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1. (WO2011025927) COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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WE CLAIM:

1. A compound of Formula Ia:


in which:

Y is selected from N and CR6;

R2 R3, R5 and R6 are independently selected from hydrogen, halo, cyano, C1. 4alkyl, halo-substituted-Ci-4alkyl, Ci_4alkoxy and halo-substituted-Ci-4alkoxy; with the proviso that when R5 is fluoro and R1 is selected from hydrogen, -X1Rg1, -X1OX2RSa, -X!C(O)NR8aR8b, -X1NRSaX2RSb, -X1NRSaC(O)X2ORSb and -X1NRSaS(O)0-2RSb, R3 and R6 are not both hydrogen;

R4 is selected from -R9 and -NR1OR11; wherein R9 is selected from Ci-βalkyl, C3-scycloalkyl, Cs-sheterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R9 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, Ci_4alkyl, halo-substituted-C^alkyl, Ci_4alkoxy and halo-substituted-Ci^alkoxy; and R10 and R11 are independently selected from hydrogen and R9;

R7 is selected from hydrogen, Ci_4alkyl, C3_5cycloalkyl and C^sheterocycloalkyl; wherein said alkyl, cycloalkyl or heterocycloalkyl of R7 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, hydroxyl, Ci_4alkyl, halo-substituted-Cμ 4alkyl, Ci_4alkoxy and halo-substituted-Ci-4alkoxy; or the tautomers, prodrugs, stereoisomers or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 in which R4 is -R9; wherein R9 is selected from C1. 3alkyl and C3-scycloalkyl; wherein said alkyl or cycloalkyl of R9 is optionally substituted with 1 to 3 radicals independently selected from halo and halo-substituted-Ci^alkyl.

3. The compound of claim 2 in which: R2 is selected from hydrogen and fluoro; R3 is selected from chloro, fluoro and methyl; R5 is selected from hydrogen, chloro and fluoro; Y is selected from N and CR6; and R6 is selected from hydrogen and fluoro.

4. The compound of claim 3 selected from: methyl N-[(2S)-l-({4-[3-(3-chloro-5-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-[(4-{3-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-l-(propan-2-yl)-lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2-fluoro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-[(4-{ 3-[3-chloro-5-(propane- l-sulfonamido)phenyl]- l-(propan-2-yl)- lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2,6-difluoro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-[(4-{3-[2,6-difluoro-3-(propane-l-sulfonamido)phenyl]-l-(propan-2-yl)-lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate; methyl N-[(2S)-l-{ [4-(3-{2-fluoro-3-[(3,3,3-trifluoropropane)sulfonamido]phenyl}-l-(propan-2-yl)-lH-pyrazol-4-yl)pyrimidin-2-yl]amino}propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(3-chloro-2-methanesulfonamidopyridin-4-yl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(3-fluoro-2-methanesulfonamidopyridin-4-yl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2-chloro-3-ethanesulfonamido-4,5-difluorophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2,4-difluoro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[l-(propan-2-yl)-3-(2,4,5-trifluoro-3-methanesulfonamidophenyl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(3-ethanesulfonamido-2,4-difluorophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-2-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-l- (propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl]carbamate; methyl N-[(2S)-1- ({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-l-(oxan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-[(4-{3-[2,4-difluoro-3- (propane-l-sulfonamido)phenyl]-l-(propan-2-yl)-lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(3-cyclopropanesulfonamido-2,5-difluorophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(5-chloro-3-cyclopropanesulfonamido-2-fluorophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; and methyl N-[(2S)-l-[(4-{3-[5-chloro-2-fluoro-3-(propane-l-sulfonamido)phenyl]-l-(propan-2-yl)-lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate.

5. The compound of claim 1 of Formula Ib:


Ib

in which:

R3 is selected from chloro, fluoro and methyl;

R5 is selected from fluoro and chloro; and

R7 is selected from ethyl and isopropyl.

6. The compound of claim 5 selected from: methyl N-[(2S)-l-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)- 1 -(propan-2-yl)- lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2,5-difluoro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(5-chloro-2-fluoro-3-

methanesulfonamidophenyl)-l-ethyl-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2-fluoro-3-methanesulfonamido-5-methylphenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2-chloro-3-methanesulfonamido-5-methylphenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2-chloro-5-fluoro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl] carbamate; methyl N-[(2R)-l-({4-[3-(5-chloro-2-fruoro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2,5-dichloro-3-methanesulfonamidophenyl)-l-(propan-2-yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; and methyl N-[(2S)-l-({4-[3-(5-chloro-2-fruoro-3-methanesulfonamidophenyl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate.

7. A compound selected from: N-[5-chloro-3-(4-{2-[(2-cyanoethyl)amino]pyrimidin-4-yl}-l-(propan-2-yl)-lH-pyrazol-3-yl)-2-fluorophenyl]methanesulfonamide; N-{5-chloro-3-[4-(2-{ [2-(dimethylamino)ethyl]amino}pyrimidin-4-yl)-l-(propan-2-yl)-lH-pyrazol-3-yl]-2-fluorophenyljmethanesulfonamide; N-(5-chloro-2-fluoro-3-{4-[2-(methylamino)pyrimidin-4-yl]-l-(propan-2-yl)-lH-pyrazol-3-yl}phenyl)methanesulfonamide; and N-{3-[4-(2-aminopyrimidin-4-yl)-l-(propan-2-yl)-lH-pyrazol-3-yl]-5-chloro-2-fluorophenyljmethanesulfonamide.

