BG108206A - Novel tyrosine kinase inhibitors - Google Patents

Abstract

The invention provides compounds of formula and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase enzymes thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases which can be treated by inhibiting tyrosine kinase enzymes.

Description

The invention relates to novel tyrosine kinase inhibitors. In particular, it relates to the inhibition of a tyrosine kinase enzyme using new small molecules.

BACKGROUND OF THE INVENTION

Tyrosine kinases are a class of enzymes that catalyze the conversion of the final phosphate of adenosine triphosphate into the phenolic hydroxyl group of the tyrosine residue present in the target protein. Tyrosine kinases play a critical role in signaling in some of the cell functions, including cell proliferation, carcinogenesis, apoptosis and cell differentiation (Plowman, GD; Ulrich, A .; Shawver, LK: Receptor Tyrosine Kinases As Targets For Drug Intervention. DN&P (1994) 7: 334-339). Therefore, inhibitors of these enzymes will be useful for treating or preventing proliferative diseases that are dependent on these enzymes. Serious epidemiological evidence indicates that overexpression or activation of receptor protein tyrosine kinases leading to significant mitogenic signaling is an important factor in the increasing number of human malignancies. Tyrosine kinases involved in these processes include Abl, CDK, EGF, EMT, FGF, FAK, Flk-1 / KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src, and VEGF (Traxler, PM Tyrosine Kinase Protein Inhibitors in Cancer Treatment. Exp. Opin. Ther. Patents (1997) 7: 571-588; incorporated herein by reference. Therefore, there is an ongoing need to investigate novel compounds that can be used to regulate or inhibit tyrosine kinase enzymes.

SUMMARY OF THE INVENTION

The present invention relates to compounds that inhibit tyrosine kinase enzymes, compositions that contain compounds that inhibit tyrosine kinase, and to the use of tyrosine kinase enzyme inhibitors for the preparation of pharmaceutical forms for the treatment of diseases characterized by overexpression or promotion of tyrosine such as cancer, diabetes, restenosis, arteriosclerosis, psoriasis, angiogenic diseases and immunological disorders (Powis, G.; Workman, R. Signaling targets for The Development of Cancer Drugs. Anti-Cancer Drug Design (1994), 9: 263-277; Merenmies, J.; Parade, L F.; Henkenmeyer, M. Tyrosine Kinase Signa-ling Receptor in Vascular Development Cell Growth Differ (1997) 8: 3-10; Shawver, LK; Lipsosn, KE; Fong, TAT; McMachon, G .; Plowman, GD ; Srawn, LM Receptor Tyrosine Kinases As Targets For Inhibition Of Angiogenesis Drug Discovery Today (1997)

2: 50-63; all of which are incorporated herein by reference).

In addition to their use as separate agents, it has been observed that tyrosine kinase inhibitors can enhance the action of cytotoxic and cytostatic treatments when used with standard therapies known to those skilled in the art.

The present invention relates to compounds of formula I:

R.

to their enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and solvates, in which:

X is selected from the group consisting of: N, C, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl substituted with one or more R ₇ , as well as a direct bond;

Y is selected from the group consisting of O and S;

W is selected from the group consisting of N, C, O and S, provided that when W is O or S, R _g is absent;

R-ι, R _2, R _3, R _4, R _5i R _6, R _7, R _8, Rg are each independently selected from the group consisting of: H, C ^ g alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, OR ₆₀ , NO ₂ , OH, SR ₆₀ , NR ₆₀ R ₆₁ , CN, CO ₂ R ₆₀ , CONRg ₀ R ₆₁ , CO ₂ NR ₆₀ R ₆₁ , NRg ₂ CONRgoRgi, NRggSO ₂ Rg ^, SO ₂ NRggRgj, C (NR ₆₂ ) NR 6 oR ₆₁ , aryl, heteroaryl, (CH ₂ ) _n OR ₆₀ , (CH ₂ ) _n NR ₆ oR ₆₁ , (CH ₂ ) _n SR ₆₀ , (CH ₂ ) _n aryl, ( CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocycloalkyl, NH-Z-aryl and NH-Z heteroaryl;

where η is 1 to 3 and

Ζ is selected from the group consisting of C ₁ -C ₄ alkyl, alkenyl and alkynyl; Ζ has one or more of the following groups: hydroxy, thiol, alkoxy, thioal coke, amino, halo, NR ₆₀ SO ₂ R ₆ i; Z optionally includes one or more of the groups selected from the group consisting of: CO, CNOH, CNOR ₆₀ , CNNR ₆₀ , CNNCOR ₆₀ and CNNSO ₂ R ₆₀ and

R ₆₀ , R ₆₁ and R ₆₂ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl and alkyl-P ₂₅ , wherein:

R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , - NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃ oR ₃ i, heteroaryl or heterocycloalkyl, and

R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or alkyl-H ₂₅ .

In preferred embodiments, R _n R ₇ , R ₈ and R ₉ are Η;

R ₂ and R ₄ are H or F;

Ye Ο;

X is selected from the group consisting of N and CH;

WeN;

R ₅ is selected from the group consisting of H, methyl, ethyl, isopropyl, secondary butyl, cyclopropyl, F and CF ₃ ;

R ₆ is selected from the group consisting of H, 2-aminomethylpyridine, NHCH (CH ₂ OH) CH ₂ Ph, NHCH ₂ CH (OH) apnn and NHCH (CH ₂ OH) CH ₂ apnn and

R ₃ is selected from the group consisting of: OR ₆₀ , CiNHJNHReo, C (O) NHR ₆₀ , imidazole, imidazoline, tetrahydropyrimidine, piperazine, morpholine, homomorpholine, piperidine, pyrrolidine, homopiperazine and amino, where

R ₆₀ is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl and alkyl- _{1 2} 5, wherein R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, thioalkoxy, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, - NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃₁ or heteroaryl or heterocycloalkyl and

R ₃₀ and R ₃₁ independently represent hydrogen, alkyl, cycloalkyl or apn-R ₂₅ .

The invention also provides a pharmaceutical composition comprising a compound of formula I as defined above and a pharmaceutically acceptable carrier.

The invention further provides a pharmaceutical composition comprising a compound of formula I as defined above in combination with a pharmaceutically acceptable carrier and at least one anticancer agent optionally prepared as a fixed dose.

In addition, there is provided a method of treating a condition associated with at least one tyrosine kinase enzyme comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I as defined above. The invention further provides a method of treating a condition associated with at least one tyrosine kinase enzyme comprising administering to a mammal in need of such treatment at least one anticancer agent in combination with a compound of formula I, as defined herein. above.

The present invention provides compounds of formula I, as defined above, pharmaceutical compositions using these compounds and methods of using such compounds.

The definitions of the various terms used to describe the compounds of the present invention are given below. These definitions refer to the terms as used in the description (unless limited to specific cases), whether it is a single compound or part of a larger group.

The term "alkyl" used alone or as part of another group refers to a radical derived from a monovalent alkane (hydrocarbon) containing from 1 to 12 carbon atoms, unless otherwise defined. An alkyl group is a saturated hydrocarbon group which may be substituted by a unbranched, branched or cyclic chain. When substituted, the alkyl groups may be substituted by up to four substituent groups R as defined above at any available binding site. When it is mentioned that the alkyl group is substituted by an alkyl group, this term is interchangeable with a "branched alkyl group". Examples of unsubstituted groups include methyl, ethyl, propyl, iso-propyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Examples of substituent groups may include, but are not limited to, one or more of the following: hydroxy, halo (e.g. F, Cl, Br, I), haloalkyl (e.g. CCl ₃ and CF ₃ ), alkoxy, alkylthio , cyano, carboxy (-COOH), alkylcarbonyl (-C (O) R), alkoxycarbonyl (-OCOR), amino, carbamoyl (-NHCOOR or -OCONHR), urea (-NHCONHR), thiol (-SH), sulfoxy, sulfonyl, aryl, heteroaryl and heterocycloalkyl. The alkyd groups as defined above may also include one or more carbon-carbon double bonds or one or more carbon-carbon triple bonds. The alkyl groups may also be represented by the formula alkyl-B ₂₅ . In preferred embodiments, the alkyl group is methyl, ethyl, propyl or butyl and include substituted methyl, ethyl, propyl or butyl.

The term "alkenyl", used alone or as part of another group, refers to a hydrocarbon radical having a branched, branched or cyclic chain having from 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may optionally be substituted in the same manner as described for the alkyl group.

The term "alkynyl", used alone or as part of another group, refers to a hydrocarbon radical having a branched, branched or cyclic chain containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. The alkynyl group may optionally be substituted in the same manner as described for the alkyl group.

The term "alkoxy", used alone or in combination, refers to an unbranched, branched or cyclic alkyl group linked covalently to the parent molecule by an oxygen atom and containing from one to ten carbon atoms, and the terms " _C6 alkoxy" and "lower alkoxy" refer to such groups containing from one to six carbon atoms, examples of which include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, bugoxy, tert-butoxy and the like. The term "optionally substituted" when used in connection with an alkoxy substituent refers to the substitution of at most two hydrogen, preferably at different carbon atoms, with a radical selected from the group: lower alkyl, phenyl, cyano, halo , trifluoromethyl, nitro, hydroxy, alkanoyl, amino, monoalkylamino and dialkylamino. The alkoxy groups may be substituted in the same manner as described for the alkyl groups above.

The term "sulfoxy", used alone or as part of a group, refers to -SO, which may be substituted, e.g. with alkyd or aryl groups.

The term "sulfonyl", used alone or as part of a group, refers to -SO ₂ which may be substituted, e.g. with alkyd or aryl groups.

The term "amino", used alone or as part of a group, refers to -NH ₂ . The amino group may optionally be substituted by one or two substituents which may be the same or different, e.g. alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroapylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. Preferred substituents include alkylamino and dialkylamino, such as methylamino, ethylamino, dimethylamino and diethylamino. These substituents may be further substituted by carboxylic acid or by any of the alkyl or aryl substituents provided herein. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4morpholinyl, 4-thiamorpholinyl, 4-sulfoxymorpholine, 4-sulfonylmorpholine, 1-piperazinyl, 1-piperazinyl. , 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4diarylalkyl-1-piperazinyl, 1-homopiperazinyl, 4-alkyl-1-homopiperazinyl, 4-arylalkyl-1-homopiperazinyl, 4-diarylalkyl-1-piperazinyl ; 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl optionally substituted by alkyl, alkoxy, alkylthio, halo, trifluoromethype or hydroxy.

The term "aryl", used alone or as part of a group, refers to monocyclic or bicyclic aromatic rings, e.g. phenyl, substituted phenyl and the like, and to groups which are fused, e.g. naphthyl, phenanthrenyl and the like. One aryl group contains at least one ring having at least 6 atoms, and there may be up to five such groups containing up to 22 atoms with repeating (conjugated) double bonds between adjacent carbon atoms or suitable heteroatoms. The aryl groups may be optionally substituted by one or more groups, including, but not limited to, halogen, alkylalkenyl, alkynyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, alkylaminocarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, amino, cycloalkyl, amino alkyl S (O) _m (m = 0.1, 2) or thiol. The aryl groups may also be substituted by heterocycloalkyl and heterocycloaryl groups to form fused rings, such as dihydrobenzfuranyl, oxyindolyl, indolyl, indolinyl, oxyindolyl, benzoxazolidininoyl, benzoxazolinyl and benzoxazolinone.

The term "cycloalkyl", used alone or as part of another group, refers to fully saturated and partially unsaturated carbon hydrogen rings of 3 to 9, preferably of 3 to 7 carbon atoms. In addition, cycloalkyl may be substituted. The term substituted cycloalkyl refers to rings having one, two or three substituents, preferably one selected from the group consisting of: halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo (= O), hydroxy, alkoxy, thioalkyl, -CO ₂ H, -OC (= O) H, CO ₂ -alkyl, -OC (= O) alkyl, = N-OH, = 1-10-alkyl, aryl, heteroaryl, heterocyclo, five or six membered ketal (i.e. 1,3-dioxolane or 1,3-dioxane), -NR'R ", -C (= O) NR'R", -OC (= O) NR'R ", -NR'CO ₂ 'R ", -NR'C (= O) R", -SO ₂ NR'R "and -NR'SO ₂ 'R", where each of R 'and R "is independently selected from hydrogen , alkyl, substituted alkyl and cycloalkyl or R ' and R ' uvat together heterocyclic or heteroaryl ring. Cycloalkyl groups may also be substituted by heteroatoms such as Ο, N and S to form heterocycloalkyl groups. Preferred heterocycloalkyl groups include optionally substituted morpholine, homomorpholine (7-element ring), thiomorpholine, piperazine, homopiperazine (7-element ring) and piperidine.

The term "heteroaryl", used alone or as part of another group, refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one of the rings. Each ring of a heteroaryl group containing a heteroatom may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. Condensed rings complementary to bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms quaternary. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring, but the other condensed ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached to any available nitrogen or carbon atom or to any ring. The heteroaryl ring system may contain zero, one, two or three substituents selected from the group consisting of halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, hydroxy, alkoxy, thioalkyl, -CO ₂ H, -OC ( = O) H, CO ₂ -alkyl, -OC (= O) alkyl, phenyl, benzyl, phenylethyl, phenoxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclic compound, heteroaryl, -NR'R ", -C (= O) NR'R ", -OC (= O) NR'R", NR'CO ₂ 'R ", -NR'C (= O) R", -SO ₂ NR'R "and -NR'SO ₂ ' R "Wherein each R 'and R" is independently selected from hydrogen, alkyl, substituted alkyl and cycloalkyl or R' and R "form together a heterocyclic yl heteroaryl ring.

The exemplary examples of monocyclic heteroaryl groups include pyrrolinyl, pyrrolidinyl, imidazolinyl, pyrazolinyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolinyl, butyl, butylcarbamide, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinol,

Examples of bicyclic heteroaryl groups include indolyl, indolinyl, oxindolyl, benzoksazolidinon, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.

Examples of tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term "halogen" or "halo", used alone or as part of another group, refers to chlorine, bromine, fluorine or iodine selected independently.

The term "hydroxy", used alone or as part of another group, refers to -OH.

The term "thioalkoxy", used alone or as part of another group, refers to an alkyl group as defined herein attached to the parent molecular group via a sulfur atom. Examples of thioalkoxy include, but are not limited to, thiomethoxy, thioethoxy and the like.

Abbreviations: "Ph" stands for phenyl, "Me" stands for methyl and "Et" stands for ethyl.

The term " anticancer agent " used in the description includes known anticancer treatments, such as radiation or cytostatic or cytotoxic agents, e.g. but without limitation, DNA interactive agents such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT11 or topotecan; tubulin interactive agents such as paclitaxel, docetaxel or epothilones; hormonal agents such as tamoxifen; thymidylate synthetase inhibitors such as 5-fluorouracil; antimetabolites such as methotrexate, tyrosine kinase inhibitors such as Iressa and OSI-774 (Iressa, OSI-774); angiogenic inhibitors, EGF inhibitors; VEGEF inhibitors, CDK inhibitors; Hg1 / 2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Hg2).

When a functional group is designated as "protected", it means that the group is modified in order to prevent undesirable side effects in the protected area. Suitable protecting groups for the compounds of the present invention will be recognized in the present description, taking into account the level of the skilled person, as well as standard textbooks, e.g. Green, T.W., et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

When substituted C 1-4 alkyl, alkenyl, alkynyl and cycloalkyl, it is preferable to replace them with one or more substituents: hydroxy, cyano, carbamoyl, hydroxy, alkoxy, thiol, alkenyl, thioalkoxy, amino, alkylamino, amido, sulfonyl, sulfonyl, sulfonyl, sulfonyl, sulfonamido, halo, heterocycloalkyl, aryl or heteroaryl.

When aryl or heteroaryl are substituted, it is preferable to be substituted by one or more substituents: alkyl, alkenyl, alkynyl, cyano, carbamoyl, hydroxy, alkoxy, thioalkoxy, amino, amido, sulfonamido, halo or R ', R' where R 'and R' form a ring which is fused to the aryl group. When CH ₂ -aryl or heteroaryl is substituted, it is preferable to be substituted by one or more substituents: alkyl, alkenyl, alkynyl, cyano, carbamoyl, hydroxy, alkoxy, thioalkoxy, amino, amido, sulfonamido or halogen.

The numbers in the index after the letter "C" define the number of carbon atoms that a group can contain. For example, "C 1-4 alkyl" means a saturated carbon unbranched or branched chain containing from one to six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-pentyl, isopentyl and n-hexyl. Depending on the context, "C 1-6 alkyl" may also refer to Rock Flax which connects two groups; examples include propane-1,3-diyl, butane-1,4-diyl, 2-methylbutane-1,4-diyl and the like. "With ₂ . ₆ alkenyl 'means a straight or branched carbon chain having at least one double carbon-carbon bond and containing from two to six carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl. Depending on the context of "C ₂ . ₆ alkenyl 'may also refer to C ₂ . ₆ alkenediyl linking two groups; examples include ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl, 2-hexene-1,6-diyl, etc. "With ₂ . ₆ alkynyl ,, means straight or branched carbon chain having at least one carbon-carbon triple bond and containing from two to six carbon atoms; examples include ethynyl, propynyl, bouginyl and hexinyl.

The term "alkyl-B ₂ 5" includes optionally substituted alkyl groups such as methyl, ethyl, propyl, and boogyl linked to the R ₂₅ group. In general, R ₂₅ includes hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, -NHCOOH, -NHC (O) - NHSO ₂ -, - C (O) NH ₂ , heteroaryl or heterocycloalkyl groups such as morpholinyl or groups of the formulas:

oh

The terms "imidazole" and "imidazoline" used alone or as part of another group include substituted imidazoles and substituted imidazolines. Similarly, the term "tetrahydropyrimidine" includes substituted tetrahydropyrimidines. Similarly, the terms "piperazine ..... piperidine ..... morpholines", "homopiperazines", "homomorpholines" and "pyrrolidine", include substituted piperazines, substituted piperidines, for substituted morpholines, substituted homomorpholines and substituted pyrrolidines.

The compounds of the present invention have the general formula I:

ι as well as its enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and solvates;

wherein:

X is selected from the group consisting of: N, C, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl substituted with one or more R ₇ , as well as a direct bond;

Y is selected from the group consisting of 0 and S;

W is selected from the group consisting of N, C, O and S, provided that when W is O or S, R _g is absent;

R _n R ₂ , R ₃ , R _4i R _5i R ₆ , R 7, R ₈ > R 9 are independently selected from the group consisting of: Η, Ο _ν6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino , OR ₆₀ , NO ₂ , OH, SR ₆₀ , NR ₆₀ R ₆₁ , CN, CO ₂ R ₆₀ , CONR ₆₀ R ₆₁ , CO ₂ NR ₆₀ R ₆₁ , NR ₆₂ CONR ₆₀ R ₆₁ , NRgQSO ₂ Rg ^, S0 ₂ NR ₅₀ R ₆₁ , C (NR ₂ ) NR ₆₀ R ₆₁ , aryl, heteroaryl, (CH ₂ ) _n OR ₆₀ , (CH ₂ ) _n NR ₆₀ R ₆₁ , (CH ₂ ) _n SR ₆₀ , (CH ₂ ) _p aryl, ( CH ₂ ) _n heteroaryl, (CH ₂ ) _n heterocycloalkyl, NH-Z-aryl and NH-Z-heteroaryl; where η is 1 to 3 and

Ζ is selected from the group consisting of C ₁ -C ₄ alkyl, alkenyl and alkynyl; Ζ has one or more of the following groups: hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, NR ₆₀ SO ₂ R ₆₁ ; Z optionally includes one or more of the groups selected from the group consisting of: CO, CNOH, CNOR ₆₀ , CNNR ₆₀ , CNNCOR ₆₀ and CNNSO ₂ R ₆₀ and

R ₆₀ and R ₆₁ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl and alkyl-P ₂₅ , wherein:

R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , - NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl, and

R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or alkyl- ₁ 5.

In some embodiments of the present invention, R ₃ is -OR ₆₀ . R _{6 is} alkyl or alkyl-N ₂₅ , where R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, alkylsulfoxy, alkylsulfonyl, -R ₃ oCOOR _31l- NR ₃₀ C (O) R ₃₁ , -NR ₃ oSO ₂ R ₃ i, C (O) NR ₃ oR ₃₁ , heteroaryl or heterocycloalkyl; R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or alkyl-B ₂₅ . In preferred embodiments, R ₆₀ is methyl, - (CH ₂ ) _N CH ₂ OH, or - (CH ₂ ) _n CH ₂ N (CH ₂ CH ₂ ) ₂ O and η is 0.1 or 2.

In some embodiments, R ₃ is piperazine, homopiperazine, 3-methylpiperazine or 3,5-dimethylpiperazine, which is optionally substituted on the 4-N site by a compound selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkyl- B ₂₅ , -C (O) -R ₁₅ or -CO ₂ R ₁₅ , where R ₁₅ is hydrogen, alkyl, aryl, apkyl-A ₂₅ , amino or aryl; and R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, cyano, halo, sulfoxy, sulfonyl, arylsulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃ oC (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃ oR ₃₁₎ heteroaryl or heterocycloalkyl and R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or apkyl-B ₂₅ . In preferred embodiments, piperazine is substituted by Me, CH ₂ cyclopropyl, CH ₂ CH ₂ NMe ₂ , CH ₂ CH ₂ NEt ₂ , CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ NHMe, CH ₂ CH ₂ NHEt, N-CH ₂ CH ₂ N (CH ₂ CH ₂ ) ₂ O, (CH ₂ ) _n CH ₂ -R ₂₅ , where R ₂₅ is OH, OMe, F, CN, CF ₃ , SOCH ₃ or SO ₂ CH ₃ , not 0 , 1 or 2.

In some embodiments, R ₃ is an amino group. Preferred amino groups include NHCH ₂ CH ₂ OH, NMeCH ₂ CH ₂ OH, NEtCH ₂ CH ₂ OH, NHCH ₂ CH ₂ NH ₂ , NMeCH ₂ CH ₂ NH ₂ , NEtCH ₂ CH ₂ NH ₂ , NHCH ₂ CH ₂ NMe ₂ , NMeCH ₂ CH ₂ NMe ₂ , NEtCH ₂ CH ₂ NMe ₂ , NHCH ₂ CH ₂ NEt ₂ , NMeCH ₂ CH ₂ NEt ₂ , NEtCH ₂ CH ₂ NEt ₂ , NHCH ₂ CH ₂ N (CH ₂ CH ₂ ) ₂ O, NMeCH ₂ CH ₂ N (CH ₂ CH 2) ₂ O, NEtCH ₂ CH ₂ N (CH ₂ CH ₂ ) ₂ O.

In some embodiments, R ₃ is optionally substituted piperidine. Preferred substituents are selected from the group consisting of hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, 1,3-dioxolane (-OCHR ₁₅ ) _2> 1,3-dioxane (-OCHR ^ CHR ^ CHR ^ O- ), -NHC (O) R ₁₅ , -NHCO ₂ R ₁₅ , where R ₁₅ is hydrogen, alkyl or alkyl-N ₂₅ , with R ₂₅ being hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano , apkylsulfoxy, alkylsulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃ qSO ₂ R 3i, C (O) NR ₃₀ R ₃ i, heteroaryl or heterocycloalkyl and R ₃₀ and R ₃₁ denote independently one from another, hydrogen, alkyl, cycloalkyl or alkyl-N ₂₅ .

In some embodiments, R ₃ is optionally substituted morpholine, homomorpholine, thiomorpholine, sulfoximorpholine or sulfonylmorpholine. Preferred substituents include hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, alkyl-N, where R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, alkylsulfoxyl, alkylsulfoxyl ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl, and R ₃₀ and R ₃₁ denote, independently, hydrogen, alkyl, cycloalkyl or apkyl-B ₂₅ .

In some embodiments, R ₃ is pyrrolidine. Preferred pyrrolidines include 3-hydroxylpyrrolidine, 3-apkoxypyrrolidine and 3-apkylaminopyrrolidine.

According to one embodiment of the present invention, R ₃ is optionally substituted N-tetrahydropyrimidine or N-imidazoline, wherein the preferred substituents are alkyl, hydroxyalkyl, apkoxyalkyl, haloalkyl, cyanoalkyl, carboxyl or carboxamide.

In some embodiments, R ₆ is selected from the group consisting of H, 2aminomethylpyridine, NHCH ₂ CH (OH) apnn and NHCH (CH ₂ OH) CH ₂ apnn, optionally substituted by an aryl group. In preferred embodiments, the aryl group is substituted with Br, Cl, F or methoxy. In some embodiments, R ₆ has one of the following formulas:

^ NH

wherein R ₄₀ is hydrogen or alkyl, preferably methyl and R ₁₇ is hydrogen or halogen, e.g. Br, CI or F.

Preferred compounds of the present invention have-

IV ν

in which:

R ₁₂ and R ₁₃ denote independently of one another hydrogen, alkyl or alkyl-N ₂₅ ;

R ₁₅ is hydrogen, alkyl or alkyl-P ₂₅ ;

R ₁₆ is hydrogen or methyl;

R ₁₇ , R ₁₈ and R ₁₉ independently represent a hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocycloalkyl or heteroaryl group;

R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl and

R ₃₀ and R ₃₁ are each independently hydrogen, alkyl, cycloalkyl or alkyl-N ₂₅ .

In preferred embodiments, R ₁₂ is hydrogen, methyl, hydroxymethyl, watt independently hydrogen or alkyl-N ₂₅ .

R ₁₃ θ Η;

R ₁₇ is Br, Cl or F;

R ₁₈ is halogen or methoxy and

R-ig is N.

Suitable examples of salts of the compounds of the invention include salts of inorganic or organic acids. They include, without limitation, hydrochloride, hydrobromide, sulfate, methanesulfonate, maleate, fumarate, phosphate and other pharmaceutically acceptable salts. Salts that are unsuitable for pharmaceutical applications but which can be used, for example, to isolate or purify free compounds of formula I or their pharmaceutically acceptable salts are also included herein.

All stereoisomers of the compounds of the present invention are included, whether in admixture, in pure or generally pure form. The definition of the compounds according to the invention includes all possible stereoisomers and mixtures thereof. Particularly racemic forms are included and the isolated optical isomers possessing

specific activity. Racemic forms can be separated by physical methods, for example, by fractional crystallization, separation or crystallization of diastereomeric derivatives or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, for example, by forming a salt with an optically active acid followed by crystallization.

It is to be understood that the present invention includes prodrug forms of the compounds of formula I. The various prodrug forms are well known in the art. For example, for such prodrugs, see:

(a) Design of Prodrugs, published by H. Bundgaard (Elsevier, 1985); Methods in Enzymology, Vol. 42, pp. 309-396, ed. K. Widder et al., (Academic Press, 1985);

(b) A Textbook of Drug Design and Development, published by KrosgaardLarsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991);

(c) H. Bundgaard, Advanced Drug Deliver Reviews, 8, pp. 1-38 (1992);

(d) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77,285 (1988); and (e) N. Kayeka et al., Chem. Phar. Bull., 32, 692 (1984).

The invention also provides a pharmaceutical composition comprising a compound of formula I as defined above and a pharmaceutically acceptable carrier and at least one fixed-dose anticancer agent. The preferred anticancer agents are: idarubicin, mitomycin-C, dactinomycin, mitramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosocarbamide, thiotephane, vincristine, taxol, taxotere, etoposide, tenosine reverberation, epothilone; a tyrosine kinase inhibitor such as Iressa and OSI-774 (Iressa, OSI-774); angiogenesis inhibitor, EGF inhibitor; VEGF inhibitor, CDK inhibitor; Hg1 / 2-inhibitor and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Hg2).

The invention further provides a method of treating a condition by modulating at least one tyrosine kinase enzyme, comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I, as defined above, in combination (concurrently or successively) with at least one other anti-aging agent.

A preferred disease state treated by said method of the present invention is cancer. In addition, the tyrosine kinase enzyme may include (without limitation): Abl, CDK, EGF, EMT, FGF, FAK, Flk-1 / KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src and VEGF.

The invention also provides a method of treating cancer comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one of the pharmaceutical compositions,

defined above.

The invention further provides a method of treating proliferative diseases comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one of the pharmaceutical compositions defined above.

Certain compounds of formula I can generally be prepared according to the schemes and knowledge of one skilled in the art below. The solvates (e.g., hydrates) of the compounds of formula I are also within the scope of the present invention. Solvation methods are generally known in the art. In this connection, the compounds of the present invention may be in free or hydrated form and may be prepared by methods explained by the exemplary schemes given below.

In particular, Schemes I-VII illustrate the preparation of the compounds claimed in this invention. The examples that follow show the compounds that can be synthesized according to these schemes. The schemes are not limited to the examples given or to any of the substitutes used for illustrative purposes.

Scheme I describes the preparation of benzimidazoles. Source diamines 1 are readily available using the methods described in the literature and are commercially available. The diamine is then condensed with aldehyde 2 to produce the benzimidazole 3. Subsequently, further modification of the functional groups in the aryl moiety of the benzimidazole or in the heterocyclic ring is envisaged.

Respectively, benzimidazole can

come in stages (see

Scheme II) by amide formation using acid chloride 5 or some of the widely used peptide coupling reagents such as DCC (dicyclohexylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, etc.). Once the amide 6 is obtained, the nitro group can be reduced by catalytic hydrogenation, transfer hydrogenation or chemical reduction with SnCI ₂ or iron powder, as well as by other known methods of reducing aryl nitro groups. Treatment of aniline with acid will result in the formation of benzimidazole.

Scheme II

Y

For example, Scheme III shows the use of 4-iodine-2-methoxypyridine-3-carbaldehyde 7 to obtain functionalized benzimidazole 8. Hydrolysis of the methoxy group in an acidic medium created by protic acid in the presence of TMSI (trimethylsilyl iodide), BBr ₃ or in other conditions known from the practice of methyl ether cleavage will give halopyridone 9. The addition of heteroatom nucleophiles, using amines, alcohols or thiols, will result in substituted pyridones 10. The aldehyde may also include other functional groups, the above-described example is included for illustration only.

Scheme III

10

The aryl ring of the benzimidazole prepared according to Schemes I or II can also be modified. For example, the introduction of a cyano group in place of R ₃ in benzimidazole allows the formation of such heterocyclic compounds such as imidazole, imidazolines, oxa sols, thiazolines, amides or amidines. These transformations are shown in Scheme IV. Starting from the cyano-substituted benzimidazole 11, the heterocyclic compound can be modified as shown in Scheme IV to give 12. The formation of an imidate with the preferred use of ethanol and an acid gives intermediate 13. The imidate 13, by diamines may become imidazolines, with amino alcohols it will give oxazolines, with aminoacetals it will give imidazoles and with aminothiols it will form thiazolines 14. Respectively, the imidate can be hydrolyzed to acid and bind to amines using standard reagents amide decomposition (DCC, EDCI, etc.) to afford the amides 15. The imidate 13 is also useful as an intermediate for the preparation of amidines 16 by reaction with amines.

Scheme IV

X = NH, O, S

Scheme V shows further conversions of a benzimidazole containing a halogen atom using a palladium catalyst under the conditions developed by Suzuki [Yang et al., Acta Chem. Scan. (1993) 221; Suzuki et al., Synth. Commun. (1981) 11: 513] Buchwald / Hartwig [Buchwald et al., J. Am. Chem. Soc. (1994) 116: 7901; Hartwig et al., J. Am. Chem. Soc. (1994) 116: 5969; Hartwig. Angew. Chem., Int. Ed. Engl. (1998) 37: 2064], as well as modifications of these methods. The preparation of bromine-substituted benzimidazole 17, which will form the basis of Suzuki coupling with aryl, vinyl and heterocyclic boronic acids to give benzimidazoles, must start. Similarly, amines and heterocyclic compounds can be prepared, e.g. piperazine or morpholine derivatives 19 of the same bromide using amines under the conditions described by Buchwald and Hartwig or modified ones.

Scheme V

HNYZ, Pd

ZYN

FL

R.

RX

X = NH, O, S

Accordingly, amine and heterocyclic derivatives, such as those denoted 19, may be prepared using the intermediate 6 described in Scheme II. When R ₃ in formula 6 is halogen, preferably F, it may be substituted by amines, alcohols, heterocyclic amines and other nitrogen-containing heterocyclic compounds such as piperazine, piperidine, 4-ami2-piperidine, morpholine, imidazole and the like. (Scheme VI). The terminal nitrogen atom of piperazine or 4-aminopiperidine can then be alkylated under standard alkylation conditions or reacted with aldehydes in a reductive amination reaction to give alkylated derivatives. Respectively, the final nitrogen atom of piperazine or 4-aminopiperidine can be alkylated or carbamoylated under routine conditions known to those skilled in the art of organic synthesis. Following the example illustrated in Scheme II, compounds such as those denoted 19 may be prepared.

Respectively, amines, heterocyclic compounds, and alcohols may be introduced into the R ₃ site by a nucleophilic substitution reaction in the aromatic ring, leaving the intermediate 20, wherein R ₃ is halogen, preferably F; halogen may be displaced by amines, alcohols, heterocyclic amines and other nitrogen-containing heterocyclic compounds such as piperazine, piperidine, 4-aminopiperidine, morpholine, imidazole and the like. (Scheme VII). The terminal nitrogen atom of piperazine or 4-aminopiperidine can then be alkylated under standard alkylation conditions or reacted with aldehydes in a reductive amination reaction to give alkylated derivatives. Respectively, the final nitrogen atom of piperazine or 4-aminopiperidine can be alkylated or carbamoylated under routine conditions known to one skilled in the art of organic synthesis. The resulting nitroaniline can be reduced to diamine 21 and treated as shown in Scheme III.

Scheme VII

The compounds of the invention have pharmacological properties, in particular the compounds of formula I are inhibitors of tyrosine kinase enzymes. Therefore, the new compounds of formula I are useful in the treatment of various proliferative diseases (including, but not limited to), such as cancer, autoimmune diseases, viral, fungal, neurodegenerative and cardiovascular diseases.

In particular, the compounds of formula I are useful for the treatment of various cancers, including, but not limited to, the following:

a) cancer, including that of the bladder, breast, colon, kidney, liver, lung, including small lung cancer, esophagus, gall bladder, ovary, pancreas, stomach , the cervix, thyroid, prostate and skin, including squamous cell carcinoma;

(b) haematopoietic tumors of lymphoid origin, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy lymphoma;

c) hematopoietic tumors of myeloid origin, including acute and chronic myeloid leukemias, myelodysplastic syndrome and promyelocytic leukemia;

d) tumors of mesenchymal origin, including fibrosarcoma and slave domiosarcoma;

(e) Central and peripheral nervous system tumors, including astrocytoma, neuroblastoma, glioma and schwannomas

(f) other tumors, including sarcoma, melanoma, seminomas, teratocarcinoma, osteosarcoma, Xenoderoma pigmentosum, keratoxanthoma, thyroid follicular carcinoma and Kaposi's sarcoma.

Due to the key role of tyrosine kinases in regulating cell proliferation, inhibitors could act as reversible cytostatic agents that are useful in the treatment of any disease process characterized by abnormal cell proliferation, e.g. benign prostatic hyperplasia; familial adenomatous polyposis; neurofibroblastosis; atherosclerosis; pulmonary fibrosis; arthritis; psoriasis; glomerulonephritis; fungal infections.

The compounds of formula I can induce apoptosis. The apoptotic response is atypical in many human diseases. The compounds of formula I, as modulators of apoptosis, will be useful for the treatment of cancer (including, without limitation, the above mentioned species), viral infections (including, but not limited to, herpes virus, measles virus , Epstein-Barr virus, Sindbis virus and adenovirus), to prevent the development of AIDS in HIV-infected subjects, autoimmune diseases (including, without limitation, systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, rheumatoid arthritis, the intestines and the car wash diabetes, neurodegenerative diseases (including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, pigmented retinitis, spinal muscular atrophy, and cerebral degeneration, degeneration, cerebral degeneration, , ischemic damage associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis caused by toxins or alcoholic liver disease, haematological diseases (including but not limited to , Chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

Compounds of formula I can alter the level of cellular RNA and DNA synthesis. Therefore, these agents will be useful in the treatment of viral infections (including, without limitation, HIV, human papilloma virus, herpes virus, measles virus, Epstein-Barr virus, Sindbis virus and adenovirus).

The compounds of formula I may also be useful in the chemoprevention of cancer. Chemotherapy is defined as inhibiting the development of invasive cancer either by blocking the initial mutagenic event or by blocking the progression of premalignant cells that have already suffered a stroke or inhibiting tumor recurrence.

The compounds of the invention of formula I may also be useful for inhibiting tumor angiogenesis and metastasis.

The compounds of the invention may also be useful when combined (given together or separately) with known anticancer treatments, such as radiation or cytotoxic or cytotoxic agent therapy, e.g., but not limited to, DNA-interactive agents such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interactive agents such as paclitaxel, docetaxel

4.

<..... η, ............................

or epothilones; hormonal agents such as tamoxifen; thymidylate synthase inhibitors such as 5-fluorouracil; antimetabolites such as methotrexate, tyrosine kinase inhibitors such as Iressa and OSI-774 (Iressa, OSI-774); angiogenic inhibitors, EGF inhibitors; VEGF inhibitors, CDK inhibitors; Hg1 / 2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Hg2).

When prepared as a fixed dose, these combination products include the compounds of the invention with the dosage range given below, and the other pharmaceutically active agent is within its established dosage range. The compounds of formula I may also be administered sequentially with known anti-cancer cytotoxic agents when the combination composition is in a suitable form. The invention is not limited to the sequence of administration; the compounds of formula I may be administered either before or after administration of the known anticancer or cytotoxic agent.

Another object of the invention also includes pharmaceutical compositions for use as described above, including the control of cancer, inflammatory disease and arthritis, which contain at least one compound of formula I, as defined above or at least one of its pharmaceutically acceptable acid addition salts and use of the compound of formula I as defined above for the preparation of a medicament having an effect against proliferative diseases as described above, including against cancer, inflammatory disease and / or arthritis.

The pharmacological properties of the compounds of this invention can be confirmed by numerous pharmacological studies. The following pharmacological studies are performed with the compounds of the present invention or salts thereof.

Biological research

A. C0K2 / cyclin E-kinase assay

The kinase reactions consist of 5 ng (nanograms) of baculovirus-expressed GST-CDK2 / uhiuihh E complex, 0.5 μg GST-RB fusion protein (amino acids 776-928 of retinoblastomatic protein), 0.2 μθί ³³ P γ-λΤφ, 25 μg-ΑΤφ 50 μl kinase buffer (50 mmol Hepes, pH 8.0, 10 mmol MgCI ₂ , 1 mmol EGTA, 2 mmol DTT). The reaction media were incubated for 45 minutes at 30 ° C and quenched with the addition of cold trichloroacetic acid (THC) to a final concentration of 15%. THC precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a Universal Filtermate harvester (Packard Instrument Co., Meriden, CT) and the filters were quantified with a 96-well TopCount liquid scintillation counter. (Packard Instrument Co., Meriden, CT). Dose-response curves were plotted to determine the concentration required for 50% inhibition of kinase action (IC ₅₀ ). The compounds were dissolved to a concentration of 10 mmol in dimethyl sulfoxide (DMSO) and tested at 6 concentrations, each of which was performed three times. The final concentration of DMSO in the studies is 2%. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = 6) = 14%. (CO = mean deviation).

B. EMT kinase assay

We used a filter-based kinase assay to measure the phosphorylation of Gst-SLP76 with the Gst / Emt-kinase assay to determine the inhibitory action of the compound against Emtkinase. The kinase reaction was performed in a 96-well plate at room temperature for 15 minutes. This was quenched by the addition of 100 μl of 20% trichloroacetic acid (THC) containing 0.1 M sodium pyrophosphate. The kinase reaction mixture (60 μl) contains 25 mmol HEPES, pH 7.0, 0.1 mg / ml bovine serum albumin, 5 mmol MgCI ₂ , 5 mmol

MnCI ₂ , 8 ng enzyme (Gst-Emt-kinase), 5 μg of substrate protein (Gst-SLP76), 1 μmol ATf, 0.4 μθί [γ-Ρ ³³ ] Α иφ, and the test compound (in different concentrations). After completion of the reaction, the proteins were precipitated in the presence of THC for 1 hour at 4 ° C. The precipitated proteins were then collected on a filter plate (UniFilter-96, GF / C, Packard Instrument) and washed to remove excess [γ-Ρ] ATf. The radioactivity was determined with a TopCount NXT counter (Packard Instrument) after the addition of 35 μl of Microscint 20 (Packard Instrument).

B. Tyrosine kinase assay of FAK (focal adhesion kinase) Focal adhesion kinase was assayed with a synthetic polymer rouy (Sigma Chemicals) as a phosphorus acceptor substrate. Each reaction mixture has a total volume of 50 μl and contains 100 ng baculovirus expressed enzyme, 2 μg poly (Glu / Tyr), 1 μmol ATf and 0.2 μ & [γ- ³³ Ρ] ΑΤφ. The mixtures also contained 40 mmol of Tris.HCI, pH 7.4, 1 mmol of MnCl ₂ , 0.5 mmol of DTT (dithiothreitone) and 0.1 mg / ml of bovine serum albumin. The reaction mixtures were incubated for 1 hour at 26 ° C and kinase activity was determined by quantitative measurement of the radioactive phosphate incorporated into poly (Glu / Tyr) -cy6cTpaTa. Inclusion was measured by precipitation of proteins with the addition of cold trichloroacetic acid (THC), which were captured on GF / C-filter plates (Packard Instrument Co., Meriden, CT) using a Universal Filtermate harvester, and quantification was performed with 96-well TopCount liquid scintillation counter (Packard Instrument Co., Meriden, CT). The compounds were dissolved in dimethyl sulfoxide to a concentration of 10 mmol and tested at three concentrations, each assay being triplicate. The final concentration of DMSO added to the kinase samples was 0.5%, and this did not appear to affect kinase activity. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = b) = 16%.

D. Kinase assay with HER-1 / HER-2

The kinase reactions consist of 10 ng baculovirus expressed GST-HER1, 100 ng HER2, 100 ng / ml poly (Glu / Tyr) (Sigma), 0.2 μθΐ ³³ P γ-ΑΤφ, 1 μmol ATP in 50 μl kinase buffer (50 mmol Tris.HCI, pH 7.5, 10 mmol MpCl ₂ , 0.5 mmol DTT). The reaction mixtures were incubated for 1 hour at 27 ° C and the reaction was quenched by the addition of cold trichloroacetic acid (THC) to a final concentration of 15%. THC precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a Universal Filtermate harvester (Packard Instrument Co., Meriden, CT) and the filters were quantified with a 96-well TopCount liquid scintillation counter. (Packard Instrument Co., Meriden, CT). Dose-response curves were plotted to determine the concentration required for 50% inhibition of kinase action (IC ₅₀ ). The compounds were dissolved to a concentration of 10 mmol in dimethyl sulfoxide (DMSO) and tested at 6 concentrations, each of which was performed three times. The final concentration of DMSO in the test formulations is 1%. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = 6) = 16%.

E. IGF-receptor tyrosine kinase assay

IGF-1 receptor tyrosine kinase was assayed using a synthetic polymer poly (Glu / Tyr) (Sigma Chemicals) as a phosphorus acceptor substrate. Each reaction mixture has a total volume of 50 μl and contains 125 ng baculovirus expressed enzyme, 2 μg poly (Glu / Tyr), 25 μmol ATf and 0.1 μθ [γ- ³³ Ρ] ΑΤφ. The mixtures also contain 20 mmol MOPS (3-1M-morpholinpropanesulfonic acid), pH 7.5, 5 mmol MnCI ₂ , 0.5 mmol DTT and 0.1 mg / ml bovine serum albumin. The reaction mixtures were incubated for 45 minutes at 30 ° C and the kinase activity was determined by quantitative measurement of the radioactive phosphate converted into the ro1u (O1i / Tu) substrate. Inclusion was measured by precipitation of cold trichloroacetic acid (THC) proteins, which were captured on GF / Filter plates (Packard Instrument Co., Meriden, CT) using a Filtermate universal harvester, and quantification was performed with 96- well scintillation counter TopCount (Packard Instrument Co., Meriden, CT). The compounds were dissolved in dimethyl sulfoxide to a concentration of 10 mmol and tested at three concentrations, each assay being triplicate. The final concentration of DMSO added to the kinase samples was 0.5%, with no effect on the kinase activity. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = 6) = 16%.

