Inhibitors of Bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-9353087-B2
Application number	US-201314406081-A
Country	US
Kind code	B2
Filing date	Jun 7, 2013
Priority date	Jun 8, 2012
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

The present invention provides a compound, solid forms, and compositions thereof, which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same. The present invention also provides methods of making provided compound and solid forms.

First claim

What is claimed is:

1. A compound:

or a pharmaceutically acceptable salt thereof.

2. A solid form of Compound I:

wherein Compound I is a free base.

3. The solid form of claim 2 , wherein the solid form is Form 1.

4. The solid form of claim 3 , having one or more peaks in its X-ray powder diffraction pattern selected from those at 9.708, about 11.174, about 12.485, about 15.558, about 16.293, about 16.790, about 17.470, about 18.550, about 18.966, about 20.776, about 22.439, about 23.347, about 24.551, about 25.028, about 26.167, about 28.152, about 29.739, and about 33.922 degrees 2-theta.

5. The solid form of claim 4 , having substantially all of the peaks in its X-ray powder diffraction pattern selected from those at about:

Angle 2-Theta °
Angle 2-Theta °

9.708
20.776

11.174
22.439

12.485
23.347

15.558
24.551

16.293
25.028

16.790
26.167

17.470
28.152

18.550
29.739

18.966
33.922.

6. The solid form of claim 2 , wherein the solid form is Form 2.

7. The solid form of claim 6 , having one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.834, about 8.826, about 9.886, about 13.030, about 14.429, about 16.779, about 18.108, about 19.835, about 20.561, about 22.426, and about 24.089 degrees 2-theta.

8. The solid form of claim 7 , having substantially all of the peaks in its X-ray powder diffraction pattern selected from those at about:

Angle 2-Theta °
Angle 2-Theta °

7.834
18.108

8.826
19.835

9.886
20.561

13.030
22.426

14.429
24.089.

16.779

9. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

10. A composition comprising the solid form of claim 2 and a pharmaceutically acceptable carrier or excipient.

11. A method of decreasing the enzymatic activity of Bruton's tyrosine kinase comprising contacting Bruton's tyrosine kinase with an effective amount of a compound of claim 1 or a composition thereof.

12. A method of treating a disorder selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, leukemia, or lymphoma comprising administering to a human subject an effective amount of a compound of claim 1 or a composition thereof.

13. A method comprising the steps of:
a) providing a pyrrolidinone of formula A:

wherein —OR LG is a suitable leaving group; and
b) contacting the pyrrolidinone of formula A with a suitable reducing agent to provide a hemiaminal of formula B:

14. The method of claim 13 , further comprising the steps of:
a) providing an amino alcohol of formula C:

wherein PG is a suitable protecting group; and
b) reacting the amino alcohol of formula C with the hemiaminal of formula B under suitable conditions to provide an ester of formula D:

15. The method of claim 14 , further comprising the step of reacting the ester of formula D under suitable conditions to provide a lactam of formula E:

16. The method of claim 15 , further comprising the step of deprotecting the lactam of formula E to provide a compound of formula F:

17. The method of claim 16 , further comprising the steps of:
a) providing pyrimidine G:

and
b) contacting the pyrimidine G with the compound of formula F under suitable conditions to provide compound I:

18. The method of claim 13 , further comprising the steps of:
a) providing amino alcohol J:

and
b) reacting amino alcohol J with the hemiaminal of formula B under suitable conditions to provide an ester of formula K:

19. The metho

Assignees

• Biogen Idec Inc
• Sunesis Pharmaceuticals Inc
• Biogen Ma Inc

Inventors

• Hopkins Brian T
• Cai Xiongwei
• Chan Timothy R
• Conlon Patrick
• Humora Michael
• Jenkins Tracy J
• Macphee Michael J
• Shi Xianglin
• Miller Ross A
• Thompson Andrew

Classifications

• C07D211/56

  Nitrogen atoms (nitro radicals C07D211/38) · CPC title

• C07D207/28

  2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D207/16

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title