3.99 (2H, s)

Example 27 (2-Benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid

Step 1: 5,6-Dichloroindole-2-carboxylic acid

The title compound was prepared by the method described in Step 1 of Example 25 from ethyl 5,6-dichloroindole-2-carboxylate (Ishii et al., Chem. Pharm. Bull. 1974, 22, 1981).

¹ H NMR (DMSO-dg): δ 12.06 (1H, brs), 7.95 (1H, s), 7.62 (1H, s), 7.09 (1H, s)

Step 2: 5,6-Dichloro-2-[(N-methoxy-N-methylamino)carbonyl] indole

The title compound was prepared as described in Step 1 of Example 7 from 5,6-dichloroindole-2-carboxylic acid (from Step 1).

¹ H NMR (CDCl ₃ ): δ 11.86 (1H, brs), 7.96 (1H, s), 7.66 (1H, s), 7.16 (1H, s), 3.80 (3H, s), 3.34 (3H, s)

Step 3: 2-Benzoyl-5,6-dichloroindole ···· ·· · ·· • · · · · · *

The title compound was prepared as described in Step 2 of Example 17 from 5,6-dichloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (from Step 2) and phenyllithium and after recrystallization from ethyl acetate/hexane had a melting point of 206-210°C.

¹ H NMR (CDCl ₃ ): δ 9.35 (1H, brs), 8.00 - 7.93 (2H, m), 7.81 (1H, s), 7.69 - 7.51 (3H, m), 7.26 (1H, s), 7.08 (1H, s)

Step 4: Diethyl α-acetoxy-(2-benzoyl-5,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-benzoyl-5,6-dichloroindole (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.76 (1H, brs), 8.05 (1H, s), 7.90 - 7.82 (2H, m), 7.67 - 7.59 (1H, m), 7.54 - 7.44 (3H, m), 4.30 4.10 (4H, m), 1.69 (3H, s), 1.35 - 1.20 (6H, m)

Step 5: Diethyl-(2-benzoyl-5,6-dichloro-1H-indol-3-yl)malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-(2-benzoyl-5,6-dichloro-1H-indol-3-yl)malonate (from Step 4).

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, brs), 7.95 (1H, s), 7.82 - 7.76 (2H, m), 7.70 - 7.61 (1H, m), 7.58 - 7.46 (3H, m), 5.26 (1H, s), 4.30 - 4.05 (4H, m), 1.24 (6H, t, J = 7.1 Hz)

Step 6: (2-Benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl (2-benzoyl-5,6-dichloro-1H-indol-3-yl) malonate (from Step 5) and after recrystallization from ethyl acetate/hexane had a melting point of 208-210°C.

• · ···· ···· · — •235 -* · · · · · · ** ·· ·· ··· ·· ··· ¹ H NMR (DMSO-d ₆ ): δ 11.91 (1H, brs), 8.04 (1H, s), 7.77 7.50 (6H, m), 3.81 (2H, s)

Example 28 dl-2-(2-Benzoyl-6-chloro-1H-indol-3-yl)propanoic acid

Step 1: Diethyl-α-methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate

The title compound was prepared as described in Step 4 of Example 2 (Method B) from 2-benzoyl-6-chloroindole (from Step 3 of Example 2, Method B) and diethyl methyl malonate and had a melting point of 193-196°C.

^Χ Η NMR (CDC1 ₃ ): δ 8.42 (1H, brs) , 7.87 (2H, m) , 7.66 - 7.48 (3H, m), 7.42 (1H, d, J = 8.8 Hz), 7.35 (1H, d, J = 1.8 Hz),

7.11 (1H, dd, J = 1.8, 8.8 Hz), 4.30 - 4.02 (4H, m), 1.98 (3H, s), 1.15 (6H, t, J = 7.1 Hz)

Step 2: dl-2-(2-Benzoyl-6-chloro-1H-indol-3-yl)propanoic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl α-methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)malonate (from Step 1) and after recrystallization from a mixture of dichloromethane and hexane had

IR (KBr) at: 1720, 1620, 1475, 1260, 1230 cm m.p. 204-208°C.

^•H NMR (DMSO-dg): δ 12.29 (1H, 7.76 (2H, m), 7.75 - 7.68 (2H, (1H, d, J = 1.8 Hz), 7.12 (1H, (1H, q, J = 7.1 Hz), 1.44 (3H,

brs), 11.72 (1H, brs), 7.82 m), 7.65 - 7.57 (2H, m), 7.48 dd, J = 1.8, 8.4 Hz), 4.15 d, J = 7.1 Hz) •· ···· ·· • · · · ·

Example and example

The less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid and the more polar antipode of 2-(2-benzoyl-6chloro-1H-indol-3-yl)propanoic acid

Chiral separation of dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid (from Example 28) using DAICEL CHIRALCEL OJ (4.6 x 250 mm, eluent: hexane/isopropyl alcohol/trifluoroacetic acid in the ratio 85:15:0.1, flow rate 1.0 ml/min) gives a less polar compound (retention time 17 minutes) and a more polar compound (27 minutes).

Example 31 [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

Step 1: Methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate

To a stirred solution of methyl trans-2-amino-4-chlorocinnamate (R. W. Carling et al., J. Med. Chem., 1993, 36,

3397, 32.6 g, 0.15 mol), pyridine (14.9 ml, 0.17 mol) and 4-dimethylaminopyridine (0.5 g) in dichloromethane (500 ml) were added dropwise at room temperature with ethyl chloroformate (16.2 ml,

0.17 mol). The reaction mixture was stirred for 2 hours and then concentrated. The residue was diluted with ethyl acetate (1000 mL) and the resulting mixture was washed with 10% aqueous citric acid (500 mL).

The organic layer was washed successively with water (500 mL), saturated sodium bicarbonate (500 mL), water (500 mL), and brine (500 mL), dried over magnesium sulfate, and the solvent was removed. The residue was recrystallized from ethyl acetate-hexane to give 39.13 g (92%) of the title compound.

• « · 9

¹ H NMR (CDCl ₃ ): δ 7.95 (1H, brs), 7.76 (1H, d, J = 15.8 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.22 (1H, dd, J = 2.1, 8.5 Hz),

6.69 (1H, br), 6.37 (1H, d, J = 15.7 Hz), 4.26 (2H, q, J =

7.3 Hz), 3.82 (3H, s), 1.34 (3H, t, J = 7.25 Hz)

Step 2: Methyl-[6-chloro-1-ethoxycarbonyl-2-(4-methylpyridine-2-carbonyl)indolin-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (from step 1, 1.5 g, 5.3 mmol), 2-bromoacetyl-4-methylpyridine hydrobromide*, potassium carbonate (7.3 g, 53 mmol) and acetonitrile (50 mL) was heated to reflux for 17 h, then cooled and concentrated. The residue was diluted with ethyl acetate (200 mL) and the ethyl acetate mixture was washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate and the solvent was removed. The crude product was purified by flash column chromatography using ethyl acetate:hexane 1:5 as eluent to give 433 (20%) of the title compound.

MS (EI) m/z: 416 (M ⁺ )

2-Bromoacetyl-4-methylpyridine hydrobromide is prepared by the following procedure:

To a stirred solution of 2-acetyl-4-methylpyridine (F.

H. Case et al., J. Am. Chem. Soc., 1956, 78, 5842, 7.8 g,

57.7 mmol) in 25% hydrogen bromide in acetic acid (40 ml) was added dropwise to a solution of bromine (10.1 g, 63.5 mmol) in acetic acid (10 ml) under ice-cooling. The resulting mixture was stirred for 1 hour, then diethyl ether (100 ml) was added. The precipitate formed was collected by filtration to give 10.8 g (63%) of the title compound.

¹ H NMR (DMSO-dg): δ 8.71 (1H, d, J = 5.1 Hz), 8.14 (1H, s), 7.75 (1H, d, J = 5.1 Hz), 5.07 (2H, s), 2.52 (3H, s) ··» ···· • 4 *

-*233 • · ♦

Step 3: [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

To a stirred solution of methyl-[6-chloro-1-ethoxycarbonyl-2-(4-methylpyridine-2-carbonyl)indolin-3-yl]acetate (from step 2, 930 mg, 2.2 mmol) in ethanol (20 mL) and 2M aqueous sodium hydroxide (10 mL) was heated to reflux for 72 h. The resulting mixture was cooled to room temperature and neutralized with 2M aqueous hydrochloric acid (10 mL) and concentrated. The residue was diluted with 10:1 dichloromethane:methanol (300 mL), dried over magnesium sulfate, and the solvent was removed. The crude product was purified by flash column chromatography using 20:1 dichloromethane:methanol as eluent, then washed with isopropyl alcohol (ca. 20 mL). 120 mg (17%) of the title compound are obtained as a yellow powder, melting point 223°C (decomposition). IR (KBr) at: 1707, 1647, 1595, 1533, 1487, 1429, 1276, 1289, 1196 cm ^{1 1} H NMR (DMSO-d 6 ): δ 12.30 (1H, s), 8.70 (1H, d, J = 4.9 Hz), 7.96 (1H, br s), 7.85 - 7.70 (2H, m), 7.65 - 7.55 (1H, m), 7.17 - 7.07 (1H, m), 4.08 (2H, s), 2.47 (3H, s)

Example 32 [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

Step 1: Methyl-[6-chloro-1-ethoxycarbonyl-2-(5-methylpyridine-2-carbonyl)indolin-3-yl]acetate

Two diastereomers of the title compound were prepared by the method described in Step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (from Step 1 of Example 31) and 2-bromoacetyl-5-methylpyridine*.

-’239..-*

Less polar product - t.l.e.: Rf = 0.30 (ethyl acetate/hexane, 1:2), MS (El) m/z: 416 (M ⁺ )

More polar product - tle: Rf = 0.25 (ethyl acetate/hexane, 1:2), MS (El) m/z: 416 (M ⁺ ) *2-Bromoacetyl-5-methylpyridine is prepared by the following procedure:

A mixture of 2-bromo-5-methylpyridine (5.00 g, 29.06 mmol), tributyl-(1-ethoxyvinyl)tin (10.49 g, 29.07 mmol) and tetrakis(triphenylphosphine)palladium (3.36 g, 2.91 mmol) in toluene (40 mL) was heated to reflux for 18 h, then cooled and filtered through a pad of celite. The filtrate was concentrated and the residue (ca. 10 g) was dissolved in a mixture of tetrahydrofuran (100 mL) and water (20 mL). The resulting solution was cooled to 0°C and N-bromosuccinimide (5.43 g, 30.52 mmol) was added over 20 min. The reaction mixture was stirred at the same temperature for 0.5 h, then concentrated to a volume of ca. 20 mL and diluted with ethyl acetate (300 mL). The ethyl acetate mixture was washed with water (100 mL x 3), dried over magnesium sulfate, and the solvent was removed. The crude product was purified by flash column chromatography using ethyl acetate:hexane (1:15 to 1:10) as eluent to give 2.30 g (37%) of the title compound as an oil.

¹ H NMR (CDCl ₃ ): δ 8.49 (1H, brs), 8.01 (1H, d, J = 8.1 Hz), 7.68 - 7.64 (1H, m), 4.84 (2H, s), 2.44 (3H, s)

Step 2: [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

Both diastereoisomers of methyl [6-chloro-1-ethoxycarbonyl-2-(5-methylpyridine-2-carbonyl)indolin-3-yl]acetate (from step 2) were converted to the title compound as described in step 3 of Example 31.

MS (EI) m/z: 328 (M ⁺ )

- 240 melting point 235 to 238°C (after recrystallization from ethyl acetate) IR (KBr) at: 3281, 1699, 1638, 1529, 1310, 1150, 797, 701 cm ^{-1 1} H NMR (DMSO-dg): δ 12.26 (1H, brs), 8.68 (1H, brs), 8.04 (1H, d, J = 8.1 Hz), 7.94 (1H, brd, J = 9.1 Hz), 7.79 (1H, d, J = 8.7 Hz), 7.74 (1H, brs), 7.11 (1H, brd, J = 8.6 Hz), 4.10 (2H, s), 2.47 (3H, s). Due to the influence of NH or COOH, one signal was not observed.

Example 33

Methyl [6-chloro-2-(4-chloropyridin-2-carbonyl)-1H-indol-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A, 675mg, 1.92mmol), 2-bromoacetyl-4-chloropyridine hydrobromide (907mg, 2.88mmol) and potassium carbonate (2.65g, 19.18mmol) in acetone (20ml) was heated to reflux for 4 hours, then cooled and concentrated. The residue was diluted with ethyl acetate (150ml), the ethyl acetate mixture was washed with water (70ml x 6), dried over magnesium sulphate and the solvent was removed. The crude product was purified by flash column chromatography using ethyl acetate:hexane in a ratio of 1:

to 1:3, as eluent. 195 mg (28%) of the title compound were obtained as a yellow solid and 264 mg (27%) of methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate (as brown crystals).

Methyl [6-chloro-2-(4-chloropyridin-2-carbonyl)-1H-indol-3-yl]acetate: MS (E1) m/z: 362 (M ⁺ ) ¹ H NMR (CDCCl ₃ ): δ 12.09 (1H, brs), 8.62 (1H, d, J = 5.3 Hz), 8.28 (1H, d, J = 2.1 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.52 (1H, dd, J = 2.0, and 5.3 Hz), 7.45 (1H, d, J = 1.8 Hz), 7.08 (1H, dd, J = 1.8 and 8.7 Hz), 4.27 (2H, s), 3.75 (3H, s)

- 241

Methyl-[6-chloro-2-(4-chloropyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate: t.e.: Rf = 0.35 (ethyl acetate/hexane, 1:2), MS (EI) m/z (intensity): 504 (M ⁺ , 0.1), 363 (90),

335 (30), 304 (100), 275 (10), 223 (15) * 2-Bromoacetyl-4-chloropyridine hydrobromide is prepared by the following procedure:

4-Chloro-2-pyridinecarbonitrile: To a mixture of 4-chloropyridine-N-oxide (5.00 g, 38.6 mmol) and trimethylsilyl cyanide (4.84 g, 46.3 mmol) in dichloromethane (60 ml) cooled to 0°C was added dropwise N,N-dimethylcarbamoyl chloride (3.8 ml, 40.5 mmol). The resulting mixture was allowed to warm to ambient temperature, stirred for 16 hours, cooled to 0°C and 1 30% aqueous potassium carbonate solution (100 ml) was added. The crude product was extracted with dichloromethane (100 ml x 2). The organic extracts were dried over magnesium sulfate and evaporated. 4-chloro-2-pyridinecarbonitrile (5.35 g, 100%) was obtained.

¹ H NMR (CDCl ₃ ): δ 8.63 (1H, d, J = 4.8 Hz), 7.72 (1H, d, J = 2.6 Hz), 7.55 (1H, dd, J = 1.8, 5.1 Hz)

2-Acetyl-4-chloropyridine: To a solution of 4-chloro-2-pyridinecarbonitrile (5.35 g, 38.6 mmol) in benzene (50 ml) and ether (50 ml) cooled to 0°C was added dropwise a 2M solution of methylmagnesium iodide in ether (23 ml, 46.3 mmol) over 20 minutes. After 0.5 hour the reaction mixture was allowed to warm to ambient temperature and stirring was continued for 2 hours. The reaction mixture was cooled to 0’C and 2M aqueous hydrochloric acid (100 ml) was added. The resulting mixture was basified with saturated aqueous sodium bicarbonate (ca. 80 ml). The organic layer was separated, dried over magnesium sulfate and the solvent was removed. The residue was purified by flash chromatography using a 1:5 mixture of ethyl acetate and hexane. 3.60 g (60%) of 2-acetyl-4-chloropyridine are obtained.

242 ¹ H NMR (DMSO-d ₆ ): δ 8.59 (1H, d, J = 5.1 Hz), 8.04 (1H, d, J = 1.8 Hz), 7.47 (1H, dd, J = 1.8, 5.1 Hz), 2.72 (3H, s)

2-Bromoacetyl-4-chloropyridine hydrobromide: This compound was prepared from 2-acetyl-4-chloropyridine by the method described in H. McKennis, Jr., LB Turnbull, ER Bowman and E. Tamaki (J. Org. Chem., 1963, 28, 383-387) ¹ H NMR (DMSO-d 6 ): δ 8.74 (1H, d, J = 5.5 Hz), 8.05 (1H, d, J = 1.8 Hz), 7.88 (1H, dd, J = 2.2 and 5.5 Hz), 5.02 (2H, s)

Example 34 [6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

A suspension of methyl-[6-chloro-2-[4-chloropyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Example 33, 195 mg, 0.537 mmol) in ethanol (20 mL) and 2M sodium hydroxide (4 mL) was heated at 50°C for 1 hour, cooled to room temperature, and 2M hydrochloric acid (4 mL) was added. The mixture was concentrated and the residue was diluted with ethyl acetate (100 mL). The ethyl acetate mixture was washed with water (50 mL x 2), dried over magnesium sulfate, and the solvent was removed. The crystalline residue was recrystallized from ethyl acetate. 175 mg (94%) of the title compound was obtained, melting at 233-234°C.

IR (KBr) v: 3306, 1709, 1641, 1531, 1254, 1236, 741 cm" ^{1 1} H NMR (DMSO-dg): δ 12.20 (1H, brs), 12.16 (1H, brs), 8.80 (1H, d, J = 5.4 Hz), 8.12 (1H, d, J = 2.1 Hz), 7.90 (1H, dd, J = 2.1, 5.3 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.70 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 2.0, 8.7 Hz), 4.07 (2H, s)

243

Example 35 [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

Step 1: Methyl-[6-chloro-1-ethoxycarbonyl-2-(pyridine-2-carbonyl)indolin-3-yl]acetate

The title compound was prepared as described in Step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (from Step 1 of Example 31) and 2-bromoacetylpyridine hydrobromide (H. McKennis et al., J.

Org. Chem., 1963, 387).

tle: Rf = 0.3 (ethyl acetate/hexane, 1:3)

Step 2: [6-Chloro-2-(pyridin-2-carbonyl)-1H-indol-3-ylacetic acid

The title compound was prepared according to the method described in Step 3 of Example 31 from methyl [6-chloro-1-ethoxycarbonyl-2-(pyridine-2-carbonyl)indolin-3-yl]acetate (from Step 1).

IR (KBr) at: 3280, 1697, 1643, 1531, 1234, 1150 cm' ^{1 1} H NMR (DMSO-dg): δ 12.22 (IH, s), 8.84 (IH, d, J = 4.9 Hz), 8.15 - 8.05 (2H, m), 7.85 - 7.65 (3H, m), 7.11 (1H, dd, J = 1.9, 8.7 Hz), 4.04 (2H, s)

Example 36 [5-Chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl)]acetic acid

Stage 1: Methyl-trans-5-chloro-2-nitrocinnamate

A mixture of 5-chloro-2-nitrobenzaldehyde (9.68 g, 52.16 mmol) and methyl(triphenylphosphoralidene)acetate (18.31 g, 54.77

244

mmol) in toluene (200 mL) was heated to reflux for 2 h and then concentrated. The crystalline residue was purified by flash column chromatography using a 1:5 mixture of ethyl acetate and hexane as eluent. After recrystallization from ethyl acetate and hexane, 7.54 g (60%) of the title compound was obtained as a pale yellow solid.

¹ H NMR (CDCl ₃ ): δ 8.09 (1H, d, J = 15.8 Hz), 8.04 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 2.1 Hz), 7.51 (1H, dd, J = 2.1, 8.7 Hz), 6.36 (1H, d, J = 15.8 Hz), 3.84 (3H, s)

Stage 2: Methyl-trans-2-amino-5-chlorocinnamate

A mixture of methyl trans-5-chloro-2-nitrocinnamate (from step 1, 3.00 g, 12.42 mmol), iron powder (3.65 g, 62.08 mmol), ammonium chloride (332 mg, 6.21 mmol), ethanol (60 mL) and water (10 mL) was heated to reflux for 2 hours, then cooled and filtered through a pad of celite. The filtrate was concentrated and the residue was diluted with ethyl acetate (200 mL). The ethyl acetate mixture was washed with water (100 mL x 2), dried over magnesium sulfate and the solvent was removed. 2.57 g (98%) of the title compound was obtained as crystals.

^-H NMR (CDCl ₃ ): δ 7.73 (1H, d, J = 15.8 Hz), 7.34 (1H, d, J = 2.5 Hz), 7.12 (1H, dd, J = 2.3, 8.6 Hz), 6.64 (1H, d, J = 8.6 Hz), 6.35 (1H, d, J = 15.8 Hz), 3.95 (2H, brs), 3.81 (3H, s)

Step 3: Methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl 2-trans-2-amino-5-chlorocinnamate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 7.72 - 7.67 (2H, m), 7.58 - 7.51 (1H, m), 7.47 - 7.40 (4H, m), 7.36 (1H, d, J = 8.6 Hz), 7.31 (1H, dd, J = 2.1, 8.6 Hz), 6.14 (1H, d, J = 15.8 Hz), 3.78 (3H, s).

Due to the influence of NH, one signal was not observed.

Step 4: Methyl-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate

The title compound was prepared by the method described in Step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (F. H. Čase et al., J. Am. Chem. Soc., 1956, 78, 5842).

tle: Rf = 0.32 (ethyl acetate/hexane, 1:2)

Step 5: [5-Chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3yl]acetic acid

The title compound was prepared according to the method described in Step 3 of Example 31 from methyl [5-chloro-2-(4-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate (from Step 4).

MS (El) m/z: 328 (M ⁺ ) melting point: 230 to 231°C (after recrystallization from ethyl acetate) IR (KBr) in: 3292, 1699, 1597, 1533, 1282, 1198, 1059, 802,

704 cm ^{1 X} H NMR (DMSO-d ₆ ): δ 12.26 (1H, brs), 8.69 (1H, d, J = 5.1 Hzk), 7.93 (1H, brs), 7.82 (1H, d, J = 2.0 Hz), 7.66 (1H, d,

J = 8.7 Hz), 7.56 (1H, brd, J = 4.9 Hz), 7.31 (1H, dd, J =

2.0, 8.7 Hz), 4.02 (2H, s), 2.46 (3H, s). Due to the influence of NH or COOH, one signal was not observed.

Example 37

Methyl-[5-chloro-2-(6-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

246 -*

Step 1: Methyl-[5-chloro-2-(6-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate

The title compound was prepared as described in Step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-6-methylpyridine hydrobromide (H. Erlenmeyer, J. Jenni and B. Prijs, J. Med. Pharm. Chem., 1961, 3, 561-566).

tle: Rf = 0.39 (ethyl acetate/hexane, 2:3)

Step 2: Methyl-[5-chloro-2-(6-methylpyridine-2-carbonyl)-1Hindol-3-yl]acetate

The title compound was prepared according to the method described in Step 3 of Example 8 (Method A) from methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 12.62 (1H,b rs), 8.15 (1H, d, J = 7.9 Hz), 7.84 (1H, t, J = 7.7 Hz), 7.67 (1H, d, J = 1.8 Hz), 7.43 (1H, d, J = 8.9 Hz), 7.40 (1H, d, J = 8.9 Hz). 7.7 Hz), 7.32 (1H, dd,

J = 2.0, 8.7 Hz), 4.28 (2H, s), 3.73 (3H, s), 2.76 (3H, s)

Example 38 [5-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 34 from methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate.

MS (EI) m/z: 328 (M ⁺ )

Melting point: 225 to 226°C (after recrystallization from ethyl acetate) IR (KBr) at: 1705, 1636, 1529, 1333, 1236, 1180, 1061, 669 cm' ^{1 1} H NMR (DMSO-dg): δ 12.13 (1H, brs), 12.09 (1H, brs), 7.99

- 247 ·· ·1 (1Η, t, J = 7.7 Hz), 7.87 (1H, d, J = 7.7 Hz), 7.84 (1H, d,

J = 2.0 Hz), 7.66 (1H, d, J = 8.9 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.33 (1H, dd, J = 2.0, 8.9 Hz), 4.03 (2H, s), 2.69 (3H, s)

Example 39 [6-Chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid

Step 1: Methyl-[6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate

The title compound was prepared as described in Step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (from Step 1 of Example 31) and 2-bromoacetyl-1-methylimidazole hydrobromide*.

MS (EI) m/z: 405 (M ⁺ )

2-Bromoacetyl-1-methylimidazole hydrobromide is prepared as follows:

To a stirred suspension of 2-acetyl-1-methylimidazole (D.

H. Davis, J. Halí and E. H. Smith, J. Chem. Soc. Perkin.

Trans. 1, 1991, 2691, 3.0 g, 26.8 mmol) in 25% hydrogen bromide in acetic acid was added dropwise with ice-cooling to a solution of bromine (4.7 g, 29.5 mmol). The reaction mixture was stirred for 0.5 h, allowed to warm to room temperature, stirred for another hour, and diethyl ether (150 ml) was added. The resulting mixture was cooled in an ice bath. The precipitate that separated was collected by filtration. 5.2 g (66%) of the title compound was obtained as a pale yellow powder.

³ H NMR (DMSO-d ₆ ): δ 7.61 (1H, s), 7.27 (1H, s), 4.68 (1H, s), 3.81 (3H, s) • · • · ···· ·· • * ♦ · ·

248 Step 2: [6-Chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 3 of Example 31 from [6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate (from Step 1) and had a melting point of 236°C (dec.).

MS (EI) m/z: 317 (M ⁺ )

IR (KBr) v: 3238, 1695, 1630, 1537, 1402, 1229, 1146 cm ^{1 1} H NMR (CDCl ₃ +DMSO-d ₆ ): δ 12.30 (1H, s), 7.65 (1H, d, J =

8.7 Hz), 7.50 (1H, d, J = 1.8 Hz), 7.42 (1H, s) , 7.28 - 7.23 (1H, m), 7.16 (1H, s), 7.09 (1H, dd, J = 1.8 , 8.6 Hz), 4.25 (2H, s), 4.13 (3H, s)

Example 40

Methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate).

Step 1: Methyl-[5-chloro-1-phenylsulfonyl-2-(thiazole-2-carbonyl)indolin-3-yl]acetate

The title compound was prepared as described in Step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetylthiazole hydrobromide (A. Dondoni, A. Marra and P. Merino, J. Am. Chem. Soc., 1994, 116, 3324). t.l.: Rf = 0.07 (ethyl acetate/hexane, 1:2)

Step 2: Methyl-[5-chloro-2-(thiazole-2-carbonyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Step 3 of Example 8 from methyl [5-chloro-1-phenylsulfonyl-2-(thiazole-2-carbonyl)indolin-3-yl]acetate (from Step 1).

249 ·· ···· · * » ·· • * · · ♦ · ···

NMR (CDCl ₃ ): δ 11.78 (1H, brs), 8.12 (1H, d, J = 3.1 Hz), 7.75 (1H, d, J = 3.1 Hz), 7.68 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.34 (1H, dd, J = 2.0, 8.9 Hz), 4.29 (2H, s), 3.74 (3H, s)

Example 41 [5-Chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [5-chloro-1-phenylsulfonyl-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate (from step 2).

MS (EI) m/z: 320 (M ⁺ )

Melting point: 230 to 231°C (after recrystallization from ethyl acetate) IR (KBr) at: 3302, 1703, 1636, 1541, 1387, 1335, 1267, 1232, 1186, 1003, 766 cm ^-1

NMR (DMSO-d ₆ ): δ 12.23 (1H, brs), 12.10 (1H, brs), 8.33 (1H, d, J = 3.1 Hz), 8.31 (1H, d, J = 3.1 Hz), 7.89 (1H, d,

J = 2.0 Hz), 7.77 (1H, d, J = 8.9 Hz), 7.36 (1H, dd, J =

2.0, 8.7 Hz), 4.17 (2H, s)

Example 42

Methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate

A mixture of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2, 50 mg, 0.16 mmol) and 10% hydrogen chloride in methanol (3 mL) was stirred at room temperature for 3 hours and then concentrated. The residue was purified by flash column chromatography using ethyl acetate:hexane (1:5) as eluent to give 23 mg (44%) of the title compound as a white solid, mp 134-137°C.

IR (KBr) at: 1735, 1620, 1529, 1434, 1325, 1147, 1013, 945 cm ^-1 • · · · · • · * · ·

250 ·· ··· · · ··· ¹ H NMR (CDC1 ₃ ): δ 8.96 (1H, brs) , 7.85 - 7.74 (2H, m) , 7.66 - 7.47 (4H, m), 7.38 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J = 1.8, 8.6 Hz), 3.18 (2H, s), 3.65 (3H, s)

Example 43 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N,N-dimethylacetamide

To a solution of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2, 140 mg, 0.5 mmol), dimethylamine hydrochloride (45 mg, 0.54 mmol) and triethylamine (0.1 mL, 0.54 mmol) in dimethylformamide (2 mL) at 0°C was added diethylphosphorocyanide (DEPC, 0.1 mL, 0.54 mmol). The resulting mixture was stirred at room temperature for 1 h and then poured into water (20 mL). The aqueous mixture was extracted with diethyl ether (50 mL x 2). The organic extracts were washed with water (30 mL x 2), dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate/hexane to give 50 mg (33%) of the title compound, m.p. 190-200°C.

193°C (after recrystallization from ethyl acetate/hexane). IR (KBr) at: 1631, 1232, 1007, 908 cm ^-1

¹ H NMR (CDCl ₃ ): δ 11.72 (1H, brs; ), 7.72 - 7.64 (4H, m) , 7.60 - 7.52 (2H, m), 7.45 (1H, d, J = 1.2 Hz), 7.08 (1H, d, J = 8.6 Hz), 3.32 (2H, s), 2.80 (3H, s), 2.76 (3H, s)

Example 44 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N-methylacetamide

The title compound was prepared as described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2) and methylamine hydrochloride and after recrystallization from ethyl acetate/hexane had a melting point of 242-246°C.

IR (KBr) at: 1618, 1527, 1409, 1325 cm" ¹

251

¹ H NMR (CDCl ₃ ): δ 11.71 (1H, brs), 7.82 - 7.75 (2H, m) , 7.62 - 7.52 (5H, m), 7.49 - 7.46 (1H, m), 7.15 - 7.08 (1H, m) ,

3.64 (2H, s), 3.31 (3H, s)

Example 45 (2-Benzoyl-6-chloro-1H-indol-3-yl)acetamide

The title compound was prepared as described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2) and a solution of ammonia in tetrahydrofuran. The product obtained had a melting point of 234-237°C.

IR (KBr) v: 1665, 1618, 1566, 1523, 1325, 1259, 943 cm ^{-1 1} H NMR (CDC1 ₃ ): δ 11.66 (1H, brs), 7.82 - 7.75 (2H, m), 7.74 - 7.65 (2H, m), 7.62 - 7.53 (2H, m), 7.46 (1H, d, J = 1.8 Hz), 7.27 (1H, brs), 7.12 (1H, dd, J = 1.8, 8.6 Hz), 6.85 (1H, brs), 3.63 (2H, s)

Example 46 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N-methoxy-N-methylacetamide

The title compound was prepared as described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2) and N,O-dimethylhydroxylamine hydrochloride. The product obtained had a melting point of 109.9-112.2°C (dec.).

IR (KBr) at: 3179, 2970, 2937, 1634, 1599, 1570 cm' ¹ 'ή NMR (CDC1 ₃ ): δ 9.20 - 8.90 (1H, m) , 7.84 - 7.75 (2H, m) , 7.66 - 7.45 (4H, m), 7.33 (1H, d, J = 1.3 Hz), 7.12 (1H, dd, J = 8.6, 1.8 Hz), 3.94 (2H, s), 3.51 (3H, s), 3.13 (3H, s)

Example 47

2-(2-Benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone

252

Step 1: 7-chloro-1-phenyl-9H-pyrazo[3,4-b]indol-3-one

A solution of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2, 200 mg, 0.64 mmol), diethylphosphorocyanide (DEPC, 0.12 mL, 0.76 mmol) and triethylamine (0.11 mL, 0.76 mmol) in dimethylformamide (3.0 mL) was stirred at room temperature for 5 min. The resulting mixture was poured into water (20 mL) and the orange precipitate was collected by filtration. 20 mg, (11%) of the title compound was obtained as an orange solid.

^Χ Η NMR (CDC1 ₃ ): δ 10.79 (1H, brs), 8.10 (1H, d, J = 8.4 Hz), 7.93 - 7.84 (2H, m), 7.67 - 7.50 (3H, m), 7.29 (1H, s), 7.13 (1H, d, J = 8.4 Hz), 6.87 (1H, with)

Step 2: 2-(2-Benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone

A mixture of 7-chloro-1-phenyl-9H-pyrano[3,4-b]indol-3-one (step 1, 0.30 g, 1.0 mmol) and piperidine (1.0 mL, 10 mmol) in methanol (20 mL) was heated to reflux for 2 h and then cooled to room temperature. The yellow mixture was concentrated and the solid residue was recrystallized from methanol/hexane to give 0.12 g (32%) of the title compound, mp 223-224°C.

IR (KBr) v: 3310, 2928, 1655, 1570, 1533, 1447, 1323, 1256, 1225, 1059, 945, 858, 737, 700 cm ^{-1 X} H NMR (DMSO-d ₆ ): δ 11.7 (1H, brs), 7.74 - 7.63 (4H, m),

7.55 (2H, t, J = 8.7 Hz), 7.46 (1H, d, J = 1.8 Hz), 7.09 (1H, dd, J = 8.7, 1.8 Hz), 3.80 (2H, s), 3.45 - 3.20 (4H, m), 1.55 - 1.20 (6H, m)

Example 48

2-(2-Benzoyl-6-chloro-1H-indol-3-yl)-1-(4-methyl-1-piperazinyl)-1-ethanone

253 • · · · · · · · · • * ··· ··· • · ·· ·«· · · · ···

The title compound was prepared as described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2) and 1-methylpiperazine and after recrystallization from methanol/hexane had a melting point of 184-185°C.

IR (KBr) Vi 2939, 2795, 1634, 1531, 1435, 1325, 1229, 1144, 1001, 737, 700 cm ^{1 1} H NMR (CDC1 ₃ ): δ 9.37 (1H, brs), 7.78 - 7.75 (1H, m), 7.73 (1H, d, J = 1.5 Hz), 7.62 - 7.52 (2H, m), 7.52 - 7.43 (2H, m), 7.18 - 7.10 (1H, m), 7.10 - 7.02 (1H, m), 3.81 (2H, s), 3.54 (2H, brs), 3.36 (2H, t, J = 4.8 Hz), 2.36 - 2.22 (4H, m

Example 49 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N-(2-cyanoethyl)acetamide

The title compound was prepared as described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2) and aminopropionitrile and after recrystallization from methanol/hexane had a melting point of 233-233.5°C.

¹ H NMR (DMSO-dg): δ 11.7 (1H, brs), 8.16 (1H, t, J = 6.3 Hz), 7.81 - 7.75 (2H, m), 7.72 - 7.64 (2H, m), 7.62 - 7.53 (2H, m), 7.47 (1H, d, J = 1.9 Hz), 7.10 (1H, dd, J = 8.7,

1.9 Hz), 3.67 (2H, s), 3.23 (2H, q, J = 6.3 Hz), 2.58 (2H, t, J = 6.3 Hz)

Example 50 (2-Benzoyl-6-chloro-1H-indol-3-yl)-N-(2-hydroxyethyl)acetamide

The title compound was prepared as described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2) and 2-aminoethanol and after recrystallization from methanol/hexane had a melting point of

254

9 «99

178 to 179.5°C.

*Ή NMR (DMSO-dg): δ 11.7 (1H, brs), 7.84 - 7.75 (3H, m) , 7.72 - 7.64 (2H, m) , 7.61 - 7.52 (2H, m) , 7.46 (1H, d, J = 2.0 Hz), 7.11 (1H, dd, J = 8.6, 2.0 Hz), 3.64 (2H, s), 3.38 - 3.30 (3H, m), 3.06 (2H, q, J = 5.9 Hz)

Example 51

2-(2-Benzoyl-6-chloro-1H-indol-3-yl)-1-morpholino-1-ethanone

The title compound was prepared as described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (from Example 2) and morpholine and after recrystallization from methanol-hexane had a melting point of 187.7-189.5°C.

IR (KBr) at: 3339, 2964, 2849, 1653, 1612, 1568 cm" ^{1 1} H NMR (CDCl ₃ ): δ 9.08 - 8.92 (1H, m), 7.81 - 7.72 (2H, m), 7.69 - 7.58 (2H, m), 7.56 - 7.47 (2H, m), 7.29 (1H, d, J = 1.8 Hz), 7.12 (1H, dd, J = 8.6, 1.8 Hz), 3.87 (2H, s), 3.67 - 3.46 (6H, m), 3.41 - 3.31 (2H, m)

Example 52 [2-(4-Chlorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 2-(4-Chlorobenzoyl)-1-(phenylsulfonyl)indole

To a solution of 1-(phenylsulfonyl)indole (500 mg, 1.94 mmol) in tetrahydrofuran (5 mL) was added tert-butyllithium (1.4 mL, 2.33 mmol) dropwise under nitrogen at -78°C. The resulting yellow solution was added directly via cannula to a solution of p-chlorobenzoyl chloride (0.3 mL, 2.33 mmol) in tetrahydrofuran (3 mL) cooled to -78°C. The reaction mixture was stirred at -78°C for 2 h, then quenched with saturated ammonium chloride and extracted with ethyl acetate (100 mL). The organic layer was

- 255

washed with water (50 ml) and aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed. The crude product was purified by flash column chromatography using hexane:ethyl acetate (10:1) as eluent to give 339 mg (44.1%) of the title compound as a yellow amorphous solid.

^•H NMR (CDCl ₃ ): δ 8.13 (1H, d, J = 8.4 Hz), 8.04 - 8.00 (2H, m), 7.93 - 7.90 (2H, m), 7.58 - 7.44 (7H, m), 7.30 (1H, d, J = 7.4 Hz), 6.95 (1H, s)

Step 2: 2-(4-Chlorobenzoyl)indole

A mixture of 2-(4-chlorobenzoyl)-1-(phenylsulfonyl)indole (step 1, 334 mg, 0.84 mmol) and 2M sodium hydroxide (1.5 mL, 2.78 mmol) in ethanol (5 mL) was heated to reflux for 15 min and then concentrated. The residue was diluted with ethyl acetate (100 mL). The organic layer was washed with water, dried over magnesium sulfate and concentrated to give 211 mg (98.2%) of the title compound as a yellow solid.

¹ H NMR (CDCl ₃ ): δ 9.45 (1H, brs), 7.97 - 7.92 (2H, m), 7.74 - 7.70 (1H, m), 7.54 - 7.47 (3H, m), 7.42 - 7.36 (1H, m), 7.21 - 7.13 (2H, m)

Step 3: Diethyl-α-acetoxy-[2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) using 2-(4-chlorobenzoyl)indole (from Step 2).

^-H NMR (CDCl ₃ ): δ 8.94 (1H, brs), 7.90 (1H, d, J = 8.4 Hz), 7.81-7.77 (2H, m), 7.43-7.36 (3H, m), 7.32-7.26 (1H, m), 7.22-7.16 (1H, m), 4.27 - 4.14 (4H,m), 1.75 (3H,s), 1.29 - 1.16 (6H,m)

256

Step 4: Diethyl-[2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 5 of Example 2 (Method B) using α-acetoxy-[2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (from Step 3).

^Τ Η NMR (CDCl ₃ ): δ 8.73 (1H, brs), 7.85 - 7.82 (1H, m), 7.79

- 7.76 (2H, m), 7.52 - 7.46 (2H, m), 7.39 - 7.37 (1H, m), 7.26 - 7.19 (2H, m), 5.27 (1H, s), 4.26 - 4.16 (4H, m), 1.26

- 1.21 (6H, m)

Step 5: [2-(4-Chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) using diethyl [2-(4-chlorobenzoyl)-1H-indol-3-yl]malonate (from Step 4) and after recrystallization from ethyl acetate/hexane had a melting point of 221-224°C.

IR (KBr) v: 3321, 1697, 1607, 1576, 1529, 1433, 1408, 1339, 1263, 1223, 1202 cm ^{1 1} H NMR (DMSO-dg): δ 11.61 (1H, s), 7.79 - 7.75 (2H, m), 7.71

- 7.63 (3H, m), 7.46 (1H, d, J = 8.2 Hz), 7.35 - 7.29 (1H, m), 7.14 - 7.08 (1H, m), 3.84 (2H, s)

Example 53 [6-Chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid

Step 1: 6-chloro-2-(2-furylcarbonyl)-1-(phenylsulfonyl)indole

The title compound was prepared as described in Step 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 2, Method B) and 2-furoyl chloride.

^. _​

- 6.64 (IH, m)

Step 2: 6-Chloro-2-(2-furylcarbonyl)indole

The title compound was prepared according to the method described in Step 3 of Example 2 (Method B) from 6-chloro-2-(2-furylcarbonyl)-1-(phenylsulfonyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 9.33 (1H, brs), 7.65 - 7.73 (3H, m), 7.46

- 7.48 (2H, m), 7.12 - 7.16 (IH, m), 6.64 - 6.66 (IH, m)

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(2-furylcarbonyl)indole (from Step 2).

¹ H NMR (CDC1 ₃ ): δ 9.60 (IH, brs), 7.76 (IH, d, J = 8.9 Hz), 7.62 - 7.63 (IH, m), 7.43 (IH, d, J = 1.3 Hz), 7.28 - 7.29 (IH, m), 7.13 (IH, dd, J = 1.8 Hz, 8.7 Hz). 6.59 (IH, dd, J = 1.6 Hz, 3.5 Hz), 4.18 - 4.32 (4H, m), 1.88 (3H, s), 1.18 1.28 (6H, m)

Step 4: Diethyl [6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate (from Step 3).