F. Insulin receptor tyrosine kinase assay

Insulin receptor tyrosine kinase was assayed using a synthetic polymer poly (Glu / Tyr) (Sigma Chemicals) as a phosphorus acceptor substrate. Each reaction mixture has a total volume of 50 µl and contains 90 ng baculovirus expressed enzyme, 2.5 µg ro1u (Cl and Jug), 25 µmol ATP and 0.1 µΰΐ [γ- ³³ Ρ] ΑΤφ. The mixtures also contained 20 mmol Tris.HCI, pH 7.4, 5 mmol MnCl ₂ , 0.5 mmol DTT and 0.1 mg / ml bovine serum albumin. The reaction mixtures were incubated for 1 hour at 26 ° C and kinase activity was determined by quantitative measurement of the radioactive phosphate converted to poly (Glu / Tyr) -cy6cTpaTa. Inclusion was measured by precipitation of proteins with the addition of cold trichloroacetic acid (THC), which were captured on GF / C-filter plates (Packard Instrument Co., Meriden, CT) using a Universal Filtermate harvester, and quantification was performed. performed with a 96-well TopCount liquid scintillation counter (Packard Instrument Co., Meriden, CT). The compounds were dissolved in dimethyl sulfoxide to a concentration of 10 mmol and tested at three concentrations, each assay being triplicate. The final concentration of DMSO added to the kinase samples was 0.5%, with no effect on the kinase activity. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = 6) = 16%.

G. LCK kinase assay

The kinase reactions consisted of 10 ng baculovirus expressed 10 ng GST / Lck, 100 ng / ml poly (Glu / Tyr) (Sigma), 0.2 μθΐ ³³ P γ-ΑΤΦ, 1 μmol ATP in 50 μl kinase buffer (50 mmol Tris, pH 7.5, 10 mmol MpCl ₂ , 0.5 mmol DTT). The reaction mixtures were incubated for 1 hour at 27 ° C and the reaction was quenched by the addition of cold trichloroacetic acid (THC) to a final concentration of 15%. THC precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a Universal Filtermate harvester (Packard Instrument Co., Meriden, CT) and the filters were quantified with a 96-well TopCount liquid scintillation counter. (Packard Instrument Co., Meriden, CT). Dose-response curves were plotted to determine the concentration required for 50% inhibition of kinase action (IC ₅₀ ). The compounds were dissolved to a concentration of 10 mmol in dimethyl sulfoxide (DMSO) and tested at 6 concentrations, each of which was performed three times. The final concentration of DMSO in the mixtures tested is 1%. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = 6) = 16%.

3. MET kinase assay

The kinase reactions consist of 10 ng baculovirus expressed GST-Met, 2.5 µg poly (Glu / Tyr) (Sigma), 0.2 µC | ³³ P γ-ΑΤφ, 10 μmol ATP in 50 μl kinase buffer (50 mmol Tris, pH 7.5, 1 mmol MnCI ₂ , 0.5 mmol DTT). The reaction mixtures were incubated for 1 hour at 27 ° C and the reaction was quenched by the addition of cold trichloroacetic acid (THC) to a final concentration of 3.5%. THC precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a Universal Filtermate harvester (Packard Instrument Co., Meriden, CT) and the filters were quantified with a 96-well TopCount liquid scintillation counter. (Packard Instrument Co., Meriden, CT). Dose-response curves were plotted to determine the concentration required for 50% inhibition of kinase action (IC ₅₀ ). The compounds were dissolved to a concentration of 10 mmol in dimethyl sulfoxide (DMSO) and tested at 7 concentrations, each of which was performed three times. The final concentration of DMSO in the mixtures tested is 1%. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = 6) = 16%.

I. PDGF Receptor Kinase Assay

The kinase reactions contained 70 ng baculovirus expressed GSTPDGFbR, 0.3 μg biotinylated poly (Glu / Tyr) (Sigma) in 50 μl kinase buffer (20 mmol Hepes, pH 7.5, 0.7 μmol ATP, 10 mmol MnCI ₂ , 0.5 mmol DTT, 0.15 mmol DTT, 0.15 mmol DTT, 0.15 mmol DTT, 0.15 mmol DTT). , 0.1 mg / ml bovine serum albumin). The reaction mixtures were incubated for 30 minutes at room temperature with shaking and quenched with the addition of 10 μl of 0.2M EDTA, pH 8.0. 150 μl of HTRF detector buffer was added and incubated for 1 hour and 30 minutes at room temperature. Counting is performed with the Discovery HTRF Packard Instrument.

K. VEGFR-2 (KDR) kinase assay

The kinase reactions consist of 7.5 ng baculovirus expressed GST-KDR, 1.5 μg poly (Glu / Tyr) (Sigma), 0.04 μΌί ³³ P γ-ΑΤφ, 2.5 μmol ATf in 50 μl kinase buffer (25 mmol Tris, pH 7.5, 1.8 mmol MnCI ₂ , 0.625 mmol DTT). The reaction mixtures were incubated for 1 hour at 27 ° C and the reaction was quenched by the addition of cold trichloroacetic acid (THC) to a final concentration of 15%. TXK pellets were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a Universal Filtermate harvester (Packard Instrument Co., Meriden, CT) and the filters were quantified with a 96-well TopCount liquid scintillation counter. (Packard Instrument Co., Meriden, CT). Dose-response curves were plotted to determine the concentration required for 50% inhibition of kinase action (IC ₅₀ ). The compounds were dissolved to a concentration of 10 mmol in dimethyl sulfoxide (DMSO) and tested at 6 concentrations, each of which was performed three times. The final concentration of DMSO in the mixtures tested is 1%. IC ₅₀ values are obtained by nonlinear regression analysis and have a coefficient of deviation (CO / mean, n = 6) = 16%.

A. Cytotoxic assay (HT-29 colon; Colo205; MCF-7 breast)

Tumor cell lines were maintained in McCoy medium (GIBCO) with 10% heat-inactivated fetaphen bovine serum (GIBCO). In vitro cytotoxicity in tumor cells was determined by tetrazole assay using the metabolic conversion of MTS (3-4,5 dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfenyl) -2H- tetrazole, an internal salt) (Promega) in its reduced form, which absorbs light at 492 nm (1). Cells were seeded 24 hours before drug addition. After 72 h incubation at 37 ° C with serially diluted test compound, MTS was added to the cells (Riss, TL et al., Comparison of MTT, XTT, and novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assays, Mol Biol. Cells (Suppl.): 184a, 1992) in combination with the electron-binding agent phenazine methosulfate. The incubation was continued for another 3 hours, after which the absorbance of the medium at 492 nm was measured with a spectrophotometer to obtain the number of live cells compared to the control population. Results are presented as mean cytotoxic concentrations (IC ₅₀ values).

Table 1 - Biological activity (mmol); all compounds in the table have kinase activity <25 mmol against one or more of the following kinases: CDK, EMT, FAK, NEP, Her2, IGF, IR, LCK, MET, PDGF, VEGF. HT-29 and Soyu205 are human colon cancer cell lines, and MCF-7 is a breast cancer tumor cell line

An example NT-29 MCF Soya205 1 1.0 3 2.0 399 0.4 0.8 400 0.8 0.9 411 0.7 0.9 517 0.3 519 0.3 0.6 520 0.6 0.2 521 0.5 522 0.7 0.1 0.1 523 0.6 524 0.6 525 1.1 526 1.4 527 1.3 0.1 0.3 534 0.4 538 0.9 544 0.3 0.6 553 0.9 0.3 0.2 554 0.7 0.2 0.3 555 0.2 0.1 0.2 559 0.6 0.3 574 0.2 581 0.2 582 0.1 583 0.1 0.2 584 0.3 0.2 585 0.7 0.3 590 0.8 0.2 0.2 593 0.7

General Methods for the Preparation of 2-Hydroxy-2- (substituted-phenyl) ethylamines:

NO ₂

1- (3-Chlorophenyl) -2-nitroethanol: To a solution of 3-chlorobenzaldehyde (20 g, 0.142 mmol) in nitromethane (100 ml) was added magnesium sulfate (37.6 g, 0.312 mmol) and phosphazene base P _g tert. butyl tris (tetramethylene) (4.43 g, 0.014 mmol). The reaction mixture was stirred for 2 hours at room temperature. After concentration in vacuo, the residue was purified by flash chromatography (25% EtOAc (ethyl acetate) / hexane to give the title compound (26.4 g, 100%) as a green-yellow oil. ¹ H NMR (300 MHz, DMSO-dg). δ 7.53 (1H, s), 7.35-7.42 (3H, m), 6.23 (1H, broad s), 5.32-5.33 (1H, m), 4.90 (1 dd, dd, J = 3.2,12.4 Hz), 4.60 (1H, dd, J = 1.2, 12.4 Hz).

[1- (3-Chlorophenyl) -2-nitroethoxy] triethylsilane: To a solution of 1- (3chlorophenyl) -2-nitroethanol (26 g, 0.14 mmol) in DMF (dimethylformamide) (50 ml) was added imidazole (28.6 g. 0.42 mol) and chlorotriethylsilane (CI-TES). The reaction mixture was stirred for 2 hours at room temperature. After quenching with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and filtered. After removal of the solvent, the crude product was tapped with flash chromatography (2% EtOAc / hexane) to give the title compound (37 g, 91%) as a colorless oil. ¹ H NMR (300 MHz, CDCI ₃ ) δ 7.40 (1H, s), 7.27-7.32 (3H, m), 5.40 (1H, dd, J = 3.2, 9.5 Hz), 4.51 (1H, dd, J = 9.5 , 12.1 Hz), 4.36 (1H, dd, J = 3.3, 12.1 Hz), 0.85 (9H, t, J = 7.5 Hz), 0.54 (6H, q, J = 7.5 Hz).

nh ₂

2- (3-chlorophenyl) -2-triethylsilanyloxyethylamine: Raney nickel (1 g) was washed five times with distilled water and three times with methanol. [1- (3chlorophenyl) -2-nitroethoxy] triethylsilane (10 g, 0.032 mol) and Raney nickel in methanol (100 ml) were hydrogenated (35 psi = 2.45 bar) for 14 hours at room temperature. The reaction mixture was filtered through a pad of celite and washed with methanol. Concentration of the filtrate to dryness gave the title compound (5.6 g, 62%) as a colorless oil, which was used in the next step without further purification. ¹ H NMR (300

MHz, CDCI ₃ ) δ 7.32 (1H, s), 7.18-7.26 (3H, m), 4.70 (1H, t, J = 5.8 Hz), 2.86 (2H, m),

0.89 (9H, t, J = 7.9 Hz), 0.56 (6H, q, J = 7.8 Hz). MS-HP (low resolution mass spectrum) (M + H) ⁺ m / z 286.

General method for the preparation of 2-hydroxy-2- (substituted-phenyl) ethylamines:

MeO

Br.

CI

4-Methoxy-3-bromophenylchloroacetophenone: To a suspension of AICI ₃ (13.4 g,

0.10 mol) in methylene chloride (40 ml) at 0 ° C was added a solution of 2 bromanisole (12.5 ml, 0.10 mol) and chloroacetyl chloride (8 ml, 0.10 mol). The solution was warmed to room temperature for 2 hours, poured onto ice and extracted with methylene chloride, washed with saturated sodium bicarbonate solution, brine and dried over MgSO ₄ . The solution was filtered, concentrated and recrystallized from ethanol to give 15.37 g of a white solid. MS-HP [MH] - 260.8. IChspektar (KBr) 1697, 1048, 1255 cm ^{-1; 1} H NMR (300 MHz, CDCI ₃ ) δ 8.18 (s, 1 Η), 7.94 (dd, J = 8.67 Hz, 1H), 6.96 (d, J = 8.67 Hz, 1H), 4.62 (s, 2H). 3.98 (s, 3H); ¹³ C

NMR (CDCI ₃ , 75.5 ΜΗζ) δ 188.8,160.3,134.1,129.9,128.2,112.4,111.3, 56.6, 45.3.

Common method for chiral reduction of chloroketones and ammonolysis:

(S) -1- [4-Methoxy-3-bromophenyl] -2-chloroethanol: To a solution of (S) methyl-CB6-oxazaborolidine (1M in toluene, 0.745 ml, 0.745 mmol) and BH _3- THF (8 ml) , 8 mmol) were added simultaneously: a solution of BH ₃ -THF (19 mL, 19 mmol) and a solution of chloroketone (10.03 g, 37.98 mmol) in 19 mL THF. The two solutions were added dropwise over 30 minutes. The resulting solution was stirred for 1 hour and quenched by slow addition of methanol (50 ml). The solution was concentrated and the residue was chromatographed on a short silica gel column (1: 1 hexane / ethyl acetate) to give a quantitative yield (10.0 g) of chlorhydrin as a clear oil. IR (KBr) 1053, 1258, 3406 cm ^{-1; 1} H NMR (300 MHz, CDCl 3) δ 7.59 (s, 1 Η), 7.30 (dd, J = 2.16 Hz, 1H), 6.90 (d, J = 8.46 Hz, 1H), 4.83 (dd, J = 3.57 Hz) , 1H), 3.90 (s, 3H), 3.64 (ddd, J = 3.6, 11.1, 8.7, 2H), 2.04 (bs, 1H); ¹³ C NMR (CDCl 3, 75.5 MHz) δ 155.9, 133.5, 131.1, 126.3, 111.9, 73.1,60.4, 56.3, 50.7.

NH ₂ .HCI (S) -2-amino-1- [3-chloro-4-methoxyphenyl] ethanol hydrochloride: To a solution of chlorhydrin (10.0 g, 37.9 mmol) in 120 ml of methanol at -40 ° C was added 100 r ammonia. The solution was sealed in a pressure flask, warmed to room temperature and stirred for 48 hours. The solution is cooled and opened. The ammonia was allowed to evaporate and the solution concentrated. The residue was crystallized from ethanol / ethyl acetate to give 3.83 g of a white solid (35%). The material was reacted with Boc ₂ O (Boc = tert-butoxycarbonyl) in ethyl acetate and with saturated sodium bicarbonate solution and analyzed with chiral HPLC, with a column of Chiralcel OJ and a 95% hexane / ethanol eluent to determine that it was 98% enantiomerically pure. Additional yields are collected: 2.96 g and 1.41, so the total yield is 75%. MS-HP [M + H] ⁺ 246; IR (KBr) 1055, 1261, 3001.2948, 3356 cm @ ^-1 ; ¹ H NMR (500 MHz, DMSO) δ 8.09 (bs, 2H), 7.58 (s, 1H), 7.36 (dd, J = 2.05, 6.45 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H). 6.10 (s, 1H), 4.80 (m, 1H), 3.84 (s, 3H), 3.00 (ddd, J = 2.7, 12.6, 9.5, 2H); ¹³ C NMR (DMSO, 75.5 MHz) δ 154.8, 135.4, 130.4, 126.6, 112.4, 110.4, 67.9, 56.2, 45.4.

(S) -2-Amino-1- [3-chlorophenyl] ethanol hydrochloride: prepared according to the general method described above. MS-HP [M + H] ⁺ 172; IR (KBr, cm ^-1) 3048, 3351, 2952; ¹ H NMR (300 MHz, MeOD) δ 7.48 (s, 1 Η), 7.35 (m, 3H), 3.31

(S) -2-Amino-1- [3-bromophenyl] ethanol hydrochloride: prepared according to the general method described above. MS-HP [M + H] ⁺ 217.9; IR (KBr, cm ¹ ) 3025, 3443, 2891; ¹ H NMR (500 MHz, DMSO) δ 7.93 (bs, 2H), 7.60 (s, 1H), 7.52 (d, 1H), 7.41 (s, 1H), 7.35 (d, J = 7.7 Hz, 1 Η) , 6.17 (s, 1 Η), 4.82 (m, 1 Η), 3.08 (ddd, J = 2.6, 12.7, 9.6, Hz 2H); ¹³ C NMR (DMSO, 75.5 MHz) δ 144.4, 130.5, 128.7,

125.0, 121.6, 68.3, 45.1.

(S) -2-Amino-1- [3-chloro-4-methylthiophenyl] ethanol hydrochloride: was prepared according to the general method described above. MS-HP [M + H] ⁺ 217.9; ICH43 Spectrum (KBr, cm ^-1) 3007, 3358; ¹ H NMR (500 MHz, DMSO) δ 8.12 (bs, 2H), 7.46 (s, 1H), 7.37 (s, 1H), 7.35 (d, 1H), 6.19 (d, 1H), 4.83 (t, 1H) ), 3.01 (ddd, J = 3.2,

12.8, 9.3 Hz 2H); ¹³ C NMR (DMSO, 75.5 ΜΗζ) δ 139.6, 136.5, 129.8, 126.6, 125.4,

68.0, 45.2, 14.2.

(S) -2-Amino-1- [3-chloro-4-fluorophenyl] ethanol hydrochloride: was prepared according to the general method described above. MS-HP [M + H] ⁺ 189.9; IR (KBr, cm &lt; ^{-1 &gt;} ) 1509, 3008, 3359; ¹ H NMR (500 MHz, DMSO) δ 8.21 (bs, 2H), 7.61 (d, J = 7.85 Hz, 1 Η), 7.42 (m, 2Η), 6.29 (s, 1 Η), 4.88 (m, 1Η ), 3.03 (ddd, J = 3.4, 12.8, 9.2 Hz 2H); ¹³ C NMR (DMSO, 75.5 MHz) δ 157.5, 155.5, 139.7, 128.1, 126.7,

119.3,116.7,109.0, 67.8, 45.2.

(S) -2-Amino-1- [3-chloro-4-methoxyphenyl] ethanol hydrochloride: was prepared according to the general method described above. MS-HP [M + H] ⁺ 202; IR (KBr, cm ^-1 ) 3354, 3003, 2949, 1288, 1064; ¹ H NMR (500 MHz, DMSO) δ f 8.18 (br s, 3H), 7.43 (d, J = 2.0 Hz, 1 Η), 7.31 (dd, J = 8.5, 2.0 Hz 1H), 6.11 (s, 1H ),

4.81 (m, 1H), 3.84 (s, 2H), 2.99 (dd, J = 13, 3.5 Hz 1H), 2.83 (dd, J = 12.5, 9 Hz, 1H);

¹³ C NMR (DMSO, 125 MHz) δ 153.9, 135.0, 127.3, 125.8, 120.8, 112.6, 68.0, 56.1,

45.5; Elemental analysis: calculated for C ₉ H ₁₂ CINO ₂ -HCI: C, 45.39; H, 5.50; N,

(c) -2-amino-1- [7-bromo-2,3-dihydrobenzofuran-5-yl] aminoethanol hydrochloride: prepared according to the general method described above. MS-HP [M + H] ⁺ 258; IR (KBr, cm ^-1) 3349, 3006, 2928, 1485, 1045, 983; ¹ H NMR (500 MHz, DMSO) δ 8.13 (br s, 3H), 7.29 (s, 1 Η), 7.23 (s, 1 Η), 6.08 (d, J = 4 Hz,

Hz 1H), 2.82 (dd, J = 13.9.5 Hz, 1H); ¹³ C NMR (DMSO, 125 MHz) δ 156.3, 135.9,

129.1, 128.1, 122.1, 100.9, 71.5, 68.2, 45.6, 29.9; Elemental analysis: calculated for

C ₁₀ H ₁₂ BrNO ₂ -HCl: C, 40.77; H, 4.44; N, 4.75. Found: C, 40.77; H, 4.63; N, 4.63.

General method for the preparation of 2-amino-3- (substituted-phenyl) propanol:

Βι

HE

(5) - [2- (3-Bromophenyl) -1-hydroxymethylethyl] carbamic acid tert-butyl ester: To a solution of (S) -3- (3-bromophenyl) -2-tert-butoxycarbonylaminopropic acid (500 mg , 1.45 mmol) in THF (30 mL) was added borane-tetrahydrofuran complex (1.0 M solution) (4.35 mL, 4.35 mmol). The reaction mixture was stirred for 14 hours at room temperature and quenched with acetic acid (1 ml). After removal of most of the solvent, the residue was extracted with EtOAc, washed with brine and dried over Na ₂ SO ₄ . After concentration, the crude product (400 mg, 83%) was used in the next step without purification. LCMS (liquid chromatography / mass analysis) (M + H) ⁺ m / z 330 (t = 1.61 min).

on (B) -2-amino-3- (3-bromophenyl) propan-1-ol: To a solution of (c) - [2- (3-bromophenyl) -1-hydroxymethylethyl] carbamic acid tert-butyl ester ( 400 mg, 1.21 mmol) in methanol (30 ml) was added 4M HCl in dioxane (2 ml, excess). The reaction mixture was stirred for 14 hours at room temperature. After concentration in vacuo, the residue was used in the next step without purification. LCMS (M + H) ⁺ m / z 230 (t = 0.78 min).

5-Chloroacetyl-7-chloroxyindole: To a suspension of AlCl ₃ (13.4 g, 0.10 mol) in methylene chloride (40 ml) was added, at 0 ° C, a solution of 7-chloroxindole (0.10 mol) and chloroacetyl chloride (8 ml, 0.10 mole). The solution was warmed to room temperature for two hours, poured onto ice and extracted with methylene chloride, washed with saturated sodium bicarbonate solution, brine, and dried over MgSO ₄ to give the desired chloroketone.

(S) -7-Chloro-5- (2-chloro-1-hydroxyethyl) -2-oxoindole: To a solution of (t-methyl-SVB-oxazaborolidine (1M in toluene, 0.745 ml, 0.745 mmol) and BH ₃ THF (8 mL, 8 mmol) were added simultaneously to a solution of BH _3- THF (19 mL, 19 mmol) and a solution of 5-chloroacetyl-7-chloroxindole (37.98 mmol) in 19 mL THF. The two solutions were added dropwise. The resulting solution was stirred for 1 hour and quenched by slow addition of methanol (50 ml), the solution was concentrated and the residue was chromatographed on a short silica gel column (1: 1 hexane / ethyl acetate).

(5) -2-amino-1- (7-chloroxyindol-5-yl) ethanol hydrochloride: To a solution of chlorhydrin (37.9 mmol) in 120 ml of methanol, 100 g of ammonia was added at -40 ° C. The solution was sealed in a pressure flask, warmed to room temperature and stirred for 48 hours. The solution was cooled and the flask opened. The ammonia was allowed to evaporate and the solution was concentrated to give the hydrochloride salt, which could be crystallized from ethanol / ethyl acetate.

CI £ 1

HN

6-Chloroacetyl-4-chloro-2-benzooxazolinone: To a suspension of AICI ₃ (13.4 g, 0.10 mol) in methylene chloride (40 ml) was added, at 0 ° C, a solution of 4 chloro-2-benzooxazolinone (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol). The solution was warmed to room temperature for two hours, poured onto ice and extracted with methylene chloride, washed with saturated sodium bicarbonate solution, brine, and dried over MgSO ₄ to give the desired chloroketone.

he

CI, C1

HN '(S) - 6- (2-chloro-1-hydroxyethyl) -4-chloro-2-benzooxazolinone: To a solution of (S) -methyl-CB8-oxazaborolidine (1M in toluene, 0.745 ml, 0.745 mmol) and BH _3- THF (8 ml, 8 mmol) was added simultaneously to a solution of BH ₃ THF (19 ml, 19 mmol) and a solution of 6-chloroacetyl-4-chloro-2-benzoxazolinone (37.98 mmol) in 19 ml of THF. The two solutions were added dropwise over 30 minutes. The resulting solution was stirred for 1 hour and quenched by slow addition of methanol (50 ml). The solution was concentrated and the residue was chromatographed on a short silica gel column (1: 1 hexane / ethyl acetate).

(5) -2-amino-1- (4-chloro-2-benzooxazolinon-6-yl) ethanol hydrochloride: To a solution of chlorhydrin (37.9 mmol) in 120 ml of methanol, at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask, warmed to room temperature and stirred for 48 hours. The solution was cooled and the flask opened. The ammonia was allowed to evaporate and the solution was concentrated to give the hydrochloride salt, which could be crystallized from ethanol / ethyl acetate.

N-methyl-7-chloroindoline: To a solution of 7-chloroindoline (0.10 mol) in 500 ml of acetone was added K ₂ CO ₃ (0.15 mol) and Mel (0.15 mol), then the mixture was heated to reflux until exhausted. the source material.

The reaction mixture is filtered and washed with water and saturated hydrogen carbonate solution, and drying on MgSO ₄ will give N-Me-7-chloroindoline.

N-methyl-5-chloroacetyl-7-chloroindoline: To a suspension of AICI ₃ (13.4 g, 0.10 mol) in methylene chloride (40 ml) was added, at 0 ° C, N-Me-7-chloroindoline (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol). The solution was warmed to room temperature for two hours, poured onto ice and extracted with methylene chloride, washing with saturated sodium bicarbonate solution, brine, and drying over MgSO ₄ gave the desired chloroketone.

(S) - N-methyl-5- (2-chloro-1-hydroxyethyl) -7-chloroindoline: To a solution of (S) -methyl-CB8-oxazaborolidine (1M in toluene, 0.745 ml, 0.745 mmol) and BH ₃ -THF (8 mL, 8 mmol) was added simultaneously to a solution of BH _3- THF (19 mL, 19 mmol) and a solution of N-methyl-5-chloroacetyl-7-chloroindoline (37.98 mmol) in 19 mL THF. The two solutions were added dropwise over 30 minutes. The resulting solution was stirred for 1 hour and quenched by slow addition of methanol (50 ml). The solution was concentrated and the residue was chromatographed on a short silica gel column (1: 1 hexane / ethyl acetate).

nh ₂ .hci (5) -2-amino-1- (7-chloro-N-methylindolin-5-yl) ethanol hydrochloride: To a solution of chlorhydrin (37.9 mmol) in 120 ml of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask, warmed to room temperature and stirred for 48 hours. The solution was cooled and the flask opened. The ammonia was allowed to evaporate and the solution was concentrated to give the hydrochloride salt, which could be crystallized from ethanol / ethyl acetate.

(S) - 2-Chloro-1- (7-chloro-N-methylindolin-5-yl) ethanol: A solution of (S) -Nmethyl-5- (2-chloro-1-hydroxyethyl) -7-quorindoline (0.10 mmol) in 100 mL of tert, butyl methyl ether was treated at room temperature with o-chloroanil (0.10 mmol). The solution was concentrated and the residue chromatographed on silica gel (1: 1 hexane / ethyl acetate) to give the corresponding indole.

nh ₂ .hci (B) -2-amino-1- (7-chloro-N-methylindolin-5-yl) ethanol hydrochloride: To a solution of chlorhydrin (37.9 mmol) in 120 ml of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask, warmed to room temperature and stirred for 48 hours. The solution was cooled and the flask opened. The ammonia was allowed to evaporate and the solution was concentrated to give the hydrochloride salt, which could be recrystallized from ethanol / ethyl acetate.

4-Chloro-2-methylbenzooxazole: To a solution of 4-chloro-2-benzooxazolinone (0.10 mol) in 200 ml ethanol was added LiOH (0.20 mol) in 100 ml water. The solution was heated to reflux for 8 hours and cooled. It was neutralized with 1N HCl and extracted with ethyl acetate, followed by drying over MgSO ₄ . The solution was concentrated and taken up in 200 ml of toluene and 0.10 molar acetic acid. It was refluxed with DeanStark trap for 12 hours, concentrated and purified by flash chromatography.

6-Chloroacetyl-4-chloro-2-methylbenzooxazole: To a suspension of AICI ₃ (13.4 g, 0.10 mol) in methylene chloride (40 ml) was added, at 0 ° C, 2-methyl-4chlorobenzooxazole (0.10 mol) and chloroacetyl chloride ( 8 ml, 0.10 mol). The solution was warmed to room temperature for two hours, poured onto ice and extracted with methylene chloride; washing with saturated sodium bicarbonate solution, brine and drying on MgSO ₄ desired

chloroketone.

(S) -6- (2-xAOp-1-hydroxyethyl) -4-chloro-2-methylbenzooxazole: To a solution of (? -Methyl-CB6-oxazaborolidine (1M in toluene, 0.745 ml, 0.745 mmol) and BH ₃ - THF (8 mL, 8 mmol) was added simultaneously to a solution of BH _3- THF (19 mL, 19 mmol) and a solution of 6-chloroacetyl-4-chloro-2-methylbenzooxazole (37.98 mmol) in 19 mL THF. the solution was added dropwise over 30 minutes The resulting solution was stirred for 1 hour and quenched by slow addition of methanol (50 ml) The solution was concentrated and the residue was chromatographed on a short silica gel column (1: 1)

hexane / ethyl acetate).

nh ₂ .hci (B) -2-amino-1- (4-chloro-2-benzooxazol-6-yl) ethanol hydrochloride: To a solution of chlorhydrin (37.9 mmol) in 120 ml of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask, warmed to room temperature and stirred for 48 hours. The solution was cooled and the flask opened. The ammonia was allowed to evaporate and the solution was concentrated to give the hydrochloride salt, which could be crystallized from ethanol / ethyl acetate.

Preparation of 3- (6-imidazol-1-yl-4-methyl-1H-benzimizazol-2-yl) -

4-Iodine-1H-pyridin-2-one

1- (3-methyl-4-nitrophenyl) -1H-imidazole: To a solution of 4-fluoro-2methyl-1-nitrobenzene (300 mg, 1.84 mmol) in DMSO (2 ml) was added KOH (20 mg, 3.87 mmol). ) and imidazole (263 mg, 3.88 mmol). The reaction mixture was heated at 100 ° C for 3.5 hours, cooled to room temperature and diluted with ice-cold water. The resulting precipitate was filtered off, washed with ice-cold water and dried in vacuo to give the title compound (310 mg, 80%) as a yellow powder. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (1H, S), 8.16 (1H, d, J = 8.9Hz), 7.90-7.92 (2H, m), 7.78 (1H, dd, J = 1.5, 8.9 Hz), 7.17 (1H, s), 2.61 (3H, s). MS-HP (M + H) ⁺ m / z 204.

4-Imidazol-1-yl-2-methylphenylamine: To degassed methanol (3 mg) was added to 1- (3-methyl-4-nitrophenyl) -1Nimidazole (200 mg, 0.98 mmol) and 10% palladium on charcoal (3 mg). ml). The suspension was purged with hydrogen and evacuated. The suspension was stirred for 14 hours at room temperature and under a hydrogen atmosphere (hydrogen balloon). The dark reaction mixture was filtered through a pad of celite and washed with methanol. Concentration of the filtrate gave the title compound (166 mg, 98%), which was used in the next step without purification. ¹ H NMR (300 MHz, flMCO-d ₆ ) δ 7.95 (1 Η, s), 7.48 (1 Η, s), 7.16 (1 Η, narrow d, J = 2.5 Hz), 7.09 (1H, dd, J = 2.5, 8.4 Hz), 7.01 (1H, s), 6.67 (1H, d, J = 8.4 Hz), 5.03 (2H, broad s), 2.10 (3H, s).

N- (4-imidazol-1-yl-2-methyl-6-nitrophenyl) acetamide: To a solution of 4-imidazol-1-yl-2-methylphenylamine (1 g, 5.78 mmol) in CH ₂ Cl ₂ (20 ml ) was added at 0 ° C, Ac ₂ O (0.7 ml, 7.28 mmol). The reaction mixture was stirred for 14 hours at room temperature and diluted with water. The aqueous layer was extracted with CH ₂ Cl ₂ and the combined organic layers were washed with saturated NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give a solid. The solid was suspended in H ₂ SO ₄ (conc) (15 ml). HNO ₃ (conc.) (0.312 ml) was then added to the suspension at 0 ° C. The reaction mixture was warmed slowly to room temperature and stirred at this temperature for 4 hours. After cooling to -10 ° C, the reaction mixture was neutralized with ammonium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (1: 9: 5 MeOH / THF / hexane) to give the title compound (0.61 g, 41%). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.11 (1H, s), 7.45-7.56 (2Η, m), 7.38 (1H, dd, J = 2.4, 8.4 Hz), 7.14 (1H, s), 2.33 (3H, s), 2.18 (3H, s).

4-Imidazol-1-yl-2-methyl-6-nitrophenylamine: To a suspension of N- (4-imidazol-1-yl-2-methyl-6-nitrophenyl) acetamide (279 mg, 1.07 mmol) in ethanol (3 ml) 2N HCl (2 ml) was added. The reaction mixture was refluxed for 14 hours, cooled to room temperature and neutralized with saturated NaHCO ₃ solution. The resulting light orange solid was filtered and dried under vacuum. The title compound (179 mg, 76% was obtained as an orange solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.78 (1H, s), 8.24 (1Η, s), 7.78 (1H, s), 7.64 (1Η, s), 7.46 (1Η, s), 2.36 (3H, s).

5-Imidazol-1-yl-3-methylbenzene-1,2-diamine: To 4-imidazol-1-yl-2methyl-6-nitrophenylamine (350 mg, 1.61 mmol) and 10% palladium on charcoal (40 mg) degassed methanol (5 ml) and TFA (trifluoroacetic acid) (5 drops) were added. The reaction mixture was purged with hydrogen and evacuated. The suspension was stirred for 14 hours at room temperature and under a hydrogen atmosphere (hydrogen balloon). The dark reaction mixture was filtered through a pad of celite and washed with methanol. Concentration of the filtrate gave a residue which was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO ₃ solution, brine and dried over Na ₂ SO ₄ . Concentration to dryness gave the title compound (275 mg, 91%) as a solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.87 (1H, s), 7.34 (1 Η, s), 7.05 (1 Η, s), 6.72 (1 Η, d, J = 2.4, © Hz). 6.65 (1H, d, J = 2.4 Hz), 2.21 (3H, s). TX / MC (M + H) ⁺ m / z 189 (t = 0.23 min).

4-Iodine-2-methoxypyridine-3-carbaddehyde (WO 95/29917): A 5-liter, three-necked round-bottom flask is mounted with a mechanical suspension stirrer and charged under nitrogen atmosphere with THF (1 l) and cooled to -78 ° S. To this stirred solution was added through a tube at -78 ° C, tert-butyllithium (1.7 M solution in pentane) (800 ml, 1.36 mol), followed by 2-methoxypyridine (132.2 g, 1.21 mol). The mixture was stirred at -78 ° C for 1 hour. To her

was added dropwise at -78 ° C, N (N -formyl-N), N ', N' - trimethylethylenediamine (176 ml, 1.37 mol). The reaction mixture was stirred for about 30 minutes at -78 ° C before warming to -23 ° C for about 30 minutes. Ethylene glycol dimethyl ether (1 L) was added to the mixture at -23 ° C, followed by n-butyllithium (2.5M solution in hexane) (800 ml, 2.0 mol). The resulting mixture was stirred for about 2 hours, during which time it turned dark green. A 12 liter 4-neck flask was charged with iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 l) and the resulting solution cooled to -78 ° C. The contents of the 5 liter flask were transferred through a tube into the mixture of iodine and dimethylether of ethylene glycol in the 12 liter flask at -78 ° C. After mixing was complete, the reaction mixture was stirred for an additional 1 hour at -78 ° C. The cooling bath was removed and the mixture warmed to about 0 ° C, then treated with 2 l of water and 2 l of 1N hydrochloric acid. Tert-Butyl ether (2 L) was added and the layers separated. The aqueous layer was extracted with 2 x 1 l methyl tert-butyl ether. The combined organic layers were washed with saturated Na ₂ S ₂ O _{3 solution} (1.2 l), brine (1.2 l) and dried over Na ₂ SO ₄ . After concentration in vacuo, the thick suspension was diluted with hexane (1 L), the mixture was cooled in an ice bath for about 30 minutes. The precipitate was filtered off and dried in vacuo to give the title compound as a pale yellow solid. ¹ H NMR (300 MHz, CDCI ₃ ) δ 10.22 (s, 1 Η), 7.86 (1Η, d, J = 5.3 Hz), 7.54 (1H, d, J = 5.3, Hz), 4.06 (3H, s) . TX / MC (M + H) ⁺ m / z 364 (t = 2.26 min).

6-imidazol-1-yl-2- (4-iodo-2-methoxypyridin-3-yl) -4-methyl-1H-benzimidazole: To a solution of 5-imidazol-1-yl-3-methylbenzene-1,2- diamine (175 mg, 0.93 mmol) in methanol (8 ml) was added, at 0 ° C, a solution of 4-iodine

2-methoxypyridine-3-carbapdehyde (245 mg, 0.93 mmol) in methanol (5 ml). The reaction mixture was stirred for 1.5 hours at 0 ° C and then for 2 hours at room temperature. After concentration, the residue was purified by flash column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the title compound (291 mg, 60%). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.13 (1H, s), 7.98 (1 Η, d, J = 5.4 Hz), 7.62 (1H, d, J = 5.4, Hz), 7.59 (2H, s ), 7.33 (1H, s), 7.16 (1H, s), 3.90 (3H, s), 2.67 (3H, s). TX / MC (M + H) ⁺ m / z 432 (t = 0.99 min).

3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4-iodine-1H-pyridin-2-one: Suspension of 6-imidazol-1-yl-2- (4-iodo-2-methoxypyridin-3yl) -4-methyl-1H-benzimidazole in 1N HCl (6 ml) was heated at 70 ° C for 3 days, cooled to room temperature and diluted with ethyl acetate. After extraction, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (1% NH ₄ OH / 10% MeOH / CH ₂ Cl ₂ ) to give the title compound (78 mg, 81%) as a solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.12 (1H, s), 7.58 (2H, s), 7.29-7.31 (2H, m), 7.16 (1H, s), 7.01 (1 Η, J = 6.8 Hz), 2.66 (3H, s). TX / MC (M + H) ⁺ m / z 418 (t = 0.75 min).

Preparation of 2- (4-chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzimidazole-5-carbonitrile:

4-amino-3-methylbenzonitrile: To a solution of 3-methyl-4-nitrobenzonitrile (20 g, 0.123 mol) in HOAc (200 ml) was added iron powder (17.55 g,

0.309 mol). The reaction is exothermic; after 10 minutes the reaction time is darkened. The reaction mixture was stirred for 14 hours at room temperature and then diluted with EtOAc (200 ml). The brown precipitate was filtered through a pad of celite and the filter residue was washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc / hexane) to give the title compound (15.3 g, 92%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.30-7.34 (2H, m), 6.64 (1 Η, d, J = 8.7 Hz), 2.16 (3H, m). TX / MC (M + H) ⁺ m / z 133 (t = 0.93 min).

NC

NO.

N- (4-cyano-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide: To ice-cold trifluoroacetic anhydride (60 ml) was added portionwise 4-amino-methylmethylbenzonitrile (14.33 g, 0.108 mol). The resulting white suspension was stirred at 0 ° C for 30 minutes. Ammonium nitrate (17.28 g, 0.216 mol) was then added. The reaction mixture was stirred for 1 hour at 0 ° C and for 14 hours at room temperature. After removal of most of the solvent, the reaction mixture was cooled with ice and quenched with ice. The yellow precipitate was filtered off, washed with cold water and dried in vacuo. The crude product (15.5 g, 52%, purity about 80%) was used in the next step without purification. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.05 (1H, s), 7.74 (1 Η, s), 2.30 (3H, s). MS-HP (negative ECI = electrospray ionization) (M-H) 'm / z 272.

NC

4-Amino-3-methyl-5-nitrobenzonitrile: A mixture of 1- (1- (4-cyano-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide (5 g, 18.3 mmol) and 2M ammonia in methanol (80 ml) was heated at reflux for 14 hours, then cooled to room temperature. After concentration in vacuo, the residue was purified by flash chromatography (20% EtOAc / hexane) to give the title compound (3.24 g, 100%, ca. 80% purity). ¹ H NMR (300 MHz,

CDCI ₃ ) δ 8.40 (1H, s), 7.47 (1H, s), 6.6-6.8 (2H, broad s), 2.89 (3H, s).

3,4-Diamino-5-methylbenzonitrile: To a solution of 4-amino-3-methyl-5nitrobenzonitrile (3.24 g, 18.3 mmol) in ethanol (80 mL) was added tin chloride dihydrate (8.67 g, 49.75 mmol). The reaction mixture was refluxed for 14 hours, then cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (100 ml) and treated with triethylamine (20 ml). The resulting suspension was filtered through a pad of celite and the filter residue was washed three times with ethyl acetate (50 ml). The filtrate was washed with saturated NaHCO ₃ solution, water, brine, dried over Na ₂ SO ₄ and filtered. After removal of the solvent, the residue was purified by flash chromatography on silica gel (30% - 50% EtOAc / hexane) to give the title compound © (2.17 g, 81%) as a light yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.94 (1H, s), 6.85 (1 Η, s), 2.16 (3H, s). LC / MS (M + H) + m / z 148 (t = 0.67 min).

2- (4-iodo-2-methoxypyridin-3-yl) -7-methyl-3H-benzimidazole-5-carbonitrile: To a solution of 3,4-diamino-5-methylbenzonitrile (2.00 g, 13.6 mmol) in MeOH ( 40 ml) was added, at 0 ° C, 4-iodine-2-methoxypyridine-3-carbaldehyde (3.6 g, 13.6 mmol) in MeOH (20 ml). The resulting suspension was stirred for 1 hour at 0 ° C. Iodine (1.73 g, 8.8 mmol) in MeOH (10 ml) was added dropwise at 0 ° C through a dropping funnel to the reaction mixture. The reaction mixture was stirred for 14 hours at room temperature. After removal of MeOH, the residue was diluted with saturated Na ₂ S ₂ O _{3 solution} and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na ₂ SO ₄ . The crude product was purified by flash column chromatography (3% MeOH / CH ₂ Cl ₂ ) to give the title compound (1.81 g, 46%). ¹ H NMR (300 MHz, CDCI ₃ ) δ 7.90 (1H, s), 7.49 (1 Η, d, J = 5.4 Hz), 7.46 (1H, s), 7.41 (1H, d, J = 5.3 Hz). 3.78 (3H, s), 2.68 (3H, s). TX / MC (M + H) ⁺ m / z 391 (t = 1.27 min).

2- (4-Chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzimidazole-5-carbonitrile: Suspension of 2- (4-iodo-2-methoxypyridine-

3-yl) -7-methyl-3H-benzimidazole-5-carbonitrile (1.8 g, 4.63 mmol) in 4 M HCl dioxane (40 ml) was heated at 80 ° C for 6 hours and cooled to room temperature. The precipitate was filtered off and dried. The crude product (1.08 g, 82%) was used in the next step without purification. MS-HP (ref. ECJ, (MH)) m / z 283.

Preparation of (S) -4- (1-benzyl-2-trityloxyethylamino) -3- (6-bromo-

4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one:

^ΒΓ Ύ ^ ^ΝΗ 2 γ ^ ΝΗ ₂

5-Bromo-3-methylbenzene-1,2-diamine: To a solution of 4-bromo-2-methyl-6-nitrophenylamine (20 g, 0.086 mol) in ethanol (200 ml) was added tin chloride dihydrate (49.2 g, 0.258 mol ). The reaction mixture was refluxed for 14 hours, then cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (150 ml) and treated with triethylamine (40 ml). The resulting suspension was filtered through a pad of celite and the filter residue was washed three times with ethyl acetate (50 ml). The filtrate was washed with saturated NaHCO ₃ solution, water, brine, dried over Na ₂ SO ₄ and filtered. After removal of the solvent, the residue was purified by flash chromatography on silica gel (30% EtOAc / hexane then 5% MeOH / CH ₂ Cl ₂ ) to give the title compound (10.26 g, 59%) as a yellow oil. ¹ H NMR (300

MHz, CDCI ₃ ) δ 6.77 (1H, d, J = 2.0 Hz), 6.74 (1H, s), 2.16 (1H, d, J = 2.0 Hz), 2.16 (3H, s). TX / MC (M + H) ⁺ m / z 201 (t = 0.83 min).

MeO

Nr.

I r

6-Bromo-2- (4-iodo-2-methoxypyridin-3-yl) -4-methyl-1H-benzimidazole: To a solution of 5-bromo-3-methyl-1,2-phenylenediamine (4 g, 19.9 mmol) in methanol (80 ml) was added dropwise at 0 ° C, 4-iodo-2-methoxypyridine-3carbaldehyde (5.23 g, 19.9 mmol) in methanol (20 ml). The resulting suspension was stirred for 30 minutes at room temperature. Then iodine (2.53 g, 9.95 mmol) in methanol (20 mL) was added via a drop funnel. After 14 hours, the reaction mixture was concentrated in vacuo, diluted with 5% Na ₂ S ₂ O ₃ and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na ₂ SO ₄ . After removal of the solvent, the residue was carefully purified by flash chromatography (20% EtOAc / hexane) to give the title compound (4.05 g, 46%) as a yellow foam. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (1H, d, J = 5.31 Hz), 7.53 (1H, d, J = 5.3 Hz), 7.26 (2H, br s), 3.91 (3H, s). 2.63 (3H, s). TX / MC (M + H) ⁺ m / z 444 (t = 1.39 min).

