Pyrazolo[1,5-a]pyrimidines useful as inhibitors of protein kinases
The present invention relates to compounds useful as inhibitors of protein kinases. 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 the compounds of the invention.
1. A compound of formula I′:
or a pharmaceutically accepted salt thereof, wherein
R is —(C═Q)R 2a , CN, or Y; wherein
Y is a 5-6 membered aryl or heteroaryl ring; wherein said heteroaryl ring is selected from
each Y is independently and optionally substituted with 0-4 J Y ;
Q is O, NH, NR′, or S;
R′ is C 1-6 alkyl optionally substituted with 0-4 occurrences of halo, C 1-6 aliphatic, NO 2 , NH 2 , —N(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , SH, —S(C 1-6 alkyl), OH, —O(C 1-6 alkyl), —C(O)(C 1-6 alkyl), —C(O)NH 2 , —C(O)N(C 1-6 alkyl), or —C(O)N(C 1-6 alkyl) 2 ;
R 2a is C 1-6 aliphatic, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, OR 5 , or N(R 5 ) 2 ; and each R 2a is independently and optionally substituted with 0-5 J 2a ;
R 1 is H, —C(O)(C 1-6 alkyl), —C(O)O(C 1-6 alkyl), —C(O)NH 2 , —C(O)N(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 ; or C 1-6 aliphatic; each R 1 is optionally substituted with 0-4 occurrences of halo, C 1-6 haloalkyl, C 1-6 aliphatic, NO 2 , NH 2 , —N(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , SH, —S(C 1-6 alkyl), OH, or —O(C 1-6 alkyl);
Z is a bond;
R 3 and R 4 are each independently H, halogen, C 1-6 alkoxy, N(R 5 ) 2 , CN, NO 2 , or U m —V wherein m is 0 or 1;
V is H, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloaliphatic, 5-10 membered heterocyclyl, or C 1-12 aliphatic wherein: up to two methylene units of the alkylidene chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; V is optionally substituted with 0-4 R 8 ;
U is C 1-12 alkylidene chain wherein up to two methylene units of the chain are optionally and independently replaced by —NH—, —NR 5 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 5 —, —C(═N—CN), —NHCO—, —NR 5 CO—, —NHC(O)O—, —NR 5 C(O)O—, —SO 2 NH—, —SO 2 NR 5 —, —NHSO 2 —, —NR 5 SO 2 —, —NHC(O)NH—, —NR 5 C(O)NH—, —NHC(O)NR 5 —, —NR 5 C(O)NR 5 , —OC(O)NH—, —OC(O)NR 5 —, —NHNH—, —NHNR 5 —, —NR 5 NR 5 —, —NR 5 NH—, —NHSO 2 NH—, —NR 5 SO 2 NH—, —NHSO 2 NR 5 —, —NR 5 SO 2 NR 5 —, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR 5 —; U is optionally substituted with 0-6 J U ;
R 5 is C 1-4 haloalkyl, —C(O)COR 6 , —C(O)R 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —SO 2 R 6 , C 0-6 alkyl-heterocyclyl, C 0-6 alkyl-heteroaryl, C 0-6 alkyl-aryl, C 0-6 alkyl-cycloaliphatic or C 1-6 aliphatic wherein up to three methylene unit of the aliphatic chain are optionally and independently replaced by —NR″—, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR″—, —NR″CO—, —NR″C(O)O—, —SO 2 NR″—, —NR″SO 2 —, —C(O)NR″NR″—, —NR″C(O)NR″—, —OC(O)NR″—, —NR″NR″—, —NR″SO 2 NR″—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR″— in a chemically stable arrangement; each R 5 is independently and optionally substituted with 0-5 J R5 ; or two R 5 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J′;
R 6 is H, C 1-6 alkoxy, C 1-4 haloalkyl, C 0-6 alkyl-heterocyclyl, C 0-6 alkyl-heteroaryl, C 0-6 alkyl-aryl, C 0-6 alkyl-cycloaliphatic, or C 1-6 aliphatic wherein up to two methylene units of the aliphatic chain are optionally and independently replaced by a heteroatom selected from O, N, or S in a chemically stable arrangement; each R 6 is independently and optionally substituted with 0-5 J R6 ; or two R 6 groups taken together with the atom to which they are attached optionally join to form a 5-10 membered carbocyclic or heterocyclic ring; wherein said ring is optionally substituted with 0-4 J″;