¹ H NMR (CDC1 ₃ ): δ 9.83 (IH, brs), 7.67 (IH, t, J = 0.8 Hz), 7.36 (IH, d, J = 8.9 Hz), 7.40 (IH, d, J = 3.6 Hz), 7.3O(1H, d, J = 1.8 Hz), 7.01 (IH, dd, J = 1.8, 8.9 Hz), 6.62 (IH,

258 dd, J = 1.6 Hz, 2.1 Hz), 6.19 (1H, s), 4.20 - 4.32 (4H, m), 1.27 (6H, t, J = 7.3 Hz)

Step 5: [6-Chloro-2-(2-furylcarbonyl)indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(2-furylcarbonyl)indol-3-yl]malonate (from Step 4). ¹ H NMR (DMSO-d ₆ ): δ 12.22 (1H, brs), 11.76 (1H, brs), 8.13 (1H, d, J = 1.0 Hz), 7.75 (1H, d, J = 8.6 Hz), 7.56 (1H, d,

J = 1.8 Hz), 7.48 (1H, d, J = 3.6 Hz), 7.14 (1H, dd, J = 1.8 Hz, 8.6 Hz), 6.85 (1H, dd, J = 1.8 Hz, 3.6 Hz), 4.02 (2H, s)

Example 54 [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid

Step 1: 6-chloro-2-cyclohexanecarbonyl-1-(phenylsulfonyl)indole

The title compound was prepared as described in Step 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 2, Method B) and cyclohexanecarbonyl chloride.

tle: Rf = 0.4 (ethyl acetate/hexane, 1:4)

Step 2: 6-Chloro-2-cyclohexanecarbonylindole

The title compound was prepared by the method described in Step 3 of Example 2 (Method B) from 6-chloro-2-cyclohexanecarbonyl-1-(phenylsulfonyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 10.08 (1H, brs), 8.08 - 7.04 (4H, m), 2.28 - 1.20 (11H, m)

259

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(cyclohexanecarbonyl)indole (from Step 2).

^X H NMR (CDCl ₃ ): δ 8.94 (1H, brs), 8.12 - 7.09 (3H, m), 4.34 - 4.21 (4H, m), 2.20 (3H, s), 1.81 - 1.20 (17H, m)

Step 4: Diethyl [6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, brs), 7.72 (1H, d, J = 8.7 2 Hz), 7.36 - 7.09 (2H, m), 5.70 (1H, s), 4.28 - 4.19 (4H, m), 1.91 - 1.22 (17H, m)

Step 5: [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl] malonate (from Step 4). The product obtained had a melting point of 206-209°C.

IR (KBr) v: 3314, 2924, 2856, 1734, 1650, 1537, 1396, 1248 cm' ¹ H NMR (DMSO-d ₆ ): δ 11.78 (1H, s), 7.71 (1H, d, J = 8.64 Hz), 7.46 - 7.07 (2H, m), 4.01 (2H, s), 1.78 - 1.16 (11H)

Example 55

Methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate

260

The title compound was prepared as described in Step 8 of the Example from methyl trans-4-chloro-2-(phenylsulfonylamine)cinnamate (from Step 1 of Example 8) and 4-methoxyphenacyl bromide.

^X H NMR (CDCl ₃ ): δ 8.85 (1H, s), 7.82 (2H, d, J = 8.9 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J = 1.8, 8.6 Hz), 6.99 (2H, d, J = 8.6 Hz). 8.6 Hz), 3.90 (3H, s), 3.86 (2H, s), 3.67 (3H, s)

Example 56 [6-Chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate (from Step 1). The product obtained had a melting point of 187-190°C.

^Χ Η NMR (DMSO-d ₆ ): δ 11.72 (1H, s), 7.78 (2H, d, J = 8.7 Hz), 7.70 (1H, d, J = 8.6 Hz), 7.49 - 7.45 (1H, m), 7.15 - 7.07 (3H, m), 3.87 (3H, s), 3.81 (2H, with)

Example 57

Methyl-[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A, 700 mg, 1.99 mmol), 2-bromoacetyl-4-ethylpyridine (545 mg, 2.39 mmol), potassium carbonate (1.37 g, 13.9 mmol) and acetone (20 mL) was stirred at room temperature for 3 hours, after which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.6 mL, 3.98 mmol) was added. The resulting mixture was stirred for an additional 7 hours and then concentrated. The residue was diluted with dichloromethane (200 mL) and the dichloromethane mixture was washed with water (100 mL x 2). The organic layer was

261 • · ··*· ·· • · · · · · · dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using ethyl acetate:hexane:dichloromethane (1:4:1) as eluent to give the title compound containing impurities. The crude product was washed with ethyl acetate to give 297 mg (42%) of the title compound as a yellow solid.

^X H NMR (CDCl ₃ ): δ 12.52 (1H, brs), 8.64 (1H, d, J = 4.9 Hzh), 8.21 (1H, brs), 7.62 (1H, d, J = 8.7 Hz), 7.52 (1H, d, J = 1.8 Hz), 7.39 - 7.35 (1H, m), 7.13 (1H, dd, J = 1.8, 8.6 Hz), 4.31 (2H, s), 3.73 (3H, s), 2.78 (2H, q, J = 7.6 Hz), 1.32 (3H, t, J = 7.6 Hz)

2-Bromoacetyl-4-ethylpyridine is prepared by the following procedure:

To a solution of 2-acetyl-4-ethylpyridine (E. C. Constable et al., J. Am. Chem. Soc., 1977, 119, 5606, 8.37 g, 56.1 mmol) in 25% hydrobromic acid-acetic acid (150 ml) is added dropwise a solution of bromine (9.86 g,

61.7 mmol) in acetic acid (30 mL). The reaction mixture was allowed to warm to room temperature, stirred for 2 hours, and diethyl ether (500 mL) was added. The resulting mixture was cooled in an ice bath. The brown oil that separated from the solution was collected by decantation and mixed with saturated aqueous sodium bicarbonate (50 mL). The resulting mixture was extracted with diethyl ether (300 mL). The organic layer was dried over magnesium sulfate and concentrated to give 15.3 g (88%) of the title compound.

^X H NMR (CDCl ₃ ): δ 8.56 (1H, d, J = 5.1 Hz), 7.95 (1H, brs), 7.36 - 7.34 (1H, m), 4.86 (2H, s), 2.74 (2H, q, J = 7.7 Hz), 1.29 (3H, t, J = 7.6 Hz)

262

Example 58 [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

Yellow suspension of methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 57, 297 mg,

0.83 mmol) in 2M aqueous sodium hydroxide (2.5 mL) and ethanol (20 mL) was heated to reflux for 3 h, then cooled to room temperature and neutralized with 2M aqueous hydrochloric acid (2.5 mL). The resulting mixture was concentrated and the residue was diluted with tetrahydrofuran (150 mL). The tetrahydrofuran mixture was dried over magnesium sulfate and concentrated. The solid residue was recrystallized from ethyl acetate to give 251 mg (88%) of the title compound as a yellow solid, mp 215-216°C (dec).

MS (EI) m/z: 342 (M ⁺ )

IR (KBr) v: 3206, 1707, 1643, 1595, 1535, 1421, 1227, 1192, 1140, 912, 777 cm ^{1 1} H NMR (DMSO-dg): δ 12.30 (1H, brs), 12.18 (1H, brs), 8.73 (1H, d, J = 4.9 Hz), 7.98 (1H, brs), 7.79 (1H, d, J = 8.7 Hz), 7.74 (1H, d, J = 1.8 Hz), 7.62 (1H, br d, J = 5.1 Hz), 7.12 (1H, dd, J = 1.8, 8.6 Hz), 4.08 (2H, s), 2.78 (2H, q, J = 7.7 Hz), 1.26 (3H, t, J = 7.7 Hz)

Example 59

Methyl-[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4-ethylpyridine (the preparation of which is described in Example 57). ¹ H NMR (CDCl ₃ ): δ 12.57 (1H, brs), 8.65 (1H, d, J = 5.1 Hz),

263

8.21 (1H, brs), 7.68 (1H, brs), 7.45 (1H, d, , J = 8.9 Hz), 7.40 - 7.36 (1H, m), 7.31 (1H, dd, J = 2.0, 8.7 Hz), 4.28 (2H, S), 3.74 (3H, s) , 2, 78 (2H, q, J = 7.7 Hz), 1.32 (3H, t, J = 7.7 Hz)

Example 60 [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid (from Example 59). MS (EI) m/z: 342 (M ⁺ )

Melting point: 217 to 218°C

IR (KBr) v: 3269, 1705, 1643, 1595, 1533, 1418, 1335, 1225, 1200, 1059, 779 cm" ^{1 1} H NMR (DMSO-d ₆ ): δ 12.33 (1H, brs), 8.73 (1H, d, J=4.9 Hz), 7.98 (1H, brs), 7.86 (1H, d, J = 2.0 Hz), 7.69 (1H, d,

J = 8.9 Hz), 7.61 (1H, dd, J = 4.8, 1.6 Hz), 7.33 (1H, dd, J = 2.0, 8.7 Hz), 4.07 (2H, s), 2.78 (2H, q, J = 7.6 Hz), 1.26 (3H, t, J = 7.6 Hz)

Example 61

Methyl-[6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method B) and 2-bromoacetyl-4-isopropylpyridine.

¹ H NMR (CDCl ₃ ): δ 12.53 (1H, brs), 8.65 (1H, d, J = 4.9 Hz), 8.24 (1H, d, J = 1.6 Hz), 7.62 (1H, d, J = 8.7 Hz), 7.52 (1H, d, J = 1.6 Hz), 7.40 (1H, dd, J = 1.6 Hz). 1.8, 4.9 Hz), 7.13

264 ·· ···· (1H, dd, J = 1.8, 8.7 Hz), 4.30 (2H, s), 3.73 (3H, s), 2.97 - 3.07 (1H, m), 1.32 (6H, d, J = 6.9 Hz) *2-Bromoacetyl-4-isopropylpyridine is prepared from 2-acetyl-4-isopropylpyridine (K. Ishihama et al., J. Agric. Food Chem., 1992, 40, 1647) by the method described in Example 57 for the preparation of 2-bromoacetyl-4-ethylpyridine.

¹ H NMR (CDCl ₃ ): δ 8.57 (1H, d, J = 5.8 Hz), 7.97 - 7.98 (1H, m), 7.36 - 7.38 (1H, m), 4.86 (2H, s), 2.94 - 3.04 (1H, m), 1.27 - 1.32 (6H, m)

Example 62 [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 61) and had a melting point of 194-169°C.

IR (KBr) Vi 3244, 2965, 1692, 1647, 1597, 1537, 1254, 1200, 1178, 1150, 764 cm ^{-1 1} H NMR (DMSO-dg): δ 12.28 (1H, brs), 8.74 (1H, d, J = 5.3 Hz), 8.01 (1H, s), 7.8th (lH, d, J = 8.9 Hz), 7.74 (1H, d, J = 1.6 Hz), 7.64 - 7.66 (1H, m), 7.12 (1H, dd, J = 1.8, 8.6 Hz), 4.08 (2H, s), 3.02 - 3.13 (1H, m), 1.28 (6H, d, J = 6.9 Hz)

Example 63

Methyl-[5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared by the method described 57 from methyl-trans-5-chloro-2-(phenylsulfonylamino)• · ·

- 26% From dynamate (from step 3 of Example 36) and 2-bromoacetyl-4-isopropylpyridine (the preparation of which is described in Example 61).

¹ H NMR (CDC1 ₃ ): δ 12.57 (1H, brs), 8.65 (1H, d, J = 5.1 Hz), 8.24 (1H, d, J = 1.6 Hz), 7.67 (1H, d, J = 2.0 Hz), 7.44 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 8.2 Hz). 1.8, 4.9 Hz), 7.31 (1H, dd, J = 2.0, 8.7 Hz), 4.28 (2H, s), 3.74 (3H, s), 2.97 - 3.07 (1H, m), 1.32 (6H, d, J = 6.9 Hz)

Example 64 [5-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 63).

MS (EI) m/z: 356 (M ⁺ )

Melting point: 227 to 228°C

IR (KBr) v: 2964, 1703, 1643, 1595, 1537, 1202, 1059, 768 cm ¹ H NMR (DMS0-d ₆ ): δ 12.32 (1H, brs), 12.15 (1H, brs), 8.74 (1H, d, J = 4.9 Hz), 8.00 (1H, s), 7.86 (1H, s), 7.64 - 7.71 (2H, m), 7.31 - 7.35 (1H, m), 4.08 (2H, s), 3.03 - 3.13 (1H, m), 1.28 (6H, d, J = 6.9 Hz)

Example 65

Methyl-[6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-4-propylpyridine hydrobromide.

^Τ Η NMR (CDC1 ₃ ): δ 12.53 (1H, brs), 8.64 (1H, d, J = 4.9 Hz), 8.19 (1H, s), 7.62 (1H, d, J = 8.7 Hz), 7.53 (1H, d, J = 1.6 ····· ···································· · · · · · v — 26δ ·* · · * · · Z • · · · · » ··· ·« ·»

Hz), 7.35 - 7.37 (1H, m), 7.13 (1H, dd, J = 1.8, 8.7 Hz),

4.31 (2H, s), 3.73 (3H, s), 2.71 (2H, t, J = 7.3 Hz), 1.69 1.77 (2H, m), 0.98 (3H, t, J = 7.3 Hz)

2-Bromoacetyl-4-propylpyridine hydrochloride is prepared by the following procedure:

4-Propyl-2-pyridinecarbonitrile

The title compound was prepared from 4-propylpyridine-N-oxide (S. Ghersetti et al., J. Heterocycl. Chem., 1969, 6, 859) using the procedure described in Example 33 for the preparation of 4-chloro-2-pyridinecarbonitrile.

η NMR (CDCl ₃ ): δ 8.59 (1H, d, J = 5.1 Hz), 7.53 (1H, s),

7.32 - 7.34 (1H, m), 2.66 (2H, t, J = 7.3 Hz), 1.62 - 1.76 (2H, m), 0.97 (3H, t, J = 7.3 Hz)

2-Acetyl-4-propylpyridine

The title compound was prepared from 4-propyl-2-pyridinecarbonitrile by the method described in Example 33 for the preparation of 2-acetyl-4-chloropyridine.

¹ H NMR (CDCl ₃ ): δ 8.56 (1H, d, J = 4.9 Hz), 7.88 (1H, s), 7.27 - 7.30 (1H, m), 2.72 (3H, s), 2.66 (2H, t, J = 7.4 Hz), 1.62 - 1.76 (2H, m), 0.95 (3H, t, J = 7.4 Hz)

2-Bromoacetyl-4-propylpyridine hydrobromide

The title compound was prepared from 2-acetyl-4-propylpyridine using the method described in Step 2 of Example 31 for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide.

¹ H NMR (DMSO-d ₆ ): δ 8.64 (1H, d, J = 4.9 Hz), 7.90 (1H, d, J = 1.0 Hz), 7.59 (1H, dd, J = 1.6, 4.9 Hz), 5.02 (2H, s),

2.70 (2H, t, J = 7.4 Hz), 1.57 - 1.71 (2H, m), 0.89 (3H,t ,

J = 7.3 Hz)

26V

Example 66 [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl 2-[6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 65) and had a melting point of 189-191°C.

IR (KBr) at: 2964, 2928, 1711, 1645, 1595, 1533, 1281, 1225, 1192, 799 cm" ¹

NMR (DMSO-d ₆ ): δ 12.28 (1H, brs) , 8.73 (1H, d, J = 5.1 Hz) , 7.96 (1H, s) , 7.73 - 7.81 (2H, m) , 7.59 (1H, d, J = 4.9 Hz) , 7.10 - 7.13 (1H, m), 4.08 (2H, S), 2.73 (2H, t, J= 7.1 Hz) , 1.63 - 1.72 (2H, m), 0.92 (3H, t, J = 7.3 Hz: ) When to 1 and . d 6 7

Methyl-[5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4-propylpyridine hydrobromide (the preparation of which is described in Example 65).

¹ H NMR (CDCl ₃ ): δ 12.56 (1H, brs), 8.64 (1H, d, J = 4.9 Hz), 8.18 (1H, s), 7.67 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 8.7 Hz), 7.29 - 7.37 (2H, m), 4.28 (2H, s), 3.74 (3H, s), 2.71 (2H, t, J = 7.4 Hz), 1.80 - 1.66 (2H, m), 0.97 (3H, t, J = 7.3 Hz)

Example 68 [5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

26»

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 67) and had a melting point of 208-209°C.

IR (KBr) v: 3296, 2957, 1705, 1645, 1595, 1535, 1329, 1273, 1204, 1057, 795 ^cm_1 ^H NMR (DMSO-d ₆ ): δ 12.33 (1H, brs), 12.15 (1H, brs). 8.73 (1H, d, J = 4.9 Hz), 7.95 (1H, s), 7.86 (1H, s), 7.69 (1H, d, J = 8.7 Hz), 7.58 - 7.61 (1H, m), 7.31 - 7.35 (1H, m), 4.08 (2H, s), 2.73 (2H, t, J = 7.4 Hz), 1.64 - 1.72 (2H, m), 0.92 (3H, t, J = 7.4 Hz)

Example 69

Methyl-[2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-4-tert-butylpyridine*.

¹ H NMR (CDCl ₃ ): δ 12.55 (1H, brs), 8.67 (1H, d, J = 5.3 Hz), 8.39 (1H, d, J = 2.1 Hz), 7.63 (1H, d, J = 8.7 Hz), 7.53 7.55 (2H, m), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 4.31 (2H, s), 3.73 (3H, s), 1.38 (9H, s)

2-Bromoacetyl-4-tert-butylpyridine was prepared from 2-acetyl-4-tert-butylpyridine (E. C. Constable et al., J. Am. Chem. Soc., 1997, 119, 5606) by the method described in Example 57 for the preparation of 2-bromoacetyl-4-ethylpyridine.

¹ H NMR (CDCl ₃ ): δ 8.58 (1H, d, J = 4.8 Hz), 8.11 (1H, d, J = 1.6 Hz), 7.51 (1H, dd, J = 1.8, 5.1 Hz), 4.86 (2H, s), 1.35 (9H, s)

- 269.• · · · ···· · • in · · · · · *· · · · ·· ···

Example 70 [2-(4-tert-Butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate (from Example 69).

MS (EI) m/z: 370 (M ⁺ )

Melting point 203 to 205°C

IR (KBr) v: 2966, 1699, 1647, 1591, 1535, 1229 cm ^{1 1} H NMR (DMSO-dg): δ 12.29 (1H, brs), 8.76 (1H, d, J = 5.3 Hz), 8.10 (1H, d, J = 2.0 Hz), 7.74 - 7.81 (3H, m), 7.12 (1H, dd, J = 1.8, 8.6 Hz), 4.08 (2H, s), 1.36 (9H, s)

Example 71

Methyl-[2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4-tert-butylpyridine (the preparation of which is described in Example 69).

¹ H NMR (CDCl ₃ ): δ 12.59 (1H, brs), 8.67 (1H, d, J = 5.3 Hz), 8.38 (1H, d, J = 2.0 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.54 (2H, dd, J = 2.0, 5.3 Hz), 7.45 (1H, d, J = 2.0 Hz). J = 8.9 Hz), 7.32 (1H, dd, J = 2.0, 8.9 Hz), 4.29 (2H, s), 3.74 (3H, s), 1.38 (9H, s)

Example 72 [2-(4-tert-Butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid « « # · · ·

- 27δ :

• · *♦

The title compound was prepared as described in Example 57 from methyl [2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate (from Example 71).

MS (EI) m/z: 370 (M ⁺ )

Melting point: 209 to 211 °C

IR (KBr) v: 3269, 2968, 1746, 1705, 1589, 1531, 1236, +207, 1177, 1150, 1059, 737 cm ¹ ^-H NMR (DMSO-d ₆ ): δ 12.3 3 (1H, brs), 8.76 (1H, d, J = 5.3 Hz), 8.10 (1H, d, J = 2.0 Hz), 7.86 (1H, d, J = 2.0 Hz),

7.78 (1H, dd, J = 2.0, 5.1 Hz), 7.69 (1H, d, J = 8.7 Hz),

7.33 (1H, dd, J = 2.0, 8.7 Hz), 4.08 (2H, s), 1.36 (9H, s)

Example 73

Methyl [6-chloro-2-(3-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-3-methylpyridine hydrobromide*.

¹ H NMR (CDCl ₃ ): δ 11.19 (1H, brs), 8.54 (1H, d, J = 4.6 Hz),

7.65 (1H, d, J = 7, ,7 Hz), 7 .55 (1H, d, J = 8.6 Hz), 7.33 - 7.38 (2H, m), 7.06 (1H, dd, J = 1.8, 8.7 Hz), 4.15 (2H, s), 3.69 (3H, s), 2.59 (3H, s)

2-Bromoacetyl-3-methylpyridine hydrobromide was prepared from 2-acetyl-3-methylpyridine (T. A. Carbb et al., Org. Magn. Reson., 1982, 20, 242) using the procedure described in step 2 of Example 31 for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide.

¹ H NMR (DMSO-dg): δ 8.56 (1H, d, J = 3.6 Hz), 7.84 (1H, d, J = 7.7 Hz), 7.56 - 7.60 (1H, m), 5.01 (2H, s), 4.01 (3H, s) ······ ·· · · · · · · 9 t Λ β « « «

Example 74 [6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 73).

MS (EI) m/z: 328 (M ⁺ )

Melting point: 195 to 196°C

IR (KBr) v: 3314, 1703, 1636, 1526, 1418, 1396, 1231, 1196, 1150, 1109 cm ^{1 X} H NMR (DMSO-d ₆ ): δ 12.14 (1H, brs), 11.76 (1H, brs), 8.53 (1H, d, J = 3.8 Hz), 7.85 (1H, d, J = 7.9 Hz), 7.74 (1H, d,

J = 8.6 Hz), 7.52 - 7.56 (2H, m), 7.10 (1H, dd, J = 1.8, 8.6 Hz), 3.66 (2H, s), 2.33 (3H, s)

Example 75

Methyl-[5-chloro-2-(3-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-3-methylpyridine hydrobromide (the preparation of which is described in Example 73).

^X H NMR (CDCl ₃ ): δ 11.28 (1H, brs), 8.56 (1H, d, J = 3.1 Hz), 7.61 - 7.69 (2H, m), 7.23 - 7.41 (3H, m), 4.15 (2H, s), 3.70 (3H, s), 2.61 (3H, s)

Example 76

15-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid * * ·

- 272.

The title compound was prepared by the method described in 58 from methyl [5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 75) and had a melting point of 209-211°C (dec.).

IR (KBr) v: 3379, 3271, 1728, 1649, 1638, 1528, 1231, 1195, 118è, 1165, 1015 cm ^{-1 1} H NMR (DMSO-dg): δ 11.81 (1H, brs), 8.53 (1H, d, J = 4.4 Hz), 7.85 (1H, d, J = 7.7 Hz), 7.80 (1H, d, J = 2.0 Hz),

7.49 - 7.56 (2H, m), 7.31 (1H, dd, J = 2.1, 8.7 Hz), 3.66 (2H, s), 2.33 (3H, s)

Example 77

Methyl [6-chloro-2-(6-methylpyridin-2-carbonyl)-1H-indol-3-yl] acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-6-methylpyridine hydrobromide (H. Erlenmeyer,

J. Jenni and B. Prijs, J. Med. Pharm. Chem., 1961, 3, 561-566).

¹ H NMR (CDC1 ₃ ): δ 12.58 (1H, brs), 8.15 (1H, d, J = 7.9 Hz), 7.83 (1H, t, J = 7.7 Hz), 7.62 (1H, d, J = 8.7 Hz), 7.51 (1H, d, J = 1.8 Hz), 7.40 (1H, d, J = 1.8 Hz) 7.7 Hz), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 4.31 (2H, s), 3.72 (3H, s), 2.76 (3H, s)

Example 78 [6-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 77).

- 273· — · ·

MS (EI) m/z: 328 (M ⁺ )

Melting point: 230 to 231°C

IR (KBr) v: 3273, 1697, 1643, 1535, 1308, 1227, 1183, 1150, 979, 760, 671 cm ^{1 1} H NMR (DMSO-dg): δ 12.06 (1H, brs), 7.99 (1H, d, J = 7.7 Hz), 7.87 (1H, d, J = 7.6 Hz), 7.78 (1H, d, J = 8.9 Hz),

7.74 (1H, d, J = 2.0 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.13 (1H, dd, J = 2.0, 8.7 Hz), 4.04 (2H, s), 2.69 (3H, s)

Example 79

Methyl-[5-chloro-2-(5-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-5-methylpyridine (the preparation of which is described in Step 1 of Example 32).

¹ H NMR (CDCl ₃ ): δ 12.48 (1H, brs), 8.59 (1H, d, J = 2.1 Hz), 8.24 (1H, d, J = 8.1 Hz), 7.75 (1H, dd, J = 2.1, 8.1 Hz), 7.67 (1H, d, J = 2.0 Hz), 7.44 (1H, d, J = 2.1, 8.1 Hz). J = 8.7 Hz), 7.31 (1H, dd, J = 2.0, 8.9 Hz), 4.29 (2H, s), 3.74 (3H, s), 2.48 (3H, s)

Example 80 [5-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 79).

MS (EI) m/z: 328 (M ⁺ )

Melting point: 247 to 248°C

IR (KBr) v: 3288, 1699, 1638, 1531, 1427, 1329, 1285, 1246, 1209, 1177, 1059, 1016, 800, 700 cm ^{_1 1} H NMR (DMSO-dg): δ 12.3O(1H, br)s, 12.15 (1H, brs), 8.68 (1H, brs), 8.04 (1H, d, J = 7.9 Hz), 7.93 (1H, brd, J = 8.9 Hz), 7.84 (1H, brs), 7.69 (1H, d, J = 8.9 Hz), 7.33 (1H, dd, J = 2.0, 8.9 Hz), 4.09 (2H, s), 2.46 (3H, s)

Example 81

Methyl-[6-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-5-(trifluoromethyl)pyridine*.

¹ H NMR (CDCl ₃ ): δ 11.97 (1H, brs, 9.07 (1H, brs), 8.48 (1H, d, J = 8.4 Hz), 8.23 (1H, dd, J = 2.1, 8.4 Hz), 7.63 (1H, d,

J = 8.6 Hz), 7.52 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J =

1.8, 8.6 Hz), 4.31 (2H, s), 3.74 (3H, s)

2-Bromoacetyl-5-(trifluoromethyl)pyridine was prepared from 2-chloro-5-(trifluoromethyl)pyridine using the procedure described in Step 1 of Example 32 for the preparation of 2-bromoacetyl-5-methylpyridine.

¹ H NMR (CDCl ₃ ): δ 8.96 (1H, brs), 8.23 (1H, brd, J = 8.2 Hz), 8.13 (1H, dd, J = 2.1, 8.1 Hz), 4.83 (2H, s)

Example 82 [6-Chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[6-chloro-2-[5-(trifluoromethyl)

275..-pyridine-2-carbonyl]-1H-indol-3-yl acetate (from Example 81).

MS (EI) m/z: 382 (M ⁺ )

Melting point: 228 to 229 °C

IR (KBr) at: 3325, 1707, 1636, 1529, 1333, 1310, 1138, 1078, 1020 cm ^{1 1} H NMR (DMSO-dg): δ 12.05 (1H, brs), 9.17 (1H, brs), 8.54 (1H, dd, J = 2.0, 8.4 Hz), 8.24 (1H, d, J = 8.2 Hz), 7.82 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 1.8 Hz), 7.14 (1H, dd, J = 2.0, 8.7 Hz), 4.06 (2H, s)

Example 83

Methyl-[5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 3 of Example 36) and 2-bromoacetyl-5-(trifluoromethyl)pyridine (the preparation of which is described in Example 81).

¹ H NMR (CDC1 ₃ ): δ 12.01 (1H, brs), 9.05 (1H, brs), 8.45 (1H, d, J = 8.2 Hz), 8.21 (1H, dd, J = 2.3, 8.4 Hz), 7.65 (1H, brs), 7.43 (1H, d, J = 8.7 Hz), 7.32 (1H, dd, J = 2.0, 8.7 Hz), 4.27 (2H, s), 3.76 (3H, s)

Example 84 [5-Chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Example 83).

MS (EI) m/z: 382 (M ⁺ )

276

Melting point: 230 to 231°C

IR (KBr) vz 3300, 1720, 1701, 1641, 1531, 1327, 1235, 1163, 1130, 1078, 1020, 864 cm ^{1 Σ} Η NMR (DMSO-dg): δ 12.09 (IH, brs), 9.17 (IH, brs), 8.54 (IH, dd, J = 2.0, 8.2 Hz), 8.23 (IH, d, J = 8.2 Hz), 7.89 (IH, d, J = 1.8 Hz), 7.62 (IH, d, J = 8.9 Hz), 7.36 (IH, dd, J = 1.8, 8.9 Hz), 4.06 (2H, s)

Example 85

Methyl [5-chloro-2-(5-chloropyridin-2-carbonyl)-1H-indol-3-yl] acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 3 of Example 36) and 2-bromoacetyl-5-chloropyridine*.

^τ Η NMR (CDC1 ₃ ): δ 12.01 (IH, brs), 8.72 (IH, d, J = 2.5 Hz), 8.29 (IH, d, J = 8.6 Hz), 7.93 (IH, dd, J = 2.5, 8.6 Hz),

7.65 (1H, d, J = 2.0 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.31 (1H, dd, J = 2.0, 8.7 Hz), 4.27 (2H, s), 3.75 (3H, s) *2-Bromoacetyl-5-chloropyridine is prepared from 2-bromo-5-chloropyridine (Case, J. Am. Chem., Soc., 1946, 68, 2574) by the procedure described in step 1 of Example 32 for the preparation of 2-bromoacetyl-5-methylpyridine.

NMR (CDCl ₃ ): δ 8.63 (IH, dd, J = 0.6, 2.5 Hz), 8.06 (IH, dd, J = 0.6, 8.4 Hz), 7.85 (IH, dd, J = 2.3, 8.4 Hz), 4.79 (2H, s)

Example 86 [5-Chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid

277\The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 85).

MS (EI) m/z: 348 (M ⁺ )

Melting point: 259 to 260 °C

IR (KBr) in: 3314. 1703. 1632. 1528. 1331. 1236. 1178. 1111

1059, 1015, 806, 698 cm ^{1 Τ} H NMR (DMSO -d ₆ ): δ 12.18 (1H, (1H, d, J = 2.5 Hz), 8.25 (1H, (1H, d, J = 8.6 Hz), 7.87 (1H, J = 8.7 Hz), 7.34 (1H, dd, J =

brs), 12.08 (1H, brs), 8.84 dd, J = 2.5, 8.4 Hz), 8.10 d, J = 2.0 Hz), 7.63 (1H, d, 2.1, 8.9 Hz), 4.06 (2H, s) d 8 7

Methyl-[6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-5-chloropyridine (the preparation of which is described in Example 85).

¹ H NMR (CDCl ₃ ): δ 11.98 (1H, brs), 8.74 (1H, dd, J = 0.7 and 2.3 Hz), 8.31 (1H, dd, J = 0.7, 8.6 Hz), 7.94 (1H, dd,

J = 2.3, 8.4 Hz), 7.63 (1H, d, J = 8.7 Hz), 7.52 (1H, d,

J = 1.6 Hz), 7.14 (1H, dd, J = 1.8, 8.7 Hz), 4.30 (2H, s), 3.73 (3H, s)

Example 88 [6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[6-chloro-2-(5-chloropyridine-

278,.-· *,. *..* ,·. » · * · · -2-carbonyl)-1H-indol-3-yl acetate (from example 87) . MS (E1) m/z: 348 (M ⁺ ) Melting point: 242 up to 244°C IR (KBr) at: 3306, 1703, 1636, 1529, 1307, 1234 , 1151, 1109, 698 cm" ^{1 1} H NMR (DMSO-d 6 ): δ 12.05 (1H, brs), 8.84 (1H, d, J = 2.3 Hz), 8.26 (1H, dd , J = 2.3, 8.4 Hz), 8.10 (1H, d, J = 8.4 Hz), 7.80 (1H, d, J = 8.7 Hz), 7.67 (1H,d, J = 1.8Hz) , 7,+3 (1H, dd, J = 1.8, 8.7 Hz), 4.06 (2H, s)

Example 89

Methyl [5-chloro-2-(4-chloropyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4-chloropyridine hydrobromide (the preparation of which is described in Example 33).

¹ H NMR (CDCl ₃ ): δ 12.20 (1H, brs), 8.67 (1H, d, J = 5.3 Hz), 8.33 (1H, d, J = 2.1 Hz), 7.66 (1H, d, J = 2.0 Hz),

7.56 (1H, dd, J = 2.1, 5.3 Hz), 7.43 (1H, d, J = 8.7 Hz),

7.32 (1H, dd, J = 2.0, 8.9 Hz), 4.27 (2H, s), 3.75 (3H, s)

Example 90 [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 89).

MS (EI) m/z: 458 (M ⁺ )

Melting point: 243 to 244°C

• « · · · • · - 27?.;-**.. • · · • · • · • 1 · · • · · • · · • · · · • · · · · IR (KBr) in: 3000, 1719, 1643, 1528, 1242, 1202 , 741 cm ^{-1 X} H NMR (DMSO-d 6 ): δ 12.20 (1H, brs), 8.80 (1H, d, J = 5.3 Hz), 8.12 (1H, d, J = 2.1 Hz), 7.90 (1H, dd, J = 2.1, 5.4 Hz), 7.66 (1H, d, J = 8.9 Hz), 7.34 (1H, dd, J = 2.0, 8.7 Hz), 4.06 (2H, s) Example 9 1

Methyl-[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 3-bromoacetylpyridine hydrobromide (G. B. Barlin, L. P. Davies, S. J. Ireland, M. M. L. Ngu, Aust. J. Chem., 1989, 42, 1735).

^T H NMR (CDCl ₃ ): δ 9.26 (1H, brs), 9.00 (1H, dd, J = 0.8, 2.1

Hz) , 8.80 (1H, dd, J = 1.6, 4.8 Hz) , 8, 10 (1H, dt , J = 2, 2.0, 7.9 Hz), 7.58 (1H, d, J = 8.7 Hz) , 7.47 (1H, ddd, J : 0.8, 4.9, 7.9 Hz) , 7.37 (1H, d, J = ^: 1.8 Hz), 7.16 (1H, dd = i, 8, 8.6 Hz) , 3, 84 (2H, s), 3.65 (3H, s) Example 9 2

[6-Chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate (from Example 91).

MS (EI) m/z: 314 (M ⁺ )

Melting point: 267 to 268°C

IR (KBr) v: 3346, 1705, 1609, 1566, 1528, 1433, 1418, 1327, 1267, 1215, 943, 761 cm" ^{1 1} H NMR (DMSO-dg): δ 12.28 (1H, brs), 11.86 (1H, brs), 8.90 (1H, brs), 8.85 (1H, brd, J = 4.9 Hz), 8.12 (1H, dt, J =

280

2.0, 2.0, 7.9 Hz), 7.77 (1H, t, J = 8.6 Hz), 7.62 (1H, dd, J = 4.9, 8.0 Hz), 7.49 (1H, d, J = 2.0 Hz), 7.15 (1H, dd, J = 1.6, 8.4 Hz), 3.85 (2H, s)

Example 93

Methyl-[6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 4-bromoacetylpyridine hydrobromide (L. W. Deady, M. S. Stanborough, Aust. J. Chem., 1981, 34, 1295).

^T H NMR (CDCl ₃ ): δ 9.21 (1H, brs), 8.82 - 8.79 (2H, m), 7.59 - 7.57 (2H, m), 7.56 (1H, d, J = 8.7 Hz), 7.33 (1H, d, J =

1.8 Hz), 7.16 (1H, dd, J = 1.8, 8.7 Hz), 3.80 (2H, s), 3.65 (3H, s)

Example 94 [6-Chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate (from Example 93).

MS (E1) m/z: 314 (M ⁺ ) Melting point: 256 up to 257°C IR (KBr) at: 3352, 1709, 1607, 1528, 1431, 1329, 1259, 1202, 772, 687 cm ^{1 1} H NMR (DMSO-d 6 ): δ 11.82 (1H, brs), 8.82 (2H, d, J = 5.8 Hz), 7.77 (1H, d, J = 8.6 Hz), 7.64 - 7.62 (2H, m), 7.48 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J = 2.0, 8.7 Hz), 3.83 (2H, s)

• · ·

Example 95

Methyl-[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

Step 1: Methyl-[6-chloro-2-[4-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine*. ¹ H NMR (CDCl ₃ ): δ 12.47 (1H, brs), 8.70 (1H, d, J = 4.9 Hz), 8.21 - 8.22 (1H, m), 7.55 - 7.58 (2H, m), 7.50 - 7.51 (1H, m), 7.10 (1H, dd, J = 1.8, 8.7 Hz), 4.83 (2H, s), 4.31 (2H, s), 3.72 (3H, s), 0.98 (9H, s), 0.15 (6H, s) *2-Bromoacetyl-4-(tert.butyldimethylsilyloxymethyl)pyridine is prepared as follows:

According to Example 33 for the preparation of 2-acetyl-4-chloropyridine, 2-acetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine is prepared from 4-(tert-butyldimethylsilyloxymethyl)pyridinecarbonitrile (A. Hadri et al., J. Heterocycl. Chem., 1993, 30, 631).

η NMR (CDCl ₃ ): δ 8.64 (1H, d, J = 4.8 Hz), 7.96 (1H, s), 7.50 (1H, d, J = 4.8 Hz), 4.80 (2H, s), 2.73 (3H, s), 0.96 (9H, s), 0.12 (6H, s)

To a solution of 2-acetyl-4-(tert-butyldimethylsilyoxymethyl)pyridine (1.84 g, 6.932 mmol) in tetrahydrofuran (50 mL) at -78°C was added dropwise a solution of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 8.3 m, 8.3 mmol). The resulting mixture was stirred for 1 hour, then chlorotriethylsilane (1.7 mL, 10.4 mmol) was added at -78°C. The reaction mixture was stirred for 1 hour.

- 282. stirred at this temperature, then allowed to warm to 0°C, stirred for 1 hour and saturated aqueous ammonium chloride (50 ml) was added thereto. The resulting mixture was extracted with diethyl ether (100 ml). The organic layer was washed with water (50 ml), dried over magnesium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (20 ml) and water (4 ml) and NBS were added to the tetrahydrofuran solution. The resulting mixture was stirred for 1 hour, diluted with diethyl ether (200 ml), washed with water (50 ml), dried over magnesium sulfate and the solvent was removed. The crude product was purified by flash column chromatography using a mixture of ethyl acetate and hexane in a ratio of 1 : 20 as eluent.

0.74 g (31%) of the title compound is obtained in the form of crystals.

^X H NMR (CDCl ₃ ): δ 8.63 (1H, d, J = 4.8 Hz), 8.02 (1H, g, J = 0.8 Hz), 7.53 (1H, dt, J = 0.8, 4.9 Hz), 4.87 (2H, s), 4.81 (2H, s), 0.96 (9H, s), 0.13 (3H, with)

Step 2: Methyl-[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

To a solution of methyl-[6-chloro-2-[4-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate (from step 1, 171.5 mg, 0.3625 mmol) in tetrahydrofuran (5 mL) at room temperature was added a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 0.54 mL, 0.54 mmol). The resulting mixture was stirred for 1 hour and then concentrated. The residue was diluted with ethyl acetate (100 mL), the ethyl acetate mixture was washed with water (20 mL x 2), dried over magnesium sulfate and the solvent was removed. The crude product was purified by flash column chromatography using a 1:1:1 mixture of ethyl acetate, hexane and dichloromethane as eluent. 696.6 mg (54%) of the title compound are obtained in the form of crystals.

¹ H NMR (CDCl ₃ ): δ 12.43 (1H, brs), 8.74 (1H, d, J = 5.1 Hz), 8.29 (1H, s), 7.59 - 7.64 (2H, m), 7.52 (1H, d, J = 1.5 Hz),

285

7.13 (IH, dd, J = 1.6, 8.6 Hz), 4.86 (2H, d, J = 5.1 Hz), 4.31 (2H, s), 3.73 (3H, s)

Example 96 [6-Chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Example 95).

MS (EI) m/z: 344 (M ⁺ )

Melting point: 210 to 212°C

IR (KBr) vz 3304, 1728, 1713, 1622, 1583, 1526, 1194 cm ^{1 1} H NMR (DMSO-d ₆ ): δ 12.31 (IH, brs), 8.78 (IH, d, J = 4.8 Hz), 8.08 (IH, s), 7.780 (IH, d, J = 8.6 Hz), 7.74 (IH, d, J = 1.8 Hz), 7.67 (IH, d, J = 4.9 Hz), 7.12 (IH, dd, J = 1.8, 8.7 Hz), 4.69 (2H, s), 4.09 (2H, s)

Example 97

Methyl-[5-chloro-2-[4-(hydroxymethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate

Step 1: Methyl-[5-chloro-2-[4-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine (the preparation of which is described in Step 1 of Example 95).

