Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors

Patent metadata

Field	Value
Publication number	US-9023840-B2
Application number	US-201414186338-A
Country	US
Kind code	B2
Filing date	Feb 21, 2014
Priority date	Jun 20, 2011
Publication date	May 5, 2015
Grant date	May 5, 2015

Abstract

The present invention provides azetidinyl phenyl, pyridyl, or pyrazinyl carboxamide derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAKs) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

First claim

What is claimed is:

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)-1

Assignees

• Incyte Corp

Inventors

• Yao Wenqing
• Burns David M
• Zhuo Jincong

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title