TWI330174B - 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands - Google Patents

Description

1330174 发明Inventive Description: [Technical Field] The present invention relates to a novel substituted cyclobutenedione compound, a pharmaceutical composition containing the same, and a compound and a compound for treating CXC chemokine-mediated diseases The purpose of the use. [Prior Art] Chemokines are chemotactic cytokines, which are released by a wide variety of cells to blast cells, T-cells, eosinophils, immunophilic cells, neutrophils, and endothelial cells. Attracted to the location of inflammation and tumor growth. There are two major chemokine classes, 'CXC-chemokines and CC-chemokines. This species is determined by whether the first two cysteine acids are separated by a single amino acid (CXC-chemokine) or by an adjacent (CC-chemokine). CXC-chemokines include interleukokinin-8 (IL-8), neutrophil activating protein-1 (NAP-1), neutrophil activating protein-2 (NAP-2), GRO a, GRO Cold, GRO r, ENA-78, GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES, MIP-1 alpha, MIP-2 /5, unicellular chemotaxis protein-1 (MCP-1), MCP-2, MCP-3, and eotaxin. It is known that individual members of the chemokine population are bound by at least one chemokine receptor, wherein the CXC-chemokine is generally bound by members of the receptor CXCR species, while the CC-chemokine is restricted by the receptor CCR species. Member combination. For example, IL-8 is bound by CXCR-1 to the CXCR-2 receptor. Since CXC-chemokines promote the accumulation and activation of neutrophils, these chemokines are associated with a wide range of acute and chronic inflammatory conditions, including psoriasis and rheumatoid arthritis. Baggiolini et al, FEBS Lett. 307, 97 (1992); Miller et al, Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al. 86836 1330174, Annu_Fev. Immunol. 9, 617 (1991); Seitz Et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet, 341, 643 (1993). Contains IL-8 , ELROXC chemokines of GRO a, GRO /3, GRO, NAP-2 and ENA-78 (Strieter et al., 1995 JBC 270, pp. 27348-57) have also been associated with tumor angiogenesis (new blood vessel growth). Association. All of these chemokines are exerted via the receptor CXCR2 (also known as IL-8RB) that binds to the 7-transmembrane G-protein coupling, while IL-8 also binds to CXCR1 (also known as IL-8RA). . Therefore, its angiogenic activity is manifested on the surface of vascular endothelial cells (EC) in peripheral blood vessels due to its binding to CXCR2 and activation, and to CXCR1, which is likely to be IL-8. Many different types of tumors have been shown to produce ELRCXC chemokines, and their production has been associated with stronger phenotypes (Inoue et al., 2000 Clin Cancer Res 6 Pages 2104-2119) and poor prognosis (Yoneda et al., 1998 J). Nat Cancer Inst 90 pp. 447-454) is associated. Chemokines are potent chemotaxis factors, and ELRCXC chemokines have been shown to induce EC chemotaxis. Therefore, these chemotactic factors may induce the chemotaxis of endothelial cells toward their production sites in the tumor. This may be an important step in tumor-induced angiogenesis. Inhibitors of CXCR2, or dual inhibitors of CXCR2 and CXCR1, will inhibit the angiogenic activity of ELRCXC chemokines and thus block tumor growth. This antitumor activity has been described as being for IL-8 (Arenberg et al., 1996 J Clin Invest 97, pp. 2792-2802), ENA-78 (Arenberg et al., 1998 J Clin Invest 102, pp. 465-72) and An antibody to GRO a (Haghnegahdar et al., J. Leukoc Biology 2000 67, pp. 53-62). 86836 1330174 Many tumor cells have also been shown to express CXCR2, and thus when tumor cells secrete ELRCXC chemokines, they can also stimulate their own growth. Therefore, with the reduction of angiogenesis, inhibitors of CXCR2 directly inhibit the growth of tumor cells. Thus, the CXC-chemokine is represented by the system as a promising target for the development of novel anti-inflammatory and anti-tumor agents. There is still a need for compounds that are capable of modulating CXC_chemokine receptor activity. For example, symptoms associated with IL-8 production, which is associated with an increase in neutrophilic white blood cells and a subset of τ_cell subsets to tumors with particularly inflammatory sites and growth, are mediated by IL-8 receptors. Benefit from the combination of compounds with inhibitors. SUMMARY OF THE INVENTION The present invention provides a method of treating a disease in a therapeutic condition in a patient in need of treatment (e.g., a mammal, preferably a human), comprising administering to the patient at least one effective amount. (e.g., 1-3, and usually a type II compound of the formula described below (or a pharmaceutically acceptable salt thereof or a solvate-mediated factor) is selected from the group consisting of: chronic inflammation, various sexes Inflammatory pain, chronic inflammatory pain, acute neuropathic pain, slow: oracle pathogenic pain, acute dyspnea syndrome, delayed allergy, atherosclerosis, brain and cardiac stenosis, ~ s ^ s off That is, inflammation, multiple hard, herpes virus, meningitis, official dysfunction, herpes, encephalitis, restenosis, angiogenesis, osteoporosis, (four) inflammation, respiratory virus hepatitis virus, HIV, snoring female Ba and two mothers Associated Kaposi's fiber fibrosis, premature birth, cough, cancer pain, more crying: injury, labor injury, sprain, contusion, psoriatic arthritis: · 5 pulse, traumatic brain injury, CNS Tumor, object 86836 13 30174 Subarachnoid hemorrhage, post-operative trauma, group, and interstitial pneumonia, allergic, crystal-induced sclerotherapy, acute and chronic membrane face* ^ pancreatitis, acute alcoholism hepatitis, dying enterocolitis, Chronic sinusitis buys long-term angiogenic ocular disease, retinal premature retinopathy, retinopathy of diabetic patients, spot degeneration with better moist and corneal neovascularization, polymyositis, vasculitis, hemorrhoids, stomach And duodenal ulcer, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, branch tracheal dilation, twig bronchitis, occlusive twig bronchitis, chronic bronchitis, pulmonary heart disease, cough, Difficulty breathing, emphysema, hyperacidity, hyperventilation, hypoxemia, inflammation caused by excessive oxygen, hypoxia, reduction of lung volume in surgery, pulmonary fibrosis, lung 1" blood pressure, right heart, room hypertrophy, and Continuous metastatic peritoneal dialysis (CAPD) related peritonitis, granulocyte Ehrlich disease, sarcoidosis, small airway disease, ventilatory perfusion disorders, wheezing, colds, money, alcohol Liver disease, acne, burn treatment, periodontitis, graft reperfusion injury and early graft rejection, acute inflammation and rheumatoid arthritis. The present invention provides a disease in a patient in need of treatment (e.g., a mammal, preferably A method for treating acute inflammatory pain, chronic inflammatory pain, acute neuropathic pain, or chronic neuropathogenic pain, which comprises administering to the patient at least one effective amount (eg, M, and usually a method of formula IA (or a pharmaceutically acceptable salt or solvate thereof) as described below. The present invention provides a method of treating a chemokine-mediated disease in a condition in need of treatment, comprising The patient is administered an effective amount of at least one (eg, I-3 'generally a quinone') compound selected from the group consisting of compounds of Formula 1A, 3, and examples 360.109-mm, 368.32.36845, 12 The final compound of 〇〇12u, ΐ3〇〇ΐ3ΐι 86836 1330174 and 2001-2088, or a pharmaceutically acceptable salt or solvate of the compound. The present invention provides a method of treating acute inflammatory pain, chronic inflammatory pain, acute neuropathic pain or chronic neuropathogenic pain in a patient in need of treatment, such as a mammal, preferably a human, including The patient is administered an effective amount of at least one (e.g., 1-3, and usually one) compound selected from the group consisting of compounds of formulas 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200-1211, The last compound of 1300-1311 and 2001-2088, or a pharmaceutically acceptable salt or solvate of the compound. The invention also provides a method of treating cancer in a patient in need of treatment comprising administering to the patient an effective amount of at least one (eg, 1-3, usually one) compound selected from the group consisting of Formula 1.0A , a compound of 3.0A, and a final compound of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088, or a pharmaceutically acceptable salt or solvate of the compound. The invention also provides a method of treating cancer in a patient in need of treatment comprising administering to the patient an effective amount of at least one (eg, 1-3, usually one) compound selected from the group consisting of Formula 1.0A , a compound of the formula 360, and the final compounds of the examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311 and 2001-2088, or a pharmaceutically acceptable salt or solvate of the compound, simultaneously or sequentially Use: (4) microtubule imaging agents, or (8) anti-tumor agents, or (c) anti-angiogenic agents, or (d) VEGF receptor kinase inhibitors, or (e) antibodies to VEGF receptors, or (f) Interferon and / or g) radiation. The invention also provides a method for inhibiting angiogenesis in a patient in need of treatment, in the method of 86836 -12-1330174, which comprises administering to the patient an effective amount of at least one (for example, 1-3, usually one) compound a compound selected from the group consisting of compounds of formula 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088, or a pharmaceutically acceptable salt or solvent of the compound The present invention also provides a method for treating angiogenic ocular diseases in patients in need of treatment (for example, inflammation of the eyes, retinopathy of prematurity, retinopathy of diabetic patients, and spots having better moist type and corneal neovascularization) A method of denaturation) which comprises administering to a patient an effective amount of at least one (e.g., 1-3, usually one) compound selected from the group consisting of compounds of formulas 1.0A, 3.0A, and examples 360.109-360.117, The final compound of 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088, or a pharmaceutically acceptable salt or solvate of the compound. The invention also provides a method for treating a disease in a patient in need of treatment, the disease selected from the group consisting of: gingivitis, respiratory virus, herpes virus, hepatitis virus, HIV, Kaposi's sarcoma associated with the virus, and atherosclerosis. Tumor sclerosis, which comprises administering to the patient an effective amount of at least one (e.g., 1-3, usually one) compound selected from the group consisting of compounds of formulas 1.0A, 3.0A, and examples 360.109-360.117 '368.32- The last compound of 368.45, 1200-1211, 1300-1311, and 2001-2088, or a pharmaceutically acceptable salt or solvate of the compound. The present invention also provides novel compounds selected from the group consisting of the compounds of Formulas 1.0A, 3.0A, and the final compounds of Examples 360.109-360.117, 368.32-368.45, 1200-121, 1300-1311, and 2001-2088. 86836 -13- 1330174 The present invention also provides novel compounds selected from the group consisting of compounds of Formula 1A, 3.0A, and the final compounds of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088. A pharmaceutically acceptable salt (such as a sodium or calcium salt) or a solvate. The invention also provides a pharmaceutical composition comprising at least one (e.g., μ3, usually one) compound selected from the group consisting of a compound of the formula 〇 3〇A, and examples 360.109-360.117, 368.32-368.45, 1200- The final compound of 1211, 1300-1311 and 2001-2088, or a pharmaceutically acceptable salt or solvate of the compound, and a pharmaceutically acceptable carrier. The invention also provides a method for treating a chemokine-mediated disease in a patient in need of treatment, comprising administering to the patient an effective amount of at least one (eg, 1-3 'generally i) as follows Said Ιβ compound. The present month also provides a method for treating cancer in a patient in need of treatment, which comprises administering to the patient at least one effective amount (for example, 1-3, usually one) as described below. a compound of formula IB. The present invention also provides a method of treating cancer in a patient in need of treatment, which comprises administering at least one effective amount (for example, 1-3, usually 1) to the patient ("HF"" ' t; a compound of the formula 'also used simultaneously or sequentially: (8) microtubule shadow, 4, /Ί_, ^ or (9) antitumor agent or (6) anti-angiogenic agent, or (6) VEGF-dependent kinase inhibitor, or (8) antibodies to VEGF receptors, or (f) interferons and/or (g) radiation. The present invention also provides a method for inhibiting angiogenesis in a patient in need of treatment, and to administer at least one effective amount of the patient (for example, a species, one for $1) as follows The compound of formula IB is described. 86836 1330174 . The month also provides an treatment for angiogenic ocular diseases in patients in need of treatment (eg, eye inflammation, retinopathy of prematurity, vision of diabetic patients, better moist type and corneal neovascularization) Spotted denaturation of the effect). ' /, comprising administering to the patient an effective amount of at least one (e.g., 1-3, usually one) of a compound of formula IB as described below. The invention also provides a method for treating diseases in a patient in need of treatment, 2 diseases selected from the group consisting of: gingivitis 'respiration virus, herpes virus, hepatitis virus HIV, Kaposi's sarcoma associated with virus and artery A atheroma hardening comprising administering to the patient an effective amount of at least one species (e.g., one to three, usually one inclusive) of a compound of formula IB as described below. The invention also provides novel compounds of formula IB as described below. The invention also provides novel compounds selected from the group consisting of the compounds of formula IB, as described below, pharmaceutically acceptable salts (e.g., sodium or calcium salts) or solvates. The present invention also provides a pharmaceutical composition comprising at least one (e.g., 1 to 3) of a compound of the formula IB as described below and a pharmaceutically acceptable carrier. When any variable occurs more than once in any part of the group, its position in each place is independent of its definition in each other place. Moreover, combinations of substituents and/or variables are permissible only if such combinations result in a stability compound. Unless otherwise indicated, the following definitions apply to the entire scope of this patent specification and patent application. These definitions apply regardless of whether a term is used alone or in combination with other terms. For example, the definition of "alkyl, is also applicable to the alkoxy 86836 -15- 1330174 ” 垸 &" part. The patient" includes humans and other mammals, preferably humans. "Mammals" include humans, and preferably means humans. "Alkyl" means a straight or branched saturated hydrocarbon chain having from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 丨 to 6 carbon atoms. "Base" means a fluorenyl-hydrazine group wherein the alkyl group is as defined above. Non-limiting examples of alkoxy groups include: methoxy 'ethoxy, n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety is via ether oxygen. ί "women" means a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon double bond, and 2 to 20 carbon atoms 'preferably 2 to 12 carbon atoms, and 1 is preferably 2 to 6 carbon atoms. Non-limiting examples of the terminator include: ethenyl, propenyl, n-butenyl, 3-methylbutenyl, n-pentenyl, octanoyl and decyl. "alkynyl" means a straight or branched aliphatic hydrocarbon group having at least one carbon·carbon bond, and 2 to 15 carbon atoms, preferably 2 to 12 carbon atoms, and more preferably 2 Up to 4 carbon atoms. Non-limiting examples of block groups include ethynyl, propynyl, 2. butynyl, 3, methylbutynyl, n-pentynyl and anthracene. "Aryl" By means of an aromatic monocyclic or polycyclic ring system, at least one of which is aromatic, containing from about 6 to about 14 carbon atoms, and preferably from about 6 to about 1 carbon atoms. Non-limiting examples of the base include: phenyl, anthracenyl, imprinting, tetrahydronaphthyl, hydroquinone, anthracenyl and adiyl. "aromatic base" means "as defined above" And an aryl group, which is bonded to the alkyl group as defined above, wherein the alkyl group is bonded to the parent moiety. Suitable aryl group 86836 • 16-1330174 Non-limiting examples, including benzyl, phenylethyl And a naphthylmethyl group. "cycloalkyl" means a saturated carbocyclic ring having 3 to 1 (for example 3 to 7) carbon atoms 'preferably 5 to 10 carbon atoms, and more Non-limiting examples of 5 to 7 carbon atoms 'and having one to three cyclic anthracenyl groups include: cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, n-decyl and gold steel alkyl. "Cycloalkylalkyl" means a cycloalkyl group bonded to the parent moiety through an alkyl group. Non-limiting examples include: cyclopropylmethyl and cyclohexylmethyl.

"cycloalkenyl" means a non-aromatic mono- or polycyclic ring system comprising from 3 to 10 carbon atoms, and preferably from 5 to 10 carbon atoms, and having at least one carbon-carbon double bond. Preferred cycloalkenyl rings have from 5 to 7 carbon atoms. Non-limiting examples of cycloalkyl groups include % pentenyl, cyclohexenyl, cycloheptyl and n-decyl. ••商基" means that the fluorenyl, chloro, bromo or pyridyl group is preferably a fluorine group, a gas group or a bromine group, and more preferably a fluorine group and a gas group. "岗素" means fluorine 'chlorine' bromine or iodine. Preferred is fluorine, chlorine or bromine, and more preferably fluorine and gas.

A "alkyl group" means a group as defined above wherein one of the hydrogen atoms on the alkyl group is replaced by a group as defined above. • 'Heterocyclyl, or "heterocyclic" or " Heterocyclic alkyl groups mean non-aromatic saturation! a 100- or polycyclic ring system (ie, a saturated carbocyclic or ring system) containing 3 to 1 ring atoms (eg, 3 to 7 ring atoms), preferably (10) ring atoms, j: in this ring (4) Medium- or multiple atomic systems, elements other than carbon, for example: oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in this system. Preferably, the heterocyclic group has; the first nitrogen of the root name, the oxygen cut / the vertical (tetra) atom. In the heterocyclic group 4 & means that at least one nitrogen, oxygen or stone i 86836 -17-1330174 atoms are individually present as a ring precursor to the hydrazine group. Your nitrogen or sulfur atom may not be emulsified into its corresponding N_oxidation. , 3_oxide or s, s• dioxide. Non-limiting examples of mono-heterocyclic heterocyclyl rings include: hexahydro-yl, tetra-gas/hydropyridyl, morpholinyl, thiomorpholinyl, pyrazolyl, 3-di Milky root, dioxyl, tetrasyl phenyl and tetrahydrothiopyranyl. The term "acidic functional group" is intended to include groups such as hip hop, savory, sir, four ton, and the like. ", aryl" means an aromatic monocyclic or polycyclic ring system comprising 5 magical 4% atoms 'preferably 5 to 1 () ring atoms, wherein - or more ring atomic systems are A unit other than carbon, such as nitrogen, oxygen or sulfur, alone or in combination. Preferably, the group contains 5 to 6 ring atoms. The prefix nitrogen, oxygen or sulfur in the name of the heteroaryl radical means at least a nitrogen, oxygen or sulfur atom, individually present as a ring atom, a nitrogen atom of a heteroaryl group may optionally be oxidized to its corresponding non-limiting example of a hydrazine heteroaryl group, including: p ratio base, P Phynal, pyranyl, pyrenyl, pyrimidinyl, isoxazolyl, isoxazolyl, oxazolyl, thiazolyl, pyrazolyl, furazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-pyrimidazolyl, pyridinium, hydrazine, quinoxaline, hydrazine, carbazino[l,2-a]acridinyl, imidazo[2,lb] P-pyrazolyl, benzofurazinyl, anthracenyl, aziridine, benzimidazolyl, benzindenyl, porphyrin, supramyl, p-phenophene P Tu Linji, p sputum and p secret base, tons of p and Anthracenyl, imidazopyridyl, isoindolyl, benzazepine, 1,2,4, di-n- yl and benzoxazolyl. Heteroaralkyl π means heteroaryl as defined above And an alkyl group as defined in 86836 1330174 above, wherein the bond to the parent moiety is via an alkyl group. The N-oxide may be present on the tertiary nitrogen in the R substituent, or in the heteroaryl The substituent in the base ring is formed on =N- and is included in the compound of the formula. The term "prodrug" as used herein means a rapid transition in vivo, for example via hydrolysis in the blood. Compounds of the above parent compounds are fully discussed in T. Higuchi and V. Stella, prodrugs as novel delivery systems, ACS series in Volume 4, and in Edward B R〇che. Reversible Carriers, available from the American Medical Association and Pergam〇n Press, 1987, both of which are incorporated herein by reference. The entire content of "composition" as used herein is intended to encompass a particular component. Product, as well as directly or indirectly by specific ingredients Any product formed by a combination of quantifications. An "effective amount" as used in the methods of the invention means a therapeutically acceptable amount (ie, an amount that provides the desired therapeutic effect). Moreover, with reference to chemical structures or chemical formulas, "Bn" as used herein means benzyl, "Et" means ethyl, "Me" means methyl, and "punching" means phenyl. Representative embodiments of the invention are described in Hereinafter, these specific examples have been numbered for the purpose of reference. Formula 1_〇Α 'The compounds of 2.0A, 3·ΟΑ, 4.0A, 5.0A and 6.0A are:

86836 -19- 1330174

V^N J, A %_ά S lb

N OH H s

And dry ^ ,

OO f N OH H 5.0A (Example 2050) 6.0A (Example 2047) For a method of treatment as described above using a compound of formula IA, the compound of formula IA is:

(ΙΑ) and a pharmaceutically acceptable salt thereof (e.g., sodium or calcium salt) and a solvate thereof, wherein: the lanthanide is selected from the group consisting of: (1) R7 R8 R7 R8 R7 R8

86836 -20- 1330174

86836 -21 - [1330174

86836 -22- 『1330174

Wherein the ring system of the above A group is substituted by 1 to 6 substituents, each of which is independently selected from the group consisting of: R9 group; (3) 86836

1330174

and

Wherein one or both of the above A groups are substituted by 1 to 6 substituents, each of which is independently selected from the group consisting of: R9 groups; (4)

86836 - 24 1330174 wherein the benzene ring system of the above A group is substituted by 1 to 3 substituents each independently selected from the group consisting of: R9 groups;

R5

N-NH

RIN

86836 -25- 1330174

R12

R12

〇

p is 1 to 5; X is Ο, NH or S; Z is 1 to 3; R2 is selected from the group consisting of hydrogen, OH, -C(0)0H, -SH, -S02NR13R14, -NHC^R13, -NHS02 NR13 R14, -NHS02 R13, -NR13 R14, -〇 (0_3 R14, -C(0)NH0R13, -C(0)NR13OH, -S(02)0H, -〇C(0)R13, unsubstituted a heterocyclic acidic functional group and a substituted heterocyclic acidic functional group; wherein, there are 1 to 6 substituents on the substituted heterocyclic acidic functional group, and 86836 -26 - 1330174 each substituent is independently selected Self-contained: R9 group; halogen, alkyl, oxygenated WOR13, -CXCONHR17 Each R3 and R4 are independently selected from the group consisting of: hydrogen, an aryl group, J, -C(〇)ORU, -CCCONHR1 -SO(t) Ri3 . -C(0)NR130R14 ' group, -OH, -CF3, -〇CF3, _n〇2, -c(o)nr13r14, -SO(1) nrur14, _s unsubstituted or substituted aryl group, unsubstituted Substituted or substituted heteroaryl,