η NMR (CDC1 ₃ ): δ 12.47 (IH, brs), 8.66 (IH, d, J = 4.9 Hz), 8.18 (IH, s), 7.60 - 7.61 (IH, m), 7.54 - 7.57 (IH, m), 7.39

284 * « 0 · 0 · «« 0 0 0 (1H, d, J = 8.9 Hz), 7.25 (1H, dd, J = 2.0, 8.9 Hz), 4.82 (2H, S), 4.27 (2H, s), 3.74 (3H, s), 0.98 (9H, s), 0.14 (6H, s)

Step 2: Methyl-[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Step 2 of Example 95 from methyl [5-chloro-2-[4-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Step 1).

^H NMR (CDCl ₃ ): δ 12.48 (1H, brs), 8.75 (2H, d, J = 4.9 Hz), 8.31 (1H, s), 7.68 (1H, s), 7.60 - 7.62 (1H, m), 7.45 (1H, d, J = 8.9 Hz), 7.32 (1H, dd, J = 2.0, 8.9 Hz), 4.87 (2H, d,

J = 5.4 Hz), 4.28 (2H, s), 3.74 (3H, s)

Example 98 [5-Chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Example 97.

MS (EI) m/z: 344 (M ⁺ )

Melting point: 218 to 219°C

IR (KBr) v: 3263, 1705, 1641, 1595, 1528, 1327, 1198, 1061 cm ¹ H NMR (DMSO-dg): δ 12.34 (1H, brs), 8.77 (1H, d, J = 4.9 Hz), 8.08 (1H, s), 7.85 (1H, s), 7.66 - 7.71 (2H, m), 7.33 (1H, dd, J = 1.8, 8.9 Hz), 5.63 (1H, brs), 4.68 (2H, s), 4.09 (2H, s)

Example 99

Methyl-[5-chloro-2-(3,4-dimethylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

289

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-3,4-dimethylpyridine hydrobromide.

^τ Η NMR (CDCl ₃ ): δ 12.20 (1H, brs), 8.67 (1H, d, J = 5.3 Hz), 8.33 (1H, d, J = 2.1 Hz), 7.66 (1H, d, J = 2.0 Hz), 7.56 (1H, dd, J = 2.1, 5.3 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.32 (1H, dd, J = 2.0, 8.9 Hz), 4.27 (2H, s), 3.75 (3H, s) *2-Bromoacetyl-3,4-dimethylpyridine hydrobromide is prepared by the following procedure:

3,4-dimethylpyridine-2-carbonitrile

The method described in Example 33 for the preparation of 4-chloro-2-pyridinecarbonitrile from 3,4-dimethylpyridine-N-oxide (Abramovitch et al., J. Org. Chem., 1972, 37, 1690) gives the title compound containing 4,5-dimethylpyridine-2-carbonitrile in a ratio of 5.5:1.

2-Acetyl-3,4-dimethylpyridine

The title compound was prepared together with 2-acetyl-4-chloropyridine in Example 33 using the method described for the preparation of 2-acetyl-4-chloropyridine from 3,4-dimethylpyridine-2-carbonitrile containing 4,5-dimethylpyridine-2-carbonitrile in a ratio of 5.5:1.

2-acetyl-3,4-dimethylpyridine: 4 NMR (CDC1 ₃ ): δ 8.34 (1H, d, J = 4.6 Hz), 7.19 (1H, d, J = 4.8 Hz), 2.69 (3H, s), 2.43 (3H, s), 2.34 (3H, s)

2-acetyl-4,5-dimethylpyridine: ¹ H NMR (CDCl ₃ ): δ 8.39 (1H, s), 7.83 (1H, s), 2.70 (3H, s), 2.33 (3H, s), 2.32 (3H, s)

2-Bromoacetyl-3,4-dimethylpyridine hydrobromide ·« ···· ·· » ·· 4 * · · «··· ····

- 28th 4. *: ·: : :-:: : ·· ·« · · ·»· ·· «··

The title compound was prepared from 2-acetyl-3,4-dimethylpyridine by the method described in H. McKennis, Jr., L. B. Turnbull, E. R. Bowman and E. Tamaki (J. Org. Chem., 1963, 23, 383-387).

NMR (DMSO-dg): δ 8.39 (1H, d, J = 4.8 Hz), 7.46 (1H, d, J = 4.8 Hz), 4.96 (2H, s), 2.38 (3H, s), 2.35 (3H, s)

Example 100 [5-Chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 99).

MS (EI) m/z: 342 (M ⁺ )

Melting point: 236 to 237°C

IR (KBr) at: 3395, 1710, 1641, 1526, 1339, 1281, 1196, 1053, 1007 cm ^{1 1} H NMR (DMSO-dg): δ 11.76 (1H, brs), 8.37 (1H, d, J = 4.9 Hz), 7.79 (1H, d, J = 2.0 Hz), 7.48 (1H d, J = 8.7 Hz), 7.41 (1H, d, J = 4.9 Hz), 7.31 (1H, dd, J= 2.0, 8.7 Hz), 3.56 (2H, s), 2.35 (3H, s), 2.16 (3H, s)

Example 101

Methyl-[5-chloro-2-(4,5-dimethylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4,5-dimethylpyridine.

^H NMR (CDCl ₃ ): δ 12.59 (1H, brs) , 8.47 (1H, s), 8.12 (1H, s), 7.67 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 9.4 Hz), 7.30 • ti titititi titi · ti· * ti ti titititi tititi (1H, dd, J = 2.0, 8.7 Hz), 4.28 (2H, s), 3.73 (3H, s), 2.38 (6H, s) *2-Bromoacetyl-4,5-dimethylpyridine was prepared from 2-acetyl-4,5-diinethylpyridine (the preparation of which is described in Example 99) using the procedure of Example 57 for the preparation of 2-bromoacetyl-4-ethylpyridine.

¹ H NMR (CDCl ₃ ): δ 8.39 (1H, s), 7.87 (1H, s), 4.83 (2H, s), 2.35 (3H, s), 2.34 (3H, s)

Example 102 [5-Chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 101). MS (EI) m/z: 342 (M ⁺ )

Melting point: 245 to 246 °C

IR (KBr) in: 3281, 1697, 1638, 1589, 1535, 1254, 1232,

1188, 1060, 802 cm" ^{1 1} H NMR (DMSO-dg): δ 12.34 (1H, brs), 12.15 (1H, brs), 8.57 (1H, s), 7.93 (1H, s), 7.84 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 8.7 Hz), 7.32 (1H, dd, J = 2.0, 8.7 Hz), 4.09 (2H, s), 2.39 (3H, s), 2.38 (3H, s)

Example 103

Methyl [6-chloro-2-(4,5-dimethylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonyl)aminocinnamate (from Step 1 of Example 8, Method A) and 2-28-fe-bromoacetyl-4,5-dimethylpyridine (the preparation of which is described in Example 99).

¹ H NMR (CDCl ₃ ): δ 12.55 (1H, brs), 8.47 (1H, s), 8.12 (1H, s), 7.62 (1H, d, J = 8.6 Hz), 7.52 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.6 Hz), 4.31 (2H, s), 3.72 (3H, s), 2.39 (6H, s)

Example 104 [6-Chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 103). MS (EI) m/z: 342 (M ⁺ )

Melting point: 226 to 228°C

IR (KBr) v: 3275, 1697, 1638, 1537, 1258, 1188, 799 cm ^{1 1} H NMR (DMSO-dg): δ 12.30 (1H, brs), 8.57 (1H, s), 7.94 (1H, s), 7.78 (1H, d, J = 8.7 Hz), 7.74 (1H, d, J = 1.8 Hz) , 7.11 (1H, dd, J = 2.0, 8.6 Hz), 4.09 (2H, s), 2.39 (3H, s), 2.38 (3H, s)

Example 105

Methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-4-methoxypyridine hydrobromide*.

^Τ Η NMR (CDC1 ₃ ): δ 12.61 (1H, brs), 8.57 (1H, d, J = 5.9 Hz) 7.89 (1H, d, J = 2.6 Hz), 7.63 (1H, d, J = 8.6 Hz), 7.52 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 1.8 Hz) 1.8, 8.7 Hz), 7.04

4 · · · ·

4 4

- 28a·- ¹ ..

• 4 4 4» (1H, dd, J = 2.6, 5.8 Hz), 4.30 (2H, s), 3.96 (3H, s), 3.73 (3H, s) •jlp

2-Bromoacetyl-4-methoxypyridine hydrobromide is prepared from 2-acetyl-4-methoxypyridine (B. Čase et al., J. ORg. Chem., 1961, 26, 4415) by the method described in step 2 of Example 31 for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide.

¹ H NMR (DMSO-dg): δ 8.59 - 8.62 (1H, m), 7.63 - 7.65 (1H, m), 7.33 - 7.37 (1H, m), 5.03 (2H, s), 3.96 (3H, s)

Example 106 [6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared according to the method described in Example 58 from methyl [6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 105).

MS (EI) m/z: 344 (M ⁺ )

Melting point: 213°C (decomposition)

IR (KBr) v: 3200, 1709, 1645, 1589, 1533, 1225, 1207 cm ^-1 NMR (DMSO-dg): δ 12.35 (1H, brs), 12.18 (1H, brs), 8.66 (1H, d, J = 5.6 Hz), 7.80 (1H, d, J = 5.6 Hz) 8.9 Hz), 7.74 (1H, d,

J = 1.8 Hz), 7.63 (1H, d, J = 2.6 Hz), 7.31 (1H, dd, J =

2.9, 5.1 Hz), 7.12 (1H, dd, J = 1.3, 8.7 Hz), 4.09 (2H,s ), 3.96 (3H, s)

Example 107

Methyl [5-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and hydrobromide.

2-bromoacetyl-4-methoxypyridine (the preparation of which is described in Example 105).

¹ H NMR (CDCl ₃ ): δ 12.65 (1H, brs), 8.57 (1H, d, J = 5.8 Hz), 7.88 (1H, d, J = 2.5 Hz), 7.68 (1H, d, J = 2.0 Hz), 7.45 (1H, dd, J = 0.5, 8.7 Hz), 7.32 (1H, dd, J = 1.8, 8.7 Hz), 7.05 (1H, dd, J = 2.8, 5.8 Hz), 4.28 (2H, s), 3.96 (3H, s), 3.75 (3H, s)

Example 108 [5-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 107) and had a melting point of 228°C (dec.).

IR (KBr) at: 3230, 1707, 1647, 1595, 1566, 1533, 1477, 1331, 1300, 1219, 1180, 1038, 1013 cm" ¹

-'-Η NMR (DMSO-dg): δ 12.39 (1H, brs) , 12.16 (1H, brs) , 8.66 (1H, d, J = 5.8 Hz), 7.86 (1H, d, J = 1.5 Hz), 7.70 (1H, d,

J = 8.7 Hz), 7.63 (1H, d, J = 2.5 Hz), 7.29 - 7.35 (2H, m), 4.09 (2H, s), 3.96 (3H, s)

Example 109

Methyl [6-chloro-2-(3,5-dimethylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-3,5-dimethylpyridine hydrobromide.

¹ H NMR (CDCl ₃ ): δ 11.43 (1H, brs), 8.43 (1H, s), 7.60 (1H, d, J = 8.7 Hz), 7.51 (1H, s), 7.45 (1H, d, J = 1.8 Hz), 7.12

- 291 • <

(1H, dd, J = 1.8, 8.7 Hz), 4.22 (2H, s), 3.69 (3H, s), δ.62 (3H, s), 2.43 (3H, s)

2-Bromoacetyl-3,5-dimethylpyridine hydrobromide is prepared as follows:

2-Acetyl-3,5-dimethylpyridine

The title compound was prepared from 3,5-dimethylpyridinecarbonitrile (K. Takahashi et al., J. Heterocycl. Chem., 1978, 15, 893) using the method described in Example 33 for the preparation of 2-acetyl-4-chloropyridine.

¹ H NMR (CDCl ₃ ): δ 8.32 (1H, s), 7.37 (1H, s), 2.69 (3H, s), 2.56 (3H, s), 2.36 (3H, s)

2-Bromoacetyl-3,5-dimethylpyridine hydrobromide

The title compound was prepared from 2-acetyl-3,5-dimethylpyridine by the method described in H. McKennis, Jr., L. B. Turnbull, E. R. Bowman and E. Tamaki, J. Org. Chem., 1963, 23, 383-387.

¹ H NMR (DMSO-d ₆ ): δ 8.43 (1H, s), 7.69 (1H, s), 5.00 (2H, s), 2.52 (3H, s), 2.39 (3H, s)

Example 110 [6-Chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 57 from methyl [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 109).

MS (EI) m/z: 342 (M ⁺ )

Melting point: 199 to 200°C

IR (KBr) at: 3279, 1705, 1639, 1526, 1238, 1177, 827, 797 cm"

- 292 • · · · ¹ H NMR (DMSO-d ₆ ): δ 12.12 (1H, brs), 11.72 (1H, brs), 8.38 (1H, s), 7.74 (1H, d, J = 8.6 Hz), 7.68 (1H, s), 7.52 (1H, d, J = 2.0 Hz), 7.10 (1H, dd, J = 1.8, 8.6 Hz), 3.72 (2H, s), 2.38 (3H, s), 2.33 (3H, s)

Example 111

Methyl-[5-chloro-2-(4-ethyl-3-fluoropyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4-ethyl-3-fluoropyridine*.

¹ H NMR (CDCl ₃ ): δ 11.29 (1H, brs), 8.45 (1H, d, J = 4.8 Hz),

7.64 (1H, d, J = 1.8 Hz) , 7.44 (1H, t, J = 4.8 Hz), 7.38 (1H, d, J = 8.9 Hz) , 7.29 (1H, dd, J = 2.0, 8.7Hz) , 4.21 (2H, s), 3.72 (3H, s; >, 2, 81 (2H, q, J = 7.6 Hz), 1, 31 (3H, t, J = 7.6 Hz)

2-Bromoacetyl-4-ethyl-3-fluoropyridine is prepared by the following procedure:

4-Ethyl-3-fluoropyridine-N-oxide

A mixture of 4-ethyl-3-fluoropyridine (R. P. Dikinson et al., Bioorg. Med. Chem. Lett., 1996, 6, 2031, 28.51 g,

205.9 mmol) and 30% hydrogen peroxide (30 mL) in acetic acid (300 mL) were heated to reflux for 3 h, then cooled to room temperature. The resulting mixture was concentrated. The residue was diluted with dichloromethane (300 mL), the resulting mixture was dried over magnesium sulfate, and the solvent was removed. 32.30 g (100%) of the title compound was obtained as an oil. ¹ H NMR (DMSO-dg): δ 8.43 - 8.46 (1H, m), 8.08 (1H, d, J = 6.1 Hz), 7.38 (1H, dd, J = 6.6, 9.7 Hz), 2.61 (2H, q, J =

7.6 Hz), 1.17 (3H, t, J = 7.6 Hz)

4-Ethyl-3-fluoro-2-pyridinecarbonitrile

The title compound was prepared from 4-ethyl-3-fluoropyridine-N-oxide by the method described in Example 33 for the preparation of 4-chloro-2-pyridinecarbonitrile.

^Χ Η NMR (CDC1 ₃ ): δ 8.42 (1H, d, J = 4.8 Hz), 7.43 (1H, t, J = 5.1 Hz), 2.78 (2H, q, J = 7.6 Hz), 1.30 (3H, t, J = 7.6 Hz)

2-Acetyl-4-ethyl-3-fluoropyridine

The title compound was prepared from 4-ethyl-3-fluoro-2-pyridinecarbonitrile by the method described in Example 33 for the preparation of 2-acetyl-4-chloropyridine.

¹ H NMR (CDCl ₃ ): δ 8.376 (1H, d, J = 4.6 Hz), 7.36 (1H, t, J = 4.8 Hz), 2.76 (2H, q, J = 7.6 Hz), 2.71 (3H, s), 1.28 (3H, t, J = 7.6 Hz)

2-Bromoacetyl-4-ethyl-3-fluoropyridine

The title compound was prepared from 2-acetyl-4-ethyl-3-fluoropyridine by the method described in Example 57 for the preparation of 2-bromoacetyl-4-ethylpyridine.

^T H NMR (CDCl ₃ ): δ 8.38 (1H, d, J = 4.6 Hz), 7.43 (1H, d, J =

4.6 Hz), 4.75 (2H, s), 2.78 (2H, q, J = 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz)

Example 112 [5-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

A stirred solution of methyl-[5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 111, 391.2 mg, 1.044 mmol) in acetic acid (12 mL) and 2M aqueous acetic acid (12 mL) and 2M aqueous hydrochloric acid • · *

- 29¾ ϊ• · · « (4 ml) was heated to reflux for 24 hours, then cooled to room temperature and concentrated. The residue was diluted with tetrahydrofuran (100 ml), the tetrahydrofuran mixture was dried over magnesium sulfate and concentrated. The crude product was purified by recrystallization. 349.2 mg (93%) of the title compound was obtained.

MS (EI) m/z: 361 (M ⁺ )

Melting point: 208°C

IR (KBr) v: 3217, 1720, 1632, 1516, 1429, 1234, 1180, 1057 cm ¹ H NMR (DMSO-d ₆ ): δ 11.78 (1H, brs), 8.35 (1H, d, J = 4.8

Hz) , 7.73 (1H, d, J = 2.0 Hz) , 7.56 (1H, t, J = 5.1 Hz), 7.39 (1H, d, J = 8.9 Hz), 7.22 (1H, dd, J = 2.0, 8.9 Hz), 3.65 (2H, s), 2.65 (2H, q , J = 7.6 Hz), 1.14 (3H, t, J = 7.6 Hz)

Example 113

Methyl-[6-chloro-2-(4-ethyl-3-fluoropyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A).

^H NMR (CDCl ₃ ): δ 11.23 (1H, brs), 8.46 (1H, d, J = 4.8 Hz), 7.60 (1H, d, J = 9.2 Hz), 7.42 - 7.46 (2H, m), 7.10 - 7.14 (1H, m), 4.23 (2H, s), 3.71 (3H, s), 2.81 (2H, q, J = 7.7 Hz), 1.31 (3H, t, J = 7.7 Hz)

Example 114 [6-Chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[6-chloro-2-(4-ethyl-3-fluoro-29-5.-..

pyridine-2-carbonyl)-1H-indol-3-yl]acetate and has a melting point of 165°C.

IR (KBr) v: 3300, 2974, 1705, 1645, 1529, 1339, 1178 cm ^{1 1} H NMR (DMSO-dg): δ 11.65 (IH, brs), 8.32 (IH, d, J = 4.6 Hz), 7.73 (IH, d, J = 8.9 Hz), 7.47 -7.52 (2H, m), 7.10 (IH, dd, J = 1.8, 8.6 Hz), 3.89 (2H, q, J = 6.9 Hz), 3.70 (2H, s), 2.72 (2H, q, J = 7.6 Hz), 1.13 - 1.26 (6H, m)

Example 115

Methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide*.

¹ H NMR (CDC1 ₃ ): δ 10.05 (IH, brs), 8.47 (IH, d, J = 4.9 Hz), 7.53 (IH, d, J = 8.7 Hz), 7.32 - 7.34 (2H, m), 7.05 (IH, dd, J = 1.8, 8.7 Hz), 3.79 (2H, s), 3.61 (3H, s), 2.83 (2H, q, J = 7.6 Hz), 1.28 (3H, t, J = 7.6 Hz)

2-Bromoacetyl-3-chloro-4-ethylpyridine hydrobromide is prepared as follows:

3-Chloro-4-ethylpyridine-N-oxide

The title compound was prepared from 3-chloro-4-ethylpyridine (F. Marsais et al., J. Organomet. Chem., 1981, 216, 139) by the method described in Example 111 for the preparation of

4-ethyl-3-fluoropyridine-N-oxide.

¹ H NMR (DMSO-dg): δ 8.46 (IH, d, J = 1.8 Hz), 8.16 (IH, d, J = 6.6 Hz), 7.40 (IH, dd, J = 1.8, 6.6 Hz), 2.67 (2H, q, J =

7.6 Hz), 1.14 - 1.19 (3H, m)

- $29.

3-Chloro-4-ethyl-2-pyridinecarbonitrile

The title compound was prepared from 3-chloro-4-ethylpyridine-N-oxide following the procedure described in Example 33 for the preparation of 4-chloro-2-pyridinecarbonitrile.

¹ H NMR (CDCl ₃ ): δ 8.50 (1H, d, J = 4.9 Hz), 7.41 (1H, t, J = 4.9 Hz), 2.84 (2H, q, J = 7.4 Hz), 1.30 (3H, t, J = 7.6 Hz)

2-Acetyl-3-chloro-4-ethylpyridine

The title compound was prepared from 3-chloro-4-ethyl-2-pyridinecarbonitrile by the method described in Example 33 for the preparation of 2-acetyl-4-chloropyridine.

¹ H NMR (CDCl ₃ ): δ 8.41 (1H, d, J = 4.8 Hz), 7.29 (1H, d, J = 4.8 Hz), 2.83 (2H, q, J = 7.6 Hz), 2.67 (3H, s), 1.27 (3H, t, J = 7.6 Hz)

2-Bromoacetyl-3-chloro-4-ethylpyridine hydrobromide

The title compound was prepared from 2-acetyl-3-chloro-4-ethylpyridine by the method described in step 2 of Example 31 for the preparation of 2-bromo-4-methylpyridine hydrobromide. ¹ H NMR (DMSO-d 6 ): δ 8.55 (1H, d, J = 4.9 Hz), 7.66 (1H, d, J = 4.8 Hz), 4.93 (2H, s), 2.82 (2H, q, J = 7.3 Hz), 1.21 (3H, t, J = 7.4 Hz)

Example 116 [6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 115) and had a melting point of 158°C.

297

IR (KBr) v. 3335, 1730, 1630, 1529, 1325, 1200 cm ^-x 'ή NMR (DMSO-dg): δ 11.83 (1H, brs), 8.54 (1H, d, J = 4.8 Hz), 7.75 (1H, d, J = 8.7 Hz), 7.63 (1H, d, J = 4.9 Hz), 7.46 (1H, s), 7.12 (1H, dd, J = 1.8, 8.7 Hz), 3.57 (2H, s), 2.82 (2H, q, J = 7.4 Hz), 1.25 (3H, t, J = 7.4 Hz)

Example 117

Methyl [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide (the preparation of which is described in Example 115).

^H NMR (CDCl ₃ ): δ 9.87 (1H, brs), 8.50 (1H, d, J = 4.9 Hz), 7.64 (1H, s), 7.29 - 7.40 (3H, m), 3.86 (2H, s), 3.63 (3H, s), 2.88 (2H, q, J = 7.6 Hz), 1.32 (3H, t, J = 7.6 Hz)

Example 118 [5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 117) and had a melting point of 220°C.

IR (KBr) v: 3341, 1695, 1626, 1533, 1458, 1429, 1229 cm ^{-1 1} H NMR (DMSO-dg): δ 11.88 (1H, brs), 8.54 (1H, d, J = 4.9 Hz), 7.82 (1H, s), 7.63 (1H, d, J = 4.9 Hz), 7.46 (1H, d, J = 8.9 Hz), 7.34 (1H, dd, J = 2.0, 8.9 Hz), 3.60 (2H, s),

2.82 (2H, q, J = 7.4 Hz), 1.25 (3H, t, J = 7.4 Hz) • · ·· · · ··

- 29W

Example 119

Methyl-[5-chloro-2-(4,6-dimethylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4,6-dimethylpyridine.

¹ H NMR (CDCl ₃ ): δ 12.73 (1H, brs), 7.98 (1H, s), 7.67 (1H, brs), 7.42 (1H, d, J = 8.9 Hz), 7.30 (1H, dd, J = 1.8 and 8.7 Hz), 7.22 (1H, s), 4.27 (2H, s). 3.73 (3H, s), 2.70 (3H, s), 2.43 (3H, S) ifc X

2-Bromoacetyl-3,4-dimethylpyridine was prepared from 2-acetyl-4,6-dimethylpyridine (Sundberg et al., J. Am. Chem. Soc., 1969, 91, 658) by the method described in Example 57 for the preparation of 2-bromoacetyl-4-ethylpyridine.

¹ H NMR (CDCl ₃ ): δ 7.72 (1H, s), 7.19 (1H, s), 5.13 (2H, s), 2.55 (3H, s), 2.38 (3H, s)

Example 120 [5-Chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 119).

MS (EI) m/z: 342 (M ⁺ )

Melting point: 233 to 235°C

IR (KBr) v: 3288, 2919, 1742, 1630, 1599, 1529, 1333, 1232, 1180, 1067, 772 cm ^{-1 Χ} Η NMR (DMSO-d ₆ ): δ 11.99 (1H, brs), 7.69 (1H, s), 7.57 (1H, s), 7.52 (1H, d, J = 8.9 Hz), 7.28 (1H, s), 7.18 (1H, dd,

J = 2.1, 8.9 Hz), 3.87 (2H, s), 2.49 (3H, s), 2.27 (3H, s)

Example 121

Methyl-[6-chloro-2-(4,6-dimethylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-4,6-dimethylpyridine (the preparation of which is described in Example 119).

1 H NMR (CDCl ₃ ): δ 12.69 (1H, brs), 7.98 (1H, s), 7.62 (1H,

d, J = 8 ,7 Hz), 7.50 (1H, d, J = 0.7 Hz), 7.22 (1H, s), 7.12 (1H, dd, J = 1.6, 8.6 Hz), 4.30 (2H, s), 3.72 (3H, s), 2.70 (3H, s) , 2 .43 (3H, s)

Example 122 [6-Chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 121). MS (EI) m/z: 342 (M ⁺ )

Melting point: 219 to 220°C

IR (KBr) v: 3300, 1701, 1639, 1603, 1535, 1225, 1180 cm ^{1 1} H NMR (DMSO-dg): δ 11.95 (1H, brs), 7.62 (1H, d, J = 8.7 Hz), 7.58 (1H, d, J = 1.3 Hz), 7.56 (1H, s), 7.27 (1H, s), 6.96 (1H, dd, J = 2.0, 8.7 Hz), 3.87 (2H, s), 2.49 (3H, s),

2.26 (3H, s)

Example 123

Methyl-[5,6-dichloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Stage 1: Methyl-trans-4,5-dichloro-2-nitrocinnamate

The title compound was prepared as described in step 1 of Example 36 from 4,5-dichloro-2-nitrobenzaldehyde (J. Keneth et al, J. Med. Chem., 1968, 11, 946). ¹ H NMR (CDCl ₃ ): δ 8.20 (1H, s), 8.04 (1H, d, J = 15.8 Hz), 7.72 (1H, s), 6.36 (1H, d, J = 15.8 Hz)

Stage 2: Methyl trans-2-amino-4,5-dichlorocinnamate

The title compound was prepared as described in step 2 of Example 36 from methyl trans-4,5-dichloro-2-nitrocinnamate (from step 1) ^T H NMR (CDCl ₃ ): δ 7.65 (1H, d, J = 15.8 Hz), 7.42 (1H, s),

7.26 (1H, s), 6.81 (1H, s), 6.28 (1H, d, J = 15.8 Hz)

Step 3: Methyl trans-4,5-dichloro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-amino-4,5-dichlorocinnamate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 7.80 - 7.70 (2H, m), 7.60 - 7.40 (6H, m), 7.02 (1H, brs), 6.13 (1H, d, J = 16.1 Hz), 3.79 (3H, s)

Step 4: Methyl-[(5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4,5-dichloro-2-(phenylsulfonylamino)cinnamate (from Step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (the preparation of which is described in Step 2 of Example 31).

¹ H NMR (DMSO-dg): δ 12.45 (1H, brs) , 8.69 (1H, d, J = 5.1

Hz), 8.14 (1H, s), 8.00 - 7.93 (2H, m), 7.59 (1H, d, J = 4.3 Hz), 4.16 (2H, s), 3.59 (3H, s), 3.32 (3H, s)

Example 124 [5,6-Dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 123) and had a melting point of 220-224°C.

¹ H NMR (DMSO-d ₆ ; ): δ 12.41 (1H, s), 12.20 (lh, brs), 8.69 (1H, d, J = 5.1 Hz) , 8.11 (1H, s), 7.96 - 7.58 (2H, m) , 7.58 (1H, d, J = 4.8 Hz) , 4.08 (2H, s), 2.47 (3H, s) P r i k 1 and d 12 5

Methyl-[5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl acetate

Stage 1: Methyl-trans-2-amino-5-methylcinnamate

The title compound was prepared as described in Step 2 of Example 36 from methyl trans-5-methyl-2-nitrocinnamate (C. Venkatasubban, J. Annamalai Univ.,

1933, 2, 227).

¹ H NMR (CDCl ₃ ): & 7.82 (1H, d, J = 15.8 Hz), 7.20 - 7.19 (1H, m), 7.01 - 6.98 (1H, m), 6.63 (1H, d, J = 8.2 Hz), 6.35 (1H, d, J = 15.8 Hz), 3.83 (2H, m), 3.80 (3H, s), 2.24 (3H, s)

Step 2: Methyl trans-5-methyl-2-(phenylsulfonylamino)cinnamate

- 302-.7--..

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-2-amino-5-methylcinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.70 - 7.67 (2H, m), 7.55 - 7.38 (4H, m),

7.26 - 7.14 (3H, m), 6.55 (1H, brs), 6.14 (1H, d, J = 16.0 Hz), 3.77 (3H, s), 2.33 (3H, s)

Step 3: Methyl-[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-methyl-2-(phenylsulfonylamino)cinnamate (from Step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (the preparation of which is described in Step 2 of Example 31).

^•H NMR (CDCl ₃ ): δ 12.3 2 (1H, brs), 8.61 (1H, d, J = 5.0 Hz), 8.17 (1H, s), 7.46 (1H, s), 7.40 (1H, d, J = 8.6 Hz), 7.33 - 7.32 (1H, m), 7.22 - 7.19 (1H,m ), 4.31 (2H,s), 3.72 (3H,s), 2.46 (6H,m)

Example 126 [5-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 125) and had a melting point of 220-226°C.

IR (KBr) v: 3736, 3649, 1697, 1533, 1507, 1398, 1194, 802 cm ¹ H NMR (DMSO-d ₆ ): δ 12.08 (1H, brs), 8.69 (1H, d, J = 4.8 Hz), 7.94 (1H, Ξ), 7.56 - 7.49 (3H, m), 7.17 (1H, dd, J =

8.4 Hz), 4.05 (2H, ε), 2.46 (3H, s), 2.40 (3H, s)

4 44·« ·» • · 4 4 4 4

- 303..- ⁴

Example 127

Methyl-[5-fluoro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Stage 1: Methyl-trans-5-fluoro-2-nitrocinnamate

The title compound was prepared as described in Step 1 of Example 36 from 5-fluoro-2-nitrobenzaldehyde.

¹ H NMR (CDCl ₃ ): δ 8.17 - 8.10 (2H, m), 7.32 - 7.19 (2H, m), 6.36 (1H, d, J = 15.8 Hz), 3.84 (3H, s)

Stage 2: Methyl-trans-5-fluoro-2-aminocinnamate

The title compound was prepared as described in Step 2 of Example 36 from methyl trans-5-fluoro-2-nitrocinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.77 (1H, dd, J = 15.8, 1.5 Hz), 7.10 7.06 (1H, m), 6.94 - 6.87 (1H, m), 6.68 - 6.63 (1H, m), 6.33 (1H, d, J = 15.8 Hz), 3.85 (2H, m), 3.81 (3H, s)

Step 3: Methyl trans-5-fluoro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl trans-5-fluoro-2-aminocinnamate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 7.68 - 7.65 (2H, m), 7.55 - 7.49 (2H, m), 7.44 - 7.33 (3H, m), 7.18 - 7.13 (1H, m), 7.10 - 7.04 (1H, m), 6.10 (1H, d, J = 15.8 Hz), 3.78 (3H, s)

Step 4: Methyl-[5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate » » · · · · • · ·

- 304·- ··

The title compound was prepared as described in Example 57 from methyl trans-5-fluoro-2-(phenylsulfonylamino)cinnamate (from Step 3).

1 H NMR (CDCl ₃ ): δ 12.46 (1H, brs), 8.58 - 8.56 (1H, m), 8.12 (1H, s), 7.43 - 7.39 (1H, m), 7.33 - 7.26 (2H, m), 7.14 7.06 (1H, m), 4.26 (2H, s), 3.74 (3H, s), 2.45 (3H, s)

Example 128 [5-Fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 127) and had a melting point of 223°C (dec.).

IR (KBr) v: 1705, 1643, 1570, 1277, 1227, 1204, 1186 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 12.28 (1H, brs), 8.70 (1H, d, J = 4.9 Hz), 7.95 (1H, s), 7.71 - 7.66 (1H, m), 7.58 - 7.52 (2H, m), 7.25 - 7.17 (1H, m), 7.25 - 7.17 (1H, m ), 4.06 (2H, s), 2.47 (3H, s)

Example 129

Methyl-[5-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Stage 1: Methyl-trans-5-methoxy-2-nitrocinnamate

The title compound was prepared as described in Step 1 of Example 36 from 5-methoxy-2-nitrobenzaldehyde.

^Τ Η NMR (CDC1 ₃ ): δ 8.21 (1H, d, J = 15.8 Hz), 8.16 - 8.12 (1H, m), 7.00 - 6.96 (2H, m), 6.30 (1H, d, J = 15.8 Hz),

3.93 (3H, s), 3.83 (3H, s)

- 305.^-··..·

Stage 2: Methyl-trans-5-methoxy-2-aminocinnamate

The title compound was prepared as described in Step 2 of Example 36 from methyl trans-5-methoxy-2-nitrocinnamate (from Step 1).

¹ H NMR (CDC1 ₃ ): δ 7.83 (1H, d, J = 15.8 Hz), 6.92 - 6.91 (1H, m), 6.82 (1H, dd, J = 8.7, 2.8 Hz), 6.66 (1H, d, J = 8.7 Hz), 6.35 (1H, d, J = 15.8 Hz), 3.80 (3H, s), 3.76 (3H, s)

Step 3: Methyl trans-5-methoxy-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl trans-5-methoxy-2-aminocinnamate (from Step 2).

^Τ Η NMR (CDC1 ₃ ): δ 7.67 - 7.64 (2H, m), 7.54 - 7.37 (4H, m), 7.24 (1H, d, J = 8.7 Hz), 6.95 (1H, d, J = 2.8 Hz), 6.89 (1, dd, J = 8.7, 2.8 Hz), 6.82 (1H,brs), 6.10(1H, d, J = 15.8 Hz), 3.81 (3H, s), 3.77 (3H, s)

Step 4: Methyl-[5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-methoxy-2-(phenylsulfonylamino)cinnamate (from Step 3).

^H NMR (CDCl ₃ ): δ 12.38 (1H, brs), 8.61 (1H, d, J = 4.9 Hz), 8.17 (1H, s), 7.40 (1H, d, J = 8.7 Hz), 7.34 - 7.32 (1H, m), 7.08 - 7.03 (2H, m), 4.31 (2H, s), 3.88 (3H, s), 3.73 (3H, s), 2.47 (3H, s)

Example 130 [5-Methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

306 ······ ·* · ·· • · · · · · ·

The title compound was prepared as described in Example 58 from methyl [5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 129) and had a melting point of 235°C (dec.).

IR (KBr) at: 1701, 1638, 1595, 1528, 1448, 1423, 1340, 1279, 1263, 1234, 1223, 1192, 1111 cm ^{-1 1} H NMR (DMSO-d 6 ): δ 12, 11 (1H, brs) , 8.69 (1H, d, J = 4.9 Hz), 7.95 (1H, s) , 7.58 - 7.55 (2H, m) , 7 ,18 (1H, m), 7.02

6.98 (1H, m), 4.07 (2H, s), 3.79 (3H, s), 2.46 (3H, s)

Example 131

Methyl-[6-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Step 1: Methyl trans-(4-methoxy-2-nitro)cinnamate

A mixture of 4-bromo-3-nitroanisole (4.177 g, 18.0 mmol), methyl acrylate (3.24 mL, 36.0 mL), palladium acetate (606.1 mg, 2.7 mmol), triphenylphosphine (1.416 g, 5.4 mmol), triethylamine (3.76 mL, 27.0 mmol) in dimethylformamide (45.0 mL) was stirred at 130°C for 4 h, cooled to ambient temperature and concentrated. Water (30 mL) was added to the residue and the aqueous mixture was extracted with a 3:1 mixture of ethyl acetate and toluene (40 mL). The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over magnesium sulfate and concentrated to give 6.42 g (quant.) of the title compound as a brown oil.

^Χ Η NMR (CDC1 ₃ ): δ 8.07 - 6.97 (4H, m) , 6.31 (1H, d, J = 15.8 Hz), 3.90 (3H, s), 3.82 (3H, s)

Stage 2: Methyl-trans-2-amino-4-methoxycinnamate

The title compound was prepared as described in step 2 of Example 36 from methyl-trans-(4-methoxy307

-2-nitro)cinnamate (from step 1).

¹ H NMR (CDCl ₃ ): δ 7.80 - 6.21 (5H, m), 4.03 (2H, brs), 3.79 (6H, s)

Step 3: Methyl trans-4-methoxy-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-4-methoxy-2-aminocinnamate (from Step 2).

^X H NMR (CDCl ₃ ): δ 7.62 - 6.73 (9H, m), 6.07 (1H, d, J = 15.8 Hz), 3.80 (3H, s), 3.77 (3H, s), 2.37 (3H, s)

Step 4: Methyl-[6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-methoxy-2-(p-toluenesulfonylamino)cinnamate (from Step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (the preparation of which is described in Step 2 of Example 31).

¹ H NMR (CDCl ₃ ): δ 12.32 (1H, brs), 8.61 (1H, d, J = 4.94 Hz), 8.19 - 7.55 (2H, m), 7.34 - 6.82 (3H, m), 4.31 (2H, s), 3.89 (3H, s), 3.72 (3H, s), 2.47 (3H, s)

Example 132 [6-Methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 131) and had a melting point of 204°C.

IR (KBr) in: 3198, 1709, 1630, 1593, 1531, 1460, 1423, 1334,

308 • · ···· · · • · · · · ·

1275, 1213, 1161, 1136, 1039, 1001 cm ^{x 1} H NMR (DMSO-d ₆ ): δ 12.11 (IH, brs), 8.68 (IH, d, J = 4.94 Hz), 7.94 (IH, m), 7.62 (IH, d, 8.88 Hz), 7.56 - 7.52 (IH, m), 7.14 (IH, d, J = 2.30 Hz), 6.76 (IH, dd, J = 8.88 Hz, 2.30 Hz), 4.05 (2H, s), 3.82 (3H, s), 2.47 (3H, s)

Example 133

Methyl-[5-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Stage 1: Methyl-trans-5-ethyl-2-aminocinnamate

A mixture of 2-bromo-4-ethylaniline (1.0 g, 5.10 mmol), methyl acrylate (1.15 mL, 12.74 mmol), palladium acetate (137 mg, 0.61 mmol), tri-o-tolylphosphine (745 mg, 2.45 mmol), and triethylamine (2.5 mL) in acetonitrile (10 mL) was heated to 110°C. After stirring for 2 h, methyl acrylate (0.6 mL, 6.37 mmol), palladium acetate (69 mg, 0.30 mmol), tri-o-tolylphosphine (372 mg, 1.22 mmol), and triethylamine (1.3 mL) were added to the reaction mixture. The resulting mixture was stirred at 110°C for 7 h, after which the solvent was removed. The residue was diluted with ethyl acetate (100 mL), the ethyl acetate mixture was washed with water (100 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using ethyl acetate/hexane (1:5/1:4) as eluent to give 793 mg (75.8%) of the title compound as a yellow solid.

¹ H NMR (CDCl ₃ ): δ 7.83 (IH, d, J = 15.8 Hz), 7.21 (IH, m), 7.04 - 7.01 (IH, m), 6.64 (IH, d, J = 8.2 Hz), 6.36 (IH, d,

J = 15.8 Hz, 3.87 (2H, m), 3.80 (3H, s), 2.51 (2H, q, J =

7.6 Hz), 1.19 (3H, t, J = 7.6 Hz)

Step 2: Methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate

309

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-5-ethyl-2-aminocinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.70 - 7.48 (4H, m), 7.42 - 7.36 (2H, m), 7.29 - 7.26 (2H, m), 7.20 - 7.17 (2H, m), 6.14 (1H, d, J = 15.8 Hz), 3.76 (3H, s), 2.62 (2H, q, J = 7.6 Hz), 1.21 (3H, t, J = 7.6 Hz)

Step 3: Methyl-[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 12.32 (1H, brs), 8.59 - 8.57 (1H, m), 8.14 (1H, m), 7.47 - 7.39 (2H, m), 7.30 - 7.21 (2H, m), 4.32 (2H, s), 3.73 (3H, s), 2.75 (2H, q, J = 7.6 Hz), 2.43 (3H, s), 1.27 (3H, t, J = 7.6 Hz)

Example 134 [5-Ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 133) and had a melting point of 215°C (dec.).

IR (KBr) v: 1701, 1638, 1597, 1535, 1443, 1420, 1398, 1331, 1279, 1236, 1205 cm ^{1 1} H NMR (DMSO-dg): δ 12.09 (1H, brs), 8.69 (1H, d, J = 4.9 Hz), 7.94 (1H, m), 7.58 - 7.51 (3H, m), 7.23 - 7.20 (1H, m), 4.06 (2H, s), 2.69 (2H, q, J = 7.6 Hz), 2.46 (3H, s), 1.23 (3H, t, J = 7.6 Hz)

310

Example 135

Methyl-[5-ethyl-2-(4-ethylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate (from Step 2 of Example 133) and 2-bromoacetyl-4-ethylpyridine (the preparation of which is described in Example 57).

