Compounds and compositions as TRK inhibitors

1. A compound of Formula (I):

wherein:

A is

X 1 is CH or N;

R 1 is —C(O)NH 2 , —C(O)N(R 7 ) 2 , —C(O)N(R 8 ) 2 , —NR 7 C(O)R 8 , —NR 7 C(O)N(R 7 ) 2 , —NR 7 C(O)N(R 8 ) 2 , —NR 7 C(O)N(R 9 ) 2 ; —C(O)OR 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)OR 8 , —C(O)NR 7 R 8 , —C(O)NR 7 C(O)OR 7 , —C(O)NR 7 C(O)NH 2 , —C(O)NR 7 C(O) N(R 7 ) 2 or H;

each R 2 is independently selected from H and C 1 -C 6 alkyl;

each R 3 is independently selected from H, C 1 -C 6 alkyl, —CN, —C(O)N(R 7 ) 2 , —OR 7 and halo, or the two R 3 together with the C atom they are attached form a cyclopropyl group spiro attached to the pyrrolidine;

or a R 2 and a R 3 together with the C atom they are attached form a cyclopropyl ring fused to the pyrrolidine;

each R 4 is independently selected from H, halo, —OR 7 , C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 halo, C 1 -C 6 alkoxy substituted with 1-3 halo, —CN and —C(O)N(R 7 ) 2 ;

each R 5 is independently selected from H and C 1 -C 6 alkyl;

each R 6 is independently selected from H, C 1 -C 6 alkyl, —CN, —OR 7 and halo;

each R 7 is independently selected from H, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with 1-3 —OH;

each R 8 is independently selected from H, C 1 -C 6 alkyl, phenyl, benzyl, phenyl substituted with 1-3 groups independently selected from R 6 , benzyl substituted with 1-3 groups independently selected from R 6 , an unsubstituted 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from O and N, a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from O and N which is substituted with 1-3 groups independently selected from R 6 , an unsubstituted C 3 -C 6 cycloalkyl, a C 3 -C 6 cycloalkyl substituted with 1-3 groups independently selected from R 6 , an unsubstituted 5-6 membered heteroaryl having 1 to 2 heteroatoms independently selected from O and N, a 5-6 membered heteroaryl having 1 to 2 heteroatoms independently selected from O and N which is substituted with 1-3 groups independently selected from R 6 ;

each R 9 is a C 1 -C 6 alkyl and together with the N atom they are attached form an unsubstituted 5-6 membered heterocycloalkyl or a 5-6 membered heterocycloalkyl substituted with 1-3 groups independently selected from R 6 ;

m is 0, 1, 2, 3 or 4,

n is 0, 1 or 2,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:

A is

X 1 is CH or N;

R 1 is —C(O)NH 2 , —C(O)N(R 7 ) 2 , —C(O)N(R 8 ) 2 , —NR 7 C(O)R 8 , —NR 7 C(O)N(R 7 ) 2 , —NR 7 C(O)N(R 8 ) 2 , —NR 7 C(O)N(R 9 ) 2 ; —C(O)OR 7 , —NR 7 C(O)OR 7 , —C(O)NR 7 C(O)OR 7 , —C(O)NR 7 C(O)NH 2 , —C(O)NR 7 C(O)N(R 7 ) 2 or H;

each R 2 is independently selected from H and C 1 -C 6 alkyl;

each R 3 is independently selected from H, C 1 -C 6 alkyl, —CN, —OR 7 and halo, or the two R 3 together with the C atom they are attached form a cyclopropyl group spiro attached to the pyrrolidine;

or a R 2 and a R 3 together with the C atom they are attached form a cyclopropyl ring fused to the pyrrolidine;

each R 4 is independently selected from H, halo, —OR 7 , C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 halo, C 1 -C 6 alkoxy substituted with 1-3 halo, —CN and —C(O)N(R 7 ) 2 ;

each R 5 is independently selected from H and C 1 -C 6 alkyl;