Wherein 'there is 1 to 6 substituents on the substituted aryl group, and each substituent is independently selected from the group consisting of: R9 groups; and wherein 1 to 6 substituents are substituted on the substituted heteroaryl group And each substituent is independently selected from the group consisting of: R9 groups; each R5 and R6 are the same or different and independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3, -OCF3, -N〇 2,-(:(0)111 3,((COOR1 3, -CXC^NR1 3 R14 , -SO(1)NR13R14, _C(0)NR13〇r14, cyano, unsubstituted or substituted aryl and unsubstituted Or a substituted heteroaryl group; wherein, there are 1 to 6 substituents on the substituted aryl group, and each substituent is independently selected from the group consisting of: an R9 group; and wherein the substituted heteroaryl group There are 1 to 6 substituents on the group, and each substituent is independently selected from the group consisting of: a R9 base diagram; each of R7 and R8 is independently selected from the group consisting of: anthracene, unsubstituted or substituted alkyl, unsubstituted or Substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aralkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted naphthenic a substituted, substituted or substituted cycloalkylalkyl group, -C02R13, -c〇nr13r14, alkynyl, alkenyl and cycloalkenyl; and wherein, on the substituted R7 and R8 groups, a plurality of (for example, 86836 • 27· 1330174 1 to 6) substituents, wherein a) halogen, each substituent is selected from the group consisting of: b) -CF3, c) -COR13, d) -OR13, e) -NR13R14 , f) -N02, g) -CN, h) -S020R13, 0 -si (burning base h ' wherein each of the alkyl groups is independently selected, j) is (aryl) 3, wherein each aryl is independently Select, k) where each R1S is independently selected l) -C02R13, m) -C(0)NR13R14, n) -S02NR13R14, 〇) -S02R13, ρ) -OC(0)R13 > q) -0C( 0) NR13R14, r) -NR13C(0)R14, and s) -NR13C02R14, (fluoroalkyl is a non-limiting example of an alkyl group substituted by dentate); R8a is selected from the group consisting of: hydrogen, alkane R9 is independently selected from the group consisting of: a) -R13, -28.86836 1330174 b) halogen, c) -CF3, d) -COR13, e) -OR13, f ) -NR13R14, g) -N02, h) -CN, i) -S02R13, j) -S02NR13R14, k) -NR13 COR14, l) -CONR1 3R14, m) -NR13C02R14, n) -C02R13,

N-N /

HP) an alkyl group substituted with one or more (eg, one)-OH groups (eg, _(CH 2 ) q 〇 H, wherein 1-6, usually 1 to 2, and preferably !), q) an alkyl group substituted by one or more (e.g., -) 13 R14 groups (e.g., -(CH2)aNR13R14, and wherein n & ^^q T q is 丨_6' is usually 1 to 2, And preferably 1), and r) "^(R1 3 )S〇2 R14 (for example, Ri 3 is η, and R1 4 is a burnt group, such as a methyl group); each R and R1 1 are independently selected from the group consisting of R1 3, hydrogen, alkyl (eg Cl to, 86836 1330174 such as methyl), _, -ci?3, -οα?3, -nr13r14, -NR13c(o)NR13Ri4 ' -OH ^ -C(0) 0R13 N _SH . _s〇(t)NR13R14 ' -S02R13 ' -NHC(〇)R13 ' -NHS02NR13Ri4 x .NHS02R13 ' -C(0)NR13R14 ' -C^NR13 〇Rl 4 , -〇C(0)Ri3 and Cyano; R12 is selected from the group consisting of: hydrogen, -(χο)ΟΙΙ13, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aralkyl, un Substituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl and unsubstituted or via a heteroarylalkyl group; wherein, there are 1 to 6 substituents on the substituted R12 group, and each substituent is independently selected from the group consisting of: R9 groups; each of R13 and R14 is independently selected from the group consisting of: Unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aralkyl, unsubstituted or substituted Heteroaryl, unsubstituted or substituted cyclohexyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl And an unsubstituted or substituted heterocycloalkylalkyl group (wherein "heterocycloalkyl" is meant to be a heterocyclic group; wherein there are 1 to 1 on the substituted scale 13 and the 14 base group 6 substituents, each substituent being independently selected from the group consisting of alkyl, -CF3, -oxime, alkoxy, aryl, aralkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, hetero Aryl, heteroaralkyl, -NCR40)2, -C(0)0R15, -C(0)NR15R16, _S(〇)tNRi5Ri6, _c(〇)R15, -S〇2R15 ', provided that R15 is not For H, halogen and R13 and R14 together with the nitrogen to which they are attached are employed in the group -C(0)NR13R14 and ·S〇2NR13R14 to form an unsubstituted or substituted saturated heterocyclic ring (preferably 3 86836 • 30-1330174 to 7) a heterocyclic ring), which is selected from the group consisting of a substituted cyclized R1 3 to 7 fluorene, which optionally contains one other hetero atom selected from the group consisting of ruthenium, S and NR18; There are 1 to 3 substituents on the cyclized ring ^ and the (1) 4 group (that is, together with the "4 group and the nitrogen to which it is combined"

Selected from: alkyl, aryl, hydroxy, (tetra), alkoxy, alkoxyalkyl, aralkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl , amine group, -C(〇)〇R丨5, -(χθ)ΝΙΙ1 5 R16, -SOtNR15 6 , _c((^Rl 5 ' -S02R15, provided that Ri5 is not, halogen and heterocyclic fluorenyl (i.e., a heterocyclic group having at least one, and preferably one, double bond in the ring, for example

Each of R15 and R16 is independently selected from the group consisting of hydrazine, alkyl, aryl, aralkyl, cycloalkyl and heteroaryl; and R17 is selected from the group consisting of: -S〇2 alkyl, -S〇2 aryl, -S02 cycloalkyl and -so2 heteroaryl; R18 is selected from the group consisting of: anthracene, alkyl, aryl, heteroaryl, -C(0)R19, -S〇2R19 and -C(0)NR19R2〇; Each of R19 and r2 is independently selected from the group consisting of alkyl, aryl and heteroaryl; and R30 is selected from the group consisting of alkyl, cycloalkyl, _CN, _N〇2 or _s〇2r15, provided that R15 is not Each R31 is independently selected from the group consisting of unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or taken 86836-31· (10) 174 戈 ^ ; ; ;; wherein there are 1 to 6 substituents on the substituted R 31 group and each substituent is independently selected from the group consisting of: alkyl, halogen and -CF3; The oxime is independently selected from the group consisting of hydrazine, alkyl and cycloalkyl; and t is hydrazine, 1 or 2. Specific embodiments of the methods of treatment as described above using a compound of formula IA are described below. These specific embodiments have been numbered to provide their reference. DETAILED DESCRIPTION OF THE INVENTION No. 1 is directed to a method of treatment using a compound of formula IA, wherein B is selected from the group consisting of: (1) R5

The condition is that the R3 system for this group is selected from the group consisting of .OR13 'R14 R31 • P-R31 R1〆 II 0

R (2) 13 and 30〆1

86836 32 · (3)1330174

(6) R12

All substituents therein are as defined for the novel compounds of formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 2 is directed to a method of treatment using a guanidine compound, wherein the oxime is: 86836 - 33 - 1330174

And all other substituents are as defined in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 3 is directed to a method of treatment using a guanidine compound, wherein Β is: R5

DETAILED DESCRIPTION OF THE INVENTION No. 4 is directed to a method of treatment using a guanidine compound, wherein Β is: R5

R13 and Ri4 are each the same or different alkyl groups, and all other substituents are as defined in the formula. 86836 - 34 - 1330174 DETAILED DESCRIPTION OF THE INVENTION No. 5 is directed to a method of treatment using a compound of formula IA, wherein B is: 4 R1

And (1) R2 is -ΟΗ, and all other substituents are as defined in the formula, or (2) R2 is -OH, and R13 and R14 are each the same or different alkyl groups, and all other substituents are as Definition in Formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 6 is directed to a method of treatment using a compound of formula IA, wherein B is: R5

R3 is selected from the group consisting of:

And all other substituents are as defined in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 7 is directed to a method of treatment using a hydrazine compound, wherein the enthalpy is: 86836 - 35 · 1330174

R2 is -OH and all other substituents are as defined in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 8 is directed to a method of treatment using a guanidine compound, wherein Β is:

I , Ν R14

R2 'R13 and R14 are as defined for the compound of the formula, and all other substituents are as defined in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 9 is directed to a method of treatment using a guanidine compound, wherein Β is:

R2 is -OH'. Both R13 and R14 are as defined for the formula compound, and all other substituents are as defined in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 10 is directed to the treatment of a compound of the formula 并, and B in 86836 - 36 - 1330174 is:

R2 is as defined for the compound of formula R R13 and R14 are the same or different alkyl and all other substituents are as defined for the compound of formula 。. DETAILED DESCRIPTION OF THE INVENTION No. 11 is directed to a method of treatment using a compound of the formula wherein:

R1, R2 are -OH, R13 and R14 are the same or different alkyl groups, and all other substituents are as defined for the compound of the formula. DETAILED DESCRIPTION OF THE INVENTION No. 12 is directed to a method of treatment using a compound of the formula μ, wherein the lanthanide is as described in the specific example number 6, R4 is H, R5 is oxime, % is Η' and all other substituents are as defined Definition of IA compounds. DETAILED DESCRIPTION OF THE INVENTION No. 13 is directed to a method of treatment using a compound of the formula wherein the lanthanide is as described in the specific example No. 7, r4 is η, R5 is η, R6 is Η' and all other substituents are as defined Definition of bismuth compounds. DETAILED DESCRIPTION OF THE INVENTION No. 14 is directed to a method of treatment using a guanidine compound wherein the lanthanide is as described in specific examples 4, 5, 8 and 9 except that ri 3 and Ri 4 are each thiol' and all other substituents They are all defined as in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 15 is directed to a method of treatment using a guanidine compound wherein the lanthanide is selected from the group consisting of: 86836 - 37 - 1330174

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 16 is directed to a method of treatment using a guanidine compound, wherein Β is: R11

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 17 is directed to a method of treatment using a guanidine compound, wherein Β is: R11

R11 is deuterium and all other substituents are as defined in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 18 is directed to a method of treatment using a guanidine compound, wherein the oxime is: 86836 - 38 - 1330174

R3 R2 R2 is -OH, and all other substituents are as defined in the formula. DETAILED DESCRIPTION OF THE INVENTION No. 19 is directed to a method of treatment using a compound of formula IA, wherein B is:

R3 R3 is -c(o)nr13r14 and all other substituents are as defined in formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 20 is directed to a method of treatment using a compound of formula IA, wherein B is:

R11 R3 R3 is -S(0)tNR13R14 (for example, 2), and all other substituents are as defined in the formula r. DETAILED DESCRIPTION OF THE INVENTION No. 21 is directed to a method of treatment using a compound of formula IA, wherein B is:

R2 is -OH, R3 is -C(〇)NR13rM, and all other substituents are as defined in the formula. 86836 • 39- 1330174 DETAILED DESCRIPTION OF THE INVENTION No. 22 is directed to a method of treatment using a hydrazine compound, wherein Β is:

R11 R3 R is -ΟΗ, and R3 is -sco^nr1 3 R14 (e.g., t is 2), and all other substituents are as defined in formula IA. The specific embodiment number 23 is for the usage! a method of treating a compound, wherein B is: R 11 R3

R2 is -OH, R, -C(0)NRl3Rl4, R11 is η, and all other substituents are as defined in the formula. The exemplified embodiment No. 24 is directed to a treatment method using a hydrazine compound, wherein β is

R3 is -S(0)tNR13R14 (e.g., t is 2), and each of Rl3 and r14 is the same or not selected from the group consisting of hydrazine and an alkyl group (e.g., methyl, ethyl, isopropyl, and butyl). In this embodiment, each ruler and "4 are generally / self-sprayed 3 Η and ethyl' and R4R" is preferably ethyl, and all other substitutions are defined in formula IA. Earth 86836 - 40 - 1330174 DETAILED DESCRIPTION OF THE INVENTION No. 25 is directed to B in use: a method of treatment of a compound of formula IA, R3

R2 R3 is -SCOXNR1 3 R1 4 (eg, t A 9 , nt is 2), R" is H, and each r13 and r14 are the same or different, and are selected from the group consisting of: fate >, sweet, yt Η and Base (eg, methyl, ethyl, isopropyl, and tert-butyl). In this specific embodiment, each ruler "and ... 4 are generally selected from the group consisting of: Η and ethyl, and R13* 〇14 private ^ '' and anaesthesia 14 are preferably ethyl, and all The other substituents are as defined in the formula. The specific example number 26 is for the treatment method of the 田 斗, τ α 仏 仏, 1 町 使用 使用 , , , , , , , , , , ,

R2 is -OH, R3 is -S(0)fNR13Ri4, ν , , , , θ V AM R (e.g., q2), Rll*H, and all other substituents are as defined in the formula. Specific Example No. 27 is directed to the treatment method using < ΙΑ合合16, wherein Β is: '

Independently selected, and wherein R2 is -OH, W is _C(0)NRi3Rl4, R11 is η, and Rl3 and Rl4 are self-contained: alkyl, unsubstituted heteroaryl, and substituted heteroaryl 86836-41 1330174 There are other substituents as defined in the formula. In general, one of R1 3 or R1 4 is an alkyl group (e.g., methyl). An example of a substituted heteroaryl group is

DETAILED DESCRIPTION OF THE INVENTION No. 28 is directed to a method of treatment using a compound of formula IA, wherein B is: R2 ruler 2 is _〇11, R3 is aoxnrUrh (eg, 2), 1111 is 11, and each r13 and R14 are the same or different And selected from the group consisting of: H and an alkyl group (e.g., methyl, ethyl, propyl, and sec-butyl), and all other substituents are as defined in Formula IA. In this embodiment, each R1% R" is generally selected from the group consisting of ruthenium and ethyl, and R13 and R14 are preferably ethyl. DETAILED DESCRIPTION OF THE INVENTION No. 29 is directed to the treatment of a compound using a formula, which is: μ and R4 R3

R2 Meaning All substituents are as defined in the formula. Specific Example No. 30 is for use. The medium is: The treatment of the compound of the formula is 86836 '42- 1330174

And all substituents are as defined in formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 31 is directed to a method of treatment using a compound of formula IA, wherein B is as described in any of the specific examples 1 to 30, and A is as described in the specific examples below. Any of those described. DETAILED DESCRIPTION OF THE INVENTION No. 32 is directed to a method of treatment using a compound of formula IA, wherein B is as described in any of the specific examples 1 to 30, and A is: , R7 R8

Wherein the ring-forming ring is unsubstituted or substituted as described in the definition of A for formula u, and all other substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 33 is directed to a method of treatment using a compound of the formula wherein B is as described in any of the specific examples from 丨 to Deng, and a is /, R7 R8 wherein the furan ring is substituted. DETAILED DESCRIPTION OF THE INVENTION No. 34 is the B system as in the specific examples and all other substituents are (d) in the formula IA ... θ wind using any of the formulas 1 to 30 of the compound of the formula 1A, and 86836 -43 - 1330174 R7 R8

To 2) alkyl groups wherein the fluorene ring system is at least one (eg, 1 to 3, or 1 generation) and all other substituents are as defined for Formula IA, specific example number 35 is directed to the use of a compound of formula IA The method of treatment, wherein B is as described in any one of the specific examples Nos. 1 to 3, a is

Wherein the furan ring system is substituted by one alkyl group and all other substituents are as defined for formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 36 is directed to a method of treatment using a compound of formula IA, wherein B is as described in any of the specific examples numbered 丨 to 3, and a is R7 R8 wherein the furan ring system is a ci to alkane Substituents such as methyl or isopropyl are substituted, and all other substituents are as defined for formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 37 is directed to a method of treatment using a compound of formula IA, wherein B is as described in any of the specific examples numbered 丨 to 3, and A is R7 R8 as in the specific examples, numbers 32 to 36. As defined in any one, R7 and R8 86836 • 44 - 1330174 are the same or different, and each is selected from the group consisting of: only with a base. DETAILED DESCRIPTION OF THE INVENTION No. 38 is directed to the treatment of a compound of formula IA. B is as in any of the specific examples 1 to 30, where f ' ', and A is

However, R7 is 者 as defined in any one of Specific Examples Nos. 32 to 36' and R8 is a dry group (e.g., ethyl or tert-butyl). The method of treatment, the specific example of which is directed to the use of the compound of formula IA: includes, (1) wherein 取代 is substituted with < substituent Α is preferably selected from (8)

R7 R8

Rj R8

•0 R7 R8

86836 •45- 1330174

And R8

Wherein the above ring is not (four) generation or substituted, such as a related person; and (b)

And wherein in (8) and (b) above: each R7 and r8 are independently selected from the group consisting of: n, un, 'disubstituted or substituted alkyl, unsubstituted or substituted aryl, un Substituted or substituted heteroaryl, unsubstituted or substituted aralkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted a cycloalkylalkyl group, -co2r13, -C〇NR13R14, a fluoroalkyl group, an alkynyl group, an alkenyl group and a cycloalkenyl group, wherein the substituents on the R7 and R8 substituted groups are selected from the group consisting of: a) Cyano, 1?) <02 ft 13'(:)-C(0)NR13R14,d)-S02NR13RM,e)_N〇2,f)_CF3,g)_OR13,h)-NR13RM,〇_〇( : (0B13, 】) 〇 (: (〇) νιι13κμ, and k) halogen; and R8a and R9 are as defined in Formula IA, and (2) Substituent B in Formula IA is preferably selected Self-contained: 86836 • 46- 1330174 R5

Wherein R 2 to R 6 and R 1 G to R 14 are as defined above for the compound of the novel formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 40 is directed to a method of treatment using a hydrazine compound, wherein: (1) The substituents in the formula are more preferably selected from the group consisting of: (8)

86836 •47- 1330174

Wherein the above ring is unsubstituted or the ring system is substituted by 1 to 3 substituents, the substituents being independently selected from the group consisting of: dentin, alkyl, cycloalkyl, _Cf3, cyano, -OCH3 and -NOr; Each of 117 and R8 is independently selected from the group consisting of: η, an alkyl group (eg, methyl, ethyl, tert-butyl, and isopropyl), a fluoroalkyl group (such as _Cf3 and _Cf2Ch3), a cycloalkyl group (eg, Cyclopropyl and cyclohexyl) and cycloalkylalkyl (for example cyclopropyl fluorenyl), and R9 are selected from the group consisting of hydrazine, halogen, alkyl, cycloalkyl, _Cf3, cyano, -OCH3 and -N02 ; and (b)

Wherein each R7 and the lanthanide are independently selected from the group consisting of: η, an alkyl group (eg, decyl, ethyl, tert-butyl, and isopropyl), a fluoroalkyl group (such as _CF3 and _CF2CH3), a cycloalkyl group ( For example, cyclopropyl and cyclohexyl) and cycloalkylalkyl (for example cyclopropylmethyl); the center of which is as defined in formula IA' and wherein r9 is selected from the group consisting of: hydrazine, arginine, alkyl, ring a radical, -eh, cyano, _ 〇CH3 and Ν〇2; each 尺 7 and rS are independently selected from the group consisting of: hydrazine, alkyl (eg methyl, ethyl, tert-butyl and 1-propyl) ), fluoroindenyl (such as cut and % 珥), (iv) group (such as cyclopropyl disk 86836 -48-1330174 cyclohexyl) and cycloalkyl group (such as cyclopropyl fluorenyl); and (2) formula IA Preferably, the substituent b is selected from the group consisting of: R5

R12

Wherein R2 is selected from the group consisting of ruthenium, OH, -NHC(0)R13 and -NHS02R13. ~C(0)NR1 3 R1 4 R3 is selected from the group consisting of: -so2nr13r14, -no2, cyano, -S02R13 and -C (0) 0R13; R4 is selected from the group consisting of ruthenium, -N〇2, cyano, -CH3, halogen and _CF. The R5 is selected from the group consisting of ruthenium, -CF3, -N〇2, halogen and cyano; R6 is selected from the group consisting of: hydrazine, alkyl and -CF3; each of R10 and R11 is independently selected from the group consisting of: R13, hydrogen, halogen, _CI?3, _NRl 3 r1 4 '-NR^C^NR^rm, _C( 0)0R13 > -SH > ^^NR13Ri 4 . .s〇2Rl3 ' -NHC(0)R13 ^ -NHS02NR13R14 ' -NHSOjR1^ . -C(0)NR13R14 . -QCONR13 OR14,_0C(0)Ri3, -COR13, -OR13 and cyano; 86836 •49- each R13 and R14 are independently a third butyl; or self-assembled 1, methyl, ethyl, isopropyl and R and R14 when attached thereto In the case of Weng Yizhong, a saturated heterocyclic ring (preferably 3 to 7 fluorene) which is substituted or substituted, preferably has a 〇, 3 or _; and is selected from the group consisting of: I 〇 Iq is selected from the group consisting of: H, alkyl, aryl, heteroaryl; '-so2r^.C(O)nr19r20; ^ t ^Rl9^R2〇if ^ is selected from the group consisting of: alkyl, aryl and hetero The ring m substituted with a ring has 1 to 3 substituents on the R and R groups (that is, the substituent is on the ring formed when Ri3 and R14 are used together with the nitrogen to which they are bonded), and Each substituent is independently selected from the group consisting of alkyl, aryl, hydroxy, hydroxyalkyl, alkoxyalkyloxyalkyl, aralkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl Base, heteroarylalkyl, amine group, _C(0)0Rl5, -^^^6 ' <:(0)1^5, _s〇2r15, with the proviso that Rl5 is not Η, -^^^ (〇) serving 15 feet 16 and halogen; and wherein each of the feet 15 and 16 is independently selected from the group consisting of: 11, alkyl, aryl, aralkyl, cycloalkyl and heteroaryl. DETAILED DESCRIPTION OF THE INVENTION No. 41 is directed to a method of treatment using a compound of the formula wherein: the substituent A in formula IA is more preferably selected from the group consisting of: (8)

R7 R8 86836 -50· 1330174

Wherein the above ring is unsubstituted or the ring system is substituted by 1 to 3 substituents, and the substituents are independently selected from the group consisting of ruthenium, F, Cl, Br, alkyl, cycloalkyl and -CF3 'R It is selected from the group consisting of hydrazine, fluoroalkyl, sulfhydryl and cycloalkyl; r8 is selected from the group consisting of hydrazine, hydrazine, alkyl, -CF2CH3 and -CF3; and R9 is selected from the group consisting of hydrazine, F, Cl, Br, Alkyl or _Cf3;

Wherein R7 is selected from the group consisting of hydrazine, fluoroalkyl, alkyl and cycloalkyl; and Rs is selected from the group consisting of hydrazine, alkyl, -CF2CH3 and _Cf3; and is as defined for formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 42 is directed to a method of treatment using a compound of formula IA, wherein: 86836 - 51 · 1330174 (1) The substituent A in the formula is further preferably selected from the group consisting of:

Wherein the above ring is unsubstituted, or the above ring system is substituted by 1 to 3 substituents independently selected from the group consisting of ruthenium, F, Cl, Br, alkyl, cycloalkyl and -CF3; Including: hydrazine, -CF3, -CF2 CH3, decyl, ethyl, isopropyl, cyclopropyl and tert-butyl; and R8 is hydrazine; and (b) R7 R8 \^R8a wherein R7 is selected from Including: H, methyl, ethyl, isopropyl 'cyclopropyl and third · τ groups; and R ^ H; and R8a are as defined in relation to the formula. (2) The substituent B in the formula IA is preferably selected from the group consisting of:

R11

S 86836 52· 1330174 wherein: R 2 is selected from the group consisting of: hydrazine, OH, -NHC(0)R13 and -NHS02R13; and R3 is selected from the group consisting of: -C(0)NR13R14, -so2nr13r14, -no2, cyano, - S02R13 and -C(〇)〇r13; R4 is selected from the group consisting of: H, -no2, cyano, -CH3 or -CF3; R5 is selected from the group consisting of: H, -CF3, -N02, halogen and cyano; R6 is selected from the group consisting of hydrazine, alkyl and _cf3; R11 is selected from the group consisting of hydrazine, halogen and alkyl; and each of R13 and R14 is independently selected from the group consisting of hydrazine, methyl, ethyl, isopropyl and a third-butyl group; or 'R13 and R14 are used together with the nitrogen to which they are attached, in the group _c(〇)NRl3Rl4 and -S〇2 NR1 3 R14' to form an unsubstituted or substituted salt. a heterocyclic ring (preferably a 3 to 7 membered ring), optionally having one other hetero atom selected from hydrazine, 8 or NR18, wherein RU is selected from the group consisting of η, alkyl, aryl, heteroaryl, <(0) ^9, -S02R19 and _C(〇)Nr19r20, wherein each r1^r20 is independently selected from the group consisting of an alkyl group, an aryl group and a heteroaryl group, wherein the substituted Rl3 and Rl4 groups have 1 to 3 substituents (meaning 'when R13 and Rl4 are combined with the nitrogen to which they are combined The ring formed), and each substituent is independently selected from the group consisting of alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkyl, fluoroalkyl, cycloalkyl, a cycloalkylalkyl group, a heteroaryl group, a heteroarylalkyl group, an amine group, _C(0)0R1 5 , -C(0)NR15R16, -SOtNR15R16, _c(〇)R15, -SC^Rb, provided that R15 is not hydrazine, -NHC(0)NR15R16 and halogen; and wherein each of the feet 15 and 16 is independently selected from the group consisting of hydrazine, alkyl, aryl, aralkyl, cycloalkyl and heteroaryl. DETAILED DESCRIPTION OF THE INVENTION No. 43 is directed to a method of treatment using a guanidine compound, which is 86836 • 53· 1330174: (1) The substituent A in the formula is still more preferably selected from the group consisting of: (8)

Wherein the above ring is unsubstituted, or the above ring system is substituted by 1 to 3 substituents, the substituents are independently selected from the group consisting of F, a, Br, alkyl, cycloalkyl and -CF3; R7 is selected from the group consisting of : Η, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and tert-butyl; and R8 is H; and (b) R7 R8

R8a wherein R7 is selected from the group consisting of: hydrazine, -CF3, -CF2CH3, decyl, ethyl, isopropyl, cyclopropyl and tert-butyl; and R8 is hydrazine; and is as defined for the formula; (2) Substituent B in formula IA is still more preferably selected from the group consisting of: R5

86836 -54. 1330174

Wherein: R2 is selected from the group consisting of ruthenium, OH, -NHC(0)R13 and -NHS02R13; R3 is selected from the group consisting of: -c(o)nr13r14, -so2nr13r14, -no2, cyano and -S02R13; Self-contained: H, -N02, cyano, -CH3 or -CF3; R5 is selected from the group consisting of: H, -CF3, -N02, halogen and cyano; and R6 is selected from the group consisting of hydrazine, alkyl and -CF3 R11 is selected from the group consisting of hydrazine, halogen and alkyl; and each of R13 and R14 is independently selected from the group consisting of methyl and ethyl. Specific 'Example No. 44 is directed to a method of treatment using a hydrazine compound, wherein the substituent Α in the formula (1) is preferably selected from the group consisting of:

1330174

86836 - 56- 1330174 (2) The substituent B in the formula is preferably selected from the group consisting of: R5

Wherein: R2 is -OH; R3 is selected from the group consisting of: -S02NR13R14 and -CONR13R14; R4 is selected from the group consisting of: ruthenium, -CH3, and -CF3; R5 is selected from the group consisting of ruthenium and cyano; and R6 is selected from the group consisting of: Η, -CH3 and -CF3; R11 is Η; and R13 and R14 are fluorenyl. DETAILED DESCRIPTION OF THE INVENTION No. 45 is directed to a method of treatment using a hydrazine compound, wherein the substituent oxime in the formula (1) is selected from the group consisting of: (8)

86836 -57- 1330174

Wherein the above ring is unsubstituted or substituted, as described in relation to the formula; and (b)

R9, and wherein in (8) and (b) above: each R7 and R8 are independently selected from the group consisting of: anthracene, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted Or substituted heteroaryl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cyclotyl, unsubstituted or substituted ring An alkylalkyl group, a -co2r13, a _conr13r14, a gas alkyl group, an alkynyl group, a dilute group and a cyclodecyl group, wherein the substituents on the r7 and rS substituted groups are selected from the group consisting of: a) a cyano group, -匸〇2尺13'£;)-c(〇)NRI3r14 » d)-S02 NR13 R14 , e)_N〇2 , f)-CF3 5 g)-〇Rl 3 * h) -NRUr",〇_ 〇〇: (0)1113,, and k) halogen; and R8a-58-86836 1330174 and R9 are as defined in the formula; and (2) the substituent Β in the formula:

Wherein R2, R3 and R11 are as defined above for the novel oxime compound. DETAILED DESCRIPTION OF THE INVENTION No. 46 is directed to a method of treatment using a guanidine compound, wherein: (1) the substituent oxime in the formula is selected from the group consisting of: (8) i R7 R8 R7 R8 R7 R8

86836 -59- 1330174

Wherein the above ring is unsubstituted or substituted, as described in relation to the formula;

And wherein in (8) and (b) above: each R7 and R8 are independently selected from the group consisting of: anthracene, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or taken - a substituted heteroaryl, unsubstituted or substituted aralkyl, unsubstituted or substituted heteroarylalkyl 'unsubstituted or substituted cycloalkyl' unsubstituted or substituted naphthenic An alkyl group, _C〇2 Rn, -CONR13 R14, a fluoroalkyl group, a aryl group, an alkenyl group and a cycloalkenyl group, wherein the substituent on the R8 substituted group is selected from the group consisting of: a) a cyano group ,^))-(^〇2尺13,(〇-c(0)NR13R14 > d)-S02NR13R14 , e)-N02 > f)-CF3 » g)-OR13 » h)- NR13R14,i) -0C(0)R13,j)-0C(0)NR13Ri4, and k) _ 素; and R8a and R9 are as defined in the formula IA; and the substituent Β in the formula (2) is:

R2 is selected from the group consisting of: hydrazine, OH, ·NHC(〇)r13&_nhs〇2r13; R3 is selected from the group consisting of .-S〇2 NR1 3 Rl 4, cyano, _c(〇)NRl 3 Rl 4 ,- S〇2r13 and -C(0)0R13; 86836-60. 1330174 R is selected from the group consisting of: R13 'hydrogen, halogen, -CF3, -NR13R14, _NR13 C^NR13 R14, _C(〇)〇r13 . _SH . -S〇(t)NR13Ri4 , .S〇2r13 ' -NHC(°)R13 ' -nhso2nr13r14 ^ -NHS02R13 ^ -C(0)NR13R14 x -CCC^NR13 OR14,_〇c(9)Rl 3,_c〇Rl 3,_ 〇Rl 3 and cyano; each R13 and R14 are independently selected from the group consisting of: 11, methyl, ethyl, isopropyl and tri-butyl; or R13 and R14 are used together with the nitrogen to which they are attached. In the group 3 r1 4 and S〇2 NR R , an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) is formed, optionally having one other hetero atom selected from the group consisting of: S or NR! 8 Γ selected from the group consisting of: H, alkyl, aryl, heteroaryl, -C(0)R19, _S〇2R19&_c(〇)nr19r20; wherein each Rl9 and r2〇 are independently selected Including: alkyl, aryl and heteroaryl; wherein there are up to 3 substitutions on the substituted cyclic R13 and R14 groups a base (ie, the substituent is on the ring formed when "3 is used together with Rl4 and the nitrogen to which it is bonded", and each substituent is independently selected from the group consisting of alkyl, aryl, hydroxy, hydroxyalkane. Alkyl, alkoxy, alkoxyalkyl, aralkyl 'fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaryl, amine, _C(〇)〇Rl 5, _C (〇)NRl 5 R1 6, _S〇tNRl 5 Rl 6 , -¢: (0)1115, -S〇2 R15 ', provided that Ri 5 is not H, -NHqCONR15 R16 and halogen; and each of them R15 The Ri 6 is independently selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl and heteroaryl. DETAILED DESCRIPTION OF THE INVENTION No. 47 is directed to a method of treatment using a compound of the formula wherein: (1) Formula IA Substituent A is selected from the group consisting of: 86836 • 61- 1330174

Wherein the above ring is unsubstituted, or the above ring system is taken from 1 to 3 substituents independently selected from the group consisting of halogen, alkyl, cycloalkyl, _CF3, cyanide, -OCH3 and -N02; R8 is independently selected ' 曰匕 · · Η, pit base (example ^ methyl, ethyl, third _ butyl and isopropyl), ^

a ring-based group (e.g., a cyclopropyl group and a cyclohexyl group) (e.g., -CF3 and AO methyl group); and an R9 group selected from the group consisting of hydrazine and a fluorenyl group (e.g., propylene;

'1:1, halogen, A cyano, -OCH3 and -N〇2; and, valence, cycloalkyl, -CF3 86836 -62- 1330174

Wherein each of R7 and R8 is independently selected from the group consisting of hydrazine, alkyl (eg, decyl, ethyl, tert-butyl, and isopropyl), fluoroalkyl (eg, -CF3 and -CF2CH3), cycloalkyl ( For example, cyclopropyl and cyclohexyl) and cycloalkylalkyl (eg cyclopropylmethyl); wherein R8a is as defined in formula IA, and wherein R9 is selected from the group consisting of: H, halogen, alkyl, naphthenic a group, -CF3, cyano, -〇CH3 and -N〇2; each of R7 and R8 is independently selected from the group consisting of hydrazine, alkyl (for example, methyl, ethyl, tert-butyl and isopropyl), a fluoroalkyl group (such as -CF3 and -CF2CH3), a cycloalkyl group (such as a cyclopropyl group and a cyclohexyl group), and a cycloalkylalkyl group (such as a cyclopropylmethyl group); and (2) a substituent B in the formula IA for:

Wherein R2 is selected from the group consisting of ruthenium, OH, -NHC(0)R13 or -NHS02R13; R3 is -S02NR13R14; and R11 is selected from the group consisting of: R13, hydrogen, halogen, -〇3, ->^131114, ^1113(:(0)-NR13R14, -C(0)0R13, -SH, -SO(1) NR13R14, -S02R13, -NHC(0)R13 '-NHS02NR13R14 ' -NHS02R13 ' -C(0)NR13R14 ' -C( 0) NR130R14, -OCCCOR13, -COR13, -OR13 and cyano; each of R13 and R14 is independently selected from the group consisting of: hydrazine, methyl, ethyl, isopropyl and tert-butyl; or 86836-63- 1330174 R13 and R14, when used together with the nitrogen to which they are attached, form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) 'as the case has one other hetero atom, Including: ◦, S or nr1 8 ; wherein R18 is selected from the group consisting of Η 'alkyl, aryl, heteroaryl, ·qo〆9, -S02R19 and -C(〇)NR19R2〇; ". independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are from 1 to 3 substituents on the substituted cyclic Rl 3 and Rl 4 groups (ie, the substituent is Ring formed by Ri3 and Ri4 together with the combination of nitrogen And each substituent is independently selected from the group consisting of alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl 'aralkyl, fluoroalkyl', cycloalkyl, cycloalkylane a base, a heteroaryl group, a heteroarylalkyl group, an amine group, -C(0)0R15, -C(〇)nri5r16, _s〇tNRi5Ri6, _c(〇)r15, -so2r15, provided that Rl5 is not h, _nhc(〇)nr15r16 and halogen; and wherein each of R15 and R16 are independently selected from the group consisting of: H, alkyl, aryl, aralkyl, cycloalkyl and heteroaryl. Specific embodiment number 48 is for use A method for treating a compound, wherein the substituent a in the formula (IA) is selected from the group consisting of:

86836 -64 - 1330174 wherein the above ring is unsubstituted or the above ring system is substituted by 1 to 3 substituents independently selected from the group consisting of ruthenium, F, Cl, Br, alkyl, cycloalkyl and -CF3 R7 is selected from the group consisting of: hydrazine, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and tert-butyl; and R8 is H;

Wherein R7 is selected from the group consisting of: hydrazine, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and tert-butyl; and R8 is H; and R8a is as defined for the formula. (2) Substituent B in formula IA is:

Wherein: R2 is selected from the group consisting of ruthenium, OH, -NHC(0)R13 and -NHS〇2r13; R3 is selected from the group consisting of: -CXCONRUrm, -SC^NR13!^, _N〇2, cyano, -S02R13 and _C(0)0R13; R11 is selected from the group consisting of hydrazine, halogen and alkyl; and each of R13 and R14 is independently selected from the group consisting of hydrazine, methyl, ethyl, isopropyl and tert-butyl. DETAILED DESCRIPTION OF THE INVENTION No. 43 is directed to a method of treatment using a hydrazine compound, wherein: '(1) a substituent in the formula Α is selected from the group consisting of: 86836 - 65 - 1330174

Wherein the above ring is unsubstituted or the above ring system is substituted by 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl and -CF3; and the R7 is selected from the group consisting of: Η, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and tert-butyl; and R8 is H; and (b) R7 R8

R 8a wherein R 7 is selected from the group consisting of ruthenium, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, propyl, and tert-butyl, and R is ruthenium, and R 8a is as defined Definitions; (2) Substituent B in formula IA is:

Wherein: R2 is selected from the group consisting of: Η, -NHC(0)R13 and -NHS02Ri3 (preferably _OH); R3 is -S02NR13R14; 86836-66- 1330174 R11 is selected from the group consisting of Η, halogen and alkane The base (preferably oxime); and each of R13 and R14 are independently selected from the group consisting of ruthenium and ethyl, and R13 and R14 are preferably ethyl. DETAILED DESCRIPTION OF THE INVENTION No. 50 is directed to a method of treatment using a guanidine compound, wherein:

86836 -67- 1330174

-68- 86836 1330174 R2 is -OH; R3 is: -S02NR13R14; R11 is H; and Rl3 and Rl4 are ethyl. DETAILED DESCRIPTION OF THE INVENTION No. 51 is directed to a method of treatment using a compound of formula IA, wherein the lanthanide is selected from the group consisting of: (1) R5

The condition is that the R3 group relating to the group is selected from the group consisting of: -C(0)NR13R14,

/OR13 N II \14 (2)

86836 -69- 1330174

86836 -70- 1330174

86836 -71 - 1330174 wherein all other substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 52 is directed to a method of treatment using a guanidine compound wherein the lanthanide is selected from the group consisting of:

86836 -72- (5) 1330174 Ο

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 53 is directed to a method of treatment using a compound of formula ία, wherein Β is:

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 54 is directed to a method of treatment using a guanidine compound, wherein Β is:

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION Numeral 55 is directed to a method of treatment using a compound of the formula μ, wherein:

86836 -73- 1330174 wherein all substituents are as defined for the formula. Specific Example No. 56 is directed to a method of treatment using a hydrazine compound wherein B is:

R12 I

〇 R3 All of the substituents are as defined for the formula. Specific Example No. 57 is directed to a method of treatment using a compound of the formula wherein B is:

OH wherein all substituents are as defined for formula IA. Specific Example No. 58 is directed to a method of treatment using a compound, wherein B is: ^

Η All of the substituents are as defined for formula u. The specific embodiment number 59 is directed to the treatment method using the hydrazine compound. The sputum is: "86836 -74 - 1330174 R5

All substituents therein are as defined for formula IA. DETAILED DESCRIPTION OF THE INVENTION No. 60 is directed to a method of treatment using a guanidine compound, wherein Β is: R5

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 61 is directed to a method of treatment using a guanidine compound, wherein Β is: R5

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 62 is directed to a method of treatment using a guanidine compound wherein the lanthanide is selected from the group consisting of:

86836 -75- (1) 0174 wherein all substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 63 is directed to a method of treatment using a compound of the formula wherein B is described in any of the specific embodiment numbers 51 to 62, and a is as described in any of the specific example numbers 32-44. DETAILED DESCRIPTION OF THE INVENTION No. 64 is directed to any one of the specific examples Nos. 1 to 63 wherein the compound of formula IA is a pharmaceutically acceptable salt. DETAILED DESCRIPTION OF THE INVENTION No. 65 is directed to any one of the specific examples from 丨 to 63 where the compound of formula IA is the sodium salt. DETAILED DESCRIPTION OF THE INVENTION No. 66 is directed to any one of the specific examples, wherein the compound of formula IA is a salt. DETAILED DESCRIPTION OF THE INVENTION No. 67 is directed to a method of treatment using a compound of formula IA, wherein the B is selected from the group consisting of:

All of the substituents are as defined for the formula. DETAILED DESCRIPTION OF THE INVENTION No. 68 is directed to a method of treatment using a hydrazine compound wherein B is selected from the group consisting of: 86836 * 76 - 1330174 R5

among them:

R2' R4, R5 and R6 are all as defined by the formula; and R3 is selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, -OH, _c; p3 '-OCF3 > -N〇 2 ' -C(0)R13 , _C(〇)〇Rl3 Λ _〇(〇)ΝΗκ17 > -SO(t)NRl3RU , -SO(1)R13, _C(0)NR13〇R14, unsubstituted or substituted aromatic a heteroaryl group which is unsubstituted or substituted, wherein there are 1 to 6 substituents on the substituted aryl group, and each substituent is independently selected from the group consisting of: an R9 group; and wherein The substituted heteroaryl has up to 6 substituents, and each substituent is independently selected from the group consisting of: R9. DETAILED DESCRIPTION OF THE INVENTION No. 69 is directed to a method of treatment using a compound of formula IA, wherein: (1) Substituent A is as defined in the specific example No. 39; and (2) Substituent B in formula IA is preferably selected from Includes: r->5

86836 -77- 1330174

ο

Wherein R 2 to R 6 and R 13 to R 14 are as defined for the formula 。. DETAILED DESCRIPTION OF THE INVENTION No. 70 is directed to a method of treatment using a hydrazine compound, wherein: (1) the substituent oxime is as defined in the specific example number 40; and (2) the substituent B in the formula IA is more preferably selected from the group consisting of include:

86836 •78 - 1330174

Wherein R2 is selected from the group consisting of: hydrazine, OH, -NHC(0)R13 or -NHS02R13; R is selected from the group consisting of: _S〇2 NR13 R14, -N〇2, cyano, -CXC^NR13 R14, -S02R13 And -C(〇X)Ri3; R4 is selected from the group consisting of: H, ·νο2, cyano, -CH3, halogen and -cf3; R5 is selected from the group consisting of ruthenium, -CF3, -N02, halogen and cyano; R6 is selected from the group consisting of ruthenium, alkyl and -CF3; each ruler (7) and 1111 are independently selected from the group consisting of hydrogen, halogen, -CF3, -NR13R14, -NR13C(0)NR13R", _C(0)0R13, _SH , _3〇() service 131114, s〇2Rl3, -NHC(0)R13, -Nhs〇2NR13r14, _nhs〇2r13, _c(〇)nr13r14, -qCONR13 OR14,_0C(0)R13, _c〇Rl 3, _ 〇Rl 3 and cyano; each R13 and R14 are independently selected from the group consisting of: H, decyl, ethyl, isopropyl and tert-butyl; or R13 and R14 are employed together with the nitrogen to which they are attached团—NrUrM, -C^NR^R^ , _s〇2NR13R14 . -〇C(0)NR13R14 . -CONR13R14 ^ -NR13C(0)NR13R14, _S〇tNRi3Ri4, _Yang 8〇2 service 131114 Unsubstituted or substituted saturated heterocyclic ring (preferably 3 to 7 membered ring), optionally having one other hetero atom Including: 〇, S or nri 8; wherein R1 S is selected from the group consisting of hydrazine, alkyl, aryl, heteroaryl, 9, _s〇2 R1 9 and -C(0)NR19R2〇; The ruler is independently selected from the group consisting of an alkyl group, an aryl group and a heteroaryl group; wherein, in the substituted ring-shaped ring and the 4-group group, 86836 • 79-1330174 to 3 substituents are present (ie, The substituent is on the ring formed when 3 is used together with rM and the nitrogen to which it is bonded, and each substituent is independently selected from the group consisting of: fluorenyl, aryl 'hydroxy, hydroxyalkyl, alkoxy , alkoxyalkyl, aralkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amine-C(0)Ri5, _s〇2Rl5 -C(0)0R15 And -C(0)NR15R16, -SOtNR15Ri6, with the proviso that R15 is not hydrazine, _NHC(0)NR15R16 and halogen; and wherein each of R15 and R16 is independently selected from the group consisting of hydrazine, alkyl, aryl, aromatic Alkyl, cycloalkyl and heteroaryl. DETAILED DESCRIPTION OF THE INVENTION No. 71 is directed to a method of treatment using a compound of formula ία, wherein: (1) a substituent is as defined in the specific example number 42; and (2) a substituent B in formula IA is preferably selected. Self-contained:

Wherein: R2 is selected from the group consisting of: Η, OH, -nhqC^R1 3 and -NHS02 R13; R3 is selected from the group consisting of: -ccconrurm, _s〇2Nr13r14, _N〇2, chloro, -S02R13 and -C(0) 0R13; R4 is selected from the group consisting of ruthenium, -N02, cyano, _CH3 or -CF3; R5 is selected from the group consisting of ruthenium, -CF3, _n〇2, halogen and cyano; and R6 is selected from the group consisting of ruthenium, Alkyl and -CF3; R11 is selected from the group consisting of: ruthenium, ruthenium and alkyl; and 86836-80 - 1330174. Each mR14 is independently selected from the group consisting of: η, methyl, ethyl, isopropyl and third. Or R13 and R14 are used together with the nitrogen to which they are attached, in the group C(0)NR13R14, .S〇2NR13R14 λ .0C(0)NR13R14 , .C〇NRl 3 R14 .. NR13C(0)NR&quot When R14, _s〇tNRj3Rl4, and -2Nr13r14 are deleted, an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) is formed, optionally having one other hetero atom selected from the group consisting of hydrazine, Wherein Rls is selected from the group consisting of an oxime, an alkyl group, an aryl group, a heteroaryl group, a _c(〇)Rl9, a ring, and a hair (9) coffee 9^, wherein each of the R19 and r2 lanthanides is independently selected from the group consisting of an alkyl group, an aryl group and a heteroaryl group. a group having a ruthenium on the substituted ring R!3 and RH groups 3 substituents (that is, on the ring formed when R13 and R14 are used together with the nitrogen to which they are combined), and each substituent is independently selected from the group consisting of alkyl, aryl 'hydroxy, hydroxyalkane Alkyl, alkoxy, alkoxyalkyl, aralkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl 'heteroarylalkyl, amine, _C(0) 〇 R15, _c ( 〇) nr15r16, _ SOtNR15R16, · 〇: (0) Κΐ 5, _s 〇 2Rl5, provided that Ri5 is not η, _ NHC (0) NRi5Ri6 and _ prime; and each of them is ^! ^6 is independently selected from the group consisting of: H, alkyl, aryl, aryl, cycloyl and heteroaryl. DETAILED DESCRIPTION OF THE INVENTION No. 72 is directed to a method of treatment using a compound of formula IA, wherein: (1) substituent A is as defined in specific example number 43; and (2) substituent B in formula IA is preferably selected from Includes: R5

