Pyrazolylaminobenzimidazole derivatives as JAK inhibitors

Patent metadata

Field	Value
Publication number	US-10323019-B2
Application number	US-201715775990-A
Country	US
Kind code	B2
Filing date	Jul 10, 2017
Priority date	Jul 14, 2016
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

The present invention provides compounds of the formula below (I′): where R, and R1-R3 are as described herein, methods of treating patients for certain types of autoimmune diseases and cancer, and processes for preparing the compounds.

First claim

What is claimed is:

1. A compound of the formula, or a pharmaceutically acceptable salt thereof

wherein R is selected from:

R1 is selected from: H or —CH 3 ;
R2 is —CHF 2 or —CF 3 ; and
R3 is H or —CH 3 .

2. A compound according to claim 1 of the formula, or a pharmaceutically acceptable salt thereof,

wherein:
R is selected from:

R1 is selected from: H or —CH 3 ;
R2 is —CHF 2 or —CF 3 ; and
R3 is H or —CH 3 .

3. A compound according to claim 2 wherein R is

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 wherein R2 is —CF 3 , or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 which is

or a pharmaceutically acceptable salt thereof.

7. A compound which is (2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol 2-hydroxypropane-1,2,3-tricarboxylate hydrate.

8. A compound according to claim 6 which is (2R)-1,1,1-Trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol in crystalline form characterized by an X-ray powder diffraction pattern obtained from a CuKα source (λ=1.54056 Å), which comprises peaks at:
a) 15.5, 18.1, 18.3, 20.5, and 22.9+/−0.2° in 2 theta, or
b) 13.2, 15.5, 18.1, 18.3, 18.5, 20.5, 22.9, and 23.6, 23.7, +/−0.2° in 2 theta, or
c) 13.2, 15.5, 18.1, 18.3, 18.5, 19.0, 20.5, 22.9, 23.6, 23.6, 23.7, 24.7, and 26.5+/−0.2° in 2 theta.

9. A compound according to claim 7 which is (2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol 2-hydroxypropane-1,2,3-tricarboxylate hydrate in crystalline foam characterized by an X-ray powder diffraction pattern obtained from a CuKα source (λ=1.54060 Å), having a peak at 17.9 in combination with one or more of the peaks selected from the group consisting of 26.1, 26.6, and 22.7, with a tolerance for the diffraction angles of 0.2 degrees.

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

11. A pharmaceutical composition comprising greater than 80% w/w of a compound which is (2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol 2-hydroxypropane-1,2,3-tricarboxylate hydrate in crystalline form.

12. A pharmaceutical composition comprising greater than 90% w/w of a compound which is (2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol 2-hydroxypropane-1,2,3-tricarboxylate hydrate in crystalline form.

13. A method of treating a patient in need of treatment for arthritis wherein the method comprises administering to the patient an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 6 which is:

15. A method of treating a patient in need of treatment for ulcerative colitis wherein the method comprises administering to the patient an effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt thereof.

16. A method of treating a patient in need of treatment for Crohn's disease wherein the method comprises administering to the patient an effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt thereof.

17. A method of treating a patient in need of treatment for systemic lupus erythrematosus wherein the method comprises administering to the patient an effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier, diluent or excipient.

Assignees

• Lilly Co Eli

Inventors

• Bastian Jolie Anne
• Clayton Joshua Ryan
• Coates David Andrew
• Sall Daniel Jon
• Woods Timothy Andrew

Classifications

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title