Pyrazole derivatives as MALT1 inhibitors

1. A compound of Formula (I)

wherein

R 1 is 1-oxo-1,2-dihydroisoquinolin-5-yl or 1-hydroxyisoquinolin-5-yl;

R 2 is selected from the group consisting of C 1-4 alkyl, 1-methoxy-ethyl, difluoromethyl, fluoro, chloro, bromo, cyano, and trifluoromethyl;

G 1 is N or C(R 4 );

G 2 is N or C(R 3 ); such that only one of G 1 and G 2 are N in any instance;

R 3 is independently selected from the group consisting of trifluoromethyl, cyano, C 1-4 alkyl, fluoro, chloro, bromo, methylcarbonyl, methylthio, methylsulfinyl, and methanesulfonyl; or, when G 1 is N, R 3 is further selected from C 1-4 alkoxycarbonyl;

R 4 is selected from the group consisting of

(i) hydrogen, when G 2 is N;

(ii) C 1-4 alkoxy;

(iii) cyano;

(iv) cyclopropyloxy;

(v) (4-aminobutyl)aminocarbonyl;

(vi) (4-amino)butoxy;

(vii) methoxycarbonyl;

(viii) (E)-(4-aminobut-1-en-1-yl-aminocarbonyl; and

(ix) difluoromethoxy;

R 5 is independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, methoxy, methylsulfonyl, cyano, C 1-4 alkyl, ethynyl, trifluoromethyl, hydroxyethyl, methylcarbonyl, methylsulfinyl methylthio, and 1,1-difluoroethyl;

R 6 is hydrogen, C 1-4 alkyl, fluoro, 2-methoxy-ethoxy, chloro, cyano, or trifluoromethyl; and

R 7 is hydrogen or fluoro;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

2. The compound according to claim 1 wherein R 2 is independently selected from the group consisting of methyl, isopropyl, cyano, bromo, chloro, and trifluoromethyl.

3. The compound according to claim 2 wherein R 2 is independently selected from the group consisting of methyl, isopropyl, cyano, and trifluoromethyl.

4. The compound according to claim 3 wherein R 2 is trifluoromethyl.

5. The compound according to claim 1 wherein R 3 is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfinyl, methanesulfonyl, and chloro; or, when G 1 is N, R 3 is further selected from C 1-4 alkoxycarbonyl.

6. The compound according to claim 1 wherein R 3 is independently selected from the group consisting of trifluoromethyl, cyano, and chloro.

7. The compound according to claim 1 wherein G 2 is N or C(R 3 ), and wherein R 3 is chloro.

8. The compound according to claim 7 wherein G 2 is N.

9. The compound according to claim 1 wherein R 4 is selected from the group consisting of

(i) hydrogen, when G 2 is N;

(ii) C 1-4 alkoxy;

(iii) cyano;

(iv) cyclopropyloxy;

(v) (4-aminobutyl)aminocarbonyl;

(vi) (4-amino)butoxy; and

vii) methoxycarbonyl.

10. The compound according to claim 9 wherein R 4 is selected from the group consisting of

(i) hydrogen, when G 2 is N;

(ii) C 1-4 alkoxy;

(iii) cyano;

(iv) cyclopropyloxy;

(v) (4-amino)butoxy; and

(vi) methoxycarbonyl.

11. The compound according to claim 1 wherein R 4 is selected from the group consisting of

(i) methoxy; and

(ii) methoxycarbonyl.

12. The compound according to claim 1 wherein R 5 is hydrogen, chloro, fluoro, bromo, cyano, methyl, ethyl, or trifluoromethyl.

13. The compound according to claim 12 wherein R 5 is hydrogen, chloro, bromo, cyano, or trifluoromethyl.

14. The compound according to claim 12 wherein R 5 is hydrogen, chioro, fluoro, or cyano.

15. The compound according to claim 14 wherein R 5 is hydrogen, chloro, or cyano.

16. The compound according to claim 1 wherein R 6 is hydrogen or methyl.

17. The compound according to claim 1 wherein R 7 is hydrogen.

18. A compound of Formula (I)

wherein

R 1 is 1-oxo-1,2-dihydroisoquinolin-5-yl or 1-hydroxyisoquinolin-5-yl;

R 2 is independently selected from the group consisting of methyl, isopropyl, cyano, bromo, chloro, and trifluoromethyl;

G 1 is N or C(R 4 );

G 2 is N or C(R 3 ); such that only one of G 1 and G 2 is N in any instance;

R 3 is independently selected from the group consisting of trifluoromethyl, cyano, methylcarbonyl, methylthio, methylsulfinyl, methanesulfonyl, and chloro; or, when G 1 is N, R 3 is further selected from C 1-4 alkoxycarbonyl;

R 4 is independently selected from the group consisting of

(i) hydrogen, when G 2 is N;

(ii) C 1-4 alkoxy;

(iii) cyano;

(iv) cyclopropyloxy;

(v) carboxy;

(vi) (4-aminobutyl)aminocarbonyl;

(vii) (4-amino)butoxy; and

(viii) methoxycarbonyl;

R 5 is hydrogen, chloro, fluoro, bromo, cyano, methyl, ethyl, or trifluoromethyl;