And R3 86836 -81 - υουι /4 where: R2 is selected from the group consisting of R3 and is selected from the group consisting of -S〇2Ri3; Η, OH, -NHC(0)Ru and 〇2Rl3; .-C(0)NR13R&quot ;, _s〇2^^13r14, _n〇2 cyano-Ν02, cyano, -ch3 or _CF: Η R is selected from the group consisting of R5, including R6, including R, -CF3, _n〇2 , halogen and cyano; and hydrazine, alkyl and _CF3; R11 is selected from the group consisting of: Η 'self- and burn-based;

Each of the ... and the heart is independently selected from the group consisting of methyl and ethyl. The specific embodiment number 73 is for the treatment method using the compound of the formula u, (1) the substituent A is defined in the specific example number 44; and the substituent b in the formula (II) is preferably selected from the group consisting of : R5

Wherein: R2 is -OH; R3 is selected from the group consisting of: -S02NRi3Ri4 and _c〇nr13r14; R4 is selected from the group consisting of ruthenium, -CH3, and _cp3. The R5 is selected from the group consisting of ruthenium and cyano; Including: Η, -CH3, and R11 are Η; and 86836.82 - 1330174 R1 3 and R14 are methyl. The specific example number 74 is any one of the examples 67 to wherein the compound of the formula IA is a pharmaceutically acceptable salt. DETAILED DESCRIPTION OF THE INVENTION No. 75 is directed to any one of the specific examples Nos. 67 to π' wherein the compound of the formula IA is a face salt. DETAILED DESCRIPTION OF THE INVENTION No. 76 is directed to any one of the specific examples Nos. 1 to 73' wherein the compound of the formula IA is a calcium salt. The invention also relates to the novel compounds of formula IB: 〇Vf〇 'Β. (IB) and pharmaceutically acceptable salts thereof (such as sodium or calcium salts), and solvates thereof, wherein: A is selected from the group consisting of:

R7 R8 R7 R8

Wherein the ring system of the group is substituted by 1 to 6 substituents, each of which is independently selected from 86836 83 to 1330174, including: R9 based on hydrazine; and the substituents B, R' R8, ruthenium and Ru are all as in Formula IA The definition. Therefore, for the compound of formula IB, Id 2 is taken. Substituent B, R2, R3, R'R5r6r78 R;: R-R^R^RI35RU3r15}R16>r17jR18r19^^^ R, q and t are as defined for formula IA. , 'Substituent B is as described above for the substituent B, such as the above-mentioned substituent B, as defined above in any of the specific embodiments of the compound of formula IB, in any one of the embodiments 1 to 30. Other embodiments of the compound are those defined in any one of the embodiments 51 to 62, wherein the other one of the compounds of the formula IB is defined in any one of the embodiments of the compound of the formula IB, in any one of the present inventions A specific embodiment is directed to a pharmaceutical composition comprising at least one (e.g., one) formula compound and a pharmaceutically acceptable carrier. Another embodiment of the invention is directed to a salt of the formula. Another embodiment of the present invention (four) nano-salt of the sine-like condensate. The present invention (an additional embodiment is directed to a pharmaceutical composition comprising at least one (e.g., one) sodium salt of a guar compound and a pharmaceutically acceptable carrier. Another embodiment of the present invention is a needle A pharmaceutical composition comprising at least one (e.g., one) calcium salt of a compound of formula IB and a pharmaceutically acceptable carrier. By administering at least one (e.g., one) compound, selected from the group consisting of Formula 1A, 3.0 The compound of Compound A and the final compound of Examples 36〇1〇9_36〇·ΐΐ7, 36832-368.45, 1200-1211, 1300-1311 and 2001-2088, or the pharmaceutically acceptable salt of the compound 86836 • 84-1330174 or Solvates, diseases mediated by the chemokines treated include sputum inflammation, acute inflammatory pain, chronic inflammatory pain, acute neuropathic pain, chronic neuropathic pain, psoriasis, atopic Dermatitis, asthma, lion, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxin shock,

, Qiaoyin steep septicemia, toxic shock syndrome, stroke, heart and kidney reperfusion injury, spheroid nephritis, thrombosis #, Alzheimer's disease, migration, host response, allograft rejection, cancer Dysentery, acute dyspnea syndrome, delayed allergic reaction, atherosclerosis, brain and heart: osteoarthritis, multiple sclerosis, restenosis, angiogenesis, osteoporosis = dental inflammation, respiratory virus, cancer therapy Virus, hepatitis virus 'HIV, Kaposi's sarcoma associated with the mother, meningitis, gallbladder fibrosis, premature birth, % sputum, scrapie, multiple organ dysfunction, trauma, labor, twist, contusion, psoriasis Inflammation, cancer, encephalitis, c

:: Injury, tumor, blood, post-operative trauma, group II, ^ allergic, crystal-induced arthritis, acute and chronic adrenitis: / phlegm poisoning hepatitis, necrotizing enterocolitis, chronic inflammatory disease, Blood: two eyes of Shao disease, eye inflammation, premature retinopathy, diabetic spotted tendon have a better moist and corneal neovascularization celiac disease, is::: inflammation, hemorrhoids, stomach and duodenal ulcer, trachea Dilation, twig tracheal fork airway high responsiveness, colitis, pulmonary heart disease 2, occlusive bronchitis, chronic bronchial tube "^ person, dyspnea, emphysema, hypercapnia, bloating, blood oxygenation ,>,& π > Inflammation, hypoxia, and surgical lungs caused by Gongdu ^86836 •85-1330174 Dirty volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, and continuous metastatic peritoneal dialysis ( CAPD) associated peritonitis, granulocyte Ehrlich disease, sarcoidosis, small airway disease, ventilatory perfusion disorders, wheezing, cold, gout, alcoholic liver disease, lupus, burn treatment, periodontitis, Graft refill Injury and early graft rejection, acute inflammation, and rheumatoid arthritis. Diseases mediated by administration of at least one (eg, one) compound of formula IB include: chronic inflammation, acute inflammatory pain, chronic inflammatory pain , acute neuropathic pain, chronic neuropathic pain 'psoriasis, atopic dermatitis, asthma, c〇PD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic Shock endotoxin shock, Gram-negative blood disease, toxic shock syndrome, stroke, heart and kidney reperfusion injury, spheroid nephritis, blood test formation, Alzheimer's disease, transplantation to host response, allograft Rejection, cancer, acute dysphagia, delayed allergic reaction, atherosclerosis: brain and cardiac stenosis, (4) phlegm, multiple sclerosis, stenosis, angiogenesis, osteoporosis, gingivitis , respiratory disease 4, herpes virus, mother, chat, Kaposi's sarcoma associated with the virus, meningitis, money: degeneration, premature birth, cough, phlegm, Multiple organ dysfunction, pulse two strain, sprain, contusion, psoriatic arthritis, cancer treatment 'encephalitis, CNS: injury, traumatic brain injury, CNS tumor, subarachnoid hemorrhage, post-operative "woven space" Pneumonia, allergic, crystal-induced arthritis, spasticity and k-type pancreatitis, acute alcoholism, hepatitis, ..., sputum sex, human death, enterocolitis " fire & generate eye diseases, eyes Clear and Inflammatory, Premature Vision Network 86836 • 86 - 1330174 Membrane disease, retinopathy of diabetic patients, speckle degeneration polymyositis with better moist and corneal neovascularization' vasculitis, hemorrhoids, stomach and eleven Deduction of fine ulcer, celiac disease, esophagitis, glossitis, airflow obstruction, airway responsiveness, branch tracheal dilation, twig bronchitis, occlusive tibial bronchitis, k-sexual bronchitis, pulmonary heart disease, cough , breathing difficulties, emphysema, hypercapnia, hyperventilation, hypoxemia, inflammation caused by excessive oxygen, hypoxia, reduction of surgical lung volume, pulmonary fibrosis, pulmonary hypertension, right heart

Room hypertrophy, peritonitis associated with continuous metastatic peritoneal dialysis (CAPD), granulocyte Ehrlich disease, sarcoidosis, small airway disease, ventilatory perfusion disorders, wheezing, cold, gout, alcoholic liver disease, Lupus, burn treatment, periodontitis, graft reperfusion injury and early graft rejection, acute inflammation and rheumatoid arthritis. λ

Another embodiment of the present invention is directed to a treatment for acute inflammatory pain in a subject in need of treatment (e.g., a mammal, preferably a human): the method comprising administering an effective amount to the patient At least one (e.g., W, hang one) hydrazine compound (or a pharmaceutically acceptable salt or solvate thereof). Another embodiment of the present invention is directed to a disease in need of treatment (e.g., breastfeeding) Treating chronic inflammatory = pain in an animal, preferably a human): comprising administering to the patient an effective amount of at least one (eg, U species, universal) compound of formula IA (or a pharmaceutically acceptable compound thereof) Salt or Solvent Another specific embodiment of the invention is directed to treating various diseases, such as pain, and pain, in a patient in need of treatment (for example, a mammal, preferably a human). An effective amount of at least one (for example, and usually one) compound of formula IA (or a pharmaceutically acceptable 86836-87-1330174 conjugate thereof) is administered to the patient. Another embodiment of the invention Is aimed at a disease that requires treatment For example, in mammals, preferably humans, for the treatment of chronic neuropathic pain, ±1 1 'includes at least one effective amount administered to the patient (eg, species, sputum, s, and sling) A hydrazine compound (or a pharmaceutically acceptable sleep or solvate thereof). / Another embodiment of the present invention is directed to a method for treating acute inflammatory pain in a patient in need of treatment, such as a mammal, preferably a human, comprising administering an effective amount to the patient At least one (eg, one) port is selected from the group consisting of compounds of formula 1 〇Α, 3.0 ,, and the last of examples 36〇1〇9_36〇U7, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 a compound (or a pharmaceutically acceptable salt or solvate of a child compound). Another embodiment of the invention is directed to a method of treating chronic inflammatory pain in a condition in need of treatment, such as a mammal, preferably a human, which comprises administering to the patient at least one effective amount (e.g., one) the mouthpiece is selected from the group consisting of compounds of the formula 1.0Α, 3.0Α, and the last of the examples 36〇1〇9-36〇117, ground 32-368.45 '1200-1211, 1300-1311 and 2001-2088 A compound (or a pharmaceutically acceptable salt or solvate of the compound). Another embodiment of the invention is directed to an acute treatment of a condition in need of treatment (e.g., a mammal, preferably a human) A method of neuropathic pain, comprising administering to the patient an effective amount of at least one (eg, one) compound selected from the group consisting of a compound comprising the formula 1.0Α, 3.0Α, and the example 36〇.1〇9_360.117, The final compound (or a pharmaceutically acceptable salt or solvate of the compound) of 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088. 86836 - 88 - 1330174 Another embodiment of the present invention is a method for treating chronic neuropathic pain in a disease in need of treatment (a mammalian 'preferably human), which includes the disease The at least one (eg, one) sputum administered in an effective amount is selected from the group consisting of a compound comprising the formula 1 〇Α, 3 ,, and the examples 〇1〇9_ 17 368.32-368.45, 1200-1211, 13〇〇_1311 and 2 The last compound of 〇〇1_2〇88 (or a pharmaceutically acceptable salt or solvate of the compound). Another embodiment of the present invention is directed to a method of treating c〇pD in a condition in need of treatment (e.g., a mammal, preferably a human), comprising administering to the patient an effective amount at least - a compound (eg, a species) selected from the group consisting of compounds of G.1.O.O.OA, and the last compound of Examples 36〇.1〇9_36〇ιΐ7, Dish 32·12001211, 1300-1311, and 2001-2088 (or A pharmaceutically acceptable salt or solvate of the compound). Another embodiment of the present invention is directed to a method of treating acute inflammatory pain in a patient in need of treatment (e.g., a mammal, preferably a human), which comprises administering to the patient an effective amount of at least A compound of the formula IB (or a pharmaceutically acceptable salt or solvate thereof) (for example, 丨3, and usually), is another specific embodiment of the present invention, which is directed to a patient in need of treatment A method of treating chronic inflammatory pain, for example, in a mammal, preferably a human, comprising administering to the patient an effective amount of at least one (eg, M, and hanging one) compound of formula IB (or pharmaceutically thereof) An acceptable salt or solvate) Another embodiment of the present invention is directed to a method of treating acute neuropathic pain in a patient in need of treatment (e.g., a mammal, preferably a human) It comprises administering to the patient an effective amount of at least one (e.g., 1-3 and usually one) of a compound of formula IB (or a pharmaceutically acceptable salt thereof or a solvate of 86836-89-/4). Implementation For example, the treatment of chronic neuropathic pain in a disease requiring treatment, such as feeding a sputum, pain, or preferably a human, comprises administering at least one effective amount to the patient (for example, 1_3) 'And 诵赍 & pharmaceutically acceptable compound IB compound (or its pharmaceutically acceptable salt or soluble invention) 2 吉 - specific embodiment, for a disease in need of treatment (such as feeding animals A method of treating COPD, preferably human, comprising administering to a patient an effective amount of at least one (e.g., 1-3, and usually one) of a compound of formula IB (or i a pharmaceutically acceptable salt thereof). Or a solvate. The present invention relates to a method of treating cancer in a patient in need of treatment, such as a mammal, such as a human, which comprises administering the patient simultaneously or sequentially to the treatment. An effective amount of (4) at least one (eg, one) chemical & substance selected from the group consisting of compounds of formula L0A, and the last compounds of examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or Pharmaceutically acceptable a salt or solvate), and (9) a microtubule-targeting agent, or an anti-tumor agent, or an anti-angiogenic agent, or a VEGF receptor kinase inhibitor, or an antibody to a VEGF receptor, or an interferon, and/or Uniform radiation. In other specific embodiments for the treatment of cancer, at least one (e.g., one) compound is administered from a compound selected from the group consisting of 1 A, 3 〇A, and examples 360.109-360.117, 368.32-368.45, 1200- a final compound of 1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable salt or solvate of the compound), and in combination with an antitumor agent (eg, one or more, such as one, or one or two) , selected from the group consisting of: gemcitabine, paclitaxel 86836 -90-1330174 (Taxol®), 5-fluorourine p-bite (5-FU), cyclophosphamide (Cytoxan) ®), temozolomide, taxotere and new tests in Changchun. In another specific embodiment, the invention provides a method of treating cancer in a patient in need of treatment, such as a mammal, such as a human, comprising administering an effective amount of (8) at least one (eg, one) simultaneously or sequentially. a compound selected from the group consisting of compounds of formula 1 〇Α, 3.0A, and the final compounds of examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or the pharmaceutically acceptable compound) a salt or solvate), and (b) a microtubule shadowing agent (e.g., paclitaxel). A specific embodiment of the invention is directed to a method of treating cancer in a patient in need of treatment, such as a mammal, such as a human, comprising administering to the patient a therapeutically effective amount of at least one of (8) simultaneously or sequentially ( For example, 1-3, and usually one) a compound of formula IB (or a pharmaceutically acceptable salt or solvate thereof), and (b) a microtubule-targeting agent, or an anti-tumor agent, or an anti-angiogenic agent, or A VEGF receptor kinase inhibitor, or an antibody to a VEGF receptor, or an interferon, and/or c) radiation. In other specific embodiments for the treatment of cancer, at least one (e.g., 1-3, and usually one) of a compound of formula ffi (or a pharmaceutically acceptable salt or solvate thereof) is administered, and an antitumor agent is used in combination. (eg one or more, such as one, or one or two, for example), selected from the group consisting of: gemcitabine, paclitaxel (Taxol®), 5-fluorouric p-precipitate (5 -FU), Cytoxan®, temozolomide, taxotere and vincristine. In another specific embodiment, the present invention provides a method of treating cancer in a mammalian 'such as a human in need of treatment, 8686 - 91 - 1330174, comprising administering an effective amount of at least one of (8) simultaneously or sequentially (eg, Κ3, and usually *) a compound of formula m (or a pharmaceutically acceptable salt or solvent thereof) and (9) a microtubule-inducing agent (for example, paclitaxel). Embodiments are directed to a method of treating melanoma, gastric cancer, and non-small cell lung cancer in a condition in need of treatment, the treatment comprising administering to the patient an effective amount of at least one species (eg, a lang compound (or the compound) A pharmaceutically acceptable salt or solvate.) Another embodiment of the present invention is directed to a method for treating melanoma 'gastric cancer and non-small cell lung cancer in a condition in need of treatment, the treatment comprising The patient is administered an effective amount of at least one (e.g., a) sputum compound (or a pharmaceutically acceptable salt or solvate of the compound), and a combined administration of at least one anticancer agent. Another embodiment of the present invention is directed to a method of treating melanoma, gastric cancer, and non-small cell lung cancer in a patient in need of treatment, the treatment comprising administering to the patient an effective amount of at least one species (eg, a compound of the formula (or a pharmaceutically acceptable salt or solvate of the compound), and in combination with at least one anticancer agent, wherein the red carcinogen is selected from the group consisting of: an alkylating agent, an anti-metabolite , natural products and derivatives thereof, hormones, anti-hormone anti-angiogenic agents and steroids, and synthetic substances. Another specific embodiment of the present invention is directed to treating melanoma, gastric cancer, and the like in a patient in need of treatment. In a method of non-small cell lung cancer, the treatment comprises administering to the patient an effective amount of at least one (eg, one) compound selected from the group consisting of compounds of Formulas 1.0A, 3.0A, and Examples 360 ι〇9·36〇.117 , 86836 - 92 · 1330174 368.32 - 368.45, 1200-1211, 1300-1311 and 2001-2088 the last compound (or a pharmaceutically acceptable salt or solvate of the compound). A specific embodiment is directed to a method of treating melanoma, gastric cancer, and non-small cell lung cancer in a condition in need of treatment, the treatment comprising administering to the patient an effective amount of at least one (eg, one) compound selected from the group consisting of A compound comprising a compound of formula 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable salt or solvate of the compound) And in combination with administering at least one anticancer agent. Another embodiment of the present invention is directed to a method of treating melanoma, gastric cancer, and non-small cell lung cancer in a patient in need of treatment, the treatment comprising the patient Administering an effective amount of at least one (eg, one) compound selected from the group consisting of compounds of Formulas 1.0A, 3.0A, and the final compounds of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 ( Or a pharmaceutically acceptable salt or solvate of the compound, and a combination of at least one anticancer agent, wherein the anticancer agent is selected from the group consisting of: an alkylating agent, an antimetabolite Natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids, as well as synthetic substances. Representative compounds used to treat diseases mediated by chemokines, including but not limited to: 86836 -93 - 1330174

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One of the servants of the present invention may be present in different stereoisomeric forms (e.g., for palm isomers, diastereomers, for drought, for all traces, for the isomers). The present invention is intended to have such inter-isomers as both in pure form and in a mixture, in a mixture. Isomers can be prepared using conventional methods. The invention also includes prodrugs of the compounds of the invention. Some of the compounds are acidic in nature, for example, and have a compound of the formula: ==: Examples may include sodium, potassium, platinum, such as n ^ aluminum, gold, and silver salts. Also intended to be covered, for the medicinal connection