3- (6-Bromo-4-methyl-1H-benzimidazol-2-yl) -4-chloro-1H-pyridin-2-one: Suspension of 6-bromo-2- (4-iodo-2-methoxypyridin-3 -yl) -4-methyl-1H-benzimidazole (4 g, 9.03 mmol) and 60 ml of 4M HCl in dioxane was heated at 80 ° C for 6 hours and cooled to room temperature. The precipitate was filtered off and dried to give the title compound (3.0 g, 100%) as a brown powder. The crude product is used in the next step without purification. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.55 (1H, s), 7.42 (1H, d, J = 6.0 Hz), 7.17 (1H, s), 6.91 (1H, d, J = 6.0 Hz). 2.55 (3H, s). TX / MC (M + H) ⁺ m / z 338 (t = 1.33 min).

(S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (6-bromo-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: To a solution of 3- ( 6-Bromo-4-methyl-1 N-benzimidazol-2-yl) -4-chloro-1H-pyridin-2-one (1.42 g, 3.78 mmol) in DMF (15 ml) was added (8) - (-) - 2-amino-3-phenyl-1-propanol (1.43 g, 9.45 mmol) and Nmethylmorpholine (1.5 ml). The reaction mixture was heated at 80 ° C for 6 hours and cooled to room temperature. The solvent was removed in high vacuum and the residue was purified by flash chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (1.26 g, 74%) as a yellow foam. ¹ H NMR (300 MHz, CDCl 3) δ 6.9-7.2 (8H, m), 5.86 (1H, d, J = 7.1 Hz), 3.7-3.9 (3H, m), 2.9-3.1 (2H, m), 2.57 (3H, s). TX / MC (M + H) ⁺ m / z 453 (t = 2.03 min).

Nr

(S) -4- (1-Benzyl-2-trityloxyethylamino) -3- (6-bromo-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: To a solution of (S) -4 - (1-Benzyl-2-hydroxyethylamino) -3- (6-bromo-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin2-one (0.9 g, 1.98 mmol) in THF (30 ml) was added Cs ₂ CO ₃ (1.29 g, 3.96 mmol) followed by triphenylmethyl chloride (1.10 g, 3.96 mmol). The reaction mixture was heated at reflux and nitrogen for 14 hours, then cooled to room temperature. After removal of the solvent, the residue was diluted with ethyl acetate and washed with water. The aqueous fraction was extracted with ethyl acetate and the combined organic layers were washed with water and brine and dried over Na ₂ SO ₄ . After concentration in vacuo, the residue was purified by flash column chromatography (30% EtOAc / hexane) to give the title compound (1 g, 73%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.77 (1H, br s), 11.73 (1H, d, J = 5.2 Hz), 11.46 (1H, br s), 7.13-7.54 (23H, m). 5.87 (1H, d, J = 4.5 Hz), 4.09-4.14 (1H, m), 3.07-3.42 (4H, m), 2.54 (3H, s). TX / MC (M + H) ⁺ m / z 695 (t = 2.79 min).

Preparation of 3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4-chloro-1H-pyridin-2-one:

Fr.

- [4- (4-amino-3-methyl-5-nitrophenyl) piperazin-1-yl] ethanone: A mixture of 4-bromo-2-methyl-6-nitrophenylamine (5 g, 21.64 mmol), 1-acetylpiperazine ( 4.2 g, 32.46 mmol), palladium acetate (244 mg, 1.08 mmol), tri-tert-butylphosphine (440 mg, 2.16 mmol) and sodium tert-butoxide (4.2 g, 43.29 mmol) in toluene (70 ml) were added. heated for 14 hours at 100 ° C and under nitrogen. The reaction mixture was cooled to room temperature and diluted with EtOAc. After extraction, the combined organic layers were washed with water, brine and dried over Na ₂ SO ₄ . Concentration afforded a brownish residue which was purified by flash column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the title compound (4.21,70%). ¹ H NMR (400 MHz, CD ₃ OD) δ

7.42 (1H, d, J = 2.8 Hz), 7.23 (1H, d, J = 2.8 Hz), 3.71 (2H, t, J = 5.1 Hz), 3.67 (2H, t.

J = 5.1 Hz), 3.04 (2H, t, J = 5.2 Hz), 2.98 (2H, t, J = 5.2 Hz), 2.24 (3H, s), 2.13 (3H, s). TX / MC (M + H) ⁺ m / z 279 (t = 1.46 min).

1- (4- (3,4-Diamino-5-methylphenyl) piperazin-1-yl] ethanone: To 1- (4- (4amino-3-methyl-5-nitrophenyl) piperazin-1-yl] ethanone (4.5 g, 16.2 mmol) and 10% palladium on charcoal (400 mg), methanol (50 ml) and acetic acid (5 ml) were added under nitrogen atmosphere and the reaction mixture was stirred for 14 hours under hydrogen atmosphere (hydrogen balloon). was filtered through a pad of celite and the filter residue was washed with methanol Concentrating the filtrate gave the title compound (4.00 g, 100%), which was used in the next step without purification. TX / MC (M + H) ⁺ m / z 207 (t = 0.41 min).

1- {4- [2- (4-iodo-2-methoxypyridin-3-yl) -7-methyl-3H-benzimidazole-

5-yl] pyrazazin-1-yl} ethanone: To a solution of 1- [4- (3,4-diamino-5-methyl phenyl) piperazin-1-yl] ethanone (4 g, 16.18 mmol) in methanol (100 ml) was added 4-iodo-2-methoxypyridin-3-ylcarbaldehyde (4.25 g, 16.18 mmol). The reaction mixture was stirred for 14 hours at room temperature. After concentration, the residue was purified by flash column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the title compound (5.25 g, 66%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 (1H, d, J = 5.4 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.26 (1H, s), 6.85 (1H, s). 3.85 (3H, s), 3.78 (2H, t, J = 5.0 Hz), 3.64 (2H, t, J = 5.0 Hz), 3.16 (2H, t, J = 5.2 Hz), 3.11 (2H, t, J = 5.2 Hz), 2.62 (3H, s), 2.13 (3H, s). TX / MC (M + H) ⁺ m / z 492 (t = 1.71 min).

O 'Cl

3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4chloro-1H-pyridin-2-one: To a solution of 1- {4- [2 - (4-iodo-2-methoxypyridin-3-yl) -7-methyl-3H-benzimidazol-5-yl] pyrazin-1-yl} ethanone (5.2 g, 10.6 mmol) in 4 M HCl dioxane (60 ml) was added water (5 ml). The reaction mixture was stirred for 14 hours at room temperature. Concentration of the reaction mixture gave the title compound (4.02 g, 100%), which was used in the next step without purification. TX / MC (M + H) ⁺ m / z 486 (t = 1.55 min).

Preparation of (6) -4 * (1-hydroxymethyl-2-phenylethylamino) -3- (4methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one:

(S) -3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -

4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one: To a solution of 3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2- yl] -4chloro-1H-pyridin-2-one (1 g, 2.6 mmol) in DMF (10 ml) was added (S) - (-) - 2amino-3-phenylpropanol (0.78 mg, 5.2 mmol) and N -methylmorpholine (2 ml). The reaction mixture was heated at 80 ° C for 12 hours, cooled to room temperature and concentrated in high vacuum. The residue was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.90 g , 69%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.36 (1H, s), 7.02-7.23 (6Η, m), 6.80 (1H, s), 5.98 (1H, d, J = 7.5 Hz), 4.10-4.12 (3H, m), 3.67-3.78 (6H, m), 3.06-3.11 (3H, m), 2.90 (1H, dd, J = 7.8, 13.6 Hz), 2.54 (3H, s), 2.12 (3H, s ). TX / MC (M + H) ⁺ m / z 501 (t = 1.30 min).

(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: To a solution of (S) -3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridine- 2-one (900 mg, 18 mmol) in 4M

HCl (dioxane solution, 10 ml) was added water (1 ml). The reaction mixture was heated at 80 ° C for 14 hours and cooled to room temperature. Concentration under high vacuum gave the title compound (0.83 g,

100%), which is used in the next step without purification. LC / MS (M + H) ⁺ m / z 459 (t = 1.13 min).

Preparation of 2- (4,6-dichloropyrimidin-5-yl) -6-imidazol-1-yl-4methyl-1H-benzimidazole:

CI

4,6-Dichloropyrimidine-5-carbaldehyde: To POCl ₃ (21 ml, 0.23 mol), DMF (7 ml, 0.09 mol) was added at 0 ° C. The reaction mixture was stirred for 0.5 h at room temperature. 4,6-Dihydroxypyrimidine-5-carbaldehyde (5 g, 0.045 mol) was added in small portions. The reaction mixture was heated at 90 ° C for 6 hours and cooled to room temperature. The reaction mixture was added very slowly and with cooling with an ice bath, a large excess of crushed ice. The mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water, brine and dried over

At ₂ SO ₄ . After concentration, the residue was purified by column chromatography (20% EtOAc / hexane) to give the title compound (4 g, 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (1H, s), 7.87 (1 Η, s), MS-HP; (Μ + Η) ⁺ m / z 177.

2- (4,6-Dichloropyrimidin-5-yl) -6-imidazol-1-yl-4-methyl-1H-benzimidazole: To a solution of 5-imidazol-1-yl-3-methylbenzene-1,2- diamine (180 mg, 0.96 mmol) in methanol (4 mL) was added a solution of 4,6-dichloropyrimidine-5-carbaldehyde (183 mg, 0.96 mmol) in methanol (1 mL). The reaction mixture was stirred for 14 hours at room temperature. After concentration, the residue was purified by flash column chromatography (5% methanol /

CH ₂ Cl ₂ ) to give the title compound (180 mg, 55%). LC / MS (M + H) ⁺ m / z 344 (t = 1.31 min).

Process for the preparation of 2-amino-4-fluoro-6-methylnitrobenzene:

3- (3,5-Difluoro-2-nitrophenyl) malonic acid di-tert-butyl ester: To a suspension of NaH (54.6 g, 60%, 1.35 mol) in 600 ml of DMF, at 0 ° C was added di t-butylmalonate (118 g, 0.546 mol) and the mixture was stirred for 30 minutes. To this was added for 3 hours 2,4,6-trifluoro-benzene as a solution in 400 ml of DMF (75 g, 0.42 mol) and the solution was stirred for 12 hours at room temperature. The reaction mixture was extracted with ethyl acetate (x 3). The ethyl acetate was washed with water (x 3), brine, dried over MgSO ₄ and concentrated to give 62 g of crude product. LC / MS [M + Na] 396; ¹ H NMR (500 MHz, DMSO) δ 7.81 (m, 1 Η), 7.27 (m, 1 Η), 5.00 (s, 1 Η), 1.41 (m, 1H).

2- (3-Amino-5-fluoro-2-nitrophenyl) malonic acid di-tert-butyl ester: To the crude 3- (3,5-difluoro-2-nitrophenyl) malonic acid di-tert-butyl ester ( 62 g, 0.42 mol) was added 700 ml of 2M ammonia in methanol in a pressure vessel. The vessel was sealed and heated for 18 hours at 85 ° C. The reaction mixture was cooled and the vessel was carefully opened, after which the methanol solution was concentrated to give 140 g of crude material. LC / MS [M + Na] &lt; 39 &gt;; ¹ H NMR (500 MHz, DMSO) δ 6.76 (dd, J = 10.8, 2.8 Hz, 1 Η), 6.29 (dd, J = 10.8, 2.8 Hz, 1H), 4.99 (br s, 2H), 4.80 (s , 1H), 1.40 (m, 1H).

3-Amino-5-fluoro-2-nitrophenylacetic acid: To 2- (3-amino-5-fluoro-2-nitrophenyl) malonic acid di-tert-butyl ester (140 g) in 500 ml of 4N HCl in dioxane 50 ml of water are added and the mixture is heated at 40 ° C for 2 days. The solution was extracted with ethyl acetate (x 3) and the ethyl acetate was washed with water (x 3) and brine. The organic fraction was dried over MgSO ₄ and concentrated to give 78 g of crude product (66% pure according to LC / MS); ¹ H NMR (500 MHz, DMSO) δ 12.40 (br s, 1 Η), 7.04 (s, 2Η), 6.68 (dd, J = 10.9, 2.8 Hz, 1H), 6.47 (dd, J = 10.9, 2.8 Hz , 1H), 3.80 (s, 2H).

2-amino-4-fluoro-6-methylnitrobenzene: To the crude 3-amino-5-fluoro-2-nitrophenylacetic acid (3.6 g, 16.8 mmol) was added Cu ₂ O (10.1 g,

70.6 mmol) in 120 ml of acetonitrile together with 50 μl of methanol and the suspension heated at reflux for 12 hours. The reaction mixture was filtered through celite and the celite was washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give 2.95 g of a material which was 80% pure according to ¹ H NMR. MS-ESI [M + Na] &apos;193; ¹ H NMR (500 MHz,

DMSO) δ 6.67 (s, 2H), 6.56 (dd, J = 11, 2.8 Hz, 1 Η), 6.39 (dd, J = 11, 2.8, 1 Η), 2.50 (s, 3H).

Process for the Preparation of 4-Chloro-3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one and 4-iodo-3- (4-methyl- 6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one

2-Methyl-4-morpholin-4-yl-6-nitrophenylamine: Tris- (dibenzylideneacetone) dipalladium (2.63 g, 2.88 mmol), 2- (di-tert-) were charged into an 800 ml pressure flask. butylphosphino) biphenyl (1.42 g, 4.75 mmol) and sodium tert-butoxide (17.5, 182 mmol). Dry THF (500 mL), 4-bromo-2-methyl-6-nitroaniline (30.0 g, 130 mmol) and morpholine (34 mL, 390 mmol) were then added. Argon was bubbled through the solution for 1 minute and the flask was sealed. The reaction mixture was stirred for 3 days at 85 ° C. The THF was evaporated in vacuo and the crude product was reabsorbed onto silica gel, which was then transferred to the top of the silica gel column. Elution with hexane / ethyl acetate (gradient 6: 4 to 4: 6 to 0: 1) gave, after evaporation of the solvents, the title compound (15.2 g, red-brown solid, 49.3%). LC / MS (M + H) ⁺ m / z © 238 (t = 0.64 min) ¹ H NMR (500 MHz, flMCO-d ₆ ) δ 7.32 (1H, S), 7.22 (1H, s), 6.96 (2H , s), 3.72 (4H, br s), 2.96 (4H, br s), 2.21 (3H, s).

2- (4-iodo-2-methoxypyridin-3-yl) -4-methyl-6-morpholin-4-yl-1H-benzoimidazole: 2-methyl-4-morpholin-4-yl-6-nitrophenylamine (15.2 g, 64 mmol) was suspended in methanol (200 ml) in a Parr flask. Palladium on carbon (1.0 g, 10% Pd) was added and the suspension was shaken under hydrogen pressure of 60 psi (3.5 bar) overnight. The mixture was filtered through a pad of celite (under argon) in a three-necked flask, the celite was washed with

methanol and the filtrate was diluted with methanol to a total volume of 500 ml and cooled to 0 ° C. A solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (14.6 g, 55.5 mol) in methanol (500 ml) was added slowly (over 3 hours) to it. After adding about 1/4 of the solution, the system opens to the atmosphere and stirs for one weekend, during which time it is brought to room temperature. The reaction mixture was concentrated in vacuo, filtered through a pad of silica gel (eluent: methylene chloride / ethyl acetate / methanol 55-40-5), then recrystallized from ethyl acetate. The title compound was isolated as a brown solid (12.68 g, 51%). Flash chromatography on mother liquor gave an additional 2.90 g (12%). [the column is filled with methylene chloride, the compound is eluted with methylene chloride / ethyl acetate 6-4, then methylene chloride / ethyl acetate / methanol 58-40-2]. LC / MS (M + H) ⁺ m / z 451 (t = 1.03 min). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.76 (1H, d, J = 5.3 Hz), 7.42 (1H, d, J = 5.3 Hz), 6.85 (1H, br s), 6.82 (1H, s). 3.86 (4H, t, J = 4.5 Hz), 3.79 (3H, s), 3.12 (4H, t, J = 4.5 Hz), 2.60 (3H, s), 2.21 (3H, s).

Cl

4-Chloro-3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one and 4-iodo-3- (4-methyl-6-morpholine -4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one: 2- (4-iodo-2-methoxypyridin-3-yl) -4-methyl-6-morpholin-4-yl-1 N-benzoimidazole (15.58 g, 34.6 mmol) was suspended in 1,4 dioxane (300 mL) and conc. HCl (aqueous solution, 50 ml). The mixture was stirred overnight at room temperature, then at 50 ° C for 3 hours. After cooling to room temperature, the mixture was poured into ice-cold NaHCO ₃ solution (67 g, 0.8 mol) and filtered. The aqueous phase was extracted with ethyl acetate. The solid material was dissolved in CH ₂ Cl ₂ with a known amount of methanol, then extracted between water and CH ₂ Cl ₂ .

The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give an inseparable mixture of 4-chloro- and 4-iodo-title compounds. The product is used without further purification.

LC / MS (M + H) ⁺ m / z 437 and m / z 345 (t = 0.92 min).

Process for the preparation of 4- [2- (4-chloro-2-oxo- tert-butyl ester)

1,2-Dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxylic acid and 4- [2- (4-iodo-2-oxo-1 tert-butyl ester, 2-Dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperazine-1-carboxylic acid

nh ₂ no ₂

4- (3-Amino-5-methyl-4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester: To a stirred solution of 3-fluoro-5amino-6-nitrotoluene (10 g, 58.79 mmol) in anhydrous NMP (1'-methyl-2-pyrimidinone) (160 ml), BOC-piperazine (tert-butoxycarbonyl-piperazine) (39 g, 209.4 mmol) and 4-methyl-morpholine (25.9 ml) were added under nitrogen atmosphere. The resulting dark solution was heated at reflux for 72 hours, cooled to room temperature and diluted with ethyl acetate (4000 ml). The organic layer was washed with water (8 x 1500 mL), brine (1 x 1500 mL), dried over sodium sulfate and evaporated in vacuo. The resulting dark oil was dissolved in boiling absolute ethanol (800 ml) and concentrated to a total volume of 400 ml, then allowed to stand at room temperature overnight. The solution was cooled to -20 ° C for 5 hours and the resulting solid was filtered off and dried in vacuo to give 16.3 g (83%) of a light yellow solid. ¹ H NMR (500 MHz, CDCI ₃ ) δ 6.16 (br s, 1H), 6.04 (br s, 1H), 3.70-3.60 (m, 4H), 3.38-3.25 (m, 4H), 2.53 (s, 3H ), 1.48 (s, 9H); LC / MC (M + H) ⁺ m / z 337.

NH ₂ nh ₂

4- (3,4-Diamino-5-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester: To a stirred solution of 4- (3-amino-5-methyl-4-nitrophenyl) piperazine tert-butyl ester -1-carboxylic acid (15 g, 44.6 mmol) in methanol (2200 mL) was added 20% Pd (OH) ₂ / C (1.6 g) and the suspension was flushed very well with nitrogen followed by hydrogen. The resulting slurry was stirred overnight at room temperature and under a hydrogen atmosphere (ca. 1 atm). The resulting suspension was filtered under nitrogen atmosphere through a pad of celite and washed with methanol (400-500 ml). The product is used as soon as it is received. LC / MS (M + H) ⁺ m / z 307.

4- [2- (4-Iod-2-methoxypyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxylic acid tert-butyl ester

To a stirred solution of 4- (3,4-diamino-5-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester (44.6 mmol - assuming 100% conversion to the previous step) in methanol (ca. 2700 ml), at 0 ° C and under nitrogen atmosphere was added slowly (2 hours), through an additional funnel, a solution of 4-iodine-2-methoxypyridine-3-carbaldehyde (15.0 g, 57.1 mmol) in anhydrous methanol (225 ml). The resulting solution was then stirred for 30 minutes at 0 ° C; the cooling bath was removed and the reaction mixture was stirred for 72 hours at room temperature and in the presence of air. The resulting solution was concentrated in vacuo and the residue was dissolved in dichloromethane (1500 ml) and the solvent was removed in vacuo (three times). The resulting foamy solid product is dried under high vacuum. ¹ H NMR (500 MHz, CDCI ₃ ) δ 7.82 (d, 1H, J = 5.4 Hz), 7.50 (d,

1H, J = 5.4 Hz), 6.98 (br s, 1H), 6.90 (br s, 1H), 4.05 (s, 3H), 3.67-3.58 (m, 4H), 3.183.09 (m, 4H), 2.63 (s, 3H), 1.49 (s, 9H); LC / MC (M + H) ⁺ m / z 550.

4-iodo-3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: To a stirred solution of 4- tert -butyl ester 4- (2- (4 iodo-2-methoxypyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1 carboxylic acid (24 g, 43.7 mmol) was added 1,4-dioxane (750 ml ) and 6 N HCl (30 ml) and the mixture was heated at 75 ° C overnight. The solution was cooled to room temperature, the supernatant was poured and the resulting dark gummy substance was washed with anhydrous diethyl ether (3 x 500 ml) and dried. under vacuum to obtain 17.7 (93%) of the title compound as a dark solid m, which is used as described to obtain 4- [2- (4-chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazole tert-butyl ester- 5-yl] piperazine-1-carboxylic acid and 4- [2- (4-iodo-2-oxo-1,2-dihydropyridin-3-yl) -7methyl-3H-benzoimidazol-5-t-butyl ester -yl] piperazine-1-carboxylic acid TX / MS (M + H) ⁺ m / z 436. (Note: a small peak of 4-chloropyridin-2-one in TX / MS shows m / z 344, 346).

4- [2- (4-Chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxylic acid tert-butyl ester and tert. 4- [2- (4-Iod-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperazine-1-carboxylic acid butyl ester: To stirred suspension of 4-iodo-3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one (17.7 g, 40.7 mmol) in dichloromethane (750 ml ) was added di-tert-butyl dicarbonate (9.8 g, 44.8 mol) and triethylamine (67.4 ml, 483.6 mmol). The mixture was stirred for 30 minutes at room temperature and purified by flash chromatography on silica gel. After elution with dichloromethane followed by 2.5% methanol / ethyl acetate, the homogeneous fractions were collected and partially evaporated in vacuo, which after filtration gave the product as a yellow solid (8.9 g, ca. 41%, 2 yields). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.25 (d, 1H, J = 6.9 Hz), 6.97 (d, 1H, J = 6.9 Hz), 6.97 (br s, 1H), 6.89 (br s, 1H ), 3.65-3.56 (m, 4H), 3.16-3.07 (m, 4H), 2.55 (s, 3H), 1.49 (s, 9H); LC / MC (M + H) ⁺ m / z 536. (Note: a small peak of 4-chloropyridin-2-one in TX / MS showed m / z 444, 446).

Process for the preparation of 3- [6- (4-aminopiperidin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-iodo-1H-pyridin-2-one and of 3- [6- (4 -aminopiperidin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-chloro-1H-pyridin-2-one

nh ₂ no ₂

[1- (3-Amino-5-methyl-4-nitrophenyl) piperidin-4-yl] -carbamic acid tert-butyl ester: 5-fluoro-3-methyl-2-nitrophenylamine (0.97 g, 5.7 mmol) , 4-M-BOC-aminopiperidine (BOC = tert-butoxycarbonyl) (1.60 g, 8.0 mmol), diisopropylethylamine (2.5 ml, 14 mmol) and DMSO (10 ml) were combined and stirred for 3 hours at 85 ° C. The reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layers were washed with water (x 3) and brine, dried over Na ₂ SO ₄ and concentrated. Flash chromatography on silica gel (eluent: hexane / ethyl acetate / triethylamine 50-50-1, then 33-66-1) afforded the title compound as a yellow solid (1.57 g, 79%). LC / MS (M + H) ⁺ m / z 536 (t = 1.55 min); ¹ H NMR (500 MHz, CD ₃ OD) δ 6.70 (br s, 1H), 6.22 (1H, d, J = 2.5 Hz), 6.13 (1H, d, J = 2.5 Hz), 3.88 (2H, d. J = 13.3 Hz), 3.58 (1H, br s), 2.98 (2H, t, J = 11.8 Hz), 2.48 (3H, s), 1.92 (2H, d, J = 11.3 Hz), 1.48 (2H, m ), 1.45 (9H, s).

{1- [2- (4-Iod-2-methoxypyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperidin-4-yl} -carbamic acid tert-butyl ester [1- (3-Amino-5-methyl-4-nitrophenyl) piperidin-4-yl] carbamic acid butyl ester (1.54 g, 4.4 mmol) was dissolved in methanol (100 ml). Palladium on charcoal (0.3 g, 10% Pd) was added and the suspension was vigorously stirred overnight with hydrogen in a balloon. The mixture was filtered through a pad of celite (under argon) in a three-necked flask, the celite was washed with methanol and the filtrate was cooled to 0 ° C. A solution of 4-iodine-2-methoxypyridine-3-carbaldehyde (1.21 g, 4.6 mmol) in methanol (50 ml) was added slowly (over 2 hours) to it. The mixture was stirred overnight at room temperature, then concentrated in vacuo. Flash chromatography on silica gel (eluent: hexane / ethyl acetate / methanol 5-4-1) afforded the title compound (0.79 g, 32%). LC / MS (M + H) ⁺ m / z 564 (t = 1.31 min).

3- [6- (4-Aminopiperidin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4 iodo-1H-pyridin-2-one and 3- [6- (4-aminopyridine) -1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-chloro-1H-pyridin-2-one: {1- [2- (4-iodo-2-methoxypyridine-) 3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperidin-4-yl} carbamic acid (330 mg, 0.59 mmol) was suspended in 4M HCl in 1,4-dioxane (20 ml) and added. water (3 ml) (exothermic reaction). The mixture was stirred overnight at room temperature, then concentrated in vacuo to give an inseparable mixture of 4-chloro 4-iodo-title compounds. The product is used without further purification. LC / MS (M + H) ⁺ m / z 450 and m / z 358 (for both t = 0.69 min).

3-Methyl-5- (2-morpholin-4-ethoxy) -2-nitrophenylamine: To a solution of 2-morpholin-4-ylethanol (5 g, excess) in THF (30 ml) was added NaH (0.21 g, 8.82 mmol), in portions, under ice bath cooling. The reaction mixture was stirred for 30 minutes at room temperature. 5fluoro-3-methyl-2-nitrophenylamine was then added. The reaction mixture was refluxed for 6 hours, cooled to room temperature and concentrated. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over Na ₂ SO ₄ . After concentration, the residue was purified by flash column chromatography (20% EtOAc / hexane) to give the title compound (0.70 g, 85%). ¹ H NMR (400 MHz, CD ₃ OD) δ 6.10 (1H, s), 6.09 (1 Η, s), 4.38-4.42 (2Η, m), 3.92-4.08 (4H, m), 3.72 (1H, d , J = 12 Hz), 3.53-3.56 (2H, m), 3.05-3.10 (2H,

m), 2.48 (3H, s). TX / MC (M + H) ⁺ m / z 282 (t = 0.73 min).

(S) -7-Bromo-2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzimidazole-5-carbaldehyde: Towards a solution of (S) -7-bromo-2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzimidazole-5-carbonitrile (150 mg, 0.31 mmol) in THF (50 ml) was added at -78 ° C DIBAL-H (diisobutylaluminum hydride) (1M solution in toluene, 1.55 ml, 1.55 mmol). The reaction mixture was stirred for 10 hours at -40 ° C and cooled to -78 ° C. EtOAc (0.5 ml) was added. The reaction mixture was stirred for 30 minutes at -78 ° C, then water (1 ml) was added. The mixture was warmed to room temperature and concentrated. The residue is passed through a thin layer of celite. The filtrate was concentrated and purified by preparative HPLC to give the title compound (67 mg, 43%). ¹ H NMR (400 MHz, CD ₃ OD) δ 9.45 (1H, s), 7.62 (1 Η, s), 7.56 (1 Η, narrow d, J-1.6 Hz), 7.44 (1H, narrow d, J = 1.0 Hz), 7.32-7.42 (2H, m), 7.24-7.30 (3H, m), 6.24 (1H, d, J = 7.6 Hz), 5.01 (1H, m), 3.65-3.76 (2H, m). TX / MC (M + H) ⁺ m / z 487 (t = 1.76 min).

5- (1,4,5,6-Tetrahydropyrimidin-1-yl) -methyl-2-nitananiline: To a stirred solution of 2.0 g (11.76 mmol) of 5-fluoro-3-methyl-2-nitroaniline in 10 ml of DMSO was added. 1.2 g (14.11 mmol) of 1,4,5,6-tetrahydropyrimidine and 2.43 g (17.64 mmol) of potassium carbonate were added, then the mixture was heated for 10 hours at 100 ° C, cooled, diluted with water and extracted with ethyl acetate. containing 5% methanol. The combined organic extracts were washed with water, brine and dried (Na ₂ SO ₄ ). Evaporation of the solvent gave a residue which was chromatographed (20% 2M ammonia in methanol and dichloromethane) to give 1.85 g (67%) of a red solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (1H, s), 6.53 (1H, d, J = 2.57 Hz), 6.44 (1H, d, J = 2.1 Hz), 7.04 (1H, d, J = 2.1 Hz), 3.70 (2H, t, J = 6.0 Hz), 3.41 (2H, t, J = 5.65 Hz), 2.43 (3H, s), 2.05 (2H, m). TX / MC (M + H) ⁺ m / z 235 (t = 0.78 min).

Q EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

Example 1 (Common Method for Examples 1-21)

N.

HE

(5) -4- (2-Hydroxy-1-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: To a solution of 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4-iodine-1H-pyridin-2-one (30 mg, 0.072 mmol) in DMF (1 ml ) (5) - (-) - 2-phenylglycinol (26 mg, 0.18 mmol) and N-methyl-morpholine (0.1 ml) were added. The reaction mixture was heated at 80 ° C for 6 hours and cooled to room temperature. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the compound of the invention (16 mg, 52%). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.07 (1H, narrow t, J = 1.7 Hz), 7.76 (2H, s), 7.27-7.48 (7H, m), 7.21 (1H, d, J = 7.5)

Hz), 6.11 (1H, d, J = 7.5 Hz), 4.92 (1H, m), 4.03 (1H, dd, J = 4.5, 11.2 Hz), 3.95 (1H, dd, J = 6.2,11.2 Hz). 2.75 (3H, s). TX / MC (M + H) ⁺ m / z 427 (t = 1.44 min).

Example 2

Ί8

(±) -4- [2-hydroxy-2- (3-iodphenyl) ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one : ¹ H NMR (300 MHz, CD 3 OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.88 (1H, s), 7.76 (1H, s), 7.71 (1H, s), 7.59 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.32 (1H, s), 7.29 (1H, d, J = 7.6 Hz), 7.09 (1H, t, J = 7.8 Hz) , 6.24 (1H, d, J = 7.6 Hz), 4.97 (1H, dd, J = 5.0, 6.0 Hz), 3.75 (1H, dd, J = 5.0, 13.5 Hz), 3.67 (1H, dd, J = 6.0 , 13.5 Hz), 2.68 (3H, s). TX / MC (M + H) ⁺ m / z 553 (t = 1.43 min).

Example 3

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-

4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz, CD3OD) δ 9.39 (1H, narrow t, J = 1.4 Hz), 8.04 (1H, narrow t , J = 1.7 Hz), 7.76 (1H, narrow t, J = 1.7 Hz), 7.69 (1H, narrow t, J = 1.9 Hz), 7.55 (1H, s), 7.23-7.42 (5H, m), 6.25 (1H, d, J = 7.6 Hz), 5.01 (1H, dd, J = 4.8, 6.4 Hz), 3.76 (1H, dd, J = 4.8, 13.4 Hz), 3.66 (1H, dd, J = 6.4, 13.4) Hz), 2.67 (3H, s). TX / MC (M + H) ⁺ m / z 461 (t = 1.46 min).

Example 4

(±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-

4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 8.02 (1H, s), 7.74 (1H, s), 7.69 (1H , s), 7.66 (1H, narrow d, J = 1.4 Hz), 7.20-7.48 (5H, m), 6.21 (1H, d, J = 7.6 Hz), 4.99 (1H, dd, J = 4.8, 6.3 Hz ), 3.73 (1H, dd, J = 4.8, 13.5 Hz), 3.64 (1H, dd, J = 6.3, 13.5 Hz), 2.65 (3H, s). TX / MC (M + H) ⁺ m / z 505 (t = 1.44 min).

Example 5

(±) -N- (2-chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -2-oxo-1 , 2-dihydropyridin-4-ylamino] ethyl} phenyl) methanesulfonamide:

¹ H NMR (300 MHz, CD ₃ OD) δ 9.39 (1H, s), 8.05 (1H, s), 7.76 (1H, s), 7.68 (1H, s),

7.62 (1H, narrow d, J = 1.5 Hz), 7.52 (1H, s), 7.42-7.49 (2H, m), 7.31 (1H, s), 7.30 (1H, d, J = 7.6 Hz), 6.26 ( 1H, d, J = 7.6 Hz), 5.01 (1H, dd, J = 5.0, 5.6 Hz), 3.76 (1H, d, J = 5.0 Hz), 3.74 (1H, dd, J = 5.6,13.4 Hz). 2.98 (3H, s). TX / MC (M + H) ⁺ m / z 554 (t = 1.11 min).

Example 6

N- [3- (6-Imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-yl] 3-bromobenzoic acid hydrazide:

¹ H NMR (300 MHz, CD ₃ OD) δ 9.40 (1H, narrow t, J = 1.4 Hz), 8.14 (1H, narrow t, J = 1.7 Hz), 8.05 (1H, narrow t, J = 1.7 Hz) , 7.95 (1H, d, J = 7.9 Hz), 7.81 (1H, d, J = 7.9 Hz), 7.74-7.77 (2H, m), 7.49 (1H, s), 7.30 (1H, t, J = 7.9 Hz), 7.41 (1H, d, J = 7.4 Hz), 7.34 (1H, s), 6.38 (1H, d, J = 7.4 Hz), 2.70 (3H, s). TX / MC (M + H) ⁺ m / z 504 (t = 1.44 min).

Example 7

4-Aminobenzoic acid N- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-yl] hydrazide: ¹ H

NMR (300 MHz, CD3OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.76-7.79 (4H, m), 7.39 (1 Η, d, J = 7.4 Hz), 7.36 (1H, s) , 6.81 (2H, d, J = 8.6 Hz), 6.36 (1H, d, J = 7.4 Hz), 2.70 (3H, s). TX / MC (M + H) ⁺ m / z 441 (t = 0.96 min).

Example 8

(S) - 4- [2- (2-chlorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazole-

1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 © MHz, CD ₃ OD) δ 9.41 (1H, s), 8.05 (1H, narrow t, J = 1.7 Hz), 7.76 (1H, narrow t,

J = 1.7 Hz), 7.72 (1H, narrow d, J = 1.9 Hz), 7.08-7.36 (6H, m), 6.10 (1H, d, J = 7.7

Hz), 3.98-4.24 (1H, m), 3.84 (1H, dd, J = 4.4, 11.2 Hz), 3.79 (1H, dd, J = 4.8, 11.2

Hz), 3.35 (1H, dd, J = 5.4, 13.6 Hz), 3.09 (1H, dd, J = 7.8, 13.6 Hz), 2.72 (3H, s).

TX / MC (M + H) ⁺ m / z 457 (t = 1.56 min).

Example 9

(c) -4- [2- (3-chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-one: ¹ H NMR (300 MHz, CD3OD) δ 9.42 (1H, s), 8.07 (1 Η, narrow t, J = 1.7 Hz), 7.75-7.78 (2H, m),

7.14-7.37 (6H, m), 6.18 (1H, d, J = 7.7 Hz), 4.07-4.11 (1H, m), 3.76-3.77 (2H, m), 3.17 (1H, dd, J = 5.1, 13.7) Hz), 2.98 (1H, dd, J = 8.2, 13.7 Hz), 2.71 (3H, s). TX / MC (M + H) ⁺ m / z 475 (t = 1.75 min).

Example 10

(S) - 4- [2- (4-chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 9.42 (1H, s), 8.07 (1H, narrow t, J = 1.6 Hz), 7.77 (1H, narrow t,

J = 1.6 Hz), 7.73 (1H, narrow t, J = 1.9 Hz), 7.16-7.37 (6H, m), 6.19 (1H, d, J = 7.7 Hz), 4.06-4.10 (1H, m), 3.72 -3.77 (2H, m), 3.14 (1H, dd, J = 5.3, 13.8 Hz), 2.98 (1H, dd, J = 7.8, 13.8 Hz), 2.69 (3H, s). TX / MC (M + H) ⁺ m / z 475 (t = 1.61 min).

Example 11

(S) - 4- [2- (2-bromophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1 H -pyridin-2-one: ¹ H NMR (300 MHz, CD 3 OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.75-7.77 (2H, m), 7.52 (1H, dd,

J = 1.5, 7.5 Hz), 7.36 (1H, d, J = 1.9 Hz), 7.34 (1H, s), 7.03-7.16 (3H, m), 6.09 (1H, d, J = 7.7 Hz), 4.15- 4.27 (1H, m), 3.82 (2H, m), 3.35 (1H, dd, J = 5.0, 13.6 Hz), 3.10 (1H, dd, J = 9.0, 13.6 Hz), 2.74 (3H, s). TX / MC (M + H) ⁺ m / z 519 (t = 1.56 min).

Example 12

(S) - 4- [2- (3-bromophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2nd: ¹ H NMR

O (300 MHz, CDgOD) δ 9.41 (1H, s), 8.06 (1H, s), 7.74-7.77 (2H, m), 7.47 (1H, s),

7.24-7.31 (4H, m), 7.11 (1H, d, 3 = 7.7 Hz), 6.16 (1H, d, 3 = 7.7 Hz), 4.05-4.11 (1H.

m), 3.76 (2H, m), 3.15 (1H, dd, J = 5.0, 13.6 Hz), 2.96 (1H, dd, J = 8.3, 13.6 Hz), 2.70 (3H, s). TX / MC (M + H) ⁺ m / z 519 (t = 1.54 min).

Example 13

(±) -4- (1-Hydroxymethyl-2-pentafluorophenyl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ N.

NMR (300 MHz, CD3OD) δ 9.40 (1H, s), 8.06 (1H, narrow t, J = 1.8 Hz), 7.77 (1H, narrow t, J = 1.8 Hz), 7.74 (1H, narrow d, J = 1.8 Hz), 7.35 (1H, s), 7.29 (1H, d, J = 7.6)

Hz), 6.22 (1H, d, J = 7.6 Hz), 4.24 (1H, m), 3.82 (2H, dd, J = 2.6, 4.5 Hz), 3.23 (2H, t, J = 6.5 Hz), 2.70 ( 3H, s). TX / MC (M + H) ⁺ m / z 531 (t = 1.61 min).

Example 14

(S) -4- (1-Hydroxymethyl-2-pyridin-4-ylethylamino) -3- (6-imidazole-

1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (400 © MHz, CD ₃ OD) δ 9.42 (1H, s), 8.67 (2H, d , J = 6.6 Hz), 8.07 (2H, d, J = 6.6 Hz), 8.06 (1H, s), 7.77 (2H, s), 7.36 (1H, s), 7.28 (1H, d, J = 7). 6 Hz), 6.24 (1H, d, J = 7.6 Hz), 4.35 (1H, m), 3.82 (2H, d, J = 4.4 Hz), 3.50 (1H, dd, J = 4.4, 13.6 Hz), 3.40 (1H, dd, J = 8.7, 13.6 Hz), 2.71 (3H, s). TX / MC (M + H) ⁺ m / z 442 (t = 0.96 min).

Example 15

(S) - 4- (2-hydroxymethyl-2-naphthalen-2-ylethylamino) -3- (6-imidazole-

1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300

MHz, CD3OD) δ 7.99 (1H, t, J = 1.7 Hz), 7.26-7.75 (11H, m), 7.15 (1H, d, J = 7.6 Hz), 6.19 (1H, d, J = 7.6 Hz) ), 4.16-4.20 (1H, m), 3.75-3.86 (2H, m), 3.30 (1H, dd, J = 5.4, 13.6 Hz), 3.15 (1H, dd, J = 7.6, 13.6 Hz), 2.60 ( 3H, s). TX / MC (M + H) ⁺ m / z 491 (t = 1.71 min).

Example 16

(S) -4- (2-cyclohexyl-1-hydroxymethyl-ethylamino) -3- (6-imidazole-

1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 © MHz, CD ₃ OD) δ 9.40 (1H, s), 8.06 (1H, narrow t, J = 1.7 Hz), 7.76 (1H, narrow t,

J = 1.7 Hz), 7.73 (1H, narrow d, J = 1.7 Hz), 7.34 (1H, d, J = 7.6 Hz), 7.33 (1H, s), 6.34 (1H, d, J = 7.6 Hz). 3.89-3.94 (1H, m), 3.68 (2H, d, J = 4.9 Hz), 2.68 (3H, s), 1.62-1.83 (7H, m), 0.95 -1.26 (6H, m). TX / MC (M + H) ⁺ m / z 447 (t = 1.71 min).

Example 17

(3S, 4H) -4- (3-Hydroxy-2,2-dimethylchroman-4-ylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one: ¹ H NMR (300 MHz, CD 3 OD) δ 9.36 (1H, s), 8.02 (1H, narrow t, J = 1.7 Hz), 7.73 (1H, narrow t, J = 1.7 Hz) ), 7.69 (1H, narrow d, J = 2.0 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.18-7.30 (3H, m), 6.89 (1H, t, J = 7.6 Hz), 6.85 ( 1H, d, J = 8.4 Hz), 6.61 (1H, d, J = 7.6 Hz), 4.93 (1H, d, J = 8.2 Hz), 3.80 (1H, d, J = 8.2 Hz), 2.46 (3H. s), 1.48 (3H, s), 1.35 (3H, s). TX / MC (M + H) ⁺ m / z 447 (t = 1.70 min).

Example 18

3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (2-thiophen-2ylethylamino) -1H-pyridin-2-one: ¹ H NMR (500 MHz, DMSO-d ₆₎ δ 13.17 (1H, © br s), 11.32 (1H, br s), 11.03 (1H, br s), 9.59 (1H, br s), 8.22 (1H , br s), 7.91 ( 1H,

s), 7.82 (1H, d, J = 2.0 Hz), 7.41 (1H, t, J = 6.9 Hz), 7.36 (1H, dd, J = 1.0, 5.1 Hz), 7.30-7.40 (1H, m). 7.05 (1H, br s), 7.01 (1H, t, J = 4.2 Hz), 6.23 (1H, d, J = 7.5 Hz), 3.74 (2H, t, J = 6.5 Hz), 3.25 (2H, t. J = 6.5 Hz), 2.58 (3H, s).

Example 19

3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- [2- (1H-indol-3-yl) ethylamino] -1H-pyridin-2- it: ¹ H NMR (500 MHz, flMCO-d ₆ ) δ

13.17 (1H, br s), 11.27 (1H, br s), 11.00 (1H, br s), 10.89 (1H, s), 9.58 (1H, br s), 8.30 (1H, br s), 7.91 (1H , s), 7.80 (1H, s), 7.63 (1H, d, J = 7.9 Hz), 7.40 (1H, t, J = 6.9)

Hz), 7.34 (1H, d, J = 8.0 Hz), 7.30-7.40 (2H, m), 7.07 (1H, t, J = 7.5 Hz), 6.99 (1H, t, J = 7.6 Hz), 6.23 ( 1H, dd, J = 0.8, 7.2 Hz), 3.76 (2H, br s), 3.17 (2H, t, J = 6.7 Hz), 2.50 (3H, s).

Example 20

3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (pyridin-2ylmethoxy) -1H-pyridin-2-one: To a solution of 3- (6-imidazole- 1-yl-4methyl-1H-benzimidazol-2-yl) -4-iodine-1H-pyridin-2-one (25 mg, 0.06 mmol) in DMF (2 ml) was added pyridinecarbinol (26 mg, 0.24 mmol) and cesium fluoride (36 mg, 0.24 mmol). The reaction mixture was heated at 130 ° C for 14 hours and cooled to room temperature. After concentration in vacuo, the residue was purified by preparative HPLC to give the title compound (8.2 mg, 34%). ¹ H NMR (300 MHz, CD ₃ OD) δ 9.58 (1H, narrow d, J = 1.2 Hz), 8.92 (1H, d, J = 4.9 Hz), 8.19 (1H, narrow t, J = 1.2 Hz).