¹ H NMR (CDCl ₃ ): δ 12.35 (1H, brs), 8.63 (1H, d, J = 5.1 Hz), 8.20 (1H, m), 7.48 (1H, s), 7.42 (1H, d, J = 8.6 Hz), 7.34 (1H, dd, J = 5.1, 1.8 Hz), 7.26 - 7.22 (1H, m), 4.32 (2H,

S), 3.73 (3H, s), 2.76 (4H, q, J = 7.6 Hz), 1.30 (6H, t, J = 7.6 Hz)

Example 136 [5-Ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 135) and had a melting point of 206.2°C.

IR (KBr) v: 1703, 1636, 1595, 1533, 1431, 1333, 1283, 1236, 1188, 1117 cm" ^{1 1} H NMR (DMSO-dg): δ 12.09 (1H, brs), 8.73 (1H, d, J = 4.9 Hz), 7.97 (1H, s), 7.60 - 7.52 (3H, m), 7.22 (1H, d, J = 8.6 Hz), 4.06 (2H, s), 2.82 - 2.65 (4H, m), 1.28 - 1.21 (6H, m)

Example 137

Methyl-[6-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl] acetate • * ·

311

Stage 1: Methyl trans-(4-acetyl-2-nitro)cinnamate

The title compound was prepared as described in Example 131 from 4-bromo-3-nitroacetophenone and methyl acrylate.

¹ H NMR (CDCl ₃ ): δ 8.58 - 8.10 (3H, m), 7.77 - 7.74 (1H, m), 6.48 - 6.42 (1H, m), 3.85 (3H, s), 2.68 (3H, s)

Step 2: Methyl-trans-4-(1-hydroxyethyl)-2-nitrocinnamate

To a solution of methyl trans-4-acetyl-2-nitrocinnamate (462.2 mg, 854 mmol) in methanol (55 mL) at room temperature was added sodium borohydride (176.3 mg, 4.66 mmol). The resulting mixture was stirred for 10 min and then concentrated. The residue was diluted with dichloromethane (20 mL) and the dichloromethane mixture was washed with brine (20 mL). The aqueous layer was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over magnesium sulfate and concentrated to give 442 mg (quant.) of the title compound.

¹ H NMR (CDCl ₃ ): δ 8.12 - 6.33 (5H, m), 5.0 (1H, m), 3.83 (3H, s), 1.54 (3H, d, J = 9.56 Hz)

Step 3: Methyl trans-(4-ethyl-2-nitro)cinnamate

To a mixture of sodium iodide (1.668 g, 11.1 mmol) and acetonitrile (581 μΐ, 11.1 mmol) at room temperature was added chlorotrimethylsilane (1.41 mL, 11.1 mmol). The resulting mixture was stirred for 10 min, and then a solution of methyl trans-4-(1-hydroxyethyl-2-nitro)cinnamate (563.6 mg, from step 1) in 1:1:1 hexane:toluene:acetonitrile (6.0 mL) was added. The resulting mixture was stirred for an additional 48 h, diluted with 2:3 toluene:ethyl acetate (25 mL) and poured into water (25 mL). The organic layer was separated and washed with 5% aqueous sodium thiosulfate (30 mL), aqueous sodium chloride (30 mL),

312 was dried over magnesium sulfate and the solvent was removed to give 460 mg (quant.) of the title compound as a brown oil.

NMR (CDCl ₃ ): δ 8.12 - 6.32 (5H, m), 3.83 (3H, s), 2.76 (2H, q, 7.59 Hz), 1.29 (3H, t, J = 7.59 Hz)

Stage 4: Methyl-trans-2-amino-4-ethylcinnamate

The title compound was prepared as described in Step 2 of Example 36 from methyl trans-4-ethyl-2-nitrocinnamate (from Step 3).

^X H NMR (CDCl ₃ ): δ 7.84 - 6.29 (5H, m), 3.80 (3H, s), 2.57 (2H, m), 1.21 (3H, t, J = 7.59 Hz)

Step 5: Methyl trans-4-ethyl-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-2-amino-4-ethylcinnamate (from Step 4).

¹ H NMR (CDCl ₃ ): δ 7.57 (2H, d, J = 8.40 Hz), 7.46 (1H, d, J = 15.8 Hz), 7.39 - 7.08 (5H, m), 6.43 (1H, s), 6.43 (1H, d,

J = 15.8 Hz), 3.78 (3H, s), 2.61 (2H, m), 2.37 (3H, s), 1.18 (3H, t, J = 7.75 Hz)

Step 6: Methyl-[6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-ethyl-2-(p-toluenesulfonylamino)cinnamate (from Step 5) and 2-bromoacetyl-4-methylpyridine hydrobromide (the preparation of which is described in Step 2 of Example 31).

¹ H NMR (CDCl ₃ ): δ 12.30 (1H, brs), 8.62 (1H, d, 4.94 Hz),

8.18 - 7.32 (4H, m), 7.05 - 7.02 (2H, m), 4.33 (2H, s), 3.72

313

(3H, s), 2.79 (2H, q, 7.59 Hz), 2.48 (3H, s), 1.31 (3H, t, 7.59 Hz)

Example 138 [6-Ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 137) and had a melting point of 204-207°C.

IR (KBr) at: 3240, 1709, 1636, 1593, 1531, 1394, 1204, 1144, 1001 cm ^{1 1} H NMR (CDC1 ₃ ): δ 12.07 (1H, brs), 8.69 (1H, d, 4.94 Hz), 7.93 (1H, m), 7.63 (1H, d, 8.40 Hz), 7.5 (1H, m), 7.45 (1H, s), 7.00 - 6.96 (1H, m), 4.05 (2H, s), 2.73 (2H, q, 7.56 Hz), 2.46 (3H, s), 1.24 (3H, t, 7.56 Hz)

Example 139

Methyl-[5-isopropyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Stage 1: Methyl-trans-5-isopropyl-2-aminocinnamate

The title compound was prepared according to the method described in Step 1 of Example 133 from 2-bromo-4-isopropylaniline.

¹ H NMR (CDCl ₃ ): δ 7.83 (1H, d, J = 15.8 Hz), 7.23 (1H, m), 7.08 - 7.05 (1H, m), 6.66 (1H, d, J = 8.4 Hz), 6.37 (1H, d, J = 15.8 Hz), 3.85 (2H, m), 3.81 (3H, s), 2.84 - 2.76 (1H, m), 1.21 (6H, m)

314

Step 2: Methyl trans-5-isopropyl-2-(phenylsulfonylamino)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl trans-5-isopropyl-2-aminocinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.71 - 7.68 (2H, m), 7.58 (1H, d, J = 15.8 Hz), 7.51 - 7.20 (6H, m), 7.09 (1H, brs), 6.16 (1H, d, J = 15.8 Hz), 4.11 (3H, s), 2.94 - 2.83 (1H, m), 1.24 - 1.21 (6H, m)

Step 3: Methyl-[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-isopropyl-2-(phenylsulfonylamino)cinnamate (from Step 2).

¹ H NMR (CDC1 ₃ ): δ 12.33 (1H, brs), 8.61 (1H, d, J = 5.1 Hz), 8.17 - 8.16 (1H, m), 7.50 - 7.42 (2H, m), 7.33 - 7.26 (2H, m), n.32 (2H, s), 3.73 (3H, s). 3.08 - 2.97 (1H, m), 2.46 (3H, s), 1.33 - 1.30 (6H, m)

Example 140 [5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 139) and had a melting point of 213°C (dec.).

IR (KBr) v: 1717, 1641, 1597, 1537, 1327, 1273, 1196 cm ^{1 1} H NMR (DMSO-d ₆ ): δ 12.10 (1H, brs), 8.70 (1H, d, J = 4.9 Hz), 7.95 - 7.94 (1H, m), 7.59 - 7.54 (2H, m), 7.27 (1H, dd,

315

J = 8.6, 1.7 Hz), 4.07 (2H, s), 3.03 (1H, m), 2.46 (3H, s), 1.27 - 1.25 (6H, m)

Example 141

Methyl-[2-(4-methylpyridin-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate

Step 1: Methyl trans-2-amino-4-(trifluoromethyl)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 133 from 2-bromo-5-(trifluoromethyl)aniline.

¹ H NMR (CDCl ₃ ): δ 7.79 (1H, d, J = 15.8 Hz), 7.46 - 7.43 (1H, m), 7.00 - 6.94 (2H, m), 6.41 (1H, d, J = 15.8 Hz),

4.18 (2H, m), 3.82 (3H, m)

Step 2: Methyl trans-2-phenylsulfonylamino-4-(trifluoromethyl)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl trans-2-amino-4-(trifluoromethyl)cinnamate (from Step 1).

^Τ Η NMR (CDC1 ₃ ): δ 7.77 - 7.68 (2H, m) , 7.65 - 7.53 (4H, m) , 7.47 - 7.41 (3H, m) , 6.24 (1H, d, J = 15.8 Hz), 3.80 (3H, s)

Step 3: Methyl-[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-2-phenylsulfonylamino-4-(trifluoromethyl)cinnamate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 12.74 (1H, brs), 8.58 (1H, d, J = 4.9 Hz), 8.12 (1H, s), 7.81 - 7.74 (2H, m), 7.35 - 7.32 (2H, m), 4.32 (2H, s), 3.75 (3H, s), 2.46 (3H, s)

316 ·· ·«·« ·· · ·· • · · ···· ··· «« ·· ·· · · · · · · · · ·

Example 142 [2-(4-Methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate (from Example 141)

and has a melting point of 210 to 220°C. IR (KBr) Vi 1697, 1651, 1599, 1103, 1055 cm ^-1 1537, 1506, 1339, 1283 , 1196, ¹ H NMR (DMSO-d ₆ ): δ 12.62 (1H, brs) , 8.71 (1H, d, J = 4.9 Hz), 8.10 (1H, s), 7.99 - 7.97 (2H, m) , 7.61 - 7.59 (1H, m), 7.39 - 7.36 (1H, m), 4.14 (2H, s) , 2.48 (3H, s)

Example 143

Methyl-[5-tert.butyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Stage 1: Methyl-trans-5-tert.butyl-2-aminocinnamate

The title compound was prepared as described in Step 1 of Example 133 from 2-bromo-4-tert-butylaniline.

¹ H NMR (CDCl ₃ ): δ 7.85 (1H,d, 15.8 Hz), 7.38 (1H, d, 2.30 Hz), 7.23 (1H, dd, 8.56 Hz, 2.30 Hz), 6.67 (1H, d, 8.56 Hz), 6.37 (1H, d, 15.8 Hz), 3.87 (2H, brs), 3.81 (3H, s), 1.28 (9H, s)

Step 2: Methyl-trans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared as described in step 1 of Example 8 (Method A) and methyl-trans317

-5-tert.butyl-2-aminocinnamate and p-toluenesulfonyl chloride. ¹ H NMR (CDCl ₃ ): δ 7.60 - 7.20 (8H, π), 6.53 (1H, s), 6.17 (1H, d, 15.8 Hz), 3.79 (3H, s), 2.46 (3H, s), 1.29 (s, 9H)

Step 3: Methyl-[5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate (from Step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (the preparation of which is described in Step 2 of Example 31).

¹ H NMR (CDCl ₃ ): δ 12.33 (1H, brs), 8.63 (1H, d, 4.94 Hz),

8.18 (1H, m), 7.62 - 7.32 (4H, m ), 4.43 (2H, s), 3.74 (3H, s), 2.47 (3H, s), 1.40 (s, 9H)

Example 144 [5-tert-Butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 143) and had a melting point of 191°C.

IR (KBr) in: 2963, 1717, 1645, 1597, 1533, 1437, 1281,

1211, 1080, 1032, 1003 cm" ^{1 1} H NMR (DMSO-d ₆ ): δ 12.10 (1H, brs), 7.70 (1H, d, 5.1 Hz), 7.95 - 7.44 (6H, m), 4.09 (2H, s), 2.46 (3H, s), 1.35 (9H, s)

Example 145

Methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethoxy-1-hindol-3-yl]acetate

318

Step 1: Methyl trans-2-amino-5-(trifluoromethoxy)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 133 from 2-bromo-4-(trifluoromethoxy)aniline.

¹ H NMR (CDCl ₃ ): δ 7.74 (1H, d, 15.8 Hz), 7.23 - 7.02 (2H, m), 6.68 (1H, d, 8.72 Hz), 6.36 (1H, d, 15.8 Hz), 4.00 (2H, brs), 3.81 (3H, s)

Step 2: Methyl trans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-2-amino-4-(trifluoromethoxy)cinnamate (from Step 1) and p-toluenesulfonyl chloride.

¹ H NMR (CDCl ₃ ): δ 7.59 - 7.19 (8H, m), 6.76 (1H, s), 6.15 (1H, d, 15.8 Hz), 3.80 (3H, s), 2.39 (3H, s)

Step 3: Methyl-[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (from Step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (the preparation of which is described in Step 2 of Example 31).

¹ H NMR (CDCl ₃ ): δ 12.7 (1H, brs), 8.64 (1H, d, 5.10 Hz),

8.19 (1H, m), 7.55 - 7.23 (4H, m), 4.30 (2H, s), 3.74 (3H, s), 2.49 (3H, s)

Example 146 [2-(4-Methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid

319

The title compound was prepared as described in Example 9 (Method B) from methyl [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate (from Example 145) and had a melting point of 235-238°C.

IR (KBr) v: 3248, 1701, 1645, 1597, 1537, 1447, 1420, 1333, 1259, 1203, 1115, 1034, 1003 cm ^-1 ^•H NMR (DMSO-d ₆ ): δ 12.40 (1H, brs), 8.71 (1H, d, 4.94 Hz), 7.97 - 7.96 (1H, m), 7.80 - 7.30 (4H, m), 4.09 (2H, s),

2.47 (3H, s)

Example 147

Methyl-[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (from Step 2 of Example 145) and 2-bromoacetyl-4-ethylpyridine (the preparation of which is described in Example 57).

¹ H NMR (CDCl ₃ ): δ 8.66 (1H, d, 4.97 Hz), 8.2 (1H, brs), 7.55 - 7.26 (4H, m), 4.30 (2H, s), 3.74 (3H, s), 2.79 (2H, q,

7.59 Hz), 1.32 (3H, t, 7.59 Hz)

Example 148 [2-(4-Ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate (from Example 147) and had a melting point of 223°C.

IR (KBr) at: 3271, 1697, 1645, 1597, 1539, 1423, 1400, 1337, 1258, 1198, 1117, 1028, 1003 cm ^-1

320

¹ H NMR (DMSO-dg): δ 12.41 (1H, 7.99 (1H, m), 7.80 - 7.75 (2H, (2H, s), 2.78 (2H, q, 7.59 Hz) brs), 8.74 (1H, d, 4.94 Hz), m), 7.63 - 7.30 (2H, m), 4.10 , 1, 26 (3H, t, 7.59 Hz)

Example 149

Methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

Stage 1: Methyl-trans-2-amino-4-methylcinnamate

The title compound was prepared as described in Step 2 of Example 36 from methyl trans-4-methyl-2-nitrocinnamate.

¹ H NMR (CDCl ₃ ): δ 7.81 (1H, d, J = 15.8 Hz), 7.30 - 7.26 (1H, m), 6.60 - 6.57 (1H, m), 6.52 (1H, m), 6.31 (1H, d, J = 15.8 Hz), 3.92 (2H, brs), 3.79 (3H, s), 2.26 (2H, s)

Step 2: Methyl trans-4-methyl-2-(phenylsulfonylamino)cinnamate

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-2-amino-4-methylcinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.72 - 7.68 (2H,m ), 7.55 - 7.49 (1H,m), 7.44 - 7.34 (4H,m), 7.26 - 7.22 (1H,m), 7.07 - 7.04 (1H,m), 6.62 (1H,m), 6.12 (1H, d, J = 15.8 Hz), 3.76 (3H, s), 2.34 (3H, s)

Step 3: Methyl-[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-methyl-2-(phenylsulfonylamino)cinnamate (from Step 2).

321 ♦ · ♦«»· · ·

·· ·· ♦·

NMR (CDCl ₃ ): δ 12.26 (1H, brs), 8.61 (1H, d, J = 4.9 Hz), 8.17 (1H, m), 7.58 (1H, d, J = 8.4 Hz), 7.34 - 7.29 (2H, m), 7.01 - 6.98 (1H, m), 4.32 (2H, s), 3.72 (3H, s), 2.49 (3H, s), 2.47 (3H, s)

Example 150 [6-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 149) and had a melting point of 208°C (dec.).

IR (KBr) v: 1707, 1638 1593, 1531, 1277, 1205, 1142 cm ^{1 1} H NMR (DMSO-dg): δ 12.02 (1H, brs), 8.68(1H, d, J = 4.9 Hz), 7.93 (1H, s), 7.61 (1H, d, J = 8.2 Hz), 7.56 - 7.54 (1H, m), 7.42 (1H, s), 6.96 - 6.93 (1H, m), 4.04 (1H, s),

2.46 (3H, s), 2.43 (3H, s)

Example 151

Methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate

Step 1: Methyl trans-2-amino-5-(trifluoromethyl)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 133 from 2-bromo-4-(trifluoromethyl)aniline.

¹ H NMR (CDCl ₃ ): δ 7.77 (1H, d, J = 15.8 Hz), 7.61 (1H, s), 7.39 (1H, d, J = 8.4 Hz), 6.74 (1H, d, J = 8.4 Hz), 6.41 (1H, dd, J = 15.8, 1.5 Hz), 4.29 (2H, m), 3.82 (3H, m)

322 ·» ·# ·· *

Step 2: Methyl trans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl trans-2-amino-5-(trifluoromethyl)cinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.79 - 7.76 (2H, m), 7.66 (1H, m), 7.60 7.44 (6H, m), 7.06 (1H, brs), 6.26 (1H, d, J = 15.8 Hz),

3.81 (3H, s)

Step 3: Methyl-[2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (from Step 2).

1H NMR (CDCl ₃ ): δ 12.70 (1H, brs), 8.62 (1H, d, J = 4.9 Hz), 8.17 (1H, s), 8.00 (1H, s), 7.61 - 7.54 (2H, m), 7.38 - 7.36 (1H, m), 4.34 (2H, s), 3.75 (3H, s), 2.48 (3H, s)

Example 152 [2-(4-Methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate (from Example 151) and had a melting point of 218-225°C.

IR (KBr) V. 1697, 1645, 1599, 1541, 1337, 1277, 1202, 1161, 1111, 1053 cm ^{-1 1} H NMR (DMSO-dg): δ 12.52 (1H, brs), 8.71 (1H, d, J = 4.9 Hz), 8.23 (1H, s), 7.97 (1H, m), 7.85 (1H, d, J = 8.9 Hz), 7.62 - 7.58 (2H, m), 4.16 (2H, s), 2.48 (3H, s) • · • · · · · ·

Example 153

Methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (from Step 2 of Example 151) and 2-bromoacetyl-4-ethylpyridine (the preparation of which is described in Example 57).

^H NMR (CDCl ₃ ): δ 12.65 (1H, brs), 8.64 (1H, d, J = 5.1 Hz), 8.21 (1H, m), 8.01 (1H, s), 7.61 - 7.52 (2H, m), 7.40 - 7.37 (1H, m), 4.34 (2H, s), 3.76 (3H, s), 2.78 (2H, q, J = 7.6 Hz), 1.31 (3H, t, J = 7.6 Hz)

Example 154 [2-(4-Ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl-[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate (from Example

153) and has temperature melting point 203.6°C • IR (KBr) in: 1703, 1647, 1599, 1537, 1340, 1202, 1105, 1051 cm ^-1 1H NMR (DMSO-d ₆ ) : δ 12.52 (1H, brs), 8.74 (1H, d, J = 5.1 Hz), 8.24 (1H, sec) , 8.00 - 7.99 (1H, m), 7.86 (1H, d, J = 8.7 Hz), 7.64 - 7.58 (2H, m), 4.16 (2H, s), 2.79 (2H, q, J = 7.6 Hz), 1.26 (3H, t, J= 7.6 Hz) Example 1 d 15 5

Methyl-(2-benzoyl-1H-indol-3-yl)acetate

Stage 1: Methyl trans-2-(phenylsulfonylamino)cinnamate • · ·

- 3 2*1

The title compound was prepared as described in step 1 of Example 8 (Method A) from methyl trans-2-aminocinnamate.

¹ H NMR (CDC1 ₃ ): δ 7.71 - 7.67 (2H, m), 7.58 (1H, d, J = 15.8 Hz), 7.52 - 7.32 (6H, m), 7.28 - 7.22 (1H, m), 7.08 (1H, brs), 6.15 (1H, d, J = 15.8 Hz), 3.78 (3H, s)

Step 2: Methyl-(2-benzoyl-1H-indol-3-yl)acetate

The title compound was prepared as described in Example 57 from methyl trans-2-(phenylsulfonylamino)cinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, brs), 7.80 - 7.77 (2H, m), 7.67 - 7.58 (2H, m), 7.53 - 7.48 (2H, m), 7.43 - 7.34 (2H, m), 7.21 - 7.15 (1H, m), 3.86 (2H, s), 3.65 (3H, s)

Example 156 (2-Benzoyl-1H-indol-3-yl)acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl (2-benzoyl-1H-indol-3-yl)acetate (from Example 155) and had a melting point of 194-196°C.

IR (KBr) v: 1713, 1597, 1541, 1450, 1402, 1267, 1180, 729 cm' ¹ H NMR (DMSO-d ₆ ): δ 11.62 (1H, brs), 7.77 - 7.74 (2H, m), 7.69 - 7.66 (2H, m), 7.60 - 7.55 (2H, m), 7.48 - 7.45 (1H, m), 7.34 - 7.28 (1H, m), 7.13 - 7.08 (1H, m), 3.80 (2H, s)

Example 157

Methyl-[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl-trans-4-methyl-2-(phenylsul-3-yl)-2-yl-2-methyl-2-phenylsul-3-yl-2

phenylamino)cinnamate (from step 2 of Example 149) and 4-chlorophenacyl bromide.

¹ H NMR (CDCl ₃ ): & 8.84 (1H, brs), 7.74 - 7.71 (2H, m ), 7.53 - 7.45 (3H, m), 7.14 (1H, m), 7.03 - 7.00 (1H, m), 3.81 (2H, s), 3.65 (3H, s), 2.46 (3H, s)

Example 158 [2-(4-Chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate (from Example 157) and had a melting point of 193-195°C.

IR (KBr) at: 3302, 1697, 1587, 1335, 1263, 1090, 999, 770 cm' ^{1 1} H NMR (DMSO-d ₆ ): δ 11.47 (1H, brs), 7.76 - 7.73 (2H, m),

7.65 - 7.61 (2H,m), 7.57 (1H, d, J = 8.4 Hz), 7.23 (1H, s), 6.96 - 6.93 (1H, m), 3.79 (2H, s), 2.42 (3H, s)

Example 159 [2-(4-Chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid

Step 1: 2-(4-Chlorobenzoyl)-5-methyl-1-(phenylsulfonyl)indole

The title compound was prepared as described in step 2 of Example 2 (method B) from 5-methyl-1-(phenylsulfonyl)indole (E. Wenkert, P. Moeller and S. Piettre, J. Am. Chem. Soc., 1988, 110, 7188-7194) and 4-chlorobenzoyl chloride.

^X H NMR (CDCl ₃ ): δ 8.02 - 7.96 (3H, m), 7.96 - 7.88 (2H, m), 7.57 - 7.43 (5H, m), 7.33 - 7.25 (2H, m), 6.88 (1H, s), 2.41 (3H, S)

Step 2: 2-(4-Chlorobenzoyl)-5-methylindole

2 δ..-*

The title compound was prepared according to the method described in Step 3 of Example 2 (Method B) from 2-(4-chlorobenzoyl)-5-methyl-1-(phenylsulfonyl)indole (from Step 1).

1 H NMR (CDCl ₃ ): δ 9.43 (1H, brs), 7.94 - 7.91 (2H, m), 7.51

- 7.47 (3H, m), 7.37 (1H, d, J = 8.4 Hz), 7.21 (1H, dd, J = 8.4, 1.5 Hz), 7.04 - 7.03 (1H, m), 2.44 (3H, s)

Step 3: Diethyl-α-acetoxy-[4-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-(4-chlorobenzoyl)-5-methylindole (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.74 (1H, brs), 7.79 (2H, d, J = 8.4 Hz), 7.67 (1H, s), 7.42 (2H, d, J = 8.4 Hz), 7.27 - 7.24 (1H, m), 7.14 - 7.11 (1H, m), 4.24 - 4.16 (4H, m), 2.45 (3H, s), 1.28

- 1.18 (6H, m)

Step 4: Diethyl-[2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[4-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 8.80 (1H, brs), 7.73 (2H, d, J = 8.4 Hz), 7.54 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.21 - 7.18 (1H, m), 7.13 - 7.10 (1H, m), 4.25 - 4.13 (4H, m), 2.42 (3H, s), 1.28

- 1.21 (6H, m)

Step 5: [2-(4-Chlorobenzoyl)-5-methyl-1H-indol-3-ylacetic acid

The title compound was prepared as described in step 6 of Example 2 (method B) from diethyl-[2-(43 27.

-chlorobenzoyl)-5-methyl-1H-indol-3-yl]malonate (from step 4) and has a melting point of 194-197°C.

IR (KBr) v: 3308, 1695, 1609, 1529, 1402, 1263, 1223, 1088, 1015 cm' ^{1 X} H NMR (DMSO-d ₆ ): δ 12.18 (1H, brs), 11.49 (1H, s), 7.77 7.73 (2H, m), 7.66 - 7.62 (2H, m), 7.45 (1H, s), 7.35 (1H, d,

J = 8.6 Hz), 7.15 (1H, dd, J = 8.6, 1.5 Hz), 3.81 (2H,s), 2.39 (3H, s)

Example 160

Methyl [6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-methoxy-3-(p-toluenesulfonylamino)cinnamate (from Step 3 of Example 131) and 4-chlorophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.89 (1H, brs), 7.74 - 7.43 (5H, m), 6.86 - 6.77 (m, 2H), 3.85 (3H, s), 3.79 (3H, s), 3.65 (3H, s)

Example 161 [6-Methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl-[6-methoxy-2-(4-

-chlorobenzoyl)-1H-indol-3-yl]acetate (from Example 160) and has melting point 193° C. IR (KBr) at: 3308, 1701, 1628, 1603, 1526, 1427, 1335, 1271, 1205, 1148, 1092, 1032, 999 cm ^{1 1} H NMR (DMSO-d 6 ): δ 11.43 (1H, brs), 7.75 - 7.56 (5H, m) , 6.87 (1H, d, 2.13) Hz), 7.76 (1H, dd, 8.88, 2.13 Hz), 3.80 (3H,s), 3.79 (2H, s)

28.. ^J

Example 162 [2-(4-Chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid

Step 1: 1-Phenylsulfonyl-6-(trifluroxenethyl)indole

To a stirred mixture of 6-(trifluoromethyl)indole (500 mg, 2.70 mmol), 50% aqueous sodium hydroxide (5 mL), water (7 mL), and tetrabutylammonium bromide (87 mg, 0.27 mmol) was added a solution of phenylsulfonyl chloride (379 μΐ, 2.97 mmol) in toluene (5 mL) at room temperature. The resulting mixture was stirred for 1 hour and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated sodium bicarbonate (30 mL), water (30 mL), and brine (30 mL), dried over magnesium sulfate, and concentrated to give 835 mg (95%) of the title compound.

1H NMR (CDCl ₃ ): δ 8.29 (1H, s) , 7.91 - 7.88 (2H, m) , 7.71 (1H, d, J = 3.6 Hz), 7.64 - 7.54 (2H, m ), 7.49 - 7.44 (3H, m), 6.72 (1H, d, J = 3.6 Hz)

Step 2: 2-(4-Chlorobenzoyl)-1-phenylsulfonyl-6-(trifluoromethyl)indole

The title compound was prepared by the method described in Step 2 of Example 2 (Method B) from 1-phenylsulfonyl-6-(trifluoromethyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 8.42 (1H, s), 8.05 - 8.01 (2H, m), 7.92 7.89 (2H, m), 7.71 - 7.47 (7H, m), 6.95 (1H, s)

Step 3: 2-(4-Chlorobenzoyl)-6-(trifluoromethyl)indole

The title compound was prepared as described in Step 3 of Example 2 (Method B) from 2-(4-chlorobenzoyl)-1-phenylsulfonyl-6-(trifluoromethyl)indole (from Step 2). ¹ H NMR (CDCl ₃ ): δ 9.53 (1H, brs), 7.99 - 7.95 (2H, m), 7.85 - 7.79 (2H, m), 7.56 - 7.53 (2H, m), 7.42 - 7.39 (1H, m),

7.19 - 7.18 (1H, m)

Step 4: Diethyl-α-acetoxy-[2-(4-chlorobenzoyl)-6-(trifluoromethyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 2-(4-chlorobenzoyl)-6-(trifluoromethyl)indole (from Step 3).

¹ H NMR (CDCl ₃ ): δ 9.27 (1H, brs), 8.00 (1H, d, J = 8.7 Hz), 7.78 (2H, d, J = 8.6 Hz), 7.68 (1H, s), 7.45 - 7.39 (3H, m), 4.24 - 4.12 (4H, m), 1.74 (3H, s), 1.21 - 1.14 (6H, m)

Step 5: Diethyl-[2-(4-chlorobenzoyl)-6-(trifluoromethyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[2-(4-chlorobenzoyl)-6-(trifluoromethyl)-1H-indol-3-yl]malonate (from Step 4).

^X H NMR (CDCl ₃ ): δ 9.37 (1H, brs), 7.83 (1H, d, J = 8.6 Hz), 7.77 - 7.73 (2H, m), 7.51 - 7.48 (3H, m), 7.33 - 7.30 (1H, m), 5.27 (1H, s), 4.25 - 4.06 (4H, m), 1.31 - 1.15 (6H, m)

Step 6: [2-(4-Chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [2-(4-chlorobenzoyl)-6-(trifluoromethyl)-1H-indol-3-yl] malonate (from Step 5) and had a melting point of 155-160°C.

IR (KBr) at: 3379, 1705, 1611, 1589, 1516, 1337, 1229, 1119, 1092, 1055 cm ^-1

330 ¹ H NMR (DMSO-dg): δ 12.09 (1H, brs), 7.96-7.93 (1H, m), 7.82-7.78 (3H, m), 7.68-7.64 (2H, m), 7.41-7.37 (1H, m), 3.86 (2H, s)

Example 163

Methyl-[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 157 from methyl trans-5-ethyl-2-(phenylsulfonylamino)cinnamate (from Step 2 of Example 133).

¹ H NMR (CDCl ₃ ): δ 8.86 (1H, brs), 7.74 - 7.71 (2H, m ), 7.48 7.41 (3H, m), 7.32 - 7.21 (2H, m), 3.85 (2H, s), 3.66 (3H, s), 2.75 (2H, q, J = 7.6 Hz), 1.28(3H, t, J = 7.6 Hz)

Example 164 [2-(4-Chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate (from Example 163) and had a melting point of 165-168°C.

IR (KBr) v: 3321, 1693, 1605, 1531, 1221, 1088, 1011 cm ^{1 1} H NMR (DMSO-dg): δ 11.49 (1H, brs), 7.76 - 7.72 (2H, m), 7.65 - 7.61 (2H, m), 7.46 (1H, m), 7.36 (1H, d, J = 8.6 Hz), 7.18 (1H, dd, J = 8.6, 1.5 Hz), 3.81 (2H, s), 2.67 (2H, q, J = 7.6 Hz), 1.21 (3H,t, J = 7.6 Hz).

Example 165

Methyl-[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-methoxy-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 129).

¹ H NMR (CDCl ₃ ): δ 8.81 (IH, brs), 7.75 - 7.72 (2H, m), 7.49 - 7.46 (2H, m), 7.29 (IH, d, J = 8.9 Hz), 7.04 (IH, dd, J = 8.9, 2.5 Hz), 6.98 (IH, d, J = 2.5 Hz), 3.86 (3H, s), 3.85 (2H, s), 3.67 (3H, s)

Example 166 [2-(4-Chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate (from Example 165) and had a melting point of 200-204°C.

IR (KBr) vz 3325, 1724, 1607, 1526, 1429, 1356, 1265, 1229, 1092, 1011 cm ^-1 ^•H NMR (DMSO-dg): δ 11.46 (1H, brs), 7.74 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz), 7.35 (IH, d, J = 8.9 Hz),

7.13 (IH, d, J = 2.5 Hz), 6.96 (IH, dd, J = 8.9, 2.5 Hz), 3m83 (2H, S), 3.77 (3H, s)

Example 167

Methyl-[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-isopropyl-2-(phenylsulfonylamino)cinnamate (from Step 2 of Example 139).

^Τ Η NMR (CDC1 ₃ ): δ 8.87 (IH, brs), 7.74 - 7.70 (2H, m ), 4.79 - 7.44 (3H, m), 7.33 - 7.25 (2H, m), 3.85 (2H, s), w.66 (3H, s), 3.07 - 2.96 (IH, m), 1.32 - 1.29 (6H, m)

Example 168 [2-(4-Chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid ·· ···· • τ · • · · • ·

- 33 2. The title compound was prepared as described in Example 58 from methyl [2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate (from Example 169) and had a melting point of 197-200°C.

IR (KBr) v: 1697, 1609, 1533, 1429, 1348, 1265, 1090, 1011 cm' ^H NMR (DMSO-d ₆ ): δ 12.18 (1H, brs) , 11.50 (1H, brs) , 7.77 7.74 (2H, m), 7.65 - 7.62 (2H,m ), 7.50 (1H,m), 7.40 - 7.37 (1H,m), 7.26 - 7.23 (1H,m ), 3.83 (2H,s), 3.03 - 2.92 (1H,m), 1.26 - 1.24 (6H,m)

Example 169

Methyl-[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-2-phenylsulfonylamino-5-(trifluoromethyl)cinnamate (from Step 2 of Example 151).

¹ H NMR (CDCl ₃ ): δ 9.34 (1H, brs), 7.90 (1H, s), 7.77 - 7.70 (2H, m), 7.51 - 7.43 (3H, m), 7.33 (1H, d, J = 8.7 Hz), 3.85 (2H, s), 3.66 (3H, s)

Example 170 [2-(4-Chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate and had a melting point of 198-200°C.

IR (KBr) v: 3317, 1697, 1611, 1333, 1271, 1113, 1051, 1007 cm' •'ή NMR (DMSO-dg): δ 12.08 (1H,brs), 8.18 (1H, s), 7.80 7.77 (2H, m), 7.68 - 7.57 (4H, m), 3.92 (2H, s) ·· ···· ·· · ·· ·· · · · · · ···

Example 171

Methyl-[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-3-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (from Step 2 of Example 145) and 4-chlorophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, brs), 7.76 (2H, d, 8.75 Hz),

7.52 - 7.40 (5H, m), 3.82 (2H, s), 3.68 (3H, s)

Example 172 [2-(4-Chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate (from Example 171) and had a melting point of 195°C.

IR (KBr) in: 3339, 1705, 1622, 1589, 1533 , 1435, 1342 , 1256, 1225, 1177, 1092, 1013 cm" ^{1 1} H NMR (DMSO-d ₆ ): δ 11.91 (1H, brs) , 7.80 - 7.64 (5H, m) , 7.55 (1H, d, 8.91 Hz), 7.32 - 7.24 (m, 1H) , 3.87 (2H, s)

Example 173

Methyl [6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate

Step 1: Methyl 2-[6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl-trans-4-chloro-2-(phenylsul·· ···· · · • · <í · ·

-: 534

phenylamino)cinnamate (from step 1 of Example 8, method A) and 2-methoxyphenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 9.02 (1H, brs), 7.60 - 7.46 (2H, m ), 7.42 - 7.34 (2H, m), 7.15 - 6.99 (3H, m), 3.78 (3H, s), 3.66 (2H, s), 3.60 (3H, m)

Example 174 [6-Chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate (from Example 172) and had a melting point of 214-217°C.

IR (KBr) v: 3398, 2939, 2642, 1711, 1680, 1624, 1537, 1461, 1315, 1230, 937 cm ¹ ^•H NMR (DMSO-dg): δ 11.61 (1H, s), 7.67 (1H, d, J = 8.7 Hz), 7.60 - 7.51 (1H, m), 7.45 (1H, d, J = 2.0 Hz), 7.28 (1H, dd, J = 7.4, 1.6 Hz), 7.18 (1H, d, J = 8.2 Hz), 7.12 7.04 (2H, m), 3.70 (3H, s), 3.60 (2H, s)

Example 175

Methyl [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 3-methoxyphenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.86 (1H, s), 7.57 (1H, d, J = 8.7 Hz), 7.46 - 7.26 (4H, m), 7.19 - 7.12 (2H, m), 3.86 (3H, s), 3.83 (2H, s), 3.67 (3H, s)

Example 176 [6-Chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate (from Example 175) and had a melting point of 227-231°C.

IR (KBr) v: 3354, 2933, 2636, 1709, 1607, 1569, 1427, 1321, 1269, 1218, 1049 cm ^{1 1} H NMR (DMSO-d ₆ ): δ 11.76 (1H, s), 7.72 (1H, d, J = 8.6 Hz),

7.54 - 7.45 (2H, m), 7.35 - 7.22 (3H, m), 7.16 - 7.10 (1H, m), 3.83 (3H, s), 3.79 (2H, s)

Example 177

Methyl [6-chloro-2-(3-benzoyloxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 3-benzyloxyphenacyl bromide (A. Hernandez et al., J. Org. chem., 1994, 59, 1058).

¹ H NMR (CDCl ₃ ): δ 8.79 (1H, s), 7.56 (1H, d, J = 8.6 Hz),

7.46 -7.33 (9H, m), 7.26 - 7.19 (1H, m), 7.16 (1H, dd, J = 8.6, 1.8 Hz), 5.12 (2H, s), 3.82 (2H, s), 3.64 (3H, s)

Example 178 [6-Chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(3-benzoyloxybenzoyl)-1H-indol-3-yl]acetate (from Example 177) and had a melting point of 174-177°C.

• * · • · ·

-.33¾. ¹

IR (KBr) v: 3308, 3028, 2897, 1697, 1612, 1566, 1444, 1328, 1269, 1223, 732 cm ^{1 1} H NMR (DMSO-dg): δ 11.76 (1H, s), 7.71 (1H, d, J = 8.6 Hz) ,

7.54 - 7.30 (10H, m), 7.13 (1H, dd, J = 8.6, 1.6 Hz), 5.18 (2H, s), 3.78 (2H, s)

Example 179

Methyl [6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate

A mixture of methyl-[6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate (from Example 177, 0.37 g, 0.85 mmol) and 10% palladium on carbon (80 mg) in a 5:1 mixture of ethyl acetate and methanol (30 mL) was stirred under hydrogen for 2.5 h. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated. The solid residue was washed with dichloromethane (10 mL). 70 mg (24%) of the title compound was obtained as a white solid.

¹ H NMR (CDCl ₃ ): δ 10.36 (1H, brs), 9.06 (1H, s), 7.55 (1H, d, J = 8.7 Hz), 7.50 - 7.46 (1H, m), 7.36 - 7.22 (3H, m), 7.15 - 7.05 (2H, m), 3.89 (2H, s), 3.65 (3H, s)

Example 180 [6-Chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate (from Example 179) and had a melting point of 213-215°C.

IR (KBr) v: 3311, 3069, 1715, 1624, 1583, 1529, 1448, 1325, 1278, 1220, 761 cm ^{1 1} H NMR (DMSO-dg): δ 11.71 (1H, s), 9.86 (1H, brs), 7.71 )1H, d, J = 8.6 Hz), 7.47 (1H, d, J = 1.5 Hz), 7.41 - 7.32 (1H, m), 7.20 - 7.02 (4H, m), 3.82 (2H, s)

- -yyi -Example 181

Methyl [6-chloro-2-(4-benzoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 4-benzyloxyphenacyl bromide (A. Brossi et al., J. Heterocycl. Chem. 1965, 2, 310).

^H NMR (CDC1 ₃ ): δ 8.87 (1H, brs), 7.81 (2H, d, J = 8.6 Hz),

7.55 (1H, d, J = 8.7 Hz), 7.48 - 7.32 (6H, m), 7.14 (lH, dd, J = 8.7, 1.8 Hz), 7.06 (2H, d, J = 8.6 Hz), 5.16 (2H, s), 3.86 (2H, s), 3.65 (3H, s)

Example 182 [6-Chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-benzoxybenzoyl)-1H-indol-3-yl]acetate (from Example 181) and had a melting point of 220-222°C.

IR (KBr) v: 3331, 3013, 2914, 1717, 1699, 1599, 1564, 1508, 1253, 1167, 941 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 11.72 (1H, s), 7.76 (2H, d, J = 8.9 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.52 - 7.32 (6H, m), 7.17 (2H, d,

J = 8.9 Hz), 7.11 (1H, dd, J = 8.4, 2.2 Hz), 5.23 (2H, s), 3.81 (2H, s)

Example 183

Methyl [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 179 from methyl [6-chloro-2-(4-benzoxybenzoyl)-1H-indol-3-yl]acetate (from Example 181).