Further, a salt formed by an amine such as ammonia, an alkylamine, a hydroxy-burning A-amine, or N-mercaptoglucosamine is used. Soil Some basic compounds also form pharmacy, and, in addition, such as acid addition. For example, a pyrido-nitrogen atom can be used to synthesize a compound and a salt with a weaker acid. Examples of suitable acids for salt formation are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid: malonic acid, salicylic acid, vermiculic acid, transbutanic acid, succinic acid, ascorbic acid, butylene Diacid, methane sulfonic acid and cooked 谙, other mineral acids and carboxylic acids. This salt is prepared in a conventional manner by contacting the free form with a sufficient amount of the desired acid to produce a salt. Free state: Formula 2 is regenerated by treating the salt with an aqueous solution of a suitable dilute alkali, such as dilute Na〇H, double acid, ammonia, and carbonate. The free form and its individual salt form 86836 -119 - 1330174 are slightly different in some physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the acid and base salts are otherwise equivalent Its individual free-form base forms. All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention, and for the purposes of the present invention, all acid and base salts are considered equivalent to the free form of the corresponding compound. The compounds of the invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, a solvated compound form having a pharmaceutically acceptable solvent such as water, ethanol or the like is equivalent to the unsolvated form for the purpose of the present invention. In a specific embodiment of treating cancer, it will be selected from the group consisting of compounds of formula IB, 1.0A, 3.0A, and examples 360.109_360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088. A compound of the final compound (or a pharmaceutically acceptable salt or solvate of the compound) is administered in combination with one of the following antitumor agents: gemcitabine, paclitaxel (Taxol®) ), 5-fluorourine p-dense (5-FU), Cytoxan®, temozolomide or Changchun. In another specific embodiment, the invention provides a method of treating cancer comprising administering an effective amount of a compound simultaneously or sequentially, selected from the group consisting of compounds comprising the formulas ro, 1.0A, 3.0A, and examples 360.109-360.117 a final compound (or a pharmaceutically acceptable salt or solvate of the compound) of 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088, and a microtubule-targeting agent, such as pecitracine ( Paclitaxel). Another embodiment of the present invention is directed to a method of treating cancer 86836-120-1330174 comprising administering to a patient in need thereof a therapeutically effective amount of (8) a compound, selected from the group consisting of IB, simultaneously or sequentially. a compound of 1.0A, 3.0 A, and the final compounds of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable salt or solvate of the compound), And (8) an antitumor agent, a microtubule agent or an anti-angiogenic agent. For the preparation of pharmaceutical compositions from the compounds described herein, the inert pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. The powders and tablets may contain from about 5 to about 95 percent of the active ingredient. Suitable solid carrier vehicles are known in the art, such as magnesium carbonate, stearic acid, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers, and methods of making the various compositions, can be found in A. Gennaro (eds.), Seiko Tseng, 18th Edition, (1990), Mack Publishing Company (Easton, Pennsylvania). Liquid form preparations include solutions, suspensions, and emulsions. As an example, the water or water-propylene glycol solution may be indicated for parenteral injection, or a sweetener and opacifier may be added for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol formulations suitable for inhalation may include solutions and solids in powder form in admixture with a pharmaceutically acceptable carrier such as an inert compressed gas such as nitrogen. Solid form preparations are also included which are intended to be converted, shortly before use, to liquid form preparations, whether administered orally or parentally. Such liquid forms include solutions, suspensions and emulsions. 86836 - 121 - 1330174 The compounds of the invention may also be delivered transdermally. The transdermal compositions can take the form of a creamed U oxysol and/or emulsion and can be included in a transdermal patch of a matrix or reservoir type, as is the method used in the art. Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation is subdivided into unit doses of the appropriate size, containing an appropriate amount of active ingredient, such as an effective amount to achieve the desired purpose. The amount of active compound in a unit dosage formulation may be varied or adjusted, from about 0. 01 gram to about 1000 mg, preferably from about 0 01 mg to about 75 mg, more preferably from about 0 mg to about 500 mg. And preferably from about 1 mg to about 25 pg, depending on the particular application. The actual dosage employed can vary depending on the amount of the patient's needs and the severity of the condition being treated. Determination of the appropriate dosage regimen for a particular condition is within the skill of this art. For convenience, the total dose can be divided and administered in divided doses, as needed. The dosage and frequency of the compound of the present invention and/or its pharmaceutically acceptable salt are adjusted according to the judgment of the responsible clinician, taking into account factors such as lack of age, symptoms and size, and the severity of the treated condition. . A typical recommended daily dose regimen for oral administration can range from 4 mg/day to about 4000 mg/day in two to four divided doses. The types of compounds that can be used as chemotherapeutic agents (antitumor agents) include: alkylating agents, antimetabolites, natural products and derivatives thereof, hormones and steroids (including synthetic analogs), and synthetic substances. Examples of compounds 86836 '122- 1330174 in these classes are shown below. Alkylating agents (including nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazides): uracil mustard, chloroform, cyclodamine (Cytoxan®), Ifosfamide, amphetamine, chlorambucil, bromopropyl, triethylene-melamine, triethyl thiophosphoramide, Busulfan, Nitroso-nitrogen mustard, cyclohexyl nitrosourea, streptavidin, aziridine and temozolomide. Antimetabolites (including folic acid antagonists, micro-amplifier analogs, purine analogs, and adenosine deaminase inhibitors): Aminoguanidine, 5-fluorouracil, 5-fluorodeoxyuridine, Arsenic, 6&quot ; 嗓呤 嗓呤, 6-peep guanine, fludarabine citrate, pentostatin and gemcitabine. Natural products and their derivatives (including vinca plant, anti-tumor antibiotics, enzymes, lymphokine and epipodophyllotoxin): Changchun flower test, Changchun new test, vinca, bleomycin, Dak Tentamicin, daunorubicin, erythromycin, epirubicin, idadamycin, paclitaxel (peclitaxel) is commercially available from Taxol® And is described in more detail in the following subtitle "Microtubule Effect Agent", mithramycin, deoxy-inter-mycin, mitomycin-C, L-aspartate, interference (especially IFN-a), etoposide and fentanyl. Hormones and steroids (including synthetic analogues): 17 alpha-ethinylestradiol, diethylhexyl female, fluorenone, prednisone, chaperone, Dromostanolone, propionate, sputum Fat, sputum, progesterone acetate vinegar, tamoxifen, mercaptohydroprednisolone, methyl-fluorenone, prednisolone, fluorohydrodehydrocorticosterol, tri-p-methoxyphenyl chloride, hydroxy Progesterone, amine-induced sleep energy, female 86836 -123 - 1330174 nitrogen mustard (estramustine), medroxyprogesterone acetate, leuprolide, flutamide, toremifene ) 'Zoladex. Synthetic substances (including inorganic complexes, such as intrinsic dislocation complexes): cis chloramine, carbon sulphide, basal vein, amsacrine, methyl; hydrazine, mitoxantrone, silk Mitoxantrone, dextrotetracycline and melamine. The safe and effective administration of most of these chemotherapeutic agents is known to those skilled in the art. In addition, its administration is described in the standard literature. For example, many chemotherapeutic agents are described in the "Physician's Table References" (PDR), eg 20 €) 2 (Medical Economics, Montvale, NJ07645-1742, USA); The microtubule-introducing agent used herein is a compound which interferes with the formation and/or action of microtubules and interferes with mitosis of cells, which means that it has anti-mitotic effect. For example, microtubule stabilizers or agents that disrupt microtubule formation. Microtubule imaging agents useful in the present invention are well known to those skilled in the art and include, but are not limited to, colchicine (NSC 406042), Harry. Chondroitin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (eg NSC 33410), doxorubicin 10 (NSC 376128), maytan (NSC 153858), serotonin ( Rhizoxin) (NSC 332598), paclitaxel (Taxol®, NSC 125973), Taxol® derivatives (eg derivatives (eg NSC 608832), thio-colchicine (NSC 361792), triphenylsulfonium) Cysteine acid (NSC 83265), vinblastine sulfate (NSC) 49842), vincristine sulfate (NSC 67574), epsilon A, Epothilone and discodermolide (see 86836 • 124-1330174)

Service, (1996) Science, 274: 2009) estramustine, nocodazole, MAp4, and the like. Examples of such agents are also described in the scientific and patent literature, see, for example, Bulinski (1997)··· Ce/Z&i. 110: 3055-3064; Panda (1997) Proc. Natl. Acad. 5c/.USA 94 : 10560-10564 ; Muhlradt (1997) Cancer Res. 57: 3344-3346; Nicolaou (1997) iVlaiwre 387: 268-272; Vasquez (1997) Mo/. Biol Cell 8 : 973-985 ; Panda (1996)/. Biol Chem. 271: 29807-29812. A particularly preferred agent is a compound having pecitoxime activity. These include, but are not limited to, peclistatin and peclistatin derivatives (like pecitoxime compounds) and the like. Pecliter and its derivatives are commercially available. In addition, methods for making peclitaxel and peclistatin derivatives and analogs are known to those skilled in the art (see, for example, U.S. Patent Nos. 5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506). More specifically, "paclicaxel" is used herein to refer to a drug commercially available from Taxol® (NSC: 125973). The Taxol® system inhibits eukaryotic cell replication by enhancing the polymerization of tubulin-based groups into a stabilized microtubule bundle that is not capable of recombining into a proper structure for mitosis. Among many available chemotherapeutic drugs, perredoxocin has been important because of its efficacy in clinical trials of drug-resistant tumors, including ovarian and breast tumors (Hawkins (1992) Owco/ogy, 6: 17-23, Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl Cane. New 82: 1247-1259). 86836 -125 - 1330174 Other microtubule-forming agents can be evaluated using one of many such assays known in the art, such as semi-automated assays, which measure the tubulin polymerization activity of peboxamicin analogs, Cellular assays are also used in combination to measure the likelihood that these compounds will block cells during mitosis (see, Lopes (1997) Cancer Chemother. pharmacol. 4\3Ί-4Ί). In general, the activity of a test compound is determined by contacting the cell with the compound and determining whether the cell cycle is disrupted, particularly by mitotic events. Such inhibition can be disrupted by the disruption of the mitotic device, such as the formation of a normal spindle. Cells in which mitosis is interrupted can be characterized by altered morphology (e.g., tight microtubules, increased number of chromosomes, etc.). Compounds with possible tubulin polymerization activity can be screened in vitro. In a preferred embodiment, the compound is screened against cultured WR21 cells (derived from cell line 69-2 wap-ras mice) for inhibition of proliferation and/or altered cell morphology, particularly micro The tube is tight. In vivo screening of positive test compounds can then be performed using hairless mice bearing WR21 tumor cells. A detailed description of this screening method is described by Porter (1995) in & ί,·, 45 (2): 145-150. Other methods for screening compounds for activity are known to those skilled in the art. Typically, such assays involve detection of inhibition of microtubule assembly and/or decomposition. The detection of microtubule assembly is described, for example, by Gaskin et al. (1974) / Μο/ec• and 〇/·, 89: 737-758. U.S. Patent No. 5,569,720 also provides in vitro and in vivo detection of compounds having activity like pecitoxime. A safe and effective method of administering the microtubule-inducing agent mentioned above is known from the art of 86836-126-1330174. In addition, its administration is described in the standard literature. For example, many chemotherapeutic agents are described in the "Physician's Table References" (PDR), such as the 1996 edition (Medical Economics Corporation, Montvali NJOTGAS-nAZ^SA); the disclosures of which are incorporated herein by reference. References. Compounds of formula IA, IB, 1.0A, 3.0A, and the final compounds of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or pharmaceutically acceptable salts of the compounds) Or the solvate), and the amount and frequency of administration of the chemotherapeutic agent and/or radiation therapy, adjusted according to the judgment of the responsible clinician (physician), taking into account factors such as the age, symptoms and size of the patient, and The severity of the disease being treated. Compounds of formula IA, IB, 1.0A, 3.0A, and the final compounds of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or pharmaceutics of the compound) The acceptable dosage of the salt or solvate may be from 10 mg to 2000 mg/day, preferably from 10 to 1000 mg/day, more preferably from 50 to 600 mg/day, to two. Up to four (better Two doses to separate tumors to block tumor growth. Intermittent therapy (eg from one week in three weeks, or from three weeks in four weeks) may also be used. Chemotherapeutic agents and / or radiation therapy may be according to the art The known treatment is to be administered. It will be apparent to those skilled in the art that the administration of chemotherapeutic agents and/or radiation therapy may be based on the disease being treated, and the chemotherapeutic agent and/or radiation therapy for the disease. Knowing the effects, and depending on the knowledge of the skilled clinician, the treatment plan (e.g., the dose and number of doses administered) may be based on the effect of the administered therapeutic agent (i.e., anti-tumor agent or radiation) on the patient. And in view of the response of the disease to the findings of the administration of the therapeutic agent. 86836 -127- 1330174 A specific embodiment of the invention is directed to a method of treatment wherein a compound of formula IB, 1.0A, 3.0A, and example 360.109- 360.117 ' 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or the pharmaceutically acceptable salt or solvate of the compound) is the last compound 'currently or sequentially accompanied by chemical treatment And/or radiation administration. Thus, for example, a chemotherapeutic agent and the compound, or radiation, and the compound do not necessarily have to be administered simultaneously or substantially simultaneously. The advantages of simultaneous or substantially simultaneous administration are well Within the discretion of the clinician. Moreover, in general, the compound of the formula IB, 1.0A, 3.0A and the final compounds of the examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311 and 2001-2088 (or The pharmaceutically acceptable salts or solvates of the compounds and chemotherapeutic agents are not necessarily administered in the same pharmaceutical composition and may have to be administered by different routes due to different physical and chemical properties. For example, a compound of the formula IB, 1.0A, 3.0A, and the final compounds of the examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable salt or solvent of the compound) Compounds can be administered orally to produce and maintain a good blood level, whereas chemotherapeutic agents can be administered intravenously. The mode of administration and the appropriateness of the administration of the drug, if possible, in the same pharmaceutical composition, are well within the knowledge of the skilled clinician. Initial administration can be performed according to established procedures known in the art, and based on the effects found, the dosage, mode of administration, and frequency of administration can be corrected by the skilled clinician. a compound of formula IB, 1.0A, 3.0A, and a final compound of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable compound of the compound 86836-128-1330174) The specific choice of salt or solvate, and chemotherapeutic agent and/or radiation will depend on your physician's diagnosis and judgment of the patient's symptoms and appropriate treatment. a compound of formula IB, 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable salt or solvate of the compound) The compound and the chemotherapeutic agent and/or radiation may be administered simultaneously (eg, simultaneously, substantially simultaneously or within the same therapeutic plan) or sequentially, depending on the nature of the proliferative disease, the symptoms of the patient, and the desire to be accompanied by the formula IB, Compounds of 1.0A, 3.0A, in combination with the final compounds of Examples 360.109-360.117, 368.32-368.45, 1200-1214, 1300-1311, and 2001-2088 (or pharmaceutically acceptable salts or solvates of the compounds) It depends on the actual choice of chemotherapeutic agent and/or radiation (that is, within a single treatment plan). a compound of the formula EB, 1.0A, 3.0A, and a final compound of the examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable salt or solvent of the compound) And chemotherapeutic agents and/or radiation, when not simultaneously or substantially simultaneously, the compounds of formula IB, 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311 And the initial administration of the compound of 2001-2088 (or a pharmaceutically acceptable salt or solvate of the compound) and the chemotherapeutic agent and/or radiation may not be important. Thus, a compound of formula IB, 1.0A, 3.0A, and a final compound of examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088 (or a pharmaceutically acceptable compound of the compound) can be administered first. a salt or solvate), followed by administration of a chemotherapeutic agent and/or radiation; or a chemotherapeutic agent and/or radiation may be administered first followed by administration of a compound of formula IB, 1.0A, 86836-129-1330174 3.0A And the final compounds (or pharmaceutically acceptable salts or solvates of the compounds) of Examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001-2088. This alternate administration can be repeated during a single treatment trial. During the treatment trial, the order of administration of each therapeutic agent and the number of repeated administrations are well within the knowledge of the skilled physician after assessing the symptoms of the disease being treated and the condition of the patient. For example, a chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment is administered with a compound of formula IB, 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200 The last compound of -1211, 1300-1311 and 2001-2088 (or a pharmaceutically acceptable salt or solvate of the compound) is continued, and if determined to be advantageous, the chemotherapeutic agent and/or radiation is administered Wait until the treatment is completed. Thus, as the treatment proceeds, based on experience and knowledge, the executing physician can modify the ingredients for the treatment (therapeutic agents - meaning compounds of formula IB, 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, The final compounds of 1200-1211, 1300-1311 and 2001-2088 (or pharmaceutically acceptable salts or solvates of the compounds) and chemotherapeutic agents or radiation are formulated according to the needs of individual patients. . In determining whether the treatment is effective at the dose administered, the responsible clinician will consider the general welfare of the patient, as well as more specific signs, such as the relief of disease-related symptoms, inhibition of tumor growth, actual reduction of the tumor, or The inhibition of transfer. The size of the tumor can be measured by standard methods, such as radio-logical studies, such as CAT or MRI scans, while continuous measures can be used to determine if the growth of the tumor has been slowed or even reversed. Disease-related symptoms such as pain 86836 -130- 1330174 The relief of pain, and the improvement of the entire symptoms, can also be used to help determine the effectiveness of treatment. [Embodiment] Biological examples The compounds of the present invention are useful for treating the symptoms and diseases mediated by CXC-chemokines. This utilization is demonstrated by its ability to inhibit IL-8 and GRO-α chemokines as evidenced by in vitro assays below. Receptor binding assay: CXCR1 SPA detects 100 μl of reaction mixture of 10 μg hCXCR1-CHO overexpressing cell membrane (Biosignal) and 200 μg/well WGA-SPA beads (Amersham) in wells of 96 well plates, at CXCR1 Prepared in assay buffer (25 mM HEPES, pH 7.8, 2 Mm CaCl2, 1 mM MgCl2, 125 mM NaCl, 0.1% BSA) (Sigma). The 0.4 nM stock solution of the ligand [125I]-IL-8 (NEN) was prepared in CXCR1 assay buffer. The 20X stock solution of the test compound was prepared in DMSO (Sigma). The 6 X stock solution of IL-8 (R&D) was made in CXCR2 Assay Buffer. Add the above solution to a 96-well assay plate (Perkin Elmer) as follows: 10 microliters of test compound or DMSO, 40 microliters of CXCR1 assay buffer or IL-8 stock solution, 100 microliters of reaction mixture, 50 microliters Ascending the seat stock solution (final [coordination] = 0.1 nM). The assay plate was shaken on a plate vibrator for 5 minutes and then incubated for 8 hours, followed by determination of the compound/well in a Microbeta Trilux counter (Perkin Elmer). The % inhibition of total binding-NSB (250nMIL-8) was determined for IC5 enthalpy. The compound of the present invention has IC5 〇 < 20 " M. The most preferred compound has a range of from 3 nM to 1120 nM. 86836 -131 - 1330174 CXCR2 SPA Detection For each well of the 96 well plate, 4 μg hCXCR2-CHO overexpressing cell membrane (Biosignal) and 200 μg / well WGA-SPA beads (Amersham) 100 μl

The mixture was prepared in CXCR2 Assay Buffer (25 mM HEPES, pH 7.4, 2 mM CaCl2, 1 mM MgCl2). The 0.4 nM stock solution of the ligand [125I]-IL-8 (NEN) was prepared in CXCR2 assay buffer. The 20X stock solution of the test compound was prepared in DMSO (Sigma). The 6 X stock solution of GRO-a (R&D) was made in CXCR2 Assay Buffer. The above solution was added to a 96-well assay plate (Perkin Elmer or Coming) as follows: 10 microliters of test compound or DMSO, 40 microfiltration CXCR2 detection buffer or GRO-alpha stock solution, 100 microliters of reaction mixture, 50 microliters of the ligand stock solution (final [coordinator] = 0.1 nM). When preparing a 40X stock solution of the test compound in DMSO, the above procedure was used, except that 5 microliters of the test compound or DMSO was replaced, and 45 microliters of CXCR2 detection buffer was used. Prior to assaying the compound/well in a Microbeta Trilux counter (Perkin Elmer), the assay plate was shaken blue on a plate shaker for 5 minutes and then incubated for 2-8 hours. The % inhibition was determined by subtracting the % inhibition from non-specific binding (250 nM Gro-α or 50 antagonist) and calculating the IC5 〇 value. The compounds of the invention have an IC50 <5 " The most preferred compound has a core in the range of from 0.8 nM to 40 nM. The compound of Example 360.31 has & 3ηΜ. Calcium Acousto-Optic Detection (FLIPR) ΗΕΚ293 cells transfected with hCXCR2 and Gai/q were plated in poly-D-lysine black/transparent plates (Becton Dickinson) at 10,000 cells per well. 5% C02, cultured at 37 ° C for 48 hours. Then, the culture was mixed with 4 mM fluo-4, AM (molecular probe) in dye loading buffer (1% FBS, 86836 -132 - 1330174 HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), 2.5 mM Probenicid ( In Sigma)), culture for 1 hour. The culture was washed three times with wash buffer (HBS SwCa & Mg, 20 mM HEPES, Probenicid (2.5 mM)) followed by 100 μl/well wash buffer. During the incubation period, the compounds were made into 4X stock solutions in 0.4% DMSO (Sigma) and wash buffer and added to individual wells in their first addition plates. The IL-8 or GRO-α (R&D system) concentration was made 4X in Wash Buffer + 0.1% BSA and added to individual wells in its second addition plate. The plate and the two addition plates are then placed in the FLIPR photosystem to determine the change in calcium fluorescence when the compound is added followed by the ligand. Briefly, 50 microliters of compound solution or DMSO is used. The solution was added to individual wells and the change in calcium fluorescence was measured by FLIPR for 1 minute. After 3 minutes of incubation in the instrument, '50 microliters of the ligand were added, and the change in calcium fluorescence was measured by FLIPR instrument. 'After 1 minute. Determine the area under each stimulation curve and use the values to determine the % stimulation by compound (activator) and the total calcium of the ligand (0.3 iiM IL-8 or GRO-α) % inhibition of response to provide IC5 enthalpy of the test compound. Chemotactic detection of chemotaxis against 293-CXCR2 using Fluorblok insert (Falcon) 'on 293-CXCR2 cells (overexpression of HEK- for human CXCR2) 293 cells were established. The standard protocols currently used are as follows: 1. The insert is coated with collagen 1v (2 μg/ml) for 2 hours at 37 ° C. 2. Remove collagen and Allow the insert to air dry overnight. 86836 -133· 1330174 3. The cells were labeled with 10 yM calcein AM (molecular probe) for 2 hours. The identification was performed in complete medium with 2% FBS. 4. The dilution of the compound was made in minimal medium BSA) and placed Inside the insert, the insert is placed inside the well of the 24 well plate. In the well, the IL_8 at a concentration of 0.25 nM in the medium is minimal. The cells are washed and resuspended in minimal medium, and at each insert 5 〇, at the concentration of one cell, placed on the inside of the insert. 5. The plate was incubated for 2 hours, and the insert was removed and placed in the new 24 well. The ray was at stimulation = 485 nM, And emission = 530 nM under debt test. Cellularity test' The cytotoxicity test for CXCR2 compound is performed on 293_CXCR2 cells. At high concentrations, the concentration of the compound is tested for toxicity to determine whether it can bind to cells. In the basic test, it is used for further evaluation. The project is as follows: 1_The 293-CXCR2 cells are covered in complete medium at a concentration of 5 cells per well overnight. Liquid system Prepare in minimal medium w/〇19% BSA. Pour out the complete medium and add a dilution of the compound. Incubate the plates for 4, 24 and 48 hours. Label the cells with 1 〇 “calcium chlorophyll a, for 15 minutes, To determine cell viability. The detection method is the same as above. Soft Trace Detection A SKMEL-5 cell/well was placed in a mixture of 1.2/5 Xia and the whole medium with different dilutions of the compound. The final concentration of agar was 0.6%. After 21 days, 86836 • 134·1330174 viable cell colonies were stained with MTT solution (1 mg/ml in pBs). Then, the plate will be described to determine the number of colonies. The heart palpitations are measured by comparing the total area to the compound concentration. Compounds of 1.0 Å, 3.0 A, and Examples 36 〇 1 〇 9 36 〇 117 36, 68.45, 12 〇 (M2u, (3) the final compound of the fiber, which can be obtained by the method known to the artist, by the method disclosed in WO 02/083624, published on the date of 2, 2 years, 1 month, The invention is exemplified by the following preparations and examples. The invention disclosed herein is exemplified by the following examples of preparation and examples, and should not be construed as limiting the scope of the disclosure. Alternative mechanism pathways and similar structures are familiar to the artist. Obvious.

'Manufacturer Example 13.17A-13.17B The procedure set forth in Example 3.13 was prepared in accordance with WO 02/083624, published on January 24, 2002, but using the aldehydes produced or commercially available, the following table was obtained. Optically pure amine product. The number in the "Aldehyde" column "34.8" refers to Preparation Example 34.8 in WO 02/083624. Preparation Example Aldehydeamine Product Yield (%) 13.17A 34.8 gF3 H2N^^ qf3 38% 13.17B 〇cf3 Cf3 31% person/〇, CIHH2N^< Jj 86836 -135- 丄/4 Preparation Example 13.29

tMA was carried out in a solution of 7 3: methoxythiophene (3 g) in dioxane (175 ml), and chlorosulfonic acid (85 ml) was added dropwise at 78 c. The mixture was mixed under a 15 knife buckle and allowed to stand at room temperature for 15 hours. Then, the mixture was carefully chopped up and extracted with a chloranil. The extract was washed with brine, dehydrated with magnesium sulfate and filtered through a pad of 1-inch. The mash was concentrated in vacuo to give the desired compound (4.2 g). Step Β The product from the above step (4.5 g) was dissolved in dichloromethane (140 ml) and triethylamine (8.8 ml) was added followed by diethylamine (2M, 21 ml) in THF. The resulting mixture was stirred at room temperature overnight. The mixture was washed with brine and saturated bicarbonate (aq.) and washed again with brine. The filtrate was concentrated in vacuo to give the desired compound (4.4 g).

