Substituted imidazo[1,2-b]pyrazoles as bruton'S tyrosine kinase modulators
The invention is fused heterocyclic compounds of formula (I), and salts thereof, compositions thereof, and methods of use therefor. In particular, disclosed herein are certain fused heterocyclic compounds that can be useful for inhibiting protein kinase, including Bruton's tyrosine kinase (Btk), and for treating disorders mediated thereby.
1. A compound of Formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms selected from N, S or O;
each W is independently —(CH 2 )— or —C(O)—;
L is a bond, CH 2 , NR 12 , O, or S;
S/D is a single or double bond, wherein when S/D is a double bond, R 5 and R 7 are absent;
m is 0;
n is 0, 1, 2, 3 or 4, wherein when n is 2, 3 or 4, each R 2 may be different;
p is 1;
R 1 , R 4 , R 5 , R 6 and R 7 are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ;
R 2 is halogen, alkyl, —S-alkyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 ;
R 12 is H or lower alkyl;
R 13 , R 14 and R 15 are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl; wherein (R 13 and R 14 ), and/or (R 14 and R 15 ) together with the atom(s) to which they are attached, may independently form a ring selected from cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl rings, each optionally substituted with at least one substituent R 16 ; and
R 16 is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″,NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, or —NR′SO 2 R″, wherein R′, R″, and R′″ are each independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; halogen, alkyl, alkenyl, alkynyl, cycloalkyl, wherein R′, R″, and R′″ are each independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein (R′ and R″) and/or (R″ and R′″) together with the atom(s) to which they are attached, may independently form a ring selected from cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl rings.
2. The compound of claim 1 , wherein:
(i) S/D is a double bond and R 5 and R 7 are absent; or
(ii) R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are each optionally substituted with at least one substituent R 16 ; or
(iii) A is phenyl; or
(iv) each R 2 is independently halogen, lower alkyl, or lower alkoxy; or
(v) S/D is a single bond.
3. The compound of claim 1 , wherein:
(i) S/D is a double bond and R 5 and R 7 are absent; or
(ii) S/D is a single bond;
A is phenyl; and
each R 2 is independently halogen, lower alkyl, or lower alkoxy.
4. The compound of claim 1 , wherein:
(i) S/D is a double bond and R 5 and R 7 are absent; and
A is phenyl; or
(ii) S/D is a single bond; and
A is phenyl.
5. The compound of claim 1 , wherein:
(i) S/D is a double bond and R 5 and R 7 are absent;
R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are each optionally substituted with at least one substituent R 16 , wherein R 16 is halogen, lower alkyl, or lower alkoxy; or
(ii) S/D is a double bond and R 5 and R 7 are absent;
A is phenyl; and
each R 2 is independently halogen, lower alkyl, or lower alkoxy; or
(iii) S/D is a single bond;
A is phenyl;
each R 2 is independently halogen, lower alkyl, or lower alkoxy; and
R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are each optionally substituted with at least one substituent R 16 , wherein R 16 is halogen, lower alkyl, or lower alkoxy.
6. The compound of claim 1 , wherein R 4 is C 1 -C 8 alkyl-NR′R″, saturated or unsaturated C 3 -C 8 heterocyclyl containing at least one nitrogen atom, or phenyl, each optionally substituted with a —COR′ substituent.
7. The compound of claim 1 , wherein R 4 is —CH 2 NH 2 , anilinyl, azetidinyl, pyrrolidinyl, piperidinyl, or azacycloheptenyl, each optionally N-substituted with a —COR′ substituent.
8. The compound of claim 1 , wherein R 4 is selected from:
9. The compound of claim 1 , wherein R 6 is C 1 -C 8 alkyl-NR′R″, saturated or unsaturated C 3 -C 8 heterocyclyl containing at least one nitrogen atom, or phenyl, each optionally substituted with a —COR′ substituent.
10. The compound of claim 1 , wherein R 6 is —CH 2 NH 2 , anilinyl, azetidinyl, pyrrolidinyl, piperidinyl, or azacycloheptenyl, each optionally N-substituted with a —COR′ substituent.
11. The compound of claim 1 , wherein R 6 is selected from:
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in unit dosage form and one or more pharmaceutically acceptable carriers.
13. A combination comprising a therapeutically effective amount of a compound of claim 1 and at least one additional therapeutically active agent.
14. A method of modulating Bruton's tyrosine kinase activity in a person, which comprises administering to a person in need thereof a therapeutically effective amount of a compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof.
15. A compound selected from the group consisting of:
or a stereoisomer or pharmaceutically acceptable salt thereof.