8.12 (1H, s), 7.97-8.02 (2H, m), 7.85 (1H, narrow t, J = 1.8 Hz), 7.81 (1H, narrow t,

J = 1.0 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.54 (1H, t, J = 6.2 Hz), 6.81. (1 H, J = 7.5 Hz),

5.86 (2H, s), 2.86 (3H, s). TX / MC (M + H) ⁺ m / z 399 (t = 1.07 min).

Example 21

(±) -4- [2- (3-bromophenyl) -2-fluoroethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz

CD ₃ OD) δ 9.40 (1H, t, J = 1.4 Hz), 8.06 (1H, t, J = 1.9 Hz), 7.76 (1H, t, J = 1.7 Hz)

7.72 (1H, d, J = 1.9 Hz), 7.66 (1H, s), 7.27-7.50 (5H, m), 6.29 (1H, d, J = 7.6 Hz), 5.75

-5.94 (1H, m), 3.86-4.06 (2H, m), 2.64 (3H, s). TX / MC (M + H) ⁺ m / z 507 (t = 1.70 min).

Example 22 (General Method for Examples 22-28)

(S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile:

To a solution of 2- (4-chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzimidazole-5-carbonitrile (0.7 g, 2.19 mmol) in DMF (15 ml) Nmethylmorpholine (0.66 g, 6.57 mmol) and (S) - (-) - 2-amino-3-phenyl-1-propanol (0.40 g, 2.63 mmol) were added. The reaction mixture was heated at 80 ° C for 6 hours and then cooled to room temperature. After concentration in vacuo, the residue was purified by flash chromatography (3% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.59 g, 68%) as a yellow foam. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.74 (1H, s), 7.63 (1H, s), 7.12-7.27 (6H, m), 6.07 (1H, d.

J = 7.5 Hz), 3.97 (1H, m), 3.74 (2H, t, J = 5 Hz), 3.14 (1H, dd, J = 5.5, 14.0 Hz), 2.94 (1H, dd, J = 7.9,14.0 Hz), 2.60 (3H, s). TX / MC (M + H) ⁺ m / z 400 (t = 1.71 min).

Example 23

Cl (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile : ¹ H NMR (300 MHz, DMSO-d6) δ 7.92 (1H, s), 7.59 (1H, s), 7.28-7.47 (5H, m), 6.19 (1H, d,

J = 7.3 Hz), 4.92-4.96 (1H, m), 3.53-3.73 (2H, m), 2.58 (3H, s). TX / MC (M + H) ⁺ m / z

420 (t = 1.99 min).

Example 24

(S) -2- {4- [2- (3-chlorophenyl) -1-hydroxymethylethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile:

¹ H NMR (400 MHz, CD ₃ OD) δ 7.86 (1H, s), 7.10-7.33 (6H, m), 6.12 (1H, d, J = 7.6 Hz), 4.01-4.05 (1H, m), 3.75 (2H, d, J = 4.9 Hz), 5.15 (1H, dd, J = 4.9, 13.5 Hz), 2.863.00 (1H, m), 2.63 (3H, s). TX / MC (M + H) ⁺ m / z 434 (t = 1.81 min).

Example 25

(+) - 2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-

1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.86 (1H, s), 7.75 (1H, s) , 7.67 (1H, s), 7.287.40 (2H, m), 6.95 (1H, d, J = 8.5 Hz), 6.24 (1H, d, J = 7.4 Hz), 4.93 (1H, m), 3.653. 97 (2H, m), 3.82 (3H, s), 2.57 (3H, s). TX / MC (M + H) ⁺ m / z 494 (t = 2.10 min).

Example 26

(±) -2- {4- [2- (3-fluorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile: ¹ H

NMR (400 MHz, CD ₃ OD) δ 7.70 (1H, s), 7.49 (1H, s), 7.22-7.32 (4H, m), 6.92 (1H, d, J = 7.2 Hz), 4.92 (1H, t , J = 6.3 Hz), 3.66 (2H, d, J = 5.9 Hz), 2.56 (3H, s). TX / MC (M + H) ⁺ m / z 404 (t = 1.65 min).

Example 27

© (±) -2- {4- [2- (3-bromophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile :

¹ H NMR (300 MHz, CD 3 OD) δ 7.92 (1H, s), 7.72 (1H, s), 7.26-7.50 (5H, m), 6.19 (1 Η,

Hz), 3.47-373 (2H, m), 2.58 (3H, s). TX / MC d, J = 7.1 Hz), 4.93 (1H, t, J = 4.3 (M + H) ⁺ m / z 464 (t = 2.00 min).

Example 28

(S) -2- [4- (2-hydroxy-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile: ¹ H NMR ( 400

MHz, CD3OD) δ 8.04 <1H, s), 7.74 (1H, s), 7.24-7.51 (6H, m), 6.22 (1H, d, J = 7.5)

Hz), 5.00 (1H, m), 3.64-3.74 (2Η, t), 2.60 (3H, s). TX / MC (M + H) ⁺ m / z 386 (t = 1.65 min).

Examples 29-35 were obtained from commercially available or readily available diamines, which were prepared and condensed with 4-iodine-2-methoxypyridine-3-carbaldehyde as described in Scheme 3.

Example 29

(±) -2- [4- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4,5,6trifluoro-1H-benzimidazol-2-yl) -1H-pyridin-2-one : ¹ H NMR (500 MHz, CD ₃ COCD ₃ ) δ 13.26 (1H, br s), 10.93 (1H, br s), 10.27 (1H, br s), 7.76 (1H, s), 7.547.56 (2H , m), 7.41-7.42 (1H, m), 7.06 (1H, d, J = 8.2 Hz), 6.29 (1H, d, J = 7.5 Hz), 5.05-5.07 (1H, m), 3.87 (3H. s), 3.74-3.79 (1H, m), 3.65-3.69 (1H, m).

Example 30

OMe (±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4,6-dibromo-1H-benzimidazol-2-yl) -1H-pyridin-2-one : ¹ H NMR (500 MHz,

CD3COCD3) δ 13.18 (1H, br s), 11.18 (1H, br s), 10.20 (1H, br s), 7.92 (1H, s), 7.78 (1H, s), 7.52-7.55 (3H, m). 7.03 (1H, d, J = 8.5 Hz), 6.28 (1H, d, 4 = 7.4 Hz), 5.06-5.08 (1H, m), 3.86 (3H, s), 3.73-3.77 (1H, m), 3.66 -3.70 (1H, m).

Example 31

(±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (5,6-dichloro-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (500 MHz, CD 3 COCD 3) δ 7.79 (3H, m), 7.53 (1H, dd, J = 2.0, 8.4 Hz), 7.41-7.44 (1H, m), 7.08 (1H, d, J = 8.4 Hz) ), 6.29 (1H, d, J = 7.5 Hz), 5.05-5.08 (1H, m), 3.89 (3H, s), 3.74-3.78 (1H, m), 3.70-3.72 (1H, m).

Example 32

(±) -3- (1H-benzimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one: ¹ H NMR (500 MHz, CD ₃ COCD ₃ ) δ 7.80 (1Η, s), 7.647.69 (2Η, m), 7.60 (1H, d, 4 = 7.7 Hz), 7.46-7.48 (2H, m), 7.33 (1H, t, J = 7.8) Hz), 7.19-7.22 (2H, m), 6.59 (1H, d, J = 4.5 Hz), 5.12-5.14 (1H, m), 5.13 (1H, dd, J = 4.5, 7.2 Hz), 3.82 (1H , dd, J = 4.5, 13.6 Hz), 3.71 (1H, dd, J = 7.2, 13.6 Hz).

Example 33

3- (1H-benzimidazol-2-yl) -4 - [(pyridin-2-ylmethyl) amino] -1H-pyridin-2-one: ¹ H NMR (500 MHz, CD ₃ COCD ₃ ) δ 8.96-8.98 ( 1H, m), 8.46-8.49 (1Η, m), 8.03 (1Η, d, J = 8.0 Hz), 7.93 (1H, t, J = 6.4 Hz), 7.69-7.73 (2H, m), 7.53 ( 1H, d, © J = 7.5 Hz), 7.28-7.32 (2H, s), 6.34 (1H, d, J = 7.5 Hz), 5.29 (2H, m).

Example 34

(S) -3- (1H-benzimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylamino) 1H-pyridin-2-one: ¹ H NMR (500 MHz, CD ₃ COCD ₃ ) δ 7.67-7.69 (2H, m), 7.15-7.44 (8H, m), 6.31 (1H, d, J = 7.5 Hz), 4.10-4.13 (1H, m), 3.76-3.82 (2H, m), 3.23 ( 1H, dd, J = 5.6,13.7 Hz), 3.04 (1H, dd, J = 8.1,13.7 Hz).

Example 35

OMe (±) -3- (1H-benzimidazol-2-yl) -4- [2- (3-bromo-4-methoxyphenyl) -2hydroxyethylamino] -1H-pyridin-2-one: ¹ H NMR (500 MHz , CD ₃ COCD ₃ ) δ

7.78 (1H, s), 7.68 (2Η, s), 7.50-7.55 (2H, m), 7.21-7.24 (2H, m), 7.06 (1H, d, J = 8.4 Hz), 6.44 (1H, d. J = 7.5 Hz), 5.08 (1H, dd, J = 4.6, 7.2 Hz), 3.87 (3H, s), 3.79 (1H, dd, J = 4.6, 13.4 Hz), 3.71 (1H, dd, J = 7.2 , 13.4 Hz).

Examples 36 to 43 were prepared according to Scheme V.

Example 36 (General Method for Examples 36-43).

HN

HE

(5) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazol-5yl} piperazine isopropylamide -1-Carboxylic acid: To a solution of (S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1 N-Pyridin-2-one (30 mg, 0.063 mmol) in methanol (2 ml) was added isopropyl isocyanate (2 drops). The reaction mixture was stirred for 5 minutes at room temperature. Concentration afforded a residue which was purified by preparative HPLC to afford the title compound (23.8 mg, 69%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.14-7.28 (7H, m), 6.12 (1H, d, J = 7.8 Hz), 4.01-4.03 (1H, m), 3.92 (quintet, J = 6.6 Hz ), 3.80 (4H, m), 3.76 (1H, dd, J = 4.8, 11.2 Hz), 3.70 (1H, dd, J = 5.2, 11.2 Hz), 3.61-3.64 (4H, m), 3.09 (1H. dd, J = 5.6,13.7 Hz), 2.91 (1H, dd, J = 8.0,13.7 Hz), 2.64 (3H, s), 1.19 (6H, d, J = 6.8 Hz). TX / MC (M + H) ⁺ m / z 545 (t = 1.99 min).

Example 37

(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazol-5-yl} piperazine-ethyl ethylamide -carboxylic acid: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.55 (1H, s), 7.12-7.28 (7H, m), 6.12 (1H, d, J = 7.8 Hz), 4.01-4.05 (1H, m), 3.62-3.81 (10H, m), 3.24 (2H, q, J = 7.2 Hz), 3.08 (1H, dd, J = 5.6, 13.7 Hz), 2.91 (1H, dd, J = 8.0, 13.7 Hz) ), 2.65 (3H, s), 1.14 (3H, t, J = 7.2 Hz). TX / MC (M + H) ⁺ m / z 531 (t = 1.93 min).

Example 38

(5) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- {4-methyl-6- [4- (1-phenylmethanoyl) -piperazin-1-yl] 1H-benzimidazol-2-yl} -1H -pyridin-2-one: To a solution of (S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- (4methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1 N-Pyridin-2-one (30 mg, 0.063 mmol) in methanol (2 ml) was added benzoyl chloride (1 drop). The reaction mixture was stirred for 5 minutes and concentrated. The residue was purified by preparative HPLC to afford the title compound 96 (11 mg, 33%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.54 (5H, m), 7.37 (1H, s),

7.13-7.26 (7Η, m), 6.08 (1H, d, J = 7.7 Hz), 3.79-4.02 (5H, m), 3.76 (1H, dd, J = 4.7.

11.2 Hz), 3.67 (1H, dd, J = 5.7, 11.2 Hz), 3.54 (4H, m), 3.03 (1H, dd, J = 5.7,13.7 Hz),

2.89 (1H, dd, J = 8.0, 13.7 Hz), 2.62 (3H, s). TX / MC (M + H) ⁺ m / z 563 (t = 2.19 min).

Example 39

(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (4-isopropylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -1H-pyridine- 2-one: To a solution of (3) -4- (1-hydroxymethyl-2-phenylethylamino) -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridine -2-one (25 mg, 0.054 mmol) in methanol (0.5 ml) was added acetone (0.25 ml) and 1M THF NaHCO ₃ solution (0.2 ml). The reaction mixture was stirred for 1 hour at room temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 44%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.10-7.24 (6H, m), 7.08 (1H, s), 7.06 (1 Η, s), 6.06 (1 Η, d, J = 7.9 Hz), 3.58 -4.01 (10H, m), 3.34 (1H, m), 3.14 (1H, m), 2.98 (1H, dd, J = 5.9, 13.7 Hz), 2.83 (1H, dd, J = 7.9, 13.7 Hz). 2.60 (3H, s), 1.44 (6H, d, J = 6.7 Hz). TX / MC (M + H) ⁺ m / z 501 (t = 1.80 min).

Example 40

(S) -3- [6- (4-Benzylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -

4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.57 (6H, m), 7.04-7.27 (7H, m), 6.07 (1H, d, J = 7.8 Hz), ® 4.22 (2H, s), 3.97-4.00 (1H, m), 3.34-3.77 (2H, m), 2.82-3.04 (10H, m), 2.58 (3H , s).

TX / MC (M + H) ⁺ m / z 549 (t = 1.93 min).

Example 41

(±) -3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -

4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD 3 OD) δ 7.50 (1H, s), 7.25-7.49 (5H, m) , 7.20 (1H, s), 6.25 (1H, d, J = 8.0 Hz), 4.94 (1H, dd, J = 4.6, 7.1 Hz), 3.88-3.92 (4H, m), 3.50-3.65 (6H, m ), 2.62 (3H, s), 2.20 (3H, s). TX / MC (M + H) ⁺ m / z 521 (t = 2.13 min).

Example 42

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2 -one: ¹ H NMR (400 MHz,

CD ₃ OD) δ 7.47 (1H, s), 7.25-7.38 (4H, m), 7.07 (2H, s), 6.25 (1H, d, J = 7.6 Hz), 4.90 (1H, m), 3.42-3.66 (10H, m), 2.59 (3H, s). TX / MC (M + H) ⁺ m / z 479 (t = 1.90 min).

Example 43

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4-isopropylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -1 H-pyridin-2-one:

¹ H NMR (400 MHz, CD 3 OD) δ 7.47 (1H, s), 7.25-7.38 (4H, m), 7.06 (2H, s), 6.26 (1 Η, d, J = 7.6 Hz), 4.91-4.93 ( 1H, m), 3.89-3.92 (2H, m), 3.51-3.64 (5H, m), 3.31-3.37 (2H, m), 3.09-3.30 (2H, m), 2.59 (3H, s), 1.44 ( 6H, d, J = 6.6 Hz). TX / MC (M + H) ⁺ m / z

521 (t = 1.95 min).

Example 44

(S) -6- (1-Hydroxymethyl-2-phenylethylamino) -5- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -3H-pyrimidin-4-one: (5) -2- [6-chloro-5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) pyrimidin-4-ylamino] -3-phenylpropan-1-ol: To a solution of 2- (4,6-Dichloropyrimidin-5-yl) -6-imidazol-1-yl-4-methyl-1H-benzimidazole (40 mg, 0.16 mmol) in isopropanol (5 ml) was added (N - (-) - 2- amino-3-phenylpropanol (35 mg, 0.23 mmol) and triethylamine (0.5 ml) The reaction mixture was heated at 80 ° C for 4 hours, cooled to room temperature and concentrated under high vacuum. purified nd. LC / MS (M + H) ⁺ m / z 460 (t = 2.13 min).

(S) -6- (1-Hydroxymethyl-2-phenylethylamino) -5- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -3H-pyrimidin-4-one: To a solution of ( 5) -2- [6-chloro-5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) pyrimidin4-ylamino] -3-phenylpropan-1-ol in 4N HCl (0.5 ml) and acetic acid (0.5 ml) were added two drops of water. The reaction mixture was heated at 100 ° C for 8 hours, cooled to room temperature and neutralized with ammonia in methanol. After concentration, the residue was purified by preparative HPLC to give the title compound (26 mg, 37% for both steps). ¹ H NMR (400 MHz, CD ₃ OD) δ 9.41 (1H, narrow t, J = 1.5 Hz), 8.06 (1H, narrow dd, J = 1.6, 1.9 Hz), 7.93 (1H, s), 7.77 (1H , narrow dd, J = 1.6, 1.8 Hz), 7.73 (1H, narrow d, J = 1.9 Hz), 7.11-7.21 (6H, m), 4.70-4.74 (1H, m), 3.74 (2H, d, J = 4.7 Hz), 3.11 (1H, dd, J = 6.1, 13.5 Hz), 3.00 (1H, dd, J = 7.8, 13.5 Hz), 2.70 (3H, s). TX / MC (M + H) ⁺ m / z 442 (t = 2.17 min).

Examples 45-383 were prepared according to the general methods described above (Scheme III)

TX / MS conditions:

a) YMC C18 S5 4.6 x 50 mm; 0-100% gradient in 4 min *; flow rate (flow rate) 4 ml / min;

100

b) YMC ODS-A C18 S7 3.0 x 50 mm; 0-100% gradient in 2 min *; flow rate 5 ml / min;

c) YMC C18 S5 4.5 x 50 mm; 0-100% gradient in 8 min *; flow rate 2.5 ml / min;

d) YMC C18 S7 3.0 x 50 mm; 0-100% gradient in 3 min *; flow rate 5 ml / min;

e) YMC ODSA S3 6.0 x 150 mm; 0-100% gradient in 5 min *; flow rate 1.5 ml / min;

f) PHS-PRIMESPHERE C18 4.6 x 30 mm; 0-100% gradient in 2 min *; flow rate 5 ml / min;

g) YMC C18 S7 3.0 x 50 mm; 0-100% gradient in 4 min *; flow rate 5 ml / min;

h) YMC ODS-A C18 S7 3.0 x 50 mm; 0-100% gradient in 2 min *; flow rate 5 ml / min;

i) YMC ODS-A C18 S7 3.0 x 50 mm; 0-100% gradient in 1.5 min *; flow rate 5 ml / min;

j) YMC Xterra C18 S7 3.0 x 50 mm; 0-100% gradient in 2 min *; flow rate 5 ml / min;

k) YMC Pro-ODS C18 S5 4.6 x 33 mm; 0-100% gradient in 3 min *; flow rate 4 ml / min;

l) YMC ODS-A C18 S7 3.0 x 50 mm; 0-100% gradient in 4 min *; flow rate 4 ml / min;

* Gradient begins with 10% methanol / 90% water (0.1% trifluoroacetate) and finishes with 90% methanol / 10% water (0.1% TfO).

101

Etc. No. Name Structure T (min) MS (M + H) ⁺ m / z 45 4- (2-fluorobenzylamino-3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one γΑ-ι? • ΗΝ d- ^F 1.43 (I) 415 46 4- (3,4-dimethoxybenzylamino-3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one AvO / V I HN ί / MeO OMe 1 -37 (I) 457 47 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- [pyridin2-methyl) amino] -1H-pyridin-2-one 0 n 0 Χ-ΝΗ I ΗΝ 2.17 (a) 398 48 (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one I ΗΝ / = \ ^0H 1.48 (b) 441 49 (R) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) 1H-pyridin-2-one Q n h V. he V? 1.48 (b) 441 50 N- {2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4ylamino] ethyl} acetamide ΑνΟα 1.55 (I) 392

102

51 4- (3,4-dihydroxybenzylamino) - 3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1-pyridin-2-one He is 0 B — NH M-nO-Y me but him 1 -97 (I) 429 52 4- [2- (3H-imidazol-4-yl) ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one C / GOHH V-NH να V 1.91 (a) 401 53 4- (3,4-dihydro-2H-quinolin-1-yl) - 3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1-pyridin-2-one N = \ Q / ~ H ^N 1.88 (a) 423 54 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(pyridin3-ylmethyl) amino] -1H-pyridin-2one ο 1.83 (a) 398 55 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(pyridine- 4-ylmethyl) amino] -1H-pyridin-2one β 1.74 (a) 398 56 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(2-pyridin-2-ylethyl) amino] -1H-pyridin-2-one , ^Ν = \ 0 Μ-ΧΛα ъ 1.99 (a) 412 57 4- [Benzyl- (2-hydroxyethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Ν · = \ ⁰ B-MH να but — X 1.86 (a) 441

103

58 (+) - 4- [1- (4-chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one ν · = \ 0 _VNH HN γΟ ^η сг 3.3 (a) 461 59 (±) -4 - [(1-ethylpyrrolidin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one , ^Ν · = \ _u 0 I HN 1.88 (a) 418 60 (1R, 2S) -4- (2-Fluoro-CH-1-methyl-2-phenylethylamino) -3- (6-imidazol-1-yl) -4-methyl-1H-benzimidazol-2-yl) -1H -pyridin-2-one , ^N = \ 0 V “NH I HN .OH 3.01 (a) 441 61 (±) -4- (2-hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) 1H-pyridin-2-one / ^{N =} \ H f / x X Xnh I HN .OH b 2.96 (a) 427 62 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (3-imidazol-1-ylpropylamino) -1H-pyridin-2-one N = x ο ^ ⁿ \ ^h Fg HN 'X / ^ N v 1.94 (a)  415 63 (S) -4- (2-Hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) 1H-pyridin-2-one Ν · = \ o 4 ^ N ^ X4p-N KnH dr HN θ ^Η ъ 1.27 (b) 427 64 (R) -4- (2-Hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) 1H-pyridin-2-one N = \ o φ-ΝΗ I HN _9 ^H 1.27 (b) 427

104

65 (±) -4- (1-Benzylpyrrolidin-Zylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Ν = \ o __> - ΝΗ Uh-h 1.19 (b) 466 66 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- [2- (5-nitropyridin-2-ylamino) ethylamino] -1H-pyridin-2-one n H> -ΝΗ Ά _ / ^{N =} \ ^HN V / ^N0 2 1.37 (b) 472 67 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (2-morpholin-4-ylethylamino) -1H-pyridin-2-one 0 B-NH I HN A D 0 0.98 (b) 420 68 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- [2- (2-methyl-5-nitro-1H-imidazol-2-yl) ethylamino] -1H-pyridine- 2-it Ν · = λ o HN A / Ο ,, Ν ^ Α / Ν 1.31 (b) 460 69 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- [2- (3-methyl-5-nitro-3H-imidazol-4-yl) ethylamino] -1H-pyridin-2 -on Ν · = \ ⁰ b ' 0.97 (b) 415 70 (±) -4- (4-Diethylamino-1-methylbugylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) 1H-pyridin-2-one 1.13 (b) 448 71 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (2-pyrrolidin-1-ylethylamino) -1H-pyridin-2-one I HN uh 0.87 (b) 404

105

72 (+) - 4- (1,2-diphenylethylamino) -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ν · = \ о WG ΗΝ 1.72 (b) 487 73 4-Benzylamino-3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one Ν - = \ ⁰ C Az / X / N> -νη ^{τ ην} α> 1.49 (b) 397 74 4- (3-dimethylamino-propylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Ν = \ 0 I ΗΝ 1.03 (b) 392 75 4 - [(adamantan-1-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1 N-pyridin-2-one Hsf ^τ ™ α 1.87 (b) 455 76 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (indan-2ylamino) -1H-pyridin-2-one I ΗΝ 1.57 (b) 423 77 4- (3,5-Bis-trifluoromethylbenzylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Ν = \ ⁰ Χ ^Ν \ ^Η pAD ^{1 n} p <^ cf ₃ 1.68 (b) 533 78 (±) -4- (1,1-dioxotetrahydro-1 X ⁶ -thiophen-3-ylamino) -3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1 N-pyridin-2- he 1 ΝΗ ύ // \ 0 0 1.03 (b) 425

106

79 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (3,4,5-trimethoxybenzipamino) -1H-pyridin-2-one OMe OMe OMe 1.33 (b) 487 80 4 - [(furan-1-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1-pyridin-2-one Ν = \ o HN US 1.34 (b) 387 81 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(thiophen-2-ylmethyl) amino] -1H-pyridin-2one HN D) 1.42 (b) 403 82 3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -4- [3- (2-oxopyrrolidin-1-yl) propylamino] -1H-pyridin-2-one / ^{N =} \ _H q> -NH AND HN 0 1.15 (b) 432 83 4 - [(1H-benzimidazol-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one _Z ^{N =} \ _H o y-NH ^{T HN} 4O H 0.98 (b) 437 84 4- [2- (6-fluoro-1H-indol-2yl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one / ^{N =} \ H Rk HN fc. 1.53 (b) 468 85 {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} carbamic acid benzyl ester 4 ° uh 1.31 (b) 484

107

86 (15,2J) -4- (2-Hydroxy-1,2-diphenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one about NH ΊΓ ΗΝ but— 1.42 (b) 503 87 (±) -4- (2- [1,3] dioxolan-2-ylethylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Ν = \ ο ΗΝ 1.24 (b) 407 88 (±) -2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -3-phenylpropionic acid methyl ester , ^Ν = \ ο ΗΝ MeOOC ΛΛ 1.44 (b) 469 89 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (2-2H- [1,2,3] triazol-2-ylethylamino) - 1 H-pyridin-2-one Ν = λ ο ΗΝ ^ Αι-ν ο 1.05 (b) 402 90 (±) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(1-phenyl-1-pyridin-2-ylmethyl) amino] -1H-pyridine- 2-it Ν = \ 0 > -ΝΗ C ^ -N ^ / 1.35 (b) 474 91 (1R, 25) -4- (1-Hydroxyindan-2ylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Ν = \ 0 I ΗΝ ₄ ΟΗ 1.35 (b) 439

108

92 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4-phenethylamino-1H-pyridin-2-one Ν = λ 0 I HN a 1.51 (b) 411 93 (±) -4- [2-hydroxy-2- (3-hydroxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he Ν = \ o A ^N \ HN 0-oh 1.15 (b) 443 94 (S) -4- [1-Hydroxymethyl-2- (4-hydroxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -on Φιφ I Hr / ^{but -} SL ^- Λη 1-1 (b) 457 95 (R) -4- (2-Hydroxy-2-pyridin-2ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2- yl) -1H-pyridin-2-one ⁰ I HN> OH a 1.09 (a) 428 96 (S) -4- (2-Hydroxy-2-pyridin-2ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one / ^{N =} \ ⁰ V NH όφΑ I HN fn \ = - N 1.09 (a) 428 97 (S) -4- (2-Benzylsulfanyl-1 hydroxymethyl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one fff I HN 1 -4 (b) 487

109

98 4- (2-hydroxyethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one HH I ΗΝ Mon. 0.93 (b) 351 99 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) - [methyl- (2-pyridin-2-ylethylamino] -1-pyridin-2-one Ν · = \ o 4νη hours 0.43 (b) 426 100 (S) -4- (1-Hydroxymethyl-2-pyridin-2-ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1-pyridin-2-one hh I ην / ° ⁿ 0.93 (f) 442 101 (R) -4- (1-Hydroxymethyl-2-pyridin-2-ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1-pyridin-2-one hh I ΗΝ QA 0.94 (f) 442 102 dimethylamino- (6-imidazol-1-yl- 4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one hh And —N \ 0.70 (f) 335 103 (1S, 2b) -4- (2-hydroxy-1-hydroxymethyl-2-phenylethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one N - = \ Q ΗΝ _χ ΟΗ HO— 1.10 (b) 457

110

104 (±) -4- [2-hydroxy-3- (naphthalen-1-yloxy) propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one _Z ^{N =} \ n o I ΗΝ .OH 1.53 (b) 507 105 (1R, 2H) -4- (2-Benzyloxy-1 hydroxymethyl-propylamino) -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one I ΗΙ4 3.14 (a) 485 106 (4-3-Hydroxy-2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] propionic acid benzyl ester ΥνΗ ΗΝ СР ° ^ ^ОН 2.95 (a) 485 107 (4-3-Hydroxy-2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] propionic acid methyl ester Ν = \ ⁰ I ΗΝ \) Η ⁷ Ο 1.29 (a) 409 108 (S) -2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4-ylamino] -3-pyridin-2-yl propionic acid YrAb I ng / .OH ^ -Ν 0.94 (f) 456 109 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (pyridin3-ylamino) -1H-pyridin-2-one I ΗΝ b 1.15 (a) 384

111

110 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (pyridine- 4-ylamino) -1H-pyridin-2-one Ν - = \ o AA I ΗΝ B ^ -N 0.65 (f) 384 111 (S) -4- [2- (3,4-dihydroxyphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it / ^{Ν =} \ η R AyV Λ “ ^Ν \ CDD S-D I ΗΝ .ΟΗ Ο ~ ^0Η ΌΗ 1.04 (b) 459 112 (S) -4- [1-Hydroxymethyl-2- (3-methylbenzylsulfanyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ΑΑ I ΗΝ A ^S ^ ^OH 1.49 (b) 501 113 (S) -4- [1-Hydroxymethyl-2- (4methylbenzylsulfanyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ΑΑ I ΗΝ / = \ jA \ h 1.49 (b) 501 114 (±) -4- [2-hydroxy-2- (4-hydroxy3-methoxyphenyl) ethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2- he TEA I nAAA (A- ° Me ΌΗ 1.10 (b) 473 115 4- (2-hydroxy-2-naphthalen-1-ylethylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one A _n o Αγγ / ⁿ \ CDD S-D 1.49 (b) 477

112

116 (ό) -ΛΑ (1-Carbamoyl-2-phenylethyl) -3-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4 -ylamino] propionamide I Hh0P ^H / = \ NO-'HN— \ - ^NH 2 1.07 (b) 541 117 (±) -N- (4 '- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino ] ethyl} biphenyl-2-yl) methanesulfonamide but— / h / nhso ₂ ch ₃ \ _) 1.34 (b) 596 118 (±) -N- (4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} phenyl and l) methanesulfonamide T NG R ⁿ k NHSOCH3 1-11 (b) 520 119 (±) -N- (3- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} phenyl) methanesulfonamide n °% U-nM_7 I Hli P ”/) —NHSO ₂ CH ₃ 1.14 (b) 520 120 (±) -N- (5- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} -2-methoxyphenyl) methanesulfonamide / ^{N =} \ ч rh> -NH kA? y_? I HN, ^0H / ύ-NHSO ₂ CH ₃ OMe 1.12 (b) 550

113

121 (±) -N- (2- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydrolyridin-4-ylamino] ethyl} phenyl) methane-sulfonamide / ^{N =} \ N H V-NH Τ HN / ^0H V- / NHSO ₂ CH3 Q 1.19 (b) 520 122 (±) -N- (3- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} phenyl) -4-methylbenzenesulfonamide Τ HN, ^W _p 1.33 (b) 596 123 (±) 2,2,2-Trifluoro-N- (3- {1 hydroxy-2- [3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) 2-oxo-1 , 2-dihydropyridin-4-ylamino] ethyl} phenyl) acetamide n S / - ^Ν _χ ^Η 1 HNjy ^0H <jJnhcocf ₃ 2.97 (a) 538 124 (±) -N- (2-chloro-5- {1-hydroxy-2- [3 (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridine -4-ylamino] ethyl} phenyl) methanesulfonamide / ^{N =} \ H H Κνη y_V T HN I ^H ζ Vnhso ₂ ch ₃ 2.75 (a) 554 125 (±) -N- (5- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} -2-methylphenyl) methanesulfonamide / ^{N =} \ H 4 ^{J- NH T hnJ / 0H jY-} NHSO ₂ CH ₃ 2.73 (a) 534

114

126 (S) -2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4-ylamino] -3-phenylpropionic acid I HN ⁷ / = 4 —COOH 1.50 (f) 455 127 (S) -2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4-ylamino] -Nomethyl-3-phenyl propionamide J / b I HN. P 1.43 (f) 468 128 (S) -2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4-ylamino] -3-phenyl propionamide I HN ⁷ P ^NHg 1.39 (f) 454 129 (S) -2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4-ylamino] -1M, N-N-dimethyl -3-phenyl propionamide I hnl ~ P CH; ⁿ - 1.48 (f) 482 130 (R) -4- (2-Hydroxy-1-phenylethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) 1H-pyridin-2-one I HN 1.44 (f) 427 131 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (3-pyridin-1-yl-propylamino) -1H-pyridin-2-one Ν · = \ ⁰ TXrp I HN 1 -0 (b) 426

115

132 (S) -4- (1-Benzyl-4-hydroxy-2-oxobutylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ^N = \ ^{0 he} 1 -41 (f) 483 133 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (4-pyridin-1-yl-n-butylamino) -1H-pyridin-2-one N = \ 0 __V-NH 'HN A 1.06 (d) 440 134 (S) -4- (1-Aminomethyl-2-phenylethylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one N - = \ 0 As-f I Hl / 1 -27 (f) 440 135 (O) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (1-methylamino-nomethyl-2-phenyl-ethylamino) -1H-pyridin-2- he AF I Hl / 1 -27 (f) 454 136 (S) -4- (1-Dimethylaminomethyl-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Ab I Hl / - 1.25 (f) 468 137 4- (4-hydroxybutylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Ν · = \ o HN 1.19 (f) 379 138 (±) -4- [2-hydroxy-2- (3-trifluoromethylphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -on N = \ 0 C / M-uA_V-NH ΊΑ HN O “ ^CF 3 1.40 (b) 495

116

139 (±) -4- [2-hydroxy-2- (3,4,5-trimethoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1 H -pyridin-2-one / ^{Ν =} \ N H Κνη I ng / pH \ __ / OMe Q- ° ^Me OMe 1.18 (b) 517 140 (S) -4- (1-Benzyl-2-methoxyethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benz-imidazol-2-yl) - 1 H-pyridin-2-one I HN cX- 1.67 (f) 455 141 4- (3-hydroxypropylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one fsf I HN ^X \ —OH 0.95 (f) 365 142 (±) -4- [2-hydroxy-1- (4-nitrobenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benz-imidazol-2yl) -1H-pyridine- 2-it Xxx I HN ^0Ν 2 ~ ζ ^ \) H 1.51 (a) 486 143 (±) -4- [1- (2-fluorobenzyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he N - = \ 0 AH I ΗΝ q-X 1.57 (a) 459 144 (±) -4- [1- (3-fluorobenzyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he ν - = \ 0 Xxx I ΗΝ qX V 1.57 (a) 459

117

145 (S) -4- [2-hydroxy-1- (4-methoxybenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he I ΗΝ MeO— \ ° ^N 1.54 (a) 471 146 (±) -4- [2-hydroxy-1- (3-hydroxybenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he B / W I HN but 1.38 (a) 457 147 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(isoquinolin-3-ylmethyl) amino] -1H-pyridin-2-one Ν · = \ 0 ύΡ 1.15 (d) 448 148 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - {[4- (3-phenylpropyl) pyridin-2-ylmethyl] amino} -1H-pyridin-2-one / ^{Ν =} \ ο 1.31 (d) 516 149 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(3methyl pyridin-2-ylmethyl) amino] -1H-pyridin-2-one ί ην \ Ν- \ r 1.00 (d) 412 150 4 - [(3,5-dimethylpyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one , ^Ν = \ 0 V 1.00 (d) 426

118

151 4 - [(3-hydroxymethylpyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Ν = λ 0 I ΗΝ Ν · = \ HOHgC 0.93 (d) 428 152 (O) -4- [2-hydroxy-1- (4-hydroxy3-nitrobenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he N = \ 0 I HN. ^ho_ \ ° ^{h he} ₂ 1.47 (a) 486 153 (S) -4- [2-trifluoromethyl-1- (4-iodbenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -on I HN. ^l— \ ° ^H 1.73 (a) 567 154 (O) -4- [2-hydroxy-1- (4-hydroxy- 3-Iodbenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one <Js ^ / N XNH AND ^{HN_ H0_} 1.44 (a) 583 155 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(6-methylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one I hn nV 43 0.71 (b) 412 156 4- [2- (5-ethylpyridin-2-ylethyl) amino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Ovv ⁵¹ X 1 HN 4 1.01 (b) 440

119

157 (±) -4- (2,3-dihydroxypropylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one , ^N = \ 0 I HN PH \ —OH 1.11 (a) 381 158 (S) -4- [2-hydroxy-1- (4-hydroxy-3-methoxybenzyl) ethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it Ν = \ Η 4 <Υνη I ΗΝ. MeO 1.29 (f) 491 159 (S) -4- [1- (4-fluorobenzyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it ι ΗΝ. ^F— 1.57 (a) 459 160 (S) -4 - [- 2-hydroxy-1- (naphthalen-1-ylmethyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H -pyridin-2-one Ν = \ 0 In-NH I ΗΝ. 1.71 (a) 491 161 4- (2-hydroxy-1-hydroxymethylethylamino) -3- (6-imidazol-1-yl4-methyl-1H-benz-imidazol-2-yl) 1H-pyridin-2-one hh I ΗΝI / ^one "A 1.00 (f) 381 162 4- [2-hydroxy-1- (1,1-bis-hydroxymethyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he IZ Z o 0.89 (f) 411

120

163 (±) -4- [2- (3-fluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he / ^{Ν =} \ H Rx Κνη I hnQph VJ * ^{- F} 1.38 (b) 445 164 (±) -4- [2-hydroxy-2- (3-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he / ^{N =} \ H Rx B-nh I Hi / ”P ⁿ 0n-OMe 1.35 (b) 457 165 (±) -4- [2-hydroxy-2- (4-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he Ν = \ ο ζ / ΝηΡγΝ _> - ΝΗ HN P ^H 3 OMe 1.35 (b) 457 166 (±) -4- (2-hydroxy-3-phenylpropylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Ν · = \ ο ζ ^ Ν ^ / 4 / NV — ΝΗ l ^ ^N HN ^ PH 1.44 (b) 441 167 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(3-trifluoromethylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one Ν = λ ⁰ HN Ν—, '-jj F ₃ c / 1.53 (d) 466 168 4 - [(6-ethoxy-pyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one , ^N = \ 0 ο- / I HN N - = / 4_> 1.51 (d) 442

121

169 4 - [(4-chloropyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Q 1 ΗΝ Ν ^ \ Cl 1.38 (d) 432 170 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(4-phenylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one N = \ ⁰ A p ^N .H V-Fr. 1.24 (d) 474 171 3- (6-imidazol-1-yl-4-methyl-1 Nbenzimidazol-2-yl) -4 - [(4-benzyloxypyridin-2-ylmethyl) amino] -1H-pyridin-2-one N = \ ⁰ 1 HN lA 1.14 (d) 504 172 (2S, 3S) - {2hydroxy-3- [3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) 2-oxo-1,2-dihydropyridin-4ylamino] benzyl ester - 4-Phenylbutyl} carbamic acid T Hpy ^0H 1.59 (f) 604 173 (S) -4- [1- (4-Benzyloxybenzyl) -2hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he N = \ 0 C / Navn B ^- H ⁿ 1 H hi VJ / 1 -74 (f) 547 174 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(4-methylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one Ν = \ ⁰ C NH Λ- <, 'A Ν— 0.95 (d) 412

122

175 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(4-methoxypyridin-2-ylmethyl) amino] - 1 H-pyridin-2-one N = \ Q Y_U OMe ⁿ M Ν— 0.92 (d) 428 176 4 - {[6- (3-hydroxypropyl) pyridin-2-ylmethyl] amino} -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it N - = \ Q) -nh IXHJ / 0H ι hn nJ 0.96 (d) 456 177 4 - [(6-Aminomethyl-pyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one And HN N = < 0.99 (b) 427 178 N - (6 - {[3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4-ylamino] methyl} pyridin-2-ylmethyl ) formamide N = \ ⁰ J- NH \ Zn ^ —NHCHO AND HN N ^ Z 1.02 (b) 455 179 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(quinolin-2-ylmethyl) amino] -1H-pyridin-2one , ^N = \ o ζ ^ Νγ ^ Ν ^ _) - NH 1.16 (b) 448 180 4- (2-cyclohex-1-enyl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ° oZ> I HN uh 1.61 (b) 415

123

181 (B) -4- [2- (4-tert-butoxyphenyl) -1hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -on Ν = χ about Sk / C! I I ΗΝ ° ⁿ “A 1.61 (f) 513 182 (±) -4- [2- (2,3-dichlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he Ανφ I HN / ^He CH 1.52 (b) 495 183 (±) -4- [2- (3,4-difluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he , ^{N =} \ _N 0 S-NH I ΗΝ / ^one A. 'F 1.34 (b) 463 184 (S) -4- [2- (3,4-Dichlorophenyl) -1 hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -on I HN ^{7 Cl—} ^^ Λ) Η 1.67 (f) 509 185 (4- {1- [Hydroxymethyl-2- (4-hydroxy-2-trifluoromethylphenyl) ethylamino] -3- (6-imidazol-1-yl4-methyl-1H-benz-imidazol-2-yl) - 1 H-pyridin-2-one ΥχΦ I HN ^ CF ₃ 1.46 (f) 525 186 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(isoquinolin-1-ylmethyl) amino] -1H-pyridin-2-one ^HN Cg 1.14 (d) 448

124

187 (S) -4- [2- (3,4-difluorophenyl) -1 hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -on I HN_ F 1.52 (f) 477 188 4 - [(4-hydroxypyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benz-imidazol-2yl) -1H-pyridin-2-one I HN N - = \ OH 0.91 (d) 414 189 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (piperidin-1-ylethylamino) -1H-pyridin2-one I HN uh 0.92 (b) 418 190 (±) -4- (2-hydroxy-2-p-tolyl-ethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benz-imidazol-2-yl) - 1 H-pyridin-2-one T HN ^ / ^0H - 5.74 (c) 441 191 4- [2- (3,5-Bis-trifluoromethylphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1 Hbenz-imidazol-2-yl) -1 N-pyridin-2-one 0 A o J ” 6.40 (c) 563 192 (±) -4- [2- (3-chlorophenyl) -2-methoxyethylamino] -3- (6-imidazol-1-yl4-methyl-1H-benz-imidazol-2-yl) - 1 H-pyridin-2-one \ An ^ y_Z | HN / ^0Me C> ^CI 6.5 (c) 475

125

193 4 - [(4-hydroxymethyl-pyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benz-imidazol-2-yl) -1H-pyridin-2-one A _n o VyA h \ ⁿ 1 ΗΝ 0.9 (b) 428 194 (±) -4- [2- (3,5-dichlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he AA T hnA ^0H A 1.54 (b) 495 195 (±) -4 - [(4-tert-butyl-1-hydroxycyclohexylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it / A Η Α _(μ Un 3.82 (a) 475 196 (±) - {2-hydroxy-3- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-t-butyl ester ylamino] propyl} carbamic acid / A n h vyv / ⁿ \ cd-r? MC 1 HN / ^one hour '-NH Al ⁰ A 1.23 (b) 480 197 (±) -3- (6-imidazol-1-yl-4-methyl-1H-benz-imidazol-2-yl) -4- (3,3,3-trifluoro-2-hydroxypropylamino) -1H-pyridin-2-one AA T ΗΝ1 / ^He h 1.17 (b) 419 198 (±) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it T H'H t> ^C1 t 1.40 (b) 479

126

199 (±) -4- (2-hydroxy-2-m-tolylethylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one a .0 1.37 (b) 441 200 (S) -4- (1-Hydroxymethyl-3-phenylpropylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benz-imidazol-2yl) -1H-pyridin-2-one / ^Ν = \ _n o I HN. / ^Z OH 1.56 (f) 455 201 (S) -4- (1-Hydroxymethyl-2-pyrrolylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benz-imidazol-2-yl) -1H-pyridin-2-one 1 H 1 \ / -C =) ^> ° ^H 1 -57 (f) 455 202 (S) -4- [2- (3-fluorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he 1 HN O-Ah 1.48 (f) 459 203 (1S, 2H) -4- (1-Benzyl-2,4-dihydroxybutylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one , ^N = \ _H 0> -NH AAj oh 1 hn _> - 'ryd 1.39 (f) 485 204 (S) -4- [1-Hydroxymethyl-2- (3-trifluoromethylphenyl) ethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benz-imidazol-2-yl) -1H-pyridin-2- he ^Ο Ίχφ 1 HN F ₃ C 1.56 (f) 509