8. A compound selected from: 3-Bromo-5-chloro-2-fluoroaniline; cyano-(2-methylthio-pyrimidin-4-yl)-acetic acid tert-butyl ester; l-Isopropyl-4-(2-(methylthio)pyrimidin-4-yl)- lH-pyrazol-3-amine; 2-((2-Benzylidene- 1-ethylhydrazinyl)methylene)-malononitrile; l-(3-Amino-l-isopropyl-lH-pyrazol-4-yl)ethanone; l-(3-Iodo-l-isopropyl-lH-pyrazol-4-yl)ethanone; l-(3-Iodo-l-ethyl-lH-pyrazol-4-yl)ethanone; l-(3-Iodo-l-methyl-lH-pyrazol-4-yl)ethanone; 3-(Dimethylamino)-l-(3-iodo-l-isopropyl-lH-pyrazol-4-yl)prop-2-en-l-one; 3-(Dimethylamino)-l-(3-iodo-l-ethyl- lH-pyrazol-4-yl)prop-2-en- 1 -one; 3-(Dimethylamino)- l-(3-iodo- 1 -methyl- lH-p yrazol-4-yl)prop-2-en-l-one; 4-(3-Iodo-l-isopropyl-lH-pyrazol-4-yl)pyrimidin-2-amine; 4-(3-Iodo-1 -ethyl- lH-pyrazol-4-yl)pyrimidin-2-amine; 4-(3-Iodo- 1-methyl- lH-pyrazol-4-yl)pyrimidin- 2-amine; 4-(3-Iodo-l-isopropyl-lH-pyrazol-4-yl)pyrimidin-2-ol; 2-Chloro-4-(3-iodo-l-isopropyl-lH-pyrazol-4-yl)pyrimidine; (S)-Methyl l-(4-(3-iodo-l-isopropyl-lH-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; (R)-Methyl 1 -(4- (3 -iodo- 1-isopropyl- IH-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; (S)-tert-butyl l-(4-(3-iodo-l-isopropyl- lH-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; 3-(4-(3-iodo- 1-isopropyl- lH-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile; 4-(3-iodo- 1-isopropyl- IH-pyrazol-4-yl)-N-methylpyrimidin-2-amine; N1-(4-(3-iodo- 1-isopropyl- lH-pyrazol-4-yl)pyrimidin-2-yl)-N2,N2-dimethylethane- 1 ,2-diamine; N-(3-bromo-2,4-difluorophenyl)propane- 1- sulfonamide; 3-Fluoro-4-iodopyridin-2-amine; 3-chloro-4-iodopyridin-2- amine; 3-Bromo-2,5,6-trifluoroaniline; 2,4-Dibromo-3,6-dichloroaniline; 3-bromo-2-chloro-5-methylaniline; 3-bromo-2,5-difluoroaniline; 3-Bromo-5-chloro-2-fluorobenzoic acid; Tert-butyl 3-bromo-5-chloro-2-fluorophenylcarbamate; tert-butyl 3-bromo-2-fluoro-5-methylphenylcarbamate; Tert-butyl 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenylcarbamate; tert-butyl 2,6-difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenylcarbamate; N-(2,4-difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propane-l-sulfonamide; 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane; 2,5-difluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline; 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)aniline; 2,5-dichloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline; 2-chloro-5-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline; tert-butyl 2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenylcarbamate; 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine; 2,3,6-trifluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline; 3-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-amine; 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline; and 3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline.

9. A pharmaceutical composition comprising a compound of any one of claims 1-7, admixed with at least one pharmaceutically acceptable excipient.

10. The pharmaceutical composition of claim 9, wherein the excipient is selected from the group consisting of corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, silica, and combinations thereof.

11. The pharmaceutical composition of claim 9, further comprising an additional therapeutic agent.

12. The pharmaceutical composition of claim 11, wherein the additional therapeutic agent is selected from an anticancer compound, an analgesic, an antiemetic, an

antidepressant, and an anti-inflammatory agent.

13. A compound according to any one of claims 1-7 for the treatment of cancer.

14. The compound according to claim 13, wherein the cancer to be treated is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, adenomas and carcinomas of the ovary, eye, liver, biliary tract, and nervous system.

15. A method to treat cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any of claims 1-7 or a pharmaceutical composition of any one of claims 9-12.

16. The method of claim 15, wherein the cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma,

myeloid disorders, prostate cancer, thyroid cancer, melanoma, adenomas and carcinomas of the ovary, eye, liver, biliary tract, and nervous system.

17. The method of claim 15 or 16, further comprising administering to the subject an additional therapeutic agent.

18. The method of claim 17, wherein the additional therapeutic agent comprises an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent.

19. The method of claim 18, wherein the additional therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, mTOR, HSP90, AKT, PDK, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK.

20. The method of claim 19, wherein the MEK inhibitor is selected fro: AS703026; MSC1936369B; GSKl 120212; AZD6244; PD-0325901; ARRY-438162; RDEAl 19;

GDC0941; GDC0973; TAK-733; RO5126766; and XL-518.

21. The method of claim 20, wherein the additional therapeutic agent is administered to the subject concurrently with the compound.

22. A method to treat a condition mediated by Raf kinase, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-7, or a pharmaceutical composition according to any one of claims 9-12.

23. The method of claim 22 wherein the Raf kinase is a mutant b-Raf kinase.

24. The method of claim 23, wherein the mutant b-Raf kinase is b-Raf(V600E).