Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

X is N or CR 4 ;

W is N or CR 6 ;

Y is N or CR 7 ;

R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkyl-C 1-3 alkyl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 4-6 membered heterocycloalkyl, and 4-6 membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, —OH, —O(C 1-3 alkyl), —CN, —CF 3 , C 1-3 alkyl, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —C(O)N(C 1-3 alkyl) 2 , —C(O)NH(C 1-3 alkyl), —C(O)NH 2 , —C(O)O(C 1-3 alkyl), —S(O) 2 (C 1-3 alkyl), —S(O) 2 (C 3-6 cycloalkyl), —C(O)(C 3-6 cyclo alkyl), and —C(O)(C 1-3 alkyl);

R 2 is H or C 1-3 alkyl; wherein said C 1-3 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from fluoro, —OH, —O(C 1-3 alkyl), —CN, —CF 3 , NH 2 , —NH(C 1-3 alkyl), and —N(C 1-3 alkyl) 2 ; or

R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl ring; which is optionally substituted with 1, 2, or 3 substitutents independently selected from fluoro, —OH, —(C 1-3 alkyl), —CN, C 1-3 alkyl, C 1-3 haloalkyl, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , and —CH 2 CN;

R 3 is H, F, Cl, —CN, C 1-3 alkyl, —OCF 3 , —CF 3 , or —O(C 1-3 alkyl);

R 4 is H, F, Cl, —CN, C 1-3 alkyl, or —O(C 1-3 alkyl);

R 5 is H, F, Cl, —CN, C 1-3 alkyl, or —O(C 1-3 alkyl);

R 6 is H, F, Cl, —CN, or C 1-3 alkyl; and

R 7 is H, F, Cl, —CN, C 1-3 alkyl, —CH 2 CN, —C(O)N(C 1-3 alkyl) 2 , —C(O)NH(C 1-3 alkyl), or —C(O)NH 2 .

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

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH.

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

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH or CF.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is N.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH, CF, or CCl.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H or F.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H or methyl.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, —CF 3 , and methyl.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 4 ;

W is N or CR 6 ;

Y is N or CR 7 ;

R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, —OH, —O(C 1-3 alkyl), —CN, —CF 3 , C 1-3 alkyl, —NH 2 , —NH(C 1-3 alkyl), and —N(C 1-3 alkyl) 2 ;

R 2 is H or methyl;

R 3 is H, F, Cl, or methyl;

R 4 is H, F, Cl, or methyl;

R 5 is H, F, Cl, or methyl;

R 6 is H, F, Cl, or methyl; and

R 7 is H.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR 4 ;

W is N or CR 6 ;

Y is N or CR 7 ;

R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 5-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, —CF 3 , and methyl;

R 2 is H or methyl;

R 3 is H, F, or Cl;

R 4 is H or F;

R 5 is H or F;

R 6 is H; and

R 7 is H.

13. The compound according to claim 1 , having Formula IIa:

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , having Formula IIb:

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 , having Formula IIIa:

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , having Formula IIIb:

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 , having Formula IVa:

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 , having Formula IVb:

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 , selected from:

4-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamide;

5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-isopropylbenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-3-fluorobenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]-3-fluorobenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-isopropylbenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-cyclopropyl-3-fluoro-N-methylbenzamide;

5-Chloro-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluoro-N-isopropylbenzamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyridine-2-carboxamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3,3-difluorocyclobutyl)pyridine-2-carboxamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluoro-N-isopropylbenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclohexylethyl]-2-fluorobenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[1-(1-methylpiperidin-4-yl)ethyl]benzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide;

5-Chloro-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2-fluorobenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-ethylpyridine-2-carboxamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-methylpropyl]benzamide; and

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,2,2-trifluoro-1-methylethyl)benzamide;

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 , selected from:

4-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluoro-N-isopropylbenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[1-(trifluoromethyl)cyclopropyl]pyrazine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpyrazine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,2,2-trifluoroethyl)pyrazine-2-carboxamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,2-difluoroethyl)-2,5-difluorobenzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoro ethyl]benzamide;

4-{3-(Cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2-fluorobenzamide;

5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[1-(trifluoromethyl)cyclopropyl]pyridine-2-carboxamide;

5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyrazine-2-carboxamide; and

5-{3-(Cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

21. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.