Pyridazine compounds as JAK inhibitors
In one aspect, the invention provides a compound according to formula I, as well as tautomers, pharmaceutically acceptable salts, and hydrates thereof. Pharmaceutical compositions, methods of inhibiting Janus kinases (JAKs), and methods for treating a condition or disorder mediated at least in part by JAK kinase activity are also described.
1. A compound according to formula I:
or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof,
wherein:
D is selected from the group consisting of C 1-8 alkyl, C 6-10 aryl, C 3-8 cycloalkyl, and 5- to 6-membered heteroaryl,
each R 1a is independently selected from the group consisting of halo, hydroxy, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 5- to 8-membered heterocyclyl, or two R 1a moieties, together with the atoms to which they are attached, form a fused 5- to 6-membered ring;
L is selected from the group consisting of 5- to 6-membered heterocyclyl, —C(R) 2 —, and —[C(R) 2 ] 2 —, wherein each R is independently selected from the group consisting of H and C 1-4 alkyl;
the subscript s is 0 or 1
A is selected from the group consisting of C 6-10 aryl and 5- to 6-membered heteroaryl,
each R 2a is independently selected from the group consisting of halo, hydroxy, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 6-10 aryl, and 5- to 6-membered heterocyclyl, or two R 2a moieties, together with the atoms to which they are attached, form a fused 5- to 6-membered ring;
R 3 is selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, R 3a —(SO)—(R 3b ) t —, R 3a —(SO) 2 —(R 3b ) t —, R 3c —(CO)—(R 3d ) t —, (C 3-8 cycloalkyl)-(R 3e ) t —, and (5- to 8-membered heterocyclyl)-(R 3e ) t —; wherein
R 3a is selected from the group consisting of OH, C 1-8 alkyl, and N(R 0 ) 2 , wherein each R 0 is independently H or C 1-4 alkyl;
R 3b is selected from the group consisting of C 1-8 alkylene, and —NR 0 —, wherein R 0 is H or C 1-4 alkyl;
R 3c is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, 5- to 8-membered heterocyclyl, and N(R 0 ) 2 , wherein each R 0 is independently H or C 1-4 alkyl;
R 3d is selected from the group consisting of C 1-8 alkylene, and —NR 0 —, wherein R 0 is H or C 1-4 alkyl;
R 3e is selected from the group consisting of C 1-8 alkylene, and C 1-8 heteroalkylene; and
the subscript t is 0 or 1;
and wherein each heteroaryl group and each heterocyclic group are substituted with from 0 to 3 moieties independently selected from the group consisting of halo, cyano, C 1-4 alkyl, (C 1-4 alkyl)-(CO)—, and (R 4 ) 2 N—(CO)— wherein each R 4 is independently selected from the group consisting of H and C 1-4 alkyl.
2. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein A is C 6-10 aryl.
3. The compound of claim 2 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein A is phenyl.
4. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein A is 5- to 6-membered heteroaryl.
5. The compound of claim 4 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein A is selected from the group consisting of pyrazinyl, pyrazolyl, pyridinyl, and thiazolyl.
6. The compound of any one of claims 1 - 5 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein each R 2a is independently selected from the group consisting of halo, C 1-8 alkyl, and C 1-8 alkoxy, or two R 2a moieties, together with the atoms to which they are attached, form a fused 5- to 6-membered ring.
7. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is C 1-8 alkyl.
8. The compound of claim 7 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is selected from the group consisting of methyl and isopropyl.
9. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is C 6-10 aryl which is substituted with from 0 to 3 R 1a .
10. The compound of claim 9 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is phenyl.
11. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is C 3-8 cycloalkyl.
12. The compound of claim 11 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl.
13. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is 5- to 6-membered heteroaryl.
14. The compound of claim 13 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein D is selected from the group consisting of pyridinyl and thiophenyl.
15. The compound of any one of claims 1 or 7 - 14 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein each R 1a is independently selected from the group consisting of cyano, chloro, fluoro, methyl, methoxy, imidazolyl, and pyridinyl, or two R 1a moieties, together with the atoms to which they are attached, form a fused 5- to 6-membered ring.
16. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, and C 1-8 alkoxy.
17. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is selected from the group consisting of R 3a —(SO)—(R 3b ) t —, R 3a —(SO) 2 —(R 3b ) t —, and R 3c —(CO)—(R 3d ) t —.
18. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is selected from the group consisting of (C 3-8 cycloalkyl)-(R 3e ) t — and (5- to 8-membered heterocyclyl)-(R 3e ) t —.
19. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is selected from the group consisting of
20. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is selected from the group consisting of
21. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein the subscript s is 0.
22. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein the subscript s is 1 and L is selected from the group consisting of —C(R) 2 — and —[C(R) 2 ] 2 —.
23. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein the subscript s is 1 and L is 5- to 6-membered heterocyclyl.
24. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein
A is phenyl which is substituted with from 0 to 2 R 2a ; and
each R 2a is independently selected from the group consisting of halo, C 1-4 alkyl, and C 1-4 alkoxy; or two R 2a moieties, together with the carbon atoms to which they are attached, form a fused 5- to 6-membered ring.
25. The compound of claim 24 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein
D is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, and thiophenyl, each of which is substituted with from 0 to 2 R 1a , wherein
each R 1a is independently selected from the group consisting of halo, hydroxy, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 6-membered heteroaryl, and 5- to 8-membered heterocyclyl, or
two R 1a moieties, together with the atoms to which they are attached, form a fused 5- to 6-membered ring.
26. The compound of claim 24 or claim 25 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is selected from the group consisting of acetamido; (N-methylacetamido); dimethylcarbamoyl; N-methylcyclopropanecarboxamido; (N-methyl)methoxycarboxamido; (methylsulfonyl)methyl; (methylsulfinyl)methyl; (morpholino)methyl; methylsulfonyl; 1-(methylsulfonyl)ethyl; 1-methyl-1-(methylsulfonyl)ethyl; 2-(methylsulfonyl)ethyl; (methylsulfonyl)methylamino; morpholino; 4-acetylpiperazin-1-yl; piperazin-1-yl; 4-propionylpiperazin-1-yl; 4-(dimethylcarbamoyl)piperidin-1-yl; 1-propionylpiperidin-4-yl; 1,1-dioxidothiomorpholino; morpholine-4-carbonyl; pyrrolidine-1-carbonyl; and 2-(pyrrolidin-1-yl)ethoxy.
27. The compound of claim 25 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein A is phenyl with 0 R 2a moieties.
28. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein A is selected from the group consisting of pyrazolyl, pyridinyl, and thiazolyl.
29. The compound of claim 28 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein
D is selected from the group consisting of phenyl, pyridinyl, and piperidinyl, each of which is substituted with from 0 to 2 R 1a , wherein
each R 1a is independently selected from the group consisting of halo, cyano, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl, or
two R 1a moieties, together with the atoms to which they are attached, form a fused 5- to 6-membered ring.
30. The compound of claim 28 or claim 29 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, wherein R 3 is selected from the group consisting of hydrogen; methyl; ethyl; isopropyl; cyclopentyl; cyclopropylmethyl; 2-(dimethylamino)-2-oxoethyl; (tetrahydro-2H-pyran-4-yl)methyl; 1-(dimethylcarbamoyl)piperidin-4-yl)methyl; morpholino; morpholine-4-carbonyl; pyrrolidone-1-carbonyl; 1-propionylpiperidin-4-yl; piperazin-1-yl; and 4-acetylpiperazin-1-yl.
31. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, which is selected from the group consisting of:
32. The compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt or hydrate thereof, which is selected from the group consisting of:
33. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or diluent.
34. A method for treating cancer in a subject comprising the step administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 or claim 31 .
35. A method for treating organ transplants, asthma, COPD, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Crohn's disease, Type I diabetes, or psoriasis in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 or claim 31 .
36. A method for treating sickle cell disease in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 or claim 31 .
37. A kit comprising a composition of claim 33 , packing and instruction for use.
38. The method of 36 , wherein said sickle cell disease is selected from the group consisting of sickle cell anemia, sickle-hemoglobin C disease, sickle beta-plus thalassemia, and sickle beta-zero thalassemia.