PYRAZOLE COMPOUNDS

• US 20090221608A1
• Filed: 07/30/2008
• Published: 09/03/2009
• Est. Priority Date: 08/01/2007
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Johnson, Mary Catherine, Guo, Chuangxing, McAlpine, Indrawan James, Kephart, Susan Elizabeth, Cui, Jingrong Jean, Kania, Robert Steven, Pairish, Mason Alan, Gu, Danlin, Palmer, Cynthia Louise, Linton, Maria Angelica, Deal, Judith Gail
• Granted Patent: US 7,772,246 B2
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention is directed to compounds of Formula (I),

and to pharmaceutically acceptable salts thereof, their synthesis, and their use as Raf inhibitors.

Claims

1. ) A compound of Formula (II)

2. ) The compound according to claim 1, wherein X is N, or a pharmaceutically acceptable salt thereof.

3. ) The compound according to claim 1, wherein X is CR⁷, or a pharmaceutically acceptable salt thereof.

4. ) The compound according to claim 2, wherein R⁴ is H, or a pharmaceutically acceptable salt thereof.

5. ) The compound according to claim 2, wherein R⁵ is H, or a pharmaceutically acceptable salt thereof.

6. ) The compound according to claim 2, wherein R⁶ is H, or a pharmaceutically acceptable salt thereof.

7. ) The compound according to claim 2, wherein R⁴, R⁵, and R⁶ are H, or a pharmaceutically acceptable salt thereof.

8. ) The compound according to claim 7, wherein R¹ is C₁-C₆ alkyl optionally substituted with one or more R⁸, or a pharmaceutically acceptable salt thereof.

9. ) The compound according to claim 7, wherein R¹ is selected from methyl, ethyl, isopropyl, cyclopropyl, 2,2-difluoroethyl, cyanomethyl, difluorocyclobutanyl, (3-methyloxetan-3-yl)methyl, 1,1-dimethyl-2-hydroxyethyl, 1-methyl-1-cyanoethyl, difluoromethyl, tert-butyl, 3-hydroxypropan-2-yl, piperidinyl, N-acetyl-piperidinyl, H, tetrahydro-2H-pyranyl, tetrahydrofuranyl, 4-cyanophenyl, cis-fluorocyclobutanyl, trans-fluorocyclobutanyl, oxetanyl, and N-methyl-piperidinyl, or a pharmaceutically acceptable salt thereof.

10. ) The compound according to claim 9, wherein R¹ is selected from methyl, isopropyl, (3-methyloxetan-3-yl)methyl, 2,2-difluoroethyl, and cyanomethyl, or a pharmaceutically acceptable salt thereof.

11. ) The compound according to claim 7, wherein R² is selected from the group consisting of

12. ) The compound according to claim 7, wherein R³ is —

NR⁹R¹⁰.

13. ) The compound according to claim 12, wherein R³ is NH₂, H,

14. ) The compound according to claim 1, wherein the compound is selected from the group consisting of (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, 4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]-N-[2-(1H-pyrazol-1-yl)ethyl]pyrimidin-2-amine, (2S)-1-(4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, N-(2-fluoroethyl)-4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, 2-({4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)ethanol, 4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]-N-[2-(1H-pyrazol-4-yl)ethyl]pyrimidin-2-amine, (2S)-1-(4-(3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, [4-[2-((S)-2-Hydroxy-propylamino)-pyrimidin-4-yl]-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-pyrazol-1-yl]-acetonitrile, 1-[2-({4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)ethyl]pyridin-2(1H)-one, (2R)-2-({4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-1-ol, N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, N-[(2,5-dimethyl-1,3-oxazol-4-yl)methyl]-4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]-N-(tetrahydrofuran-3-ylmethyl)pyrimidin-2-amine, 4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)-N-(pyridin-2-ylmethyl)pyrimidin-2-amine, (2S)-1-(4-(1-isopropyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, 4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]-N-(2-methoxyethyl)pyrimidin-2-amine, 1-ethyl-4-[({4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)methyl]pyrrolidin-2-one, (2S)-1-(4-(1-isopropyl-3-(5-methyl-6-(methylamino)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-isopropyl-3-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-isopropyl-3-(5-methyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-isopropyl-3-(2-methylimidazo[1,2-a]pyrimidin-6-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-isopropyl-3-(6-(methylamino)pyridin-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(2,3-dimethylimidazo[1,2-a]pyrimidin-6-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-((3-methyloxetan-3-yl)methyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, 5-(4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1-isopropyl-1H-pyrazol-3-yl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one, (2S)-1-(4-(3-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol and (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, or a pharmaceutically acceptable salt thereof.

15. ) The compound according to claim 1, wherein the compound is selected from the group consisting of (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol and (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol;

or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S)-1-(4-(3-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, or a pharmaceutically acceptable salt thereof.

