IP Library › Granted Patent US 12,247,020
Granted Patent B2
US 12,247,020 · App. 18/402,493 · Granted Mar 11, 2025

Bipyrazole derivatives as JAK inhibitors

Inventors: Yun-Long Li (Chadds Ford, PA); Jincong Zhuo (Garnet Valley, PA); Ding-Quan Qian (Newark, DE); Song Mei (Wilmington, DE); Ganfeng Cao (Chadds Ford, PA); Yongchun Pan (Wilmington, DE); Qun Li (Newark, DE); Zhongjiang Jia (Kennett Square, PA)
Assignees: Incyte Corporation; Incyte Holdings Corporation
C07D403/14A61P37/06
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Quick Facts
Patent No.
US 12,247,020
App. No.
18/402,493
Granted
Mar 11, 2025
Kind
B2
Abstract

The present invention provides compounds of Formula I: or pharmaceutically acceptable salts thereof, as well as their compositions and methods of use, that inhibit the activity of Janus kinase (JAK) 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.

Claims (107)

1. A method of treating sarcoidosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

Cy 1 is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted by 1, 2, 3, or 4 groups independently selected from R 3 , R 4 , R 5 , and R 6 ;

Y is N or CH;

R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl-C 1-3 alkyl, phenyl, phenyl-C 1-3 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C 1-3 alkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, C 1-3 alkyl, —OH, —O(C 1-3 alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, —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 cycloalkyl), 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, chloro, —OH, —O(C 1-3 alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, 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 F, Cl, —OH, —O(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 , —CH 2 CN, and —CH 2 OH;

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

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

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

R 6 is H, F, Cl, —CN, C 1-3 alkyl, C 1-3 fluoroalkyl, —O(C 1-3 alkyl), or —OC(C 1-3 fluoroalkyl);

R 7 is H, F, Cl, C 1-3 alkyl, C 1-3 haloalkyl, —NR 17 R 17a , —NHC(═O) R 17b , —C(═O) NR 17a R 17b , —NHS(═O) 2 R 17b , or —S(═O) 2 NR 17a R 17b , wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, Cl, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , OH, —OCH 3 , —OCF 3 , —OCHF 2 , and —OCH 2 F;

R 8 is H, F, Cl, C 1-3 alkyl, or C 1-3 haloalkyl;

R 9 is H, F, Cl, C 1-3 alkyl, C 1-3 haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3 alkyl), or —N(C 1-3 alkyl) 2 , wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH;

R 10 is H, F, Cl, C 1-3 alkyl, C 1-3 haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3 alkyl), or —N(C 1-3 alkyl) 2 , wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH;

R 17 is C 1-6 alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R 27 substituents;

R 17a is H or C 1-3 alkyl;

R 17b is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , OH, —OCH 3 , and —OCF 3 , —OCHF 2 , and —OCH 2 F; and

each R 27 is independently selected from halo, —OH, NO 2 , —CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, CF 3 -C 1-3 hydroxyalkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, H 2 N—, (C 1-3 alkyl) NH—, (C 1-3 alkyl) 2 N—, HS-, C 1-3 alkyl-S—, C 1-3 alkyl-S(═O)—, C 1-3 alkyl-S(—O) 2 —, carbamyl, C 1-3 alkylcarbamyl, di(C 1-3 alkyl) carbamyl, carboxy, C 1-3 alkyl-C(═O)—, C 1-4 alkoxy-C(═O)—, C 1-3 alkyl-C(═O)O—, C 1-3 alkyl-C(═O) NH—, C 1-3 alkyl-S(═O) 2 NH—, H 2 N—SO 2 —, C 1-3 alkyl-NH—S(—O) 2 —, (C 1-3 alkyl) 2 N—S(═O) 2 —, H 2 N—S(═O) 2 NH—, C 1-3 alkyl-NHS(═O) 2 NH—, (C 1-3 alkyl) 2 N—S(═O) 2 NH—, H 2 N—C(—O) NH—, C 1-3 alkyl-NHC(═O) NH—, and (C 1-3 alkyl) 2 N—C(═O) NH—.

2. The method of claim 1 , wherein the compound of Formula I is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein

X is N or CR 4 ; and

W is N or CR 6 .

3. The method of claim 1 , wherein the compound of Formula I is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof; wherein:

X is N or CR 4 ;

W is N or CR 6 ;

Y is N or CH;

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, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, C 1-3 alkyl, —OH, —O(C 1-3 alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, —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 cycloalkyl), 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, chloro, —OH, —O(C 1-3 alkyl), —CN, —CF 3 , —CHF 2 , —CH 2 F, 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, —O(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;

R 7 is H, F, Cl, C 1-3 alkyl, C 1-3 haloalkyl, —NR 17 R 17a , —NHC(═O) R 17b , —C(═O) NR 17a R 17b , —NHS(═O) 2 R 17b , or —S(═O) 2 NR 17a R 17b , wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, Cl, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH;

R 8 is H, F, Cl, C 1-3 alkyl, or C 1-3 haloalkyl;

R 9 is H, F, Cl, C 1-3 alkyl, C 1-3 haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3 alkyl), or —N(C 1-3 alkyl) 2 , wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH;

R 10 is H, F, Cl, C 1-3 alkyl, C 1-3 haloalkyl, cyclopropyl, —CN, —NH 2 , —NH(C 1-3 alkyl), or —N(C 1-3 alkyl) 2 , wherein said C 1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH;