R 6 is hydrogen or methyl; and

R 7 is hydrogen;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

19. A compound of Formula (I)

wherein

R 1 is 1-oxo-1,2-dihydroisoquinolin-5-yl or 1-hydroxyisoquinolin-5-yl;

R 2 is selected from the group consisting of methyl, isopropyl, cyano, and trifluoromethyl;

G 1 is N or C(R 4 );

G 2 is N or C(R 3 ); such that only one of G 1 and G 2 is N in any instance;

R 3 is independently selected from the group consisting of trifluoromethyl, cyano, and chloro;

R 4 is independently selected from the group consisting of

(i) hydrogen, when G 2 is N;

(ii) C 1-4 alkoxy;

(iii) cyano;

(iv) cyclopropyloxy;

(v) (4-amino)butoxy; and

(vi) methoxycarbonyl;

R 5 is hydrogen, chloro, bromo, or cyano;

R 6 is hydrogen or methyl; and

R 7 is hydrogen;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

20. A compound of Formula (I)®

wherein

R 1 is 1-oxo-1,2-dihydroisoquinolin-5-yl or 1-hydroxyisoquinolin-5-yl;

R 2 is selected from the group consisting of methyl, isopropyl, cyano, and trifluoromethyl;

G 1 is N or C(R 4 );

G 2 is Nor C(R 3 ); such that only one of G 1 and G 2 is N in any instance;

R 3 is independently selected from the group consisting of trifluoromethyl, cyano, and chloro;

R 4 is selected from the group consisting of

(i) methoxy; and

(ii) methoxycarbonyl;

R 5 is hydrogen, chloro, or cyano;

R 6 is hydrogen or methyl; and

R 7 is hydrogen;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

21. A compound of Formula (I)

selected from the group consisting of:

Compound No. and Structure

Compound Name:

158

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4-yl)-1H- pyrazole-4-carboxamide;

167

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-N-(5- (trifluoromethyl)pyridin-3-yl)-1H- pyrazole-4-carboxamide;

345

N-(5-chloro-6-methoxypyridin-3-yl)-1-(1- oxo-1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

346

N-(5-cyanopyridin-3-yl)-1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

347

N-(2-methylpyridin-4-yl)-1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

353

N-(5-chloropyridin-3-yl)-1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

354

N-(6-cyano-5-(trifluoromethyl)pyridin-3- yl)-1-(1-oxo-1,2-dihydroisoquinolin-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxamide;

355

methyl 3-chloro-5-(1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamido)picolinate;

356

N-(2-cyanopyridin-4-yl)-1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

357

N-(2-(2-methoxyethox-y)-5- (trifluoromethyl)pyridin-3-yl)-1-(1-oxo- 1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide; and

428

N-(5-cyano-6-methoxypyridin-3-yl)-1-(1- oxo-1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

22. A pharmaceutical composition comprising a compound of claim 1 , 2 - 11 , 12 - 20 or 21 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

23. The pharmaceutical composition of claim 22 , wherein the composition is a solid oral dosage form.

24. The pharmaceutical composition of claim 22 , wherein the composition is a syrup, an elixir or a suspension.

25. A compound of Formula (I)

selected from the group consisting of:

Compound No. and Structure

Compound Name:

158

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4-yl)-1H- pyrazole-4-carboxamide;

355

methyl 3-chloro-5-(1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamido)picolinate; and

428

N-(5-cyano-6-methoxypyridin-3-yl)-1-(1- oxo-1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

26. A compound that is

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

27. A crystalline form of

wherein the crystalline form is a hydrate, producing an X-ray powder diffraction pattern comprising peaks at 8.4, 12.7, 13.3 and 16.7 degrees two theta 0.2 degrees two theta.

28. A pharmaceutical composition comprising a compound of claim 25 , 26 or 27 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

29. The pharmaceutical composition of claim 28 , wherein the composition is a solid oral dosage form.

30. The pharmaceutical composition of claim 28 , wherein the composition is a syrup, an elixir or a suspension.

31. A pharmaceutical composition comprising a compound of claim 27 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

32. The pharmaceutical composition of claim 31 , wherein the composition is a solid oral dosage form.

33. The pharmaceutical composition of claim 31 , wherein the composition is a syrup, an elixir or a suspension.

34. A compound selected from the group consisting of:

Compound No. and Structure

Compound Name:

348

N-(6-methyl-5-(trifluoromethyl)pyridin- 3-yl)-1-(1-oxo-1,2-dihydroisoquinolin-5- yl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxamide;

349

1-(1-oxo-1,2-dihydroisoquinolin-5-yl)-N- (pyridin-4-yl)-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide;

350

N-(2-cyclopropylpyridin-4-yl)-1-(1-oxo- 1,2-dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

351

3-chloro-N,N-dimethyl-5-(1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamido)picolinamide;

352

3-chloro-N-methyl-5-(1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamido)picolinamide; and

360

N-(2-methoxypyridin-4-yl)-1-(1-oxo-1,2- dihydroisoquinolin-5-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

35. A pharmaceutical composition comprising a compound of claim 34 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

36. The pharmaceutical composition of claim 35 , wherein the composition is a solid oral dosage form.

37. The pharmaceutical composition of claim 35 , wherein the composition is a syrup, an elixir or a suspension.