Inhibitors of bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-2016355498-A1
Application number	US-201615173182-A
Country	US
Kind code	A1
Filing date	Jun 3, 2016
Priority date	Dec 5, 2013
Publication date	Dec 8, 2016
Grant date	—

Abstract

Disclosed herein are reversible and irreversible inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are described, 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 compound of Formula (IA) having the structure:

wherein:
ring A is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
W is —C(R 2 )— or —N—;
X is —C(R 2 )— or —N—;
Y is optionally present and when present is —CH 2 O—, —OCH 2 —, —OCH 2 CH 2 O—, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —S(O)—, —S(O) 2 —, —N(R 3 )S(O) 2 —, —S(O) 2 N(R 3 )—, —C(═NH)—, —C(═NH)N(R 3 )—, —C(═NH)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene;
Z is optionally present and when present is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
G is

R 1 is —R 4 , —CH 2 R 4 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)OR 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 9 ;
R 1 ′ is —C(O)R 9′ , —C(O)C(O)R 9 , —C(O)OR 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 9 ;
each R 2 is independently H, substituted or unsubstituted C 1 -C 4 alkyl, —CN, or halogen;
each R 3 is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl;
each R 4 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
R 5 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl; or R 1 and R 5 together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 6 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; or R 1 and R 6 are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 7 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ;
R 9 is —R 4 , or

R 10 is H, halogen, —CN, or -L 1 -L 2 ;
R 11 and R 12 are independently H, halogen, —CN, or -L 1 -L 2 ; or R 11 and R 12 taken together form a bond;
each L 1 is optionally present and when present each L 1 is independently substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 1 -C 12 heteroaryl, —C(═O)—, —O—, or —S—;
each L 2 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted C 1 -C 12 heteroaryl or —N(R 13 ) 2 ;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 2 -C 7 heterocycloalkyl, C 6 -C 12 aryl, or C 1 -C 12 heteroaryl;
n is 0-3;
p is 0-3; and
q is 0-3;
or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof;
provided that
i) when W is N, and R 1 is H, t-Boc, or —C(O)—CH═CH 2 ; then X is other than C-Et or N; and
ii) when W is N, G is

then X is CH or N;
iii) when W is N, and X is CH; then R 1 ′ is other than —C(O)Me, or t-Boc; and
iv) when n is 0; then each of p and q is independently 0, 1, or 2.

2 . The compound according to claim 1 , wherein the compound is of Formula (I) having the structure:

wherein:
ring A is substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
W is —C(R 2 )— or —N—;
X is —C(R 2 )— or —N—;
Y is optionally present and when present is —CH 2 O—, —OCH 2 —, —OCH 2 CH 2 O—, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)N(R 3 )—, —S(O)—, —S(O) 2 —, —N(R 3 )S(O) 2 —, —S(O) 2 N(R 3 )—, —C(═NH)—, —C(═NH)N(R 3 )—, —C(═NH)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene;
Z is optionally present and when present is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
G is

R 1 is —R 4 , —CH 2 R 4 , —C(O)R 9 , —C(O)C(O)R 9 , —C(O)OR 4 , —C(O)N(R 3 )(R 4 ), or —S(O) 2 R 9 ;
each R 2 is independently H, —CN, or halogen;
each R 3 is independently is H, or substituted or unsubstituted C 1 -C 4 alkyl;
each R 4 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl;
R 5 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl; or R 1 and R 5 together with the nitrogen atom to which they are attached are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 6 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ; or R 1 and R 6 are combined to form a substituted or unsubstituted C 2 -C 9 heterocycloalkyl ring;
each R 7 is independently halogen, —CN, —OH, —NH 2 , substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, or —N(R 3 ) 2 ;
R 9 is —R 4 , or

R 10 is H, halogen, —CN, or -L 1 -L 2 ;
R 11 and R 12 are independently H, halogen, —CN, or -L 1 -L 2 ; or R 11 and R 12 taken together form a b

Assignees

• Pharmacyclics Llc

Inventors

• Chen Wei
• Jia Zhaozhong J
• Thomas William D

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

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