Pyrrolo[2,3-d]pyrimidine tropomysin-related kinase inhibitors

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R 1 is H, or C 1-5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CON(R 5 R 6 ), SO 2 R 7 , SR 7 , OR 7 , CH 2 OH, CO 2 R 5 , SONR 7 R 7 , NR 7 SO 2 R 5 , CN, NO 2 and R 8 , or a ring system selected from C 3-5 cycloalkyl, propellanyl, or a 4-6 membered saturated heterocyclyl ring, which ring system has up to 3 ring hetero-atoms selected from N, O and S, and which ring system is optionally substituted by up to 3 substituents independently selected from methyl, OH, CON(R 5 R 6 ), SO 2 R 7 , OR 7 , CH 2 OH, CO 2 R 5 , SONR 7 R 7 , NR 7 SO 2 R 5 , CN, NO 2 and R 8 ;

R 2 is H or methyl;

R 3 is H, NH 2 or NH(C 1-3 alkyl optionally substituted with up to 3 substituents independently selected from OH and O(C 1-3 alkyl));

R 101 is H, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN,

X is a bond, O, (CH—R 4 ) n , NR 104 , OCH 2 or CH 2 O;

R 4 is independently H, CH 3 , CH 2 OH, CH 2 OCH 3 , OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , CH 2 NH 2 , CH 2 NHCH 3 , or CH 2 N(CH 3 ) 2 ;

R 104 is H, C 1-3 alkyl or a C 4-6 saturated carbocycle, each of which is optionally substituted by up to 3 substituents independently selected from C 1-3 alkyl, CH 2 OH and NH 2 ;

n is 1 or 2;

R 102 is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-14-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O, wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond, which ring system is optionally substituted by up to 3 substituents independently selected from, where possible -halo, CN, NR 5 R 6 , SO 2 R 7 , SR 7 , C 1-4 alkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 1-3 alkyl substituted by up to 3 halogen, OH, O(C 1-3 alkyl), O(C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, O(C 1-3 alkyl substituted by up to 3 halogen), O(C 1-3 alkyl substituted by up to 3 OH and/or C 1-3 alkoxy groups), NR 5 SO 2 R 7 , ═O, R 8 , C(O)R 8 , NO 2 , NR 5 CO 2 R 7 , NR 5 COR 7 , OR 8 , S(O)R 7 , and CH 2 R 8 ;

R 5 and R 6 are each independently H, or C 1-5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CONR 7 R 7 , SO 2 R 7 , OR 7 , CH 2 OH, CO 2 R 7 , SONR 7 R 7 , NR 7 SO 2 R 7 , CN, NO 2 and R 9 , or a ring system selected from C 3-5 cycloalkyl, propellanyl, or a 4-6 membered saturated heterocyclyl ring, which ring system is optionally substituted by up to 3 substituents independently selected from OH, CON(R 7 R 7 ), SO 2 R 7 , CO 2 R 7 , SONR 7 R 7 , NR 7 SO 2 R 7 , CN, NO 2 , halo, NR 7 R 7 , SR 7 , C 1-4 alkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 1-3 alkyl substituted by 1 to 3 halogen, O(C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, O(C 1-3 alkyl substituted by up to 3 halogen, O(C 1-3 alkyl substituted by up to 3 OH and/or C 1-3 alkoxy, NR 7 SO 2 R 7 , ═O, NO 2 ,NR 7 CO 2 R 7 , and S(O)R 7 , or R 5 and R 6 together with the N to which they are attached can be a 4-7 membered ring optionally including up to 2 further ring hetero-atoms independently selected from N, O, S, which ring is optionally substituted by C 1-3 alkoxy and/or C 1-3 alkyl;

R 7 is H, C 1-5 alkyl or C 1-5 alkoxy, which C 1-5 alkyl or C 1-5 alkoxy is optionally substituted by up to 3 substituents independently selected from halogen;

R 8 is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-14-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O,

wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond, which ring system is optionally substituted by up to 3 substituents independently selected from, where possible -halo, CN, NR 5 R 6 , SO 2 R 7 , SR 7 , C 1-4 alkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 1-3 alkyl substituted by 1 to 3 halogen, OH, O(C 1-3 alkyl), O(C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, O(C 1-3 alkyl substituted by up to 3 halogen, O(C 1-3 alkyl substituted by up to 3 OH and/or C 1-3 alkoxy, NR 5 SO 2 R 7 , ═O, NO 2 , NR 7 COR 7 ,NR 5 CO 2 R 7 , and S(O)R 7 ;