^•H NMR (acetone-dg): δ 10.82 (1H, brs), 9.21 (1H, brs), 7.75 (2H, d, J = 8.7 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.13 (1H, dd, J = 8.7, 2.0 Hz), 6.97 (2H, d, J = 8.7 Hz), 3.95 (2H, s), 3.59 (3H, s)

Example 184 [6-Chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate (from Example 183) and had a melting point of 231-234°C.

IR (KBr) at: 3250, 3120, 2822, 1734, 1618, 1539, 1456, 1321, 1236, 1120, 1060 cm' ^{1 1} H NMR (DMSO-dg): δ 11.58 (1H, brs), 7.63 - 7.53 (3H, m), 7.35 (1H, d, J = 1.9 Hz), 7.00 (1H, dd, J = 8.6, 1.9 Hz), 6.80 (2H, d, J = 8.9 Hz), 3.69 (2H, s)

Example 185

Methyl [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate

To a stirred solution of [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate (from Example 183, 0.15 g, 0.44 mmol) in dimethylformamide (5 ml) was added sodium hydride (15 mg, 0.46 mmol) at room temperature under atmosphere. After 5 minutes, 2-iodopropane (78 mg) was added to the resulting mixture. The reaction mixture was stirred for 7 hours and then quenched with 2M aqueous hydrochloric acid (20 ml). The resulting mixture was extracted with ethyl acetate (50 ml). The extract was washed with water (20 ml) and aqueous sodium chloride solution (30 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using a mixture of ethyl acetate and hexane in the ratio • · ···· ·« · ·· • · · ···«· »··

1:2, as eluent. 72 mg (43%) of the title compound was obtained as a white solid.

*Ή NMR (CDC1 ₃ ): δ 8.81 (1H, brs), 7.80 (2H, d, J = 8.9 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.41 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J = 8.7, 1.8 Hz), 6.95 (2H, d, J = 8.7, 1.8 Hz) = 8.9 Hz), 4.67 (1H, heptet, J = 6.1 Hz), 3.87 (2H, s), 3.Ž7 (3H, s), 1.39 (6H, d, J = 6.1 Hz)

Example 186 [6-Chloro-2-[(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl] acetate (from Example 185) and had a melting point of 216-218°C.

IR (KBr) v: 3304, 2972, 2881, 1707, 1614, 1596, 1560, 1507, 1311, 1261, 1163 cm' ^{1 1} H NMR (DMSO-dg): δ 11.71 (1H, brs), 7.75 (2H, d, J = 8.9 Hz), 7.69 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 2.0 Hz),

7.12 (1H, dd, J = 8.6, 2.0 Hz), 7.07 (2H, d, J = 8.9 Hz),

4.78 (1H, heptet, J = 5.9 Hz), 3.82 (2H, s), 1.2 (6H, d, J = 5.9 Hz)

Example 187

Methyl [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 4-phenylacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, brs), 7.88 (2H, d, J = 8.1 Hz), 7.73 (2H, d, J = 8.1 Hz), 7.68 - 7.38 (7H, m), 7.16 (1H, dd,

J = 8.1, 1.8 Hz), 3.89 (2H, s), 3.66 (3H, s)

--.340..Example

8 [6-Chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate (from Example 187) and had a melting point of 228-231°C.

IR (KBr) v: 3317, 3030, 2868, 1707, 1620, 1600, 1527, 1431, 1323, 1256, 1194 cm' ^{1 1} H NMR (DMSO-dg): δ 11.81 (1H, s), 7.89 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz), 7.82 - 7.72 (3H, m), 7.58 - 7.40 (4H, m), 7.14 (1H, dd, J = 8.6, 1.8 Hz), 3.87 (2H, s)

Example 189

Methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 4-(trifluoromethoxy)phenacyl bromide*.

¹ H NMR (CDCl 2 ): δ 8.85 (1H, brs), 7.85 (2H, d, J = 8.9 Hz),

7.57 (1H, d, J = 8.6 Hz), 7.40 (1H, d, J = 1.8 Hz), 7.35 (2H, d, J = 8.9 Hz), 7.16 (1H, dd, J = 8.6, 1.8 Hz), w.80 (2H, s), 3.65 (3H, s)

*4-(Trifluoromethoxy)phenacyl bromide is prepared as follows:

A mixture of 4-(trifluoromethoxy)acetophenone (0.52 g, 2.55 mmol) and tetrabutylammonium tribromide (1.35, 2.80 mmol) in a 1:1 dichloromethane:methanol mixture (8 mL) was stirred for 18 h and then concentrated. The residue was diluted with ethyl acetate (50 mL). The ethyl acetate mixture was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, and the solvent was removed. 0.36 g (50%) of the title compound was obtained as a yellow oil, t.e.: Rf = 0.47 (hexane:ethyl acetate, 10:1)

Example 190 [6-Chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate (from Example 189) and had a melting point of 166-168°C.

IR (KBr) v: 3315, 3219, 1719, 1699, 1616, 1527, 1508, 1254, 1221, 1167, 943 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 11.79 (1H, s), 7.88 (2H, d, J = 8.6 Hz), 7.75 (1H, d, J = 8.9 Hz), 7.65 (2H, d, J = 8.6 Hz), 7.47 (1H, d, J = 1.8 Hz), 7.14 (1H, dd, J = 8.9, 1.8 Hz), 3.85 (2H, s)

Example 191

Methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 4-(trifluoromethoxy)phenacyl bromide (the preparation of which is described in Example 189).

¹ H NMR (CDCl 1 ): δ 8.92 (1H, brs), 7.85 (2H, d, J = 8.7 Hz), 7.61 (1H, brs), 7.38 - 7.28 (4H, m), 3.79 (2H, s), 3.67 (3H, s)

-· .3*4*2. 19 2

Example [5-Chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate (from Example 191) and had a melting point of 186.7°C.

IR (KBr) at: 3332, 3086, 2925, 1697, 1610, 1408, 1259, 1217, 1161, 1007, 941 cm -i 1H NMR (DMSO-d ₆ ) : δ 11.85 (1H, brs), 7.89 (2H, d, J = 8.7 Hz), 7.81 (1H, d, J = 2.1 Hz), 7.60 - 7.53 (2H, m), 7.48 (1H, d, J = 8.7 Hz ), 7.32 (1H, dd, J = 8.7, 2.1 Hz), 3.86 (2H, s) Example 1 d 1 9 3

Methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 4-methoxyphenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.86 (1H, s), 7.82 (2H, d, J = 8.9 Hz), 7.63 - 7.60 (1H, m), 7.37 - 7.26 (2H, m), 6.99 (2H, d, J =

8.9 Hz), 3.90 (3H, s), 3.84 (2H, s), 3.69 (3H, s)

Example 194 [5-Chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate (from Example 193) and has • ·

-*.3 4 3. . ^Λ melting point 232 to 235°C.

IR (KBr) vz 3312, 2833, 2621, 1701, 1599, 1510, 1454, 1263, 1167, 1001, 777 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 11.78 (IH, s), 7.78 (2H, d, J = 8.9 Hz), 7.75 (IH, d, J = 2.0 Hz), 7.47 (IH, d, J = 8.7 Hz), 7.29 (IH, dd, J = 8.7, 2.0 Hz), 7.11 (2H, d, J = 8.9 Hz), 3.88 (3H,s), 3.82 (2H, s)

Example 195

Methyl [6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 4-nitrophenacyl bromide.

^H NMR (CDCl ₃ ): δ 8.92 (IH, brs), 8.37 (2H, d, J = 8.9 Hz), 7.93 (2H, d, J = 8.9 Hz), 7.57 (IH, d, J = 8.7 Hz), 7.40 (IH, d, J = 1.8 Hz), 7.18 (IH, dd, J = 8.7, 1.8 Hz), w.73 (2H,s), 3.65 (3H,s)

Example 196 [6-Chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate (from Example 195) and had a melting point of 218.9°C (dec.).

IR (KBr) vz 3365, 3101, 2846, 1718, 1699, 1647, 1537, 1348, 1255, 1227, 852 cm ^{1 1} H NMR (DMSO-dg): δ 11.84 (1H, s), 8.38 (2H, d, J = 8.9 Hz), 7.97 (2H, d, J = 8.9 Hz), 7.78 (IH, d, J = 8.6 Hz), 7.48 (IH, d, J = 2.0 Hz), 7.15 (IH, dd, J = 8.6, 2.0 Hz), 3.83 (2H, s)

-*.344..*Example 197

Methyl-[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from 4-(methylsulfonyl)phenacyl bromide. ¹ H NMR (CDCl ₃ ): δ 9.10 (1H, brs), 8.08 (2H,d, J = 8.6 Hz),

7.93 (2H, d, J = 8.3 Hz), 7.57 (1H, d, J = 8.7 Hz), 7.37 (1H, br) , 7.20 - 7.10 (1H, m), 3.78 (2H, s), 3.64 (3H, s), 3.12 (3H, s)

Example 198 [6-Chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl-[6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetate (from Example 197) and had a melting point of 241°C (dec.).

IR (KBr) v: 3330, 1713, 1614, 1524, 1230, 1150.941, 781 cm ¹ H NMR (DMSO-d ₆ ): δ 11.83 (1H, s), 8.12 (2H, d, J = 8.3 Hz), 7.96 (2H, d, J = 8.3 Hz), 7.78 (1H, d, J = 8.7 Hz), 7.48 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J = 1.8, 8.7 Hz), 3.85 (2H, s), 3.33 (3H, s)

Example 199

Methyl-[6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, • · · 0 · ·

-*3.49.method A) and 4-(methylsulfonylamino)phenacyl bromide.

^-H NMR (CDCl ₃ ): δ 8.86 (1H, brs), 7.82 (2H, d, J = 8.72 Hz), 7.58 (1H, d, J = 8.72 Hz), 7.42 - 7.15 (4H, m), 6.80 (1H, brs), 3.83 (2H, s), 3.67 (3H, s). 3,13 (3H, s) *4-(Methylsulfonylamino)phenacyl bromide is prepared from (4-acetylphenyl)methanesulfonamide (R. Lis et al., J. Org.

Chem., 1987, 52, 4377) by the method described in Example 189 for the preparation of 4-(trifluoromethoxy)phenacyl bromide.

'-Η NMR (CDCl ₃ ): δ 8.01 (2H, d, 8.72 Hz), 7.28 (2H, d, J = 8.7 Hz), 4.40 (2H, s), 3.13 (2H, s)

Example 200 [6-Chloro-2-[4-methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl-[6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate (from Example 199) and had a melting point of 207-210°C.

IR (KBr) in; 3333, 3248, 1715, 1603, 1570, 1529, 1508, 1394, 1323, 1259, 1231, 1159, 1061 cm" ^{1 1} H NMR (DMSO-d ₆ ): δ 11.6 (1H, brs), 7.76 (2H, d, J = 8.88 Hz), 7.71 (1H, d, J = 8.56 Hz), 7.46 (1H, 1.65 Hz), 7.12 (1H, dd, J = 8.56 HZ, 1.65 Hz), 3.81 (2H, s), 3.13 (3H, s)

Example 301 [6-Chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(2-chlorobenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared by the method described in step 2 of Example 1 (method B) from 6-chloro-1-(fe• · · ·· · «· « ·· • · · ···« ···

nylsulfonyl)indole (from step 1 of example 1, method B) and 2-chlorobenzoyl chloride. The crude product was used in the next step without further purification.

tle: Rf = 0.25 (hexane : ethyl acetate, 4:1)

Step 2: 6-Chloro-2-(2-chlorobenzoyl)indole

The title compound was prepared as described in Step 3 of Example 1 (Method B) from 6-chloro-2-(2-chlorobenzoyl)-1-(phenylsulfonyl)indole (from Step 1). The crude product was used in the next step without further purification.

tle: Rf = 0.37 (hexane : ethyl acetate, 4:1)

Step 3: Diethyl-α-acetoxy-2-[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 1 (Method B) from 6-chloro-2-(2-chlorobenzoyl)indole (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.61 (1H, brs), 7.79 (1H, d, J = 8.88 Hz),

7.52 - 7.33 (5H, m), 7.15 (1H, dd, J = 1.97 Hz), 4.26 (4H, m), 2.02 (3H, s), 1.22 (6H, t, J = 7.07 Hz)

Step 4: Diethyl [6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl] malonate

The title compound was prepared as described in Step 5 of Example 1 (Method B) from diethyl α-acetoxy-[6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]malonate (from Step 3).

^Τ Η NMR (CDC1 ₃ ): δ 8.95 (1H, brs), 7.75 (1H, d, J = 8.88 Hz),

7.53 - 7.39 (5H, m), 4.83 (1H, s), 4.15 (4H, m), 1.20 (6H, t, J = 7.26 Hz) • ♦ · 00 · 0« 0 ·· • 0 · *»Φ0 ···

Step 5: 2-[6-Chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 1 (Method B) from diethyl [6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl] malonate (from Step 4) and had a melting point of 138-140°C.

IR (KBr) v: 3315, 1713, 1632, 1564, 1526, 1435, 1325, 1254, 1215, 1151, 1061 cm ^{-1 1} H NMR (DMSO-dg): δ 11.67 (1H, s), 7.61 (1H, d, J = 8.72), 7.51 - 7.34 (5H, m), 7.50 (1H, dd, J = 1.97, 8.72 Hz), 3.75 (2H, s)

Example 202 [6-Chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid

Step 1: 6-Chloro-2-(2,4-dichlorobenzoyl)-1-(phenylsulfonyl)indole

The title compound was prepared as described in Step 2 of Example 1 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 1, Method B) and 2,4-dichlorobenzoyl chloride. The crude product was used in the next step without further purification.

tle: Rf = 0.34 (hexane : ethyl acetate, 4:1)

Step 2: 6-chloro-2-(2,6-dichlorobenzoyl)indole

The title compound was prepared as described in Step 3 of Example 1 (Method B) from 6-chloro-2-(2,4-dichlorobenzoyl)-1-(phenylsulfonyl)indole (from Step 1). The crude product was used in the next step without further purification.

tle: Rf = 0.45 (hexane : ethyl acetate, 4:1) • · ····

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 1 (Method B) from 6-chloro-2-(2,4-dichlorobenzoyl)indole (from Step 2).

^Τ Η NMR (CDC1 ₃ ): δ 8.92 (1H, brs), 7.79 - 7.11 (6H, m), 4.24 (4H, m), 2.02 (3H, s), 1.22 (6H, t, J = 7.10 Hz)

Step 4: Diethyl-[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate

The title compound was prepared as described in Step 5 of Example 1 from diethyl α-acetoxy-[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate (from Step 3). ¹ H NMR (CDCl ₃ ): δ 8.92 (1H, brs), 7.75 (1H, d, J = 8.92 Hz), 7.55 - 7.36 (4H, m), 7.13 (1H, dd, 8.92 Hz, 1.81 Hz), 4.85 (1H, s), 4.17 (4H, m), 1.21 (6H, t, J = 7.10 Hz)

Step 5: [6-Chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 1 (Method B) from diethyl 2-[6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]malonate (from Step 4) and had a melting point of 190-192°C.

IR (KBr) VI 3304, 1709, 1630, 1589, 1526, 1427, 1321, 1231, 1150, 1061 cm ^{1 1} H NMR (DMSO-dg): δ 11.66 (1H, s), 7.72 (1H, d, J = 2.00 Hz), 7.64 (1H, d, 8.9 Hz), 7.51 - 7.33 (3H,m ), 7.01 (1H, dd, J = 2.00, 8.91 Hz), 3.61 (2H, s)

Example 203

Methyl [6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetate

- 349.*·

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 4-chloro-3-fluorophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.87 (1H, brs), 7.65 - 7.36 (4H, m), 7.17 (1H, dd, J = 8.72 Hz, 1.81 Hz), 3.80 (2H, s), 3.68 (3H, s) *4-Chloro-3-fluorophenacyl bromide is prepared as follows:

4-Acetyl-1-chloro-2-fluorobenzene

To a solution of 1-bromo-4-chloro-3-fluorobenzene (2.09 g, 10 mmol) in dry diethyl ether (12.0 mL) at -78°C under nitrogen was added a solution of n-butyllithium (1.55M in hexane, 6.77 mL, 10.5 mmol). The resulting mixture was allowed to warm to -20°C, stirred for 45 min, and then Ν,Ν-dimethylacetamide (1.04 mL, 11.2 mmol) in diethyl ether (1.5 mL) was added. The reaction mixture was stirred for an additional 1 h and poured into saturated aqueous ammonium chloride (20 mL). The resulting mixture was extracted with diethyl ether (30 mL x 3). The combined organic layers were washed with 2M aqueous hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL), brine (20 mL), dried over magnesium sulfate and the solvent removed to give the title compound as a yellow oil (quant.).

¹ H NMR (CDCl ₃ ): δ 7.75 - 7.09 (3H, m), 2.59 (3H, s)

4-Chloro-3-fluorophenacyl bromide

The title compound was prepared from 4-acetyl-1-chloro-2-fluorobenzene by the method described in Example 189 for the preparation of 4-(trifluoromethoxy)phenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 7.79 - 7.71 (2H, m ), 7.58 - 7.52 (1H, m), 4.38 (2H, s)

- 350·-*

Example 204 [6-Chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-(4-methylsulfonylaminophenacyl)-1H-indol-3-yl]acetate (from Example 203) and had a melting point of 179-182°C.

MS (E1) m/z: 365 (M ⁺ ) ¹ H NMR (DMSO-dg): δ 11.80 (1H, brs), 7.85 -7.48 (5H, m), 7.14 (1H, dd, J = 8.72 Hz, 1.97 Hz), 3.84 (2H, s)

Example 205

Methyl [6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 4-cyanophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.88 (1H, brs), 7.89 - 7.80 (4H,m ), 7.58(1H, d, J = 8.75 Hz), 7.41 (1H, d, J = 1.65 Hz), 7.18 (1H, dd, 8.75 Hz), 3.74 (2H, s), 3.36 (3H, s)

Example 206

Methyl-[6-chloro-2-[4-(bromo)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 4-bromophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.89 (1H, brs), 7.66 (4H, s), 7.55 (1H, d, J = 8.6 Hz), 7.36 (1H, d, J = 1.6 Hz), 7.15 (1H, dd, J =

8.6, 1.6 Hz), 3.81 (2H, s), 3.66 (3H, s)

- 351

Example 207

Methyl-[6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate

A mixture of methyl [6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (from Example 206, 0.40 g, 0.98 mmol), thiophene-2-boronic acid (0.14 g, 1.08 mmol), saturated aqueous sodium bicarbonate (4 mL), and dichlorobis(triphenylphosphine)palladium(II) (70 mg, 0.098 mmol) in DME (15 mL) was heated to reflux for 3 h and then poured into water (30 mL). The aqueous mixture was extracted with ethyl acetate (50 mL x 2). The combined extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography using ethyl acetate:hexane (1:6) as eluent. 0.33 g (83%) of the title compound is obtained as a yellow solid.

¹ H NMR (CDC1 ₃ ): δ 8.88 (1H, brs), 7.83 (2H, d, J = 8.2 Hz), 7.75 (2H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.6 Hz), 7.46 (1H, dd, J = 3.6, 1.2 Hz), 7.42 - 7.38 (2H, m), 7.19 - 7.12 (2H, m), 3.87 (2H, s), 3.67 (3H, s)

Example 208 [6-Chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared by the method described in Example 9 (Method B) from methyl [6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate (from Example 207) and had a melting point of 246-249°C.

IR (KBr) v: 3319, 3068, 2628, 1705, 1610, 1593, 1427, 1323, 1257, 1186, 941 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 11.79 (1H, s), 7.87 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 8.6 Hz), 7.77 - 7.68 (3H, m), 7.48 (1H, d, J =

- 35»2

1.5 Hz), 7.26 - 7.20 (1Η, m), 7.13 (1H, dd, J = 8.6, 2.0 Hz), 3.86 (2H, s)

Example 209

Methyl-[6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 207 from [6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (from Example 206) and furan-2-boronic acid.

¹ H NMR (CDCl ₃ ): δ 8.90 (1H, brs), 7.83 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7 Hz), 7.60 - 7.54 (2H, m), 7.40 (1H, d,

J = 1.8 Hz), 7.15 (1H, dd, J = 8.6, 1.8 Hz), 6.83 (1H,d, J =

3.5 Hz), 6.57 - 6.52 (1H,m ), 3.86 (2H,s), 3.66 (3H,s)

Example 210 [6-Chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate (from Example 209) and had a melting point of 230-232°C.

IR (KBr) v: 3315, 2873, 2630, 1709, 1616, 1597, 1527, 1431, 1321, 1257, 1232 cm ^{-1 1} H NMR (DMSO-dg): δ 11.80 (1H,s), 7.93 - 7.79 (3H,m), 7.83 (2H, d, J = 8.1 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.48 (lH,d, J = 1.8 Hz), 7.21 (lH,d, J = 3.5 Hz), 7.14 (1H, dd, J = 8.6,

1.8 Hz), 6.72 - 6.66 (1H, m), 3.84 (2H, s)

Example 211

Methyl-[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 207 from [6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (from Example 206) and pyridine-3-boronic acid.

¹ H NMR (CDCl ₃ ): δ 8.95 (1H, brs), 8.90 (1H, d, J = 2.5 Hz), 8.69 - 8.65 (1H, m), 7.98 - 7.92 (1H, m), 7.92 (2H, d, J =

8.6 Hz), 7.73 (2H,d, J = 8.6 Hz), 7.59 (lH,d, J = 8.7 Hz), 7.48 - 7.40 (2H, m), 7.17 (1H, dd, J = 8.7, 1.8 Hz), 3.88 (2H, s), 3.67 (3H, s)

Example 212 [6-Chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate (from Example 211) and had a melting point of 194.8°C.

IR (KBr) v: 3224, 2960, 1604, 1568, 1527, 1382, 1321, 1259, 1004, 920 cm' ^{1 1} H NMR (CD ₃ OD): δ 8.93 - 8.89 (1H, m), 8.57 (1H, dd, J =

4.8, 1.5 Hz), 8.24 - 8.17 (1H, m),7.98 (2H,d,J = 8.6 Hz), 7.85 (2H, d, J = 8 Hz) , 7.68 (1H, d, J = 8.6 Hz), 7.60 7.53 (1H, m), 7.46 - 7.42 (1H, m), 7.04 (1H, dd, J = 8.6, 1.8 Hz), 3.67 (2H, s)

Example 213

Methyl-[6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate

To a stirred solution of thiazole (0.11 g, 1.23 mmol) in diethyl ether (4 mL) at -78°C under nitrogen was added n-butyllithium (1.55M in hexane, 0.79 mL). The resulting mixture

- 354 was stirred for 30 min, then zinc chloride (0.1M in diethyl ether, 3.7 mL, 3.7 mmol) was added. The resulting mixture was stirred at 0°C for 30 min, and palladium catalyst prepared in tetrahydrofuran (5 mL) by mixing a suspension of dichlorobis(triphenylphosphine)palladium(II) (0.22 g, 0.31 mmol) with n-butyllithium (1.55M in hexane, 0.39 mL) was added. To this mixture was added methyl-[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate (from Example 206, 0.25 g, 0.61 mmol). The reaction mixture was heated to reflux for 4 h and then poured into water (50 mL). The aqueous mixture was extracted with ethyl acetate (50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash column chromatography (1:3 ethyl acetate:hexane) to give 0.18 g (72%) of the title compound as a yellow solid.

¹ H NMR (DMSO-dg): δ 11.87 (1H, brs), 8.16 (2H, d, J = 8.4 Hz), 8.04 (1H, d, J = 3.1 Hz), 7.93 (1H, d, J = 3.1 Hz),

7.86 (2H, d, J = 8.4 Hz), 7.77 (lH, d, J = 8.6 Hz), 7.49 (lH, d, J = 1.6 Hz), 7.15 (1H, dd, J = 8.6, 1.6 Hz), 3.97 (2H, s), 3.54 (3H, s)

Example 214 [6-Chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate (from Example 213) and had a melting point of 230-233°C.

IR (KBr) Vi 3331, 3126, 2546, 1693, 1635, 1535, 1350, 1313, 1213, 1150, 912 cm ^{1 1} H NMR (DMSO-dg): δ 11.82 (1H, s), 8.15 (2H, d, J = 8.6 Hz), 8.04 (lH,d, J = 3.3 Hz), 7.93 (1H, d, J = 3.3 Hz), 7.88 (2H,d, J = 8.6 Hz), 7.75 (lH,d, J = 8.7 Hz), 7.49 (IH, d, J = 2.0 Hz), 7.14 (IH, dd, J = 8.7, 2.0 Hz), 3.86 (2H, s)

Example 215

Methyl [6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 3-bromophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.91 (1H, brs), 7.93-7.87 (IH, m), 7.77-7.67 (2H,m), 7.57 (1H,d, J = 8.7 Hz), 7.43-7.35 (2H,m), 7.19-7.13 (IH,m), 3.78 (2H, s), 3.69 (3H, s)

Example 216

Methyl-[6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 207 from methyl [6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate (from Example 215) and furan-2-boronic acid.

¹ H NMR (CDCl ₃ ): δ 8.93 (IH, brs), 8.05 - 8.01 (IH, m), 7.94 - 7.88 (1H, m ), 7.68 - 7.62 (IH, m), 7.60 - 7.47 (3H, m), 7.45 - 7.41 (IH, m), 7.16 (IH, dd, J = 8.6, 1.6 Hz), 6.74 (IH, d, J = 3.3 Hz), 6.52 - 6.47 (IH, m), 3.80 (2H, s), 3.57 (3H, S)

Example 217 [6-Chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid

- 35-6 —

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate (from Example 216) and had a melting point of 246-249°C.

IR (KBr) v: 3310, 2984, 2632, 1695, 1624, 1568, 1327, 1227, 1062, 806, 739 cm ^{-1 1} H NMR (DMSO-dg): δ 11.81 (1H, s), 8.05 - 7.96 (2H, m), 7.82 - 7.77 (1H, m), 7.74 (1H, d, J = 8.7 Hz), 7.68 - 7.61 (2H, m), 7.49 (1H, d, J = 2.0 Hz), 7.14 (1H, dd, J = 8.7, 2.0 Hz), 7.09 (1H, d, J = 3.3 Hz), 6.66 - 6.61 (1H, m), 3.83 (2H, s)

Example 218

Methyl-dl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl] propionate

Step 1: Methyl-[1-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate

To a stirred suspension of methyl 2-[4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate (from Example 8, Method B, 2.0 g, 5.5 mmol) in dichloromethane (20 ml) at room temperature was added ditert-butyl dicarbonate (2.4 g, 11 mmol) and 4-dimethylaminopyridine (670 mg, 5.5 mmol). The resulting mixture was stirred for 5 min and then poured into 10% citric acid (200 ml). The resulting mixture was extracted with dichloromethane (200 ml). The extract was washed with water (200 ml) and brine (200 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using ethyl acetate:hexane (1:4) as eluent. 2.3 g (90%) of the title compound are obtained as a yellow solid.

^Χ Η NMR (CDC1 ₃ ): δ 8.26 (1H,d, J = 2.2 Hz) , 7.74 (2H, d, J =

8.6 Hz), 7.53 (1H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.6 Hz),

35*7 ·-· · '· · 9 9

7.32 (1H, dd, J = 1.6, 8.4 Hz), 3.72 (2H, s), 3.56 (3H, s), 1.30 (9H, s)

Step 2: Methyl [1-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]propionate

To a stirred solution of methyl-[1-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate (from step 1, 200 mg, 0.43 mmol) in tetrahydrofuran (3 mL) at -78°C was added a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 0.5 mL). The resulting mixture was stirred for 0.5 h, then iodomethane (0.14 mL, 2.2 mmol) was added at the same temperature. The reaction mixture was allowed to warm to -10°C, stirred for 0.5 h, and poured into saturated aqueous ammonium chloride (50 mL). The resulting mixture was extracted with diethyl ether (50 mL). The extract was washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, and concentrated. The residue was purified by thin layer chromatography on silica gel using ethyl acetate:hexane (1:4) as the developing agent to give 146 g (71%) of the title compound as a colorless oil.

¹ H NMR (CDCl ₃ ): δ 8.28 (1H, d, J = 1.9 Hz), 7.75 (2H, d, J = 8.4 Hz), 7.59 (1H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.28 (1H, dd, J = 1.9, 8.4 Hz), 3.86 (1H, g, J = 7.3 Hz), 3.54 (3H, S), 1.54 (3H, d, J = 7.4 Hz), 1.30 (9H, s)

Step 3: Methyl dl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate

Methyl [1-tert-butoxycarbonyl-2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]propionate (from step 2, 270 mg, 0.72 mmol) was dissolved in trifluoroacetic acid (5 mL). After stirring for 10 min, the resulting mixture was concentrated. Saturated sodium bicarbonate (30 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (100 mL). The extract was washed

358

hydrogen (50 mL) and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using ethyl acetate:hexane (1:3) as eluent to give 210 mg (78%) of a yellow solid.

¹ H NMR (CDCl ₃ ): δ 8.89 (1H, br) , 7.78 (2H,d, J = 8.7 Hz) , 7.67 (1H,d , J = 8.7 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.40 7.37 (1H, m), 7.11 (1H, dd, J = 1.8, 8.7 Hz), 4.20 (1H, q, = 7.2 Hz), 3.64 (3H, s), 1.54 (3H, d, J = 7.2 Hz)

Example 219 dl-2-[2-(4-Chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid

The title compound was prepared as described in Example 9 (Method B) from methyl dl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate (from Example 218) ¹ H NMR (CDCl ₃ ): δ 8.77 (1H, brs), 7.82 (2H, d, J = 8.6 Hz), 7.75 (1H, d, J = 8.7 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.40 (1H, brs), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 4.29 (1H, q, J = 7.2 Hz), 1.61 (3H, d, J = 7.2 Hz)

Example 220

Methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 3-bromoacetylisoquinoline hydrobromide*.

¹ H NMR (CDCl ₃ ): δ 12.72 (1H, brs), 9.37 (1H, s), 8.80 (1H, s), 8.15 - 8.02 (2H, m), 7.87 - 7.76 (2H, m), 7.69 (1H,d,J • · ··«·

2.0 Hz), 7.48 (1H, d, J = 8.9 Hz), 7.32 (1H, dd, J = 2.0,

8.7 Hz), 4.33 (2H, s), 3.76 (3H, s) •Jlp _#

3-Bromoacetylisoquinoline hydrobromide is prepared from 3-acetylisoquinoline (D. L. Klayman et al., Arzneim. Forsch.,

1986, 36, 10) by the method described in H. McKennis, Jr., L. B. Turnbull, E. R. Bowman and E. Tamaki, J. Org. Chem., 1963, 28, 383-387.

¹ H NMR (DMSO-dg): δ 9.49 (1H, s), 8.68 (1H, s), 8.34 - 8.26 (2H, m), 7.99 - 7.88 (2H, m), 5.14 (2H, s)

Example 221 [5-Chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate (from Example 219).

MS (EI) m/z: 364 (M ⁺ )

Melting point: 239 to 240°C

IR (KBr) v: 3277, 1699, 1641, 1531, 1329, 1202, 1059, 961, 787 cm' ^{1 1} H NMR (DMSO-dg): δ 12.46 (1H, brs), 9.56 (1H, s), 8.69 (1H, s), 8.39 - 8.26 (2H, m), 7.99 - 7.90 (2H,m ), 7.87 (1H, d, J = 2.1 Hz), 7.72 (lH,d, J = 8.7 Hz), 7.35 (1H, dd, J = 2.1, 8.9 Hz), 4.13 (2H, s)

Example 222

Methyl [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl-trans-4-chloro-2-(phenylsul- 36ti.

phenylamino)cinnamate (from step 1 of Example 8, Method A) and 3-bromoacetylisoquinoline (the preparation of which is described in Example 210).

¹ H NMR (CDC1 ₃ ): δ 12.69, (1H, brs), 9.38 (1H, s), 8.81 (1H, s), 8.16 - 8.04 (2H, m ), 7.88 - 7.77 (2H, m), 7.65 (1H, d, J = 8.9), 7.57 (1H, d, J = 8.9 Hz). 2.0 Hz), 7.15 (1H, dd, J = 2.0 and 8.7 Hz), 4.36 (2H, s), 3.75 (3H, s)

Example 223 [6-Chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate (from Example 222).

MS (EI) m/z: 364 (M ⁺ )

Melting point: 236 to 237°C

IR (KBr) v: 3229, 1709, 1641, 1618, 1531, 1198, 793 cm ^{1 1} H NMR (DMSO-dg): δ 12.43 (1H, brs), 9.56 (1H, s), 8.70 (1H, s), 8.41 - 8.26 (2H, m), 7.99 - 7.87 (2H, m), 7.82 (1H, d, J = 8.7 Hz), 7.77 (1H, d, J = 1.5 Hz), 7.14 (1H, dd, J =

2.0, 8.6 Hz), 4.14 (2H, s)

Example 224

Methyl [5-chloro-2-(5-methylisoxazol-3-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 3-bromoacetyl-5-methylisoxazole (M. D. Amici et al., J. Org. Chem., 1989, 54, 2646).

¹ H NMR (CDCl ₃ ): δ 10.75 (1H, brs), 7.68 (1H, brs), 7.42 (1H, d, J = 8.2 Hz), 7.34 (1H, dd, J = 1.8, 8.1 Hz), 6.60 (1H, s), 4.25 (2H, S), 3.74 (3H, s). 2.56 (3H, s)

Example 225 [5-Chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate (from Example 224).

MS (EI) m/z: 318 (M ⁺ )

Melting point: 253 up to 255°C IR (KBr) at: 3379, 1699, 1639, 1539, 1425, 1259, 1207, 1059, 804 cm ^{-1 1} H NMR (DMSO-d 6 ): δ 11.76 (1H, brs), 7.81 (1H, d, J = 2.0 Hz), 7.59 (1H, d, J = 8.9 Hz), 7.29 (1H, dd, J = 2.0, 8.7 Hz), 6.67 (1H, s) , 4.00 (2H, s), 2.49 (3H, s)

Example 226

Methyl-[6-chloro-2-(5-methylisoxazol-3-carbonyl)-1H-indol-3-yl acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 3-bromoacetyl-5-methylisoxazole (M. D. Amici et al., J. Org. Chem., 1989, 54, 2646).

^Τ Η NMR (CDC1 ₃ ): δ 10.70 (1H, brs), 7.62 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J = 1.8 and 8.7 Hz), 6.60 (1H, brs), 4.27 (2H, s), 3.72 (3H, s), 2.56 (3H, s)

- ·36·2· —

Example 227 [6-Chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate (from Example 226).

MS (El) m/z: 318 (M ⁺ ) Melting point: 227 to 229°C IR (KBr) v: 3331, 1713, 1645, 1543, 1404, 1259, 1202, 891, 804 cm ^-1 *-Η NMR (DMSO-d ₆ ): δ 11.70 (1H, brs), 7.74 (1H, d, J = 8.7 Hz), 7.62 (1H, d, J = 1.3 Hz), Hz), 6.67 (1H, brs), 4.01 (2H, 7.07 (1H, dd, J = 1.8, s), 2.49 (3H, s) 8.6 Example 1 d 2 2 8

Methyl-[5-Chloro-2-(4-methyl-1,2,3-thiadiazol-5-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 5-bromoacetyl-4-methyl-1,2,3-thiadiazole hydrobromide*.

1H NMR (CDCl ₃ ): δ 9.00 (1H, brs), 7.63 (1H, brs), 7.34 (1H, dd, J = 1.8, 8.9 Hz), 7.28 (1H, d, J = 8.9 Hz), 3.81 (2H, s), 3.66 (3H, s), 2.78 (3H, s)

5-Bromoacetyl-4-methyl-1,2,3-thiadiazole hydrobromide is prepared as follows:

N-Methoxy-N-methyl-4-methyl-1,2,3-thiadiazole-5-carboxamide • · ·

To a solution of 1,2,3-triadiazole-5-carbonyl chloride (10.00 g, 61.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.20 g, 73.8 mmol) in dichloromethane (200 ml) at 0°C was added triethylamine (20.6 ml, 147.6 mmol). The resulting mixture was stirred at room temperature for 2 hours and then diluted with dichloromethane (300 ml). The dichloromethane mixture was washed with water (200 ml x 2), dried over magnesium sulfate, and the solvent was removed. 11.31 g (98%) of the title compound was obtained as brown crystals.

¹ H NMR (CDCl ₃ ): δ 3.75 (3H, s), 3.40 (3H, s), 3.01 (3H, s)

5-Acetyl-4-methyl-1,2,3-thiadiazole

To a solution of N-methoxy-N-methyl-4-methyl-1,2,3-thiadiazole-5-carboxamide (11.31 g, 60.4 mmol) in tetrahydrofuran (100 mL) was added a 2M solution of methylmagnesium bromide in diethyl ether (45.3 mL, 90.6 mmol) over 0.5 h at 0°C. The reaction mixture was allowed to warm to room temperature, stirred for 3 h, and quenched with ammonium chloride (100 mL). The resulting mixture was extracted with diethyl ether (200 mL x 2). The extracts were dried over magnesium sulfate and concentrated to give 7.49 g (87%) of the title compound as a light brown oil. ¹ H NMR (CDCl ₃ ): δ 2.96 (3H, s), 2.67 (3H, s)

5-Bromoacetyl-4-methyl-1,2,3-thiadiazole

To a solution of 5-acetyl-4-methyl-1,2,3-thiadiazole (1.00 g, 7.03 mmol) in chloroform (20 mL) was added dropwise a solution of bromine (1.24 g, 7.73 mmol) in chloroform (10 mL) over 0.5 h at room temperature. The reaction mixture was refluxed for 2 h, cooled to room temperature and basified with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (100 mL x 2). The extracts were dried over sodium sulfate and concentrated to give 1.55 g (100%) of the title compound as a brown oil.

- 3&Í ^Χ Η NMR (CDC1 ₃ ): δ 4.28 (2H, s), 2.98 (3H, s)

Example 229 [5-Chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid

A mixture of methyl-[5-Chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate (from Example 228, 190 mg, 0.54 mmol), 2M aqueous hydrochloric acid (4 mL) and acetic acid (20 mL) was heated to reflux for 2 hours, then cooled to room temperature and concentrated. The crystalline residue was diluted with tetrahydrofuran. The resulting mixture was dried over magnesium sulfate and concentrated. The solid residue was washed with ethyl acetate. 145 mg (79%) of the title compound was obtained as a yellow solid.

MS (E1) m/z: 335 (M ⁺ ) Melting point: 229 up to 230°C IR (KBr) at: 3300, 1715, 1622, 1526, 1329, 1261, 1204, 1063 , 1009, 822 cm ^-1 ^-H NMR (DMSO-dg ) : δ 11.92 (1H, brs) , 7.89 (1H, d, J = 2.0 Hz), 7.48 (1H, d, J = 8.9 Hz), 7.36 (1H, dd, J = 2.0, 8.9

Hz), 3.95 (2H, s), 2.63 (3H, s)

Example 230

Methyl [6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 5-bromoacetyl-4-methyl-1,2,3-thiadiazole (the preparation of which is described in Example 228).

tle: Rf = 0.56 (ethyl acetate : hexane, 1:2)

- 3.S5·.-.·

Example 231 [6-Chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 229 from methyl-[6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate (from Example 230) MS (EI) m/z: 335 (M ⁺ )

Melting point: 215 to 216 °C

IR (KBr) Vi 3300, 1709, 1645, 1531, 1327, 1211, 1065, 922,

789 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 12.35 (1H,b rs), 11.86 (1H, brs), 7.82 (1H, d, J = 8.7 Hz), 7.47 (1H, d, J = 1.8 Hz), 7.17 (1H, dd,

J = 1.8, 8.6 Hz), 3.93 (2H, s), 2.63 (3H, s)

Example 232

Methyl-[5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-5-methylthiazole hydrobromide.

^•H NMR (CDCl ₃ ): δ 11.74 (1H, brs), 7.76 (1H, d, J = 1.1 Hz), 7.67 (1H, d, J = 1.8), 7.43 (1H, d, J = 8.7 Hz), 7.32 (1H, dd, J = 2.0, 8.7 Hz), 4.28 (2H, s). 3.73 (3H, s), 2.62 (3H, d, J = 1.0 Hz) *2-Bromoacetyl-5-methylthiazole is prepared from 2-acetyl-5-methylthiazole (Metzger et al., Bull. Soc., Chim. Fr.,

1953, 702) by the method described in H. McKennis, Jr., L. B. Turnbull, E. R. Bowman and E. Tamaki, J. Org. Chem., 1963, 28, 383-387.

• ·

- w·-.

¹ H NMR (DMSO-dg): δ 7.91 (1H, d, J = 1.2 Hz), 4.87 (2H, s), 2.58 (3H, d, J = 0.8 Hz)

Example 233 [5-Chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 232).

MS (EI) m/z: 334 (M ⁺ )

Melting point: 231 to 233°C

IR (KBr) v: 3348, 1699, 1630, 1541, 1404, 1333, 1271, 1057, 1003, 804 cm ^{-1 Σ} Η NMR (DMSO-d ₆ ): δ 12.05 (1H, brs), 8.04 (1H, s), 7.88 (1H, brs), 7.77 (1H, d, J = 8.7 Hz), 7.35 (1H, brd, J = 8.9 Hz), 4.15 (2H, s), 2.63 (3H, s)

Example 234

Methyl [6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-5-methylthiazole (the preparation of which is described in Example 232).