each R 6 is independently selected from H, C 1 -C 6 alkyl, —CN, —OR 7 and halo;

each R 7 is independently selected from H, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with 1-3 —OH;

each R 8 is independently selected from H, C 1 -C 6 alkyl, phenyl, phenyl substituted with 1-3 groups independently selected from R 6 , an unsubstituted 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from O and N, a 5-6 membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from O and N which is substituted with 1-3 groups independently selected from R 6 , an unsubstituted C 3 -C 6 cycloalkyl, a C 3 -C 6 cycloalkyl substituted with 1-3 groups independently selected from R 6 , an unsubstituted 5-6 membered heteroaryl having 1 to 2 heteroatoms independently selected from O and N, a 5-6 membered heteroaryl having 1 to 2 heteroatoms independently selected from O and N which is substituted with 1-3 groups independently selected from R 6 ;

each R 9 is a C 1 -C 6 alkyl and together with the N atom they are attached form an unsubstituted 5-6 membered heterocycloalkyl or a 5-6 membered heterocycloalkyl substituted with 1-3 groups independently selected from R 6 ;

m is 0, 1, 2, 3 or 4,

n is 0, 1 or 2,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound of Formula (I) is a compound having the structure of Formula (II):

4. The compound of claim 3 , wherein the compound of Formula (II) is a compound having the structure of Formula (II-a) or Formula (II-b):

5. The compound of claim 4 , wherein the compound of Formula (II-a) is a compound having the structure of Formula (II-c):

6. The compound of claim 5 , wherein each R 4 is independently selected from H, F, —CN, —C(O)NH 2 , —OCF 3 , —OCHF 2 and —OCH 2 F.

7. The compound of claim 6 , wherein each R 3 is independently selected from H, —CN, —C(O)NH 2 and F, and wherein each R 2 is H.

8. The compound of claim 7 , wherein each R 3 is independently selected from H and F, and wherein each R 2 is H.

9. The compound of claim 8 , wherein R 1 is —C(O)NH 2 , —C(O)N(R 7 ) 2 or —C(O)OR 7 , wherein each R 7 is independently selected from H, methyl and ethyl.

10. The compound of claim 9 , wherein R 1 is —C(O)NH 2 .

11. The compound of claim 1 selected from:

5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;

ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate;

(R)-ethyl 5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate;

5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

(R)-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid;

5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;

(R)-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;

ethyl 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate;

(R)-ethyl 5-(2-(3-cyano-5-fluorophenyI)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate;

(R)-5-(2-(3-carbamoyl-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine -3-carboxamide, and

(R)-5-(2-(3-cyano-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide.

12. The compound of claim 1 selected from:

5-[2-(3-fluorophenyl)piperidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxamide

5-{2-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl}pyrazolo[1,5-a]pyridine-3-carboxamide;

N-ethyl-5-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;

5-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]-N,N-dimethylpyrazolo[1,5-a]pyridine-3-carboxamide;

N-tert-butyl-5-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;

5-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-carboxamide;

5-(4,4-difluoro-2-{5-fluoro-2-[(propan-2-yl)carbamoyl]phenyl}pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide;

ethyl 5-[(2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxylate;

ethyl 5-[(2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxylate;

benzyl N-{5-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridin-3-yl}carbamate;

5-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]-N-phenylpyrazolo[1,5-a]pyridine-3-carboxamide;

{-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridin-3-yl}urea;

5-[(2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxamide;

5-[(2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxamide, and

(3S,5R)-1-{3-carbamoylpyrazolo[1,5-a]pyridin-5-yl}-5-(3-fluorophenyl)pyrrolidine-3-carboxamide.

13. The compound of claim 1 selected from:

5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide.

14. The compound of claim 1 selected from:

N-ethyl-5-[(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxamide.

15. The compound of claim 1 selected from:

ethyl 5-[(2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxylate.

16. The compound of claim 1 selected from:

ethyl 5-[(2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyridine-3-carboxylate.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 11 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 12 and a pharmaceutically acceptable carrier.