Pyrazolopyrimidine derivatives useful as inhibitors of Bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-9975897-B2
Application number	US-201515317323-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 11, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

This invention relates to compounds of formula (I). The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.

First claim

The invention claimed is:

1. A compound according to formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
A is N or CR a ,
D is either a substituted or unsubstituted C 1-6 alkylene chain which is saturated or unsaturated and which optionally contains, where chemically possible, 1, 2, or 3 N, O, or S atoms in the chain, wherein the N, O, or S atoms are independently chosen at each occurrence;
or D represents a substituted or unsubstituted carbocyclic or heterocyclic moiety which is saturated or unsaturated and which contains from 3 to 8 atoms in the carbocyclic or heterocyclic ring, wherein the ring is optionally substituted with —NR b —, wherein —NR b — is bonded to the ring; and
wherein, when substituted, the alkylene chain or the carbocyclic or heterocyclic moiety includes 1 to 5 substituents independently selected at each occurrence from: halo, —OR b , —SR b , —NR b R c , NO, ═O, —CN, acyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, —SO 2 R b , SO 3 R b , —C(O)R b , and C(O)OR b ;
E is selected from C 1-4 alkyl, and:

Y is either O or NR b ;
X is selected from H, methyl, and CN;
L 1 is selected from a bond, —O—, —O(CR d R e ) m —, —NR b —, and —(CR d R e ) m —;
L 2 represents —NR b C(O)—;
n is selected from 1, 2, and 3;
m is selected from 1, 2, 3, and 4;
o is selected from 0, 1, 2, 3, and 4;
R a is selected from: H, halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, SH, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, NR b R c , —CN, acyl, —C(O)R b , —C(O)OR b , —SO 2 R b , and —SO 3 R b ;
R b and R c are independently selected at each occurrence from: H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 acyl, C 3-7 cycloalkyl, and C 3-7 halocycloalkyl;
R d and R e are independently selected at each occurrence from: H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 acyl, C 3-7 cycloalkyl, and C 3-7 halocycloalkyl;
R 1 is a group selected from a substituted or unsubstituted carbocyclic or heterocyclic moiety which either contains from 3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclic ring system, wherein, when substituted, R 1 contains 1 to 5 substituents independently selected at each occurrence from halo, OR b , —SR b , —NR b R c , —NO 2 , ═O, —CN, acyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, —SO 2 R b , SO 3 R b , —C(O)R b , —C(O)OR b , —C(O)NR b R c , and aryl optionally substituted by 1 or 2 halo atoms;
R 2 is selected from: H, halo, OR b , C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 cycloalkenyl, C 3-8 heterocycloalkenyl, —NR b R c , —CO 2 R b , —C(O)R b , and —C(O)NR b R c ; and
R 3 , R 4 , and R 5 are independently selected from: H, halo, —OR b , —CN, NR b R c , —CH 2 NR b R c , —CO 2 R b , —C(O)R b , —C(O)NR b R c , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with C 3-8 cycloalkyl, C 1-6 alkyl substituted with C 3-8 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 cycloalkenyl, C 3-8 heterocycloalkenyl, aryl, heteroaryl, alkaryl, and alkheteroaryl;
or R 3 and R 4 taken together with the carbon atoms to which they are attached form a C 3-8 cycloalkene, and R 5 is independently selected from: H, halo, —OR b , —CN, —NR b R c , —CH 2 NR b R c , —CO 2 R b , —C(O)R b , —C(O)NR b R c , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with C 3-8 cycloalkyl, C 1-6 alkyl substituted with C 3-8 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 , heterocycloalkenyl, aryl, heteroaryl, alkaryl, and alkheteroaryl;
or R 4 and R 5 taken together with the carbon atom to which they are attached form a C 3-8 cycloalkyl and R 3 is independently selected from: H, halo, —OR b , —CN, —NR b R c , CH 2 NR b R c , —CO 2 R b , —C(O)R b , —C(O)NR b R c , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with C 3-8 cycloalkyl, C 1-6 alkyl substituted with C 3-8 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 cycloalkenyl, C 3-8 heterocycloalkenyl, aryl, heteroary, alkaryl, and alkheteroaryl;
or R 3 and R 5 taken together with the carbon atoms to which they are attached form a C—C triple bond and R 4 is independently selected from: H, halo, —OR b , —CN, —NR b R c , CH 2 NR b R c , —CO 2 R b , —C(O)R b , —C(O)NR b R c , C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkyl substituted with C 3-8 cycloalkyl, C 1-6 alkyl substituted with C 3-8 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 cycloalkenyl, C 3-8 heterocycloalkenyl, aryl, heteroaryl, alkaryl, and alkheteroaryl.

2. A compound of claim 1 , wherein A is CR a and R a is H, fluoro, chloro, or C 1-4 haloalkyl.

3. A compound of claim 1 , wherein R 1 is a substituted or unsubstituted: C 3-8 cycloalkyl, C 6-14 aryl, or C 5-14 heteroaryl, wherein the C 3-8 cycloalkyl group is saturated or unsaturated, and wherein when substituted, R 1 contains 1, 2, or 3 substituents independently selected at each occurrence from: halo, —OR b , —SR b , —NR b R c , NO 2 , ═O, —CN, acyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, —SO 2 R b , SO 3 R b , —C(O)R b , —C(O)OR b , —C(O)NR b R c , and aryl optionally substituted by 1 or 2 halo atoms.

4. A compound of claim 1 , wherein R 1 is unsubstituted phenyl or phenyl substituted with 1, 2, or 3 substituents independently selected at each occurrence from: halo, —OR b , —CN, C 1-6 alkyl, and C 1-6 haloalkyl.

5. A compound of claim 1 , wherein n is 1.

6. A compound of claim 1 , wherein R 2 is hydrogen.

7. A compound of claim 1 , wherein R 3 , R 4 , and R 5 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, —CN, —CH 2 NR b R c , and C 1-6 alkyl, wherein R b and R c are independently selected from hydrogen and C 1-4 alkyl.

8. A compound of claim 1 , wherein R 3 , R 4 , and R 5 are each hydrogen.

9. A compound of claim 1 , wherein E is:

10. A compound of claim 1 , wherein E is:

11. A compound of claim 1 , wherein D is substituted or unsubstituted C 3-8 heterocycloalkyl.

12. A compound of claim 1 , wherein D is

13. A compound according to formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
A is N or CR a ;
D is cyclopentyl;
E is absent;
L 1 is selected from a bond, —O—, —O(CR d R e ) m —, —NR b —, and —(CR d R e ) m —;
L 2 represents —NR b C(O)—;
n is selected from 1, 2, and 3;
m is selected from 1, 2, 3, and 4;
R a is selected from: H, halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, SH, C 1-6 alkoxy, C 2-6 alke

Assignees

• Loxo Oncology Inc

Inventors

• Calder Mathew
• Guisot Nicolas E S

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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