Small molecule inhibitors of the JAK family of kinases
2-((1r,4r)-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions mediated by JAK, such as inflammatory bowel disease.
1. A compound selected from the group consisting of
2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide;
2-((1r,4r)-4-(2-(1H-Imidazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;
2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(cyclopropylmethyl)acetamide; and
N-(2-Cyano-2-methylpropyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide.
2. A compound as claimed in claim 1 , wherein said compound is
2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide.
3. A compound as claimed in claim 1 , wherein said compound is
2-((1r,4r)-4-(2-(1H-Imidazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile.
4. A compound as claimed in claim 1 , wherein said compound is
2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(cyclopropylmethyl)acetamide.
5. A compound as claimed in claim 1 , wherein said compound is
N-(2-Cyano-2-methylpropyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide.
6. A compound as claimed in claim 2 , wherein said compound is in form 1s or in form 9.
7. A pharmaceutically acceptable salt of a compound selected from the group consisting of
2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(2-hydroxy-2-methylpropyl)acetamide;
2-((1r,4r)-4-(2-(1H-Imidazol-4-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile;
2-(1-((1r,4r)-4-(Cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-N-(cyclopropylmethyl)acetamide; and
N-(2-Cyano-2-methylpropyl)-2-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetamide.
8. A compound of formula (G)
wherein Q is selected from the group consisting of
made by a process comprising
heterocyclocondensation of compound Intermediate 2 to form compound Intermediate 3
9. A compound as claimed in claim 8 , wherein said heterocyclocondensation is performed by reacting said compound Intermediate 2 with compound (I3A)
10. A compound as claimed in claim 8 , wherein said process further comprises reacting compound Intermediate 3 with amine Q-NH2 and hydrolyzing the sulfonamide of compound Intermediate 3 to provide compound of formula (G), and wherein Q is
11. A compound as claimed in claim 10 , wherein said reacting compound Intermediate 2 with compound (I3A) is made in dimethylacetamide.
12. A compound as claimed in claim 10 , wherein said process further comprises subjecting said compound (G) to solvent equilibration at room temperature in 1,4-dioxane to yield said compound (G) in form 2.
13. A compound as claimed in claim 12 , wherein said process further comprises heating said compound (G) in form 2 to a temperature of about 200° C., followed by cooling to room temperature to yield said compound (G) in form 9.
14. A compound as claimed in claim 12 , wherein said process further comprises subjecting said compound (G) in form 2 to cyclic differential scanning calorimetry according to the temperature pattern 25° C.-200° C.-25° C.-300° C.-25° C. to yield said compound (G) in form 9.
15. A compound as claimed in claim 11 , wherein said reacting compound Intermediate 3 with amine Q-NH2 and said hydrolyzing the sulfonamide of compound Intermediate 3 take place in a basic medium.
16. A compound as claimed in claim 8 , wherein said process further comprises hydrolyzing the ester and sulfonamide moieties of compound Intermediate 3 to obtain compound Intermediate 4
17. A compound as claimed in claim 16 , wherein said process further comprises reacting compound Intermediate 4 with amine Q-NH 2 , wherein Q is selected from the group consisting of
18. A compound as claimed in claim 17 , wherein said hydrolyzing the ester and sulfonamide moieties is performed in a basic medium, and said reacting compound Intermediate 4 with amine Q-NH 2 is performed with an amide coupling reagent.
19. A compound as claimed in claim 18 , wherein said coupling reagent is bromotripyrrolidinophosphonium hexafluorophosphate.
20. A compound as claimed in claim 8 , wherein said process further comprises reducing compound Intermediate 1 to form compound Intermediate 2
21. A compound as claimed in claim 20 , wherein said reducing is performed with a palladium catalyst.
22. A compound as claimed in claim 20 , wherein said process further comprises displacing the chloro substituent in compound (I1DD) with the amine of compound (I1D) to form compound Intermediate 1
23. A compound as claimed in claim 22 , wherein said process further comprises deprotecting the amine of compound (I1C) to form compound (I1D)
24. A compound as claimed in claim 23 , wherein said process further comprises converting compound (I1B) to compound (I1C)
25. A compound as claimed in claim 24 , wherein said converting compound (I1B) to compound (I1C) is performed in dimethyl sulfoxide solvent.
26. A compound as claimed in claim 25 , wherein said dimethyl sulfoxide solvent also contains sodium cyanide.
27. A compound as claimed in claim 24 , wherein said process further comprises mesylating compound (I1A) to form compound (I1B)
28. A compound as claimed in claim 27 , wherein said mesylating compound (I1A) is performed with methanesulfonyl chloride.
29. A compound as claimed in claim 27 , wherein said process further comprises reducing the carboxylic group in amino-protected compound (I1AA) to form compound (I1A)
30. A compound of formula Ex.2
made by a process comprising a nitro-reductive cyclization of compound (R1)
with compound Intermediate 1
to form compound (R2),
and hydrolyzing the sulfonamide in said compound (R2).
31. A compound as claimed in claim 30 , wherein said hydrolyzing is performed with a base.
32. A compound as claimed in claim 30 , wherein said process further comprises displacing the chloro substituent in compound (I1DD) with the amine of compound (I1D) to form compound Intermediate 1
33. A compound as claimed in claim 32 , wherein said process further comprises deprotecting the amine of compound (I1C) to form compound (I1D)
34. A compound as claimed in claim 33 , wherein said process further comprises converting compound (I1B) to compound (I1C)
35. A compound as claimed in claim 34 , wherein said process further comprises mesylating compound (I1A) to form compound (I1B)
36. A compound as claimed in claim 35 , wherein said process further comprises reducing the carboxylic group in amino-protected compound (I1AA) to form an alcohol compound (I1A)
37. A compound as claimed in claim 30 , wherein said nitro-reductive cyclization is performed in the presence of sodium hydrosulfite.