¹ H NMR (CDCl ₃ ): δ 11.73 (1H, brs), 7.77 (1H, s), 7.62 (1H, d, J = 8.2 Hz), 7.51 (1H, brs), 7.14 (1H, brd, J = 8.7 Hz), 4.31 (2H, s), 3.72 (3H, s), 2.62 (3H, s)

- w-.’

Example 235 [6-Chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 234).

MS (EI) m/z: 334 (M ⁺ )

Melting point: 225 to 226°C

IR (KBr) at: 3277, 1707, 1630, 1541, 1398, 1350, 1231, 1219, 1138, 878, 800 cm •1 ¹ H NMR (DMSO-d ₆ ): δ 12, 25 (IH, brs), 11.99 (IH, brs), 8.04 (IH, s), 7.82 (IH, s) , 7.81 (1H, d, J = 9, 0Hz), 7.13 (IH, brd, J = 8.7 Hz), 4.15 (2H, s), 2.63 (3H, s) P ř Example 236

[6-Chloro-2-(2-thienyl)carbonylindol-3-ylacetic acid

Step 1: 6-chloro-2-(2-thienylcarbonyl)-1-(phenylsulfonyl)indole

The title compound was prepared according to the method described in Step 2 of Example 2 (Method B) from 6-chloro-1-(phenylsulfonyl)indole (from Step 1 of Example 2, Method B) and 2-thienoyl chloride.

¹ H NMR (CDCl ₃ ): δ 8.13 - 8.16 (3H, m), 7.77 - 7.80 (2H, m), 7.50 - 7.63 (4H, m), 7.29 (IH, dd, J = 1.8, 8.4 Hz), 7.19 (IH, t, J = 5.4 Hz), 7.03 (IH, s)

Step 2: 6-Chloro-2-(2-thienylcarbonyl)indole

The title compound was prepared according to the method described in Step 3 of Example 2 from 6-chloro-2-(2-thienylcarbonyl)-1-(phenylsulfonyl)indole (from Step 1).

¹ H NMR (CDCl ₃ ): δ 10.96 (1H, brs), 8.01 (1H, dd, J = 1.2,

3.8 Hz), 7.73 (1H, dd , J = 1.2, 4.9 Hz), 7.64 (1H, d, J = 8.6 Hz) , 7.54 - 7.55 (1H, m), 7 .35 · - 7.37 (1H, m), 7.23 (1H, dd, J = 3.8, 4.9 Hz), 7.10 (1H, dd, J = 1.8, 8 .6 Hz)

Step 3: Diethyl-α-acetoxy-[6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 4 of Example 2 (Method B) from 6-chloro-2-(2-thienylcarbonyl)indole (from Step 2).

¹ H NMR (CDCl ₃ ): δ 8.93 (1H, brs), 7.82 (1H, d, J = 8.9 Hz), 7.76 (1H, d, J = 4.9 Hz), 7.55 (1H, d, J = 3.8 Hz), 7.39 (1H, d, J = 1.8 Hz), 7.11 - 7.18 (2H, m), 4.16 - 4.31 (4H, m), 1.87 (3H, s), 1.17 - 1.32 (6H, m)

Step 4: Diethyl [6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]malonate

The title compound was prepared according to the method described in Step 5 of Example 2 (Method B) from diethyl α-acetoxy-[6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl]malonate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 9.27 (1H, brs), 7.71 - 7.75 (2H, m), 7.60 - 7.66 (1H, m), 7.05 - 7.17 (3H, m), 5.56 (1H, s), 4.07 - 4.26 (4H, m), 1.20 - 1.28 (6H, m)

Step 5: [6-Chloro-2-(2-thienyl)carbonylindol-3-yl]acetic acid

The title compound was prepared as described in Step 6 of Example 2 (Method B) from diethyl [6-chloro-2-(2-thienylcarbonyl)-1H-indol-3-yl] malonate (from Step 4).

MS (EI) m/z: 319 (M ⁺ )

Melting point: 177 to 178°C

IR (KBr) v: 3323, 1701, 1593, 1568, 1524, 1435, 1412, 1323, 1258, 1229, 920 cm ^-1 ^H NMR (DMSO-dg): δ 12.25 (1H, brs), 11.85 (1H, brs), 8.13 (1H, d, J = 4.9 Hz), 7.89 (1H, d, J = 3.6 Hz), 7.74 (1H, d, J = 8.7 Hz), 7.51 (1H, d, J = 1.8 Hz), 7.34 (1H, t, J = 4.8 Hz), 7.15 (1H, dd, J = 1.8, 8.7 Hz), 3.96 (2H, s)

Example 237

Methyl-[6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate

The reaction is carried out according to the procedure described in Example 57 using methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-chloroacetyl-3-(1-hydroxy-1-methylethyl)furan*.

¹ H NMR (CDCl ₃ ): δ 9.89 (1H, brs), 7.59 (1H, d, J = 1.6 Hz), 7.53 (1H, d, J = 8.7 Hz), 7.34 (1H, d, J = 1.5 Hz), 7.08 (1H, dd, J = 1.6, 8.7 Hz), 6.57 (1H, d, J = 1.8 Hz), 6.39 (1H, brs), 4.22 (2H, s), 3.73 (3H, s), 1.57 (6H, s) *2-Chloroacetyl-3-(1-hydroxy-1-methylethyl)furan is prepared as follows:

To a solution of 2-(3-furyl)-2-propanol (T. M. Bargar et al., J. Med. Chem., 1986, 29, 315, 2.0 g, 15.85 mmol) in tetrahydrofuran (100 ml) at -78°C was added a solution of n-butyllithium in hexane (1.55M, 30.7 ml, 47.55 mmol). The resulting mixture was stirred for 1 hour and 2-chloro-N-methoxy-N-methylacetamide (6.54 g, 47.55 mmol) was added at 0°C. Saturated aqueous ammonium chloride (100 ml) was added to the reaction mixture. The organic layer was separated and washed with water (100 ml x 2) and brine (50 ml), dried over magnesium sulfate and the solvent was removed. The residue is purified by flash • · ···· ··

Chromatography using ethyl acetate:hexane 1:4 as eluent gave 1.03 g (32%) of the title compound as an oil.

¹ H NMR (CDCl ₃ ): δ 7.52 (1H, d, J = 1.8 Hz), 6.57 (1H, d, J = 1.8 Hz), 5.51 (1H, s), 4.74 (2H, s), 1.56 (6H, s)

Example 238 [6-Chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate (from Example 237).

MS (EI) m/z: 361 (M ⁺ )

Melting point: 229 to 230°C

IR (KBr) v: 3270, 2980, 1270, 1591, 1564, 1522, 1398, 1302, 1263, 1200, 785 cm' ^{1 1} H NMR (DMSO-d ₆ ): δ 11.78 (1H, brs), 7.97 (1H, d, J = 1.6 Hz), 7.77 (1H, d, J = 8.6 Hz), 7.56 (1H, d, J = 1.5 Hz),

7.13 (1H, dd, J = 1.8, 8.6 Hz), 6.87 (1H, d, J = 1.6 Hz), 5.69 (1H, brs), 3.96 (2H, s), 1.53 (6H, s)

Example 239

Methyl-[6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-chloroacetyl-3-(methoxymethyl)furan.

1H NMR (CDCl ₃ ): δ 9.81 (1, brs), 7.60 (1H, d, J = 1.6 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.40 (1H, d, J = 1.5 Hz), 7.10

3*7.1

(1H, dd, J = 1.8, 8.7 Hz), 6.79 (1H, d, J = 1.6 Hz), 4.81 (2H, s), 4.26 (2H, s), 3.74 (3H, s), 3.48 (3H, s) *2-Chloroacetyl-3-(methoxymethyl)furan is prepared from 3-(methoxymethyl)furan (N. Greeves et al., Synthesis,

1993, 1109) by the method described in Example 237 for the preparation of 2-chloroacetyl-3-(1-hydroxy-1-methylethyl)furan.

^H NMR (CDCl ₃ ): δ 7.52 (1H, d, J = 1.8 Hz), 6.74 (1H, d, J = 1.8 Hz), 4.73 (2H, s), 4.62 (2H, s), 3.44 (3H, s)

Example 240 [6-Chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate (from Example 239).

MS (EI) m/z: 347 (M ⁺ )

Melting point: 212 to 213°C

IR (KBr) v: 3373, 3221, 1720, 1601, 1576, 1529, 1205, 1173, 1115, 1088 cm" ^{1 1} H NMR (DMSO-dg): δ 11.72 (1H, brs), 8.04 (1H, d, J = 1.6 Hz), 7.76 (1H, d, J = 8.7 Hz), 7.59 (1H, d, J = 1.5 Hz),

7.12 (1H, dd, J = 1.8, 8.7 Hz), 6.86 (1H, d, J = 1.6 Hz), 4.70 (2H, s), 4.02 (2H, s), 3.36 (3H, s)

Example 241 [6-Chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid

Step 1: Methyl-[6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate • ·

- 372·*..’

The title compound was prepared as described in Step 2 of Example 31 from methyl trans-4-chloro-2-(ethoxycarbonylamino)cinnamate (from Step 1 of Example 31) and 2-bromoacetyl-1-methylimidazole hydrobromide.

MS (El) m/z: 405 (M ⁺ ) *2-Bromoacetyl-1-methylimidazole hydrobromide was prepared from 2-acetylmethylimidazole by the method described in step 2 of Example 31 for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide. ¹ H NMR (DMSO-d ₆ ): δ 7.69 (1H, s), 7.27 (1H, s), 4.68 (2H, s), 3.81 (3H, s)

Step 2: [6-Chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Step 3 of Example 31 from methyl [6-chloro-1-ethoxycarbonyl-2-(1-methylimidazole-2-carbonyl)indolin-3-yl]acetate (from Step 1).

Melting point: 235.5°C

IR (KBr) v: 3238, 1695, 1630, 1538, 1402, 1229, 1146 cm" ^{1 1} H NMR (CDC1 ₃ ): δ 12.3 (1H, brs), 7.64 (1H, d, J = 8.7 Hz), 7.50 (1H, d, J = 1.8 Hz), 7.41 (1H, s), 7.16 (1H, s), 7.09 (1H, dd, J = 1.8, 8.6 Hz), 4.25 (2H, s), 4.13 (3H, s)

Example 242

Methyl [6-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate

To a stirred solution of [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid (from Example 241, 651 mg, 0.21 mmol) in methanol (10 mL) at room temperature was added [trimethylsilyl]diazomethane (1.0M solution in hexanes, 1.05 mL, 2.1 mmol). The resulting mixture was stirred for 19 h and then concentrated. The residue was purified by thin layer chromatography using a 1:2 mixture of ethyl acetate and hexane as the developing agent to give 20 mg (23%) of the title compound as a yellow solid.

¹ H NMR (CDCl ₃ ): δ 12.35 (1H, brs), 7.59 (1H, d, J = 8.0 Hz) 7.49 (1H, d, J = 1.5 HZ), 7.24 (1H, s), 7.11 (1H, dd, J = 1.7, 8.1 Hz), 7.08 (1H, sj, 4.30 (2H, s), 4.12 (3H, s), 3.71 (3H, s)

Example 243

Methyl-[5-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-1-methylimidazole hydrobromide (the preparation of which is described in Example 241).

¹ H NMR (DMSO-d ₆ ): δ 12.28 (1H, brs), 7.85 (1H, s), 7.77 (1H, d, J = 8.7 Hz), 7.66 (1H, s), 7.33 - 7.29 (2H, m), 4.21 (2H, s), 4.03 (3H, s), 3.60 (3H, with)

Example 244 [5-Chloro-2-(1-methylimidazole-2-carbonyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 243).

Melting point: 230 to 233°C ¹ H NMR (DMSO-dg): δ 12.50 (1H, brs), 7.84 (1H, s), 7.76 (1H, d, J = 13.2 Hz) 7.66 (1H, s), 7.35 - 7.28 (2H, m), 4.15 (2H, s), 4.06 (3H, s)

- 37.4—.Z

Example 245

Methyl-[5-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate

Step 1: Methyl-[5-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazol-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-chloroacetyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole.

¹ H NMR (CDCl ₃ ): δ 12.38 (1H, brs), 7.66 (1H, s), 7.46 - 7.38 (2H, m), 7.34 - 7.29 (2H, m), 5.95 (2H, s), 4.29 (2H, s), 3.73 (3H, s), 3.66 (2H, t, J = 8.0 Hz), 0.98 (2H, t, J = 8.0 Hz), 0.03 (9H, s)

2-Chloroacetyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole is prepared as follows:

To a stirred solution of 1-[2-(trimethylsilyl)ethoxymethyl]imidazole (Jeffrey P. Whitten et al., J. Org. Chem., 51, 1891 (1986), 3.0 g, 15 mmol) in tetrahydrofuran (30 ml) at -78 °C was added dropwise n-butyllithium (1.55M in n-hexane, 11.0 ml, 17 mmol). The resulting mixture was stirred for 1 hour and 2-chloro-N-methoxy-N-methylacetamide (2.4 g, 17 mmol) was added at the same temperature. The reaction mixture was allowed to warm to 0 °C, stirred for a further 2 hours and poured into water (50 ml). The aqueous mixture was extracted with ethyl acetate (80 ml), dried over magnesium sulfate and concentrated. The brown oily residue was purified by flash column chromatography using ethyl acetate:hexane (1:4) as eluent to give 1.2 g (32%) of the title compound as a yellow oil. ¹ H NMR (CDCl ₃ ): δ 7.39 (1H, s), 7.25 (1H, s), 5.81 (2H, s), 4.96 (2H, s), 3.60 (2H, t, J = 8.2 Hz), 0.95 (2H, t, J = 8.2 Hz), 0.02 (9H, s) • ·

- 373..-Step 2: Methyl-[5-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate

To a solution of methyl-[5-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazole-2-carbonyl]-1H-indol-3-yl]acetate (from Step 1, 300 mg, 0.67 mmol) in methanol (10 mL) was added 2M aqueous hydrochloric acid (7 mL). The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, and concentrated. Aqueous sodium bicarbonate (10 mL) was added to the residue, and the resulting mixture was concentrated. The yellow solid residue was dissolved in tetrahydrofuran. The tetrahydrofuran solution was dried over magnesium sulfate and the solvent was removed. 220 mg (100%) of the title compound was obtained as a yellow solid.

¹ H NMR (CDCl ₃ ): δ 12.16 (1H, brs), 10.80 (1H, brs), 7.68 (1H, s), 7.50 - 7.28 (5H, m), 4.29 (2H, s), 3.70 (3H, s)

Example 246 [5-Chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 245).

Melting point: 253 to 254°C ¹ H NMR (DMSO-dg): δ 12.28 (1H, brs), 7.84 (1H, d, J = 2.0 Hz), 7.80 (1H, d, J = 9.1 Hz), 7.32 (1H, dd, J = 2.0, 9.1 Hz), 4.17 (2H, s)

Example 247

Methyl [6-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate

376»<— «« *.·* .

Step 1: Methyl-[6-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazol-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-chloroacetyl-1-[2-(trimethylsilyl)ethoxymethyl]imidazole (the preparation of which is described in Step 1 of Example 245).

^Χ Η NMR (CDCl ₃ ): δ 12.34 (1H, brs), 7.61 (1H, d, J = 8.6 Hz), 7.52 (1H, d, J = 1.6 Hz), 7.40 (1H, d, J = 1.4 Hz), 7.31 (1H, d, J = 1.4 Hz), 7.13 (1H, dd, J = 1.4 Hz). 1.6, 8.6 Hz), 5.95 (2H, s), 4.32 (2H, s), 3.72 (3H, s), 3.67 (2H, t, J = 8.0 Hz), 1.00 (2H, t, J = 8.0 Hz), 0.02 (9H, s)

Step 2: Methyl-[6-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 245 from methyl-[6-chloro-2-[1-[2-(trimethylsilyl)ethoxymethyl]imidazole-2-carbonyl]-1H-indol-3-yl]acetate (from Step 1).

^Χ Η NMR (CDC1 ₃ ): δ 12.50 (1H, brs), 7.68 - 7.48 (2H, m), 7.40 - 7.30 (1H, m), 7.19 - 7.06 (1H, m), 6.97 - 6.92 (1H, m),

4.30 (2H, s), 3.67 (3H, s)

Example 248 [6-Chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 247).

Melting point: 252 to 253°C ¹ H NMR (DMSO-dg): δ 13.63 (1H, brs), 12.40 - 12.15 (2H, br), 7.88 (1H,d, J = 1.8 Hz), 7.78 (1H, d, J = 8.6 Hz), 7.59 (1H, s), 7.40 (1H, s), 7.11 (1H, dd, J = 1.8, 8.6 Hz), 4.18 (2H, s)

37Ψ

Example 249

Methyl [5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William B. et al., Aust. J. Chem., 1985, 38, 1257).

¹ H NMR (DMSO-d ₆ ): δ 12.02 (1H, brs), 7.93 - 7.85 (2H, m), 7.75 (1H, d, J = 8.9 Hz), 7.38 (1H, dd, J = 2.0, 8.9 Hz), 4.23 (2H, s), 3.60 (3H, s), 2.61 (3H, s)

Example 250 [5-Chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 249).

Melting point: 218 to 220°C ¹ H NMR (DMSO-dg): δ 11.97 (1H, brs), 7.89 (1H, d, J = 2.0 Hz), 7.75 (1H, d, J = 8.7 Hz), 7.37 (1H, dd, J = 2.0, 8.7 Hz), 4.13 (2H, s), 2.62 (3H, s)

Example 251

Methyl [5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and

of 2-chloroacetyl-1-methylpyrrole (P. D. Croce et al., Synthesis, 1990, 212).

¹ H NMR (DMSO-d ₆ ): δ 11.8 (1H, brs), 7.80 (1H, brs), 7.55 (1H, d, J = 8.6 Hz), 7.40 - 7.32 (2H, m), 6.95 - 6.90 (1H, m), 6.35 - 6.26 (1H, m), 4.00 (2H, s), 3.43 (3H, s), 2.50 (3H, s)

Example 252 [5-Chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid

A mixture of methyl-[5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 251, 250 mg, 0.79 mmol) and potassium carbonate (900 mg, 6.4 mmol) in a 1:1 methanol-water mixture (40 mL) was heated to reflux for 1 h, then cooled to room temperature and concentrated. The residue was neutralized with 2M aqueous hydrochloric acid and extracted with ethyl acetate (50 mL x 2). The combined extracts were dried over magnesium sulfate and concentrated. The solid residue was recrystallized from ethyl acetate-hexane to give 40 mg (23%) of the title compound as a pale yellow solid, mp 203-205°C.

¹ H NMR (DMSO-dg): δ 11.56 (1H, brs), 7.57 (1H, s), 7.33 (1H, d, J = 8.6 Hz), 7.20 - 7.10 (2H, m), 6.72 (1H, s), 6.10 (1H, s), 3.81 (2H, s), 2.52 (3H, s)

Example 253

Methyl-[5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-yl3-acetate

The title compound was prepared as described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and

379

4-bromoacetyl-2-methylimidazole (Deady, Leslie W. et al., Aust. J. Chem., 1981, 34, 1295).

^Σ Η NMR (DMSO-dg): δ 12.04 (1H, brs), 8.51 (1H, s), 7.86 (1H, d, J = 2.0 Hz), 7.71 (1H, d, J = 8.9 Hz), 7.34 (1H, dd, J = 2.0, 8.9 Hz), 4.17 (2H, s), 3.59 (3H, s), 2.71 (3H, s)

Example 254 [5-Chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate (from Example 253).

Melting point: 237 to 238°C ¹ H NMR (DMSO-dg): δ 12.03 (1H, br), 12.00 (1H, s), 8.49 (1H, s), 7.83 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 8.9 Hz), 7.34 (1H, dd, J = 2.0, 8.9 Hz), 4.09 (2H, s), 2.87 (3H, s)

Example 255

Methyl [5-chloro-2-(thiazol-5-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and 5-bromoacetylthiazole hydrobromide.

¹ H NMR (CDCl ₃ ): δ 12.05 (1H, brs), 9.51 (1H, s), 8.62 (1H, s), 7.85 (1H, d, J = 1.9 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.35 (1H, dd, J = 1.9, 8.7 Hz), 4.09 (2H, s), 3.59 (3H, s)

5-Bromoacetylthiazole hydrobromide was prepared from 5-acetylthiazole by the method described in step 2 of Example 31 for the preparation of 2-bromoacetyl-4-methylpyridine hydrobromide.

¹ H NMR (DMSO-dg): δ 9.49 (1H, s), 8.34 (1H, s), 4.91 (2H, s)

- 380..-*·..«

Example 256 [5-Chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate (from Example 255).

Melting point: 175 to 180°C ¹ H NMR (DMSO-d ₆ ): δ 11.80 (1H, brs), 9.48 (1H, s), 8.74 (1H, s), 7.78 (1H, s), 7.48 (1H, d, J = 8.7 Hz), 7.30 (1H, d, J = 8.9 Hz), 3.81 (2H, s)

Example 257

Methyl [6-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method B) and 2-bromoacetyl-4-methylthiazole hydrobromide (Cowden, William B. et al., Aust. J. Chem., 1985, 38, 1257). 1H NMR (DMSO-d 6 ): δ 11.95 (1H, brs), 7.9O(1H, s), 7.84 (1H, d, J = 8.7 Hz), 7.84 (1H, d, J = 2.0 Hz), 7.15 (1H, d, J = 2.0 Hz), 4.24 (2H, s), 3.60 (3H, s), 2.62 (3H, s)

Example 258 [6-Chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate (from Example 257).

Melting point: 239 to 240°C ¹ H NMR (DMSO-dg): δ 11.80 (1H, brs), 7.75 (1H, s), 7.68 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 2.0 Hz), 7.02 (1H, dd, J = 2.0, 8.4 Hz), 4.03 (2H, s), 2.49 (3H, s)

Example 259

Methyl-[5-chloro-2-[3-(ethoxycarbonyl)isoxazol-5-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (from Step 3 of Example 36) and ethyl 5-(bromoacetyl)isoxazole-3-carboxylate.

¹ H NMR (DMSO-dg): δ 12.07 (1H, brs), 7.93 (1H,d, J = 1.9 Hz), 7.70 (1H,s), 7.39 (1H, dd, J = 1.9, 12.8 Hz), 7.62 (1H, d, J = 12.8 Hz), 4.44 (2H, q, J = 7.1 Hz), 4.15 (2H, s),

3.60 (3H, s), 1.37 (3H, t, J = 7.1 Hz)

Example 260 [5-Chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid

To a solution of methyl-[5-chloro-2-[3-(ethoxycarbonyl)isoxazole-5-carbonyl]-1H-indol-3-yl]acetate (from Example 259, 314 mg, 0.80 mmol) in acetic acid (20 mL) was added 2M aqueous hydrochloric acid (6.0 mL). The resulting mixture was heated at 110°C for 5 h, then cooled to room temperature and concentrated. The yellow solid residue was washed with ethyl acetate and recrystallized from ethyl acetate-hexane to give 120 mg (43%) of the title compound as a yellow solid, mp 200-205°C.

¹ H NMR (DMSO-dg): δ 12.01 (1H, s), 7.91 (1H, s), 7.65 - 7.56 (2H, m), 7.39 (1H, d, J = 8.9 Hz), 4.06 (2H, s)

382

Example 261

Methyl-[6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and •φς bromomethylcyclopropylketone.

¹ H NMR (CDCl ₃ ): δ 9.55 (1H, brs), 7.58 (1H, d, J = 8.56 Hz), 7.26 (1H, d, J = 1.97 Hz), 7.10 (1H, dd, J = 8.56 Hz, 1.97 Hz), 4.17 (2H, s), 3.73 (3H, s), 2.58 - 2.49 (1H, m ), 1.30 1.25 (2H, m), 1.09 - 1.02 (2H, m) *Bromomethylcyclopropylketone is prepared from cyclopropylmethylketone by the method described in Example 189 for the preparation of 4-(trifluoromethoxy)phenacyl bromide.

^Χ Η NMR (CDC1 ₃ ): δ 3.91 (2H, s), 2.65 (2H, t, J = 6.94 Hz), 1.20 - 0.98 (4H, m)

Example 262 [6-Chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid

The title compound was prepared according to the method described in Example 9 (Method B) from methyl [6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate (from Example 261).

Melting point: 207 up to 210°C IR (KBr) at: 3304, 3013, 1709, 1624, 1566, 1443, 1414 , 1387 1340, 1286, 1248, 1217, 1200, 1157, 1057, 1045, 1022 cm ^{-1 1} H NMR (DMSO-d 6 ): δ 11, 98 (1H, brs), 7.75 (1H, d, J = 8.75 Hz), 7.48 (1H, d, J = 1 .81 Hz), 7.11 (1H, dd, J = 8, 75 Hz, 1.81 Hz), 4.08 (2H, s), 2.73 (1H, quintet , 6.24 Hz), 1.07 (4H, d, J = 6.24 Hz)

- 383 Example 263

Methyl-[6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and β-bromomethylcyclobutyl ketone.

¹ H NMR (CDCl ₃ ): δ 9.35 (1H, brs), 7.53 (1H, d, J = 8.72 Hz), 7.18 (1H, d, J = 1.65 Hz), 7.07 (1H, dd, J = 8.72 Hz, 1.65 Hz), 4.10 (2H, s), 3.77 (3H, s), 3.72 (1H, m), 2.44 - 1.86 (6H, m) *Bromomethylcyclobutyl ketone is prepared from cyclobutyl methyl ketone by the method described in Example 189 for the preparation of 4-(trifluoromethoxy)phenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 3.88 (2H, s), 3.60 (1H, m), 2.33 - 1.80 (6H, m)

Example 264 [6-Chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate (from Example 263). Melting point: 225-228°C

IR (KBr) in: 3303, 2954, 1705, 1632, 1564, 1529, 1437, 1412,

1335, 1242, 1213, 1188, 1157, 1056, 1024 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 11.63 (1H, brs), 7.71 (1H, d, J = 8.72

Hz), 7.46 (1H, d, J = 1.81 Hz), 7.09 (1H, dd, J = 8.72 Hz,

1.81 Hz), 4.04 (2H, s), 2.30 - 1.78 (7H, m)

- 384./

Example 265

Methyl-[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-tert-butyl-2-(p-toluenesulfonylamino)cinnamate (from Step 2 of Example 143) and 4-chlorophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 8.82 (1H, brs), 7.8 - 7.31 (7H, m), 3.87 (2H, s), 3.67 (3H, s), 1.38 (9H, s)

Example 266 [5-(tert-Butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl-[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (from Example 265). Melting point: 171°C

IR (KBr) vz 3241, 2963, 1699, 1634, 1589/1541, 1394, 1331, 1222, 1091, 1011 cm ^{-1 1} H NMR (DMSO-dg): δ 11.48 (IH, brs), 7.78 - 7.37 (7H, m), 3.85 (2H, s), 1.34 (9H, s)

Example 267 [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N,N-dimethylacetamide

The title compound was prepared as described in Example 43 from [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid (from Example 31). Melting point: 208°C (decomposition)

- 38S

IR (KBr) v: 3233, 1655, 1638, 1524, 1398, 1200, 1134 cm ^{1 1} H NMR (DMSO-dg): δ 12.54 (1H, brs), 8.62 (lH,d, J = 5.0 Hz), 8.15 (1H, br), 7.79 (1H, d, J = 8.7 Hz), 7.49 (1H, d, J = 1.8 Hz), 7.40 - 7.30 (1H, m), 7.09 (1H, dd, J = 1.8, 8.7 Hz), 4.43 (2H, s), 3.16 (3H, s), 2.98 (3H, s), 2.48 (3H, s)

Example 268 [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methylacetamide

The title compound was prepared as described in Example 43 from [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid (from Example 31) and methylamine hydrochloride.

Melting point: 231°C

IR (KBr) Vi 3306, 1643, 1595, 1560, 1526, 1277, 1202, 979 cm ¹ H NMR (CDCl ₃ ): δ 12.45 (1H, br), 8.64 (1H, d, J = 4.9 Hz),

8.19 (1H, brs), 7.85 (1H, d, J = 8.6 Hz), 7.50 (1H, br), 7.40 (1H, brd, J = 4.6 Hz), 7.15 (1H, dd, J = 1.6, 8.9 Hz), 6.67 (1H, br) , 4.14 (2H, s), 2.73 (3H, d, J = 4.8 Hz), 2.51 (3H, s) Appendix 1 ad 2 6 9

[5-Chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)acetamide

The title compound was prepared as described in Example 43 from [5-chloro-2-(4-methylpyridin)-1H-indol-3-yl]acetic acid (from Example 36) and 2-aminoethanol. MS (EI) m/z: 371 (M ⁺ )

Melting point: 195.9°C ^X H NMR (DMSO-dg): δ 12.28 (1H, brs), 8.69 (1H, d, J = 4.9 Hz), 7.94 (1H, brs), 7.78 (2H, m ), 7.66 (1H, d, J = 8.7 Hz),

386

7.56 (1H, m), 7.31 (1H, dd, J = 2.0 Hz, 8.7 Hz), 3.94 (2H, s), 3.09 (2H, dd, J = 5.93 Hz, 11.86 Hz), 2.47 (3H, s)

Example 270 [5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methoxyacetamide

The title compound was prepared as described in Example 43 from [5-chloro-2-(4-methylpyridin)-1H-indol-3-yl]acetic acid (from Example 36) and O-methylhydroxylamine hydrochloride.

MS (E1) m/z: 357 (M ⁺ ) ^H NMR (CDC1 ₃ ): δ 12.53 (1H, brs), 9.54 (1H, brs), 9.54 (1H, brs), 8.65 (1H, d, J = 5.1 Hz), 8.19 (1H, brs), 7.92 (1H, brs), 7.42 (2H, m), 7.34 (1H, dd, J = 1.7 Hz, 8.9 Hz), 4.01 (2H, s), 3.74 (3H, s), 2.52 (3H, s)

Example 271

2-[5-Chloro-2-(4-methylpyridin-2-carbonyl-1H-indol-3-yl]-1-(1-piperazinyl)-1-ethanone

Step 1: 2-[5-Chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-1-(4-tert.butoxycarbonyl-1-piperazinyl)-1-ethanone

The title compound was prepared as described in Example 43 from [5-chloro-2-(4-methylpyridin)-1H-indol-3-yl]acetic acid (from Example 36) and tert-butyl-1-piperidinecarboxylate.

¹ H NMR (CDCl ₃ ): δ 12.61 (1H, brs), 8.62 (1H, d, J = 5.1 Hz), 8.14 (1H, brs), 7.84 (1H, s), 7.42 (1H, d, J = 8.7 Hz), 7.37 (brd, 1H, J = 4.9 Hz), 7.30 (1H, dd, J = 2.0 Hz, 8.9 Hz),

38?

4.42 (2H,s), 3.66 (3H,m), 2.50 (3H,s), 1.64 (4H,m), 1.46 (9H,s)

Step 2: 2-[5-Chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]-1-(1-piperazinyl)-1-ethanone

To a solution of 2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(4-tert-butoxycarbonyl-1-piperazinyl)-1-ethanone (from step 1, 152.6 mg, 0.042 mmol) in tetrahydrofuran (1 mL) at 0°C was added dropwise trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was diluted with dichloromethane (25 mL). The dichloromethane mixture was washed with saturated aqueous sodium bicarbonate (25 mL). The aqueous layer was extracted with dichloromethane (25 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography using a 1:10 mixture of methanol and dichloromethane as eluent. 80.8 mg of the title compound are obtained in the form of yellow crystals.

MS (EI) m/z: 396 (M ⁺ )

Melting point: 205.0°C

IR (KBr) v: 3244, 1647 1595, 1525, 1429, 1205 cm ^{-1 1} H NMR (DMSO-dg): δ 12.28 (1H, brs), 8.68 (1H, d, J = 4.9 Hz), 7.90 (1H, brs), 7.81 (1H, brs), 7.65 (lH,d, J = 8.9 Hz), 7.56 (brd, J = 4.1 Hz), 7.31 (1H, dd, J = 1.8 Hz,

8.9Hz), 4.15 (2H, brs), 3.50 - 3.15 (4H, m), 2.70 - 2.55 (4H, m), 2.46 (3H, s)

Example 272 [5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide

388,.- · · ·' · * · · * r · «

Step 1: [5-Chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-(2-tert-butoxycarbonylaminoethyl)acetamide

The title compound was prepared as described in Example 43 from [5-chloro-2-(4-methylpyridin)-1H-indol-3-yl]acetic acid (from Example 36) and N-(2-aminoethyl)carbamic acid tert-butyl ester.

^Χ Η NMR (CDC1 ₃ ): δ 12.29 (1H, brs), 8.68 (1H, d, J = 4.9 Hz),

7.94 (1H, brs), 7.78 (2H, m), 7.67 (1H, d, J = 8.9 Hz), 7.57 (1H, brd, J = 4.9 Hz), 7.32 (dd, 1H, J = 2.0 Hz, 8.7 Hz),

6.73 (1H, m), 3.94 (2H, s), 3.05 - 2.95 (4H, m), 2.47 (3H,

s), 1.35 (9H, s)

Step 2: [5-Chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide

The title compound was prepared according to the method described in Step 2 of Example 273 from [5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-tert-butoxycarbonylaminoethyl)acetamide (from Step 1).

MS (EI) m/z: 370 (M ⁺ )

Melting point: 165.7°C

IR (KBr) v: 3346, 2927, 1665, 1627, 1593, 1515, 1435, 1267, 1207 cm ^{-1 1} H NMR (DMSO-d ₆ ): δ 12.28 (1H, brs), 8.69 (1H, d, J = 4.9 Hz), 7.93 (1H, brs), 7.80 - 7.76 (2H, m), 7.66 (1H, d, J = 8.9 Hz), 7.57 (1H, m), 7.31 (dd, 1H, J = 2.0 Hz, 8.9 Hz) ,

3.94 (2H, s), 3.01 (2H, q, J = 5.77 Hz), 2.55 - 2.45 (2H, m), 2.47 (3H, s)

Example 273

2-[5-Chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone ·· ·♦··

- 389,• ··

Step 1: 2-[5-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-1-ethanone

The title compound was prepared as described in Example 43 from [5-chloro-2-(4-methylpyridin)-1H-indol-3-yl]acetic acid (from Example 36) and 3-(tert-butoxycarbonylamino)pyrrolidine.

¹ H NMR (CDCl ₃ ): δ 12.56 (1H, brs), 8.62 (1H, d, J = 4.9 Hz), 8.18 (1H, brs), 7.78 (1H, brs), 7.42 (1H, d, J = 8.9 Hz), 7.35 (1H, brd, J = 4.9 Hz), 7.29 (2H, m), 4.89 (1H, brd, J= 25.05), 4.36 - 3.45 (7H, m), 2.48 (3H, s), 2.35 - 1.80 (2H, m), 1.46 (9H, s)

Step 2: 2-[5-Chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone

The title compound was prepared as described in Example 271 from 2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-1-ethanone (from Step 1).

MS (EI) m/z: 396 (M ⁺ )

Melting point: 179.2°C

IR (KBr) v: 3238, 2876, 1638, 1595, 1526, 1423, 1203 cm' ^{1 1} H NMR (DMSO-d ₆ ): δ 12.26 (1H, brs), 8.68 (1H, d, J= 4.9 Hz), 7.89 (1H, brs), 7.81 (1H, d, J = 1.81 Hz), 7.65 (1H, d, J = 8.9 Hz), 7.55 (1H, brd, J = 5.1 Hz), 7.31 (dd, 1H, J = 2.0 HZ, 8.7 Hz), 4.07 (1H, s), 4.05 (1H, s), 3.70 -2.90 (5H, m), 2.46 (3H, S), 2.10 - 1.80 (1H, m), 1.75 - 1.45 (1H, m)

Example 274

Methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate

- 39(3Step 1: Methyl-trans-2-amino-4-chloro-5-fluorocinnamate

The title compound was prepared as described in Step 1 of Example 133 from 2-bromo-5-chloro-4-fluoroaniline (JP 01311056 A2, Nippon Kayaku Co., Ltd., Japan). ¹ H NMR (CDCl ₃ ): δ 7.69 (1H,d, J = 15.8 Hz), 7.15 (1H,d, J = 9.7 Hz), 6.74 (1H,d, J = 6.4 Hz), 6.31 (1H,d, J = 15.8),

3.81 (3H, s)

Step 2: Methyl trans-4-chloro-5-fluoro-2-(phenylsulfonylamino)cinnamate

The title compound was prepared as described in Step 1 of Example 8 (Method A) from methyl trans-2-amino-4-chloro-5-fluorocinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.71 - 7.68 (1H, m), 7.57 - 7.40 (6H, m), 7.23 (1H, d, J = 9.4 Hz), 6.09 (1H, d, J = 15.8 Hz), 3.77 (3H, s)

Step 3: Methyl-[6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from trans-4-chloro-5-fluoro-2-(phenylsulfonylamino)cinnamate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 9.05 (1H, brs), 7.74 (2H, d, J = 8.7 Hz), 7.49 (2H, d, J = 8.7 Hz), 7.35 - 7.32 (2H, m), 3.77 (2H, s), 3.66 (3H, s)

Example 275 [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid — δ 9Í·— · · ·

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate.

Melting point: 215 to 220°C

IR (KBr) V'. 1709, 1626, 1585, 1529, 1456, 1439, 1279, 1250 cm" ^{1 1} H NMR (DMSO-dg): δ 11.85 (1H, brs), 7.79 - 7.75 (3H, m) ,

7.67 - 7.63 (2H, m), 7.60 - 7.58 (1H, m), 3.83 (2H, s)

Example 276

Methyl-[6-chloro-5-fluoro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-5-fluoro-2-(phenylsulfonylamino)cinnamate (from Step 2 of Example 274).

¹ H NMR (CDCl ₃ ): δ 12.54 (1H, brs), 8.58 (1H, d, J = 4.9 Hz), 8.14 (1H, m), 7.56 - 7.53 (1H, m), 7.39 - 7.34 (2H, m), 4.25 (2H, s), 3.75 (3H, s), 2.48 (3H, s)

Example 277 [6-Chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 276). Melting point: 219.5°C

IR (KBr) at: 1732, 1709, 1647, 1597, 1529, 1279, 1252, 1204 cm ^{1 1} H NMR (DMSO-dg): δ 12.35 (1H, brs), 8.70 (1H, d, J = 5.1 Hz), 7.96 (1H, s), 7.87 (1H, d, J = 6.6 Hz), 7.81 (1H, d, J = 10.1 Hz), 7.59 - 7.58 (1H, m), 4.05 (2H, s), 2.47 (3H, s)

- 3&2

Example 278

Methyl-[6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl Jacetate

Step 1: Methyl-[6-chloro-2-[4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from Step 1 of Example 8, Method A) and 2-bromoacetyl-4-[1-tert-butyldimethylsilyloxy)ethyl]pyridine*. ¹ H NMR (CDCl ₃ ): δ 12.49 (1H, brs), 8.71 (1H, d, J = 4.9 Hz), 8.24 (1H, d, J = 1.5 Hz), 7.61 - 7.63 (2H, m), 7.53 (1H, d,

J = 1.8 Hz), 7.13 (1H, dd, J = 1.8, 8.7 Hz), 4.96 (1H, q, J = 6.4 Hz), 4.32 (2H, s), 3.73 (3H, s), 1.45 (3H, d, J = 6.4 Hz), 0.93 (9H, s), 0.10 (3H, s), 0.03 (3H, s) •^p

2-Bromoacetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine is prepared as follows:

4-[1-(trimethylsilyloxy)ethyl]-2-pyridinecarbonitrile

The title compound was prepared from 4-(1-hydroxyethyl)pyridine-N-oxide (C. W. Muth et al., J. Heterocycl. Chem., 1972, 9, 1299) by the method described in Example 33 for the preparation of 4-chloro-2-pyridinecarbonitrile.

¹ H NMR (CDCl ₃ ): δ 8.64 (1H, d, J = 5.1 Hz), 7.69 - 7.70 (1H, m), 7.45 - 7.48 (1H, m), 4.88 (2H, q, J = 6.4 Hz), 1.43 (3H, d, J = 6.6 Hz), 0.14 (9H, s)

4-[1-(tert-Butyldimethylsilyloxy)ethyl]-2-pyridinecarbonitrile

To a solution of 4-[1-(trimethylsilyloxy)ethyl]-2-pyridinecarbonitrile (39.04 g, 0.1624 mol) in tetrahydrofuran (200

- 393 ml) at room temperature, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 178.6 ml, 0.1786 mol) was added. The resulting mixture was stirred for 0.5 h and then concentrated. The residue was diluted with ethyl acetate (300 ml). The ethyl acetate mixture was washed with water (200 ml). The aqueous layer was extracted with dichloromethane (200 ml x 2). The combined organic layers were dried over magnesium sulfate and concentrated. The oily residue was dissolved in dimethylformamide (200 ml). To the resulting solution at room temperature, tert-butyldimethylsilyl chloride (36.72 g, 0.2436 mol) and imidazole (22.11 g, 0.3248 mol) were added. The resulting mixture was stirred for 19 h and diethyl ether (500 ml) and water (200 ml) were added. The organic layer was separated, washed with water (100 mL x 2), dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography using ethyl acetate:hexane (1:20) as eluent to give 39.23 g (92%) of the title compound as an oil.

