Kinase inhibitors
The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.
1. A compound represented by structural formula I:
or a pharmaceutically acceptable salt thereof wherein:
A and A′ are independently —N— or —C(R + )—;
R 1 is halogen, —CN, —NO 2 , or -T1-Q1;
T1 is absent or a C1-10 aliphatic wherein one or more methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —S(O) p —, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J T1 ;
Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, or an 8-12 membered saturated, partially saturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from the group consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J Q1 ; wherein when R 1 is T1-Q1, then T1 and Q1 are not both absent;
R 2 is —H, —(CR ++ 2 ) n CN, —(CR ++ 2 ) n N(R) 2 , —(CR ++ 2 ) n OR, —(CR ++ 2 ) n C(O)N(R) 2 , or C1-10 aliphatic optionally substituted with one or more halogen, phenyl, OR*, or N(R*) 2 ;
each R 3 and R 4 independently are —H, halogen, C1-10 aliphatic, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl, wherein R 3 and R 4 are optionally and independently substituted with one or more selected from the group consisting of C1-10 alkyl, halogen, —CN, —NO 2 , —N(R*) 2 , —S(O) p R*, —S(O) p NR*, —C(O)N(R*) 2 , —NR*C(O), —OC(O)N(R) 2 , —N(R*)C(O)OR*, —N(R*)C(O)N(R*) 2 and —OR*; or
R 3 and R 4 taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, ═N—R*, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —NO 2 , —N(R*) 2 , —S(O) p R*, —S(O) p NR*, —C(O)N(R*) 2 , —NR*C(O), —OC(O)N(R*) 2 , —N(R*)C(O)OR*, —N(R*)C(O)N(R*) 2 and —OR*;
each R 5 and R 6 are independently —H, halogen, C1-10 haloaliphatic, or C1-10 aliphatic;
each J T1 is independently halogen, —OR^, —N(R^) 2 , or —CN;
each J Q1 is independently halogen, C1-10 alkyl, C1-10 haloalkyl, —OR″, —N(R″) 2 , —CN, —NO 2 , —S(O) p R″, —S(O) p NR″, acyl, carbalkoxyalkyl, or acetoxyalkyl;
each R + is independently —H, halogen, or C1-10 alkyl optionally and independently substituted with up to five halogen groups;
each R ++ is independently —H or halogen;
each R′ is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups;
each R^ is independently —H, C1-10 alkyl, or aralkyl wherein each R^ is optionally and independently substituted with up to five halogen groups;
each R″ is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups;
each R is independently —H or C1-10 alkyl optionally and independently substituted with up to five halogen groups;
each R* is independently —H or C-10 alkyl optionally and independently substituted with up to five halogen groups;
x is 0 or 1;
y is 0, 1 or 2;
each n is independently 0, 1, 2, or 3; and
each p is independently 0, 1, or 2.
2. The compound of claim 1 , wherein:
R 2 is —H, —(CR ++ 2 ) n CN, —(CR ++ 2 ) n N(R) 2 , —(CR ++ 2 ) n OR, —(CR ++ 2 ) n C(O)N(R) 2 , or C1-10 aliphatic optionally substituted with one or more halogen, OR*, or N(R*) 2 .