R 9 is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-14-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O, wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic, heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond, which ring system is optionally substituted by up to 3 substituents independently selected from, where possible -halo, CN, NR 7 R 7 , SO 2 R 7 , SR 7 , C 1-4 alkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, C 1-3 alkyl substituted by 1 to 3 halogen, OH, O(C 1-3 alkyl), O(C 3-6 cycloalkyl optionally substituted by up to 3 OH and/or C 1-3 alkoxy groups, O(C 1-3 alkyl substituted by up to 3 halogen, O(C 1-3 alkyl substituted by up to 3 OH and/or C 1-3 alkoxy, NR 7 SO 2 R 7 , ═O, NO 2 , NR 7 CO 2 R 7 , NR 7 COR 7 , and S(O)R 7 ;

wherein each CH moiety can be replaced by a CF moiety.

2. The compound or salt according to claim 1 wherein R 1 is H or C 1-5 alkyl wherein the C 1-5 alkyl is optionally substituted with 1 or 2 OH groups; or R 1 is C 1-5 alkyl substituted with CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , CO 2 H, CO 2 CH 3 , OCH 3 , SCH 3 , or SO 2 CH 3 ; or R 1 is C 3-5 cycloalkyl, propellanyl, or oxetanyl, wherein the C 3-5 cycloalkyl, propellanyl, or oxetanyl is optionally substituted with methyl, OH or CH 2 OH.

3. The compound or salt according to claim 1 wherein R 1 is t-butyl, hydroxy-t-butyl, dihdyroxy-t-butyl, 1-hydroxyprop-2-yl or 1,3-dihydroxyprop-2-yl.

4. The compound or salt according to claim 3 wherein R 2 is H.

5. The compound or salt according to claim 4 wherein R 3 is H or NH 2 .

6. The compound or salt according to claim 4 wherein R 3 is NH 2 .

7. The compound or salt according to claim 4 wherein R 3 is H.

8. The compound or salt according to claim 7 wherein R 101 is H.

9. The compound or salt according to claim 7 wherein R 101 is OH.

10. The compound or salt according to claim 9 wherein X is a bond, O, CH 2 , C 2 H 4 , CH(CH 3 ), CH(CH 2 OH), CH 2 O, CH(NH 2 ), CH(OH) or NH.

11. The compound or salt according to claim 9 wherein X is CH 2 .

12. The compound or salt according to claim 11 wherein R 102 is an optionally substituted nitrogen-containing ring system which is linked to the X moiety via a nitrogen ring atom.

13. The compound or salt according to claim 11 wherein R 102 is an optionally substituted ring system where the ring system is selected from -benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, benzotriazolyl, biphenyl, bipyrazolyl, cinnolinyl, cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyl, cyclopentyltriazolyl, cyclopropylisoxazolyl, cyclopropyloxazolyl, cyclopropylpyrazolyl, cyclopropyltriazolyl, diazirenylphenyl, dihydronaphthyridinyl, dihydropyrrolopyrazolyl, dioxinopyridinyl, furazanyl, furopyridinyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiadiazolyl, imidazothiazolyl, indanyl, indazolyl, indolyl, isoindolyl, isoxazolopyridinyl, isoxazolyl, isoquinolinyl, naphthyridinyl, oxazolyl, phenyl, phenylcyclopropyl, phenylimidazolyl, phenylpyrazolyl, phenylpyrrolyl, phenyltetrazolyl, phthalazinyl, purinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridinyl, pyridazinyl, pyridinyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinolinyl, quinazolyl, quinoxalinyl, tetrahydrobenzisoxazolyl, tetrahydrocyclopentapyrazolyl, tetrahydrotriazolopyridinyl, tetrazolopyridazinyl, tetrazolopyridinyl, thiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, triazolopyridinyl and triazolyl.

14. The compound or salt according to claim 13 where the optional substituents are independently selected from, where possible -halo, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF 3 , CHF 2 , CH 2 F, CH 2 OCH 3 , CN, CH 2 OH, OCH 3 , ═O, NH 2 , SCH 3 , SO 2 CH 3 , phenoxy, fluorophenoxy, benzyl, SCF 3 , OCF 3 , SO 2 CF 3 , NHSO 2 CH 3 , NHSO 2 CF 3 , benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and morpholinomethyl.