¹ H NMR (CDCl ₃ ): δ 8.64 (1H, d, J = 5.1 Hz), 7.67 - 7.68 (1H m), 7.46 - 7.48 (1H, m), 4.89 (1H, g, J = 6.4 Hz), 1.42 (3H d, J = 6.4 Hz), 0.92 (9H, s), 0.10 (6H, s)

2-Acetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine

The title compound was prepared from 4-[1-(tert-butyldimethylsilyloxy)ethyl]-2-pyridinecarbonitrile by the method described in Example 33 for the preparation of 2-acetyl-4-chloropyridine.

¹ H NMR (CDCl ₃ ): δ 8.62 (1H, d, J = 4.9 Hz), 7.95 - 7.96 (1H m), 7.49 - 7.52 (1H, m), 4.91 (1H, g, J = 6.4 Hz), 2.73 (3H s), 1.41 (3H, d, J = 6.4 Hz), 0.91 (9H, s), 0.10 (6H, s)

2-Bromoacetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine

The title compound was prepared from 2-acetyl-4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine by the method described in Example 95 for the preparation of 2-bromoethyl-4-(tert-butyldimethylsilyloxy)ethyl]pyridine.

Step 2: Methyl-[6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Step 2 of Example 95 from methyl-[6-chloro-2-[4-[1-(tert-butyldimethylsilyloxy)ethyl]pyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Step 1).

NMR (DMSO-d ₆ ): δ 12.34 (1H, brs), 8.77 (1H, d, J = 5.1 Hz), 8.11 (1H, s), 7.81 (1H, d, J = 8.7 Hz), 7.75 (1H, d, J = 1.6 Hz), 7.70 (1H, dd, J = 1.2, 4.9 Hz), 7.13 (1H, dd, J = 1.8, 8.6 Hz), 5.61 (1H, d, J = 4.6 Hz), 4.84 - 4.93 (1H, m), 4.17 (2H, s), 3.59 (3H, s), 1.39 (3H, d, J = 6.4 Hz)

Example 279 [6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 58 from methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Example 278).

Melting point: 193 to 194°C

IR (KBr) v: 3464, 1707, 1632, 1591, 1526, 1250, 1225, 1192, 1144, 914 cm ^{-1 1} H NMR (DMSO-dg): δ 12.30 (1H, brs), 8.78 (1H, d, J = 5.1 Hz), 8.11 (1H, s), 7.79 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 1.6 Hz), 7.71 (1H, d, J = 5.3 Hz), 7.12 (1H, dd, J = 1.8, 8.7 Hz), 5.60 (1H, d, J = 4.4 Hz), 4.84 - 4.93 (1H, m), 4.09 (2H, s), 1.39 (3H, d, J = 6.6 Hz) • · ···· ·« · a » • · · ·«·· ···

Example 280 [6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 112 from [6-O-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate (from Example 113). Melting point: 193-194°C

IR (KBr) at: 3256, 1707, 1645, 1529, 1420, 1227, 1180, 1159, 1153 cm ¹

MS (EI) m/z: 360 (M ⁺ )

¹ H NMR (DMSO-dg): δ 11.84 (1H, brs), 8.46 (1H, d, J = 5.3 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.67 (1H, t, J = 5.1 Hz), 7.51 (1H, d, J = 1.8 Hz), 7.12 (1H, dd, J = 1.8, 8.6 Hz), 3.74 (2H, s), 2.76 (2H, q, J = 7.6 Hz), 1.25 (3H, t, J = 7.6 Hz) Example 1 d 2 8 1

[6-Chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid

Stage 1: Trans-4-chloro-2-(phenylsulfonylamino)cinnamate bound to polymer

To a mixture of Wang resin (37-74 μη, 1.37 g, ca. 0.89 mmol) and trans-4-chloro-2-(phenylsulfonylamino)cinnamic acid (600 mg, 1.77 mmol) were added dichloromethane (10 ml) and N,N-diisopropylethylamine (1.86 ml, 10.7 mmol). The resulting mixture was allowed to stand for 1 hour, after which 4-dimethylaminopyridine (22 mg, 0.18 mmol) and WSC (339 mg, 1.77 mmol) were added. The reaction mixture was stirred for 18 hours and then filtered. The separated resin was washed with water (20 ml x 3), methanol (20 ml x 3), acetone (20 ml x 3), dichloromethane (20 ml x 3) and dried. 1.65 g of the title compound was obtained.

• · ·«·· ·· ·· • · · «··· «·0

Step 2: [6-Chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid

To a mixture of polymer-bound trans-4-chloro-2-(phenylsulfonylamino)cinnamate (from step 1, 100 mg, 53 μιιοί) and 2-nitrophenacyl bromide (39 mg, 0.16 mmol) in acetone (3 mL) was added potassium carbonate (37 mg, 0.27 mmol). The resulting mixture was stirred for 18 hours and then filtered. The separated resin was washed with water (20 mL x 3), acetone (20 mL x 3), dichloromethane (20 mL x 3) and tetrahydrofuran (20 mL x 3), dried, diluted with tetrahydrofuran (4 mL) and DBU (40 μΐ, 0.27 mmol) was added. After stirring for 6 hours, the resin was filtered off, washed with tetrahydrofuran (20 mL x 3), acetone (20 mL x 3) and dichloromethane (20 mL x 3). To the resin was added 95% trifluoroacetic acid in dichloromethane (5 mL). The resulting mixture was stirred for 3 hours and then filtered. The residue was washed with dichloromethane (20 mL x 5). The filtrate was concentrated and the residue was purified by high pressure liquid chromatography using methanol and aqueous ammonium acetate solution in a ratio of 60:40 to 90:10 as eluent. 3.2 mg (17%) of the title compound was obtained.

MS (ESI) m/z: 359 (MH ⁺ )

Example 282 [6-Chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 281 from 4-chloro-2-(phenylsulfonylamino)cinnamic acid.

MS (ESI) m/z: 374 (MH ⁺ )

- w-..- ·..· .

Example 283 [6-Chloro-2-(4-difluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 289 from 4-chloro-2-(phenylsulfonylamino)cinnamic acid.

MS (ESI) m/z: 380 (MH ⁺ )

Example 284 [6-Chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 281 from 4-chloro-2-(phenylsulfonylamino)cinnamic acid.

MS (ESI) m/z: 374 (MH ⁺ )

Example 285

Methyl [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

Step 1: 4-Acetyl-2-bromoaniline

To a stirred suspension of 4-acetamido-3-bromoacetophenone in ethanol (12 mL) was added dropwise hydrochloric acid (3 mL) at 0°C. The reaction mixture was stirred at reflux for 4.5 hours, then cooled and concentrated. The solid residue was partitioned between saturated aqueous sodium bicarbonate (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over magnesium sulfate and concentrated to give 1.79 g (quant.) of the title compound as a brown oil.

·· · ¹ H NMR (CDC1 ₃ ): δ 8.06 (1H, d, J = 1.97 Hz), 7.76 - 7.72 (1H, m), 6.74 (1H, d, 8.40 Hz), 4.60 (1H, brs), 2.50 (3H, s)

Stage 2: Methyl trans-(5-acetyl-2-amino)cinnamate

The title compound was prepared as described in Step 1 of Example 133 from 4-acetyl-2-bromoaniline (from Step 1) and methyl acrylate.

^Τ Η NMR (CDC1 ₃ ): δ 8.02 (1H, d, J = 2.13 Hz), 7.81 - 7.75 (2H, m), 6.70 (1H, d, J = 8.56 Hz), 6.44 (1H, d, J = 15.8 Hz), 4.55 (2H, brs), 3.81 (3H, s), 2.53 (3H, s)

Step 3: Methyl trans-5-acetyl-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl trans-(5-acetyl-2-amino)cinnamate (from Step 2) and p-toluenesulfonyl chloride.

¹ H NMR (CDCl ₃ ): δ 8.01 (1H, d, 2.00 Hz), 7.89 (1H, dd, 8.59 Hz, 1.97 Hz), 7.68 - 7.22 (7H, m), δ.30 (1H, s), 6.15 (1H, d, 15.8 Hz), 3.81 (1H, s), 2.57 (3H, s), 2.38 (3H, s)

Step 4: Methyl-[5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-5-acetyl-2-(p-toluenesulfonylamino)cinnamate and 4-chlorophenacyl bromide.

η NMR (CDCl ₃ ): δ 9.2 (1H, brs), 8.34 - 7.75 (4H, m), 7.52 7.45 (3H, m), 3.89 (2H, s), 3.69 (3H, s), 2.68 (3H, s)

Example 286 [5-Acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared by method B of Example 9 from methyl-[5-acetyl-2-(4-chlorobenzoyl)-1H-

indol-3-yl]acetate (from example 285). Melting point: 225° C IR (KBr) at: 3281, 1703, 1666, 1643, 1614, 1574 , 1539, 1452 1425, 1402, 1364, 1263, 1240, 1178, 1092, 1011 , 959 cm -1 ^X H NMR (DMSO-d ₆ ): δ 12.01 (1H, brs), 8.49 (1H, brs), 7 .93 7.89 (1H, m), 7.78 (2H, d, 8.56 Hz), 7.65 (d, 2H, 8.56 Hz),7.52 (1H, d, 8 ,72 Hz), 3.93 (2H, S) , 2.63 (3H, s) A p p i c law 2 8 7

Methyl [6-fluoro-2-(4-methylpyridin-2-carbonyl]-1H-indol-3-yl]acetate

Step 1: Methyl trans-(4-fluoro-2-nitro)cinnamate

The title compound was prepared as described in Step 1 of Example 133 from 3-fluoro-6-iodonitrobenzene and methyl acrylate.

¹ H NMR (CDCl ₃ ): δ 8.67 (1H, d, 15.8 Hz), 7.78 (1H, dd, J 8.07 Hz, 2.65 Hz), 7.68 - 7.63 (2H, m), 6.34 (1H, d, 15.8 Hz), 3.84 (3H, s)

Step 2: Methyl trans-(2-amino-4-fluoro)cinnamate

The title compound was prepared as described in Step 2 of Example 36 from methyl trans-(4-fluoro-2-nitro)cinnamate (from Step 1).

¹ H NMR (CDCl ₃ ): δ 7.75 (1H,d, 15.8 Hz), 7.37 - 7.31 (1H, m 6.50 - 6.37 (2H, m), 6.32 - 6.26 (1H, m), 4.13 (2H, brs), 3.80 (3H, s)

Step 3: Methyl trans-4-fluoro-2-(p-toluenesulfonylamino)cinnamate

The title compound was prepared according to the method described in Step 1 of Example 8 (Method A) from methyl trans-(2-amino-4-fluoro)cinnamate (from Step 2).

¹ H NMR (CDCl ₃ ): δ 7.64 (1H, d, 8.40 Hz), 7.46 - 7.19 (4H, m), 6.94 - 6.87 (1H, m), 6.77 )1H, s), 6.16 - 6.10 (1H, m), 3.79 (3H, S), 2.38 (3H, s)

Step 4: Methyl-[6-fluoro-2-(4-methylpyridine-2-carbonyl]-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-fluoro-2-(p-toluenesulfonylamino)cinnamate (from Step 3).

¹ H NMR (CDCl ₃ ): δ 12.49 (1H, brs), 8.61 (1H, d, 4.94 Hz), 8.17 - 7.61 (2H, m), 7.36 - 7.14 (2H, m), 6.98 - 6.90 (1H, m), 4.31 (2H, s), 3.73 (3H, s). 2.47 (3H, s)

Example 288 [6-Fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-fluoro-2-(4-methylpyridine-2-carbonyl]-1H-indol-3-yl]acetate (from Example 287).

Melting point: 208°C IR (KBr) at: 3238, 1701, 163, 1597, 1533 , 1398, 1281, 1211, 1132, 1003 cm -1 ¹ H NMR (CDCl ₃ ): δ 12.28 (1H, brs), 8.70 (1H, d, 4.94 Hz) , 7.96 (1H, s), 7.83 - 7, 77 (1H, m), 7.57 (1H, d, 4.94 Hz) , 7.42 (1H, dd, 10.2 Hz, 2.13 Hz), 7 .03 -6 .95 (1H ,m ) , 4.09 (2H, s), 2.47 (3H, s)

- 401·

Example 289

Methyl [6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate

The title compound was prepared as described in Example 57 from methyl trans-4-fluoro-3-(p-toluenesulfonylamino)cinnamate (from Step 3 of Example 287) and 4-chlorophenacyl bromide.

¹ H NMR (CDCl ₃ ): δ 9.10 (1H, brs), 7.76 - 7.71 (2H, m), 7.60 - 7.54 (2H, m), 7.50 - 7.45 (2H, m), 7.04 - 6.90 (2H, m), 3.81 (2H, s), 3.66 (3H, s)

Example 290 [6-Fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 9 (Method B) from methyl [6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate (from Example 289). Melting point: 214°C

IR (KBr) at 3335, 1699, 1618, 1605, 1587, 1531, 1425, 1327, 1267, 1231, 1134, 1094, 1001 cm ^{-1 1} H NMR (DMSO-dg): δ 11.73 (1H, brs), 7.78 - 7.63 (5H, m), 7.17 (1H, dd, 9.72 Hz, 2.13 Hz), 7.04 - 6.96 (1H,), 3.84 (2H, s)

Example 291

Methyl-[2-(4-methylpyridin-2-carbonyl)-5-methylthio-1Hindol-3-yl]acetate

Step 1: Methyl trans-(2-amino-5-methylthio)cinnamate

The title compound was prepared by the method described in step 1 of Example 133 from 2-bromo-4-methylthiooxy- n-..'aniline (JP80-122756) and methyl acrylate.

¹ H NMR (CDCl ₃ ): δ 7.77 (1H, d, 15.8 Hz), 7.38 (1H, d, 2.13 Hz), 7.19 (1H, dd, 8.40 Hz, 2.13 Hz), 6.66 (1H d, 8.40 Hz), 6.36 (1H, d, 15.8 Hz), 3.97 (1H, brs), 3.80 (3H, s), 2.43 (3H, s)

Step 2: Methyl trans-2-p-toluenesulfonylamino-5-methylthiocinnamate

The title compound was prepared as described in Step 1 of Example 8 from methyl trans-(2-amino-4-methylthio)cinnamate (from Step 1) and p-toluenesulfonyl chloride ¹ H NMR (CDCl ₃ ): δ 7.81 (2H, d, 8.40 Hz), 7.56 - 6.91 (8H, m), 6.13 (1H, d, 15.6 Hz), 3.79 (3H, s), 2.46 (3H, s), 2.39 (3H, s)

Step 3: [2-(4-Methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid

The title compound was prepared as described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-methylthiocinnamate (from Step 2) and 2-bromoacetyl-4-methylpyridine hydrobromide (the preparation of which is described in Step 2 of Example 31).

¹ H NMR (CDCl ₃ ): δ 12.47 (1H, brs), 8.62 (1H, d, 4.78 Hz),

8.19 - 8.17 (1H,m), 7.65 -7.62 (1H,m), 7.47 - 7.30 (3H,m), 4.31 (2H,s), 3.73 (3H,s), 2.48 (3H,s)

Example 292 [2-(4-Methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid

The title compound was prepared by method B described in Example 9 from methyl-[2-(4-methylpyridine-2-car-

(bonyl)-5-methylthio-1H-indol-3-yl]acetate (from Example 291). ¹ H NMR (DMSO-dg): δ 12.22 (1H, brs), 8.70 (1H, d, 4.62 Hz), 7.95 - 7.17 (4H, m), 4.08 (2H, s), 2.47 (3H, s), 2.35 (3H, s) MS (El) m/z: 340 (M ⁺ )

Example 293

3-[4-Chloro-2-(toluene-4-sulfonylamino)phenyl]acrylic acid ethyl ester

To ethyl 3-(2-amino-4-chlorophenyl)acrylic acid ester (18.0 g, 79.8 mmol) in dichloromethane (144 mL) was added pyridine (9.04 mL, 112 mmol) and p-toluenesulfonyl chloride (16.0 g, 83.9 mmol). The reaction mixture was stirred at room temperature for 18 h and then poured into 1M hydrochloric acid (150 mL). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The solid residue was suspended in hexanes and the resulting suspension was filtered to give ethyl 3-[4-chloro-2-(toluene-4-sulfonylamino)phenyl]acrylic acid ester (28.3 g, 93%), mp 124-127°C. ³ H NMR (300 MHz, CDClg): δ 1.35 (t, 3, J = 7.2), 2.40 (s, 3), 4.27 (q, 2, J = 7.2), 6,+2 (dd, 1, J = 15.9, 0.9), 7.20 - 7.39 (m, 4), 7.39 (d, 1,

J = 8.6)) 7.48 - 7.53 (m, 2), 7.62 (d, 2, J = 8.3). ¹³ C NMR (75 MHz, CDCl ₃ ): δ 1550, 2279, 6224, 122.48, 127.98, 128.49, 129.34, 129.50, 131.05, 136.82, 137.00, 137.73, 138.93, 145.55, 167.59. IR 3214, 1694, 1631, 1318, 1167 cm ^-1 .

Analysis for C ₁₈ H ₁₈ C1NO ₄ S: C 56.91, H 4.78, N 3.69, found: C 57.10, H 5.08, N 3.70

Example 294 [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

- 40.4

To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)phenyl]acrylic acid ethyl ester (13.0 g, 34.2 mmol) in N,N-dimethylacetamide (120 mL) was added potassium carbonate (9.45 g, 68.4 mmol) and 2-bromo-4'-chloroacetophenone (8.78 g,

37.6 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 1M sodium hydroxide (130 ml) was added. The reaction mixture was heated at 100°C for 8 hours, then cooled to room temperature, poured into a separatory funnel and washed with methyl tert-butyl ether (2 x 200 ml). The aqueous layer was acidified to pH 1 with 6M hydrochloric acid and extracted with ethyl acetate (150 ml). The solvent was evaporated under reduced pressure and isopropyl alcohol (24 ml) and water (48 ml) were added to the oily residue. A solid precipitated. The resulting suspension was stirred for 12 hours, the precipitate was filtered off, washed with water and dried. [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid (9.73 g, 82%) was obtained, melting point 181-183°C. 1H-NMR (400 MHz, DMSO-d6): δ 3.79 (s, 2), 7.08 (dd, 1, J = 8.5, 1.9), 7.42 (d, 1, J = 1.9), 7.60 (d,

2, J = 8.5), 7.62 - 7.73 (m, 3), 11.74 (bs, 1), 12.22 (bs, 1). ¹³ C NMR (75 MHZ, DMSO-dg): δ 31.74, 113.25, 118.00, 121.93, 123.96, 127.69, 130.10, 131.30, 132.02, 133.59,

138.02, 138.37, 138.58, 173.20, 188.29. IR 3314, 1710, 1700, -1

1618, 1522, 1323, 1227, 1093, 941 cm ^C 17 ^H 11 ^C1 2 ^NO 3 ^: calculated:

C 58.58, H 3.22, N 3.93

Analysis for ^C 17 ^H 11 ^C1 2 ^NO 3 ^: calculated: C 58.64, H 3.18, N 4.02, found:

Example

2-{4-Chloro-2-[[2-(4-chlorophenyl)-2-oxoethyl](toluene-4-sulfonyl)amino]phenyl}acrylic acid ethyl ester

To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)phenyl]acrylic acid ethyl ester (3.00 g, 7.90 mmol) in N,N-dimethylacetamide (15.0 mL) was added potassium carbonate (2.18 g, 15.8 mmol) and 2-bromo-4'-chloroacetophenone (2.03 g, • 4 · ·· · «· · « · • · · «··· · · ·

8.69 mmol). The reaction mixture was stirred for 30 minutes and then poured into 1M hydrochloric acid (30 mL). The resulting mixture was extracted with methyl tert-butyl ether (2 x 30 mL). The organic extracts were dried over magnesium sulfate, filtered, concentrated to a small volume, and hexanes were added. The solid that separated was filtered off to give 2-{4-chloro-2-[[2(4-chlorophenyl)-2-oxoethyl](toluene-4-sulfonyl)amino]phenyl}acrylic acid ethyl ester (3.19 g, 76%) with a melting point of 162-165°C. ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.38 (t, 3, J = 7.2), 2.47 (S, 3), 4.28 (q, 2, J = 7.2), 5.00 (bs, 2), 6.23 (d, 1, J = 16.0), 7.29 - 7.36 (m, 4), 7.47 (d, 2, J = 8.7), 7.54 (d, 1,

J = 8.4), 7.59 (d, 2, J = 8.3), 7.74 (d, 1, J = 16.0), 7.88 (d, 2, J = 8.7, ¹³ C NMR (75 MHz, CDCl ₃ ): δ 14.33, 21.62, 57.72, 60.66, 112.49, 120.69, 128.07, 129.21, 129.58,

129.70, 131.22, 132.80, 133.83, 134.80, 135.84, 138.55, 139.28, 140.38, 144.46, 166.02, 191.70. IR 1720, 1698, 1590, 1338, 1313, 1179, 1161, 1089 cm ^-1 . Analysis for ^C 26 ^H 23 ^C1 -2 ^NO 5 ^S: calculated: C 58.65, H 4.35, N 2.63, found:

C 58.74, H 4.56, N 2.72

Example 296

Cis and trans-[6-chloro-2-(4-chlorobenzoyl)-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-3-yl]acetic acid ethyl ester

To 3-{4-chloro-2-[[2-(4-chlorophenyl)-2-oxoethyl]-(toluene-4-sulfonyl)amino]phenyl}acrylic acid ethyl ester (1.00 g, 1.88 mmol) in N,N-dimethylacetamide (5.0 mL) was added potassium carbonate (0.520 g, 3.76 mmol). The reaction mixture was stirred for 4 h and then poured into 1M hydrochloric acid (30 mL). The resulting mixture was extracted with tert-butyl ether (2 x 30 mL). The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The solid residue was purified by chromatography on silica gel using a 20:80 mixture of ethyl acetate and hexane as eluent. • ·

V · •a · • a • aaa· ·«·· • * · • · * trans-[6-chloro-2-(4-chlorobenzoyl)-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-3-yl]acetic acid ethyl ester in the form of a mixture of cis and trans isomers in the ratio 1 : 9 (0.488 g, 49%). Some significant signals ³ H NMR (300 MHz, CDCl ₃ ): δ 1.09 (t, J = 7.2), 1.19 (t, J = 7.2), 2.44 (s), 5.40 (d, J = 4.0), 5.99 (d, J = 9.7), 6.92 (dd, J = 8.1, 1.1), 7.04 (dd,

J = 8.1, 1.9), 7.52 (d, J = 8.4), 7.57 (d, J = 1.9), 7.73 (d, J = 8.3), 7.99 (d, J - 8.6). LC-MS analysis of the mixture of diastereomers showed products with identical values of 531 (M+H ⁺ ).

Example 297

[6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid ethyl ester

To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)phenyl]acrylic acid ethyl ester (3.00 g, 7.90 mmol) in N,N-dimethylacetamide (15.0 mL) was added potassium carbonate (2.18 g, 15.8 mmol) and 2-bromo-4'-chloroacetophenone (2.03 g,

8.69 mmol). The reaction mixture was stirred for 30 minutes and 1,8-diazabicyclo[5,4,0-indec-7-ene (3.54 mL, 23.7 mmol) was added. The reaction mixture was stirred for 1 hour and then poured into 1M hydrochloric acid (30 mL). The resulting mixture was extracted with methyl tert-butyl ether (2 x 30 mL). The organic extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The resulting solid was suspended in a mixture of methyl tert-butyl ether and hexanes to give [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid ethyl ester (2.42 g, 81%) with a melting point of 186-188°C. •'-Η NMR (300 MHz, CDCl ₃ ): δ 1.27 (t, 2, J = 7.1), 3.80 (S, 2), 4.11 (q, 2, J = 7.1), 7.15 (ddd, J = 8.5, 1.7, 0.5), 7.28 - 7.30 (m, 1), 7.48 (d, J = 8.3), 7.54 - 7.57 (m, 1), 7.77 (d, 2, J = 8.3), 9.16 (bs, 11). ¹³ C NMR (75 MHZ, CDCl ₃ ): δ 15.42, 32.29, 62.45, 113.27, 117.60, 122.99, 123.23, 127.85, 130.12, 131.77, 133.61,

407

137.86, 138.13, 140.10, 172.45, 188.25. IR 3305, 1732, 1618, 1323 cm ¹ . Analysis for C ₁₈ H ₁₅ Cl ₂ N0 ₃ : calculated: C 60.65, H 4.02, N 3.72, found: C 60.70, H 3.97, N 3.71

Example 298 [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid

To a solution of [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid ethyl ester (200 mg, 0.532 mmol) in methanol (2 mL) and water (0.8 mL) was added sodium hydroxide (137 mg, 3.43 mmol). The reaction mixture was stirred for 24 h, then concentrated to a small volume and water (4 mL) was added. The mixture was transferred to a separatory funnel and washed with dichloromethane (5 mL). The aqueous layer was acidified to pH 1 with 1M hydrochloric acid and extracted with ethyl acetate (15 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to give [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid (150 mg, 81%). The ¹ H NMR spectrum is identical to that obtained for the compound prepared as described in Example 2. ^In

The following table summarizes the chemical structures of the compounds prepared according to Examples 1 to 292.

408

Table

Ex. No. (X)n R ¹ From Q 1 6-C1 H ethoxy phenyl 2 6-C1 H OH phenyl 6-C1 H HER phenyl 4 6-C1 H OH 2-methyl phenyl 5 6-C1 H OH 3-methyl phenyl 6 6-C1 H OH 4-methyl phenyl 7 6-0 H OH 3-chlorophenyl 8 6-C1 H methoxy 4-chlorophenyl 9 6-C1 H OH 4-chlorophenyl 10 6-C1 H OH 3-fluorophenyl 11 6-C1 H OH 4-fluorophenyl 12 6-C1 H OH 3-bromophenyl 13 6-C1 H OH 4-bromophenyl 14 6-C1 H OH 3-CF ₃ - phenyl 15 6-C1 H OH 4-CF ₃ - phenyl 16 6-C1 H OH 3,4-dichlorophenyl 17 4-C1 H OH phenyl 18 5-C1 H OH 3-methyl phenyl 19 5-C1 H OH 4-chlorophenyl 20 5-C1 H OH 3-chlorophenyl 21 5-F H OH 4-chlorophenyl 22 5-F H OH 3-chlorophenyl 23 5-methoxy H OH 3-methyl phenyl 24 7-C1 H OH phenyl 25 4,5-di-Cl H OH phenyl 26 4,6-di-Cl H OH phenyl 27 5,6-di-Cl H OH phenyl

409

Ex. (X)n No. R ¹ From Q 28 6-C1 methyl OH phenyl (racemic) 29 6-C1 methyl OH phenyl

(less polar antipode)

30 6-C1 methyl OH phenyl (more polar 31 6-C1 antipode) H OH 4-methyl-2-pyridyl 32 6-C1 H OH 5-methyl-2-pyridyl 33 6-C1 H methoxy 4-chloro-2-pyridyl 34 6-C1 H OH 4-chloro-2-pyridyl 35 6-C1 H OH 2-pyridyl 36 5-C1 H OH 4-methyl-2-pyridyl 37 5-C1 H methoxy 6-methyl-2-pyridyl 38 5-C1 H OH 6-methyl-2-pyridyl 39 6-C1 H OH 1 -methyl-2-imidazolyl 40 5-C1 H methoxy 2-thiazolyl 41 5-C1 H OH 2-thiazolyl 42 6-C1 H methoxy phenyl 43 6-C1 H dimethylamino phenyl 44 6-C1 H methylamino phenyl 45 6-0 H amino phenyl 46 6-C1 H N-methoxy-N- phenyl 47 6-C1 H methylamino piperidino phenyl 48 6-C1 H 4-methyl-1-piperazinyl phenyl 49 6-C1 H 2-cyanoethylamino phenyl 50 6-C1 H 2-HO-ethylamino phenyl 51 6-C1 H mor folino phenyl 52 H H OH 4-chlorophenyl 53 6-C1 H OH 2-furyl 54 6-C1 H OH cyclohexyl 55 6-C1 H OH 4-methoxyphenyl 56 6-C1 H methoxy 4-methoxyphenyl 57 6-C1 H methoxy 4-ethyl-2-pyridyl 58 6-C1 H OH 4-ethyl-2-pyridyl 59 5-C1 H methoxy 4-ethyl-2-pyridyl 60 5-C1 H OH 4-ethyl-2-pyridyl 61 6-C1 H methoxy 4-isopropyl-2-pyridyl 62 6-C1 H OH 4-isopropyl-2-pyridyl 63 5-C1 H methoxy 4-isopropyl-2-pyridyl 64 5-C1 H OH 4-isopropyl-2-pyridyl 65 6-C1 H methoxy 4-n-propyl-2-pyridyl

- 410

Ex. c. (X)n R ¹ From Q 66 6-C1 H OH 4-n-propyl-2-pyridyl 67 5-C1 H methoxy 4-n-propyl-2-pyridyl 68 5-C1 H OH 4-n-propyl-2-pyridyl 69 6-C1 H methoxy 4-tert.buty 1 -2 -pyri dyl 70 6-C1 H OH 4-tert.buty 1 -2 -pyridyl 71 5-C1 H methoxy 4-terbutyl-2-pyridyl 72 5-C1 H OH 4-tert-butyl-2-pyridyl 73 6-C1 H methoxy 3-methyl-2-pyridyl 74 6-C1 H OH 3-methyl-2-pyridyl 75 5-C1 H methoxy 3-methyl-2-pyridyl 76 5-C1 H OH 3 -methyl-2 -pyridyl 77 6-C1 H methoxy 6-methyl-2-pyridyl 78 6-C1 H OH 6-methyl-2-pyridyl 79 5-C1 H methoxy 5-methyl-2-pyridyl 80 5-C1 H OH 5-methyl-2-pyridyl 81 6-C1 H methoxy 5-CF3-2-pyridyl 82 6-C1 H OH 5-CF3-2-pyridyl 83 5-C1 H methoxy 5-CF3-2-pyridyl 84 5-C1 H OH 5-CF3-2-pyridyl 85 5-C1 H methoxy 5-Cl-2-pyridyl 86 5-C1 H OH 5-Cl-2-pyridyl 87 6-C1 H methoxy 5-Cl-2-pyridyl 88 6-C1 H OH 5-Cl-2-pyridyl 89 5-C1 H methoxy 4-Cl-2-pyridyl 90 5-C1 H OH 4-Cl-2-pyridyl 91 6-C1 H methoxy 3-pyridyl 92 6-C1 H OH 3-pyridyl 93 6-C1 H methoxy 4-pyridyl 94 6-C1 H OH 4-pyridyl 95 6-C1 H methoxy 4-hydroxymethyl-2-pyridyl 96 6-C1 H OH 4-hydroxymethyl-2-pyridyl 97 5-C1 H methoxy 4-hydroxymethyl-2-pyridyl 98 5-C1 H OH 4-hydroxymethyl-2-pyridyl 99 5-C1 H methoxy 3,4-dimethyl-2-pyrides 1 100 5-C1 H OH 3,4-dimethyl-2-pyridyl 101 5-C1 H methoxy 4,5-dimethyl-2-pyridyl 102 5-C1 H OH 4,5-dimethyl-2-pyridyl 103 6-C1 H methoxy 4,5-dimethyl-2-pyridyl 104 6-C1 H OH 4,5-dimethyl-2-pyridyl 105 6-C1 H methoxy 4-methoxy-2-pyridyl 106 6-C1 H OH 4-methoxy-2-pyridyl

411 • · · · · · · · · · · · · · · · · · · ·

Ex. • (X)n r ^! From Q 107 5-C1 H methoxy 4-methoxy-2-pyridyl 108 5-C1 H OH 4-methoxy-2-pyrid 1 109 6-C1 H methoxy 3,5-dimethyl-2-pyridyl 110 6-C1 H OH 3,5-dimethyl-2-pyridyl 111 5-C1 H methoxy 3-F-4-ethyl-2-pyridyl 112 5-C1 H OH 3-F-4-ethyl-2-pyridyl 113 6-C1 H methoxy 3-F-4-ethyl-2-pyridyl 114 6-C1 H OH 3-C2H5O-4-ethyl-2-pyridyl 115 6-C1 H methoxy 3-Cl-4-ethyl-2-pyridyl 116 6-C1 H OH 3-Cl-4-ethyl-2-pyridyl 117 5-C1 H methoxy 3-Cl-4-ethyl-2-pyridyl 118 5-C1 H OH 3-Cl-4-ethyl-2-pyridyl 119 5-C1 H methoxy 4,6-dimethyl-2-pyridyl 120 5-C1 H OH 4,6-dimethyl-2-pyridyl 121 6-C1 H methoxy 4,6-dimethyl-2-pyridyl 122 6-C1 H OH 4,6-dimethyl-2-pyridyl 123 5,6-di-Cl H methoxy 4-methyl-2-pyridyl 124 5,6-di-Cl H OH 4-methyl-2-pyridyl 125 5-methyl H methoxy 4-methyl-2-pyridyl 126 5-methyl H OH 4-methyl-2-pyridyl 127 5-F H methoxy 4-methyl-2-pyridyl 128 5-F H OH 4-methyl-2-pyridyl 129 5-methoxy H methoxy 4-methyl-2-pyridyl 130 5-methoxy H OH 4-methyl-2-pyridyl 131 6-methoxy H methoxy 4-methyl-2-pyridyl 132 6-methoxy H OH 4-methyl-2-pyridyl 133 5-ethyl H methoxy 4-methyl-2-pyridyl 134 5-ethyl H OH 4-methyl-2-pyridyl 135 5-ethyl H methoxy 4-ethyl-2-pyridyl 136 5-ethyl H OH 4-ethyl-2-pyridyl 137 6-ethyl H methoxy 4-methyl-2-pyridyl 138 6-ethyl H OH 4-methyl-2-pyridyl 139 5-isopropyl H methoxy 4-ethyl-2-pyridyl 140 5-isopropyl H OH 4-methyl-2-pyridyl 141 6-CF ₃ H methoxy 4-methyl-2-pyridyl 142 6-CF3 H OH 4-methyl-2-pyridyl 143 5-tert-butyl H methoxy 4-methyl-2-pyridyl 144 5-tert.butyl H OH 4-methyl-2-pyridyl 145 5-CF3O H methoxy 4-methyl-2-pyridyl 146 5-CF3O H OH 4-methyl-2-pyridyl 147 5-CF3O H methoxy 4-ethyl-2-pyridyl 148 5-CF3O H OH 4-ethyl-2-pyridyl

- 412 years

Ex. No. (X) _n R ¹ From Q 149 6-methyl H methoxy 4-methyl-2-pyridyl 150 6-methyl H OH 4-methyl-2-pyridyl 151 5-CF ₃ H methoxy 4-methyl-2-pyridyl 152 5-CF3 H OH 4-methyl-2-pyridyl 153 5-CF3 H methoxy 4-ethyl-2-pyridyl 154 5-CF3 H OH 4-ethyl-2-pyridylI 155 H H methoxy phenyl 156 H H OH phenyl 157 6-methyl H methoxy 4-chlorophenyl 158 6-methyl H OH 4-chlorophenyl 159 5-methyl H OH 4-chlorophenyl 160 6-methoxy H methoxy 4-chlorophenyl 161 6-methoxy H OH 4-chlorophenyl 162 6-CF3 H OH 4-chlorophenyl 163 5-ethyl H methoxy 4-chlorophenyl 164 5-ethyl H OH 4-chlorophenyl 165 5-methoxy H methoxy 4-chlorophenyl 166 5-methoxy H OH 4-chlorophenyl 167 5-isopropyl H methoxy 4-chlorophenyl 168 5-isopropyl H OH 4-chlorophenyl 169 5-CF3 H methoxy 4-chlorophenyl 170 5-CF3 H OH 4-chlorophenyl 171 5-CF3O H methoxy 4-chlorophenyl 172 5-CF3O H OH 4-chlorophenyl 173 6-C1 H methoxy 2-methoxyphenyl 174 6-C1 H OH 2-methoxyphenyl 175 6-C1 H methoxy 3-methoxyphenyl 176 6-C1 H OH 3-methoxyphenyl 177 6-C1 H methoxy 3-benzyloxyphenyl 178 6-C1 H OH 3-benzyloxyphenyl 179 6-C1 H methoxy 3-hydroxyphenyl 180 6-C1 H OH 3-hydroxyphenyl 181 6-C1 H methoxy 4-benzyloxyphenyl 182 6-C1 H OH 4-benzyloxyphenyl 183 6-C1 H methoxy 4-hydroxyphenyl 184 6-C1 H OH 4-hydroxyphenyl 185 6-C1 H methoxy 4-isopropoxyphenyl 186 6-C1 H OH 4-isopropoxyphenyl 187 6-C1 H methoxy 4-brphenyl 188 6-C1 H OH 4-biphenyl 189 6-C1 H methoxy 4-CF3O- phenyl 190 6-C1 H OH 4-CF3O- phenyl

413

Ex. c. (X)n R ¹ From Q 191 5-C1 H methoxy 4-CF3O-phenyl 192 5-C1 H OH 4-CF3O- phenyl 193 5-C1 H methoxy 4-methoxyphenyl 194 5-C1 H OH 4-methoxyphenyl 195 6-C1 H methoxy 4-nitrophenyl 196 6-C1 H OH 4-nitrophenyl 197 6-C1 H methoxy 4-methyl-S(O)2-phenyl 198 6-C1 H OH 4-methyl-S(O)2-phenyl 199 6-C1 H methoxy 4-methyl-S(O)2-NH-phenyl 200 6-C1 H OH 4-methyl-S(O) ₂ -NH-phenyl 201 6-C1 H OH 2-chlorophenyl 202 6-C1 H OH 2,4-dichlorophenyl 203 6-C1 H methoxy 3-F-4-C1-phenyl 204 6-C1 H OH 3-F-4-C1-phenyl 205 6-C1 H methoxy 4-cyanophenyl 206 6-C1 H methoxy 4-bromophenyl 207 6-C1 H methoxy 4-(2-thienyl)phenyl 208 6-C1 H OH 4-(2-thienyl)phenyl 209 6-C1 H methoxy 4-(2-furyl)phenyl 210 6-C1 H OH 4-(2-furyl)phenyl 211 6-C1 H methoxy 4-(3-pyridyl)phenyl 212 6-C1 H OH 4-(3-pyridyl)phenyl 213 6-Ci H methoxy 4-(2-thiazolyl)phenyl 214 6-C1 H OH 4-(2-thiazolyl)phenyl 215 6-C1 H methoxy 3-bromophenyl 216 6-C1 H methoxy 3-(2-furyl)phenyl 217 6-C1 H OH 3-(2-furyl)phenyl 218 6-C1 methyl methoxy 4-chlorophenyl 219 6-C1 methyl OH 4-chlorophenyl 220 5-CI H methoxy isoquinolin-3-yl 221 5-CI H OH isoquinolin-3-yl 222 6-C1 H methoxy isoquinoline- 3 -y 1 223 6-C1 H OH isoquinolin-3-yl 224 5-CI H methoxy 5-methyl-3-isoxazolyl 225 5-CI H OH 5-methyl-3-isoxazolyl 226 6-C1 H methoxy 5-methyl-3-isoxazolyl 227 6-C1 H OH 5-methyl-3-isoxazolyl 228 5-CI H methoxy 4-methyl-5-(1,2,3-thiadiazolyl) 229 5-CI H OH 4-methyl-5-(1,2,3-thiadiazolyl) 230 6-C1 H methoxy 4-methyl-5-(1,2,3-thiadiazolyl) 231 6-C1 H OH 4-methyl-5-(1,2,3-thiadiazolyl) 232 5-CI H methoxy 5-methyl-2-thiazolyl

·· ··«· ··

- 414 :Q £ ^ř · (X)n R' Z

233 5-C1 H OH 5-methyl-2-thiazolyl 234 6-C1 H methoxy 5-methyl-2-thiazolyl 235 6-C1 H OH 5-methyl-2-thiazolyl 236 6-C1 H OH 2-thienyl 237 6-C1 H methoxy 3-(HO)(CH ₃ ) ₂ C-2-furyl 238 6-C1 H OH 3-(HO)(CH ₃ ) ₂ C-2-furyl 239 6-C1 H methoxy 3-methoxymethyl-2-furyl 240 6-C1 H OH 3-methoxymethyl-2-furyl 241 6-C1 H OH 1 -methyl-2-imidazolyl 242 6-C1 H methoxy 1 -methyl-2-imidazolyl 243 5-C1 H methoxy 1 -methyl-2-imidazolyl 244 5-C1 H OH 1 -methyl-2-imidazolyl 245 5-C1 H methoxy 2-imidazolyl 246 5-C1 H OH 2-imidazolyl 247 6-C1 H methoxy 2-imidazolyl 248 6-C1 H OH 2-imidazolyl 249 5-C1 H methoxy 4-methyl-2-thiazolyl 250 5-C1 H OH 4-methyl-2-thiazolyl 251 5-C1 H methoxy 1 -methyl-2-pyrrolyl 252 5-C1 H OH 1 -methyl-2-pyrrolyl 253 5-C1 H methoxy 2-methyl-4-thiazolyl 254 5-C1 H OH 2-methyl-4-thiazolyl 255 5-C1 H methoxy 5-thiazolyl 256 5-C1 H OH 5-thiazolyl 257 6-C1 H methoxy 4-methyl-2-thiazolyl 258 6-C1 H OH 4-methyl-2-thiazolyl 259 5-C1 H methoxy 3-Carboxyl-5-isoxazolyl 260 5-C1 H OH 3-Carboxyl-5-isoxazolyl 261 6-C1 H methoxy cyclopropyl 262 6-C1 H OH cyclopropyl 263 6-C1 H methoxy cyclobutyl 264 6-C1 H OH cyclobutyl 265 5-tert.butyl H methoxy 4-chlorophenyl 266 5-tert.butyl H OH 4-chlorophenyl 267 6-C1 H dimethylamino 4-methyl-2-pyridyl 268 6-C1 H methylamino 4-methyl-2-pyridyl 269 5-C1 H HO-(CH ₂ ) ₂ -NH- 4-methyl-2-pyridyl 270 5-C1 H methoxyamino 4-methyl-2-pyridyl 271 5-C1 H 1-piperazinyl 4-methyl-2-pyridyl 272 5-C1 H _H2N- ( _CH2 ) _2- NH- 4-methyl-2-pyridyl 273 5-C1 H 3-amino-1-pyrrolidinyl 4-methyl-2-pyridyl

