Bipyrazole derivatives as JAK inhibitors
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.
1. A method of treating viral diseases 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 , and —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 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, 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) a compound of Formula II:
or a pharmaceutically acceptable salt thereof; or
b) compound of Formula III:
or a pharmaceutically acceptable salt thereof; or
c) a compound of Formula IV:
or a pharmaceutically acceptable salt thereof; or
d) a compound of Formula IIa:
or a pharmaceutically acceptable salt thereof; or
e) compound of Formula IIIa:
or a pharmaceutically acceptable salt thereof; or
f) a compound of Formula IVa:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is selected from:
5-[3-(cyanomethyl)-3-(3′-methyl-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,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-isopropylpyrazine;
4-[3-(cyanomethyl)-3-(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;
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,1′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.
15. 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-[(1 S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the viral disease is Epstein Barr Virus (EBV).
17. The method of claim 1 , wherein the viral disease is Epstein Barr Virus (EBV), and wherein the compound is 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,PH-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 viral disease is Hepatitis B.
19. The method of claim 1 , wherein the viral disease is Hepatitis B, and 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.
20. The method of claim 1 , wherein the viral disease is Hepatitis C.
21. The method of claim 1 , wherein the viral disease is Hepatitis C, and 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.
22. The method of claim 1 , wherein the viral disease is HTLV 1.
23. The method of claim 1 , wherein the viral disease is HTLV 1, and 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-[(1 S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.
24. The method of claim 1 , wherein the viral disease is HIV.
25. The method of claim 1 , wherein the viral disease is HIV, and 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.
26. The method of claim 1 , wherein the viral disease is Varicella-Zoster Virus (VZV).
27. The method of claim 1 , wherein the viral disease is Varicella-Zoster Virus (VZV), and 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.
28. The method of claim 1 , wherein the viral disease is Human Papilloma Virus (HPV).
29. The method of claim 1 , wherein the viral disease is Human Papilloma Virus (HPV), and 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.