3. The compound of claim 2 , represented by structural formula I:
or a pharmaceutically acceptable salt thereof wherein:
A and A′ are independently —N— or —C(R + )—;
R 1 is halogen, —CN, —NO 2 , or -T1-Q1;
T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —S(O) p —, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J T1 ;
Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, or an 8-12 membered saturated, partially saturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from the group consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J Q1 ; wherein when R 1 is T1-Q1, then T1 and Q1 are not both absent;
R 2 is —H, C1-10 aliphatic, —(CR ++ 2 ) n CN, —(CR ++ 2 ) n N(R) 2 , —(CR ++ 2 ) n OR, or —(CR ++ 2 ) p C(O)N(R) 2 ;
each R 3 and R 4 independently are —H, halogen, C1-10 aliphatic, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl, wherein R 3 and R 4 are optionally and independently substituted with one or more selected from the group consisting of C1-10 alkyl, halogen, —CN, —NO 2 , —N(R*) 2 , —S(O) p R*, —S(O) p NR*, —C(O)N(R*) 2 , —NR*C(O), —OC(O)N(R) 2 , —N(R*)C(O)OR*, —N(R*)C(O)N(R*) 2 and —OR*; or
R 3 and R 4 taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —NO 2 , —N(R*) 2 , —S(O) p R*, —S(O) p NR*, —C(O)N(R*) 2 , —NR*C(O), —OC(O)N(R*) 2 , —N(R*)C(O)OR*, —N(R*)C(O)N(R*) 2 and —OR*;
each R 5 and R 6 are independently —H, halogen, C1-10 haloaliphatic, or C1-10 aliphatic;
each J T1 is independently halogen, —OR^, —N(R^) 2 , or —CN;
each J Q1 is independently halogen, C1-10 alkyl, C1-10 haloalkyl, —OR″, —N(R″) 2 , —CN, —NO 2 , —S(O) p R″, —S(O) p NR″, acyl, carbalkoxyalkyl, or acetoxyalkyl;
each R + is independently —H, halogen, or C1-10 alkyl optionally and independently substituted with up to five halogen groups;
each R ++ is independently —H or halogen;
each R′ is independently —H or C1-10 alkyl, optionally and independently substituted with up to five halogen groups;
each R^ is independently —H or C1-10 alkyl, optionally and independently substituted with up to five halogen groups;
each R″ is independently —H or C1-10 alkyl, optionally and independently substituted with up to five halogen groups;
each R is independently —H or C1-10 alkyl, optionally and independently substituted with up to five halogen groups;
each R* is independently —H or C-10 alkyl, optionally and independently substituted with up to five halogen groups;
x is 0 or 1;
y is 0, 1 or 2;
each n is independently 0, 1, 2, or 3; and
each p is independently 0, 1, or 2.
4. The compound of claim 1 wherein:
A is —N— or —C(R + )—; and A′ is —C(R + )—.
5. The compound of any one of claims 1 - 4 wherein:
R + is —H.
6. The compound of any one of claims 1 - 5 wherein:
R 1 is halogen, or -T1-Q1.
7. The compound of any one of claims 1 - 6 wherein:
T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —O—, —N(R′)—, or —C(O)—; and T1 is optionally and independently substituted with one or more J T1 .
8. The compound of any one of claims 1 - 7 wherein:
Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J Q1 .
9. The compound of any one of claims 1 - 8 wherein:
each J T1 is independently —OR^, —N(R^) 2 , or —CN.
10. The compound of any one of claims 1 - 9 wherein:
each J Q1 is independently C1-10 alkyl, —OR″, —N(R″) 2 , or acyl.
11. The compounds of any one of claims 1 - 10 wherein:
R 2 is C1-10 aliphatic, —(CR ++ 2 ) n CN, —(CR ++ 2 ) n N(R) 2 , —(CR ++ 2 ) n OR, or —(CR ++ 2 ) n C(O)N(R) 2 .
12. The compound of any one of claims 1 - 11 wherein:
each R 3 and R 4 independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R 3 and R 4 are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO 2 , —N(R*) 2 , and —OR*; or
R 3 and R 4 taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*) 2 , and —OR*.
13. The compound of any one of claims 1 - 11 wherein:
each R 3 and R 4 independently is —H, C1-10 aliphatic, cycloalkylalkyl, wherein R 3 and R 4 are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO 2 , —N(R*) 2 , and —OR*; or
R 3 and R 4 taken together with the carbon to which they are attached form C═O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*) 2 , and —OR*.
14. The compound of any one of claims 1 - 13 wherein:
A is —C(R + )—.
