PYRROLOPYRIMIDINE COMPOUNDS AS KINASE INHIBITORS
Disclosed herein are methods of using pyrrolo[2,3-d]pyrimidine Btk inhibitors, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, and inflammatory diseases or conditions.
1 . A method for treating an autoimmune disease or condition, a heteroimmune disease or condition, or an inflammatory disease or condition comprising administering to a patient in need a therapeutically effective amount of a compound of Formula (I) having the structure:
wherein:
R 1 is halogen, —CN, —OH, —NH 2 , —SH, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted C 3 -C 8 cycloalkyl;
G is substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —SCH 3 , —N(R 21 )S(═O) 2 R 23 , S(═O) 2 N(R 21 )(R 22 ), —S(═O)R 23 , —S(═O) 2 R 23 , —C(═O)R 23 , —OC(═O)R 23 , —CO 2 R 21 , N(R 21 )(R 22 ), —C(═O)N(R 21 )(R 22 ), —N(R 21 )C(═O)R 23 , N(R 21 )C(═O)OR 22 , N(R 21 )C(═O)N(R 21 )(R 22 ), or L a -Ar;
L a is a bond, —CH 2 —, —CH(OH)—, —C(O)—, —CH 2 O—, —OCH 2 —, —SCH 2 , —CH 2 S—, —N(R 21 )—, —N(R 21 )C(O)—, —C(O)N(R 21 )—, —N(R 21 )C(O)N(R 21 )—, —O—, —S—, —S(O) 2 —, —N(R 21 )S(O) 2 —, or —S(O) 2 N(R 21 )—;
Ar is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
each R 24 is independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —SCH 3 , —N(R 21 )S(═O) 2 R 23 , S(═O) 2 N(R 21 )(R 22 ), —S(═O)R 23 , —S(═O) 2 R 23 , —C(═O)R 23 , —OC(═O)R 23 , —CO 2 R 21 , N(R 21 )(R 22 ), —C(═O)N(R 21 )(R 22 ), —N(R 21 )C(═O)R 23 , N(R 21 )C(═O)OR 22 , —N(R 21 )C(═O)N(R 21 )(R 22 ), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl;
each R 21 and R 22 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
each R 23 is each independently substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
n is 0-4;
Y is an optionally substituted group selected from among C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 6 -C 12 arylene, C 3 -C 12 heteroarylene, C 1 -C 6 alkyleneC 6 -C 12 arylene, C 1 -C 6 alkyleneC 3 -C 12 heteroarylene, C 1 -C 6 alkyleneC 3 -C 8 cycloalkylene, C 1 -C 6 alkyleneC 2 -C 7 heterocycloalkylene, C 3 -C 8 cycloalkylene, C 2 -C 7 heterocycloalkylene, fused C 3 -C 8 cycloalkyleneC 2 -C 7 heterocycloalkylene, and spiro C 3 -C 8 cycloalkyleneC 2 -C 7 heterocycloalkylene;
Z is —C(═O)—, —N(R a )C(═O)—, or —N(R a )S(═O) x —, where x is 1 or 2, and R a is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 —C cycloalkyl;
R 6 is H or L-J-W;
R 7 and R 8 are independently H or L-J-W; or R 7 and R 8 taken together form a bond;
L and J are each independently a bond, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted C 1 -C 6 heteroalkylene, substituted or unsubstituted C 2 -C 7 heterocycloalkylene, substituted or unsubstituted C 6 -C 12 arylene, substituted or unsubstituted C 3 -C 12 heteroarylene, —CO—, —O—, or —S—;
W is H, or NR 25 R 26 ; and
R 25 and R 26 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 —C 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, or substituted or unsubstituted C 3 -C 12 heteroaryl; or
a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 , wherein G is L a -Ar.
3 . The method of claim 2 , wherein L a is —O—; and Ar is phenyl.
4 . The method of claim 3 , wherein Y is C 2 -C 7 heterocycloalkylene or phenyl.
5 . The method of claim 4 , wherein Z is —C(═O)—, —NHC(═O)—, or —N(CH 3 )C(═O)—.
6 . The method of claim 5 , wherein R 6 and R 8 are H; R 7 is H or L-J-W; L is a bond; J is —CH 2 —; and W is NR 25 R 26 .
7 . The method of claim 6 , wherein R 25 is CH 3 and R 26 is CH 3 or cyclopropyl.
8 . The method of claim 1 , wherein n is 0.
9 . The method of claim 1 , wherein R 1 is —F, —Cl, —CH 3 , or —OCH 3 .