415

Ex. No. (X)n R ¹ From Q 274 5-F,6-Cl H methoxy 4-chlorophenyl 275 5-F,6-Cl H OH 4-chlorophenyl 276 5-F,6-Cl H methoxy 4-methyl-2-pyridyl 277 5-F,6-Cl H OH 4-methyl-2-pyridyl 278 6-C1 H methoxy 4-(HOXH ₃ C)CH-2-pyridyl 279 6-C1 H OH 4-(HO)(H ₃ C)CH-2-pyridyl 280 6-C1 H OH 4-ethyl-3-F-2-pyridyl 281 6-C1 H OH 2-nitrophenyl 282 6-C1 H OH 2,4-dimethoxyphenyl 283 6-C1 H OH 4-CHF ₂ O-phenyl 284 6-C1 H OH 2,5-dimethoxyphenyl 285 5-acetyl H methoxy 4-CI-phenyl 286 5-acetyl H OH 4-Cl-phenyl 287 6-F H methoxy 4-methyl-2-pyridyl 1 288 6-F H OH 4-methyl-2-pyridyl 289 6-F H methoxy 4-C1-phenyl 290 6-F H OH 4-C1-phenyl 291 5-CH3S- H methoxy 4-methyl-2-pyridyl 292 5-CH3S- H OH 4-methyl-2-pyridyl

416

Claims (79)

1. 2,3-Substituted indoles of general formula I Z represents a hydroxy group, an alkoxy group with 1 to 6 carbon atoms, the group -NR R or a group of general formula II or III (CH ₂ ) _{r /(C} H ₂ ) _r —NYH -L. \ / Y-^-W (II) (in) where r represents the number 1, 2, 3 or 4; Y represents a direct bond, oxygen, sulfur or NR ⁴ ; and W represents a hydroxy group or -NR ² R ³ ; Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino of 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino of 1 to 4 carbon atoms, CN, HO-alkyl of 1 to 4 carbon atoms 417 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; - 418 •· 0 00 0 • 0 0 (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group listed above in (a-1) 419 ·· ««99 ·· « «· * » * β » · 9 ««· » > 9 tet «· • » 99·· » » « «« ♦ * · * ··· ·· 9« « R ¹ represents hydrogen, alkyl of 1 to 4 carbon atoms or halogen; R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN; R ⁴ represents hydrogen or an alkyl group having 1 to 4 carbon atoms; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof. 2. 2,3-Substituted indoles according to claim 1 of the general formula I, where Z represents a hydroxy group, an alkoxy group with 1 to 6 carbon atoms, a dimethylamino group, a methylamino group, an amino group, an N-methoxy-N-methylamino group, a 2-cyanoethylamino group, a 2-hydroxyethylamino group, a pyrrolidinyl group, a piperidino group, a piperazinyl group, a N-methylpiperazinyl group, a morpholino group, a methoxyamino group, a piperazinyl group, an aminopyrrolidinyl group or an aminoethylamino group; and pharmaceutically acceptable salts thereof. 3. 2,3-Substituted indoles according to claim 2 of general formula I, wherein Z represents a hydroxy group or an alkoxy group with 1 to 6 carbon atoms; Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 atoms 421 carbons and cycloalkyl groups of 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl moiety are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups of 1 to 4 carbon atoms, halogen-substituted alkyl groups of 1 to 4 carbon atoms, hydroxy groups, alkoxy groups of 1 to 4 carbon atoms, halogen-substituted alkoxy groups of 1 to 4 carbon atoms, alkylthio groups of 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups of 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups of 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkyl- 422 ·· · · · · · · thio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms of each alkyl moiety, alkylamino groups with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which is optionally substituted with one substituent selected from the group consisting of hydroxy, methyl, ethyl, propyl, fluorine, chlorine and trifluoromethyl; and (e) a benzo-fused heterocycle selected from the group consisting of quinolyl, cinnolinyl, quinoxalinyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzofuryl, benzothienyl and indolyl, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); and pharmaceutically acceptable salts thereof. 423 —· 4. 2,3-Substituted indoles according to claim 3 of general formula I, wherein Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and groups -O-(CH ₂ ) _n ~aryl, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkyl424 • · ···· ·· • « · · amino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 425 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) cyclopropyl, cyclobutyl or cyclohexyl; and (e) quinolyl or isoquinolyl, wherein said quinolyl or isoquinolyl is optionally substituted with one substituent selected from the group consisting of halogen, C1-4 alkyl, _NH2 , hydroxy, C1-4 alkoxy and halogen-substituted C1-4 alkyl; and pharmaceutically acceptable salts thereof. 5. 2,3-Substituted indoles according to claim 4 of general formula I, wherein Z represents a hydroxy group or an alkoxy group having 1 to 6 carbon atoms; Q represents (a) a phenyl group optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino group with 426 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; • · 427 (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to said heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); and (e) an isoquinolyl group; Ί R represents hydrogen or an alkyl group having 1 to 4 carbon atoms; R and R ^J each independently represent hydrogen or methyl; X, at each occurrence, is independently halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, 428 • · ·· · · ·· · ·· · · · hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOR ⁴ , alkylsulfonylamino with 1 to 4 carbon atoms or cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2 or 3; and pharmaceutically acceptable salts thereof. 6. 2,3-Substituted indoles according to claim 5 of general formula I, wherein Z represents a hydroxy group, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group; Q represents (a) a phenyl group optionally substituted with one or two substituents independently selected from the group consisting of (a-1) halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, HO-alkyl 429 with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxy and 1 to 4 carbon atoms in the alkyl part, -COOH, alkylsulfonylamino groups with 1 to 4 carbon atoms, nitro groups, alkylsulfonyl groups with 1 to 4 carbon atoms and cyano groups; (a-2) phenyl or benzyloxy, wherein the phenyl and the phenyl portion of the benzyloxy are optionally substituted with one substituent selected from alkyl having 1 to 4 carbon atoms, halogen-substituted alkyl having 1 to 4 carbon atoms, halogen, hydroxy, alkoxy having 1 to 4 carbon atoms, halogen-substituted alkoxy having 1 to 4 carbon atoms, and NH ₂ ; (a-3) a 5-membered monocyclic aromatic group selected from imidazolyl, thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, wherein the 5-membered monocyclic aromatic group is optionally substituted with one substituent selected from alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, halogen, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms and NH ₂ ; (a-4) a 6-membered monocyclic aromatic group selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein the 6-membered monocyclic aromatic group is optionally substituted with one substituent selected from alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, halogen, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms and NH ₂ ; (b) a 6-membered monocyclic aromatic group selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, said monocyclic aromatic group being optionally substituted with one or two substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group selected from the group consisting of imidazolyl, thiazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, triazolyloxazolyl, isoxazolyl, thiadiazolyl and pyrazolyl, wherein said monocyclic aromatic group is optionally substituted with one or two substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); R ¹ represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; X represents, at each occurrence, independently halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 groups; an represents the number 0, and their pharmaceutically acceptable 7. 2,3-Substituted compounds of formula I, where the carbon atoms or aminosulfonyl 1, 2 or 3; salt. indoles according to general claim 6 Z represents a hydroxy group, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group; Q represents (a) a phenyl group optionally substituted with one or two substituents independently selected from the group consisting of (a-1) fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, butyl, CH ₂ F, CHF ₂ , CF ₃ , methoxy groups, ethoxy groups, n-propoxy groups, n-butoxy groups, isopropoxy groups, CH ₂ FO-, CHF ₂ -O-, CF ₃ -O-, methylthio groups, ethylthio groups, hydroxymethyl groups, methoxymethyl groups, methoxyethyl groups, ethoxymethyl groups, hydroxy, nitro, methylsulfonyl, cyano, (HO)(H ₃ C) ₂ C-, acetyl, and methylsulfonylamino; (a-2) a phenyl group or a benzyloxy group, wherein the phenyl group and the phenyl part of the benzyloxy group are optionally substituted with one substituent selected from methyl, ethyl, propyl, CF ₃ , F, Cl, OH, 432 methoxy groups, ethoxy groups and NH ₂ ; (a-3) a 5-membered monocyclic aromatic group selected from furyl, thienyl and pyrrolyl, wherein the 5-membered monocyclic aromatic group is optionally substituted with one substituent selected from methyl, ethyl, propyl, CF ₃ , F, Cl, OH, methoxy, ethoxy and NH ₂ ; (a-4) pyridyl, which is optionally substituted with one substituent selected from methyl, ethyl, propyl, CF ₃ , F, Cl, OH, methoxy, ethoxy and NH ₂ ; (b) a pyridyl group which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl, 1,2,3-thiadiazolyl or pyrrolyl, wherein said imidazolyl, thiazolyl, furyl, thienyl, isoxazolyl, 1,2,3-thiadiazolyl or pyrrolyl is optionally substituted with one or two substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); R ¹ represents hydrogen, methyl, ethyl, n-propyl or isopropyl; X, at each occurrence, is independently fluorine, chlorine, bromine, methyl, ethyl, propyl, butyl, _CH2F , _CHF2 , _CF3 , methoxy, _CF3O , or ethoxy; and 433 n represents the number 0, 1 or 2; and pharmaceutically acceptable salts thereof. 8. 2,3-Substituted indoles according to claim 7 of general formula I, wherein Z represents a hydroxy group, an ethoxy group or a methoxy group; Q represents a phenyl group, a chlorophenyl group, a fluorophenyl group, a bromophenyl group, a methylphenyl group, a methoxyphenyl group, a (furyl)phenyl group, a trifluoromethylphenyl group, a trifluoromethoxyphenyl group, a pyridyl group, a methylpyridyl group, an ethylpyridyl group, a propylpyridyl group, a dimethylpyridyl group, a chloropyridyl group, a fluoropyridyl group, a trifluoromethylpyridyl group, a methoxypyridyl group, a (ethyl)(ethoxy)pyridyl group, a (chloro)(ethyl)pyridyl group, a thiazolyl group, a methylthiazolyl group, a furyl group, a methoxymethylfuryl group, an isoquinolyl group, a cyclohexyl group, a methoxyphenyl group, a (fluoro)(ethyl)pyridyl group, a dimethylpyridyl group or an (ethoxy)(ethyl)pyridyl group; -and R represents hydrogen; X represents fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, CF ₃ or methoxy; and n represents the number 1 or 2; and pharmaceutically acceptable salts thereof. ··«·«· 0 0 0 0 0 0 · 0000 0 0 0 434 • 0 ·· ii 000 00 ··· 9. 2,3-Substituted indoles according to claim 8 of general formula I, wherein Z represents a hydroxy group, an ethoxy group or a methoxy group; Q represents a phenyl group, a chlorophenyl group, a pyridyl group, a methylpyridyl group, an ethylpyridyl group, a propylpyridyl group or a chloropyridyl group; η R represents hydrogen; X represents fluorine, chlorine, methyl or CF ₃ ; and n represents the number 1 or 2; and pharmaceutically acceptable salts thereof. 10. 2,3-Substituted indoles according to claim 1 of general formula I selected from the group consisting of ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; sodium salts of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; ·· ···· «· · ·* « « · * « · · · W v · · * · « » · « · · · - 435 : : : : ·· ·· ·· <·· ·« ··· methyl-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2- -(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2- - (3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2- -(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [6-chloro-2- acids; -(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid [6-chloro-2- acids; -(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid [6-chloro-2- acids; -(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid (2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid; [5-chloro-2- - (3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2- -(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2- -(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-ylacetic acid; [2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; • · — · 436 · (2-benzoyl-7-chloro-1H-indol-3-yl)acetic acid; (2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid; dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; the less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; - N.-.' methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl)acetate; [5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; (2-benzoyl-6-chloro-1H-indol-3-yl)-N,N-dimethylacetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)-N-methylacetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)acetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)-N-methoxy-N-methylacetamide; 2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone; 2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-(4-methyl-1-piperazinyl)-1-ethanone; (2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-cyanoethyl)acetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-hydroxyethyl)acetamide; - «β·.-.* 2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-morpholino-1-ethanone; [2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; - ‘43*9’./ [5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate; [6-Chloro-2-(4-propylpyridin-2-carbonyl)-1H-xindol-3-ylacetic acid; methyl [5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl] acetate; [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid; methyl-[2-(4-tert-butyl-pyrexin-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate; [2-(4-tert.butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; - uo·.-.· [5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl acetate; [6-Chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl-[5-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate; [5-Chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl] acetic acid; methyl [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; • · 4 4·· [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl] acetate; [6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl] acetate; [6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl-[5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl-[5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; »· ···· • » - 442·*-.·* methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; • · · · · · methyl-[6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5,6-dichloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl acetate; [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; - 444 * • · methyl-[5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl] acetate; [6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [5-tert.butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethoxy-1-hindol-3-yl]acetate; [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; - 44·ξ.· methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid; methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl-(2-benzoyl-1H-indol-3-yl)acetate; (2-benzoyl-1H-indol-3-yl)acetic acid; methyl-[2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid; methyl [6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; - 447.-.. methyl-[2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid; methyl-[2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid; methyl-[2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid; methyl-[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl-[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-benzoyloxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-benzoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; - 449.. [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[(4-methylsulfonyl)benzoyl N-1H-indol-3-yl N]acetate; [6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(methylsulfonylamino)benzoyl N-1H-indol-3-yl]acetate; [6-Chloro-2-[4-methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-ylacetic acid; [6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate; methyl [6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate; methyl [6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl acetate; - 45η.·-·.. [6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl-[6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(2-thiazolyl)benzoyl-1-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate; methyl [6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[3-(2-furyl)benzoyl-1-1H-indol-3-yl-acetic acid; methyl dl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate; dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid; methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate - 45Ί.-·.. [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl] acetate; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-methylisoxazol-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; - 45·2 — • · [5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2-thienyl)carbonylindol-3-ylacetic acid; methyl [6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl acetate; [6-Chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate; methyl-[5-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(1-methylimidazol-2-carbonyl-1H-indol-3-ylacetic acid; - 453.«-* methyl-[5-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(thiazole-5-carbonyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; - 454.. [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-[3-(ethoxycarbonyl)isoxazol-5-carbonyl]-1H-indol-3-yl]acetate; [5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate; [6-Chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate; [6-Chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid; methyl-[5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N,N-dimethylacetamide; [6-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-methylacetamide; [5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)acetamide; [5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-methoxyacetamide; - 455.' 2-[5-chloro-2-(4-methylpyridin-2-carbonyl-1H-indol-3-yl]-1-piperazinyl-1-ethanone; [5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide; 2-[5-chloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone; [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; methyl [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-difluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; • · • · 4 · - 45 g of [6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate; methyl [6-fluoro-2-(4-methylpyridine-2-carbonyl]-1H-indol-3-yl]acetate; [6-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid; and [2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid; and their salts. 11. 2,3-Substituted indoles according to claim 10 of general formula I selected from the group consisting of ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; - 457 sodium salt of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-ylacetic acid; [6-Chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid; (2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid; [5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; - 458 - [5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-ylacetic acid; [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-ylacetic acid; [2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; (2-benzoyl-7-chloro-1H-indol-3-ylacetic acid; (2-benzoyl-4,5-dichloro-1H-indol-3-ylacetic acid; (2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-ylacetic acid; dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; the less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; • · - 459 [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate; [5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; [2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid [6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; 460 — · · methyl-[6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid; [2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; 461 [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; 462 — · · [6-Chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-ylacetic acid; [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetic acid; fc · - 463 [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; 464 [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; (2-benzoyl-1H-indol-3-yl)acetic acid; [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid; [6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid 12-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; [6-Chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid 465 16-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid; [6-Chloro-2-[4-methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid; [6-Chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl acetate; 466 • · ·· · · · · · ·· ··· Methyl-[6-chloro-2-(4-bromobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid [6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid; [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; 467 [6-Chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-ylacetic acid; [6-Chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl] acetic acid; [6-chloro-2-(2-thienyl)carbonylindol-3-ylacetic acid; [ 6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl-1-1H-indol-3-yl-acetic acid; [6-Chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(1-methylimidazol-2-carbonyl-1H-indol-3-ylacetic acid; [5-Chloro-2-(imidazol-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(imidazol-2-carbonyl)-1H-indol-3-ylacetic acid; [5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-ylacetic acid; ······ ·· · ·· 468 [5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid; [6-Chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid; [6-Chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid; [5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; » · ··· · • · · 469 [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-difluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid and [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; and their salts. 12. 2,3-Substituted indoles according to claim 10 of general formula I selected from the group consisting of ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-Chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; ·«··»· ·· · «· • « « ««·· ··· - 470 ř : : : : : : : «· · · · · · ·· «« o·· [6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid; (2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid; [5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; (2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid; dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; 471 ·· ··«· «· · • · « · ·« • · ··»· · « · e · ···««·· ··· »· «« «· ··· «4 <··· less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate; • · · · 472·*[5-Chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; [6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate; »· ···· ·· - 473”- ·’ [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl] acetate; [2-(4-tert.butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl acetate; • · ···« ·· * et • « · ···· ··· - 474 4. : : : : : : : ·· ·· ·· ·· · * ··· [6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate; [5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; - 475·*- ·* [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethyl-3-fluoropyridin-2-carbonyl)-1H-indol-3-yl]acetate; 5-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-ethyl-3-fluoropyridin-2-carbonyl)-1H-indol-3-yl]acetate; - 476 • · · · · [6-Chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5,6-dichloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; 477 [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-Methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-methoxy-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; 478 • · · · · · · · · · · · · [6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-isopropyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl-[5-tert-butyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethoxy-1-hindol-3-yl]acetate; [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; 479 [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid; methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-ylacetic acid; [2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid; methyl-[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl-[2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; 480 [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; • · · · ♦ · - 481 ·* methyl-[5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl] acetate; [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; 482 [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate; and their salts. 13. 2,3-Substituted indoles according to claim 10 of general formula I selected from the group consisting of ethyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid; [6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(3-Bromobenzoyl)-6-chloro-1H-indol-3-ylacetic acid; [2-(4-Bromobenzoyl)-6-chloro-1H-indol-3-ylacetic acid; [6-Chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-ylacetic acid; (2-benzoyl-4-chloro-1H-indol-3-ylacetic acid; [5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid; [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-ylacetic acid; [2-(3-Chlorobenzoyl)-5-fluoro-1H-indol-3-ylacetic acid; (2-benzoyl-4,5-dichloro-1H-indol-3-ylacetic acid; (2-benzoyl-4,6-dichloro-1H-indol-3-ylacetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-ylacetic acid; dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; ♦ fc ···· fc i « • · · • · « • · * · c · «· * ··· • · * That is »· ·· fc·· ♦ * « * the less polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; the more polar antipode of 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; [6-Chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-chloropyridin-2-carbonyl)-1H-indol-3-ylacetic acid; [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-Chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazol-2-carbonyl)-1H-indol-3-ylacetic acid; methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate; -*44$ [5-Chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; [6-Chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; - ·4€*7.-' [5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid; - 489 — [2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]-1H-acetic acid; [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-[4-(2-furyl)benzoyl-3-1H-indol-3-yl]acetic acid; [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; 15-Chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; - *490* — [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl]acetate; [6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; 2-{6-chloro-2-[(4-ethyl-3-fluoro-2-pyridinyl)carbonyl]-1H-indol-3-yl}acetic acid; and methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate; and their salts. 14. 2,3-Substituted indoles according to claim 10 of general formula I selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-ylacetic acid; [6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid; [6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-ylacetic acid; [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(3-Bromobenzoyl)-6-chloro-1H-indol-3-ylacetic acid; [2-(4-Bromobenzoyl)-6-chloro-1H-indol-3-ylacetic acid; [6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-ylacetic acid; 15-chloro-2-(3-methylbenzoyl)-1H-indol-3-ylacetic acid; [5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid; [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-Chlorobenzoyl)-5-fluoro-1H-indol-3-ylacetic acid; [2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; (2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-4,6-dichloro-1H-indol-3-ylacetic acid; • · ···· ·· « • · · * · · · • · · • · · · 4 9»2 —· · · · · · • · · · (2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl]acetate; [5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; [6-Chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid; - 4.93*.-. methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate; [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; - 4*94* methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[6-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate; [6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl-[5-chloro-2-[5-(trifluoromethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate; 15-Chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-ylacetic acid; methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [5-chloro-2-(4-chloropyridin-2-carbonyl)-1H-indol-3-ylacetic acid; methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; - ‘4e’ï.*·’ methyl [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5,6-dichloro-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl acetate; [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl acetate; 15-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-ethyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; - 4e.7 methyl [5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [5-tert.butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethoxy-1-hindol-3-yl]acetate; [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-methylpyridin-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; • · · fcfc · - 493 ··». methyl-[2-(4-ethylpyridin-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-ylacetic acid; methyl-[2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-Chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-ylacetic acid; methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl acetate; [6-Chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; «0 ·00» - 4^9’ N*’ methyl-[5-chloro-2-(xisoquinoline-3-carbonyl)-1H-indol-3-yl]acetate [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl] acetate; [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; 500 *'· • · · • · · methyl-[5-chloro-2-(2-methylimidazol-4-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl] acetic acid; [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate; and their salts. 15. 2,3-Substituted indoles according to claim 10 of general formula I selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; 501 *τ· [6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; (2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; • · · · · · - 502 ' [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl] acetate; 15-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-ylacetic acid; methyl [5-chloro-2-(thiazol-2-carbonyl-1H-indol-3-yl)acetate; [5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; [6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-methoxybenzoyl)-1H-indol-3-ylacetic acid; methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; • * 503 'τ. [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-Chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-(5-chloropyridine-2-carbonyl-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; 504 [6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; 505 [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3yl]acetic acid; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; 506 methyl-[5-chloro-2-(5-methylthiazol-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate; [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; and [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; and their salts. 507 • · ·· «· »·· ·· · · · 16. 2,3-Substituted indoles according to claim 1 of general formula I selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid; [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl] acetate; [6-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-ethylpyridine-2-carbonyl-1H-indol-3-yl]acetic acid; 508 methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-propylpyridine-2-carbonyl-1H-indol-3-yl]acetate; [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl-[2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1-hindol-3-yl]acetate; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; • · • · 509 methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridin-2-carbonyl]-1H-indol-3-yl acetate; [6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(5-chloropyridin-2-carbonyl)-1H-indol-3-ylacetic acid; methyl-[6-methyl-2-(4-methylpyridin-2-carbonyl)-1H-indol-3-yl]acetate; [6-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate; [6-Chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid (cj-020 099); and methyl [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; and their salts. 511 ·_ • · 17. 2,3-Substituted indoles according to claim 10 of general formula I selected from the group consisting of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; [6-Chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-chlorobenzoyl-1-1H-indol-3-ylacetic acid; [5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-ylacetic acid; [2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-ylacetic acid; [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-chloropyridin-2-carbonyl)-1H-indol-3-ylacetic acid; [6-Chloro-2-(pyridin-2-carbonyl)-1H-indol-3-ylacetic acid; [5-Chloro-2-(4-methylpyridine-2-carbonyl-1H-indol-3-yl)acetic acid; [6-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; 512 · _Γ . [5-Chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-ylacetic acid; [5-Chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methoxypyridin-2-carbonyl)-1H-indol-3-ylacetic acid; [5-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-Fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; 513 [6-Chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-Chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; and [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; and their salts. 18. A pharmaceutical composition for the treatment of medical conditions in which prostaglandins are considered to be pathogens, characterized in that it contains a 2,3-substituted indole according to claim 1 of general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically inert carrier. 19. A pharmaceutical composition according to claim 18, characterized in that it contains a 2,3-substituted indole according to claim 2 of general formula I or a pharmaceutically acceptable salt thereof. 20. A pharmaceutical composition according to claim 19, characterized in that it contains a 2,3-substituted indole according to claim 3 of general formula I or a pharmaceutically acceptable salt thereof. 514 21. A pharmaceutical composition according to claim 20, characterized in that it contains a 2,3-substituted indole according to claim 4 of general formula I or a pharmaceutically acceptable salt thereof. 22. A pharmaceutical composition according to claim 21, characterized in that it contains a 2,3-substituted indole according to claim 5 of general formula I or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition according to claim 22, characterized in that it contains a 2,3-substituted indole according to claim 6 of general formula I or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition according to claim 23, characterized in that it contains a 2,3-substituted indole according to claim 7 of general formula I or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition according to claim 24, characterized in that it contains a 2,3-substituted indole according to claim 8 of general formula I or a pharmaceutically acceptable salt thereof. 26. A pharmaceutical composition according to claim 25, characterized in that it contains a 2,3-substituted indole according to claim 9 of general formula I or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition according to claim 26, characterized in that it contains a 2,3-substituted indole according to claim 10 of general formula I or a pharmaceutically acceptable salt thereof. 515 ΦΦ φφφ® φφ · φφ · • · 4 ΦΦΦΦ «ΦΦΦ ΦΦΦ ·Φ· ΦΦ* • r «φφ· φφ·φ φ φφ·φ φφ φ φ· · 7* ΦΦ ΦΦ -»«Φ Φφ··· 28. A pharmaceutical composition according to claim 27, characterized in that it contains a 2,3-substituted indole according to claim 11 of general formula I or a pharmaceutically acceptable salt thereof. 29. A pharmaceutical composition according to claim 28, characterized in that it contains a 2,3-substituted indole according to claim 12 of general formula I or a pharmaceutically acceptable salt thereof. 30. A pharmaceutical composition according to claim 29, characterized in that it contains a 2,3-substituted indole according to claim 13 of general formula I or a pharmaceutically acceptable salt thereof. 31. A pharmaceutical composition according to claim 30, characterized in that it contains a 2,3-substituted indole according to claim 14 of general formula I or a pharmaceutically acceptable salt thereof. 32. A pharmaceutical composition according to claim 31, characterized in that it contains a 2,3-substituted indole according to claim 15 of general formula I or a pharmaceutically acceptable salt thereof. 33. A pharmaceutical composition according to claim 32, characterized in that it contains a 2,3-substituted indole according to claim 16 of general formula I or a pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition according to claim 33, characterized in that it contains a 2,3-substituted indole according to claim 17 of general formula I or a pharmaceutically acceptable salt thereof. • · · · · · • · · ί- l>16 · • · · e 35. A method of treating a medical condition in which prostaglandins are considered to be pathogens in a mammal, comprising administering to said mammal a pharmaceutical composition according to claim 1. 36. Compounds of general formula 7-VI B represents a suitable protecting group; Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkyl(b) (c) (d) (e) R ² and R ³ are thio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms of each alkyl moiety, alkylamino groups with 1 to 4 carbon atoms and CN; a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to this heteroatom optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group listed above in (a-1); each independently represents hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; each occurrence independently represents halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, X represents a hydroxy group, an alkoxy group with 1 to 4 carbon atoms, a halogen-substituted alkoxy group with 1 to 4 carbon atoms, an alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; R represents an alkyl group of 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4. 37. Compounds of general formula 7-V where B represents a suitable protecting group; Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n ~aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); R ² and R ³ each independently represent hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 alkyl substituted with halogen, hydroxy, C 1-4 alkoxy, NH ₂ or CN; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms; R ⁵ represents an alkyl group with 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4. -: 523 tons 38. Process for the production of compounds of general formula 7-IV Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen• · ·*·· • fc · -substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxy• · ···* · · · *· · · · · ·» ··· ve and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and represents the number 0, 1, 2, 3 or 4; characterized in that it includes the following stages: i) reaction of the compound of general formula 7-II (XÁTi NHB co ₂ ft (7-II) wherein B represents a suitable protecting group; R ^b represents an alkyl group having 1 to 6 carbon atoms; and X and n are as defined above; with a compound of the general formula wherein E represents halogen and Q has the meaning as defined above; using a first base and a suitable solvent; ii) reacting the product of step i) with a second base; and iii) reacting the product of step ii) with an acid. 39. The method of claim 38, wherein the first base is potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate. 40. The method of claim 38, wherein the first base is potassium carbonate. 41. The method of claim 38, wherein the second base is aqueous sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium pentoxide (followed by addition of water), sodium methoxide (followed by addition of water), or potassium tert-butoxide (followed by addition of water). by The method of claim 38, wherein the second base is sodium hydroxide. listening 43. The method of claim 38, wherein the acid is an aqueous acid, hydrobromic acid, sulfuric acid or hydrochloric acid, ammonium chloride. 44. The method of claim 38, wherein the acid is aqueous hydrochloric acid. 45. The method of claim 38, wherein the solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone, or tetrahydrofuran. 46. The method of claim 38, wherein the solvent is N,N-dimethylacetamide. 47. Process for the production of compounds of general formula 7-IV Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-í 5«Ž9 -substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents; -·53Θ tuents independently selected from the set set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); oh oh > > R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it comprises the reaction of a compound of general formula 7-VII where R ⁵ represents an alkyl group with 1 to 6 carbon atoms; and Q, X and n have the meanings given above; with a base in a suitable solvent. 48. The method of claim 47, wherein the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-pentoxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide. 49. The method of claim 47, wherein the base is sodium hydroxide. 50. The method of claim 47, wherein the solvent is an aqueous mixture of methanol, ethanol, isopropyl alcohol, or tetrahydrofuran. - ·5?2·. _Γ · 51. The method of claim 47, wherein the solvent is methanol containing water. 52. A process for the production of compounds of general formula 7-VII where Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally -· 533 substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; --534 (b) (c) (d) (e) ^R2 and ^R3 a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group listed above in (a-1); each independently represents hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; represents, at each occurrence, independently halogen, alkyl of 1 to 4 carbon atoms, halogen-substituted alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, halogen-substituted alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms - ·535 in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms; R represents an alkyl group having 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it comprises reacting a compound of general formula 7-VI where B, Q, X, and R ⁵ have the above-mentioned meaning; with a base in a suitable solvent. 53. The method according to claim 52, characterized in that the base is 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,1,3,3-tetramethylguanidine, sodium tert-pentoxide, sodium methoxide or potassium tert-butoxide. 54. The method of claim 52, wherein the base is 1,8-diazabicyclo[5.4.0]undec-7-ene or potassium tert-butoxide. - ·5?6·.γ· 55. The method of claim 52, wherein the solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran. 56. The method of claim 52, wherein the solvent is N,N-dimethylacetamide. 57. Process for the production of compounds of general formula 7-VI B represents a suitable protecting group; Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups of 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl having 1 to 4 carbon atoms, halogen-substituted alkyl having 1 to - «8\-/ 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, NO ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms; R represents an alkyl group having 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it comprises reacting a compound of general formula 7-V wherein B, Q, X, and R ⁵ have the above meanings; with a base in a suitable solvent. 58. The method of claim 57, wherein the base is potassium carbonate, hydrogen carbonate. potassium tan, sodium bicarbonate, sodium carbonate or cesium carbonate. 59. The method of claim 57, wherein the base is potassium carbonate. 60. The method of claim 57, wherein the solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone, or tetrahydrofuran. 61. The method of claim 57, wherein the solvent is N,N-dimethylacetamide. 62. A method for producing compounds of general formula 7-V where B represents a suitable protecting group; Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , ··*··· 9 9 9 9 9 · • · · · · · · 9 9 9 9 - Í54ÍL. : : ::: : • · ·· · · 9 9 9 9 9 9 9 9 dialkylamino groups with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino groups with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl group part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms of each of the alkyl parts, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms »· *··» - Š4Ž··« ·· each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to this heteroatom optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); ·· ···· ·· · 49 • · » · · *· 4 9 9 4 9 9 9 9 9 9 4 • .· · · · · · 9 9 · R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms; R ⁵ represents an alkyl group having 1 to 6 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it involves the reaction of a compound of general formula 7-II (7-II) NHB 544 9” · where Β, X, and R ⁵ have the above meanings; with a compound of the general formula O where E represents halogen and Q has the meaning given above; and a base in the presence of a solvent. 63. The method of claim 62, wherein the base is potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate or cesium carbonate. 64. The method of claim 62, wherein the base is potassium carbonate. 65. The method of claim 62, wherein the solvent is N,N-dimethylacetamide, N,N-dimethylformamide, methyl ethyl ketone, acetone or tetrahydrofuran. 66. The method of claim 62, wherein the solvent is N,N-dimethylacetamide. 67. Process for the preparation of compounds of general formula XII where (XII) represents ······ ·· « · · • · · · * · ··· - 545* • » · · ·* ··· ·· ··· (a) a phenyl group optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moieties, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl moiety are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; - 546. (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently • ···· ·· · • · · · ♦ · · - 54V « selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); R represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or halogen; after R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; R represents an alkyl group having 1 to 6 carbon atoms; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino group with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl group with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl group with 1 to 4 carbon atoms, aminosulfonyl• · · · · · - 548 group, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl group, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino group with 1 to 4 carbon atoms and cycloalkyl group with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it involves the reaction of a compound of general formula X Ί where R , R , X, Q and n are as defined above; and B represents a suitable protecting group, in the presence of a suitable base to form a compound of general formula XII. 68. A process for the preparation of compounds of general formula XII where (XII) Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted C1-4 alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , - 549 -« dialkylamino groups with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino groups with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, C1-4 alkyl, halogen-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted C1-4 alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , C1-4 dialkylamino of each alkyl moiety, C1-4 alkylamino, and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms 550 - · • · · · each of the alkyl moieties, the alkylamino groups of 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); - 551 R ¹ represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or halogen; R and R each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; R represents an alkyl group having 1 to 6 carbon atoms; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it involves the reaction of a compound of general formula IX 552 η C wherein R 1 , R 2 , X and n are as defined above; and B represents a suitable protecting group; with a compound of general formula XI eJ< _q ^(xi) where E represents halogen and Q has the above meaning; in the presence of a suitable base at a temperature of from -40 to 200°C to form a compound of general formula XII. 69. The method of claim 68, wherein the reaction is carried out at a temperature of from 0 to 100°C. 70. The method of claim 68, wherein the suitable base is potassium carbonate, cesium carbonate, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, or potassium fluoride. 71. The method of claim 68, wherein the reaction with a base is first carried out for a period of 2 minutes to one day, after which another base is added to the reaction mixture. 72. The method of claim 71, wherein the reaction is initially carried out for a period of 30 minutes to 8 hours. 73. The method according to claim 67 and 68, characterized in that the suitable protecting group is a methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, phenylsulfonyl, p-toluenesulfonyl, methanesulfonyl or trifluoromethanesulfonyl group. - 553 74. The method of claim 73, wherein the suitable protecting group is a phenylsulfonyl-p-toluenesulfonyl-, methanesulfonyl- or trifluoromethanesulfonyl group. 75. The method of claim 71, wherein the first base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine, and diethylisopropylamine; and the second base is selected from the group consisting of sodium tert-butoxide, tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine, and diethylisopropylamine; potassium butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, pyridine, pyrrolidine, triethylamine, diisopropylamine, diisopropylethylamine and diethylisopropylamine. 76. The method of claim 75, wherein the first base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium hydride, and potassium fluoride; and the second base is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, cesium carbonate, pyrrolidine, diisopropylamine, triethylamine, diethylisopropylamine, and diisopropylethylamine. 77. The method of claim 75, wherein the first base is potassium carbonate, cesium carbonate or potassium fluoride and the second base is 1,8-diazabi-554-.Γ* cyclo[5,4,0]undec-7-ene, potassium tert-butoxide or cesium carbonate. 78. The method of claim 77, wherein the combination of the first base and the second base, first base/second base, is selected from the group consisting of the combinations potassium carbonate/1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate/cesium carbonate, cesium carbonate/potassium tert-butoxide, cesium carbonate/1,8-diazabicyclo[5.4.0]undec-7-ene, potassium fluoride/1,8-diazabicyclo[5.4.0]undec-7-ene, and potassium fluoride/cesium carbonate. 79. The method of claim 78, wherein the combination of the first base and the second base, first base/second base, is selected from the group consisting of the combinations potassium carbonate/1,8-diazabicyclo[5,4,0-jundec-7-ene, potassium carbonate/cesium carbonate, and cesium carbonate/potassium tert-butoxide. Process for the preparation of compounds of general formula VIII where (VIII) Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, _hydroxy , alkoxy with 1 to 4 carbon atoms, _halogen -substituted alkoxy with 1 to 4 carbon atoms, alkyl553 ·· · alkylsulfonyl groups with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(0) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and groups -O-(CH ₂ ) _n ~aryl, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, NO ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , • · - 556..-* (b) (c) (d) (e) dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms of each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents • · · · · · - 557. independently selected from the group set forth above in (a-1); Ί R represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or halogen; R and R ^J each independently represent hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, or C1-4 alkyl substituted with halogen, hydroxy, C1-4 alkoxy, NH ₂ or CN; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² Nr3 , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it involves the reaction of a compound of general formula X 558 (X) wherein R ¹ , R ⁵ , X, Q and n are as defined above; with a suitable base under hydrolysis conditions to form a compound of general formula VIII. 81. A process for the production of compounds of general formula VIII (VIII) wherein Q represents (a) phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of (a-1) halogen, alkyl with 1 to 4 carbon atoms, halogen-substituted alkyl with 1 to 4 carbon atoms, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen-substituted alkoxy with 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl moieties, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl moiety, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl groups, -NH ₂ S(O) ₂ NR ² R ³ , acetyl groups, -COOH, -C(0)0- 55¾ -alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino groups with 1 to 4 carbon atoms and cycloalkyl groups with 3 to 7 carbon atoms, (a-2) aryl groups and -O-(CH ₂ ) _n -aryl groups, wherein the aryl group and the aryl part are optionally substituted with one, two or three substituents independently selected from halogen, alkyl groups with 1 to 4 carbon atoms, halogen-substituted alkyl groups with 1 to 4 carbon atoms, hydroxy groups, alkoxy groups with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms of each of the alkyl parts, alkylamino groups with 1 to 4 carbon atoms and CN; (a-3) a 5-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, halogen-substituted alkoxy group with 1 to 4 carbon atoms, alkylthio group with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino group with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino group with 1 to 4 carbon atoms and CN; (a-4) a 6-membered monocyclic aromatic group which is optionally substituted with one, two or three substituents independently selected from halogen, alkyl group with 1 to 4 carbon atoms, halogen-substituted alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group - 560..-·' with 1 to 4 carbon atoms, halogen-substituted alkoxy groups with 1 to 4 carbon atoms, alkylthio groups with 1 to 4 carbon atoms, N0 ₂ , NH ₂ , dialkylamino groups with 1 to 4 carbon atoms each of the alkyl moieties, alkylamino groups with 1 to 4 carbon atoms and CN; (b) a 6-membered monocyclic aromatic group containing 1, 2, 3 or 4 nitrogen atoms and optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (c) a 5-membered monocyclic aromatic group which contains one heteroatom selected from oxygen, sulfur and nitrogen and in addition to these heteroatoms optionally contains 1, 2 or 3 nitrogen atoms and is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1), (a-2), (a-3) and (a-4); (d) a cycloalkyl group of 3 to 7 carbon atoms, which is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl of 1 to 4 carbon atoms, halogen and halogen-substituted alkyl of 1 to 4 carbon atoms; and (e) a benzo-annelated heterocycle, which is optionally substituted with one, two or three substituents independently selected from the group set forth above in (a-1); R ¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or halogen; R ² and R ³ each independently represent hydrogen, hydroxy, alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms or an alkyl group with 1 to 4 carbon atoms substituted by halogen, hydroxy, alkoxy group with 1 to 4 carbon atoms, NH ₂ or CN; X, at each occurrence, is independently halogen, C1-4 alkyl, C1-4 halogen-substituted alkyl, hydroxy, C1-4 alkoxy, C1-4 halogen-substituted alkoxy, C1-4 alkylthio, N0 ₂ , NH ₂ , dialkylamino with 1 to 4 carbon atoms in each of the alkyl parts, alkylamino with 1 to 4 carbon atoms, CN, HO-alkyl with 1 to 4 carbon atoms, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxyl and 1 to 4 carbon atoms in the alkyl part, alkylsulfonyl with 1 to 4 carbon atoms, aminosulfonyl, -NH ₂ S(O) ₂ NR ² NR ³ , acetyl, -COOH, -C(O)O-alkyl with 1 to 4 carbon atoms in the alkyl part, alkylsulfonylamino with 1 to 4 carbon atoms and cycloalkyl with 3 to 7 carbon atoms; and n represents the number 0, 1, 2, 3 or 4; characterized in that it comprises the hydrolysis of a compound of general formula XII where R ⁵ represents an alkyl group of ε 1 to 6 carbon atoms; and R ¹ , X, Q and n have the meanings given above.