16. ) The compound according to claim 1, wherein the compound is selected from 4-[3-(6-amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl]-N-cyclopropylpyrimidin-2-amine, (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[3-(6-amino-5-methylpyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 3-({4-[3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[1-(2,2-difluoroethyl)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-hydroxy-1,1-dimethylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-hydroxy-1,1-dimethylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, N-{5-[4-{2-[(2-cyanoethyl)amino]pyrimidin-4-yl}-1-(2,2-difluoroethyl)-1H-pyrazol-3-yl]-4-methylpyridin-2-yl}acetamide, N-[1-(cyclopropyl-sulfonyl)piperidin-4-yl]-4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 3-({4-[1-(2,2-difluoroethyl)-3-(6-methylpyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, (2S)-1-({4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-tert-butyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 2-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1H-pyrazol-1-yl]-2-methylpropanenitrile, (2S)-1-({4-[1-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 3-({4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, and 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, or a pharmaceutically acceptable salt thereof.

17. ) The compound according to claim 1, wherein the compound is selected from 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, (2S)-1-[(4-{3-[6-amino-5-(difluoromethoxy)-pyridin-3-yl]-1-isopropyl-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-ol, 4-[1-(difluoromethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, (2S)-1-({4-[3-(6-amino-5-methoxypyridin-3-yl)-1-(difluoromethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[3-(2-aminopyrimidin-5-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(difluoromethyl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 3-({4-[1-(difluoromethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)-propanenitrile, 2-amino-5-[4-(2-{[(2S)-2-hydroxypropyl]-amino}pyrimidin-4-yl)-1-isopropyl-1H-pyrazol-3-yl]pyridin-3-ol, 3-({4-[1-(2,2-difluoroethyl)-3-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(6-amino-5-methylpyridin-3-yl)-1-(2-hydroxy-1,1-dimethylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)-propanenitrile, 2-[4-{2-[(2,2-difluoroethyl)amino]pyrimidin-4-yl}-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl]-2-methylpropan-1-ol, 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)-propanenitrile, 3-({4-[1-isopropyl-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(5-acetyl-6-aminopyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-{[4-(1-isopropyl-3-pyridin-3-yl-1H-pyrazol-4-yl)pyrimidin-2-yl]amino}-propanenitrile, 4-[3-(6-amino-5-methoxypyridin-3-yl)-1-tert-butyl-1H-pyrazol-4-yl]-N-(2,2-difluoroethyl)pyrimidin-2-amine, (2R)-2-[4-(2-aminopyrimidin-4-yl)-3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl]propan-1-ol, 4-[3-(6-amino-5-methoxypyridin-3-yl)-1-cyclopropyl-1H-pyrazol-4-yl]pyrimidin-2-amine, 3-({4-[3-(6-amino-5-methoxypyridin-3-yl)-1-cyclopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)-propanenitrile, 2-[4-(2-aminopyrimidin-4-yl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl]-2-methylpropan-1-ol, 4-[3-(6-amino-5-methoxypyridin-3-yl)-1-cyclopropyl-1H-pyrazol-4-yl]-N-(2,2-difluoroethyl)pyrimidin-2-amine, and 4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof.

18. ) The compound according to claim 1, wherein the compound is selected from (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-ethyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 4-[1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-piperidin-4-yl-1H-pyrazol-4-yl]pyrimidin-2-amine, 3-chloro-5-(1-piperidin-4-yl-4-pyrimidin-4-yl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 4-[1-tert-butyl-3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, (2S)-1-({4-[1-tert-butyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 4-[1-(1-acetylpiperidin-4-yl)-3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]-N-(2,2-difluoroethyl)-pyrimidin-2-amine, 4-[3-(6-amino-5-methoxypyridin-3-yl)-1H-pyrazol-4-yl]-N-(2,2-difluoroethyl)-pyrimidin-2-amine, 3-({4-[3-(6-amino-5-methoxypyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 4-[3-(6-amino-5-methoxypyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]-N-(2,2-difluoroethyl)-pyrimidin-2-amine, 3-({4-[1-tert-butyl-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[1-tert-butyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-[(4-{3-(5-methoxypyridin-3-yl)-1-[(3R)-tetrahydrofuran-3-yl]-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propanenitrile, 3-({4-[1-tert-butyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)-propanenitrile, 3-[(4-{3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(3R)-tetrahydrofuran-3-yl]-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propanenitrile, (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-piperidin-4-yl-1H-pyrazol-4-yl]-N-(2,2-difluoroethyl)pyrimidin-2-amine, 3-(4-(3-(5-acetyl-6-aminopyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-propanenitrile, 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 4-[3-(6-amino-5-methoxypyridin-3-yl)-4-{2-[(2-hydroxyethyl)-amino]pyrimidin-4-yl}-1H-pyrazol-1-yl]-benzonitrile, 4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]-N-(6-methoxypyridin-3-yl)pyrimidin-2-amine, 3-(4-(3-(6-amino-5-methoxypyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile, 3-(4-(3-(6-amino-5-methoxypyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-propanenitrile, (S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-((1s,3s)-3-fluorocyclobutyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (S)-1-(4-(3-(6-amino-5-methoxypyridin-3-yl)-1-((1r,3r)-3-fluorocyclobutyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-((1r,3r)-3-fluorocyclobutyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, (2S)-1-(4-(1-(2,2-difluoroethyl)-3-(3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, 3-(4-(1-(2,2-difluoroethyl)-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile, and 1-(4-(1-(2,2-difluoroethyl)-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-2-methylpropan-2-ol, or a pharmaceutically acceptable salt thereof.