Step C The product from Step B above (4.3 g) was dissolved in dichloromethane (125 mL) and cooled in a -78 ° C bath. A solution of boron tribromide (1·〇 Μ in methylene chloride ' 24.3 ml) was added. The mixture was stirred for 4 hours while increasing the temperature from -78 C slow fe to 1 〇 c. Η20 was added, the two liquid layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic layer and extract were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3 - 96 g of the desired compound. -

Step D The product from Step C above (3.96 g) was dissolved in dichloromethane (125 mL) and potassium carbonate (6.6 g) was added, followed by bromine (2 mL), and the mixture was mixed at room temperature for 5 hours. 'The reaction was quenched with 1 〇〇 ml η 2 。. The aqueous mixture was adjusted to pH ~ 5 using 〇 5 Ν aqueous hydrogen chloride and extracted with dichloromethane. The extract was washed with a 10% Na; 2 Sz 〇 3 aqueous solution and brine, dried and dried with sulphuric acid steel and filtered through a pad of celite. The filtrate was concentrated in vacuo to give 42 g of desired compound.

Step E was such that the product from Step D (4.2 g) was dissolved in 1 mL of acetone and EtOAc (10 g) was then taken, followed by methyl iodide (9 mL). The mixture was heated to reflux' and continued for 3.5 hours. After cooling to room temperature, the mixture was filtered through celite. The filtrate was concentrated in vacuo to a dark brown residue which was purified by flash column chromatography eluting with chlorobenzene-hexane (1:1, v/v), s. The desired product.

Step F The product from the step (2.7 g) was converted to the desired imamine compound (3 g.).

Step G The imine product from step F (3 g) was dissolved in 80 mL dichloromethane and cooled in a -78 ° C bath. A solution of boron tribromide (1.0 Torr in chloroform, 9.2 mL) was added dropwise. The mixture was stirred for 4.25 hours from -78 °C to 5 °C. Add H20 (50 mL) and separate the layers. The aqueous layer was extracted with dichloromethane. The organic layer was combined with the extract, washed with brine and concentrated to an oily residue. The residue was dissolved in 80 ml of methanol and stirred with sodium acetate (1.5 g) and hydroxyamine hydrochloride (0.95 g) at room temperature for 2 hours. The mixture was poured into an aqueous mixture of sodium hydroxide (1.0 mL aqueous solution, 50 mL) and ether (100 mL). The two liquid layers were separated. The aqueous layer was washed three times with acid. The combined ether washes were extracted once more with Η2 。. The aqueous layers were combined, washed once with dichloromethane, then EtOAc EtOAc EtOAc EtOAc EtOAc The organic extracts were combined, washed with brine, dried over sodium sulfate and evaporated Preparation Examples 13.30-13.32 According to the procedure set forth in Preparation Example 13.29, but using commercially available amines, the starting-amino-<» cephene product in the table below was obtained. 86836 -138- 1330174 Preparation Example Amine Product Yield (%) MH+ 13.30 Bn2NH /P 5 BnHO^ NH2 10% 375.1 13.31 MeBnNH 〇, 々〇s HO NH2 14% 299.0 13.32 EtBnNH s Bn'^ Et HO NH2 22% 13.32A (Et)2NH B HO^NH2 25% Preparation Example 13.33

Step F

86836 -139- 1330174

Step A Following the procedure set forth in Preparation Example 13.29, Step B, using ethyl; amine, mp. Milligram), converted to 3-methoxy-2-ethylbenzyl benzyl-4 (5. 5 g, 94%, MH+ = 312_1).

Step B The product from the above step A (5.5 g, 17.70 mmol) was demethylated according to the procedure given in the procedure of Example 13.29. The alcohol product was obtained at 4.55 g (87%, MH+ = 298.0). Step C^ The product from Step B above (4.55 g, 15.30 mmol) was brominated using the procedure given in Step D. The corresponding bromide (84%) was obtained in 4-8 g.

Step D The bromo-alcohol (4.84 g, 12.86 mmol) from the above step C was methylated using the procedure set forth in Preparation Example 13.29, Step E. The product was obtained at 4.82 g (96%).

Step E The product from Step D above (4.82 g, 12.36 mmol) was stirred with concentrated sulfuric acid (5 liters) at room temperature for 3 hours. Ice water (3 ml) was added to the mixture followed by CH2C12 (50 mL). The aqueous mixture was adjusted to a pH ~ 6 ^ separation layer using a 1.0 M aqueous NaOH solution. The aqueous layer was extracted with CH2C12 (50 mL x 3). The combined organic layers were washed with EtOAc (EtOAc m.) The solvent was removed to provide 3 〇3 g (82%) of debenzylated product (M+ = 300.0, M+2 = 302.0).

Step F allows the product from Step E (U4 g, 4_45 mmol) to be methylated using the procedure set forth in Preparation Example 13.29, Step E. The desired product was obtained in 136 g (97%, M+ = 314.1, M+2 = 316.0).

Step G was used to convert the product from step ρ (1.36 g, 4.33 mmol) to the imine product (1.06 g, 55%, MH+ = 415.1) using the procedure given in the procedure of Example 13.29. Step 骡Η The imine product from step G (1_〇6 g, 2_56 mmol) was converted to the desired hydroxy-aminothiophene compound (0.26 g) using the procedure outlined in Preparation Example 13.29, Step G. , 43%). Preparation Example 13.34

± ΜΛ 产物 自 自 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 〇ml is bitten in the middle. 3-Amino-5-methyl-isoxazole (3.5 g, 35.68 mmol) was added. The mixture was stirred at room temperature for 20 hours, diluted with 1 mL of CH.sub.2Cl.sub.2, and washed with <RTI ID=0.0>0> The organic solution was dried over Na 2 SO 4 and concentrated in vacuo to a brown oil. The oil was dissolved in 1 mL of CH2 (3⁄4, washed again with 〇5 M HCl aqueous solution (30 ml of X 3) and brine. After dehydration with Nq s 〇 4, the organic solution was concentrated to yellow in vacuo. 4.48 g (91%, MH+ = 275.0) of desired product. Step B. The product from Step A above (4.48 g, 16.33 mmol) was dissolved in acetone (1 mL) and potassium carbonate was added. (5·63 g, 4080 mmol) with methyl iodide (1〇1 liter, 163.84 mmol). The mixture was stirred at room temperature for 15 hours with 1 liter of hexane and 50 ml of CH2%. Diluted and filtered through a pad of EtOAc EtOAc (EtOAc)EtOAc.

Step C Add sodium to sodium hydride (130 mg, 95%, 5.4 mmol) in 8 ml of N,% dimethyl methamine in & Mercaptan (0.45 pens, 6.0 millimoles). After 5 minutes, the mixture became a clear solution and was added to the product from step B above (〇_45 g, 1 - 56 mmol) in 2 mL of di-dimercaptoamine in a round bottom flask. It is stirred in the solution. The flask was sealed with a glass stopper and the mixture was heated at 90-951 for 4 hours. After cooling to room temperature, the mixture was poured into 2 mL of aq. OM NaOH aqueous solution and further rinsed with 2 〇 86836 - 142 - 1330 174 ml HzO. The aqueous mixture was washed with diethyl ether (30 mL x 2), EtOAc (EtOAc) The combined extracts were washed with brine, dried (Na 2 S04) and concentrated to a dark yellow solution. It was dissolved in 50 ml of ethyl acetate, and the mixture was washed with H2 00 00 mL (2 ml) and brine (30 ml) and dried over Na2SO4. Evaporation of the solvent gave 0.422 g of the alcohol product (99%, ΜΗ+ = 275·0).

Step D To give the corresponding bromide (100%) from the alcohol of Step C above (0.467 g, 1.70 mmol) using the procedure set forth in Preparation Example 13.29, Step D. Ε Using the procedure set forth in Preparation Procedure 13.29, the methyl bromide (0.607 g, 1.72 mmol) from step D above was methylated to give the desired product (0.6%, Μ+= 367). , Μ+2 = 369.1).

Step F The product from the above step (0.405 g, 1.103 mmol) was converted to the imamine compound (29 g, 56%) using the procedure given in the procedure of Step 13.29.

Step G uses the procedure set forth in Step C above to demethylate the imine product from step f above (0.29 g '0.61 mmol) to give the corresponding alcohol as a dark ochre oil. It was dissolved in 5 ml of methanol and sodium acetate (12 g, 丨. 46 mmol) and hydroxylamine hydrochloride (0.075 g, 1 〇 8 mmol) were added. The resulting compound was stirred at room temperature for 3 hours' and poured into 1 mL of 丨〇μ Na〇H water-soluble 86836 • 143- 1330174 solution. 30 ml of H20 was used as the rinse and combined into the aqueous layer. The aqueous mixture was washed with diethyl ether (40 mL EtOAc) (EtOAc) The organic extract was washed with η 2 Ο (20 mL χ 2), brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give 0.112 g of the desired base-amino-P-pheneamine (64%) , MH+=290). Preparation Example 13.35

'° Ih

Step A To a solution of 2-methylfuran (1.72 g) in ether, EtOAc (········· The reaction mixture was again cooled to -78 ° C. and quenched with cyclopropyl decylamine 1 and stirred at -78 ° C for two hours and slowly warmed to room temperature. The reaction mixture was stirred at room temperature for three hours and a saturated aqueous solution of ammonium chloride was added and the mixture was quenched. The mixture was transferred to a separatory funnel, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the solvent was removed to give a crude hexane which was purified by column chromatography to afford benzene (yield: EtOAc, EtOAc)

Step B is carried out in a solution of the ketone (1-0 g) in THF (5.0 mL). Under the arm, R-methyl oxazolidine boridine (12 ml, 1 M in toluene) was added dropwise, followed by the addition of a solution of boron 86836-144-1330174 alkane with disulfide methane (185 ml, 2M in THF ). The reaction mixture was stirred at 〇 ° C for 3 Torr and then at room temperature for one hour. The reaction mixture was cooled to 〇 ° C, and Me 〇 H was carefully added. The mixture was stirred for 20 minutes and concentrated under reduced pressure. The residue was extracted with ether and washed with water, 1M EtOAc (10 liters), saturated sodium carbonate (10.0 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated, and then evaporated. Preparation Example 13.36

'0 Tri-OH Step & A molar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) was combined with SnCl4 (0.05 mL) and heated at EtOAc for 3 hr. After cooling the reaction mixture, water (10 ml) was added, followed by a saturated sodium carbonate solution until it became detectable. The reaction mixture was extracted several times with ether, and the combined steep layer was washed with water, brine, and dried over anhydrous sodium sulfate. Filtration and removal of the solvent gave crude EtOAc afforded EtOAc (EtOAc) Step 86836 - 145 - 1330174 B alcohol was obtained following a procedure similar to that described in Preparation Step 13.35, Step B. Example 13.37

Step A: in 5-methylfuran-2-aldehyde (1 g) and 3-bromo-difluoropropene (2 24 g) in (gross); in the surface liquid, adding barium powder (1.66)克) and the reaction mixture (5 〇. 〇 I grams) the reaction mixture was stirred overnight [diluted with water, and extracted with a bond. The ether layer was washed with water, brine, and purified by silica gel chromatography to yield hexane (92%). Preparation Examples 13.38-13.45 The procedures set forth in Example 13 25, and Preparation Example 13.35, were prepared in accordance with w〇02/083624, published in the January 24, 2002, and the indicated electrophiles were used to make the following table. The following alcohols. 86836 -146- 1330174 Preparation Example Furan Electrophilic Alcohol Yield 13.38 \ CHO V 乂 < xy 86% 13.39 F /^•COOEt F H0 69% 13.40 (f OMe HO^&gt;-〇Y 84% 13.41 0 (f OMe H0JU 82% 13.42 0 F /^COOEt F Less H0^\—0 60% 13.43 F /^COOEt F Less HO^VO X? 65% 86836 -147- 1330174

Preparation Examples 13.50-13.61 The following amines in the following table were prepared according to the procedure set forth in Example 13.25, similar to WO 02/083624, published on October 24, 2002, using the indicated alcohols. Preparation Example - Alcoholamine % Yield 13.50 13.45 丨CF3 H2N 28% 13.51 13.38 ηΊ 58% 13.52 13.36 / 69% 13:53 13.35 81% 13.54 13.37 ηΊ 82% 86836 -148- 1330174 13.55 13.39 FI 45% 13.56 13.41 57% 13.57 ^ 13.40 &lt;L 58% 13.58 13.44 FH- ηΊ 54% 13.59 13.42 FI s 53% 13.61 13.37 ηΊ 82%

86836 149- 1330174 Preparation Example 13.70

Step A The imine is prepared according to the procedure set forth in Example 13.19 of WO 02/083624, published on October 24, 2002, from a known bromo ester (1.0 g) as a yellow solid, and step A yields 1.1 g (79). %). Step B. The product of Step A (0.6 g) was reacted according to the procedure given in Example 13.19 of WO 02/083624, published on October 24, 2002, to give an amine product of 0.19 g (64%). Call

Step C The product of Step B (1.0 g) was obtained according to the procedure of the preparation of Example 13.19 of WO 02/083624, published on October 24, 2002, to give the acid as a yellow solid, 0.9 g (94%).

Step D The product of Step C (0.35 g) was obtained according to the procedure of the procedure of the preparation of Example 13.19 of WO 02/083624, published on October 24, 2002, to give the amino acid as a yellow solid, 0.167 g (93%). 86836 -150- 1330174 Preparation Example 19.2

The hydroxythienamine (1 〇 8 mg, 〇·37 mmol) from Preparation Example 13.34 was dissolved in 5 ml of ethanol' and with diethoxy squaric acid ester (〇14 ml, 〇95 Amol) and Potassium carbonate (52 mg, 0.38 mmol) was stirred overnight at room temperature. The mixture was diluted with AO (25 mL), EtOAc (EtOAc) (EtOAc) The combined organic extracts were washed with brine <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The solvent was removed to give 83.5 mg of the title product (MH+ = 414).

Example 23.14A 舆 23.14B The procedure set forth in Example 丨9 was prepared according to w〇〇2/〇83624 published on October 24, 2002, but using the amines from the preparation examples indicated in the table below, A diketone intermediate. Preparation Example The product from which the amine was derived. Yield (%) 2. MH+ 23.14A 13.70 Step B HO Η 1. 60% 2. 138 23.14B 13.70 Step D 〇vy° MeO H 1. 65% 86836 • 151- 1330174

Preparation Examples 23.15A-23.15F The corresponding cyclobutenedione intermediates were prepared according to the procedure set forth in Preparation Example 19.2, but using the amines from the preparation examples indicated in the table below. Preparation Example The product from which the amine is derived 1. Yield (%) 2. MH+ 23.15A 13.29 / HO Η 0~〇Et 1. 66% 2. 347 23.15B 13.30 Bn-N T t Br^ HO H rf 〇^OEt 1. 21% 2. 499 23.15C 13.31 Bri H0 H _γ° ~〇Et 1. 41% 2. 423 23.15D 13.32 Et-N 丫? Br^ H0 H rf〇~OEt 1. 26% 2. 437 23.15E 13.33 ^ HO H f〇~〇Et 1. 48% 2. 361.1 23.15F 13.32A Body;: / \ HO H t~f〇^OEt 1.68% 2. 375.1 86836 152- ^30174 Preparation Example 23.16-23.26 The procedure set forth in Example ι9 was prepared according to w〇〇2/〇83624 published on October 24, 2002, but using the instructions from the table below. The amine of the preparation example was obtained to obtain a cyclobutanedione intermediate product. Example of the preparation of the product of the prickly amine. Yield (%) 23.25 13.17A ° CP3 48% - 23.26 13.17BV % ~66%~ 34.15-34.16 According to the announcement of October 24, 2002, w〇02/ 083624 The procedure set forth in Example 34.8 was prepared, but using the nitroalkane shown in the table below, aldehydes were prepared. Preparation Example Nitro--aldehyde Yield 34.15 CJ^~~n〇2 % 17% 34.16 〇~~n〇2 % 21% 86836 -153- 1330174

Preparation Example 34.17 〇 〇' Br Step Β〇Λ^〇γΒ "Step β

EtO.

Step C

Step E HO

- Step D - HO.

Step A To a stirred suspension of 5-bromo-2-furancarboxylic acid (15.0 g, 78.54 mmol) in 225 ml of CH2Cl2, at room temperature, add chlorinated herbicide, followed by a catalytic amount N,N'-dimethyl decylamine. After 1 hour, the reaction was continued for 15 hours by adding ethanol (20 mL) followed by triethylamine (22 mL). The mixture was concentrated to a residue under reduced pressure and extracted with hexanes and hexane-CH2C12 (3:1, v/v). The extract was filtered, the filtrate was concentrated to a yellow oil and dried <RTI ID=0.0>

Step B The ester product from Step A above (17.2 g, 73.18 mmol) was converted to 2-ethyl-4-t-butylbromo-furanate (7.9 g, 37%) using the following literature Program: J_ 4m. C/zrn. Soc., 1939, 67, 473-478.

Step C The procedure set forth in Example 34.8, step c, was prepared using WO 02/083624, published on Jan. 24, 2002, to reduce the ester product from Step B above (7.9 g, 27.13 moles) to alcohol ( 6.32 grams). 86836 154- 1330174

Step D The product from Step C above (6.32 g) was dissolved in THF (140 mL) and cooled in a -78 ° C bath. A 2.5 M solution of n-butyllithium in hexane (22 mL, 55.0 mmol) was added dropwise along the side of the flask. After 15 minutes, add %0 (~70 ml). The cooling bath was removed and the mixture was stirred for an additional hour. Aqueous brine (50 mL) and CH2C12 (300 mL) were evaporated. The solvent was evaporated to give 5.33 g (yield) of the debrominated product as a red brown oil.

Step E The alcohol product from Step D above (5.33 g) was oxidized to its corresponding aldehyde (3 〇 6 g, 74% over three steps) using the procedure set forth in Preparation Example 34 8 Step D.

Step A Add butyl butyl bromide (4.0 ml, 50 mM) in 120 ml of ether in a sandalwood solution under the '78 C' drop of the third-butyl chain in ‧ M Solution (44_5 ml, 75.7 mmol). After 10 minutes, the cooling bath was removed and the sand was mixed for 1.5 hours. The mixture was brought to -78. (: Cool once again in the bath and add 3-86836 -155 - 1330174 furanal (3.5 ml, 41.9 mmol). The reaction was continued for a few hours and the reaction was quenched with saturated aqueous NH.sub.4. ML 3) Extract the aqueous mixture. Wash the organic extract with brine, dry and dry, filter and 'concentrate in vacuo' to give 5.3 g (91%) of the product as a yellow oil. Trimethyl decane (27.2 ml, 214.2 mmol) was added dropwise to sodium iodide (32 g, 213.5 mmol) in 1 ml of acetonitrile and stirred vigorously in the suspension. After 5 minutes, A solution of the alcohol from the above step a (4.93 g, 35 68 mmol) in 100 ml of acetonitrile was added dropwise. Stirring was continued for 5 min. η 2 〇 (100 mL) was added and the layers were separated and ether (100 ml x 2) extract the aqueous layer. The organic layer was combined and washed with 10% aqueous Na2S2 3 aqueous solution and brine, and dried over Na 2 S 〇 4 evaporated to give a dark brown oil, which was passed through a 5-inch smashed hose. Filter through a column and dissolve in CH2C12-hexane (1: 3.5, v/v). Remove solvent and provide 4.22 g (47%) of the base product as a pale yellow oil.

Step C The iodine product from Step B above (2.2 g, 8.8 mmol) was dissolved in &lt;RTI ID=0.0&gt;&gt; A 1.7 Torr solution of tributyl-lithium in pentane (10.4 mL, 17.7 mmol) was added dropwise. After 20 minutes, the cooling bath was removed and the reaction was continued for 2.5 hours and quenched with EtOAc (20 mL). The aqueous mixture was stirred overnight and separated. The aqueous layer was extracted with ether (30 mL). The combined organic layers were washed with brine, dried over Na 2 EtOAc and filtered over EtOAc. The solvent was removed to give 1.10 g (100%) of 3-butylfuran as a reddish yellow oil.

Step D 86836 - 156 - 1330174 3 - Butylfuran (u gram, 8.8 mmol) dissolved in 6 mL of acid in the above step C and stirred in a _78 〇c bath. A 1.7 Torr solution of tributyl-lithium in pentane (6.0 mL, 10.2 mmol) was added dropwise along the side of the flask. The mixture was stirred for 3 hours from ·781 to 〇〇c and continued at room temperature for 1 hour. A solution of N,N-dimethylformamide (1.1 mL, 14.23 mmol) was added. The reaction was allowed to continue overnight and the reaction was quenched with a saturated aqueous solution. The two layers were separated and the aqueous layer was extracted with CH.sub.2 (3.times.sup.30 (30 mL).). The combined organic layer was washed with brine. =1 : ι·5,v/v), and obtained 48 grams (36%) of Jun (contaminated by some 3-butyl-2-indole, aldehyde). Preparation Example 34.19

Step A 3-Ethyl furan is according to the literature procedure: 乂 α(10), 1983, p, 11〇6_u〇7, from 3-hydroxymethylfuran. ·

Step B The procedure set forth in Example 34, Step D, was prepared using WO 02/083624, published on Oct. 24, 2002, to convert the 3-ethylfuran from the above step into 'ethyl-2-benzofuran . 86836 -157- 1330174

Preparation Example 75.10A-75.10J The procedure set forth in Example 64 was prepared as described in WO 02/083624, issued Oct. 24, 2002, but using commercially available aldehydes, amine alcohols and organolithium in the table below. Reagents to obtain the optically pure amine product in the table below. The number in "aldehyde" is the preparation example herein or in WO 02/083624. Preparation Example Aldehyde-Alkyl Alcohol Organic Product 1. Yield 2. MH+ 75.10A (34.7) h2n oh vLi H2N^y , 〇V 1. 61% 2. 135 [M-NH2]+ 86836 158- 1330174 75.10B /~\ h2n oh EtLi 1. 24% 2. 154 75.10C (34.18) /\ h2n oh EtLi 1. 32% 2 165 [M-NH2]+ 75.10D (34.8) H\ /~\ h2n oh MeLi 1. 47% 2. 137 [m-nh2]+ 75.10E (34.8 卜H\ /\ h2n oh iPrLi v 1. 30 % 2. 165 [M-NH2]+ 75.1 OF (34.8) H\ /~\ h2n oh v&quot; V 1. 67% 2. 163.0 [M-NH2]+ 75.10G (34.17) h2n oh EtLi 1. 24% 2. 165 [M-NH2]+ 75.10H (34.15) \ '·f~\ h2n oh EtLi _〆1. 70% 2. 194 75.10J (34.16) /\ h2n oh EtLi 1. 54% 2. 208 86836 -159- 1330174 J 1^'J JOU.lUy-.jGW· II / In accordance with the procedures of the stipulations of the 〇〇 《 如 《 《 《 《 《 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 However, using the amines prepared in the table below, the following rings were obtained and the amines obtained were either available or obtained from the preparation of the butenone product.

l yield 2. MH+ CC) 12 3 67% 410.1 119-121 % 2 2 1 1 ο 7 4 1 『 * · * 12 3 1· 2· 3 64% 440.1 91-93 1. 79% 2. 412 3 . 111-113

20% 440.1 130 (decomposition) 86836 1330174 360.114 7R 1ΠΡ '------ ...Y i riV&gt; 1. 61% 2. 438.1 3. 117-119 360.115 7^ 1ΩΓΪ _ ·/ 0 OH Η Η 1. 61 % 2. 440.1 3. 117-119 360.116 75.10H Η2ΝΛΝ(\) ι nV, &quot;tVt o 1. 81% 2. 452 3. 118 360.117 m I ---- 1 sJ, 1 \JsJ —— ·/ h2nT&quot;^ Ο ^ /X w ^ AV o 1. 65% 2. 466 3. 109 ^ Example 3(10) According to the example of WO 〇2/〇83624, 261, published on October 24, 2002 nW a W4曰: Order of authority? Using the commercially available amines in the table below, and the cyclidine diketone intermediates from the indicated examples, obtain the following numbers in the column "Analysis" and "Preparation Examples". Ding Zhiyi 嗣 product. Preparations in, ice making - /, , &quot; Ben or WO 02/083624.