15. The compound of any one of claims 1 - 14 wherein:
J T1 is OR^.
16. The compounds of any one of claim 1 - 9 or 11 - 15 wherein:
R 2 is —H, C1-10 aliphatic, —(CR ++ 2 ) n CN, —(CR ++ 2 ) n N(R) 2 , or —(CR ++ 2 )—OR.
17. The compounds of any one of claim 1 - 4 , 6 - 13 , or 15 - 16 wherein the compound is represented by structural formula IB:
or a pharmaceutically acceptable salt thereof.
18. The compound of any one of claim 1 - 12 or 14 - 17 wherein:
R 3 and R 4 taken together with the carbon to which they are attached form a 3-8 membered saturated, or partially saturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*) 2 , and —OR*.
19. The compound of any one of claim 1 - 12 or 14 - 17 wherein:
R 3 and R 4 taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*) 2 , and —OR*.
20. The compound of any one of claim 1 - 9 , 11 - 12 , or 14 - 19 wherein:
R 2 is —H, or C1-10 aliphatic; and
R 3 and R 4 taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*) 2 , and —OR*.
21. The compound of any one of claim 1 - 12 or 14 - 19 wherein:
R 2 is —(CR ++ 2 ) n CN, —(CR ++ 2 ) n N(R) 2 , or —(CR ++ 2 )—OR,
R 3 and R 4 taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═O, ═S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —CN, —N(R*) 2 , and —OR*.
22. The compounds of any one of claim 1 - 9 , 11 - 12 , or 14 - 18 wherein:
R 2 is —H, C1-10 aliphatic, —(CR ++ 2 ) n CN, —(CR ++ 2 ) n N(R) 2 , —(CR ++ 2 ) n OR, or —(CR ++ 2 ) n C(O)N(R) 2 ; and
each R 3 and R 4 independently is —H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R 3 and R 4 are optionally and independently substituted with one or more selected from the group consisting of halogen, —CN, —NO 2 , —N(R*) 2 , and —OR*.
23. The compounds of any one of claims 1 - 22 wherein
R 5 is —H, Cl, C1-4 haloalkyl, or C1-4 alkyl; and
R 6 is —H or C1-4 alkyl.
24. The compounds of any one of claims 1 - 23 wherein
R 5 is —H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and
R 6 is —H.
25. The compounds of any one of claim 1 - 4 , 6 - 13 , or 15 - 24 wherein the compound is represented by structural formula IC:
or a pharmaceutically acceptable salt thereof.
26. A compound represented by a structural formula selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
27. A composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
28. A process for preparing a compound of claim 1 comprising:
a) boronation of a compound represented by a structural formula selected from the group consisting of:
in the presence of a boronation agent and a solvent, to give a compound represented by a structural formula selected from the group consisting of:
wherein:
each R x is —H or two R x s together form
b) cyclization of a compound represented by the following structural formula:
in the presence of hydrazine and a solvent to give a compound represented by the following structural formula:
c) suzuki coupling of the compound represented by formula ii with a compound represented by formula iv in the presence of a solvent, a catalyst complex and a base to give a compound of claim 1 .
29. A process for preparing a compound of claim 1 , comprising:
a) cyclization of compound represented by represented by the following structural formula:
in the presence of hydrazine and a solvent to give a compound represented by the following structural formula:
b) protection of a compound represented by iv to give a compound represented by the following structural formula:
c) boronation of a compound represented by v in the presence of a boronation agent and a solvent to give a compound represented by represented by the following structural formula:
wherein:
each R x is —H or two R x s together form
d) suzuki coupling of the compound represented by formula vi with a compound represented a structural formula selected from the groups consisting of:
in the presence of solvent, a catalyst complex and a base to give a compound represented by a structural formula selected from the group consisting of:
e) deprotection of the compound represented by vii in the presence of hydrazine to yield a compound of claim 1 .