127

205 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(pyrimidin-2-ylmethyl) amino] -1H-pyridin-2-one ν · = λ θ And HN N- = x ml N— ' 1.16 (b) 399 206 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(pyrazin-2-ylmethyl) amino] -1H-pyridin-2one N - = \ ⁰ H / L / 4 / N V-NH I HN N ^ x 1.14 (b) 399 207 3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -4- (2-phenyl-1-pyridin-2-ylethylamino) -1 N-pyridin-2-one / ^{N_ =} \ ⁰ k / N ^^ H ^NH 1.26 (b) 488 208 (±) -3- (6-imidazol-1-yl-4-methyl- 1 H-benzimidazol-2-yl) -4- (3-phenyl-1-pyridin-2-ylpropylamino) -1 H-pyridin-2-one Um / Ci) 1.34 (d) 502 209 (±) -4- [2- (3-fluorophenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one Ν = λ ⁰ XX * -p I HN N ^ X µL F 1.31 (d) 506 210 (±) -4- [2- (3-chlorophenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one / ^{N =} \ ⁰ C NH xxy? I HN N- = X Cl 1.39 (d) 522

128

211 4- [2- (2-fluorophenyl) -1-pyridin2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he / ^{N =} \ ⁰ B-NH I HN T 1.33 (d) 506 212 (±) -4- [2- (3-bromophenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one N = \ ⁰ I HN N- = 4 Br 1.40 (d) 566 213 (±) -4- [2- (2-bromophenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one θΧ / φ I HN N ^ x 1.45 (d) 566 214 (±) -3- (6-imidazol-1-yl-4-methyl- 1 H-Benzimidazol-2-yl) -4- [2- (2-phenyl) -1-pyridin-2-ylethylamino] -1 H-pyridin-2-one N = \ ⁰ AND HN N- = 4 1.47 (d) 614 215 (±) -4- [2- (2-chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it Ζχφ T hn / ^{0H c,} -O 1 21 (i) 461 216 4- [3- (4-Cyclopentylamino-6-propoxy- [1,3,5] triazin-2-yloxy) propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) ) -1H-pyridin-2-one , ^{N =} \ _H Q 2 “NH ΙΑ, λήΑ I HN V l · ⁰ Γ y — NH 1.67 (b) 585

129

217 (±) -3- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-2 -ylamino] ethyl} benzonitrile ff T nA> - ^cn 1.20 (b) 452 218 (±) -4- (2-biphenyl-3-yl-2-hydroxyethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one 4νΗ T ng ^H <40 1.51 (b) 503 219 (+) - 4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it ο 1.35 (f) 447 220 (S) -4- [1-Hydroxymethyl-2- (2methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Ab I HN € background OMe 1-52 (f) 471 221 (S) -4- [1-Hydroxymethyl-2- (3methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Ab I HN pA- MeO ⁷ 1.42 (f) 471 222 (S) -4- [1-Hydroxymethyl-2- (3-nitrophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Ab I HN F o ₂ n 1.27 (f) 486

130

223 (S) -4- [3- (2-Benzothiazol-2-ylphenoxy) -2-hydroxypropylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one I ΗΚΙ / n 1.47 0) 590 224 (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) - 1 Npyridin-2-one T nX ° ⁿ OMe 1.35 (j) 535 225 (S) -4- (1-Benzyl-2-hydroxy-2methylpropylamino) -3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -1H-pyridin-2-one I ΗΝ / 22.07 BETX 226 (R) -4- (1-Benzyl-2-hydroxy-2methylpropylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Xxx I ΗΝ / θ_ / Χ ^0Η 22.09 BETX 227 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(5-methylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one / ^{Ν =} \ H ΝΗ ΗΝ Ν = χ 0.99 (d) 412 228 (±) -3- (6-imidazol-1-yl-4-methyl- 1H-benzimidazol-2-yl) -4- (2phenyl-2-pyridin-2-ylpenten-4ylamino) -1H-pyridin-2-one Ν = \ Q 1.41 (d) 528

131

229 (±) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (2-phenyl-2-pyridin-2-ylethylamino) -1H-pyridin-2-one N = \ 0 Ο 1.22 (d) 488 230 6 - {[3- (6-imidazol-1-yl-4-methyl- 1 H-benzimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] methyl} nicotinitrile And ΗΝ ~ Ν-χ —CN 1.22 (d) 423 231 (±) -4- [2- (5-Bromo-2-methoxyphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2 -on , ^{Ν =} \ L1 0. Vnh I ΗΝ θ ^Η MeO — y— Br 1-27 (i) 535 232 (±) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (1-pyridin-2-ylethylamino) -1H-pyridin-2-one \ ___ h \\ 1.12 (d) 412 233 (±) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (1-pyridin-2-ylpropylamino) -1H-pyridin-2-one I HN N- \ HZ) 1.17 (d) 426 234 (±) -4- [2- (3-bromo-4-fluorophenyl) 2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2-one T HnQt ^0H J. 1.24 (s) 523

132

235 (±) -4- [2- (5-bromo-2-fluorophenyl) 2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2-one T ngG / ^0N F-0- Br 1.15 (2) 523 236 (±) -4- [2- (3,5-dibromophenyl) -2hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it T nGG ™ Br 1.30 (s) 583 237 (±) -4- [2- (3-bromophenyl) -2-hydroxypropylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one I ΗΝ \, he Υ 1.90 (d) 519 238 (S) -4- [2- (3-Bromophenyl) -2-hydroxyiminoethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it J V _NH ΙΑΛγζ ι ΗΝ Ν — OH.. 7.81 (s) 518 239 (2) -4- [2- (3-bromophenyl) -2-hydroxyiminoethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it I ΗΝ 7.91 (s) 518 240 (R) -4- (3-Hydroxy-1-phenylpropylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one / ^{Ντ =} λ ο ^ν φΌ I n \. {jT ^v ' ^oH 1.48 (f) 441

133

241 (S) -4- (3-hydroxy-1-phenylpropylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one / ^{N =} \ ⁰ I HN pA ^0H 1.48 (f) 441 242 (S) -4- [3-Hydroxy-1- (2-iodophenyl) propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he Ν = λ ⁰ I Hl \ f cA ^0H 1.61 (f) 567 243 (S) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it T n / A ^0H 1.35 (b) 505 244 (S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it T n / A ^0H (B- ^{c |} 1.30 (b) 461 245 (R) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it Off T ην ^ Αρπ - ^{c |} 1.37 (b) 461 246 (R) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it AHhA Vnh T nmA ⁿ - ^Br 1.35 (b) 505 247 4- [2- (3-chlorophenyl) ethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Off I HN 1.53 (b) 445

134

248 (±) -4- [2- (3-chloro-4-hydroxyphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- pyridin-2-one ^N = \ 0? “ ^Ν \ I ΗΝ / OH ΌΗ 1.15 (b) 477 249 (±) -4- [2- (3-chloro-4-hydroxyphenyl) -2-methoxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- pyridin-2-one HhP I hnP / OH (3_ ^{c |} OMe 1.24 (b) 491 250 (±) -4- {2- [3-chloro-4- (2-methylallyloxy) phenyl] -2-hydroxyethylamino} -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl ) - 1 H-pyridin-2-one 1 ΗΝ / OH Q ^ _CI °> 1.46 (b) 531 251 (±) - [2- (5-bromobiphenyl-3-yl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he ΑΦ Τ Η1 / ~ /) Η Nr 1.44 (s) 581 252 (±) -4- (2-hydroxy-2- [1,1 ', 3', 1 ”] terpenyl-5'-ylethylamino) - 3- (6-imidazol-1-yl-4methyl-1H-benz-imidazol-2-yl) - 1 H-pyridin-2-one Vnh 1 ΗΝ / OH ΗίΑ 1.48 (s) 579 253 (±) -4- [2- (3-chloro-4-propoxyphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- pyridin-2-one S-NH CRP Υ-v 1 HN / OH 1.76 (b) 519

135

254 3- [3- (6-imidazol-1-yl-4-methyl- 1 H-benzimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] - N-phenylpropionamide aa I HN A ™ ⁰ b 1.13 (0 454 255 (±) -4- [2-hydroxy-2- (3-nitrophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2- he AF ^HN Cy ^0H (C ^-N ° ² 1.20 (s) 472 256 4- [2- (5-Bromo-4-methoxyphenyl) - ethylamino] -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one AA I HN \ __ R. Br 1 -51 0) 519 257 2- [3- (6-imidazol-1-yl-4-methyl- 1 H-benzimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] - N-phenylacetamide FZaa Λ ~ ^ν \ ^ΗΝ Α ° ^ην Ο 1 -25 (s) 440 258 (R) -1 \ 1- {2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -3oxo-1,2-dihydropyridin-4ylamino] -2-phenylethyl} methanesulfonamide / ^{N =} \ n R / ^N \ AA_ / I HN JHSO ₂ CH ₃ 1.35 (s) 504 259 (S) -1 \ 1- {2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -3oxo-1,2-dihydropyridin-4ylamino] -2-phenylethyl} methanesulfonamide / A H 4 V ^N Ar / ^N \ | HN NHSO ₂ CH ₃ b 1.32 (s) 504

136

260 (±) -N- (2-Chloro-4- {1-phenyl-2- [3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -3-oxo-1,2-dihydropyridine- 4-ylamino] ethyl} phenyl) -2,2,2-trifluoroacetamide Ν - = \ η O-rD — w NHCOCF ₃ 1.30 (b) 574 261 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4 - [(piperidin-4-ylmethyl) amino] -1H-pyridin-2-one ^H v_Q _H 0.90 (b) 404 262 (±) -4- [2- (3-bromo-5-pyridin-3ylphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benz-imidazol-2-yl) - 1 H-pyridin-2-one I ^Ν ΗίΛ / θΗ ζ ^ -Br 1.18 (a) 582 263 (±) - (2-chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -3-oxo-1,2-dihydropyridin-4- ylamino] ethyl} phenyl) carbamic acid ^{Τ hZJ 0H Qj> ΗΝ- (°} Λ 1.36 (b) 548 264 (±) -LA (2-chloro-4- {1-hydroxy-2- [3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -3-oxo-1,2 · dihydropyridin-4-ylamino] ethyl} phenyl) -2,2-dimethylpropionamide Τ hQh Ζν 1.42 (b) 560

137

265 (S) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (1-hydroxymethyl-2-pyridin-zylethylamino) -1H-pyridin-2-one HH I Η | θ ° ^Η \ | = / 0.78 (b) 442 266 (S) -3-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -N-naphthalene -1 ilpropionamide Ahf T Q but— / ην-ΛΛ 1.41 (b) 520 267 (O) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- [1- (1 Nindol-3-ylmethyl) -2-hydroxy- ethylamino] -1H-pyridin-2-one Chf I ΗΝ_ ΗΝ4 / \ M— 'HE 1.22 (b) 480 268 (S) -4- [3-Hydroxy-1- (1H-imidazol-4-yl) propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it / ^{N =} \ ⁰ txhj I HNi 0.75 (b) 431 269 (±) -4- [2- (3,4-dichlorophenyl) -2hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one I ng / S ^one € Y ^{with |} ΌΙ 1.48 (b) 495

138

270 (±) -1- (2-chloroethyl) -3- (2-chloro-4- {1 hydroxy-2- [3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) 2-oxo-1,2-dihydropyridin-4ylamino] ethyl} phenyl) urea sdd-L / I ° ⁿ Q-? HN— {HN-a V-CI 1.26 (b) 581 271 (±) - (2-Chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1 isopropyl ester , 2-dihydropyridin-4-ylamino] ethyl} phenyl) carbamic acid , ^N = \ _H o / ^N \ V. / I hnQoh Q-? ^ΗΝ Φ 1.41 (b) 562 272 (±) - (2-Chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridine isobutyl ester -4-ylamino] ethyl} phenyl) carbamic acid AoVH ^N HN '34 V. HN— 1.49 (b) 576 273 (S) -3-hydroxy-2- [3- (6-imidazole- 1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -N-naphthalen-2ylpropionamide / ^{N =} \ H ° v V-NH HO— 1.36 (b) 520 274 (O) -3-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1H-naphthalene -2-propionamide HO— OMe 1.45 (b) 550

139

275 {2- [3- (6-imidazol-1-yl-4-methyl- 1 H-benzimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] - (O) -ethanesulfonic acid 1-phenylethyl} amide , ^N = \ _n 0 / H / N NH \ H? y_Z NHSO ₂ CH ₂ CH ₃ b 1.47 (b) 518 276 (±) - (2-Chloro-4 {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2 methyl ester -Dihydropyridin-4-ylamino] ethyl} phenyl) carbamic acid I NCHR - ^C1 H o H- 1.23 (b) 534 277 (±) -4- [1-Hydroxymethyl-2- (2hydroxy-3-methylphenyl) ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one hh I HN H / Mon 1.29 (b) 471 278 (S) -4- [2- (5-Bromo-2-methoxyphenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one N - = \ 0 hh I HN OMe __ ^FROM θ ^Η Br 1.48 (b) 549 279 4- (2 & hydroxy-1-indan-1-ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one HH " I Hl \ [ A 1.42 (b) 467

140

280 (±) -4- [2- (3-bromo-4-methylphenyl) -2hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H- pyridin-2-one T ng / pH Wed. 1.43 (b) 519 281 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- [2- (1 Nindol-5-yl) ethylamino] -1H-pyridin-2-one I HN 4 Ν ' ² Η 1.54 (b) 450 282 (S) -3- (5-Bromo-2-methoxyphenyl) -2 [3- (6-imidazol-1-yl-4-methyl-1 N-benzimidazol-2-yl) -2-oxo-1,2-dipropropyridin-4 -ylamino] propionic acid I HN. —COOH Nr 1.09 (b) 563 283 (5) - (2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -phenylethyl} -amide. propane-2-sulfonic acid . ^N - \ _H 0 pO-A) - 1 HN HN-S 1.34 (b) 532 284 (O) - (2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenethyl} -amide thiophene-2-sulfonic acid Έ 2.45 (a) 572 285 (S) -N- {2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylethyl } -4-methane- / ^{N =} \ Η ° Λ _u SO ₂ CH ₃ / H ^N / == / spi? V / 1 HNHN-S ^? 1.34 (b) 644

141

sulfonyl-benzenesulfonamide 286 (N-N- {2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylethyl} benzenesulfonamide I HN NHSOoPh uh 1.60 (b) 566 287 (S) -2- {3-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4 -yl-amino] propyl} benzonitrile I ΗΝ. CN 1.16 (b) 466 288 (S) -4- (1-Hydroxymethyl-2-o-tolylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one NHF I hn_ 1.33 (b) 455 289 (5) -5-Bromo-3- [6- (2-bromimidazol-1-yl-4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl2-phenylethylamino) -1H-pyridine2 -on AoH ' ^ην ΓΥ (A— ⁷ A 1.36 (b) 597 290 (b) -4- [2- (2-Chloro-6-fluorophenyl) -1 hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H -pyridin-2-one ΟγΑ M ⁿ Cl 1.40 (a) 493

142

291 (S) -4- [2- (2,5-Difluorophenyl) -1 hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he Ογγί М ^{н 4} ЗН V 1.44 (a) 477 292 (S) -4- [1-Hydroxymethyl-2- (2-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -on 1 ΗΝ_ QJ ^ OH OMe 1 -52 (f) 471 293 (S) -4- [2- (2,6-Difluorophenyl) -1 hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he Th / W 1 /ην / f 1.42 (a) 477 294 (S) -4- (2- (2,6-Dichlorophenyl) -1 hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he 1? HN_ ^x ° ⁿ ΌΙ 1.42 (a) 509 295 (S) -4- [1-Hydroxymethyl-2- (2-trifluoromethoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benz-imidazol-2-yl) - 1 H-pyridin-2-one Ν · = \ 0 х / 1 ΗΝ_ ⁴ З OCF ₃ 1.48 (a) 525 296 (S) -N- {2- [3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridin-4-ylamino] -3-phenylpropyl } methanesulfonamide / ^{N =} \ H r-NH CD '!'? eh? 1 ng / JHSO ₂ CH ₃ 1.31 (a) 518

143

297 (S) -2- {4- [2- (2-chlorophenyl) -1 hydroxymethylethylamino] -2oxo-1,2-dihydropyridin-3-yl} 7-methyl-3H-benzimidazole-5carbonitrile ^nc X ^ / N ° Vnh I HN. ⁴ ZN 1.80 (b) 434 298 (S) -2- [4- (1-Hydroxymethyl-2-pyridin-3-ylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7methyl-3H-benzimidazole-5carbonitrile S-nh I HN_ Ο-Τα, Η 1.07 (b) 401 299 (S) -2- [4- (1-Hydroxymethyl-2pyridin-4-ylethylamino) -2-oxo- 1,2-dihydropyridin-3-yl] -7methyl-3H-benzimidazole-5carbonitrile ^nc \ a / N ° LCH ^H IRT I HN ^Z OH 1.16 (b) 401 300 (S) -2- [4- (1-hydroxymethyl-2-thiophen-2-ylethylamino) -2-oxo- 1,2-dihydropyridin-3-yl] -7methyl-3H-benzimidazole-5carbonitrile ^nc \ ^ 4 / N ° Vnh lnd I hn. SL ° ⁿ 1.73 (b) 406 301 (S) -2- [4- (2-benzo [b] thiophen-3-yl- 1-hydroxymethyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] 7-methyl-3H-benzimidazole-5carbonitrile Vnh sdl? I HN 1.84 (b) 456

144

302 7-methyl-2- {2-oxo-4 - [(pyridin-2-ylmethyl) amino] 1,2-dihydropyridin-3-yl} -3H-benzimidazole-5-carbonitrile ° In-min OAp And HN N = x hz 1.30 (b) 357 303 (±) -2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2oxo-1,2-dihydropyridin-3-yl} 7-chloro-3H-benzimidazole-5carbonitrile N ^c wN V NH GrU I HN PH C / 1 \ / —Br OMe 1.74 (d) 514 304 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-chloro- 3H-benzimidazole-5-carbonitrile Vnh VA 1, hnQh cX ^a 1.78 (d) 440 305 (±) -2- {4- [2- (3-bromophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-chloro-3H-benzimidazole-5-carbonitrile Vnh Vxk 1, HN PH LX 1.77 (d) 484 306 (±) -2- {4- [2- (3-bromophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-ethyl3H-benzimidazole-5-carbonitrile ^ms \ / hA V-nh J HN PH u. 1.82 (d) 478 307 (±) -2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] 2-oxo-1,2-dihydropyridin-3-yl} -7-ethyl-3H-benzimidazole-5carbonitrile XnH Vw J HN PH χ. OMe 1.76 (d) 508

145

308 (±) -2- {4- [2- (3-chlorophenyl) -2hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-ethyl3H-benzimidazole-5-carbonitrile ^nc / N 3 -NH 1.80 (d) 434 309 (±) - (2-Chloro-4- {2- [3- (6-cyano-4-methyl-1H-benzimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-hydroxyethyl isobutyl ester } phenyl) carbamic acid “Τχφ T n / ~ pH Qa iV- € ⁰ 1.93 (b) 535 310 (S) -7-ethyl-2- [4- (1-hydroxymethyl2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -3H-benzimidazole-5-carbonitrile ° / ~ h ⁿ YA ^WS 1.75 (d) 414 311 (S) -7-6poM-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo 1,2-dihydropyridin-3-yl] -3H-benzimidazole-5-carbonitrile S-NH ХХф Зг ^Н - са ^-4зн 1.91 (b) 464 312 (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyridine- 2-it o LYM Fnh 1 HN. OA ¹ JH 1.08 (f) 473 313 (N-4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-butylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyridin-2 -on Ο ~ Άη 1.29 (K) 515

146

314 (S) -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzimidazol-2-yl} -4- (1-hydroxymethyl-2-phenylethylamino) - 1 Npyridin-2-one _n □ R Vnh VAr? y_V I ΗΝ. ^ie 1.62 (κ) 503 315 (S) -3- [6- (4-Cyclohexylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1Npyridin-2- he JLji He φχ I ng / 1.34 (f) 541 316 (S) -3- [6- (4-Benzylpiperazin-1-yl) -4-methyl-1H-benz-imidazol-2-yl] -4- (1-hydroxy-methyl-2-phenylethylamino) -1H-pyridin-2one HUNDRED << I ng / 1.93 (f) 549 317 (S) -4- {2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazol-5-yl} piperazine-1-carboxamide 0 h ₂ n Ν'φ 0 ΦχχΝ Vnh X 1.26 (f) 502 318 (O) -3- [6- (4-Benzenesulfonylpiperazin-1-yl) -4-methyl-1 Nbenz-imidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridine- 2-it ^Ph0 XH << I V-NH I hn_ ^3H 2.30 (k) 599 319 (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (4-methanesulfonylpiperazin-1-yl) -4-methyl- 1 H-benzimidazol-2-yl] -1 Npyridin-2-one o VNH I ng / ^H 1.93 (k) 537

147

320 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2yl) -1H-pyridin-2- he ^hn 4 ₀ 4 ^Ν \ ^Η I nmChon CA ^ci 1.90 (f) 479 321 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4-cyclopropylmethylpiperazin-1-yl) -4methyl-1H-benzimidazol-2-yl] - 1 H-pyridin-2-one I HN £) H 1.97 (k) 533 322 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2,2-dimethylpropyl) piperazin-1-yl] -4methyl-1H-benzimidazol-2 -or} - 1 H-pyridin-2-one DDA n ° _h 1 Hhl _Z ^OH SU ^{C |} 2.06 (k) 549 323 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4-cyclobutylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -1 Npyridin-2-one n ν \ x ^N y4 _r -N y — NH 1 HN ^ PH cU-s 1.97 (k) 533 324 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4-ethylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -1H-pyridine- 2-it 0) —NH rh 1 Hn4OH SU ^C1 1.88 (k) 507

148

325 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4methyl-1H-benzimidazol-2-yl } - 1 H-pyridin-2-one Υ 1 Η ° _Λ ^k V — NH 1 HN.OH L> - ^Cl 1.82 (k) 524 326 (±) - [4- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole ethyl ester) -5-yl) piperazin-1-yl] acetic acid 1 HNPH 2.03 (k) 565 327 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-dimethylamino-2,2-dimethylpropyl) piperazin-1-yl] -4-methyl- 1 Nbenzoimidazol-2-yl} -1 Npyridin-2-one h h 1 HN.OH cU ^{c |} 1.84 (k) 592 328 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2yl) -1H-pyridin-2- he 0 B-nh 1 Hl \ l (J-GI 1.19 (a) 480 329 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2yl) -1H-pyridin-2- he About h <\ y — NH 1 HN PH 1.21 (a) 524

149

330 (±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H- pyridin-2-one ° Ύ ₀ V- ΝΗ I nARn and Me 1.16 (a) 554 331 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4 (tetrahydropyran-4-yl) -piperazin-1-yl] -1H-benzoimidazole2 -yl} -1H-pyridin-2-one M 0 I HN PH (> ^{C |} 1.19 (f) 563 332 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4-imidazol-2-ylmethyl-piperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] - 1 H-pyridin-2-one / 7 ί n h V-NH I n / pH CA ^ci 1.19 (f) 559 333 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (4-propyl-piperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyridine- 2-it ' ^χ ^ ^χ Ν ^{/ χ} _ι η ΝΗ ΧΑΦ I HhlPH C> ^cl 1.19 (f) 521 334 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (1methylpiperidin-4-yl) piperazin-1-yl] -1H-benzimidazole -2-yl} -1H-pyridin-2-one ₀ NH LA ^ yP I HN ^ —pH CM 1.08 (f) 576 335 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl- 1 H-benzimidazol-2-yl} -1 Npyridin-2-one ^H ° ^ OH ^k —k / VN V- NH CAG? yP AND HNPH 1 -79 (f) 567

150

336 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2- he ^Η Ό n X y-NH S-E I HN pH CH 1.83 (f) 523 337 (±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (4-methyl-6-piperazin-1-yl-1 N-benzimidazol-2-yl) -1-pyridin-2 -on fl h 4 VnH xDZ uD I HN ^ ~ PH ch OMe 1 -72 (f) 553 338 (±) -3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2yl] -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridine -2-he A Ab I hnAh CH 1.90 (f) 565 339 (±) -3- (6-amino-5-methyl-1H-benzimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] - 1 H-pyridin-2-one A ^nh hnAqh ca 1 -41 (j) 454 340 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6-pyrazol-1-yl) N-benzimidazol-2-yl) -1H-pyridin-2-one HN PH 1.86 (f) 447 341 (±) -3- (6-amino-4-methyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] - 1 H-pyridin-2-one A ^NH Wo I ΗΙΪ pH SN 1 -51 (f) 410

151

342 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6- [1,2,3] triazol-1-yl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one N ^ .. / Ν _Λ V — ΝΗ HhJ) DH C> ^{c |} 2.04 (f) 448 343 (±) -LA (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5-yl) acetamide n and q ΝΗ ο I ΗΝ0Η 1.62 (f) 452 344 (±) - (2- {4- (2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5-yl) urea I ΗΝ0ΙΗ (J- ⁰¹ 1.49 (f) 453 345 (±) -1- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5-yl) -3- ethyl urea and η η 4 B — ΝΗ ϊΧΧλΌ I ΗΝ, ΟΗ o- ^ci 1.64 (f) 481 346 (±) -1- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5-yl) -3- isopropylurea Η Η Η 4 V — ΝΗ ΎϊϊΧΗά I ΗΝ, ΟΗ (J “ ⁰ ' 1 -71 (f) 495 347 (N -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (2-morpholin-2-ylethylamino) -1H-benzimidazol-2-yl] -1H-pyridin-2 -on η η R \ I ην; (4 ^ * 1.05 (f) 503

152

348 (±) -4- [2- (3-bromophenyl) -2hydroxyethylamino] -3- (4,5,6trifluoro-1H-benzimidazol-2- yl) -1H-pyridin-2-one p Η θ \ VNH _F nHrn su ^cd 1.76 (d) 479 349 4 - [(pyridin-2-ylmethyl) amino] -3 (4,5,6-trifluoro-1H-benzimidazol-2-yl) -1H-pyridin-2-one Η ⁰ Vnh I HN ^ 1.36 (d) 372 350 (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (4,5,6-trifluoro- 1 H-benzimidazol-2-yl) -1 Npyridin-2-one H ⁰ , ΪΧφ HN_ 1.73 (d) 415 351 3- (4,6-Dibromo-1H-benzimidazol2-yl) -4 - [(pyridin-2-ylmethyl) amino] -1H-pyridin-2-one AM Vnh XXpj 1.66 (d) 474 352 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (4,6-dibromo-1H-benzimidazol-2-yl) -1H-pyridin-2-one K / A VNH XX ^ P 1 HNpH Br \ ___ / su ^cd 1.95 (d) 581 353 (5) -3- (4,6-Dibromo-1H-benzimidazol-2-yl) -4- (1-hydroxymethyl2-phenylethylamino) -1H-pyridin2-one in ° x VNH xxHj 1 HN Nr * 1.92 (d) 517

153

354 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (5,6-dichloro-1H-benzimidazol-2-yl) -1H-pyridin-2-one HN \ / OH SI 1.85 (d) 493 355 3- (5,6-dichloro-1H-benzimidazol2-yl) -4 - [(pyridin-2-ylmethyl) amino] -1H-pyridin-2-one ^{C |} \ _r -h _{r e} C | O4 ^ N ^ y-V HN N = x mJ 1.48 (d) 386 356 (S) -3- (5,6-Dichloro-1H-benzimidazol-2-yl) -4- (1-hydroxymethyl2-phenylethylamino) -1H-pyridin2-one °) -NH "1XC HN. DH 1.82 (d) 429 357 (±) -3- (4,6-bis-trifluoromethyl-1H-benzimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one H ^{0 F} 3 ^C \ / 4 / NV — NH Ό / υ 1 HN .OH CF ₃ 0 / O “ ^Br 1.56 (b) 561 358 3- (4,6-Bis-trifluoromethyl-1H-benzimidazol-2-yl) -4 - [(pyridin2-ylmethyl) amino] -1H-pyridin-2one ^F a ^c VM °> -nh 1 HN N ^ ^CFs 42) 1.39 (b) 454 359 (S) -3- (4,6-Bis-trifluoromethyl-1H-benzimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one Vnh 1.53 (b) 497

154

360 (±) -3- (4,6-bis-trifluoromethyl-1H-benzimidazol-2-yl) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -1H-pyridin-2-one n ^{0 F} 3 ^C A / A ^ NV — NH SU * OMe 1.51 (b) 591 361 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Η ^{0 p with C} \ / CHA NH Xx A, ⁿ \ / ^on 1.54 (b) 527 362 3- (4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -4 - [(pyridin2-ylmethyl) amino] -1H-pyridin-2one ^f 3 ^c \ / A / NV ~ NH XXhj I HN N = X “A 1.34 (b) 420 363 (5) - (4-Chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one V-NH I HN 1.51 (b) 463 364 (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one H ^{0 F} 3 ^C \ / 4 / N V- NH KF Cl HN PH yV * OMe 1.50 (b) 557 365 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (5-trifluoromethyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one H ° x / A ^ N 7 — NH ³ hn'ph ^Br 1.42 (b) 493

155

366 4 - [(pyridin-2-ylmethyl) amino] 3- (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one n ⁰ φΧ ^ Ν Anh LF ³ ΗΝ Ν = λ 'Ο 1.16 (b) 386 367 (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (5-trifluoromethyl-1H-benzimidazol-2-yl) - 1 H-pyridin-2-one Η ⁰ _v XX: rX HN 1.41 (b) 429 368 (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (5-trifluoromethyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one n 4 7 — NH LF ³ hn 'OH OMe 1.38 (b) 523 369 (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (5-fluoro-6-imidazol-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2- he N = \ / \ H 4 φζφζ- ^ γΝ V- NH HN PH O- 1.10 (b) 509 370 3- (5-fluoro-6-imidazol-1-yl-1H-benzimidazol-2-yl) -4 - [(pyridin2-ylmethyl) amino] -1H-pyridin-2one N - = \ VvM V-NH HN N = x BSF 0.73 (b) 402 371 (5) -3- (5-fluoro-6-imidazol-1-yl) N-benzimidazol-2-yl) -4- (1 hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one Ν · ^ = ^ 0 Φ4 HN_ CH '* 1.04 (b) 445

156

372 (±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (5-fluoro-6-imidazol-1-yl-1H-benzimidazol-2-yl) -1H-pyridine -2-he N = \ / \ and 0 B — NH HN.OH f OMe 1.05 (b) 539 373 (±) -3- (4-bromo-6-trifluoromethyl1H-benzimidazol-2-yl) -4- [2- (3bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one Θ θ \ ^F 3 ^C \ / 4 / N 7 — NH Cxdr I HN pH Br \ __ / 1.97 (d) 571 374 (±) -3- (4-bromo-6-trifluoromethyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one Η θ \ ^Γ 3 ° νν.Ν y — NH ZXmj Cl · ⁰¹ 1.95 (d) 527 375 (+) - 4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (4,6-difluoro-1H-benzimidazol-2- yl) -1H-pyridin-2-one a H ⁰ H / N VnH XHj. hZ ~ J2H 1.72 (d) 461 376 (±) -4- [2- (3-chlorophenyl) -2hydroxyethylamino] -3- (4,6difluoro-1H-benzimidazol-2- yl) -1H-pyridin-2-one a H ⁰ H / N Vnh XXj _ hn '.OH SU ^{c |} 1.70 (d) 417 377 (±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (4,6-difluoro-1H-benzimidazol2-yl) -1H-pyridin-2-one H ⁰ 4 / N N-NH XHj _z HN ⁷ pH Br OMe 1.65 (d) 491

157

378 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl6- (2-methylimidazol-1-yl) -1H-benzimidazol-2-yl] -1H-pyridin-2-one N = / / \ n H VNH I HN PH C> ^CI 1.38 (d) 475 379 (±) -4- [2- (3-chloro-4-methoxyphenyl) 2-hydroxyethylamino] -3- [4methyl-6- (4-methylimidazol-1-yl) - 1 H-benzimidazol-2-yl] -1 Npyridin-2-one Ν · = \ / \ h P ZV ^N \ ZW V-NH ai I HN PH OMe 1.35 (d) 549 380 (±) -4- [2- (3-bromophenyl) -2hydroxyethylamino] -3- (5,6 difluoro-1H-benzimidazol-2yl) -1H-pyridin-2-one H ⁰ K / O / N Vnh XX nA ~ pH 1.67 (b) 461 381 3- (5,6-Difluoro-1H-benzimidazol-2-yl) -4 - [(pyridin-2-ylmethyl) amino] -1H-pyridin-2-one H 4 HN 1.18 (b) 354 382 6-hydroxy-5- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) 3H-pyrimidin-4-one Xxx 0.96 (f) 309 383 (±) -6- [2- (3-chlorophenyl) -2hydroxyethylamino] -5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one N = n I \ Η P VNH Wo I Hi / Trn (J- _Cl 2.30 (f) 462

158

Preparation of intermediate imidate (Scheme IV, 13)

NH

HN

HE

(S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carboximide ethyl ester: To suspension of (S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile (0.8 g, 2.0 mmol) ) in ethanol (anhydrous, 80 ml), at 0 ° C, bubbled HCl (anhydrous) to saturation. After a few minutes of bubbling, the mixture became a clear solution and the mixture was stirred for 14 hours at room temperature. After concentration in vacuo, the crude product (0.89 g, 100%) was used directly in the next step without purification. TX / MC (M + H) + m / z 446 (t = 1.55 min).

NH

EtO '

Cl (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboximidene ethyl ester: The title compound is prepared according to a common imidate preparation method. TX / MC (M + H) + m / z 466 (t = 1.43 min).

General Method for Examples 384-397 - Preparation of Imidazoline (Scheme IV, 14)

Example 384

159

(S) -3- [6- (4,5-Dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino 1 H-Pyridin-2-one: The crude imidate ester (60 mg, 0.135 mmol) was diluted with methanol, followed by the addition of ethylenediamine (24 mg, 0.40 mmol). The reaction mixture was refluxed for 6 hours. After concentration in vacuo, the residue was purified by preparative HPLC to give the title compound (37 mg, 62%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.94 (1H, s), 7.50 (1Η s), 7.12 - 7.30 (6H, m), 6.16 (1H, d, J = 7.7 Hz), 4.04-4.10 ( 5H, m), 3.75 - 3.77 (2H, m), 3.15 (1H, dd, J = 5.2,13.6 Hz), 2.96 (1H, dd, J = 8.1,13.6 Hz), 2.67 (3H, s) TX / MC (M + H) ⁺ m / z 443 (t = 1.50 min).

Example 385

(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2 yl] -1H-pyridin-2-one: ¹ H

NMR (300 MHz, CD ₃ OD) δ 7.93 (1H, s), 7.54 (1H, s), 7.23 - 7.45 (5H, m), 6.26 (1H, d, J = 7.6Hz), 5.01 (1H, t , J = 6.3 Hz), 4.01 (4H, s), 3.78 (1H, dd, J = 4.7,13.5 Hz), 3.67 (1H, dd, J = 6.6,13.5 Hz), 2.66 (3H, m), TX / MC (M + H) ⁺ m / z 443 (t = 1.54 min).

160

Example 386

4- [2- (3-chlorophenyl) -2H-hydroxyethylamino] -3- [4-methyl-6- (4-methyl-4,5-dihydro-1H-imidazol-1-yl) -1H- benzimidazol-2-yl] -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) -2 $ -hydroxyethylamino] -3- [4-methyl-6- (4 $ -methyl-

4,5-Dihydro-1H-imidazol-1-yl) -1H-benzimidazol-2-yl] -1Hpyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.90 (2H, s ), 7.53 (2H, s), 7.22 7.47 (10H, m), 6.23 (2H, d, J = 7.5 Hz), 5.00 (2H, t, J = 6.4 Hz), 4.49-4.57 (2H, m). 4.21 (2H, t, J = 11.0 Hz), 3.61 - 3.78 (6H, m), 2.63 (6H, s), 1.48 (6H, d, J = 6.3 Hz). TX / MC (M + H) ⁺ m / z 477 (t = 1.71 min).

Example 387

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (1-methyl-

4,5-Dihydro-1H-imidazol-2-yl) -1H-benzimidazol-2-yl] -1H-pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.94 (1 H, s), 7.57 (1 Η, s), 7.23 - 7.52 (5Η, m), 6.22 (1H, d, J = 7.5 Hz), 4.99 (1 H, m), 4.00 - 4.15 (2H, m) , 3.57 - 3.75 (4H, m), 2.77 (3H, s), 2.61 (3H, s). TX / MC (M + H) ⁺ m / z 477 (t = 1.60 min).

161

EXAMPLE 388

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl) -4-methyl- 1 H-benzimidazol-2-yl] -1 Npyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.89 (1H, s), 7.52 (1 Η, s), 7.22 - 7.45 (5Η, m), 6.19 (1H d, J = 7.4 Hz), 4.99 (1H, t, J = 6.2 Hz), 3.84 (2H, s), 3.78 (1H, dd, J = 4.4, 13.4 Hz), 3.60 (1H , dd, J = 6.7, 13.4 Hz), 2.61 (3H, s), 1.55 (6H, s). TX / MC (M + H) ⁺ m / z 491 (t = 1.73 min).

Example 389

2- (2- {4- [2- (3-chlorophenyl) -2H-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5-yl ) -4,5-Dihydro-1 Nimidazole-45-carboxylic acid and 2- (2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3- yl} -7-methyl-3H-benzimidazol-5-yl) -4,5-dihydro-1H-imidazole-45-carboxylic acid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.88 (2H, s), 7.52 (2H, s), 7.22 - 7.44 (10H, m), 6.17 (1H, d, J = 7.4 Hz), 5.05 (2H, m), 4.23 -4.38 (4H, m), 3.56 - 3.72 (6H, m ), 2.58 (6H, s). TX / MC (M + H) ⁺ m / z 507 (t = 1.64 min).

162

Example 390

(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (1,4,5,6tetrahydropyrimidin-2-yl) -1H-benzimidazol-2 -yl] -1H-pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.90 (1H, s), 7.53 (1H, s), 7.22 - 7.47 (5H, m), 6.23 (1H d, J = 7.6 Hz), 5.00 (1H, t, J = 6.3 Hz), 4.49-4.57 (1H, m), 3.603.77 (5H, m), 3.24 - 3.34 (2H, m), 2.63 (3H , s). TX / MC (M + H) ⁺ m / z 477 (t = 1.59 min).

Example 391

(±) -4- [2- (3-chloro-4-methoxyphenyl) -2-methoxyethylamino] -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H -benzimidazol-2-yl] -1 Npyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.88 (1 H, s), 7.46 (1H, s), 7.44 (1 Η, s), 7.31 (1H, d, J = 6.4 Hz), 7.28 (1H, d, J = 5.6 Hz), 7.01 (1H, d, J = 6.4 Hz), 6.19 (1H, d, J = 5.6 Hz), 4.49 ( 1H, dd, J = 3.4, 5.0 Hz), 4.09 (4H, s), 3.82 (3H, s), 3.36 (3H, s), 3.63 - 3.67 (2H, m), 2.62 (3H, s), TX / MC (M + H) ⁺ m / z 507 (t = 1.72 min).

163

Example 392

(±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H -benzimidazol-2-yl] -1Hpyridin-2-one: The title compound is obtained by hydrolysis of benzyl chloride to hydroxide. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.90 (1H, s), 7.67 (1 Η, s), 7.48 (1 Η, s), 7.38 (1 dd, dd, J = 2.0, 8.5 Hz). 7.31 (1H, d, J = 7.6 Hz), 6.95 (1H, d, J = 8.5 Hz), 6.26 (1H, d, J = 7.6 Hz), 4.94 (1H, m), 4.10 (4H, s ), 3.80 (3H, s), 3.62 - 3.74 (2H, m), 2.62 (3H, s). TX / MC (M + H) ⁺ m / z 537 (t = 1.49 min).

Example 393

(S) -3- [6- (4,4-Dimethyl-4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl) -2-phenylethylamino) -1H-pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.94 (1H, s), 7.50 (1 Η, s), 7.12 - 7.30 (6Η, m), 6.1 ( 1H, dd, J = 7.7 Hz), 4.02 - 4.10 (1H, m), 3.85 (2H, s), 3.75 - 3.77 (2H, m), 2.96 3.17 (2H, m). 2.67 (3H, s). 1.56 (6H, s) TX / MC (M + H) ⁺ m / z 471 (t = 1.62 min).

164

Example 394

(S) -2- {2- [4- (18-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydro-pyridin-3-yl] -7-methyl-3H-benzimidazol-5-yl} - 4,5-Dihydro-1H-imidazole-48-carboxylic acid. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.03 (1H, s), 7.60 (1 Η, s), 7.11 - 7.29 (6Η, m), 6.15 (1H, d, J = 7.3 Hz), 5.07 ( 1H, dd, J = 6.9, 11.8 Hz), 4.25 - 4.41 (2H, m), 4.05 -4.07 (1H, m), 3.70 - 3.82 (2H, m), 3.12 (1H, dd, J = 5.5, 13.6 Hz), 2.95 (1H, dd, J = 8.0, 13.6 Hz), 2.69 (3H, s). TX / MC (M + H) ⁺ m / z 487 (t = 1.35 min).

Example 395

(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (1,4,5,6tetrahydropyrimidin-2-yl) -1H-benzimidazol-2-yl] -1H -pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.76 (1 H, s), 7.32 (1 Η, s), 7.09 - 7.29 (6Η, m), 6.15 (1 Η, d , J = 7.6 Hz), 4.02 - 4.07 (1H, m), 3.71 - 3.79 (2H, m), 3.61 (4H, t, J = 5.6 Hz), 3.14 (1H, dd, J = 5.3,13.6 Hz) , 2.95 (1H, dd, J = 8.1, 13.6 Hz), 2.65 (3H, s), 2.09 - 2.16 (2H, m). TX / MC (M + H) ⁺ m / z 457 (t = 1.49 min).

165

Example 396

(S) - 4- (1-hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-benzoimidazol-2-yl ] -1H-Pyridin-2-one:

¹ H NMR (300 MHz, CD ₃ OD) δ 7.77 (1H, s), 7.10 - 7.30 (7H, m), 6.16 (1H, d, J = 7.6 Hz).

3.97 - 4.20 (5H, m), 3.73 - 3.77 (2H, m), 3.26 (3H, s), 3.15 (1H, dd, J = 5.3, 13.6 Hz),

2.96 (1H, dd, J = 8.0, 13.6 Hz), 2.68 (3H, s). TX / MC (M + H) ⁺ m / z 457 (t = 1.53 min).

Example 397

(S) -3- [6- (4,5-Dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (2-hydroxy-2-phenylethylamino) -1H- Pyridin-2-one: ¹ H NMR (400

MHz, CD3OD) δ 7.91 (1H, s), 7.50 (1H, s), 7.48 (2H, s), 7.24-7.35 (4H, m), 6.25 (1H, d.

J = 7.6 Hz) 5.01 (1H, dd, J = 4.6, 7.0 Hz), 4.10 (4H, s), 3.65 - 3.76 (2H, m), 2.64 (3H, s).

TX / MC (M + H) ⁺ m / z 429 (t = 1.48 min).

166

Example 398

(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (1H-imidazol-2-yl) -4methyl 1H-6enzimidazol-2-yl] -1H-pyridin-2-one a solution of the imidate ester (150 mg, 0.31 mmol) in methanol (10 ml) was added aminoacetaldehyde diethyl acetal (9 mg, 0.93 mmol). The mixture was stirred for 14 hours at room temperature. The solvent was removed in vacuo and the residue was treated with 60% HCl ₄ (5 ml) for 14 hours at room temperature. The reaction mixture was then neutralized with ammonium hydroxide (conc.). The inorganic salt was filtered. The filtrate was concentrated and purified with preparative ΒΕΊΓΧ to give the title compound (37 mg, 27%) as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.94 (1H, narrow d, J = 1.3 Hz), 7.58 (2H, s), 7.53 (1H, narrow d, J = 0.6 Hz), 7.12 - 7.31 (6H , m), 6.16 (1H, d, J = 7.7 Hz), 4.04 - 4.08 (1H, m), 3.76 - 3.79 (2H, m), 3.16 (1H, dd, J = 5.4, 13.6 Hz), 3.97 ( 1H, dd, J = 8.1, 13.6 Hz), 2.69 (3H, s). TX / MC (M + H) ⁺ m / z 441 (t = 1.60 min).

