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1. (IL218084) COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
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218084/3

We Claim:

1. A compound of Formula la:


in which:

Y is selected from N and CR6;

R2, R3, R5 and 5 are independently selected from hydrogen, halo, cyano, Ci^alkyl, halo-substituted-Ci^alkyl, C1.4alko.xy and halo-substituted-Ci.4alkoxy; with the proviso that when R5 is fluoro, R3 and R6 are not both hydrogen;

R4 is selected from -R9 and -NR10R11; wherein R9 is selected from C1-6alkyl, C3- 8cycloalkyl, C3-8heterocyclo alkyl, 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, h a I o - s u b s t i t u t e d - C| _ 4 a I k y I . Ci^alkoxy and h a I o - s u b s t i t u t e d - C 1.4 a I k o x y ; and Rio and Rn are independently selected from hydrogen and R9;

R7 is selected from hydrogen, C alkyl. C3-scycloalkyl and C3-sheterocycloalkyl; wherein said alkyl, cycloalkyl or heterocycloalkyl of R7 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, hydroxyl, CMalkyl, halo-substituted-Ci_4alkyl, Ci^alkoxy 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 Ci-3alkyl and C3- 8cycloalkyl; wherein said alkyl or cycloalkyl of R9 is optionally substituted with 1 to 3 radicals independently selected from halo and h a I o - s u b s t i t u t e d - C 1.4 a I k y I .

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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 1 selected from:

methyl N- [(2 S)- 1 -({4-[3 -(3 -chloro-5 -methanesulfonamidophenyl)- 1 -(propan-2-yl)- 1 H- pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate;

methyl N-[(2S)-l-[(4-{3-[3 -chloro-5 -(propane- 1 -sulfonamido)phenyl] - 1 -(propan-2-yl)- lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate;

methyl N- [(2 S)- 1 -({4-[3 -(3 -chloro-2-methanesulfonamidopyridin-4-yl)- 1 -(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)- 1 H-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- [(2 S)- 1 -({4-[3 -(3 -ethanesulfonamido-2,4-difluorophenyl)- 1 -(propan-2-yl)- 1 H- 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- [(2 S)- 1 -({4-[3 -(5 -chloro-2-fluoro-3-methanesulfonamidophenyl)- 1 -(oxan-2- yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate;

methyl N-[(2S)- 1 -[(4- (3-[2,4-difluoro-3-(propane-l-sulfonamido)phenyl]-l -(propan-2-

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yl)-lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate;

methyl N- [(2 S)- 1 -({4-[3 -(3 -cyclopropanesulfonamido-2,5-difluorophenyl)- 1 -(propan-2- yl)-lH-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate;

methyl N- [(2 S)- 1 -({4-[3 -(5 -chloro-3 -cyclopropanesulfonamido-2-fluorophenyl)- 1 - (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)-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- 1 -sulfonamido)phenyl] - 1 - (propan-2-yl)-lH-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate.

5. The compound of claim 1 of Formula lb:


lb

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)-l -(propan-2- yl)-lIT-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)- lIT-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate;

methyl N-[(2S)-l-({4-[3 -(5-chloro-2-fluoro-3 -methanesulfonamidophenyl)- 1 -ethyl- 1 IT- 218084/3

pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate;

methyl N-[(2S)-l-({4-[3-(2-fluoro-3-methanesulfbnamido-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)- 1 -(propan - 2-yl)- 1 H-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-fluoro-3-methanesulfonamidophenyl)-l-(propan-2- yl)- 1 H-pyrazol-4-yl]pyrimidin-2-yl} amino)propan-2-yl] carbamate; and

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.

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)- 1 H-pyrazol-3 -yl] -2-fluorophenyl } methanesulfonamide;

N-(5-chloro-2-fluoro-3-{4-[2-(methylamino)pyrimidin-4-yl]-l-(propan-2-yl)-lH-pyrazol- 3-yl}phenyl)methanesulfonamide;

N- (3 -[4-(2-aminopyrimidin-4-yl)- 1 -(propan-2-yl)- 1 H-pyrazol-3 -yl] -5-chloro-2- fluorophenyl}methanesulfonamide;

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)- 1 -(propan-2-yl)- 1 H-pyrazol-4-yl]pyrimidin-2- yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-l-({4-[3-(2,6-difluoro-3- methanesulfonamidophenyl)- 1 -(propan-2-yl)- 1 H-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- yljcarbamate; and

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.

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

9. The pharmaceutical composition of claim 8, 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.

10. The pharmaceutical composition of claim 8, further comprising an additional therapeutic agent.

11. The pharmaceutical composition of claim 10, wherein the additional therapeutic agent is selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent.

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

13. The compound according to claim 12, 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.

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14. Use of an effective amount of a compound of any one of claims 1-7 in the preparation of a medicament for treating cancer.

15. Use of a pharmaceutical composition of any one of claims 8-11 in the preparation of a medicament for treating cancer.

16. The use of claim 14 or 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 use of any one of claims 14 to 16, wherein the medicament further comprises an additional therapeutic agent.

18. The use 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 use of claim 18, wherein the additional therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, mTOR, HSP90, AKT, PI3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK.

20. The use of claim 19, wherein the MEK inhibitor is selected fro: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; R05126766; and XL-518.

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

22. A compound according to any one of claims 1-7 for use in treating a condition mediated by Raf kinase, wherein the condition is selected from the group consisting of lung carcinoma,