Inhibitors of bruton'S tyrosine kinase

Patent metadata

Field	Value
Publication number	US-9133198-B2
Application number	US-201313890498-A
Country	US
Kind code	B2
Filing date	May 9, 2013
Priority date	Sep 22, 2006
Publication date	Sep 15, 2015
Grant date	Sep 15, 2015

Abstract

Disclosed herein are compounds of Formula (A) that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

First claim

What is claimed is:

1. A method for treating acute lymphoblastic leukemia (ALL) in an individual comprising administering to a subject in need thereof a therapeutically effective amount an irreversible covalent Btk inhibitor having the structure of Formula (A):

wherein
A is N;
R 1 is L 2 -(substituted or unsubstituted heteroaryl) or L 2 -(substituted or unsubstituted aryl), where
L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 -alkenyl);
R 2 and R 3 are independently selected from H or lower alkyl;
R 4 is L 3 -X-L 4 -G, wherein,
L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, or optionally substituted or unsubstituted alkynyl;
X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O) 2 , —NH, —NR 9 , —NHC(O), —C(O)NH, —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NH, —NHS(═O) 2 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 10 C(O)NR 10 —, heteroaryl, aryl, —NR 10 C(═NR 11 )NR 10 —, —NR 10 C(═NR 11 )—, —C(═NR 11 )NR 10 —, —OC(═NR 11 )—, or —C(═NR 11 )O—;
L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycle;
or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring;
G is

wherein,
R 6 , R 7 and R 8 are each independently H;
R 9 is selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
each R 10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
two R 10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R 10 and R 11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or each R 11 is independently selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 , —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl; or a pharmaceutically acceptable solvate, hydrate, or salt thereof.

2. The method of claim 1 , wherein the inhibitor of Btk is administered orally.

3. The method of claim 1 , wherein the inhibitor forms a covalent bond to a cysteine sidechain of a Bruton's tyrosine kinase (Btk).

4. The method of claim 3 , wherein the cysteine sidechain of the Btk is the sidechain of cysteine 481.

5. The method of claim 1 , wherein the inhibitor is a compound having the structure:

6. A method for treating acute lymphoblastic leukemia (ALL) in an individual comprising administering to the individual in need thereof an inhibitor of Bruton's tyrosine kinase (Btk), having the structure:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 wherein R 1 is L 2 -substituted or unsubstituted aryl.

8. The method of claim 7 wherein L 2 is a bond.

9. The method of claim 8 wherein L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring.

10. The method of claim 9 wherein G is

Assignees

• Pharmacyclics Inc
• Pharmacyclics Llc

Inventors

• Honigberg Lee
• Verner Erik
• Pan Zhengying

Classifications

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title