General Method for the Preparation of Amidines, Examples 399 - 412 (Scheme IV, 16)

Example 399

167 (c) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7H / dimethyl-3H-benzimidazole-5-carboxamidine:

The crude imidate ester (60 mg, 0.135 mmol) was diluted with methanol (10 ml), then methylamine (2.0M methanol solution, 0.5 ml, excess) was added to the solution. After stirring for 2 hours, the reaction mixture was concentrated and purified by preparative HPLC to give the title compound (32 mg, 55%) as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.82 (1H s), 7.38 (1 Η, s), 7.10 - 7.30 (6Η, m), 6.15 (1H, J = 7.7 Hz), 4.03 - 4.07 (1H , m), 4.7 - 4.76 (2H, m), 3.06 - 3.18 (1H, m), 3.12 (3H, s), 2.96 (1H, dd, J = 8.0, 13.5 Hz), 2.67 (3H, s).

TX / MC (M + H) ⁺ m / z 431 (t = 1.34 min).

Example 400

NH.

Cl (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7 / N-dimethyl-3H-benzimidazol-5 -carboxamidine: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.81 (1 Η, s), 7.54 (1 Η, s), 7.23 - 7.54 (5Η, m), 6.26 (1H, d, J = 7.6)

Hz), 5.01 (1H, t, J = 4.8 Hz), 3.77 (1H, dd, J = 4.5, 13.4 Hz), 3.67 (1H, dd, J = 6.6, 13.4)

Hz), 3.12 (3H, s), 2.66 (3H, s). TX / MC (M + H) ⁺ m / z 451 (t = 1.32 min).

Example 401

Cl

168 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxamidine : ¹ H NMR (300

MHz, CD3OD) δ 7.90 (1H, s), 7.26 -7.57 (6H, m), 6.25 (1H, d, J = 7.6 Hz), 5.01 (1H, t.

J = 6.4 Hz), 3.75 (1H, dd, J = 4.8, 13.4 Hz), 3.66 (1H, dd, J = 6.7, 13.4 Hz), 2.66 (3H, s).

TX / MC (M + H) ⁺ m / z 437 (t = 1.59 min).

Example 402

(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-5-3-yl} -7, N, N-trimethyl-3H benzimidazole-5-carboxamidine: ^1H

NMR (300 MHz, CD3OD) δ 7.63 (1H, s), 7.54 (1H, s), 7.18-7.41 (5H, m), 6.26 (1H, d, J = 7.6 Hz), 5.01 (1H, t, J) = 6.3 Hz), 3.77 (1H, dd, J = 4.7,13.5 Hz), 3.67 (1H, dd, J = 6.6,13.5 Hz), 3.34 (6H, s), 2.66 (3H, s). TX / MC (M + H) ⁺ m / z 465 (t = 1.57 min).

Example 403

(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} - N -cyclopropyl-7-methyl-3H-benzimidazole -5-carb <zsamidine: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.78 (1H, s), 7.54 (1H, s), 7.22 - 7.41 (5H, m), 6.25 (1H, d, J = 7.6 Hz), 5.01 (1H, t, J = 6.4 Hz), 3.76 (1H, dd, J = 4.7,13.5 Hz), 3.67

169 (1H, dd, J = 6.6, 13.5 Hz), 2.77-2.83 (1H, m), 2.65 (3H, s), 1.03 -1.10 (2H, m), 0.86 0.92 (2H, m). TX / MC (M + H) ⁺ m / z 477 (t = 1.43 min).

Example 404

(±) -2- {4- [2- (3-chloro-4-methoxyphenyl) -2-methoxyethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7L / -dimethyl-3H-benzimidazole -5-carboxamidine:

¹ H NMR (300 MHz, CD ₃ OD) δ 7.79 (1H, narrow d, J = 1.0 Hz), 7.45 (1H, narrow d, J = 1.5 Hz), 7.38 (1H, s), 7.28 - 7.31 (2H , m), 7.02 (1H, d, J = 6.4 Hz), 6.22 (1H, d, J = 5.7 Hz), 4.52 (1H, t, J = 5.9 Hz), 3.83 (3H, s), 3.60 - 3.71 (2H, m), 3.36 (3H, s), 3.13 (3H, s), 2.65 (3H, s). TX / MC (M + H) ⁺ m / z 495 (t = 1.64 min).

Example 405

(±) -2- {4- [2- (3-chloro-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7 / N-dimethyl-3H- benzimidazole-5-carboxamidine:

To a solution of 2- {4- [2- (3-chloro-4-methoxyphenyl) -2-methoxyethylamino] -2-oxo 1,2-dihydropyridin-3-yl} -7, LA dimethyl-3H-benzimidazole-5-carboxamidine (40 mg mmol) in methanol (5 ml) was added 2 N NaOH (0.5 ml) and the reaction mixture

170 was stirred for 14 hours at room temperature. After concentration in vacuo, the residue was purified by preparative HPLC to give the title compound (7.2 mg, 19%) as an oil. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.78 (1H, narrow d, J = 1.6 Hz), 7.52 (1H, narrow d J = 2.1 Hz), 7.30 - 7.36 (3H, m), 6.99 ( 1 H, d, J = 8.5 Hz), 6.27 (1H, d, J = 7.6 Hz), 4.94 (1H, t, J = 5.9 Hz), 3.82 (3H, s), 3.68 - 3.72 (2H, m) , 3.13 (3H, s), 2.63 (3H, s). TX / MC (M + H) ⁺ m / z 481 (t = 1.44 min).

Example 406

(±) -2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7L / -dimethyl-3H-benzimidazol-5 -carboxamidine: ¹ H NMR (400 MHz, CD 3 OD) δ 7.77 (1H, s), 7.67 (1H, s), 7.29-7.39 (3H, m), 6.95 (1H, d,

J = 8.4 Hz), 6.23 (1H, d, J = 4.4 Hz), 4.92 (1H, m), 3.80 (3H, s), 3.69 (2H, m), 3.13 (3H, s), 2.61 (3H. s). TX / MC (M + H) ⁺ m / z 525 (t = 1.44 min).

Example 407

(S) -N-Cyclopropyl-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-

1,2-Dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carboxamidine:

171 ¹ H NMR (300 MHz, CD ₃ OD) δ 7.81 (1H, s), 7.37 (1 Η, s), 7.10 - 7.30 (6Η, m), 6.16 (1H, d.

J = 7.6 Hz), 4.03-4.08 (1H, m), 3.74 - 3.76 (2H, m), 3.15 (1H, dd, J = 5.3, 13.6 Hz),

2.96 (1H, dd, J = 8.1, 13.6 Hz), 2.78 - 2.84 (1H, m), 2.67 (3H, s), 1.03 -1.10 (2H, m),

0.87-0.92 (2H, m). TX / MC (M + H) ⁺ m / z 457 (t = 1.51 min).

Example 408

(S) -N-ethyl-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carboxamidine: ¹ N.

NMR (400 MHz, CD3OD) δ 7.82 (1H, s), 7.38 (1H, s), 7.12 - 7.30 (6H, m), 6.15 (1H, d, J =

7.8 Hz), 4.04 - 4.07 (1H, m), 3.75 - 3.77 (2H, m), 3.51 (2H, q, J = 7.3 Hz), 3.15 (1H, dd, J = 5.4, 13.7 Hz), 2.96 ( 1H, dd, J = 8.1, 13.7 Hz), 2.67 (3H, s), 1.40 (3H, t, J = 7.3 Hz). TX / MC (M + H) ⁺ m / z 445 (t = 1.44 min).

Example 409

(S) -2- {4- [2- (3-chlorophenyl) -1-hydroxymethylethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzimidazole-5-carboxamidine : ¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (1H, s), 7.38 (1 Η, s), 7.31 (1 Η, s), 7.10-7.24 (4Η, m), 6.16 (1H, d , J = 7.6 Hz), 4.06 - 4.09 (1H, m), 3.72 - 3.77 (2H, m), 3.16 (3H, s), 3.15

172 (1H, m), 2.96 (1 Η, dd, J = 8.2, 13.7 Hz), 2.67 (3H, s). TX / MC (M + H) ⁺ m / z 465 (t = 1.49 min).

Example 410

(S) -2- {4- [2- (2-chlorophenyl) -1-hydroxymethylethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7, N-dimethyl-3H-benzimidazol-5 -carboxamidine: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (1H, s), 7.41 (1H, s), 7.32 - 7.35 (2H, m), 7.06 - 7.18 (3H, m), 6.10 (1H) , d, J = 7.5 Hz), 4.20 - 4.24 (1H, m), 3.76 - 3.85 (2H, m), 3.30 - 3.34 (1H, m), 3.06 - 3.14 (1H, m), 3.13 (3H, s ), 2.64 (3H, s). TX / MC (M + H) ⁺ m / z 465 (t = 1.48 min).

Example 411

(±) -2- {4- [2- (3-bromophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzimidazol-5 -carboxamidine: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.80 (1H, s), 7.69 (1 Η, s), 7.20 - 7.45 (5Η, m), 6.25 (1H, d, J = 7.3

Hz), 5.00 (1H, t, J = 5.9 Hz), 3.64 - 3.80 (2H, m), 3.12 (3H, s), 2.66 (3H, s). TX / MC (M + H) ⁺ m / z 495 (t -1.49 min).

Example 412

173

(S) -2- [4- (2-Hydroxy-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7, N-dimethyl-3H-benzimidazole-5-carboxamidine: ¹ N.

NMR (300 MHz, CD3OD) δ 7.78 (1H, s), 7.24 - 7.49 (7H, m), 6.21 (1H, d, J = 7.0 Hz),

4.00-5.05 (1H, m), 3.51-3.74 (2H, m), 3.12 (3H, s), 2.63 (3H, s). TX / MC (M + H) ⁺ m / z 417 (t = 1.49 min).

Etc. No. Name Structure t (min) MS (M + H) ⁺ m / z 413 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (1 imino-1-morpholin-4-ylmethyl) -4methyl-1H-benzimidazol-2-yl] - 1 H-pyridin-2-one NH oSgpUH ^N \ ~ U ^OH to 1.55 (f) 507 414 (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] 3- [6- (4,5-dihydro-1H-imidazol-2yl) -4-methyl-1H -benzimidazol-2-yl] -1H-pyridin-2-one ff I ng / / OH OMe 1.49 (b) 537 415 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N- (2,2diethoxyethyl) -7-methyl-3H-benzimidazole- 5-carboxamide Φαφ I HN X O “ ^Cl 1.77 (f) 553

174

416 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (1 Nimidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2 -on ff I O ~ ^{c |} 1.71 . Yu 461 417 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (7'methyl-1H, 3'H- [2,5 '] bibenzimidazolyl-2'-yl) -1H -pyridin-2-one SF n h 1.82 (B) 511 418 (±) -cis-4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (7'methyl-N, 5,6,7,7a-hexahydro 1 H, 3'H- [2,5 ' ] bibenzimidazolyl2'-yl) -1H-pyridin-2-one 1 HN ~ P ^H CA ^ci 1.75 (B) 517 419 (±) -Trans-4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (7'-methyl-3a, 4,5,6,7,7a-hexahydro- 1H, 3'H- [2,5 '] bibenzimidazolyl2'-yl) -1H-pyridin-2-one ng 1 ng / ~ pH O ~ ^C1 1.75 (B) 517 420 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -1 \ 1-cyclopentyl-7-methyl-3H-benzimidazole- 5-carboxamidine 1 0-C1 1.55 (B) 505 421 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N-cyclohexyl-7-methyl-3H-benzimidazol-5- carboxamidine П Г Н Ч ff 1.61 (B) 519

175

422 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-propyl-3H-benzimidazole-5carboxamidine nh ₂ I H | D ~ pH C> - ^{c |} 1.48 (B) 479 423 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl} -N-dipropyl-3H-benzimidazole -5-carboxamidine HN ^ ₀ ι HN p »O ~ ^{c |} 1.61 (B) 521 424 (+) - 2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -LAisopropyl-7-methyl-3H-benzimidazole-5-carboxamidine nh ₂ 44 I nGrn SU ^{c |} 1.41 (B) 479 425 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-N- (2-morpholin-4-ylethyl) -N-benzimidazole-5-carboxamidine θ4 ^nh ₂ I hn4P ^h ν> - ^α 1.27 (B) 550 426 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl (7, N) -5- (2-morpholine- 4-ylethyl) 3H-benzimidazole-5carboxamidine 4 ° o4 _o V-NH CDD I ng / on C> ^{s |} 1.22 (B) 663

176

427 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N- ( ² · hydroxyethyl) -7-methyl-3H-benzimidazole -5-carboxamidine NHj _n I 'ngGrn Ο ^-01 1.38 (B) 481 428 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (5methyl-1H-imidazol-2-yl) -1H-benzimidazol-2-yl ] -1 Npyridin-2-one GIVE I HN ~ pH tb ^cl 1.62 (B) 475 429 (+) - 2- {4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] 2-oxo-1,2-dihydropyridin-3-yl} -4-methyl-1H-benzimidazole-6carboxamidic acid hydrazide T “hQh Q- ^C1 1.44 (f) 452 430 (±) -2- {4 [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -4-methyl- 1 H-Benzimidazole-6carboxamidic acid / CHO OD-b I HN ~ pH CB ^{c |} 1.58 (f) 480 431 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (4H [1 _; 2,4] triazol-3-yl) -1H- benzimidazol-2-yl] -1H-pyridin-2-one n H w i I HN ~ pH C b ^{c |} 1.82 (0 462 432 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N / hydroxy-7-methyl-3H-benzimidazol-5 -carboxamidine I nGG ”pH O- ^{c |} 1.34 (f) 453

177

433 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} - N / methoxy-7-methyl-3H-benzimidazol-5 -carboxamidine 4 / I ng / ~ ° n tv ^cl 1.41 (f) 467 434 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N / hydroxy-7, LA dimethyl-3H-benzimidazole-5- carboxamidine I HN 4 O ~ ^CI 1.39 (f) 467 435 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N-ethyl-7methyl-3H-benzimidazole-5carboxamidine NH ₂ I Hfi PH O “ ^{C |} 1.62 (f) 465 436 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} - (N-methyl-N) - (2,2,2-trifluoroethyl) 3-3H-benzimidazole-5-carboxamidine o yj 1.75 (f) 519 437 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} - (hydroxy-7, N), N-trimethyl-3H-benzimidazole -5-carboxamidine I HN ^ J3H v> ^ci 1.58 (f) 465

178

438 (±) -2- {4- [2- (3-fluorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -A / hydroxy-7, LA dimethyl-3H-benzimidazol-5- carboxamidine nh ₂ HUI I ΗΙΪΡΗ X 1.28 (b) 435 439 (±) -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -4- [2- (3-fluorophenyl) -2-hydroxy-ethylamino] - 1 H-pyridin-2-one / -nh 0 T HN pH 1.46 (B) 447 440 (±) -3- [6- (5,5-dimethyl) -4,5-dihydro-1H-imidazol-2-yl) -4methyl-1H-benzimidazol-2-yl] -4 [2- (3- fluorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one ~ / ^ΝΗ 0 ld I ^Η χΑ ^Η 1.59 (B) 475 441 (S) -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-phenyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino ) -1 Npyridin-2-one r-ΝΗ about Cf. 1 HN_ 2.90 (B) 505 442 (S) -3- [4-Bromo-6- (4,5-dihydro-1 Nimidazol-2-yl) -1 H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1 H -pyridine-2one Ζ ^ ΝΗ 0 XX I HN 1.57 (B) 507

179

443 (±) - [2-chloro-4- (1-hydroxy-2- {3- [4-methyl-6- (LA methylcarbamimidoyl) -1H-benzimidazol-2-yl] -2-oxo-1,2-dihydropyridine isobutyl ester- 4-ylamino} ethyl) phenyl] carbamic acid nh ₂ I H | / ~ pH C / o HnA ° b 1.64 (b) 566 444 (S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl- N- (2-morpholin-4-ylethyl) -NH-benzimidazole-5-carboxamidine op 0 1.33 (b) 530 445 (S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl- LA (2-thiophen-2-ylethyl) -NH-benzimidazole-5-carboxamidine I H | / cP * 1.62 (b) 527 446 (S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl- LA (2-Pyridin-2-ylethyl) -NH-benzimidazole-5-carboxamidine pN in ^H 2 Q I Hl / 1.40 (b) 522 447 (S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl- N - (2-Pyridin-3-ylethyl) -NH-benzimidazole-5-carboxamidine P's NH ₂ I Hl / cP ^w 1.37 (b) 522

180

448 (S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl- LA (2-Pyridin-4-ylethyl) -NH-benzimidazole-5-carboxamidine CX ^H 1.25 (b) 522 449 (S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-N, N-bis- (2-pyridin-3-yl-ethyl) ) 3H-benzimidazole-5carboxamidine Λ ₀ I ng / 1.24 (b) 627 450 (S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl- N, N '- bis- (2-pyridin-4-yl-ethyl) 3H-benzimidazole-5carboxamidine η T HN1 1.16 (b) 627 451 (S) -4- [2- (2-Chlorophenyl) -1 hydroxymethyl-ethylamino] -3- [6 (4,5-dihydro-1H-imidazol-2-yl) 4-methyl-1H-benzimidazole- 2-yl] - 1 H-pyridin-2-one r-ΝΗ ₀ I HN. Q- ^ ³⁴ ΌΙ 1.53 (b) 477 452 (S) -2- [4- (1-Hydroxymethyl-2pyridin-3-yl-ethylamino) -2oxo-1,2-dihydropyridin-3-yl] 7, LA dimethyl-3H-benzimidazole5-carboxamidine νη ₂ Χϊφ I ΗΝ 0.80 (b) 432

181

453 (S) -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-pyridine) 3-yl-ethylamino) -1H-pyridin-2-one r ~ NH about HGF I HN. Wed ~ ° ^N 0.98 (b) 444 454 (S) -2- [4- (1-Hydroxymethyl-2-pyridin-4-yl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] 7, N-dimethyl-3H-benzimidazole5-carboxamidine ^NH 2 _o Guf I HN. * 0.73 (b) 432 455 (S) -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-pyridine) -4-ylethylamino) -1H-pyridin-2-one r ~ NH ο I HN1 0.98 (b) 444 456 (S) -2- [4- (1-Hydroxymethyl-2-thiophen-2-yl-ethylamino) -2-oxo-1,2-dihydropyridin-4-yl] -7, N / dimethyl-3H-benzimidazole-5carboxamidine nh ₂ I HN. SL ⁶ⁿ 1.24 (b) 437 457 (S) -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1-hydroxymethyl-2-thiophene -2-ylethylamino) -1H-pyridin-2-one j — NH q Gaf I HN. SL ^on 1.46 (b) 449

182

458 (S) -2- [4- (2-benzo [b] thiophen-3-yl- 1-hydroxymethylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] 7, LADimethyl-3H-benzimidazole5-carboxamidine nh ₂ I HN_ ζ OH 1.47 (b) 487 459 7, N-Adimethyl-2- [2-oxo-4- (2-pyridin-2-yl-ethylamino) -1,2-dihydropyridin-3-yl] -3H-benzimidazole-5-carboxamide nh ₂ ΆΦ I HN An 0.86 (b) 402 460 3- (6- (4,5-dihydro-1H-imidazol-2yl) -4-methyl-1H-benzimidazol-2yl] -4- (2-pyridin-2-ylethylamino) -1H-pyridin-2- he ^ NH o YcHJ I HN uh 0.91 (b) 414 461 (S) -7-6poiv-2- [4- (1-hydroxymethyl-2-phenyl ethylamino) -2oxo-1,2-dihydropyridin-3-yl] N-methyl-3H-benzimidazole- 5carboxamidine 0 A ⁿ ₄ ^h ACHNA I HN Br - ^dh 1.47 (b) 495 462 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-ethyl-N / methyl-3H-benzimidazole-5carboxamidine nh ₂ J HN OH 1.51 (d) 465 463 N, N-dimethyl-2- [2-oxo-4- (2-pyridin-2-ylmethylamino) -1,2-dihydropyridin-3-yl] -3H-benzimidazole-5-carboxamidine nh ₂ I HN N - = \ mJ 0.98 (b) 388

183

464 3- (6- (4,5-dihydro-1H-imidazol-2yl) -4-methyl-1H-benzimidazol-2yl] -4 - [(pyridin-2-ylmethyl) amino)] -1H-pyridine -2-he ONH Q ff I HN N - = \ ff 1.07 '(b) 400 465 7, LADimethyl-2- [2-oxo-4- (2-thiophen-2-ylethylamino) -1,2-dihydropyridin-3-yl] -3H-benzimidazole-5-carboxamidine nh ₂ fsf I hn bh 1.53 (B) 407 466 3- (6- (4,5-dihydro-1H-imidazol-2yl) -4-methyl-1H-benzimidazol-2yl] -4- (2-thiophen-2-ylethylamino) - 1 H-pyridin-2-one L-NH ⁰ ф I HN 1.62 (B) 419 467 (±) -2- {4- [2- (3-chlorophenyl) -ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, AADimethyl-3H-benzimidazole-5-carboxamidine NHg ff I HN 1.57 (B) 435 468 (±) -4- [2- (3-chlorophenyl) ethylamino] -3- [6- (4,5-dihydro-1 Nimidazol-2-yl) -4-methyl-1 N-benzimidazol-2-yl] -1 Npyridin-2-one Z ^ NH ₀ ф I HN Λ) ^-0 1.66 (B) 447 469 (±) -3- [4-chloro-6- (4,5-dihydro-1 Nimidazol-2-yl) -1H-benzimidazol-2-yl] -4- (2- (3-chlorophenyl) -2hydroxyethylamino ] -1 NPIRIDINE; 2-0H Z ^ NH 0 ф Il ^HN V_ / ° ^H O ~ ^ci 1.66 (d) 483

184

470 (±) -3- [4-chloro-6- (5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl) -1H-benzimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one o ϊχ'γό оШ χζ'Άζ h 1.52 (d) 511 471 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] '3- [6- (5,5-dimethyl-4,5-dihydro-1 Nimidazol-2-yl) -4-ethyl-1 N-benzimidazole -2-yl] -1 Npyridin-2-one FS ₀ J ηΝ οη 4 1.57 (d) 505 472 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4ethyl-1H-benzimidazol-2-yl ] -1 Npyridin-2-one 4 ^ΝΗ 0 J Ην \ οΗ 4 1.49 (d) 477 473 (S) -3- [6- (4,5-dihydro-1 Nimidazol-2-yl) -4-ethyl-1H-benzimidazol-2-yl] -4- (1 hydroxymethyl-2-phenylethylamino) -1H- pyridin-2-one 4ΝΗ 0 Ανφ ΗΝ. fHh 1.47 (d) 457 474 (S) -7-ethyl-2- [4- (1-hydroxymethyl2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -Lamethyl-3H-benzimidazole-5-carboxamidine / \ / —Α Ο τ ¹ Αχ}. - ΞΕ ¹ 1.42 (d) 445

185

Preparation of amides

Intermediate syntheses

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid ethyl ester: (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5 ethyl ester solution -carboximidic acid (400 mg, 0.90 mmol) was diluted with 2N HCl solution (20 ml) and the mixture was stirred at room temperature for 14 hours. After concentration to dryness, the crude product (419 mg, 100%) was used in the next step without purification. A small amount was purified by preparative HPLC to give the title compound. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.11 (1 Η,

2.61

s), 7.74 (1H, s), 7.25-7.54 (5H, m), 6.25 (1H, d, J = 7.6 Hz), 4.99 (1H, t, J = 7.2 Hz).

4.38 (2H, q, J = 7.1 Hz), 3.61 - 3.76 (2H, m)

TX / MC (M + H) ⁺ m / z 467 (t = 2.23 min).

(3H, s), 1.42 (3H, q, J = 7.1 Hz).

HOOC

(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxyl vinegar

186 lins: The ethyl ester (419 mg, 0.90 mmol) obtained above was diluted with methanol (15 ml) and water (5 ml), then sodium hydroxide (180 mg, 4.5 mmol) was added to the solution. The mixture was stirred at room temperature for 14 hours. After removal of methanol, the residue was neutralized with a solution of 2N HCl. The resulting suspension was filtered and washed with ice-cold water. The solid product is obtained after drying under high vacuum. The crude product (395 mg, 100% yield, 80% purity) was used in the next step without further purification. ¹ NMR (300 MHz, CD ₃ OD) δ 8.20 (1H, s), 7.92 (1H, s), 7.27- 7.47 (5H, m), 6.27 (1H, d, J = 7.6 Hz), © 4.85 (1H , m), 3.63 (2H, m), 2.67 (3H, s). TX / MC (M + H) ⁺ m / z 439 (t = 1.88 min.).

Example 475

(S) - 2- (4- (1-Hydroxymethyl-2-phenylethylamino) -2oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carboxylic acid ethyl ester: The imidoester ( 30 mg, 0.067 mmol) was diluted with methanol (10 ml) and two drops of water were added to the solution, the reaction mixture was stirred at room temperature for 20 hours After concentration in vacuo, the residue was purified by preparative HPLC, whereby the compound of the title (18.2 mg, 61%) was obtained as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.74 (1H, s), 7.11 7.30 (7Η, m), 6.10 (1H , d, J = 6.9 Hz), 4.37 (2H, q, J = 6.6 Hz), 4.02 (1H, br s ), 3.69 - 3.81 (2H, m), 3.10 (1H, dd, J = 4.8, 13.5 Hz), 2.93 (1H, dd, J = 7.8, 13.5 Hz), 2.62 (3H, s), 1.41 (3H. t J = 6.6 Hz) TX / MC (M + H) ⁺ m / z 447 (t = 1.95 min).

Preparation of amides from starting compound (±) -2- {4- [2- (3187 chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3yl} -7-methyl-3H-benzimidazol-5 -carboxylic acid, Examples

476 -504, Scheme IV, 15

Example 476

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid methylamide: To a solution of acid (50 mg, 0.11 mmol) in DMF (5 ml) was added diphenylphosphorylase (38 mg, 0.14 mmol). The mixture was stirred for 5 minutes. Methylamine (2.0M solution in THF) (0.11 ml, 0.22 mmol) was added. The mixture was stirred at room temperature for 14 hours. After removal under high vacuum of DMF, the residue was purified by preparative HPLC to give the title compound (18 mg, 36%) as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.89 (1H, s), 7.18 - 7.53 (6Η, m), 6.23 (1H, d, J = 7.6 Hz), 4.98 (1H, m), 3.70 (1H , dd, J = 4.7, 13.5 Hz), 3.61 (1H, dd, J = 7.0, 13.5 Hz), 2.94 (3H, s), 2.61 (3H, s). TX / MC (M + H) + m / z 452 (t = 1.57 min).

Example 477

188

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.52 (1H, s), 7.24 - 7.40 (5Η, m), 7.15 (1H, s), 6.25 (1 Η, d, J = 7.6 Hz), 4.98 (1H , dd, J = 5.0, 6.9 Hz), 3.70 (1H, dd, J = 4.8, 13.5 Hz), 3.62 (1H, dd, J; 7.0, 13.5 Hz), 3.3 (3H, s), 3.08 (3H. s), 2.62 (3H, s). TX / MC (M + H) ⁺ m / z 466 (t = 1.84 min.).

Example 478

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H tert-butylamide -benzimidazole-5carboxylic acid: 1 H NMR (300 MHz, CD ₃ OD) δ 7.82 (1H, s), 7.53 (1 Η, s), 7.48 (1 Η, s), 7.24 - 7.40 (4Η, m), 6.25 (1H, d, J = 7.6 Hz), 5.00 (1H, m), 3.64 - 3.70 (2H, m), 2.62 (3H, s), 1.49 (9H, s). TX / MC (M + H) ⁺ m / z 494 (t = 1.79 min.).

Example 479

• Cl

189

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid butylmethylamide : ¹ H NMR (300 MHz, CD ₃ OD) δ 7.51 (1H, s), 7.48 (1 Η, s),

7.24 - 7.39 (4Η, m), 7.13 (1H, s), 6.22 (1Η, d, J = 7.6 Hz), 4.95 (1H, m), 3.55 - 3.70 (3H, m), 3.34 (1H, m ), 3.05 (3H, s), 2.62 (3H, s), 0.79-1.69 (7H, m). TX / MC (M + H) ⁺ m / z 508 (t = 1.88 min.).

Example 480

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7 (2-morpholin-4-ylethyl) amide -methyl-3H-benzimidazole-5-carboxylic acid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.58 (1 Η,

s), 7.52 (1 Η, s), 7.05 - 7.42 (5Η, m), 6.22 (1H, d, J = 7.6 Hz), 4.97 (1H, dd, J = 4.9,

6.7 Hz), 2.60 - 4.07 (14H, m), 2.61 (3H, s). TX / MC (M + H) + m / z 551 (t = 1.49 min).

Example 481

(±) -4- [1- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7 tert-butyl ester -7 -methyl-3H-benzimidazol-5-yl) methanoyl] piperazine-1-carboxylic acid: ¹ H NMR (300

MHz, CD ₃ OD) δ 7.52 (1H, s), 7.50 (1 Η, s), 7.24 - 7.38 (4Η, m), 7.18 (1H, m), 6.22

190 (1H, d, J = 7.6 Hz), 4.97 (1H, m), 3.49 - 3.69 (10H, m), 2.62 (3H, s), 1.47 (9H, s).

TX / MC (M + H) ⁺ m / z 607 (t = 1.90 min.).

Example 482

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (1-piperazin-1-yl-methanoyl) -1H-benzimidazol-2-yl] -1 N-Pyridin-2one: To a solution of (±) -4- [1- (2- {4- [2- (3-chlorophenyl) -2hydroxyethylamino] -2-oxo-1,2-dihydropyridine tert-butyl ester) -3-yl} -7-methyl-3H-benzimidazol-5-yl) methanoyl] piperazine-1-carboxylic acid (40 mg, 0.06 mmol) in methanol (5 ml) was added 4.0M HCl (dioxane solution, 0.1 ml). , excess). The reaction mixture was stirred at room temperature for 14 hours. After concentration, the residue was purified by preparative HPLC to give the title compound (16 mg, 63%) as a white foam. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.56 (1H, s), 7.53 (1 Η, s), 7.23 - 7.41 (4Η, m), 7.17 (1H, m), 6.26 (1Η, d, J = 7.6 Hz), 4.99 (1H, dd, J = 4.7, 6.4 Hz), 3.91 (4H, br s), 3.74 (1H, dd, J = 4.7, 13.5 Hz), 3.65 (1H, dd, J = 6.4 , 13.5 Hz), 3.31 (4H, br s), 2.63 (3H, s). TX / MC (M + H) ⁺ m / z 507 (t = 1.38 min).

Example 483

Cl

191

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid cyclopropylamide : ¹ H NMR (300 MHz, CD ₃ OD) δ 7.80 (1H, s), 7.21-7.53 (6H, m), 6.22 (1H, d, J = 7.6 Hz), 4.99 (1H, t, J = 6.4) Hz), 3.59-3.76 (2H, m), 2.832.90 (1H, m), 2.60 (3H, s), 0.81-0.89 (2H, m), 0.64-0.73 (2H, m). TX / MC (M + H) ⁺ m / z 478 (t = 1.60 min.).

Example 484

Cyclopentylamide of (±) -2- {4- [2- ( 3-chlorophenyl) -2-hydroxyethyl ^{m-yl amino]} -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-ZN- benzimidazole-5carboxylic acid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.97 (1H, s), 7.16 - 7.60 (6Η, m), 6.22 (1H, d, J = 7.6 Hz), 4.35 (1H, m ), 3.58 - 3.68 (2H, m), 2.62 (3H, s),

1.29-2.07 (9H, m). TX / MC (M + H) ⁺ m / z 506 (t = 1.86 min).

Example 485

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (1-piperidin-1-yl-methanoyl) -1H-benzimidazol-2-yl] -1 H-pyridin-2one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.53 (1H, s), 7.46 (1 Η, s), 7.18 - 7.41 (4Η, m),

7.07 (1H, s), 6.23 (1 Η, d, J = 7.6 Hz), 4.98 (1H, dd, J = 4.8, 6.6 Hz), 3.60 - 3.74 (5H,

192

m), 3.18-2.24 (1H, m), 2.60 (3H, m), 1.43 -1.7 (6H, m). TX / MC (M + H) ⁺ m / z 506 (t = 1.78 min).

Example 486

(±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid cyclohexylamide : ¹ H NMR (300 MHz, CD ₃ OD) δ 7.88 (1H, s), 7.54 (1 Η, s), 7.52 (1 Η, s), 7.16 - 7.40 (4Η, m), 6.22 (1H, J = 7.6 Hz), 4.97 (1H, dd, J = 4.7, 6.9 Hz), 3.89 (H, m), 3.69 (1H, dd, J = 4.7, 13.5 Hz), 3.61 (1H, dd, J = 6.9. 13.5 Hz), 2.61 (3H, s), 1.19-2.00 (10H, m). TX / MC (M + H) ⁺ m / z 520 (t = 1.93 min.).

Example 487

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [1- (4methylpiperidin-1-yl) -methanoyl] -1H-benzimidazol-2-yl } -1 Npyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.51 (1H, s), 7.49 (1 Η, s), 7.21 7.39 (4Η, m), 7.14 (1H, s) , 6.24 (1Η, d, J = 7.6 Hz), 4.96 (1H, dd, J = 4.7, 7.0 Hz), 3.68 (1H, dd, J = 4.7, 13.6 Hz), 3.60 (1H, dd, J = 7.0, 13.6 Hz), 2.62 (3H, s), 1.93 1.72 (9H, m), 1.00 (3H, d, J = 6.3 Hz). TX / MC (M + H) ⁺ m / z 520 (t = 1.97 min.).

Example 488

193

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4,5-dihydrothiazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -1H-Pyridin-2-one: To a solution of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile (100 mg, 0.24 mmol) in methanol (20 ml) was added 2-aminoethanethiol hydrochloride (41 mg, 0.36 mmol) and triethylamine (0.1 ml, excess). The reaction mixture was refluxed for 14 hours and then cooled to room temperature. After concentration, the residue was purified by preparative HPLC to give the title compound (76 mg, 66%) as a yellow solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.10 (1H, s), 7.71 (1 Η, s), 7.66 (1 Η, s), 7.25 - 7.53 (4Η, m), 6.33 (1H, d. J = 7.6 Hz), 5.01 (1H, dd, J = 4.2, 7.0 Hz), 4.58 (2H, t, J = 8.6 Hz), 3.91 (2H, t, J = 8.6 Hz), 3.73 (1H, dd, J = 4.2, 13.7 Hz), 3.63 (1H, dd, J = 7.0, 13.7 Hz), 2.64 (3H, s). TX / MC (M + H) ⁺ m / z 480 (t = 1.70 min.).

Example 489

(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbaldehyde:

194

To a suspension of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo,2,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile (76 mg, 0.18 mmol) in toluene (free, 20 ml) at -78 ° C under nitrogen was added diisobutylaluminum (1.4M solution in toluene) (0.65 ml, 0.97 mmol). The mixture was stirred at -78 ° C for 6 hours. Ethyl acetate (1 ml) was added followed by water (0.5 ml). The mixture was stirred at room temperature for 20 minutes. The mixture was then filtered through a celite filter and concentrated. The crude product was purified by preparative HPLC to give the title compound (4mg, 2.5%) as a brownish solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.65 (1H, s), 7.57 (1 Η, s), 7.24 - 7.50 (5Η, m), 6.26 (1H, d, J = 7.6 Hz), 5.49 ( 1H, s), 4.96 (1H, m), 3.53 - 3.79 (2H, m), 2.62 (3H, s). TX / MC (M + H) ⁺ m / z 423 (t = 1.79 min.).

Example 490

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (1-hydroxy-1-methylethyl) -4-methyl-1H-benzimidazol-2-yl] -1H- Pyridin-2-one: To a solution of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] 2-oxo-1,2-dihydropyridin-3-yl} -7 ethyl ester -methyl-3H-benzimidazole-5-carboxylic acid (40 mg, 0.08 mmol) in THF (5 ml) at -78 ° C and methylithium (1.4M solution in THF, 0.57 ml, 0.8 mmol) was added under nitrogen. The reaction mixture was allowed to reach room temperature overnight. After the addition of water, the mixture was partitioned between ethyl acetate and an aqueous layer. The organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue is purified by

195 preparative HPLC to give the title compound (13 mg, 36%) as a colorless oil. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.66 (1H, s), 7.47 (1 Η, s), 7.26 - 7.41 (5Η, m), 6.26 (1H, d, J = 7.6 Hz), 4.92 ( 1H, m), 3.54 - 3.61 (2H,

m), 2.62 (3H, s), 1.60 (6H, s). TX / MC (M + H) ⁺ m / z 453 (t = 1.46 min).

Example 491

Cl

(±) -3- (6-Aminomethyl-4-methyl-1H-benzimidazod-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] 1H-pyridin-2-one: To a solution of amide of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid (20 mg, 0.046 mmol) in THF (1 ml) was added boron-tetrahydrofuran complex (1M solution) (0.45 ml, 0.45 mmol). The reaction mixture was stirred at room temperature for 10 hours and then diluted with two drops of acetic acid. After removal of most of the solvent, the residue was extracted with EtOAc, washed with brine and dried over Na ₂ SO ₄ . After concentration, the crude product was purified by preparative HPLC to give the title compound (11.5 mg, 60%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53 (1H, s), 7.50 (1 Η, s), 7.39 (1 Η, d, J = 7.5 Hz), 7.24 - 7.32 (3H, m), 7.13 (1H, s), 6.26 (1H, d, J = 7.5 Hz), 4.99 (1H, dd, J = 4.8, 6.8 Hz), 4.19 (2H, s), 3.72 (1H, dd, J =

4.8, 13.6 Hz), 3.64 (1H, dd, J = 6.8, 13.6 Hz), 2.62 (3H, s). TX / MC (M + H) ⁺ m / z 424 (t = 2.10 min.).

Example 492

196

(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6-hydroxymethyl4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: To a solution of ethyl (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2Q dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic ester acid (25 mg, 0.054 mmol) in methanol (2 ml) and acetic acid (1 ml) at -20 ° C was added NaBH ₄ (10 mg, 0.27 mmol). The reaction mixture was stirred at -20 ° C for 30 minutes and then diluted with five drops of isopropanol. After removal of most of the solvent, the residue was extracted with EtOAc, washed with water and brine and dried over Na ₂ SO ₄ . After concentration, the crude product was purified by preparative HPLC to give the title compound (18 mg, 62%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.50 (1H, s), 7.48 (1 Η, s), 7.25 - 7.38 (4Η, © m), 7.22 (1H, s), 6.25 (1 Η, d , J = 7.6 Hz), 4.89 - 4.94 (1H, m), 4.76 (2H, s), 3.51 3.62 (2H, m), 2.62 (3H, s). TX / MC (M + H) ⁺ m / z 425 (t = 1.64 min).

Etc. No. Name Structure t (min) MS (M + H) ⁺ m / z 493 (±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2oxo-1,2-dihydropyridin-3-yl} 7-methyl-3H-benzimidazole-5-carboxylic acid amide T nGan 1.68 (f) 437

197

494 (±) -2- {4- [2- (3fluorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic ethyl ester acid 44 I nmcrn O- ^F 1.90 (b) 451 495 (±) -7-Chloro-2- {4 [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzimidazol-5- ethyl ester carboxylic acid 44 I SU 2.06 (d) 487 496 (±) -7-chloro-2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzimidazol-5- amide carboxylic acid 4 Q 1.54 (d) 458 497 (±) -7-chloro-2- {4- [2- (3-chlorophenyl) 2-hydroxy-ethylamino] -2-oxo 1,2-dihydro-pyridin-3-yl} -3H-benzimidazole-5-carboxylic acid 44 ci nh o- ° 1.69 (d) 459 498 (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-ethyl-3H-benzimidazole-5-carboxylic ethyl ester acid 44 J HN PH uh. 1.98 (d) 481

198

499 (±) -2- {4- [2- (3-Chlorophenyl) -2-hydroxyethyl-amino] 2-oxo-1,2-dihydropyridin-3-yl} -7-ethyl-3H-benzimidazole-5-carboxylic acid amide xn> The dream 1.51 (d) 452 500 (S) -7-6poM-2- [4 (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzimidazole-5-carboxylic acid ethyl ester XX I HN 2Ό6 (b) 511 501 (±) -2- {4- [2- (3bromophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid ethyl ester X / U I ng / ~ pH 1.99 (B) 511 502 (S) -2- {4- [2- (2-Chlorophenyl) -1-hydroxymethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxylic acid ethyl ester “XX ΌΙ 1.89 (B) 481 503 (S) -2- [4- (2-Hydroxy-2-phenylethylamino) -2-oxo-1,2-dihydro-pyridin-3-yl] 7-methyl-3H-benzimidazole-5-carboxylic acid ethyl ester XX I HN PH 'oh 1.84 (B) 433

199

504 (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (1Htetrazol-5-yl) -1H-benzimidazol-2-yl] -1H -pyridin-2-one N-NH ₀ T ng / ~ pH CO 1.92 (9 463

General Suzuki Accession Method, Examples 505-509 (Scheme V,

18)

Example 505

(S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-6-phenyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: To a solution of (S) -4 - (1-Benzyl2-trityloxyethylamino) -3- [6-bromo-4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2-one (50 mg, 0.072 mmol), phenyl boronic acid (13 mg, 0.11 mmol) and 2M K ₂ CO ₃ (0.108 mL, 0.22 mmol) in THF (5 mL) was added Pd (PPh ₃ ) ₄ (8.3 mg, 0.007 mmol). The mixture was heated to reflux for 14 hours. After cooling, the reaction mixture was diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was used in the next step without purification. TX / MC (M + H) + m / z 693 (t = 2.82 min). The crude product was treated for 6 hours at room temperature with 4N HCl (dioxane solution, 5 ml). After concentration in vacuo, the residue was purified by preparative HPLC to give the title compound (17 mg, 34%) as a white solid. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.13-7.67 (13H, m), 6.15 (1H, d, J = 7.4 Hz), 3.99-4.11 (1H, m), 3.74-3.77 (2H, m) , 3.16 (1H, dd, J = 5.4, 13.6 Hz), 2.97 (1H, dd, J = 7.8, 13.6 Hz), 2.69 (3H, s).

200

TX / MC (M + H) ⁺ m / z 451 (t = 2.04 min).

Example 506

(5) -4- (1-Benzyl-2-hydroxy-ethylamino) -3- (4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 6.98-7.46 (9H,

m), 6.15 (1H, d, J = 7.5 Hz), 3.99-4.04 (1H, m), 3.75 (2H, d, J = 5.1 Hz), 3.16 (1H, dd, m).

J = 5.1, 13.6 Hz), 2.95 (1H, dd, J = 8.1, 13.6 Hz), 2.61 (3H, s). TX / MC (M + H) ⁺ m / z

375 (t = 1.72 min).

Example 507

(S) -4- (1-Benzyl-2-hydroxy-ethylamino) -3- [6- (2-methoxyphenyl) -4methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz,

CD ₃ OD) δ 6.99-7.59 (12H, m), 6.16 (1H, d, J = 7.5 Hz), 4.04 (1H, m), 3.81 (3H, s),

3.76 (2H, d, J = 4.1 Hz), 2.96-3.20 (2H, m), 2.66 (3H, s). TX / MC (M + H) ⁺ m / z 481 (t = 2.00 min).

Example 508

201

(S) -4- (1-Benzyl-2-hydroxy-ethylamino) -3- [6- (4-fluorophenyl) -4methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz,

CD ₃ OD) δ 7.10-7.66 (12H, m), 6.13 (1H, d, J = 7.6 Hz), 3.99-4.04 (1H, m), 3.76 (2H.

d, J = 5.0 Hz), 3.16 (1H, dd, J = 5.0, 13.6 Hz), 2.96 (1H, dd, J = 8.1, 13.6 Hz), 2.65 (3H, s). TX / MC (M + H) ⁺ m / z 469 (t = 2.07 min).

Example 509

(S) - 4- (1-Benzyl-2-hydroxy-ethylamino) -3- [6- (4-methoxyphenyl) -4methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz,

CD3OD) δ 6.97-7.65 (12H, m), 6.14 (1H, d, J = 7.6 Hz), 4.00-4.04 (1H, m), 3.83 (3H, s), 3.76 (2H, d, J = 5.0 Hz) ), 2.95-3.19 (2H, m), 2.67 (3H, s). TX / MC (M + H) ⁺ m / z 481 (t = 2.01 min).

