IP Library › Patent Application 16577873

Patent Application

App. No. 16/577,873

INHIBITORS OF BRUTONS TYROSINE KINASE

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Patent No.: US None
App. No.: 16/577,873

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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.

Claims (77)

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 ,

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:

W is —C(R 2 )— or —N—;

X is —C(R 2 )— or —N—;

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;

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 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;

p is 0-3; and

q is 0-3;

or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof.

3 . The compound of claim 1 , wherein

G is

4 . The compound of claim 3 , wherein

G is

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

wherein A, W, X, Y, Z, R 1 , R 5 , and R 6 are as in claim 2 .

6 . The compound of claim 5 , wherein R 6 is Me.

7 . The compound of claim 5 , wherein ring A is phenyl.

8 . The compound of claim 5 , wherein Y is absent, —CH 2 O—, —OCH 2 —, —O—, —N(R 3 )—, —C(O)—, —N(R 3 )C(O)—, —C(O)N(R 3 )—, or substituted or unsubstituted C 1 -C 4 alkylene.

9 . The compound of claim 5 , wherein Z is 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.

10 . The compound of claim 5 , wherein R 1 is —C(O)R 9 .

11 . The compound of claim 10 , wherein R 9 is —R 4 , and R 4 is substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 1 -C 12 heteroaryl.

12 . The compound of claim 5 , wherein ring A is substituted or unsubstituted C 1 -C 12 heteroaryl.

13 . The compound of claim 12 , wherein ring A is pyridyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl.

14 . The compound of claim 5 , wherein X is —C(H)—.

15 . The compound of claim 5 , wherein X is —N—.

16 . The compound of claim 5 , wherein W is —C(H)—.

17 . The compound of claim 5 , wherein W is —N—.

18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.

19 . A method for treating an autoimmune disease or condition comprising administering to a patient in need a therapeutically effective amount of a compound of claim 1 .

20 . The method of claim 19 , wherein the autoimmune disease is selected from rheumatoid arthritis or lupus.