R 17 is C 1-6 alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 27 , R 17a is H or C 1-3 alkyl;

R 17b is C 1-3 alkyl optionally substituted with 1, 2, or 3 substituents selected from F, chloro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , and OH and

each R 27 is independently selected from halo, —OH, NO 2 , —CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, CF 3 -C 1-3 hydroxyalkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, H 2 N—, (C 1-3 alkyl) NH—, (C 1-3 alkyl) 2 N—, HS—, C 1-3 alkyl-S—, C 1-3 alkyl-S(═O)—, C 1-3 alkyl-S(═O) 2 —, carbamyl, C 1-3 alkylcarbamyl, di(C 1-3 alkyl) carbamyl, carboxy, C 1-3 alkyl-C(═O)—, C 1-4 alkoxy-C(═O)—, C 1-3 alkyl-C(═O)O—, C 1-3 alkyl-C(═O) NH—, C 1-3 alkyl-S(═O) 2 NH—, H 2 N—SO 2 —, C 1-3 alkyl-NH—S(═O) 2 —, (C 1-3 alkyl) 2 N—S(═O) 2 —, H 2 N—S(═O) 2 NH—, C 1-3 alkyl-NHS(═O) 2 NH—, (C 1-3 alkyl) 2 N—S(═O) 2 NH—, H 2 N—C(═O) NH—, C 1-3 alkyl-NHC(—O) NH—, and (C 1-3 alkyl) 2 N—C(═O) NH—.

4. The method of claim 3 , wherein:

R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl-C 1-3 alkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-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 or F;

R 7 is H, methyl, ethyl or HO—CH 2 —;

R 8 is H or methyl;

R 9 is H, methyl or ethyl; and

R 10 is H, methyl, ethyl or HO—CH 2 —.

5. The method of claim 2 , wherein:

a) Y is N; or

b) Y is CH.

6. The method of claim 2 , wherein:

a) X is N; or

b) X is CR 4 ; or

c) X is CR 4 and R 4 is H or F.

7. The method of claim 2 , wherein:

a) W is N; or

b) W is CR 6 ; or

c) W is CR 6 and R 6 is H, F, or Cl; or

d) W is CR 6 and R 6 is H or F; or

e) W is CR 6 and R 6 is H.

8. The method of claim 2 , wherein R 3 is H or F.

9. The method of claim 2 , wherein R 5 is H or F.

10. The method of claim 1 , wherein:

a) R 2 is H or methyl; or

b) R 2 is H.

11. The method of claim 1 , wherein:

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

b) R 1 is isopropyl, ethyl, 1-methylpropyl, 2,2,2-trifluoro-1-methylethyl, 1-cyclopropylethyl, cyclopropyl, 1-trifluoromethylcyclopropyl, 1-cyclopropyl-2,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; or

c) R 1 is isopropyl, ethyl, 1-methylpropyl, or 2,2,2-trifluoro-1-methylethyl.

12. The method of claim 1 , wherein R 7 is H, methyl, ethyl, or HO—CH 2 —.

13. The method of claim 1 , wherein the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound of Formula I is a compound of Formula III:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound of Formula I is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound of Formula I is:

a) a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof; or

b) compound of Formula IIIa:

or a pharmaceutically acceptable salt thereof; or

c) a compound of Formula IVa:

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound is selected from:

5-[3-(cyanomethyl)-3-(3′-methyl-1H, l′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide;

5-[3-(cyanomethyl)-3-(3′-methyl-1H,1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide;

4-[3-(cyanomethyl)-3-(3′-methyl-1H, 1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-isopropylbenzamide;

4-[3-(cyanomethyl)-3-(3′-methyl-1H, l′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

4-[3-(1H,1′H-4,4′-Bipyrazol-1-yl)-3-(cyanomethyl) azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

5-[3-(cyanomethyl)-3-(3,3′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide;

4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

5-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide;

5-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide;

5-[3-(cyanomethyl)-3-(3-methyl-1H, l′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-isopropylpyrazine-2-carboxamide;

5-[3-(cyanomethyl)-3-(3′-ethyl-1H, 1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide;

4-{3-(cyanomethyl)-3-[3′-(hydroxymethyl)-1H,1′H-4,4′-bipyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

4-{3-(cyanomethyl)-3-[3-(hydroxymethyl)-3′-methyl-1H, 1′H-4,4′-bipyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide;

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide.

20. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt of 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H, 1′H-4,4′-bipyrazol-1-yl) azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 4, 2024
From: LI, YUN-LONG; ZHUO, JINCONG; QIAN, DING-QUAN; MEI, SONG; CAO, GANFENG; PAN, YONGCHUN; LI, QUN; JIA, ZHONGJIANG
To: INCYTE CORPORATION
Reel/Frame 066021/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 4, 2024
From: INCYTE CORPORATION
To: INCYTE CORPORATION; INCYTE HOLDINGS CORPORATION
Reel/Frame 066021/0133 →
Continuity (8)
Continuation 18101014 · Jan 24, 2023
Continuation 17229397 · Apr 13, 2021
Continuation 16555620 · Aug 29, 2019
Continuation 15897598 · Feb 15, 2018
Continuation 15187296 · Jun 20, 2016
Continuation 14279929 · May 16, 2014
Provisional Application 61824683 · May 17, 2013
Related Publication 20240150327A1 · May 9, 2024
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