10 . A method for treating an autoimmune disease or condition, a heteroimmune disease or condition, or an inflammatory disease or condition comprising administering to a patient in need a therapeutically effective amount of a compound of Formula (I) having the structure:
wherein:
R 1 is halogen, —CN, —OH, —NH 2 , —SH, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted C 3 -C 8 cycloalkyl;
G is substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, halogen, —CN, —NO 2 ,
—OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —SCH 3 , —N(R 21 )S(═O) 2 R 23 , S(═O) 2 N(R 21 )(R 22 ), —S(═O)R 23 , —S(═O) 2 R 23 , —C(═O)R 23 , —OC(═O)R 23 , —CO 2 R 21 , N(R 21 )(R 22 ), —C(═O)N(R 21 )(R 22 ), —N(R 21 )C(═O)R 23 , N(R 21 )C(═O)OR 22 , N(R 21 )C(═O)N(R 21 )(R 22 ), or
L a -Ar;
L a is a bond, —CH 2 —, —CH(OH)—, —C(O)—, —CH 2 O—, —SCH 2 , —CH 2 S—, —N(R 21 )—, —N(R 21 )C(O)—, —C(O)N(R 21 )—, —N(R 21 )C(O)N(R 21 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 21 )S(O) 2 —, or —S(O) 2 N(R 21 )—;
Ar is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
each R 24 is independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —SCH 3 , —N(R 21 )S(═O) 2 R 23 , S(═O) 2 N(R 21 )(R 22 ), —S(═O)R 23 , —S(═O) 2 R 23 , —C(═O)R 23 , —OC(═O)R 23 , —CO 2 R 21 , N(R 21 )(R 22 ), —C(═O)N(R 21 )(R 22 ), —N(R 21 )C(═O)R 23 , N(R 21 )C(═O)OR 22 , N(R 21 )C(═O)N(R 21 )(R 22 ), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl;
each R 21 and R 22 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
each R 23 is each independently substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
n is 0-4;
Y is an optionally substituted group selected from among C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 6 -C 12 arylene, C 3 -C 12 heteroarylene, C 1 -C 6 alkyleneC 6 -C 12 arylene, C 1 -C 6 alkyleneC 3 -C 12 heteroarylene, C 1 -C 6 alkyleneC 3 -C 8 cycloalkylene, C 1 -C 6 alkyleneC 2 -C 7 heterocycloalkylene, C 3 -C 8 cycloalkylene, C 2 -C 7 heterocycloalkylene, fused C 3 -C 8 cycloalkyleneC 2 -C 7 heterocycloalkylene, and spiro C 3 -C 8 cycloalkyleneC 2 -C 7 heterocycloalkylene;
Z is —C(═O)—, —N(R a )C(═O)—, —S(═O) x —, or —N(R a )S(═O) x , where x is 1 or 2, and R a is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
R 6 is H or L-J-W;
R 7 and R 8 are independently H or L-J-W; or R 7 and R 8 taken together form a bond;
L and J are each independently a bond, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted C 1 -C 6 heteroalkylene, substituted or unsubstituted C 2 -C 7 heterocycloalkylene, substituted or unsubstituted C 6 -C 12 arylene, substituted or unsubstituted C 3 -C 12 heteroarylene, —CO—, —O—, or —S—;
W is H, or NR 25 R 26 ; and
R 25 and R 26 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 —C 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, or substituted or unsubstituted C 3 -C 12 heteroaryl; or
a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt thereof.
11 . The method of claim 10 , wherein G is L a -Ar.
12 . The method of claim 11 , wherein L a is —O—; and Ar is phenyl.
13 . The method of claim 12 , wherein Y is C 2 -C 7 heterocycloalkylene or phenyl.
14 . The method of claim 13 , wherein Z is —C(═O)—, —NHC(═O)—, or —N(CH 3 )C(═O)—.
15 . The method of claim 14 , wherein R 6 and R 8 are H; R 7 is H or L-J-W; L is a bond; J is —CH 2 —; and W is NR 25 R 26 .
16 . The method of claim 15 , wherein R 25 is CH 3 and R 26 is CH 3 or cyclopropyl.
17 . The method of claim 10 , wherein n is 0.
18 . The method of claim 10 , wherein R 1 is —F, —CH 3 , or —OCH 3 .
19 . A method for treating an autoimmune disease or condition, a heteroimmune disease or condition, or an inflammatory disease or condition comprising administering to a patient in need a therapeutically effective amount of any one compound selected from:
or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof; wherein
R is methyl, —CN, fluoro, chloro, hydroxy, —NH 2 , or —CO 2 H; and
X is methyl, ethyl, propyl, isopropyl, cyclopropyl, tert-butyl, or trifluoromethyl.