19. ) The compound according to claim 1, wherein the compound is selected from N-(2,2-difluoroethyl)-4-(1-(2,2-difluoroethyl)-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-amine, 3-(4-(1-(2,2-difluoroethyl)-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile, (S)-1-(4-(1-(2,2-difluoroethyl)-3-((R)-3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, 3-(4-(1-(2,2-difluoroethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile, 3-(4-(1-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile, 3-(4-(1-(2,2-difluoroethyl)-3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)-pyrimidin-2-ylamino)propanenitrile, (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[3-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-[(4-{3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(3-methyloxetan-3-yl)methyl]-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-ol, (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-oxetan-3-yl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[1-(2,2-difluoroethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[1-(2,2-difluoroethyl)-3-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[1-(2,2-difluoroethyl)-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 5-[1-(2,2-difluoroethyl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile, (2S)-1-({4-[3-(6-amino-5-methoxypyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, 2-({4-[1-(2,2-difluoroethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)ethanol, 2-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)ethanol, 4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 4-[1-(2,2-difluoroethyl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3-methoxypropyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[3-(6-amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, N-(2,2-difluoroethyl)-4-[1-(1-methylpiperidin-4-yl)-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-N-(2,2-difluoroethyl)pyrimidin-2-amine, 4-[3-(6-amino-5-methoxypyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 3-(4-(1-(2,2-difluoroethyl)-3-(1-cyanoethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propanenitrile, 3-({4-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-hydroxy-1,1-dimethylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)-propanenitrile, 2-[4-(2-amino-pyrimidin-4-yl)-3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl]-2-methylpropan-1-ol, 3-chloro-5-(1-isopropyl-4-pyrimidin-4-yl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-[1-(1-methylpiperidin-4-yl)-4-pyrimidin-4-yl-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine, 5-(1-tert-butyl-4-pyrimidin-4-yl-1H-pyrazol-3-yl)-3-methoxypyridin-2-amine, (2S)-1-(4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol, 3-({4-[3-(6-amino-5-methoxypyridin-3-yl)-1-methyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, N-(2,2-difluoroethyl)-4-[1-(2,2-difluoroethyl)-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, 4-[1-(2,2-difluoroethyl)-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl]-N-(tetrahydrofuran-3-yl)pyrimidin-2-amine, 2-[3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-{2-[(2-hydroxyethyl)amino]pyrimidin-4-yl}-1H-pyrazol-1-yl]-2-methylpropanenitrile, 2-[4-(2-aminopyrimidin-4-yl)-3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl]-2-methylpropanenitrile, 3-(4-(3-(6-amino-5-methylpyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-propanenitrile, 4-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyridin-2-amine, 4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyridin-2-amine, 4-(1-isopropyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine, 3-chloro-5-(1-isopropyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine, (2S)-1-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol, (2S)-1-({4-[3-(7-chloro-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-ol , or a pharmaceutically acceptable salt thereof.

20. ) The compound according to claim 1, wherein the compound is selected from 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol and 3-(4-(3-(5-acetyl-6-aminopyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-propanenitrile, or a pharmaceutically acceptable salt thereof.

21. ) The compound according to claim 1, wherein the compound is selected from 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, and 3-(4-(3-(5-acetyl-6-aminopyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-propanenitrile, or a pharmaceutically acceptable salt thereof.

22. ) The compound of claim 1, wherein the compound is 3-({4-[1-(2-hydroxy-1,1-dimethylethyl)-3-(5-methoxypyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, or a pharmaceutically acceptable salt thereof.

23. ) The compound of claim 1, wherein the compound is 3-({4-[1-(2,2-difluoroethyl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, or a pharmaceutically acceptable salt thereof.

24. ) The compound of claim 1, wherein the compound is 3-({4-[3-(5-amino-6-methoxypyrazin-2-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propanenitrile, or a pharmaceutically acceptable salt thereof.

25. ) The compound of claim 1, wherein the compound is 3-(4-(3-(5-acetyl-6-aminopyridin-3-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)-propanenitrile, or a pharmaceutically acceptable salt thereof.

26. ) A pharmaceutical composition, comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

27. ) A method of treating abnormal cell growth, or any Raf-mediated disease or condition, in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

28. ) The method of claim 27, wherein the abnormal cell growth is cancerous.

29. ) The method of claim 27, wherein the abnormal cell growth in non-cancerous.

30. ) A method of inhibiting Raf enzymatic activity, comprising contacting a Raf enzyme with a Raf-inhibiting amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.