15. The compound or salt according to claim 11 wherein R 102 is selected from the group consisting of phenyl, pyrazol-1-yl, 1,2,3-triazol-1-yl, benzotriazol-2-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, each of which is optionally substituted by halo, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF 3 , CHF 2 , CH 2 F, CH 2 OCH 3 , CN, CH 2 OH, OCH 3 , ═O, NH 2 , SCH 3 , SO 2 CH 3 , phenoxy, fluorophenoxy, benzyl, SCF 3 , OCF 3 , SO 2 CF 3 , NHSO 2 CH 3 , NHSO 2 CF 3 , benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and/or morpholinomethyl.

16. The compound or salt according to claim 15 with R 5 and R 6 groups present, wherein R 5 and R 6 are each independently H, C 1-3 alkyl optionally substituted by C 1-3 alkoxy, C 3-5 cycloalkyl, propellanyl, oxetanyl, tetrahydrofuranyl or pyranyl, or R 5 and R 6 together with the N to which they are attached can be an azetidine, pyrrolidine, piperidine, piperazine or morpholine ring, which ring is optionally substituted by C 1-3 alkoxy and/or C 1-3 alkyl.

17. A compound of Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein

R 3 is H or NH 2 ;

R 1 is C 2-4 alkyl optionally substituted by 1 or 2 OH groups;

R 101 is H or OH; and

R 102 is phenyl or an aromatic or partially unsaturated 5- or 6-membered heterocycle, which heterocycle is optionally fused to a further phenyl or 5-7 membered aromatic or partially unsaturated heterocyclic ring, wherein each heterocycle has from 1 to 3 ring heteroatoms selected from N, O and S, and which ring system is optionally substituted by up to 3 substituents independently selected from halo, CF 3 , C 1-4 alkyl and C 3-5 cycloalkyl.

18. The compound or salt according to claim 17 wherein R 101 is H.

19. The compound or salt according to claim 18 wherein

R 1 is t-butyl, hydroxy-t-butyl or 1-hydroxyprop-2-yl; and

R 102 is 4-trifluoromethylphenyl, 4-chlorophenyl, 2,4-difluorophenyl, 5-chloropyridin-2-yl, 5-fluoropyridin-2-yl, 3-trifluoromethylpyrazolyl-1-yl, 4-trifluoromethylpyrazol-1-yl, 3-trifluoromethyl-5-methylpyrazol-1-yl, 3-cyclopropylpyrazol-1-yl, 4-cyclopropylpyrazol-1-yl, 4-trifluoromethyl (1,2,3-triazol-1-yl), 4-cyclopropyl-(1,2,3-triazol-1-yl), or benzotriazol-2-yl.

20. The compound according to claim 1 , selected from the group consisting of

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4-(trifluoromethyl)phenyl]acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(4-chlorophenyl)acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(5-fluoropyridin-2-yl)acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(3-cyclopropyl-1H-pyrazol-1-yl)acetamide;

N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetamide;

N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;

N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetamide;

N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5-chloropyridin-2-yl)acetamide;

N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide;

N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetamide;

2-(4-chlorophenyl)-N-[5-({7-[(1S)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide

N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;

N-[5-({7-[(1S)-2-Hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide;

N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide;

2-(4-chlorophenyl)-N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide;

N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;

2-(5-chloropyridin-2-yl)-N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)acetamide;

N-(5-{[2-Amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(4-chlorophenyl)acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4-(trifluoromethyl)phenyl]acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(4-chlorophenyl)acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4-(trifluoromethyl)phenyl]acetamide;

N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide; and

N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetamide;

or a pharmaceutically acceptable salt thereof.

21. N-[5-({7-[(1S)-2-Hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof.

22. A compound that is

23. N-[5-({7-[(1R)-2-Hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide or a pharmaceutically acceptable salt thereof.

24. A compound that is

25. N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide or a pharmaceutically acceptable salt thereof.

26. A compound that is

27. N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide or a pharmaceutically acceptable salt thereof.

28. A compound that is

29. N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetamide or a pharmaceutically acceptable salt thereof.

30. A compound that is

31. N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide or a pharmaceutically acceptable salt thereof.

32. A compound that is

33. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. A method of antagonizing a Trk receptor in a mammal, in need thereof, comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound of claim 1 .

35. A method of treatment of pain in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.