General Method for Buchwald-Binding, Examples 510-516 Scheme V, 19

202

Example 510

(B) -4- (1-Benzyl-2-hydroxy-ethylamino) -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: Mixture of (S) -4- (1-benzyl-2-trityloxyethylamino) -3- [6-bromo-4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2-one (150 mg, 0.216 mmol) , morpholine (28.2 mg, 0.324 mmol), palladium acetate (2.4 mg, 0.01 mmol), tri-tert -bugylphosphine (4.4 mg, 0.02 mmol) and sodium tert-butoxide (104 mg, 1.08 mmol) in toluene (5 ml) is heated for 14 hours at 100 ° C and under nitrogen. The reaction mixture was cooled to room temperature and diluted with EtOAc. After extraction, the combined organic layers were washed with water, brine and dried over Na ₂ SO ₄ . Concentration of the solution gave a brownish residue, which was treated for 6 hours at room temperature with 4N HCl (dioxane solution, 3 ml). After removal of the solvent, the residue was purified by preparative HPLC to give the title compound (18 mg, 18%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.59 (1H, s), 7.12-7.28 (7H, m), 6.12 (1H, d, J = 7.6 Hz), 4.014.08 (5H, m), 3.76 (1H, dd, J = 4.8, 11.1 Hz), 3.71 (1H, dd, J = 5.2, 11.1 Hz), 3.323.10 (4H, m), 3.09 (1H, dd, J = 5.6, 13.7 Hz). 2.92 (1H, dd, J = 8.0, 13.7 Hz), 2.65 (3H, s). TX / MC (M + H) ⁺ m / z 460 (t = 1.30 min).

Example 511

203

(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (300 MHz , CD ₃ OD) δ 7.177.64 (8H, m), 6.23 (1H, d, J = 10.2 Hz), 4.94 (1H, m), 3.61 (1H, dd, J = 4.8, 13.8 Hz).

3.54 (1H, dd, J = 7.4, 13.8 Hz), 2.61 (3H, s). TX / MC (M + H) ⁺ m / z 395 (t = 1.65 min).

Example 512

(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-pyridin-3-yl-1H-benzimidazol-2-yl) -1H-pyridine- 2-one: ¹ H NMR (300 MHz, © CD ₃ OD) δ 9.14 (1H, s), 8.88 (1 Η, d, J = 8.2 Hz), 8.72 (1H, d, J = 5.4 Hz), 8.08 (1H, dd, J = 5.8, 8.2 Hz), 7.82 (1H, s), 7.56 (1H, s), 7.24-7.45 (5H, m), 6.26 (1H, d, J = 7.6)

Hz), 5.02 (1H, dd, J = 5.0, 6.5 Hz), 3.77 (1H, dd, J = 5.0, 13.5 Hz), 3.68 (1H, dd;

J = 6.5,13.5 Hz), 2.68 (3H, s). TX / MC (M + H) ⁺ m / z 472 (t = 1.66 min).

Etc. No. Name Structure t (min) MS (M + H) ⁺ m / z 513 (±) -3- (6-bromo-4-methyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -1H-pyridin-2- he S-NH I ηι /, οη 2.08 (f) 473

204

514 (±) -4- [2- (3-chlorophenyl) -2hydroxy-ethylamino] -3- [6- (4methoxyphenyl) -4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2-one S-NH I n | / pH (B ^{c |} 1.96 (f) Mr 501 515 (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4methyl-1H-benzimidazol-2yl) -1H-pyridin-2-one H ° h hc ^ -N B-NH CQ-Q I ΗΝ _χ ΟΗ Cl · ⁰¹ 1.65 (f) 395 516 (S) -4- (1-Benzyl-2-hydroxyethyl-amino) -3- (4-methyl-6-piperidin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one LA? ^- 0 I h1h 0 ^ * 1.39 (b) 458

The following Examples 517-519 are prepared according to Schemes VII and

III.

Example 517

(S) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2- it: ¹ H NMR (500

MHz, CD ₃ OD) δ 7.54 (br s, 1 Η), 7.40-7.20 (m, 4H), 7.03 (br s, 1H), 6.84 (br s, 1H),

6.25 (d, 1H, J = 7.60 Hz), 5.01-4.91 (m, 1H), 3.73 (dd, 1H), 3.65 (dd, 1H), 3.45-3.25 (m, 8H), 2.56 (s, 3H) . TX / MC (M + H) ⁺ m / z 479, 481.

205

Example 518

* = Trifluoroacetate (±) -4- [2- (3-chloromethylsulfanylphenyl) -2-hydroxy-ethylamino] -3- (4methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H- Pyridin-2-one:

¹ H NMR (500 MHz, CD ₃ OD) δ 7.47 (br s, 1 Η), 7.38-7.29 (m, 2H), 7.19 (d, 1H, J = 8.3 Hz), 7.03 (br s, 1H). 6.98 (br s, 1H), 6.26 (d, 1H, J = 7.7 Hz), 4.90-4.81 (m, 1H), 3.65-3.35 (m, 10H), 2.56 (s, 3H). TX / MC (M + H) ⁺ m / z 525, 527.

Example 519

(S) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-

6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one: ¹ H NMR (500 MHz, CD3OD) δ 7.61 (dd, 1H, J = 2.1, 7.2 Hz) , 7.40 (ddd, 1H), 7.28 (d, 1H, J = 7.5 Hz), 7.17 (dd, 1H, J = 8.9, 8.8 Hz), 7.02 (br s, 1H), 6.87 (br s, 1H). 6.25 (d, 1H, J = 7.6 Hz), 4.99-4.90 (m, 1H), 3.73-3.60 (m, 2H), 3.45-3.30 (m, 8H), 2.54 (s, 3H). TX / MC (M + H) ⁺ m / z 497, 499.

The following examples (520-522) are prepared according to Schemes VII and III and illustrate the alkylation of a piperazine derivative Example 520 (general method for examples 520-522)

206

(S) -3- [4- (2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H- Benzoimidazol-5-yl) -piperazin-1-yl] -propionitrile: To a stirred solution of 4- [2- (3-chlorophenyl) 2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1- yl-1H-benzoimidazol-2yl) -1H-pyridin-2-one (17 mg, 0.021 mmol) in anhydrous methanol (1 ml) was added to Hunigs base (36 μl). The resulting solution was cooled to 0 ° C and acrylonitrile (5 μl) was added in portions until the reaction was determined by LC / MS. The reaction mixture was warmed to room temperature and the solvent was evaporated in vacuo. The resulting residue was purified by preparative reverse phase HPLC using a methanol / water / 0.1% trifluoroacetic acid gradient, the fractions were evaporated to give the title compound as a trifluoroacetate salt (12.1 mg). ¹ H NMR (500 MHz, CD 3 OD) δ 7.49 (br s, 1H), 7.39-7.23 (m, 4H), 7.15 (br s, 1H), 7.06 (br s, 1H), 6.25 (d, 1H, J = 7.7 Hz), 4.97-4.88 (m, 1H), 3.70-3.40 (m, 12H), 3.06 (t, 2H, J = 7.0 Hz), 2.59 (s, 3H). TX / MC (M + H) ⁺ m / z 532, 534. The triacetate salt of the pure title compound was dissolved in methanol and transferred to a Varian Mega Bond-Elute SCX cassette. Elution with methanol followed by 2.0 M NHs / MeOH gave the free base. The material was suspended in MeOH and 2 equivalents of 1.00N HCl (aqueous solution) were added. The resulting solution was filtered through a 45 μm filter and evaporated to give the bis-HCl salt of the compound of the invention: ¹ H NMR (500 MHz, CD 3 OD) δ 7.50-7.25 (m, 5H), 7.16 (br s, 1H ), 7.13 (br s, 1H), 6.27 (d, 1H, J = 7.7 Hz), 4.95-4.87 (m, 1H), 3.70-3.40 (m, 12H), 3.13

207 (t, 2H, J = 7.0 Hz), 2.62 (s, 3H). TX / MC (M + H) ⁺ m / z 532, 534.

Example 521

(S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfonylethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} 1 H-pyridin-2-one: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.53 (br s, 1H), 7.41-7.20 (m, 4H), 7.13 (br s, 1H) , 6.92 (br s, 1H), 6.24 (d, 1H, J = 7.6 Hz), 5.00-4.92 (m, 1H), 3.803.25 (m, 14H), 3.13 (s, 3H), 2.57 (s. 3H). TX / MC (M + H) ⁺ m / z 585, 587.

Example 522

($) - 3- [4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] ~

2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) piperazin-1-yl] -propionitrile: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.59 ( br s,

1H), 7.41 (d, 1H, J = 7.5 Hz), 7.34 (dd, 1H, J = 2.0, 8.5 Hz), 7.17 (br s, 1H), 7.12 (br s, 1H), 7.00 (d, 1H) , J = 8.5 Hz), 6.25 (d, 1H, J = 7.5 Hz), 4.85-4.76 (m, 1H), 3.85 (s, 3H), 3.80-3.30 (m, 12H), 3.16 (t, 2H. J = 7.0 Hz), 2.55 (s, 3H). TX / MC (M + H) ⁺ m / z 606, 608.

The following examples (523-528) were prepared according to Scheme VII

208 and III and illustrate the carbamoylation of piperazine derivatives

Example 523 (General Method for Examples 523-528)

CI

(S) -4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl- (2-fluoroethyl) ester 3H-benzoimidazol-5-yl) -piperazine-1-carboxylic acid: To a stirred solution of 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazine-1 -yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (-2 TFA salt, 80 mg, ~ 0.1 mmol) in methanol (2 ml), Ν, Ν- diisopropylethylamine (170 μl) and 2-fluoroethyl chloroformate (37 mg). The cooling bath was removed and the solution was stirred for 30 minutes at room temperature, after which the LC / MS analysis indicated that the reaction was complete. The reaction mixture was then purified by preparative reverse phase HPLC with a methanol / water / 0.1% trifluoroacetic acid gradient. The fractions were evaporated to give the title compound as a trifluoroacetate salt, which was dissolved in methanol and transferred to a Varian Mega Bond-Elute SCX cartridge. Elution with methanol, followed by 2.0 M IN3 / MeOH gave the free base (46.2 g). The material was suspended in MeOH and 1.00 N HCl (aqueous solution, 1 equivalent) was added. The resulting solution was filtered through a 45 μm filter and evaporated to give the title compound's mono-HCl salt: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.50 (br s, 1H), 7.45-7.20 (m , 6H), 6.26 (d, 1H, J = 7.7 Hz), 4.98-4.91 (m, 1H), 4.64 (dm, 2H, J = 47.9 Hz), 4.39 (dm, 2H, J = 29 Hz), 3.95 -3.50 (m, 10H), 2.63 (s, 3H).

209

TX / MC (M + H) ⁺ m / z 569, 571.

Example 524

(S) -4- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl- (2-methoxyethyl) ester 3H-benzoimidazol-5-yl) -piperazine-1-carboxylic acid: ¹ H NMR (500 MHz,

CD ₃ OD) δ 7.53-7.22 (m, 7H), 6.26 (d, 1H, J = 7.6 Hz), 4.96 (dd, 1H, J = 7.0, 4.6 Hz),

4.31-4.27 (m, 2H), 4.05-3.55 (m, 12H), 3.39 (s, 3H), 2.64 (s, 3H). TX / MC (M + H) ⁺ m / z 581.583.

Example 525

(S) - 4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl tert-butyl ester -3H-benzoimidazol-5-yl) -piperazine-1-carboxylic acid: ¹ H NMR (500 MHz,

CD3OD) δ 7.51 (br s, 1H), 7.40-7.22 (m, 6H), 6.26 (d, 1H, J = 7.7 Hz), 4.96-4.90 (m.

1H), 3.90-3.50 (m, 10H), 2.64 (s, 3H), 1.51 (s, 9H). TX / MC (M + H) ⁺ m / z 579, 581.

Example 526

210

(5) -4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-propynyl ester) 3H-benzoimidazol-5-yl) -piperazine-1-carboxylic acid: ¹ H NMR (500 MHz,

About CD ₃ OD) δ 7.50 (br s, 1 Η), 7.43-7.20 (m, 5Η), 7.19 (br s, 1 Η), 6.25 (d, 1H, J = 7.6 Hz), 4.98-4.90 (m , 1H), 4.78 (d, 2H, J = 2.5 Hz), 2.62 (s, 3H). TX / MC (M + H) ⁺ m / z 561.563.

Example 527

(S) - 4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl) t-butyl ester -7-methyl-3H-benzoimidazol-5-yl) -piperazine-1-carboxylic acid: ¹ H NMR (300 MHz, CD 3 OD) δ 7.65 (br s, 1 Η), 7.48-7.28 (m, 3H), 7.25 (br s, 1H), 6.97 (d, 1H, J = 8.5 Hz), 6.25 (d, 1H, 4 = 7.7 Hz), 4.94-4.86 (m, 1H), 3.90-3.45 (m, 10H), 3.82 (s , 3H), 2.61 (s, 3H), 1.52 (s, 9H). TX / MC (M + H) ⁺ m / z 653, 655.

Example 528

211

OMe

(S) - 4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-ethyl ester- 3H-benzoimidazol-5-yl) -piperazine-1-carboxylic acid: ¹ H NMR (400 MHz, CD 3 OD) δ 7.80 (1H, m), 7.63 (1H, narrow d, J = 1.8 Hz), 7.52 (1H, s ), 7.42 (1H, d, J = 7.5 Hz), 7.37 (1H, dd, J = 1.8, 8.4 Hz), 7.00 (1H, d, J = 8.4 Hz), 6.31 (1H, d, J = 7.5 Hz) ), 4.89 (1H, m), 4.22 (2H, q, J = 7.1 Hz), 3.98 (4H, br s), 3.84 (3H, s), 3.70-3.72 (4H, m), 3.59-3.60 (2H) , m), 2.67 (3H, s), 1.31 (3H, t, J = 7.1 Hz). TX / MC (M + H) ⁺ m / z 625 (t = 1.45 min).

The following examples (529-540) are prepared according to Schemes VII and III and illustrate an alternative method of alkylating piperazine derivatives

Example 529 (General Method for Examples 529-540)

(S) -4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4 (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H -benzoimidazol-2-yl} 1H-pyridin-2-one: To a stirred solution of 4- [2- (3-chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6 -piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (100 mg, 0.162 mmol) in 1,4-dioxane (4.0 ml), ethanol

212 (0.8 ml) and methanol (0.8 ml) were added N, N-diisopropylethylamine (0.30 ml) and 1-bromo-3-fluoropropane (85 μl). The reaction mixture was heated at 80 ° C for 12 hours. It was then purified by preparative reverse phase HPLC with a methanol / water / 0.1% trifluoroacetic acid gradient. The fractions were evaporated to give the title compound as a trifluoroacetate salt, which was dissolved in methanol and transferred to a Varian Mega Bond-Elute SCX cartridge. Elution with methanol followed by 2.0 M NH ₃ / MeOH gave the free base (39.3 g). The material was suspended in MeOH and 1.00 N HCl (aqueous solution, 2 equivalents) was added. The resulting solution was filtered through a 45 μm filter and evaporated to give the bis-HCl salt of the title compound: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.43-7.47 (m, 2H), 7.28 (dd, 1H, J = 2.0, 8.6 Hz), 7.16 (br s, 1H), 7.08 (d, 1H, J = 1.7 Hz), 7.01 (d, 1H, J = 8.5 Hz), 6.24 (d, 1H, J = 7.7 Hz), 4.84-4.78 (m, 1H), 4.60 (dt, 2H, J = 5.7, 47.1 Hz), 3.95-3.88 (m, 2H), 3.83 (s, 3H), 3.78-3.71 (m, 2H) ), 3.53-3.14 (m, 8H), 2.59 (s, 3H), 2.31-2.16 (m, 2H). TX / MC (M + H) ⁺ m / z 569, 571.

Example 530

($) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoroethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.20 (m, 5H), 7.16 (br s, 1H), 7.09 (br s, 1H ), 6.25 (d, 1H, J = 7.6 Hz), 5.00-4.92 (m, 1H), 4.92-4.78 (m, 2H), 3.98-3.15 (m, 12H), 2.60 (s, 3H); TX / MC (M + H) ⁺ m / z 525, 527.

Example 531

213

(S) - 4- [2- (3-chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H -benzoimidazol-2-yl} -1 Npyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.52 (dd, 1H, J = 2.1, 7.2 Hz), 7.40 (d, 1H, J = 7.6 Hz), 7.35-7.12 (m, 3H), 7.08 (d, 1H, J = 1.7 Hz), 6.25 (d, 1H, J = 7.7 Hz), 4.90-4.82 (m, 1H), 4.60 (dt , 2H, J = 5.4, 47.1 Hz), 3.96-3.10 (m, 12H), 2.60 (s, 3H), 2.28-2.13 (m, 2H); TX / MC (M + H) ⁺ m / z 557, 559.

Example 532

(S) - 4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4 (3-fluoropropyl) piperazin-1-yl] -4-methyl-1 N-benzoimidazol-2-yl} 1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.58 (d, 1H, J = 2.0 Hz), 7.43 (d, 1H, J = 7.6 Hz), 7.34 (dd, 1H, J = 2.0, 8.5 Hz), 7.19 (br s, 1H), 7.11 (br s, 1H9, 7.00 (d, 1H, J = 8.5 Hz), 6.26 (d, 1H) , J = 7.7 Hz), 5.90-4.82 (m, 1H), 4.61 (dt, 2H, J = 5.4, 47.1 Hz), 3.95-3.12 (m, 12H), 3.85 (s, 3H), 2.62 (s. 3H), 2.30-2.14 (m, 2H); TX / MC (M + H) ⁺ m / z 613, 615.

Example 533

214

(S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4

(3,3,3-Trifluoropropyl) piperazin-1-yl] -1H-benzoimidazol-2-yl} 1 H-pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.50-7.10 ( m, 7H), 6.26 (d, 1 Η, J = 7.5 Hz), 4.96-4.88 (m, 1H), 4.00-3.15 (m, 12H), 3.00-2.82 (m, 2H), 2.61 (s, 3H) ); TX / MC (M + H) ⁺ m / z 575, 577.

Example 534

($) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1Hpyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.46-7.25 (m, 5H), 7.19 (br s, 1H), 6.27 (d, 1H, J = 7.7 Hz), 4.95-4.86 (m, 1H), 4.62 (dt, 2H, J = 5.4, 47.1 Hz), 3.98-3.15 (m, 12H), 2.62 (s, 3H), 2.35-2.12 (m , 2H); TX / MC (M + H) ⁺ m / z 539, 541.

Example 535

Cl

215 (S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4 (3,4,4-trifluoro-butyl-3-enyl) piperazine-1 -yl] -1H-benzoimidazol-2yl} -1H-pyridin-2-one: TX / MS (M + H) ⁺ m / z 587, 589.

Example 536

4- [2- (3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- {6- [4- (3-fluoro-2-hydroxypropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} 1H-pyridin-2-one: TX / MS (M + H) ⁺ m / z 555, 557.

Example 537

($) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxy-

2-methylpropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -

H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.44-7.22 (m, 5H), 7.15 (br s, 1H), 7.08 (br s, 1H), 6.25 (d, 1H , J = 7.6 Hz), 4.88-4.80 (m, 1H), 3.86-3.81 (m, 4H), 3.55-3.32 (m, 6H), 3.28 (s, 2H), 2.60 (s, 3H), 1.38 ( s, 6H); TX / MC (M + H) ⁺ m / z 551, 553.

Example 538

216

(S) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxy ethyl) piperazin-1-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.50 (1H, s), 7.25-7.35 (4Η, m), 7.04 (1 Η, s ), 6.97 (1 Η, s), 6.22 (1 Η, d, J = 6.8 Hz), 4.93-4.95 (1H, m), 3.21-3.96 (14H, m), 2.57 (3H, s); TX / MC (M + H) ⁺ m / z 523 (t = 1.11 min).

Example 539

(B) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4 (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H -Benzoimidazol-2-yl} 1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.60 (1H, narrow d, J = 2.0 Hz), 7.40 (1H, d, J = 7.6 Hz) ), 7.35 (1H, dd, J = 2.0, 8.4 Hz), 7.13 (1H, s), 7.09 (1H, s), 6.99 (1H, d, J = 8.4 Hz), 6.25 (1H, d, J = 7.6 Hz), 4.82-4.87 (1H, m), 3.76-3.97 (6H, m), 3.84 (3H, s), 3.24-3.52 (8H, m), 2.60 (3H, s); TX / MC (M + H) ⁺ m / z 597 (t = 1.09 min).

Example 540

Cl

217 ($) - [4- (2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H -benzoimidazol-2-yl) -1H-piperazin-1-yl] acetonitrile: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.25 (m, 7H), 6.28 (d, 1H, J = 8.0 Hz) , 4.95-4.88 (m, 1H), 4.32 (s, 2H), 3.75-3.62 (m, 4H), 3.60-3.35 (m,

6H), 2.63 (s, 3H); TX / MC (M + H) ⁺ m / z 518.520.

The following examples (541-553) are prepared according to Schemes VII and III and illustrate the alkylation of a piperazine derivative Example 541 (General method for Examples 541-553)

($) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (4fluorobutyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2 -yl} 1H-pyridin-2-one: To a stirred solution of 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazole -2-yl) 1H-pyridin-2-one (70 mg, 0.136 mmol) in anhydrous N, N-dimethylformamide (750 μl) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (112 mg, 0.584) mmol), 1-hydroxybenzotriazole hydrate (59 mg, 0.438 mmol), N-methyl-morpholine (0.048 ml, 0.438 mmol) and 4-fluoro-lactic acid (31 mg, 0.291 mmol; see O'Hagan, D., J. Fluorine Chem. , 43, (1989), 371-377) and the mixture was heated 3 hours at 80 ° C. The reaction mixture was then purified by preparative reverse phase HPLC with a methanol / water / 0.1% trifluoroacetic acid gradient. The fractions were evaporated to give the title compound as a trifluoroacetate salt, which was dissolved in methanol and transferred to a Varian Mega Bond-Elute SCX cartridge. Elution with methanol, followed by 2.0 M NH ₃ / MeOH affords free

218 bases (35.9 mg). The material was suspended in MeOH and 1.00 N HCl (aqueous solution, 2 equivalents) was added. The resulting solution was filtered through a 45 μm filter and evaporated to give the bis-HCl salt of the title compound (37.6 mg): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (br s, 1H), 7.47 (br s, 1H), 7.44-7.20 (m, 5H), 6.27 (d, 1H, J = 7.6 Hz), 4.92 (dd, 1H, J = 4.4, 7.3 Hz), 4.50 (dt, 2H, J = 5.9, 47.3 Hz), 4.05-3.40 (m, 10H), 2.64 (s, 3H), 2.63 (t, 2H,

J = 7.6 Hz), 2.09-1.95 (m, 2H); TX / MC (M + H) ⁺ m / z 567, 569.

Example 542

Cl

(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2,2difluoroacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl}

H-pyridin-2-one: TX / MC (M + H) ⁺ m / z 557, 559.

Example 543 (c) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfonylacetyl) piperazin-1-yl] -4-methyl-1H -benzoimidazol-2-yl}

H-pyridin-2-one: TX / MC (M + H) ⁺ m / z 599, 601.

Example 544

219

(S) - 3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2yl] -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -1H -pyridin-2-one:

¹ H NMR (500 MHz, CD 3 OD) δ 7.57 (br s, 1 Η), 7.40-7.20 (m, 5H), 6.29 (d, 1H, J = 7.6

Hz), 4.98-4.90 (m, 1H), 4.02-3.91 (m, 4H), 3.70-3.50 (m, 6H), 2.66 (s, 3H), 2.21 (s, 3H); TX / MC (M + H) ⁺ m / z 521.523.

Example 545

($) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6- {4- [2 (1-oxo-114-thiomorpholin-4-yl) acetyl ] piperazin-1-yl} -1H-benzoimidazol-2-yl) -1H-pyridin-2-one: TX / MS (M + H) ⁺ m / z 638, 640.

Example 546

220 (S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- (6- {4- [2- (1,1-dioxo-1H-thiomorpholin-4-yl) acetyl] piperazine -1-yl} -4-methyl-1H benzoimidazol-2-yl) -1H-pyridin-2-one: TX / MC (M + H) ⁺ m / z 654, 656.

Example 547

($) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (2-thiomorpholin-4-ylacetyl) piperazin-1-yl] -1H -benzoimidazol-2-yl} 1H-pyridin-2-one: TX / MC (M + H) ⁺ m / z 622, 624.

Example 548

4- [2- (3-chlorophenyl) -2 ('57-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfinylacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole- 2-yl} 1H-pyridin-2-one: TX / MC (M + H) ⁺ m / z 583, 585.

Example 549

221 (S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methoxyacetyl) piperazin-1-yl] -4-methyl-1H- benzoimidazol-2-yl} -1Hpyridin-2-one: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.49 (br s, 1H), 7.40-7.18 (m, 6H).

6.26 (d, 1H, J = 7.7 Hz), 4.98-4.90 (m, 1H), 4.25 (s, 2H), 3.95-3.46 (m, 10H), 3.44 (s.

3H), 2.63 (s, 3H); TX / MC (M + H) ⁺ m / z 551.553.

Example 550

(S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] 3- {4-methyl-6- [4- (2-methylsulfanylacetyl) piperazin-1-yl] -1H-benzoimidazol-2 -yl} 1 H-pyridin-2-one: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.49 (br s, 1H), 7.45-7.20 (m, 6H), 6.26 (d, 1H, J = 7.60) Hz), 4.98-4.90 (m, 1H), 4.25 (s, 2H), 3.97-3.40 (m, 12H), 2.63 (s, 3H), 2.20 (s, 3H); TX / MC (M + H) ⁺ m / z 567, 569.

Example 551

(c) -3- {6- [2- (3-chloroacetyl) piperazin * 1-yl] -4-methyl-1H-benzoimidazol-2-yl} -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -1 H -pyridin-2-one: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.49 (br s, 1H), 7.38-7.20 (m, 5H),

7.15 (br s, 1H), 6.25 (d, 1H, J = 7.6 Hz), 4.98-4.90 (m, 1H), 4.35 (s, 2H), 3.90-3.80 (m, 6H), 2.61 (s, 3H ); TX / MC (M + H) ⁺ m / z 555, 557.

222

Example 552

N-) - 4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7methyl-3H-benzimidazole -5-yl) piperazine-1-carbaldehyde: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (1H, s), 7.65 (1 Η, s), 7.61 (1 Η, narrow d, J = 2.0 Hz ), 7.46 (1H, s), 7.43 (1H, d, J = 7.6 Hz), 7.36 (1H, dd, J = 2.0, 8.5 Hz), 7.00 (1H, d, J = 8.5 Hz), 6.32 (d , 1H, J = 7.6 Hz), 4.86-4.89 (1H, m), 3.91-3.96 (4H, m), 3.84 (3H, s), 3.57-3.67 (7H, m), 2.66 (3H, s); TX / MC (M + H) ⁺ m / z 581, (t = 1.24 min).

Example 553

7-7- (2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7methyl-3H-benzimidazol-5-yl) -piperazine- ^1- carbaldehyde: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (1H, s), 7.24-7.38 (6Η, m), 6.23 (1H, d, J = 7.6 Hz), 4.93-4.96 (1H , m), 3.54-3.79 (10H, m), 2.58 (3H, s); TX / MC (M + H) ⁺ m / z 507, (t = 1.29 min).

The following examples were prepared according to Schemes VII and III of Example 554

223

(S) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridine- 2-one: To a suspension of 4-chloro-3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one and the corresponding iodine compound, 4-iodine-3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (4.43 g, ~ 11 mmol) in acetonitrile (100 ml ), triethylamine (7.0 mL, 50 mmol) and 2- (S) -2- (3-chlorophenyl) -2-hydroxyethylamine hydrochloride (2.55 g, 12.2 mmol) were added. The mixture was stirred overnight at 85 ° C. TX / MS showed some unreacted amount of starting pyridone. 2- (c) -2- (3-chlorophenyl) -2-hydroxyethylamine hydrochloride (0.22 g, 1.06 mmol) was added and the mixture was stirred for a further 24 hours at 85 ° C. After evaporation of the volatiles, an aqueous solution of Cs ₂ CO ₃ (200 ml, 10%) was added, the suspension was sonicated for 5 minutes and stirred overnight. The product was filtered, washed with water and recrystallized from methanol-chloroform. The title compound was isolated as yellow crystals (3.951 g, 75%). LC / MS (M + H) + m / z (t = 1.31 min). HPLC t = 4.93 min, YMC-Pack ODS-A 3.0 x 50 mm; ΟΙ 00% gradient in 8 minutes; flow rate: 2.5 ml / min. ¹ H NMR on monoHCl salt: (500 MHz, DMSO-dg) δ 13.3 (1H, br s), 11.22 (1H, s), 10.9 (1H, br s), 7.65 (1H, br s), 7.60 (1H , s), 7.45 (d, J = 7.6 Hz), 7.38-7.30 (4H, m), 6.19 (1H, d, J = 7.5 Hz), 4.92 (1H, t, J = 5.3 Hz), 4.00 (6H , br), 3.67 (1H, m), 3.52 (5H, m), 2.58 (3H, s).

Common method for the preparation of mono- and di-HCl salts:

A solution or suspension of the free base in methanol is treated with 1.00 (or respectively 2.00) equivalent to 1.00 N HCl. If a significant amount

224 of the compound remains undissolved, the same volume of dichloroethane is added to improve solubility. The mixture was filtered and concentrated in vacuo. Evaporate small amounts to dryness, concentrate the large scale in vivo assays until crystallization of most of the compound is then filtered.

Example 555

(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1 H-pyridin-2-one: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.68-7.60 (m, 2H), 7.43-7.28 (m, 3H), 6.98 (d, 1 Η, J = 8.50 Hz) , 6.26 (d, 1H, J = 7.7 Hz), 4.97-4.89 (m, 1H), 4.18-4.04 (m, 4H), 3.82 (s, 3H), 3.73-3.55 (m, 6H), 2.63 (s , 3H); TX / MC (M + H) ⁺ m / z 554, 556.

Example 556

(c) -4- [2- (3-chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H- Pyridin-2-one: ¹ H NMR (300 MHz, CD 3 OD) δ 7.65-7.50 (m, 2H), 7.43-7.20 (m, 3H), 7.18 (dd, 1H, J = 8.9, 8.8

Hz), 6.27 (d, 1H, J = 7.6 Hz), 5.00-4.91 (m, 1H), 4.15-4.02 (m, 4H), 3.75-3.60 (m, 6H), 2.64 (s, 3H); TX / MC (M + H) ⁺ m / z 498, 500.

225

Example 557

HCI

(S) - 4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1 H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.67 (br s, 1 Η), 7.45 (br s, 1H), 7.40-7.28 (m, 3H).

7.00 (d, 1H, J = 8.4 Hz), 6.27 (d, 1H, J = 7.6 Hz), 4.95-4.84 (m, 1H), 4.15-4.05 (m,

4H), 3.82 (s, 3H), 3.75-3.55 (m, 6H), 2.64 (s, 3H); TX / MC (M + H) ⁺ m / z 510, 512.

Example 558

Nr

($) - 4- [2- (7 * bromo-2,3-dihydrobenzofuran-5-yl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazole -2-yl) -1Hpyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.54 (br s, 1H), 7.35-7.30 (m, 2H), 7.27 (br s, 1H), 7.22 (br s, 1H), 6.27 (d, 1H, J = 7.6 Hz), 4.95-4.87 (m, 1H), 4.60-4.50 (m, 2H), 4.10-4.00 (m, 4H), 3.75-3.60 ( m, 6H), 3.25-3.13 (m, 2H), 2.62 (s, 3H); TX / MC (M + H) ⁺ m / z 566, 568.

Example 559

226

4- [2- (3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6 [2 (5), 6 (R) - dimethylmorpholin-4-yl] -1H- benzoimidazol-2-yl] -1Hpyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.23-7.57 (m, 7H), 6.22 (d, 1H, J = 7.6 Hz), 4.97 (m, 1H), 4.06 (m, 2H), 3.62-3.68 (m, 4H), 3.20-3.34 (m, 2H), 2.63 (s, 3H), 1.30 (d, 6H, J = 6.28 Hz); TX / MC (M + H) ⁺ m / z 508 (t = 2.12 min).

Example 560

4- [2- (3-Bromo-4-methoxyphenyl) -2 (c) -hydroxy-ethylamino] -3- [4methyl-6- [2 (R) - 6 (R) -dimethyl-morpholin-4-yl] - 1 H-benzoimidazol-2-yl] -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.73 (s, 1 Η), 7.63 (s, 1 Η), 7.42 (s, 1 Η ), 7.34 (m, 2H), 6.96 (d, 1H, J = 8.48 Hz), 6.21 (d, 1H, J = 7.48 Hz), 4.87 (m, 1H), 4.23 (m, 2H), 3.57-3.67 (m, 4H), 3.34 (s, 3H), 3.30-3.32 (m, 2H), 2.60 (s, 1H), 1.30 (d, 6H, J = 6.2 Hz); TX / MC (M + H) ⁺ m / z 582 (t = 2.03 min).

Example 561

227

4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2 -yl} -1H-pyridine-

2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2fluoromethylmorpholin-4-yl] -4-methyl-1H- benzimidazol-2-yl} -1Hpyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42 (1H, s), 7.23-7.43 (6Η, m), 6.22 (1H, d, J = 7.2 Hz), 4.87-4.94 (1H, m), 4.60 (1H, d, J = 3.4 Hz), 4.48 (1H, d, J = 3.4 Hz), 4.04-4.15 (3H, m), 3.28-3.62 ( 6H, m), 2.56 (3H, s); TX / MC (M + H) ⁺ m / z 512 (t = 1.35 min).

Example 562

4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -

2-Fluoromethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - ($) - 2 -hydroxy-ethylamino] -3- {6 - [(S) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.60 (1 Η, narrow d, J = 2.0 Hz), 7.56 (1H, s), 7.39 (1H, br s), 7.34 (1H, dd, J = 2.0, 8.4 Hz ), 6.97 (1H, d, J = 8.4 Hz), 6.27 (1H, d, J = 6.4 Hz), 4.86 (1H, m), 4.61 (1H, m), 4.50 (1H, m).

228

4.77-4.19 (3H, m), 3.82 (3H, s), 3.38-3.74 (8H, m), 2.63 (3H, s); TX / MC (M + H) ⁺ m / z

586 (t = 1.31 min).

Example 563

4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) · 2-fluoromethylmorpholin-4-yl] -4-methyl-1 N-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (c) -2-hydroxy-ethylamino] -3- {6 - [(5 ) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45 (1 Η,

s), 7.28-7.30 (3H, m), 7.10 (1H, s), 6.97 (1 Η, d, J = 8.0 Hz), 6.20 (1H, d, J = 6.4 Hz).

4.85 (1H, m), 4.58 (1H, br s), 4.46 (1H, br s), 3.93-4.10 (3H, m), 3.80 (3H, s), 3,073.29 (2H, m), 2.55 ( 3H, s); TX / MC (M + H) ⁺ m / z 542 (t = 1.28 min).

Example 564

4- [2- (7-Bromo-2,3-dihydrobenzofuran-5-yl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-fluoromethylmorpholin-4-yl ] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (7-bromo-2,3-dihydrobenzofuran-5-yl) - (5) -2 -hydroxy-ethylamino] -3- {6 - [(5) -2-fluoromethyl229 morpholin-4-yl] -4-methyl-1H-benz-imidazol-2-yl} -1H-pyridin-2-one:

¹ H NMR (400 MHz, CD 3 OD) δ 7.26-7.40 (4H, m), 7.19 (1H, s), 6.24 (1H, d, J = 7.6)

Hz), 4.81-4.82 (1H, m), 4.49-4.61 (4H, m), 3.18-4.18 (11H, m), 2.59 (3H, s); TX / MC (M + H) ⁺ m / z 598 (t = 1.32 min).

Example 565

4- [2- (3-chlorophenyl) - (5) -2-hydroxy-ethylamino] -3- {6 - [(R) - ^2- hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzimidazol-2 -yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 [(S) -2-hydroxymethyl-morpholin-4-yl] - 4-methyl-1H-benzimidazol-2yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.49 (1H, s), 7.23-7.37 (6H, m), 7.10 (1H, s), 6.24 (1H, d, J = 7.6 Hz), 4.95-4.96 (1H, m), 4.19 (1H, m), 3.944.80 (2H, m), 3.59-3.71 (8H, m ), 2.63 (3H, s); TX / MC (M + H) ⁺ m / z 510 (t = 1.21 min).

Example 566

4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R)

2-hydroxymethyl-morpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl}

230

1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(c) -2-hydroxymethyl-morpholine-4- yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.62 (1H, narrow d, J = 2.0 Hz), 7.54 (1H , s), 7.29-7.36 (3H, m), 6.95 (1H, d, J = 8.4 Hz), 6.23 (1H, d, J = 7.6 Hz), 4.88-4.89 (1H, m), 3.56-4.19 ( 11H, m), 3.80 (3H, s), 2.60 (3H, s); TX / MC (M + H) ⁺ m / z 584 (t = 1.16 min).

Example 567

4- [2- (3-Chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) 2-hydroxymethyl-morpholin-4-yl] -4-methyl-1H -benzimidazol-2-yl} 1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(5 ) -2-hydroxymethyl-morpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.68 (1H, s), 7.54 (1Η, s), 7.45 (1Η, s), 7.39 (1Η, s), 7.30-7.32 (2Η, m), 6.98 (1H, d, J = 8.4)

Hz), 6.22 (1H, d, J = 7.6 Hz), 4.89 (1H, m), 4.11-4.19 (3H, m), 3.80 (3H, s), 3.49-3.72 (8H, m), 2.60 (3H , s); TX / MC (M + H) ⁺ m / z 540 (t = 1.09 min).

Example 568

231

4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methyl-morpholin-4-yl] -4-methyl-1H-benzimidazole- 2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(6) -2-methyl-morpholine- 4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD 3 OD) δ 7.75 (1H, s), 7.48 (1H, s ), 7.42 (1H, s), 7.23-7.37 (4H, m), 6.24 (1H, d, J = 7.2 Hz), 4.94-4.97 (1H, m), 4.11-4.16 (3H, m), 3.61- 3.68 (5H, m), 3.38 (1H, m), 2.64 (3H, s), 1.29 (3H, d, J = 6.4 Hz); TX / MC (M + H) ⁺ m / z 494 (t = 1.32 min).

Example 569

Nr

OMe

4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) 2-methyl-morpholin-4-yl] -4-methyl- 1 H-Benzimidazol-2-yl} -1 H -pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(5) -2-methyl-morpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.63 (1H, s),

7.62 (1Η, s), 7.30-7.61 (3H, m), 6.95 (1H, d, J = 8.4 Hz), 6.22 (1H, d, J = 7.6 Hz).

4.88-4.90 (1H, m), 4.08-4.18 (3H, m), 3.80 (3H, s), 3.61-3.67 (5H, m), 3.32-3.34 (1H, m), 2.60 (3H, s). 1.28 (3H, d, J = 6.0 Hz); TX / MC (M + H) ⁺ m / z 568 (t = 1.31 min). Example 570

232

4- [2- (3-Chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) 2-methyl-morpholin-4-yl] -4-methyl- 1 H-benzimidazol-2-yl} -1 Npyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (N - 2-hydroxyethylamino] -3- {6 - [(5) - 2-methyl-morpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.48 (1H, narrow d, J = 2.0 Hz), 7.40 (1H, br s), 7.31 (1H, narrow d, J = 2.0 Hz), 7.29 (1H, narrow d, J = 2.0 Hz), 6.97 (1H, d, J = 8.4 Hz) ), 6.22 (1H, d, J = 7.6 Hz), 4.87-4.90 (1H, m), 4.11 (1H, m), 3.95-4.01 (2H, m), 3.80 (3H, s), 3.47 (4H. m), 3.32 (1H, m), 3.25 (1H, m), 2.57 (3H, s), 1.27 (3H, d, J = 6.4 Hz); TX / MC (M + H) ⁺ m / z 525 ( t = 1.27 min).

Example 571

4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methoxymethyl-morpholin-4-yl] -4-methyl-1H-benzimidazol-2- yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethyl-amino] -3- {6 [(S) -2-methoxymethyl-morpholin-4-yl] - 4-methyl-1H-benzimidazol-2yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.49 (1H, narrow d, J = 2.0

Hz), 7.23-7.36 (6H, m), 6.22 (1H, d, J = 7.2 Hz), 4.93-4.96 (1H, m), 4.08-4.21 (11H.

233

m), 3.38 (3H, s), 2.60 (3H, s), 1.27 (3H, d, J = 6.4 Hz); TX / MC (M + H) ⁺ m / z 524 (t = 1.35 min).

Example 572

4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R)

2-methoxymethyl-morpholin-4-yl] -4-methyl-1H-benzimidazol-2-yl}

1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy ethylamino] -3- {6 - [(5) -2-methoxymethyl-morpholine-4 -yl] -4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.63 (1H, narrow d, J = 2.0 Hz), 7.40 (1H, br s), 7.30-7.36 (3H, m), 7.19 (1H, br s), 6.95 (1H, d, J = 8.4 Hz), 6.23 (1H, d, J = 7.2 Hz), 4.87- 4.89 (1H, m), 4.18 (1H, m), 3.97

4.03 (3H, m), 3.80 (3H, s), 3.54-3.66 (7H, m), 3.39 (3H, s), 2.59 (3H, s); TX / MC (M + H) ⁺ m / z 598 (t = 1.31 min).

Example 573

4- [2- (3-Chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) 2-methoxymethyl-morpholin-4-yl] -4-methyl-1H -benzimidazol-2-yl}

234

1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(N - 2-methoxymethyl-morpholin-4-yl] - 4-methyl-1H-benzimidazol-2-yl} -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.52 (1H, s), 7.46 (1 Η, narrow d, J = 1.6 Hz), 7.29-7.34 (3H, m), 6.99 (1H, d, J = 8.4 Hz),

6.24 (1H, d, J = 7.2 Hz), 4.89 (1H, m), 4.06-4.17 (3H, m), 3.81 (3H, s), 3.54-3.68 (8H, m), 3.38 (3H, s) , 2.60 (3H, s); TX / MC (M + H) ⁺ m / z 554 (t = 1.28 min).

Example 574

HCI ^HO

Cl

4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- [4-methyl-6- (4methylpiperazin-4-yl) -1H-benzoimidazol-2-yl] -1 H-Pyridin-2-one: ¹ H

NMR (400 MHz, CD ₃ OD) δ 7.46 (1H, s), 7.24-7.36 (m, 4H), 7.04 (2H, s), 6.22 (1H, d, J = 7.64 Hz), 4.89 (1H, m ), 3.30-3.82 (10H, m), 2.97 (3H, s), 2.57 (3H, s); TX / MC (M + H) ⁺ m / z 493 (t = 1.56 min).

Example 575 • HCI ^{HQ |}

Nr

OMe

4- [2- (3-Bromo-4-methoxyphenyl) -2 (S) -hydroxy-ethylamino] -3- [4methyl-6- (4-methylpiperazin-4-yl] -1H-benzoimidazol-2-yl ] -1 Hpyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (1H, d, J = 2.0 Hz), 7.32-7.37 (2H, m), 7.05 (2H, s), 6.97 (1H, d, J = 8.52 Hz), 6.24 (1H, d, J = 7.64 Hz), 4.82 (1H,

235

m), 3.82 (3H, s), 3.30-3.64 (10H, m), 2.98 (3H, s), 2.56 (3H, s); TX / MC (M + H) ⁺ m / z

567 (t = 1.53 min).