86836 -161- 1330174

% 8 o 6 6 8 5 4 1 h2·3· % o 6 8 8 8 2 4 1 12·3· 368.36

23.15A

1. 48% 2. 494 3. 112.5 368.37

23.15B

1. 58% 2. 592 3. 177-179 368.38 75.49

H〇N

23.15C

HO 1. 69% 2. 516 3. 88-90 368.39 75.49 Η,Ν

23.15D

1. 80% 2. 530 3. 134-137 368.40 75.49

H〇N

23.15E

Et

.9 -S .N-S

HO Q. P 1. 57% 2. 454 3. 138- IHHL/ 140 86836 -162- 1330174 368.41 75.49 h2n~ 19.2 \ s / η 〇τ;&gt; / υ ΗΟ Η Η Κζ 1.26% 2. 507 3. 162-164 368.42 3 23.25 0 ΟΗ Η /丄 F 1. 82% 2. 466 3. 141-143 368.43 3 23.26 ι nVFf Ο ΟΗ Η Η 1. 67% 2. 480 3. 139 decomposition 368.44 13.29 , 23.16 χ 0 〇Vf〇F^F ΗΟ Η Η ^J/ 1. 29% 2. 480 3. 112-114 368.45 13.29 23.26 Ο S \ 9 β~\ /NrW ΗΟ Η pY〇fnX-f 1. 88% 2. 508 3. 190 decomposition preparation example 600

86836 -163- 1330174

Step A The procedure set forth in Step 13.19 of Example 13.19 was prepared according to WO 02/083624, issued Oct. 24, 2002, which is made from the known bromo ester (1 gram) to yield 1.1 g (79%). , a yellow solid.

Step B The product of Step A (0.6 g) was reacted according to the procedure of the procedure of Example 13.19, as described in the procedure of WO 02/083624, issued on October 24, 2002, to obtain 0.19 g (64%) of the amine product.

Step C The product of Step B (1.0 g) was reacted according to the procedure set forth in Step B of Example 13.19, prepared by W〇〇2/〇83624, published on January 24, 2002, to give the acid 'as a yellow solid, 0.9. Gram (94%). The product of step c (0.35 g) was reacted according to the procedure given in the procedure of Example 13.19, as described in the procedure of WO 02/083624, issued on October 24, 2002, to obtain the amino acid as a yellow solid, 0.167 g (93%). Preparation example 601

To a solution of 1 methylfuran (1.72 g) in ether, at a temperature of -78 ° C, a BuLi (8·38 liter) was added and stirred at room temperature for half an hour. The reaction mixture was again cooled to -78 ° C, and the reaction was quenched with cyclopropyl decylamine 1 and stirred at -78 ° C for 868 36 • 164 - 1330174 for two hours and slowly warmed to room temperature. . The reaction mixture was stirred at room temperature for three hours and the reaction was quenched with saturated aqueous ammonium chloride. The mixture was transferred to a separatory funnel, washed with water and brine, and dried over anhydrous silica. Filtration and removal of the solvent gave a crude hexane which was purified by column chromatography eluting with EtOAc (EtOAc)

Step B To a solution of the ketone (1.0 g) from the above Step A in THF (5.0 mL) 1 at 0 ° C, dropwise addition of R-indole 4 (1 2 mL, 1 M, In a solution, a solution of borane and disulfide methane (1.85 mL, 2 M in THF) was added. The reaction mixture was stirred at 〇 ° C for 30 minutes and then at room temperature for one hour. The reaction mixture was cooled to o ° c and MeOH was carefully added. The mixture was stirred for 20 minutes and concentrated under reduced pressure. The residue was taken as a mystery and washed with water, 1M EtOAc (10 mL), saturated sodium hydrogen carbonate (10 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate, and then evaporated, and then evaporated to the solvent to afford the crude alcohol, which was purified by gelatin chromatography to yield 91 g (91%) as a yellow oil. Preparation example 602

86836 -165· 1330174 A molar mixture of 2-methylfuran (lo) and anhydride (2.6 g) was mixed with SnCl4 (5 ml) and heated at 1 Torr for 3 hours. After the reaction mixture was cooled, 'water (10 ml) was added, followed by a saturated sodium carbonate solution until it became inspective. The reaction mixture was extracted several times with ether, and the combined layer was washed with water, brine, and dried. The sulphate was dried under reduced pressure, filtered, and the solvent was evaporated to give a crude hexane, which was purified by silica gel chromatography to afford EtOAc (yield: The program was obtained. Preparation Example 603

Indium powder (166 g) was added to a solution of 5-methylfuran-2-aldehyde (1.0 g) and 3-bromo-3,3-difluoropropene (2 24 g) in DMF (30 mL) With lithium iodide (5 〇〇 peng). The reaction mixture was stirred overnight, diluted with water and extracted with acid. The ether layer was washed with water and brine and purified by silica gel chromatography to yield 28 g (92%). 86836 - 166 - 1330174 Preparation Examples 604-611 The following alcohols were prepared according to the procedure set forth in Preparation Example 13.25 of WO 02/083624, published on October 24, 2002, or in Preparation Example 601.

Preparation Examples Furan Electrophile Alcohol Yield 604 . CHO \ / η°Λ^ 86% / 605 F /^-COOEt F H0 c- 69%

86836 167 - 1330174 606 0 0 OMe H〇l^ 84% 607 0 OMe ? HO^VO X? 82% 608 F /^COOEt F HO^\—〇Y 60% 609 0 F /^COOEt F &gt;- H 〇ja 65% 610 f 〇Me less HO^\-〇xy 82% 611 ohc^cf3 X^cf3 H0 89% Preparation Examples 620-631 Following the procedure set forth in Preparation Example 13.25, the following amines were prepared from the corresponding Alcohol 8 86836 168- 1330174 Preparation Example Alcoholamine Yield 620 丨~CF3 j~CF3 H2N 0- 28% 621 rf H〇/\-〇xy 58% 622 H0 c- H2N&quot;\&gt; 69% 623 H〇 /V &lt;1 h2n^ iy 81% 624 H〇iy , H2N^y 82% 625 F 1 ηΊ 45% 626 X? &lt; Η2Ν|/ yj 57% 86836 -169- 1330174 627 H〇^ &lt; 58% 628 F F-i_ ηΊ 54% 629 F HO^V—° YF^ 53% 630 FH〇/^V〇FI H2N0〇50% 631 pJi H〇iy FF ηΊ 82% 86836 -170- 1330174 Preparation example 640- 641 The procedure set forth in Example 19 was prepared according to WO 02/083624, published October 24, 2002, but using the amines from the preparation examples indicated in the table below to obtain the cyclobutanedione intermediate. Preparation Example =====-- Preparation of the product from the amine Example 1 Productivity (%) 2.MH+ 640 --- 600 Step B Ον /0 rS^? ^ HO Η 1. 60% 2. 138 UH 1 ----__ 600Step D ----- MeO H ----------- 1. 66 2. 138 ------ Example 1200-1211 Accepted in January 1st, 2002 24 η八止, 卞曰 艾 艾 〇 〇 〇 〇 24 24 24 24 24 24 24 24 24 24 24 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 Amine, 鞞搵丁^^ Make up the following examples of cycline diketone products

36 1. 54 2. 439.5 3. 117.8 -171· 1330174 1202 1 Ανθ 1.80 2. 439.5 3. 128-131.8 1203 Η2νΛι&gt; i nv°^ /NrVS^S^rV 0 OH Η H \_JJ 1. 75 2 423.4 3. 118-119 1204 O OH H /FV 1. 74 2. 447.4 3. 108-111 1205 h2nAcv /Nr^V 0 HO H ~/° i- 1.42 2. 415.42 3. 136-140 1206 H2N^ 0 1 /1 w O OH Η H 1.46 2. 423.4 3. 114-117 1207 F HznAT&gt;- , nVF^ ^ Y^r V 7 person-O OH Η H Kj/ 1. 35 2. 433.1 3. 123- 128 1208 Η2νΛ|^ ^r9r O OH H iY meaning 1 1.42 2. 423.4 3. 118-121

86836 -172- 1330174 1209 F Η2νΛ1^ 0 OH Η Η ^ 1. 51 2. 415.4 3. 112-117 1210 F ^ Ύι^ι 0 ΟΗ Η Η 1.44 2. 415.4% 3. 115-120 1211 0 ΗΟ Η Η ^ 1.48 2. 445.4 3. 105-110 Example 1300-1311 In accordance with the procedure set forth in Example 261 of WO 02/083624, published on October 24, 2002, but using commercially available amines from the table below, The cyclobutenedione intermediate of the preparation example is indicated to give the following cyclobutenedione product. The preparation example 23.9 is in WO 02/083624, published on October 24, 2002. Example 3 Preparation Example Product 1. Yield 2. ΜΗ+ 3. Melting point (°C) 1300 η2ν^_ 640 °\ /S1 °\ί° /^0 Γ^Ν Ν-\ ΗΟ Η Η 1. 35% 2. 390.4 3. 100 1301 641 0. .s^ °γγ° ΗΟ Ν^Ν Ν-Λ MeO Η 1.7 1.78% 2. 390.4 3. 130 1302 Vp Η2Ν&quot;ΧΧ&gt; 23.9 1 S-, 0 ΟΗ ^ Η 1 48% 2. 483.4 3. 116 86836 -173 - 1330174

1303 23.9 0 OH Η H 1. 46% 2. 443.5 3. 106 1304 H2N^C^ 23.9 1. 40% 2. 445.54 3. 102 1305 h2NX〇23.9 i s-λ °V-^ 0 OH H ;^o H 1. 51% 2. 413.4 3. 98 1306 -ο 23.9 ° OH Η H 1.78% 2. 405.5 3. 246 1307 H2N^C0 23.9 is 〇Vf° r&quot; ° OH Η H 1. 83% 2. 439.5 3 129 1308 cf3 HznACO 23.15A υ OH Η HK^-o 1. 11% 2. 519.47 3. 123 1309 V 23.15A λ ΐΛ°η° ^ 00 iH Η Η 1. 47% 2. 475 3. 113 1310 640 \-N /S^\ °V, atmosphere ^V: OO IN OH H -f° t— CO CO LO LO cn CN CM L〇 inch t— t— ^r-* Csi CO 86836 -174- 1330174

Co2h

Backup Example 1001 Step A Step B

F3C' 丫 OMe COCI

F3C, OMe CONMe2

Step C

Br

NO〇

Step E Br^^N°2 Step D F3CT 丫, 〇h CONMe2

F3C 丫 OMe CONMe2

F3C’ 〇Me CONMe2

Step F ^^NH2 Λη - CONMe2

±MA chlorinated mash (3 ml '3f27 mmol) was added dropwise to 2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6-81 mmol) (according to known methods) In a mixture of 〇, Ν, dimethyl decylamine (〇3 ml) and dichloromethane (40 ml), and stirred at room temperature. The reaction mixture was stirred overnight. Evaporation of the solvent with excess chlorinated hydrazine and drying under vacuum afforded 2-methoxy-6-(trifluoromethyl)benzene oxime chloride as the title which was purified and purified. The 2-methyl chloride obtained from the above step is most preferably -# m-g-T-yl-6-(diindolyl)benzhydrazide (about 86836 175- 1330174 6.81 mmol) in dichloromethane (2 ml) solution was added dropwise to 4_(di:amino group) than bite (42 mg, 〇·34 mmol), triethylamine (28 ml, _mole) and A mixture of 2 dimethylamine solution (7 ml, Μmole) and di-methane (3 mM) in tetrahydrofuran, and stirred at room temperature. The reaction mixture was stirred overnight. The mixture was separated and the organic phase was washed with a solution of IN HCl, water and saturated aqueous hydrogen sulphate, and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane, 3:?) , as a white solid (1·24 g, 74%, after two steps).

Step C: A mixture of guanamine (1.8 g, 728 mmol), tetra-carbonized carbon (7 ml) and iron powder (305 mg, 5.46 mmol) from the above step, cooled to 〇 ( (:. Bromine (0.94 ml, 18.34 mmol) was added dropwise, and stirred. After the addition, the mixture was stirred at room temperature for hrs and allowed to cool for 5 hours at 5 Torr. Diluted with methylene chloride, and slowly poured into a cold solution. After stirring for 5 hours, the organic layer was separated and concentrated to give a white solid (2.26 g, 95%).

Step D At a concentration of 硫酸 ° C, concentrated sulfuric acid (1 mL) was added dropwise to a flask containing the above-mentioned step C bromide (600 mg, 丨.84 mmol) and stirred. A mixture of nitric acid (0.2 ml, 4.76 mmol) and concentrated sulfuric acid (3 ml) was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hours. The mixture was added to ice water, neutralized to pH Η7 with a 15% NaHH solution, and extracted with di-methane. The organic layer was concentrated to give a white solid (621 mg, 91%). Melting point 92°C, m/e 371 (MH+y 86836 -176- 1330174

Step E A solution of the compound from Step D above (1.2 g, 3.23 mmol) in methylene chloride (5 liters) was cooled to _75. Hey. The IMBB1·3 solution (75 ml, 75 mmol) in dichloromethane was added dropwise and stirred. The mixture was stirred at 2 C for 2 hours. The mixture was added to ice water. After stirring for 5 hours at room temperature, the mixture was extracted with dichloromethane. The organics were concentrated and purified EtOAc EtOAcjjjjjjjj m/e 357 (MH+).

Step F: A mixture of the compound from the above Step E (1.08 g, 3.02 mmol), methanol (30 mL), and 10% Pd-C (250 mg) was subjected to hydrogenation at 50 psi and room temperature. hour. The mixture was filtered through a layer of diatomaceous earth. The filtrate was concentrated to give the title compound md. Melting point 132. ’ ’ m/e249. Preparation example 1002

86836 • 177· 1330174

#骤A To a solution of 3-bromothiophene (3.8 ml) in ether (45 ° C), ether (45 mL, dry), EtOAc (30 mL, hexane, hexane) The mixture was stirred at -70 ° C for 20 minutes. Add acetophenone (4·6 ml) in ether (6 ml) dropwise and stir at _70 °C for 3 hours, then warm the mixture to room temperature and add saturated NH4C1 (aq). And extracting the mixture with ether. The organic phase was dried (Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.

Step B The crude product from Step A above was combined with oxalic acid (0.375 g), and then stirred at 70 ° C under reduced pressure for 3 hours, then cooled to room temperature and extracted with acid. The organic phase was dried (NazSO4) and concentrated in vacuo to afford product (yield: 5.7 g, 78%).

Step C. TFA in dichloromethane (7.5 liters) was added to the product from step B (4-2 g) diluted with dichloromethane (30 mL) and containing triethyl decane (6 mL). (3 ml). After stirring at room temperature for 1 hr, the mixture was concentrated in vacuo to give crystals (yield:

Step D To a solution of the octopine product (1.5 g) from the above step C in ethyl ether (3.5 mL, dry), EtOAc (EtOAc) To room temperature, dmp (0.8 mL) in ether (3.5 mL) was added dropwise. After stirring for 30 minutes, a saturated aqueous solution of nHaCU was added, and the mixture was extracted with ether. The organic phase was dehydrated and dried (NhSOj, EtOAc EtOAc EtOAc (EtOAc)

Step A The aldehyde (0.50 g) was combined with methylene chloride (1 ml), benzene (40 ml) &amp; pTSA monohydrate (30 mg) and stirred under reflux for 20 hours. After cooling to rt, EtOAc was added EtOAcqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .

The product from Step A above (0.607 g) was stirred with EtOAc (EtOAc) EtOAc. Wash with brine and concentrate in vacuo to give aq.

Step C Following a procedure similar to that used in Preparation Example 1 except that the product from Step B above and dimethylamine (2M) in THF was used to afford product (1.21 g, crude).

Step D 86836 -179 - 1330174 The product from Step C above was dissolved in THF and stirred with &lt;RTI ID=0.0&gt;&gt; Concentration in vacuo gave a pale yellow oil (1.1 g, 67%). Preparation f example 1004

Step A To a cooled (-78 ° C) solution of decyloxybenzofuran-2-carboxylic acid (1 g) was added DIBAL (30 liters, 1M in THF). After stirring for 20 minutes, the mixture was warmed to room temperature and stirred for 4 hr then poured into saturated NH4CI (aq) (35 mL). After stirring at room temperature for 2 minutes, 6 M HCl (aq.) was added and the mixture was extracted with EtOAc. The organic phase was dried and dried and concentrated in vacuo. Purification by EtOAc (EtOAc-hexanes, EtOAc)

A mixture of EtOAc (EtOAc) (EtOAc) The solid was redissolved in EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) Solid (〇.6 gram, 67%). Preparation example 1005

1330174 The title compound (solid, 〇 31 g </ </ </ </ /> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

± ΜΛ The chlorinated hydrazine (1.5 g) of the procedure of Example 13.29 was prepared with A1C13 and benzene, and stirred at 20 ° C for Μmin. Treated with NaOH, EtOAc (EtOAc m. Step g Following a procedure similar to that used in the preparation of Example 13.29, Steps C-G, using the procedure from the above step A, the title compound ( 〇. 〇 4 g, 27%, MH+ = 256) was obtained. Preparation Examples 1007-1029 The procedure set forth in Example 19.1 ' or Preparation Example 19.2 was prepared according to WO 02/083624, published on October 24, 2002, but using the amine (aniline) listed in the following table. The following quartic acid ester intermediates 86836 -181 - 1330174 Example 1007 Amine/aniline product

OH NMe2 〇

〇Me 1. Yield (%) 2. (M+l)+ T~95%~ 2. 359

86836 182- 10131330174 Hey,

OH ?,; 丫 nh2 1014

OH

1. 72% 2. 353.0 1 _ 60% 2. 355.1 1015

NH 2 〇 OH 1016

NH 2 O 〇 OH 1017

NH 2 〇, 〇 OH 1019

1020

Nh2 1021

NH, O OH

1. 70% 2. 303.1 1 2 45% 327.0 1. 70% 2. 367.0 1. 32% 2. 409 1. 48% 2. 466 1 ·~60% (crude)

86836 -183- 1330174 1022 arx /^nh2 0 〇OH H 1. 21% 1023 Os 0/λ"Υ^ΝΗ2 HO Qs' HO H γΥ〇XOEt 1. 45% 2. 389 1024 Q HO Q 〇々, rW HO H f , OEt 1. 30% 2. 380 1027 / H2nAI^ °\-f° ^ -rq 1. 44% 2. 264 1028 H2N&quot;l&gt;- °YY° U Et0 1. 56% 2. 278 1029 Xl/ H2N^I&gt;- °YY° V: B. 1. 47% 2. 292 86836 184- 1330174

±ΜΑ The product of the preparation of Example 34.18 (2 g, 8 mmol) with chloroform, lin (〇 9 ml ' 10.29 mmol) and K 2 C 〇 3 (2.2 g, 15.9 mmol) in 50 ml In the same manner, the mixture was stirred at room temperature to obtain a morpholinylbutylfuran derivative (122 g '73%). 'According to the procedure as in Preparation Example 34.18, Step D, but using the product from the above step (1.2 g) to make the title (越, 9 g, 66%, 1:0.7 regioisomeric mixture) ). Preparation Example 10Ή

A solution of 5-bromobenzofuran (950 mg &apos; 4.82 mmol) in dry ether (12 mL) was cooled to -78. I.? μ third-BuLi solution (6 ml, 10 · 2 mmol) in pentane was added dropwise under argon. After the addition, the mixture was stirred at -78 °C for 20 minutes, followed by a mixture of DMF (〇 8 mL) and ether (m. The mixture was allowed to warm to room temperature and stirred for 5 hours. Add ethyl acetate. The mixture was poured into a saturated ammonium chloride solution. Separate the organic layer 86836 -185- 1330174, and / 钿 钿. The residue was purified by column chromatography (ethyl acetate-hexane, EtOAc: EtOAc: EtOAc) The procedure proposed in Example 2 was prepared by w〇〇2/〇83624 published on the 24th of the month, but using the commercially available (or prepared) aldehyde, amino alcohol and organolithium reagents in the following table, Optically pure amine product in the table. Preparation Example Aldehyde-based alcohol organolithium product 1. Yield (%) 2. (M+l) + Τϋ40 cT3 EtLi H2N^\^°\ 1. 24% 2. 267 86836 186· 1330174 1041 _/ H2NX~V0H EtLi 1. 94% 2. 176 (m/e) 1042 〇ηΛο Ph^— H2N/~ν0Η EtLi / h2n^\^s, Ph〆1. 67% 2. 229 ( M-16) 1043 u h2n/~noh i-PrLi H2N&quot;X^ 1. 60% 2. 151 [M-16] 1044 v CO_e)2 _/ H2N/&quot;\)H EtLi H2N^- CON(Me ) 2 1, 74% 2. 194 (M-16) 1045 _v H2^~V0H EtLi 1. 33% 2. 165 [M-NH2]+ 1046 _/ »2^/~V0H EtLi Η2νΛ^ 1. 31 2 179 [M-NH2]+ 1047 ~^OH t-BuLi ψ H2N/&quot;lVcl 1. 31% 2. 188 86836 -187- 1330174 1048 _/ H2N//~V0H t-BuLi ψ Η2νΛΧ&gt; 1. 10 % 2. 154 1 049 η\&gt;λ H2N broad 'OH EtLi &lt;- Η2Ν^&gt;λ 1. 73% 2. 137 [M-NH2]+ 1051 _/ H2N^~~V0H t-BuLi 4k 1. 17% 1054 _y Η2ΝΧ—V0H t-BuLi 1. 79% 2. 151 (M-16) Preparation Example 1100-1126 The procedure set forth in Example 34 was prepared in accordance with WO 02/083624, published on October 24, 2002, but is incorporated by reference. Commercially available acids and Grignard / organic reagents are obtained in the table below to obtain an amine product. Preparation Example Aldehyde Organometallic Reagent Product 1. Yield (%) 2. (M+l) + 1100 H, JSn t-BuLi Η2Ν^γ^| ^^NMe2 1. 83% 2. 190 (M-16) 86836 -188- 1330174 1101 hXco t-BuLi H2N^&gt; 1. 46% 2· 204 1102 〇OMe t-BuLi γ OMe 1. 48% 2. 194 1103 ηΛιΠ t-BuLi Η2Ν^γ^| OMe 1. 51% 2. 194 1104 Cl t-BuLi Cl 1. 12% 2. 238 1105 % OMe t-BuLi OMe 1. 39% 2. 234 1106 0 H, 0^〇Me t-BuLi Ψ M Η2Ν^ν||^^ |/〇ΜΘ 1. 44% 2. 194 (m/e) 86836 -189- 1330174

86836 - 190- 1330174 1112 〇c-pentyl-Li 9 h2n^\ o 1. 58% 2. 190 1113 h^Ct0CF3 t-BuLi 4 a0CF3 1. 20% 2. 248 1114 hVF3 t-BuLi 4 aCF3 1. 24% 2. 232 1115 hXC〇EtLi 1. 32% 2. 177 (M-NH2) 1116 hX€〇t-BuLi 1. 26% 2. 205 (M-NH2) 1117 I t-BuLi a. I 1. 50% 2. 190(M-NH2) -191 86836 1330174 1118 F t-BuLi h2n--(, F 1. 29% 2. 200 1119 Η^· Cl t-BuLi h2N^~ ^-Cl Cl 1. 28 % 2. 232 1120 \ t-BuLi y~ H2N-&lt; 0 \ 1. 76% 2. 224 1121 t-BuLi y~ H2N 八 1. 40% 2. 206 1122 t-BuLi &gt; η2ν-Λ 1. 38% 2. 236

86836 192- 1330174 1123 Ηλα t-BuLi c / 1. 70% 2. 192 1124 ηΛΧΧ&gt; t-BuLi 4 0 0 1. 81% 2. 204 1125 η&quot;Νο^βγ t-BuLi H2N^XyBr 33% 1126 Br t-BuLi Br 50% Preparation Example 1200-1203 The hydroxylaminothiophene product listed in the following table was obtained according to the procedure set forth in Preparation Example 13.29, but using commercially available amines.