The following examples (576-581) are prepared according to Schemes VII and III and illustrate the acylation of 4-aminopiperidine derivatives

Example 576 (General Method for Examples 576-581)

4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (acetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-Pyridin-2one: A solution of 4-aminopiperidine Compound (~ 50-100 μmol) in 5 ml of MeOH was cooled to 0 ° C. Then ~ 10 equivalents of Hunigs base and ~ 3 equivalents of acyl chloride are added. Shake the flask once and allow to stand for 1 hour at room temperature. Evaporation of the volatiles and purification with preparative HPLC gave 4-acylaminopiperidine Compounds. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.06 (1H, s), 7.68 (1 Η, s), 7.49 (1 Η, s), 7.44 (1 Η, d, J = 7.6 Hz), 7.27- 7.38 (4H, m), 6.33 (1H, d, J = 7.6 Hz), 4.96 (1H, dd, J = 4.1, 7.6 Hz), 4.17 (1H, m), 3.87 (4H, m), 3.65 (1H , dd, J = 4.2, 14 Hz), 3.58 (1H, dd, J = 7.8, 13.8 Hz), 2.72 (3H, s), 2.31 (2H, m), 2.19 (2H, m), 2.02 (3H, s); TX / MC (M + H) ⁺ m / z 535 (t = 1.03 min; YMC Xterra C18 S7 3.0 x 50 mm; gradient 0 -100% in 1.5 min; flow rate 5 ml / min).

Example 577

236

4- [2- (3-Hydrophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1 Npyridin-2-one: TX / MS (M + H) ⁺ m / z 551 (t = 1.27 min; BETXt = 5.01 min; Waters Xterra C18 S5 4.6 x 30 mm; gradient 0-100% in 12 min; speed at a flow rate of 5 ml / min).

Example 578

4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1 Npyridin-2-one: TX / MC (M + H) ⁺ m / z 597 (t = 1.31 min; BETXt = 6.90 min, YMCPack ODS-A 3.0 x 50 mm; gradient 0 -100% in 12 min flow rate 2.5 ml / min).

Example 579

OMe

237

4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4 (acetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2- yl} -1Hpyridin-2-one: TX / MS (M + H) ⁺ m / z 609 (t = 1.27 min; BETXt = 5.00 min, Waters

Xterra C18 S5 4.6 χ 30 mm; gradient 0 -100% in 12 min; flow rate 5 ml / min).

Example 580

4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1 Npyridin-2-one: TX / MS (M + H) ⁺ m / z 595 (t = 1.30 min; HPLC t = 5.09 min, Watres Xterra C18 S5 4.6 χ 30 mm; gradient 0-100% for 12 min; flow rate 5 ml / min).

Example 581

4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridine -2-one: TX / MS (M + H) ⁺ m / z 553 (t = 1.35 min; HPLC t = 5.90 min, YMCPack ODS-A 3.0 x 50 mm; gradient 0 -100% in 10 min; speed of 2.5 ml / min).

The following examples (582-584) were prepared according to Scheme VII

238 and III and illustrate the carbamoylation of the 4-aminopiperidine derivative

General Method for Examples 582-584

A solution of 4-aminopiperidine Compound (~ 50-100 μmol) in 5 ml of MeOH was cooled to 0 ° C. Then ~ 10 equivalents of Hunigs base and ~ 3 equivalents of carbamoyl chloride are added. The flask was shaken once and allowed to stand at room temperature overnight. Evaporation of the volatiles and purification with preparative HPLC afforded 4-carbamoylpiperidine Compounds.

© Example 582

4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methoxyethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2yl} - 1H-pyridin-2-one: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.90 (1H, s), 7.26-7.52 (6Η, m), 6.29 (1H, d, J = 7.5 Hz), 4.97 ( 1H, dd, J = 4.1, 7.0 Hz), 4.20 (2H, m), 3.93 (1H, m), 3.60-3.84 (8H, m), 3.37 (3H, s), 2.69 (3H, s), 2.33 (2H, m), 2.13 (2H, m); TX / MC (M + H) ⁺ m / z 595 (t = 1.09 min; YMC Xterra C18 S7 3.0 x 50 mm; gradient 0 -100% in 1.5 min; flow rate 5 ml / min).

Example 583

239

4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (methoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1 Npyridin-2-one: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.00 (1H, s), 7.63 (1 Η, s), 7.26-7.49 (5Η, m), 6.32 (1H, d, J = 7.6 Hz), 4.96 (1H, dd, J = 4.2, 7.6 Hz), 3.93 (1H, m), 3.793.88 (4H, m), 3.67 (3H, s), 3.56-3.65 (2H, m) , 2.71 (3H, s), 2.32 (2H, m), 2.17 (2H, m); TX / MC (M + H) ⁺ m / z 551 (t = 1.07 min; YMC Xterra C18 S7 3.0 x 50 mm; gradient 0 -100% in 1.5 min; flow rate 5 ml / min).

Example 584

4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (fluoroethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1 Npyridin-2-one: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.92 (1H, s), 7.26-7.54 (6Η, m), 6.3 (1H, d, J = 7.5 Hz), 4.97 (1H , dd, J = 4.5, 7.5 Hz), 4.63 (1H, br s), 4.53 (1H, d, J = 2.5 Hz), 4.32 (1H, br s), 4.27 (1H, br s), 3.93 (1H , m), 3.79-3.85 (4H, m), 3.58-3.72 (2H, m), 2.70 (3H, s), 2.33 (2H, m), 2.15 (2H, m); TX / MC (M + H) ⁺ m / z 583 (t = 1.29 min; YMC Xterra C18 S7 3.0 x 50 mm; gradient 0 -100% in 2 min; flow rate 5 ml / min).

The following examples (585-590) are prepared according to Schemes VII and III and illustrate the use of alcohol as a nucleophile in Scheme VII

Example 585 (Common Method for Examples 585-590)

240

(S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2-morpholin-4-ylethoxy) -1H-benzimidazol-2-yl] -1 H-pyridin-2-one: ¹ H

NMR (400 MHz, CD3OD) δ 7.53 (1H, s), 7.37-7.39 (1H, m), 7.23-7.30 (3H, m), 7.01 (1H, s), 6.75 (1H, s), 6.21 (1H , d, J = 7.2 Hz), 4.98 (1H, t, J = 5.6 Hz), 4.40 (2H, br s), © 3.97 (4H, br s), 3.45-3.73 (8H, m), 2.54 (3H , s); TX / MC (M + H) ⁺ m / z 524 (t = 1.24 min).

Example 586

(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- [4methyl-6- (2-morpholine-4-idetoxy) -1H-benzimidazol-2- yl] -1 Npyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.67 (1H, narrow d, J = 1.6 Hz), 7.36 (1H, dd, J = 1.6, 8.4 Hz), 7.25 (1H, d, J = 7.2 Hz), 6.98 (1H, s), 6.92 (1H, d, J = 8.4 Hz), 6.75 (1H, s), 6.22 (1H, d, J = 7.2 Hz), 4.89 -4.92 (1H, m), 4.41 (2H, br s), 3.97 (4H, br s), 3.79 (3H, s), 3.34-3.66 (8H, m), 2.51 (3H, s); TX / MC (M + H) ⁺ m / z 598 (t = 1.22 min).

Example 587

241

(S) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2methoxyethoxy) -1H-benzimidazol-2-yl] -1H-pyridin-2- it: ¹ H NMR (400 MHz, CD 3 OD) δ 7.48 (1H, s), 7.25-7.36 (4H, m), 6.96 (1H, s), 6.81 (1H, s), 6.20 (1H, d, J = 7.4 Hz), 4.90-4.93 (1H, m), 4.13-4.14 (2H, m), 3.76-3.77 (2H, m), 3.50-3.61 (2H, m), 3.43 (3H, s), 2.53 (3H , s); TX / MC (M + H) ⁺ m / z 469 (t = 1.52 min).

Example 588

(S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2-hydroxyethoxy) -1H-benzimidazol-2-yl] -1H-pyridin-2 -one: ¹ H NMR (400 MHz, CD 3 OD) δ 7.43-7.45 (2H, m), 7.27-7.34 (3H, m), 7.08 (1H, s), 7.04 (1H, narrow d, J = 1.0 Hz) ), 6.28 (1H, d, J = 7.6 Hz), 4.87 (1H, m), 4.13 (2H, t, J = 4.6 Hz), 3.92 (2H, t, J = 4.5 Hz), 3.45-3.54 (2H) , m), 2.60 (3H, s); TX / MC (M + H) ⁺ m / z 455 (t = 1.35 min).

Example 589

Me

242 (S) - 4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- [4methyl-6- (3-morpholin-4-ylpropoxy) -1H-benzimidazol-2 -yl] -1 Npyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.66 (1H, s), 7.35 (1 Η, dd, J = 1.6, 7.9 Hz), 7.25 (1H, br s), 6.93 (1H, s), 6.91 (1H, s), 6.68 (1H, s), 6.19 (1H, br s), 4.86 (1H, m), 4.05-4.10 (4H, br s), 3.79 (3H, s), 3.17-3.73 (12H, m), 2.50 (3H, s); TX / MC (M + H) ⁺ m / z 612 (t = 1.16 min).

Example 590

(S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (3-morpholin-4-ylpropoxy) -1H-benzimidazol-2-yl] -1 H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.52 (1H, s), 7.36-7.38 (1Η, m), 7.23-7.30 (3H, m),

6.92 (1H, s), 6.67 (1 Η, s), 6.18 (1Η, d, J = 6.9 Hz), 4.96 (1H, t, J = 5.9 Hz), 4.04-4.08 (4H, m), 3.82 ( 2H, m), 3.56-3.65 (8H, m), 3.15-3.18 (2H, m), 2.52 (3H, s); TX / MC (M + H) ⁺ m / z 538 (t = 1.19 min).

The following examples (591-593) are prepared according to Schemes VII and III in which the cyano group (Scheme IV) is converted to an aldehyde which undergoes reductive amination with an amine

Example 591 (General Method for Examples 591-593)

(S) - 3- (4-Bromo-6-morpholin-4-ylmethyl-1H-benzimidazol-2-yl) -4- [2

243 (3-Chlorophenyl) -2-hydroxy-ethylamino] -1H-pyridin-2-one: To a solution of (5) -7-bromo-2- {4- [2- (3-chlorophenyl) -2-hydroxy -ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzimidazole-5-carbaldehyde (130 mg, 0.27 mmol) in methanol (60 ml) was added morpholine (0.2 ml, excess). The reaction mixture was stirred for 1 hour at room temperature. NaCNBHg (1M solution in THF, 1.35 ml, 1.35 mmol) was then added. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (68 mg, 45%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (1H, s), 7.69 (1 Η, s), 7.68 (1 Η, S), 7.24-7.54 (4Η, m), 6.30 (1H, d. J = 7.6 Hz), 4.89-5.02 (1H, m), 4.50 (2H, s), 3.66-3.71 (4H, m), 3.17-3.43 (6H, m); TX / MC (M + H) ⁺ m / z 558 (t = 1.41 min).

Example 592

(S) -3- [4-Bromo-6- (4-methylpiperazin-1-ylmethyl) -1H-benzimidazol-2yl] -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -1H pyridin-2-one: ¹ H

NMR (400 MHz, CD ₃ OD) δ 7.70 (1H, s), 7.55 (2Η, s), 7.42 (1H, d, J = 7.6 Hz), 7.247.32 (3H, m), 6.22 (1H, d) , J = 7.6 Hz), 5.01 (1H, t, J = 6.2 Hz), 4.35 (2H, br s), 3.483.71 (10H, m), 2.98 (3H, s); TX / MC (M + H) ⁺ m / z 571 (t = 1.37 min).

Example 593

244 (S) - 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (4methylpiperazin-1-ylmethyl) -1H-benzimidazol-2-yl] - 1H-Pyridin-2one: Through a mixture of (5) -3- [4-bromo-6- (4-methylpiperazin-1-ylmethyl) -1H-benzimidazol-2-yl] -4- [2- (3- hporphenyl) -2-hydroxy-ethylamino] -1H-pyridin-2-one (80 mg, 0.14 mmol), tetramethyl-tin (2.5 ml, excess), PdCI ₂ (PPh ₃ ) ₄ (10 mg, 0.014 mmol) and KF (40 mg, 0.7 mmol) in DMF (2 ml) bubbled with nitrogen, after which the vessel was sealed and heated for two days at 100 ° C. The reaction mixture was passed through a thin layer of celite. After concentration, the residue was purified by preparative HPLC to give the title compound (34 mg, 48%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53 (1H, s), 7.45 (1 Η, s), 7.24-7.40 (4Η, m), 7.09 (1H, s), 6.22 (1 Η, d. J = 7.6 Hz), 4.99 (1H, t, J = 6.4 Hz), 4.04 (2H, br s), 3.61-3.74 (2H, m), 2.98-3.34 (8H, m), 2.80 (3H, s) , 2.58 (3H, s); TX / MC (M + H) ⁺ m / z 507 (t = 1.29 min).

The following examples (594-595) are prepared according to Schemes VII and III and illustrate the use of tetrahydropyrimidine as a nucleophile in Scheme VII

Example 594

4- [2- (3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6- (1,4,5,6tetrahydropyrimidin-1-yl) -1H-benzimidazol-2 -yl] -1H-pyridin-2one: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (1H, s), 7.52 (1 Η, s), 7.21-7.41 (5Η, m), 7.04 (1H , d, J = 1.2 Hz), 6.21 (1H, d, J = 7.6 Hz), 4.97 (1H, t, J = 4.9 Hz), 3.97 (2H, m), 3.60-3.73 (2H, m), 3.52 (2H, t, J = 5.74 Hz), 2.60 (3H, s), 2.25 (2H, m); TX / MC (M + H) ⁺ m / z 477 (t = 1.79 min).

245

Example 595

4- [2- (4-Methoxy-3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- [4methyl-6- (1,4,5,6-tetrahydropyrimidin-1-yl) -1H -benzimidazol-2yl] -1H-pyridin-2-one: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (1H, s), 7.52 (1 Η, s), 7.04-7.52 (4Η, m) , 7.04 (1H, d, J = 1.2 Hz), 6.21 (1H, d, J = 7.6 Hz), 4.98 (1H, t, J = 4.92 Hz), 3.97 (5H, m), 3.60-3.73 (2H. m), 3.52 (2H, t, J = 5.74 Hz), 2.60 (3H, s), 2.26 (2H, m); TX / MC (M + H) ⁺ m / z 507 (t = 1.67 min).

It should be understood that the examples described above do not in any way limit the true scope of the invention, but rather are presented for illustrative purposes. All sources cited are incorporated by reference in their entirety.

Claims (57)

A compound of formula I: its enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and solvates, in which: X is selected from the group consisting of: N, C, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl substituted with one or more R ₇ substituents, as well as a direct bond; Y is selected from the group consisting of O and S; W is selected from the group consisting of N, C, O and S, provided that if W is O or S, R _g is absent; R _b R ₂ , R ₃ , R ₄ , R5, R ₆ , R7, Rs. R9 ^ca selected independently of one another from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halo, amino, OR _60, NO _2, OH, SR _60, NR ₆ oR ₆ i, ON, CO ₂ R ₆₀ , CONR ₆₀ R ₆₁ , OCONR ₆₀ R ₆₁ , NRg ₂ CONR ₆₀ R ₆₁ , NR 10 SO ₂ R 6i> SO ₂ NR ₂ R 6i. C (NRe2) NR ^, aryl, heteroaryl, (CH ₂ ) _n OR ₆₀ , (CH ₂ ) n NR ₆₀ Rei, (CH ^ nSReo, (CH ₂ ) _n aryl, (CH ₂ ) _n heteroaryl, (CH ₂ ) _{n is} heterocycloalkyl, NH-Z-aryl and NH-Z-heteroaryl; where η is 1 to 3 and Ζ is selected from the group consisting of C ₁ -C ₄ alkyl, alkenyl and alkynyl; Ζ has one or more of the following groups: hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, NR ₆₀ SO ₂ R ₆ i; Z optionally includes one or more of the groups selected from the group consisting of: CO, CNOH, CNOR ₆₀ , CNNR ₆₀ , CNNCOR ₆₀ and CNNSO ₂ R ₆₀ and R ₆₀ and R ₆₁ are independently selected from the group consisting of H, alkyl, 247 alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl and alkyl-B ₂₅ , wherein: R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halo, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , - NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃ i, heteroaryl or heterocycloalkyl, and R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or alkyl-B ₂₅ . The compound of claim 1, wherein: u R _b R ₇ , Rg and RgCaH; R ₂ and R ₄ are H or F; Ye Ο; X is selected from the group consisting of N and CH; WeN; R ₅ is selected from the group consisting of H, methyl, ethyl, isopropyl, secondary butyl, cyclopropyl, F and CF ₃ ; R ₆ is selected from the group consisting of H, 2-aminomethylpyridine, NHCH ₂ CH (OH) Ph, NHCH ₂ CH (OH) (3-CI-Ph), NHCH ₂ CH (OH) (3-Br-Ph) , f NHCH ₂ CH (OH) (3-Br-4-OMe-Ph), NHCH (CH ₂ OH) CH ₂ Ph, NHCH ₂ CH (OH) apnn, 1 \ CHCH (CH ₂ OH) CH ₂ aryl and R ₃ is selected from the group consisting of: OR ₆₀ , CiNHJNHReo, C (O) NHR ₆₀ , imidazole, imidazoline, tetrahydropyrimidine, piperazine, morpholine, homomorpholine, piperidine, pyrrolidine, homopiperazine and amino, such as R ₆₀ is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl and alkyl-B ₂₅ , wherein R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, thioalkoxy, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃₁ or heteroaryl or heterocycloalkyl, and R ₃₀ and R ₃₁ independently represent hydrogen, alkyl, cyclo 248 alkyl or alkyl-P ₂₅ . The compound of claim 2, wherein R ₃ is -OR ₆₀ and R ₆₀ is alkyl or -alkyl-P ₂₅ , wherein R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , - C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl and R ₃₀ and R ₃₁ independently represent hydrogen, alkyl, cycloalkyl or alkyl-P ₂₅ . The compound of claim 3, wherein R ₆₀ is methyl, - (CH ₂ ) _N CH ₂ ' OH or - (CH ₂ ) _n CH ₂ N (CH ₂ CH ₂ ) ₂ O and η is 0.1 or 2. The compound of claim 3, wherein R ₂₅ is morpholine, wherein R ₃₃ is hydrogen, alkyl or substituted alkyl. The compound of claim 2, wherein R ₃ is piperazine, homopiperazine, 3-methylpiperazine or 3,5-dimethylpiperazine, optionally substituted at the 4-1 position by a compound selected from the group consisting of: alkyl, cycloalkyl , cycloalkylalkyl, alkyl-P ₂₅ , -C (O) -R ₁₅ , or -CO ₂ R ₁₅ , where R ₁₅ is hydrogen, alkyl, aryl, alkyl-H ₂₅ , amino or aryl, and R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, cyano, halo, sulfoxy, sulfonyl, arylsulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl, and R ₃₀ and R ₃₁ independently represent hydrogen, alkyl, cycloalkyl or alkyl-P ₂₅ . 249 The compound of claim 6, wherein said piperazine is substituted with methyl, ethyl, CH ₂ -cyclopropyl, hydroxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-aminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl, methoxyethyl, ethoxyethyl, morpholine and morpholinylethyl. The compound of claim 2, wherein R ₃ is an amino group selected from the group consisting of: hydroxyalkylamino, aminoalkylamino, dialkylaminoalkylamino and heterocycloalkylalkylamino. The compound of claim 8, wherein said amino group is selected from the group consisting of: NHCH ₂ CH ₂ OH, NMeCH ₂ CH ₂ OH, NEtCH ₂ CH ₂ OH, NHCH ₂ CH ₂ NH ₂ , NMeCH ₂ CH ₂ NH ₂ , NEtCH ₂ CH ₂ NH ₂ , NHCH ₂ CH ₂ NMe ₂ , NMeCH ₂ CH ₂ NMe ₂ , NEtCH ₂ CH ₂ NMe ₂ , NHCH ₂ CH ₂ NEt ₂ , NMeCH ₂ CH ₂ NEt ₂ , NEtCH ₂ CH ₂ NEt ₂ , NHCH ₂ CH ₂ N (CH ₂ CH ₂ ) ₂ O, NMeCH ₂ CH ₂ N (CH ₂ CH ₂ ) ₂ O, and NEtCH ₂ CH ₂ N (CH ₂ CH ₂ ) ₂ O. The compound of claim 2, wherein R ₃ is piperidine optionally substituted by hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, 1,3-dioxolane, 1,3-dioxane, -NHC (O) R ₁₅ , -NHCO ₂ R ₁₅ , wherein R ₁₅ is hydrogen, alkyl, aryl or alkyl-N ₂₅ , wherein R ₂₅ is hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl , -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl, and R ₃₀ and R ₃₁ independently represent hydrogen, alkyl, cycloalkyl or alkyl-N ₂₅ . The compound of claim 2, wherein R ₃ is morpholine, thiomorpholine, sulfoximorpholine, sulfonylmorpholine or homomorpholine or substituted morpholine, thiomorpholine, sulfoximorpholine, sulfonylmorpholine or homomorpholine. The compound of claim 11, wherein said morpholine, thiomorpholine, sulfoximorpholine, sulfonylmorpholine or homomorpholine is substituted with hydroxy, thiol, amino, alkylamino, dialkylamino, al. 250 coke, thioalkoxy, alkyl-B ₂₅ , -NHC (O) R ₁₅ , -NHCO ₂ R _15> wherein R ₁₅ is hydrogen, alkyl, aryl or alkyl-B ₂₅ , where R ₂₅ is hydrogen, alkenyl, hydroxy , thiol, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃ i, heteroaryl or heterocycloalkyl; and R ₃₀ and R ₃₁ independently represent hydrogen, alkyl, cycloalkyl or alkyl-B ₂₅ . The compound of claim 2, wherein R ₃ is (CH ₂ ) _n -morpholine or (CH ₂ ) _n -piperazine, in which η is from 1 to 3. The compound of claim 2, wherein R ₃ is optionally substituted N-tetrahydropyrimidine or N-imidazoline. The compound of claim 14, wherein at least one of said substituents is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanoalkyl, carboxyl or carboxamide. The compound of claim 2, wherein R ₃ is pyrrolidine. The compound of claim 2, wherein said pyrrolidine is selected from the group consisting of 3-hydroxylpyrrolidine, 3-alkoxypyrrolidine, 3-alkylaminopyrrolidine and 3-dialkylaminopyrrolidine. The compound of claim 2, wherein R ₆ is selected from the group consisting of H, 2-aminomethylpyridine, NHCH ₂ CH (OH) apnn and NHCH (CH ₂ OH) CH ₂ apnn. The compound of claim 18, wherein said aryl is optionally substituted phenyl. The compound of claim 19, wherein said phenyl is substituted with Br, Cl, F, alkoxy or -NHSO ₂ CH ₃ . The compound of claim 19, wherein said substituent is 3-Br, 3-Cl or 3-F. The compound of claim 19, wherein said substituent is 4-F or 4-methoxy. 251 The compound of claim 19, wherein R ₆ is: wherein R ₁₇ is H, Br, Cl or F and R ₄₀ is H or alkyl. 24. A compound having the formula: in which R ₁₂ and R ₁₃ denote independently of one another hydrogen, alkyl or apkyl-B ₂₅ , wherein R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, amino, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, -CO ₂ H, -C (O) NR ₃₀ R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ C (O) OR ₃₁ , heteroaryl or heterocycloalkyl R ₁₇ , R ₁₈ and R _1g independently represent hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocycloalkyl or heteroaryl group and 252 R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl or alkyl-B ₂₅ . The compound of claim 24, wherein R ₂₅ is morpholine, wherein R ₃₃ is hydrogen, alkyl or substituted alkyl. The compound of claim 24, wherein R ₁₂ is hydrogen, methyl, hydroxymethyl, methoxymethyl, CH ₂ F, CH ₂ CN, CO ₂ H or -CONR ₃₀ R ₃₁ , wherein R ₃₀ and R ₃₁ independently represent hydrogen or alkyl-B ₂₅ . The compound of claim 24, including in the side chain: wherein R ₄₀ is hydrogen or alkyl and R ₇₀ is hydrogen or halogen. The compound of claim 24, wherein R ₁₂ and R ₁₃ are H; R ₁₇ is Br, F or Cl; R ₁₈ is methoxy or fluorine and R ₁₉ is H; or R ₁₈ and R ₁₉ form together 253 4-0,5-dihydrofuran wounds and l. The compound of claim 24, wherein R ₁₂ and R ₁₃ are methyl; R ₁₇ is Br, F or Cl; R ₁₈ is hydrogen or methoxy and R ₁₉ is H. 30. Compound of Formula: wherein R ₁₅ is hydrogen, alkyl, aryl or alkyl-N ₂₅ , wherein R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, amino, alkoxy, thioalkoxy, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl; R ₁₆ represents independently hydrogen or methyl; R ₁₇ , R ₁₈ and R _1g independently represent hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocycloalkyl or heteroaryl group and R ₃₀ and R ₃₁ are, independently of one another, hydrogen, alkyl or alkyl-P ₂₅ The compound of claim 30, wherein R ₂₅ is morpholine, thiomorpholine, o Fr. Nθ / ~ ^N \ J ^N \ Ν 254 The compound of claim 30, including in the side chain: wherein R ₄₀ is hydrogen or alkyl and R ₁₇ is hydrogen or halogen. The compound of claim 30, wherein R ₁₅ is hydrogen, methyl, ethyl or (CH ₂ ) _n CH ₂ -R ₂₅ in which R ₂₅ is OH, OMe, F, CN, CF ₃ , SOCH ₃ or SO ₂ CH ₃ where η is 0 or 1. The compound of claim 30, wherein R ₁₅ is cyanoethyl, hydroxyethyl, CH ₂ CH ₂ SOCH ₃ , CH ₂ CH ₂ CH ₂ F, CH ₂ CH ₂ CH ₂ CN or CH ₂ CH ₂ CF ₃ ; R ₁₆ and R ₁₉ are H; R ₁₇ is Br or Cl and R ₁₈ is hydrogen or methoxy. 35. Compound of Formula: 255 in which: R ₁₅ is hydrogen, alkyl, aryl or alkyl-P ₂₅ ; R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃ i, C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl; R ₁₆ represents independently hydrogen or methyl; R ₁₇ , R ₁₈ and R ₁₉ independently represent hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocycloalkyl or heteroaryl group and R ₃₀ and R ₃₁ are independently hydrogen, alkyl, cycloalkyl or alkyl-P ₂₅ . The compound of claim 35, wherein R ₂₅ is morpholine, thiomorpholine, wherein R ₃₃ is hydrogen, alkyl, or substituted alkyl. The compound of claim 35, comprising the side 256 Chain: wherein R ₄₀ is hydrogen or alkyl and R ₁₇ is hydrogen or halogen. The compound of claim 35, wherein R ₁₅ is hydrogen or methyl; R ₁₇ is bromine, chlorine or fluorine; R ₁₈ is hydrogen or methoxy and R ₁₉ is hydrogen. 39. A compound of formula: in which: R ₁₅ is hydrogen, alkyl or -alkyl-P ₂₅ ; R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R ₃ i, heteroaryl, or 257 heterocycles cloal hernia; R ₁₆ represents independently hydrogen or methyl; R _17j R ₁₈ and R ₁₉ independently represent hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocyclic or heteroaryl group and R ₃₀ and R ₃₁ are independently hydrogen, alkyl, cycloalkyl or alkyl-H ₂₅ . The compound of claim 39, including as a side chain: wherein R ₄₀ is hydrogen or alkyl and R ₁₇ is hydrogen or halogen. The compound of claim 39, wherein R ₁₅ is hydrogen, methyl, ethyl or - (CH ₂ ) _n CH ₂ -R ₂₅ wherein η is 0, 1 or 2 and R ₂₅ is OH, OMe, F, CN, CF ₃ , SOCH ₃ or SO ₂ CH ₃ , -NR ₃₀ COR ₃₁ , -NR ₃₀ COOR ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₀ R _31, or -N 258 wherein R ₃₃ is hydrogen, alkyl or substituted alkyl. The compound of claim 39, wherein R ₁₅ is ethyl, methoxyethyl, CH ₂ CH ₂ F or CH ₂ CH ₂ CN; R ₁₇ is bromine or chlorine; R ₁₈ is methoxy or hydrogen and R ₁₉ is hydrogen. 43. Compound of Formula: wherein: R ₁₅ is hydrogen, alkyl, aryl or -alkyl-P ₂₅ ; R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl; R ₁₇ , R ₁₈ and R ₁₉ independently represent hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocyclic or heteroaryl group and R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or alkyl-P ₂₅ . The compound of claim 43, wherein R ₁₅ is - (CH 2) _n CH ₂ R ₂₅ wherein η is 0, 1, 2 or 3 and R ₂₅ is OH, OMe, F, CN, CF ₃ , SOCH ₃ or SO ₂ CH ₃ , -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , -C (O) NR ₃₁ R ₃₂ or c is the formula: 259 wherein R ₃₃ is hydrogen, alkyl or substituted alkyl. The compound of claim 43, wherein R ₁₅ is methyl, ethyl, CH ₂ F methoxyethyl, CH ₂ CH ₂ F or CH ₂ CH ₂ CH ₂ SOCH ₃ ; R ₁₇ is bromine; R ₁₈ is hydrogen, methoxy or fluorine and R ₁₉ is H. The compound of claim 45, comprising as a side chain: wherein R ₄₀ is hydrogen or alkyl and R ₁₇ is hydrogen or halogen. 47. A compound of formula: 260 in which each R ₁₅ independently represents hydrogen, alkyl, aryl or -alkylCD R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl; R ₁₇ , R ₁₈ and R ₁₉ independently represent hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocyclic or heteroaryl group and R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or alkyl-K ₂₅ . © 48. The compound of claim 1, selected from the group consisting of: compounds of claim 1, having the formulas: (S) -4- (2-hydroxy-1-phenylethylamino) -3- (6-imidazol-1-yl) -4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one; (±) -4- [2-hydroxy-2- (3-iodphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- he; (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ; (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ; (S) -4- [2- (2-chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4259 in which R ₃₃ is hydrogen, alkyl or substituted alkyl. The compound of claim 43, wherein R ₁₅ is methyl, ethyl, CH ₂ F methoxyethyl, CH ₂ CH ₂ F or CH ₂ CH ₂ CH ₂ SOCH ₃ ; R ₁₇ is bromine; R ₁₈ is hydrogen, methoxy or fluorine and R ₁₉ is H. The compound of claim 45, comprising as a side chain: wherein R ₄₀ is hydrogen or alkyl and R ₁₇ is hydrogen or halogen. 47. A compound of formula: 260 in which each R ₁₅ independently represents hydrogen, alkyl, aryl or -alkyl CD> 25, R ₂₅ is hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halo, cyano, sulfoxy, sulfonyl, -NR ₃₀ COOR ₃₁ , -NR ₃₀ C (O) R ₃₁ , -NR ₃₀ SO ₂ R ₃₁ , C (O) NR ₃₀ R ₃₁ , heteroaryl or heterocycloalkyl; R ₁₇ , R ₁₈ and R ₁₉ independently represent hydrogen, halogen or alkoxy or R ₁₈ and R ₁₉ together form a heterocyclic or heteroaryl group and R ₃₀ and R ₃₁ denote independently of one another hydrogen, alkyl, cycloalkyl or alkyl-P ₂₅ . The compound of claim 1, selected from the group consisting of: the compounds of claim 1, having the formulas: (S) -4- (2-hydroxy-1-phenylethylamino) -3- (6-imidazol-1 - yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one; (±) -4- [2-hydroxy-2- (3-iodphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ; (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ; (±) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one ; (b) -4- [2- (2-Chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4261 methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he; (S) -4- [2- (3-Chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (S) -4- [2- (4-Chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (S) -4- [2- (2-bromophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (S) -4- [2- (3-bromophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- (1-hydroxymethyl-2-pentafluorophenyl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one; (±) -4- (1-Hydroxymethyl-2-pyridin-4-yl-ethylamino) -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (S) -4- [1-Hydroxymethyl-2- (2-naphthalenyl) -ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; 3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -4- (pyridin-2ylmethoxy) -1H-pyridin-2-one; (±) -4- [2- (3-bromophenyl) -2-fluoro-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -one; (S) -2- [4- (1-Hydroxymethyl-2-phenyl-ethylamino) -2-oxo-1,2-dihydro-pyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile; (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5- carbonitrile; (S) -2- {4- [2- (3-chlorophenyl) -1-hydroxymethyl-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile; (±) -2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole- 5-carbonitrile; (±) -2- {4- [2- (3-fluorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5- carbonitrile; 262 (±) -2- {4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazol-5 -carbonitrile; (S) -2- [4- (2-hydroxy-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7methyl-3H-benzimidazole-5-carbonitrile; (±) -3- (1H-benzimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -1H-pyridin-2-one; (S) -3- (1H-benzimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino] -1H-pyridin-2-one; (±) -3- (1H-benzimidazol-2-yl) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -1H-pyridin-2-one; (S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo 1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazol-5-yl} piperazine isopropylamide -1 carboxylic acid; (S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazol-5-yl} piperazine ethylamide -1 carboxylic acid; (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- {4-methyl-6- [4- (1-phenylmethanoyl) piperazin-1-yl] -1H-benzimidazol-2-yl} - 1H-pyridin-2-one; (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (4-isopropylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2- he; (S) -3- [6- (4-Benzylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- (1 hydroxymethyl-2-phenylethylamino) -1H-pyridin-2- he; (±) -3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridine- 2-it; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl) N-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2-one; (S) -6- (1-hydroxymethyl-2-phenylethylamino) -5- (6-imidazol-1-yl-4-methyl-1H263 benzimidazol-2-yl) -3H-pyrimidin-4-one; (S) - 2- [6-chloro-5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) pyrimidin4-ylamino] -3-phenylpropan-1-ol; (3) -4- (2-hydroxy-2-phenyl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2-one; (R) -4- (2-Hydroxy-2-phenyl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2-one; (1S, 2/7) -4- (1-Hydroxyindan-2-ylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2- he; (±) -4- [2-hydroxy-2- (3-hydroxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl] -1H-pyridin-2 -one; (S) -4- (2-Hydroxy-2-pyridin-2-yl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2 -one; (±) -N- (3- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2oxo-1,2-dihydropyridine- 4-ylamino] ethyl} phenyl) methanesulfonamide; (±) -4- [2- (3-fluorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one; (S) - 4- [2- (3-fluorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one; (±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one; (S) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; (S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; 264 (N) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridine -2-he; (±) -4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl4-methyl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one; (±) - (2-chloro) -4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) 2-oxo-1 methyl ester , 2-dihydropyridin-4-ylamino] ethyl} -phenyl) carbamic acid; (S) -4- (1-Hydroxymethyl-2-phenyl-ethylamino) -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H- pyridin-2-one; (S) -4- (1-Hydroxymethyl-2-phenyl-ethylamino) -3- [4-methyl-6- (4-p-butylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1 H-pyridin-2-one; (S) -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzimidazol-2-yl} 4- (1-hydroxymethyl-2-phenyl-ethylamino) - 1H-pyridin-2-one; (S) - 4- {2- [4- (1-hydroxymethyl-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazol-5- yl} -piperazine-1-carboxylamide; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl) N-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (4-ethylpiperazin-1-yl) -4methyl-1H-benzimidazol-2-yl] -1 H-pyridin-2-one; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzimidazole -2-yl} -1H-pyridin-2-one; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl) N-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl) N-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6morpholin-4-yl-1H-benzimidazol-2-yl) -1 H-pyridin-2-one; 265 (±) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H- benzimidazol-2-yl} -1H-pyridin-2-one; (±) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl) N-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl) N-benzimidazol-2-yl) -1H-pyridine- 2-it; (±) -3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzimidazol-2-yl] -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -1H- pyridin-2-one; (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (2-morpholin-4ylethylamino) -1H-benzimidazol-2-yl] -1H-pyridin-2- he; (±) -6- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -3H-pyrimidin-4- he; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (1-hydroxy-1-methylethyl) 4-methyl-1H-benzimidazol-2-yl] - 1H-pyridin-2-one; (±) -3- (6-Aminomethyl-4-methyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one; (±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6-hydroxymethyl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one; (S) -4- (1-Benzyl-2-hydroxy-ethylamino) -3- (4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one and ( S) -4- (1-Benzyl-2-hydroxy-ethylamino) -3- (4-methyl-6-piperidin-1-yl-1H-benzimidazol-2-yl) -1H-pyridin-2-one. A compound according to claim 1 selected from the group consisting of: (S) -4- (1-benzyl-2-hydroxy-ethylamino) -3- (4-methyl-6-piperidin-1-yl-1H-benzimidazole- 2-yl) -1H-pyridin-2-one; 4- [2- (3-Chloro-4-methylsulfanylphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl) -1H-pyridine- 2-it; 4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridine- 2-it; 266 3- [4- (2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole- 5-yl) piperazin-1-yl] propionitrile; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfonylethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 3- [4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzoimidazol-5- yl) -7-methylpiperazin-1-yl] propionitrile; 4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-2-fluoroethyl ester- 5-yl) piperazine-carboxylic acid; 4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-2-methoxyethyl ester- 5-yl) piperazine-carboxylic acid; 4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole tert-butyl ester -5-yl) piperazine-1-carboxylic acid; 4- (2- {4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -2oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H- propene-2-ynyl ester) benzoimidazol-5-yl) piperazine-carboxylic acid; 4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl tert-butyl ester) -3H-benzoimidazol-5-yl) piperazine-1-carboxylic acid; (S) -4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7- ethyl ester methyl-3H-benzoimidazol-5yl) piperazine-1-carboxylic acid; 4- [2- (3-chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-fluoroethyl) piperazine267 1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one; 4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (3,3,3-trifluoropropyl) piperazin-1-yl] -1H-benzoimidazole -2-yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (3,4,4-trifluorobut-3-enyl) piperazin-1-yl] - 1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoro-2-hydroxypropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one; (S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one; (S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H -benzoimidazol-2-yl} -1H-pyridin-2-one; [4- (2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5- yl) piperazin-1-yl] acetonitrile; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (4-fluorobutyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2,2-difluoroacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2 -yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfonylacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- [2- (3268 chlorophenyl) -2-hydroxy-ethylamino] -1H-pyridin-2 -one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6- {4- [2- (1-oxo-114thiomorpholin-4-yl) acetyl] piperazin-1 - yl} -1H-benzoimidazol-2-yl) -1Hpyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6- {4- [2- (1,1-dioxo-116thiomorpholin-4-yl) acetyl] piperazin-1-yl} -4-methyl-1H-benzoimidazol-2yl) -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (2-thiomorpholin-4-ylacetyl) piperazin-1-yl] -1H-benzoimidazol-2 -yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfinylacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methoxyacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (2-methylsulfanylacetyl) piperazin-1-yl] -1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 3- {6- [4- (2-chloroacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -4- [2 (3-chlorophenyl) -2-hydroxy-ethylamino] - 1H-pyridin-2-one; (S) -4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H -benzimidazol-5-yl) piperazine-1-carbaldehyde; (S) -4- (2- {4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole -5-yl) piperazine-1-carbaldehyde; (S) -4- [2- (3-Chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl) N-benzoimidazol-2-yl) -1H-pyridine- 2-it; 4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one; 4- [2- (3-chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin4-yl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one; 4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpho269 LIN-4-IL-1H-benzoimidazol-2-1 / 1L) -1H-pyridin-2-one; 4- (2- (7-bromo-2,3-dihydrobenzofuran-5-yl) -2-hydroxy-ethylamino] -3- (4methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) - 1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2 (5) -hydroxy-ethylamino] -3- (4-methyl-6- [2 (5) ₁ 6 (R) dimethyl-morpholin-4-yl] -1H- benzoimidazol-2-yl] -1H-pyridin-2-one; 4- [2- (3-bromo-4-methoxyphenyl) -2- (6) -hydroxy-ethylamino] -3- [4-methyl-6- [2 (5) 6 ^(/:?) - dimethylmorpholine-4- yl] -1H-benzoimidazol-2-yl] -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzoimidazole- 2-yl} -1H-pyridin-2-one and 4- (2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2-fluoromethyl-morpholine- 4yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one 4- (2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2fluoromethylmorpholin-4-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2fluoromethylmorpholine- 4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2one; 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2fluoromethylmorpholin-4-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(O) -2fluoromethylmorpholine- 4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2one; 4- (2- (7-bromo-2,3-dihydrobenzofuran-4-yl) - (S) -2-hydroxy-ethylamino] -3- {6 [(R) -2-fluoromethylmorpholin-4-yl] - 4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (7-bromo-2,3-dihydrobenzofuran-4-yl) - (S) -2-hydroxyethylamino] -3 - {6 - [(5) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-hydroxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazole- 2-yl} -1H-pyridin-2-one and 4- (2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2-hydroxymethyl270 morpholine-4 -yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2hydroxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) ) - (S) -2-hydroxy-ethylamino] -3 {6 - [(S) -2-hydroxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} 1H-pyridin-2- he; 4- [2- (3-Chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-hydroxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3 {6 - [(5) -2-hydroxymethyl-morpholine -4-yl] -4-methyl-1H-benzoimidazol-2-yl} 1H-pyridin-2-one; 4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2- yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2-methyl-morpholin-4-yl ] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methyl-morpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4 [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(5) -2-methyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4- [2- (3-Chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methyl-morpholin-4-yl] -4-methyl-1 N-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- (2- (3-chloro-4-methoxyphenyl) - (b) -2-hydroxy-ethylamino] -3- {6 - [(5 ) -2-methyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) - (S) -2-hydroxy -ethylamino] -3- {6 - [(R) -2-methoxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- (2 - (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2-methoxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H- pyridin-2-one; 4- [2- (3-Bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methoxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridine 271 2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2-methoxymethyl-morpholin-4-yl] -4-methyl -1H-benzoimidazol-2-yl} -1H-pyridin2-one; 4- [2- (3-Chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methoxymethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(S) -2-methoxymethyl-morpholine- 4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin2-one; 4- [2- (3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] - 1H-pyridin-2-one; 4- [2- (3-Bromo-4-methoxyphenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6- (4methylpiperazin-1-yl) -1H-benzoimidazol-2-yl ] -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (acetamido) -piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1 H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4- (acetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2 -yl} -1H-pyridin-2-one; 4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methoxyethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2one; 4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (methoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-pyridin-2-one; 272 4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-pyridin-2-one; (S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4ylethoxy) -1H-benzimidazol-2-yl] -1H- pyridin-2-one; (6) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2morpholin-4-ylethoxy) -1H-benzimidazol-2-yl] -1H-pyridin-2-one; (S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-methoxyethoxy) -1H-benzimidazol-2-yl] -1H-pyridine- 2-it; (S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-hydroxyethoxy) -1H-benzimidazol-2-yl] -1H-pyridine- 2-it; (S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylpropoxy) -1H-benzimidazol-2-yl] -1H-pyridin-2-one; (S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylpropoxy) -1H-benzimidazol-2-yl] -1H- pyridin-2-one; (S) -3- (4-Bromo-6-morpholin-4-ylmethyl-1H-benzimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2- he; (S) -3- [4-Bromo-6- (4-methylpiperazin-1-ylmethyl-1H-benzimidazol-2-yl) -4- [2- (3-chloro-phenyl) -2-hydroxyethylamino] -1H-pyridine -2-he; (N -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-ylmethyl) -1H-benzimidazol-2-yl] -1H -pyridin-2-one; 4- [2- (3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (1,4,5,6-tetrahydropyrimidin-1-yl) -1H-benzoimidazol-2 -yl] -1H-pyridin-2-one and 4- [2- (4-methoxy-3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (1,4, 5,6tetrahydropyrimidin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyridin-2-one. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 51. The pharmaceutical composition of claim 50, further comprising at least one anti-cancer agent, in combination as a fixed dose. 273 52. The pharmaceutical composition of claim 51, wherein said anticancer agent is selected from the group consisting of: tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrazole, borazol, eczemid , bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-cytoplasin, cytatin, cytatin, cytatin, cytatin Chunky, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan, an epothilone, Iressa, OSI-774 (Iressa, OSI-774); angiogenic inhibitors, EGF inhibitors; VEGF inhibitors, CDK inhibitors, Herl and Neg2 inhibitors and monoclonal antibodies. The use of the compounds of claim 1 for the preparation of a medicament for the treatment of a condition associated with at least one tyrosine kinase enzyme, comprising administering to the mammal in need of such treatment an effective amount of a compound of claim 1. The use according to claim 53, wherein said tyrosine kinase enzyme is Abl, CDK, EGF, EMT, FGF, FAK, Flk-1 / KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src or VEGF . The use of claim 53, further comprising administering said mammals to at least one anticancer agent in combination with said compound. The use according to claim 53, wherein the disease state is cancer. Use of the pharmaceutical compositions according to claim 50 or 51 for the treatment of cancer, comprising administering to a mammal in need of such treatment a therapeutically effective amount of the composition