86836 -193 -

The title compound (0.35 g) from Preparation Example 13·32 was treated with concentrated sulfuric acid (3 liters) for 6 s, then poured on ice, and adjusted to a value of .4 with 〇11. The title compound (159 mg, 64%, MH+ = 223) was obtained from EtOAc. Preparation Example 13〇1

S6836 -194-

The procedure set forth in Example 605 was prepared but the alcohol product (1.2 g, 84%, Μ-ΟΗ = 155) was obtained using commercially available radicals π, -θ'. The procedure set forth in Example 625 was prepared without the use of the above procedure <alcohol' to obtain the amine product (35 mg, 35%, M-NH2 = 155). Preparation example 1302

A similar procedure as used in the preparation of Example 13.29, Step B, except that commercially available arylsulfonyl sulfonium chloride (0.15 g) and diethylamine (2.2 equivalents) were used to obtain dimethylsulfonamide (0.12). Gram, 71%, MH+ = 323). The phenol (0.112 g, 98%) was obtained by a procedure similar to that used in the preparation of the procedure of Example 13.29. 86836 -195- 1330174 Step c Prepare the procedure used in Example 10.55, Step C, as described in WO 02/083624, published on October 24, 2002, using the product from Step B above (0.112 g). The title compound (0.1 g, 99%, MH+ = 245). Preparation example 1303

The title compound (0.070 g, 35%, MH+ = 257) was obtained from the title compound (0.070 g, 35%). Preparation Example 1304

The title compound (1.92 g, 72%, MH+ = 217) was obtained from EtOAc (m. . 86836 -196- Example 1305

Step c

Br

Step F

The product (5.96 g, 86%, MH+ = 210) was obtained according to the procedure used in the same procedure as in the preparation of the procedure of Example 1302, except using the indicated phenethylamine (4.99 g). Step B The compound from Step A above (5 - 0 g) was added to 3 g of PPA at 150 C, and the resulting mixture was stirred for 20 min, then poured on ice and extracted with dichloromethane. . The organic phase was dried with EtOAc (EtOAc) (EtOAc:EtOAc:EtOAc

Step C The procedure used in the preparation of Example 13.3, Step D, was carried out in accordance with WO 02/083624, published on October 24, 2002, except that the compound from Step B above (〇·14 g) was used to obtain the product (0.18). Gram, 87%, MH+ = 256).

Step D The procedure used in Step 11 of Example 11 was prepared in a similar manner as in WO 02/083624, published on October 24, 2002, except that the compound from Step C above (0.18 g) was used to give the product (0.17 g). .

Step E The procedure used in the procedure of Example 13.3, Step B, was prepared as in WO 02/083624, published on October 24, 2002, except that the compound from Step D above (0.17 g) was used to give the product (0.17 g, 95%, MH+ = 315).

Step F A nitrophenol (0.165 g, 99%, division += 303) was obtained in a procedure similar to that used in the procedure of Example 13.29.

Step G The title compound (0.128 g) was obtained according to the procedure used in the procedure of Example 10.55, Step C, as described in WO 02/083624, issued on October 24, 2002, using the product from Step F above (0.165 g). '86%, MH+=193). 86836 -198- 1330174 Preparation Example 1306

Step A

Step B

Step C

The procedure used in Example U Step B was prepared in a similar manner to WO 02/083624, published on October 24, 2002, except that the indoleamine (0.179 g) was used to give the title compound (0-25 g, 25%).

Phenol (0.045 g, 99%) was obtained according to a procedure similar to that used in the preparation of Example 13.29, Step C, using the product from step A above (5 g). Step C The procedure used in the procedure of Example 10.55, Step C, was carried out in the same manner as in WO 02/083624, published on January 24, 2002, except that the product from the above step b (0.045 g) was used to give the title compound. 〇 22 grams, 57%, MH+ = 179). Preparation f example 1307

86836 -199- 1330174 The procedure used in the preparation of Example 2, as described in WO 02/083624, published on October 24, 2002, using 3(R)-hydroxytetrahydropyrrole HC1 (1.36 g), gave the title compound (2.25 g, 89%). Preparation Example 1308

The title compound (3.79 g) was obtained according to the procedure used in the preparation of Example 2, as described in WO 02/083624, published on October 24, 2002, except for the use. Preparation example 1309

Step A Following a procedure similar to that used in the preparation of Example 13.29, Step B, but using commercially available nitrophenylsulfonium chloride and diethylamine (2.2 eq.), dimethylsulfonamide (90) was obtained. %, MH+=231).

Step B The title compound (45%, MH+ = 201) was obtained according to the procedure used in the procedure of Example 10.55, Step C, as described in WO 02/083624, issued on October 24, 2002. ). 86836 -200- 1330174 Preparation Example 1310

Step B

Ο I MeO

NH2 Ο

Step A Obtained benzamide (13) using a procedure similar to that used in the preparation of Example 13.29, Step B, except using the commercially available commercially available nitrobenzyl hydrazine and commercially available amines. %, MH+ = 253).

Step C The title compound (94%, MH+ = 223) was obtained using the procedure used in the procedure of Example 10.55, Step C, as described in WO 02/083624, issued on October 24, 2002. ). Preparation Example 1311

±MA was added to A1C13 (2.0 g) at room temperature in a solution of methoxy chlorophene sulfonate (1.5 g) in benzene (20 mL). After 15 minutes, the mixture was added to 0.1 NHC1 (aq.) and stirred, then extracted with Et20. The organic phase was washed with brine <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> .

Step B The title compound (3%, MH+ = 380) was obtained from the product from the procedure Preparation Example 1312

Br Br

Step A follows a procedure similar to that used in the preparation of Example 1311, Step A, except

Diphenyl hydrazine (880 mg, 80%) was obtained using commercially available sulfonium sulfonate. Step B The procedure used in Step 11 of Example 11 was prepared in a similar manner to that obtained from the procedure of Step 11 of </ RTI> </ RTI> <RTIgt; , 97%).

Step C The procedure used in Example 10.55, Step C, was prepared in accordance with W0 〇 2 / 〇 83624 as published on January 24, 2002, except that the product from step b above was used 86836 - 202 · 1330174 (0.16 g), the title compound was obtained (0.106 g '95%) ° Preparation Example 131_3

Step A A nitro acid (~13 mmol) was obtained following a procedure similar to that used in the preparation of Example 1311 Step A except using commercially available phenol (2 g).

Step B Toluene (3.5 ml) and two drops of DMF were added to the product from the above Step A (~13 mmol) dissolved in dichloromethane (1 mL). After stirring at room temperature overnight, the mixture was concentrated in vacuo and diluted with dichloromethane <lili] After adding 3 ml of THF in THF (2 mL, and stirring with TEA (83⁄4 L) for 3 hours, the mixture was concentrated in vacuo to give aq. The pH of the aqueous layer was adjusted to pH = 2 and extracted with methylene chloride. The combined organic extracts were dehydrated and dried with brine, concentrated in vacuo, and purified by chromatography. Methylene chloride / 2 ml / 譲86836 - 203 - 1330174 / 1 ml of AcOH) gave the title compound (800 mg, 27% over two steps).

Step C The title compound (0.46 g) was obtained according to the procedure used in the procedure of Example C. , 68%). Examples 2001-2088 The following cyclobutenes were obtained according to the procedure set forth in Example 210 of WO 02/083624, published on October 24, 2002, but using the cyclobutenedione intermediates and amines indicated in the table below. Diketone product. See WO 02/083624, published on October 24, 2002, for the preparation of Examples 19, 19.2, 22, 23.14 and 87.1.

86836 -204- 1330174 2004

NMe2 2005 19 with 1. 71%

86836 -205 - 1330174 2010 2011 2012 2013 2014 86836

19 with

H2N

CON(Me)2

〇=\ OH NMe2

Ov, 0

0=&lt; OH _e2

〇 1. 57% 2. 426 1. 6% 2. 469

H2n Ί9 with

19 and H2N

19 Xing

0=&lt; OH NMe2

1. 4% 2. 462

0=ϊΤ ΌΗ NMe2

1. 29% 2. 496

1. 17% 2. 492 -206- 1330174 2015

1. 65% 2. 466

F, C

Helium OH NMe2 2016 19 with

NMe2 1. 72% 2. 452 2017 19 with

1. 22% 2. 412 2018 19 and 1. 5%

86836 207- 1330174 2020 1008 with /0 a / / % 1. 49% 2. 436 2021 22 and H2N&quot;W 1 〇H OH (V ηνΛ^〇xy 1. 45% 2. 440 2022 19 with knowledge, 0 1 35% 2. 482 - 2024 1010 with · \ into f / 1. 16% 2. 414 2026 19 with 〇 \ ) at 0 ' is \ 1. 46% 2. 482

86836 208- 1330174 2027 1010 with f / HN^V〇xy 1. 13% 2. 418 2028 1012 with H2N&quot;xy 1 OH ό &quot;OH f / HN^V〇xy 1. 39% 2. 440 2029 19 With H2N&quot;W v.义n/ into f / HN^V〇 xy 1. 55% 2. 382 2030 19 and ^-* H A // 1. 39% 2. 378 2033 19 with H2NV, 0\ / 〇 OH, v. ' °x 1. 71% 2. 482 2034 1013 and ψ H2N^t&gt;- C&gt;&amp;] ^tr\y 1. 45% 2. 487.9 86836 -209- 1330174 2035 1014

H2N

2036 1015 and

H2N 2037 87.1 and

HN, / ~NH5 2038 2039 2040 1016 and

H2N

1017 and

H2N

19 with

1. 22% 2. 461.8 1. 27% 2. 405.9 1. 26% 2. 392.0 1, 28% 2. 433.8 1. 34% 2. 473.9 1. 34% 2. 525 86836 • 210- 1330174 2041 23.15E And 〆H2N^T^ 〇, V / S--&gt; % OH 〇 〇 / 1. 67% 2. 482 2042 1300 and 1027 \ [Η s fly V^〇 / 0 HO Λ Λ 1. 33% 2. 440 2043 1203 and 1027 / s-λ 〇Vf° 1. 24% 2. 468 2044 19 and ψ H2N&gt;X&gt;- 〇OH H 1. 26% 2. 466 2046 19.2 with ψ V&quot; 〇z- (kS-〇A 1. 27% 2. 535 2047 23.15F and 1.74% 2. 468 86836 -211 - 1330174

86836 -212- 1330174

2 %o 6 4 7 4

2055 19 with

H2N

O HO p , Ν IΗ

1. 87% 2. 454 2056

2056A 86836 23.15F and ψ η2ν

Cl 23.15F and

H2N

HO ψ 1. 52% 2. 516

'N

Cl

HO H 1. 62% 2. 482

'N

-213 1330174

86836 214- 1330174 2062 2063 2064 2065 2066

86836 215- 1330174 2067 2068 2069 2070

86836 216- 1330174 2071 2072 19 with

H2hT

2074 13.32A and 1028 2075 2076 19 with

86836 2Π- 1330174 2077 19 with

H2N

〇 2079 1021 and 2080 1021

H2N 2081 1029 and

2083 2084 86836 1020 and h2n

23.14 and H2N-

O F

-218- 1330174 2085 2086 2087 2088 23.14 with

H2N

Another embodiment of the invention is directed to any of the above compounds (e.g., compounds of formula IA, ffi 'ι, 3.0, 3.0A, and examples 360.109-360.117, 368.32, 45, Jane-mi, 1300_1311, and 2〇) The use of the last compound of 姻1, or a pharmaceutically acceptable salt thereof (e.g., calcium in the treatment of 痦奈奈Caisu) or a solvate for the manufacture of an acute inflammatory table. Another specific sound of the present invention is consistently directed to any of the above compounds (examples 86836 - 219 - 1330174 such as compounds of formula IB, IB, 1.0A, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200-1211, The use of the last compound of 1300-1311 and 2001-2088, or a pharmaceutically acceptable salt thereof (e.g., calcium or sodium) or solvate, for the manufacture of an acute inflammatory agent. Another embodiment of the invention is directed to any of the above compounds (e.g., compounds of formula IA, ffi, 1.00, 3.0A, and examples 360.109-360.117, 368.32-368.45, 1200-1211, 1300-1311, and 2001) A final compound of -2088, or a pharmaceutically acceptable salt thereof (e.g., calcium or sodium) or a solvate thereof, for use in the manufacture of a medicament for the treatment of rheumatoid arthritis. Another embodiment of the present invention is directed to the final compounds of Examples 2006, 2010, 2015, 2029, 2034, 2035, 2038, 2039, 2047, 2050, 2074, 2079 and 2087, or a pharmaceutically acceptable salt thereof (eg calcium or sodium) or a solvate. Other specific embodiments are directed to the manufacture of a medicament for the treatment of acute inflammation, or for the manufacture of a medicament for the treatment of chronic inflammation, or for the manufacture of a medicament for the treatment of rheumatoid arthritis, or for the manufacture of An agent for treating acute inflammatory pain, or for the manufacture of an agent for the treatment of chronic inflammatory pain, or for the manufacture of an agent for the treatment of acute neuropathic pain, or for the manufacture of a medicament for the treatment of chronic neuropathic pain, or Use for the manufacture of a medicament for the treatment of COPD. Although the present invention has been described in connection with the specific embodiments described above, many alternatives, modifications and variations will be apparent to those skilled in the art. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the invention. 86836 -220-

Claims (1)

1330174 Patent application No. 092120797 Chinese patent application scope replacement (May 99) Pick up, patent application scope: 1. A compound of the following formula · · Year of the M Correction. Supplement B (IB) and a pharmaceutically acceptable salt thereof, wherein the A is selected from the group consisting of: B is Wherein: R2 is -OH; R3 is -C(0)NRi 3 Ri 4 ; R is Η; R5 is Η; R6 is Η; = and is independently selected from the group consisting of Η and unsubstituted Ci4 groups; Rl2 It is selected from the group consisting of ruthenium and unsubstituted Cl. 6 alkyl groups: and each R&quot;.Ri4 is independently selected from the group consisting of * η and unsubstituted (10) groups 86836-9905l9.doc 1330174. (2) A compound according to claim 1 wherein R1 and R14 are each the same or different C.6 alkyl. 3. A compound according to item 2 of the patent application, wherein the ruler door and the base 4 are ruthenium. 4 ^ compounds selected from the group consisting of: 86836-990519.doc 1330174 86836-990519.doc 1330174 86836-990519.doc -4- 1330174 86836-990519.doc 1330174 86836-990519.doc 1330174 NMe2 86836-990519.doc 1330174 86836-990519.doc 1330174 86836-990519.doc ·9· 1330174 HjC’ 86836-990519.doc -10- 1330174 86836-990519.doc -11 - 1330174 5. A compound according to item 4 of the scope of the patent application, which is selected from And 6. a compound according to item 4 of the scope of the patent application, which is selected from the following combinations Group of objects: 86836-990519.doc -12- 1330174 86836-990519.doc 13 1330174 86836-990519.doc •14- 1330174 Ο OH Η Η Μβ0 Η Η ff V Bamboo Λχ 86836-990519.doc -15- 1330174 86836-990519.doc •16- 1330174 〇Me, 86836-990519.doc •17· 1330174 86836-990519.doc -18- 1330174 86836-990519.doc •19- 1330174 86836-990519.doc -20- 1330174 0, Ο 86836-990519.doc -21 - 1330174 The compound according to any one of claims 1 to 6, wherein the compound is a calcium or sodium salt. And a pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 6 and a pharmaceutically acceptable agent. 9. The pharmaceutical composition according to item 8 of the patent application, comprising an effective amount of at least one calcium salt or sodium salt of the compound according to any one of claims 1 to 6 and pharmaceutically acceptable Carrier. 10. A compound selected from the group consisting of: 86836-990519.doc • 22- 1330174 11. A compound according to claim 10, wherein the compound is calcium or sodium 86836-990519.doc -23- 330174 salt 12.-therapeutic pharmaceutical composition, bean jelly winter death ^, ,, package 3 effective amount At least one of the compounds according to paragraphs 10 to 11 of the patent application, and the compound of the type I, which is acceptable for the type I, and the patent range of the first to sixth items of the MU, at least - Use of a compound for the manufacture of a medicament for treating a disease mediated by a chemokine, wherein the chemokine binds to a cxc receptor in a patient, and the disease mediated by the factor is selected from the group consisting of Group: chronic am 13⁄4 inflammatory pain, acute neuropathic pain 'chronic neuropathogenic pain, psoriasis, atopic dermatitis, asthma: sexual obstructive pulmonary disease (COPD), adult respiratory disease, arthritis, inflammatory Enteric disease, Crohn's disease, ulcerative colitis, septic shock, endotoxin shock, sputum negative septicemia, toxic shock syndrome, stroke, heart fish kidney reperfusion injury, spheroid nephritis, recording formation, Ziziheimer ^Systology transplantation for 7 main responses, allograft rejection, malaria, acute dyspnea> symptomatic town, delayed allergic reaction, atherosclerosis, brain and cardiac stenosis, osteoarthritis, multiple sclerosis, restenosis, Angiogenesis, osteoporosis, gingivitis, respiratory virus, cancer virus, hepatitis virus, Cong, Kaposi's sarcoma associated with the virus, meningitis, gallbladder fibrosis, premature delivery, cough, scrapie, more Organ dysfunction, trauma, labor injury, sprain, contusion 'psoriasis arthritis, cancer treatment, encephalitis, (10) vasculitis, traumatic brain injury, CNS tumor, insect subarachnoid hemorrhage, post-operative trauma, tissue Interstitial pneumonia, allergic, crystal-induced arthritis, acute and chronic pancreatitis, acute alcoholism, hepatitis, necrotizing enterocolitis, slow: 86836-990519.doc -24- 丄330174 sinus k blood e' to produce eye diseases Inflammation of the eyes, retinopathy of premature labor, retinopathy of diabetic patients, speckle degeneration with better moist and corneal neovascularization, polymyositis, vasculitis, Sore 'stomach and duodenal ulcer, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, branch tracheal dilation, twig bronchitis, occlusive twig bronchitis, chronic colitis, pulmonary heart disease , cough, difficulty breathing, emphysema, hypercapnia, hyperventilation, hypoxemia, inflammation caused by excessive oxygen, hypoxia, reduced lung volume, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, and Continuous metastatic peritoneal dialysis (CAPD) associated with peritonitis, granulocyte Ehrlich disease, sarcoidosis, small airway disease, ventilatory perfusion disorders, wheezing, cold, gout, alcoholic liver disease, lupus, burns , periodontitis, graft reperfusion injury and early graft rejection, acute inflammation and rheumatoid arthritis. 14. The use according to claim 13 wherein the chemokine binds to the CXCR2 and /4CXCR1 receptors in a patient. 15. According to the use of item 丨3 of the scope of the patent application, the phylogenetic factor is selected from the group consisting of: tooth brewing, respiratory virus, sore disease, liver disease, f, mV, and virus Associated with Kaposi's sarcoma and atheroma hardening. 1M refers to the use of the scope of the patent scope, wherein the disease mediated by the chemokine is an angiogenic ocular disease. The use according to claim 16 wherein the angiogenic ocular disease is selected from the group consisting of inflammation of the eye, retinopathy of prematurity, retinopathy of diabetic patients, speckle degeneration and corneal neovascularization 86836 -990519, doc -25· "1330174. 18. Use according to item 7 of the scope of the patent application Wet-type speckle degeneration. 19. According to the application of the third paragraph of the patent application, 祀3 祀固弟13, the disease is acute inflammatory pain. 20. According to the use of item 13 of the scope of patent application, the disease is chronic inflammatory pain. Wherein the spot is denatured as a medium for the carrier of the tidal medium. 21. According to the material of claim 13 of the patent application, the disease mediated by the chemokine is acute neuropathogenic pain. 22. According to the use of item 13 of the scope of the patent application, the disease mediated by the chemokine is chronic neuropathic pain. 23. According to the use of item 13 of the scope of the patent application, the disease mediated by the chemokine is chronic obstructive pulmonary disease. 24. Use of at least one compound according to any one of claims 1 to 6, ι and 丨丨 in the manufacture of a medicament for the treatment of cancer. 25_ Use according to the scope of claim 24, wherein the cancer treated is melanoma, gastric cancer or non-small cell lung cancer. 26. The use according to claim 24, wherein the treatment comprises administering the medicament and administering the at least one anticancer agent. 27. The use of the cancer according to claim 26, wherein the cancer treated is melanoma, lunar cancer or non-small cell lung cancer. 28. The use according to claim 26, wherein the anticancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural products and derivatives thereof, hormones, anti-hormones, anti-vascular agents Builders and steroids and compositions 86836-990519.doc •26- 1330174 I &quot;I / 口 29. For melanoma, gastric cancer or non-small cell lung cancer according to the use of Article 28 of the scope of the patent application. 30. The use of at least one compound according to any one of claims 1 to 6, 1 and 1 in the manufacture of a medicament for inhibiting angiogenesis according to the scope of claim 3, wherein The inhibition of the agent, and the combined administration of at least one type of anti-caries production / including 86863-990519.doc 27-