R 8 is halogen, C 1-4 haloalkyl, phenyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, —OR 6 , —N(R 6 ) 2 , —SR 6 , NO 2 , CN, —COOR 6 , —C(O)N(R 6 ) 2 , —SO 2 R 6 , —SO 2 N(R 6 ) 2 , —NR 6 C(O)R 6 , —C(O)R 6 , —OC(O)R 6 , —NR 6 C(O)O—R 6 , —NR 6 SO 2 —R 6 , —C(O)NR 6 N(R 6 ) 2 , —NR 6 C(O)N(R 6 ) 2 , —OC(O)N(R 6 ) 2 , —NR 6 N(R 6 ) 2 , —NR 6 SO 2 N(R 6 ) 2 or C 1-12 aliphatic, wherein up to three methylene units of the aliphatic chain can be optionally interrupted with —C(O)R 6 , —C(O)O—, —OC(O)—, —C(O)—, —C(O)N(R 6 )—, —NR 6 CO(R 6 )—, —O—, —NR 6 —, or —S—; each R 8 is independently and optionally substituted with 0-5 J R8 ;
each J Y , J 2a , J u , J R5 , J R6 , J R8 , J′, and J″ is independently selected from N(R 9 ) 2 , SR 9 , OR 9 , halo, CN, NO 2 , COOR 9 , C(O)R 9 , SO 2 R 9 , SOR 9 , —X—CF3, —X—SH, —X—OH, C 1-4 haloalkyl, C 6-10 aryl, —X—(C 6-10 aryl), 5-10 membered heteroaryl, —X-(5-10 membered heteroaryl), C 3-10 cycloaliphatic, —X—(C 3-10 cycloaliphatic), 5-10 membered heterocyclyl, —X-(5-10 membered heterocyclyl), or X;
X is C 1-12 aliphatic wherein up to two methylene units of the alkylidene chain are optionally and independently replaced by —NH—, —NR″—, —O—, —S—, —C 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR″—, —C(═N—CN), —NHCO—, —NR″CO—, —NHC(O)O—, —NR″C(O)O—, —SO 2 NH—, —SO 2 NR″—, —NHSO 2 —, —NR″SO 2 —, —NHC(O)NH—, —NR″C(O)NH—, —NHC(O)NR″—, —NR″C(O)NR″, —OC(O)NH—, —OC(O)NR″—, —NHNH—, —NHNR″—, —NR″NR″—, —NR″NH—, —NHSO 2 NH—, —NR″SO 2 NH—, —NHSO 2 NR″—, —NR″SO 2 NR″—, —SO—, —SO 2 —, —PO—, —PO 2 —, or —POR″—; in a chemically stable arrangement; wherein R″ is H or C 1-6 aliphatic;
each J Y , J 2a , J u , J R5 , J R6 , J′, and J″ is optionally and independently substituted with 0-4 occurrences of N(R 9 ) 2 , SR 9 , OR 9 , halo, CN, NO 2 , COOR 9 , C(O)R 9 , SO 2 R 9 , SOR 9 , —X—CF 3 , —X—SH, —X—OH, C 1-4 haloalkyl, C 6-10 aryl, —X—(C 6-10 aryl), 5-10 membered heteroaryl, —X-(5-10 membered heteroaryl), C 3-10 cycloaliphatic, —X—(C 3-10 cycloaliphatic), 5-10 membered heterocyclyl, —X-(5-10 membered heterocyclyl), or X; and
R 9 is H, C 1-6 aliphatic, C 1-4 haloalkyl, C 6-10 aryl, —X—(C 6-10 aryl), 5-10 membered heteroaryl, —X-(5-10 membered heteroaryl), C 3-10 cycloaliphatic, —X—(C 3-10 cycloaliphatic), 5-10 membered heterocyclyl, —X-(5-10 membered heterocyclyl) or X, or wherein two R 9 , taken together with the atom to which they are attached, form a 5-10 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 0-4 occurrences of halo, CN, NO 2 , —COOH, —COO(C 1-6 alkyl), —C(O)H, SO 2 H, SO 2 (C 1-6 alkyl), C 1-6 haloaliphatic, NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , SH, —S(C 1-6 alkyl), OH, —O(C 1-6 alkyl), —C(O)(C 1-6 alkyl), —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), or —C(O)N(C 1-6 alkyl) 2 , C 1-4 haloalkyl, C 6-10 aryl, —X—(C 6-10 aryl), 5-10 membered heteroaryl, —X-(5-10 membered heteroaryl), C 3-10 cycloaliphatic, —X—(C 3-10 cycloaliphatic), 5-10 membered heterocyclyl, —X-(5-10 membered heterocyclyl), or X,
wherein each of said heteroaryl heterocyclyl, or heterocyclic ring system contain one or more heteroatoms selected from nitrogen, oxygen, or sulfur.
2. The compound according to claim 1 , wherein R 4 is H and R 3 is other than H.
3. The compound according to claim 1 , wherein R 1 is H.
4. The compound according to claim 1 , wherein R is
5. The compound according to claim 4 , wherein R 2a is OR 5 , N(R 5 ) 2 , or 5-8 membered heterocyclyl.
6. The compound according to claim 1 , wherein R is Y.
7. The compound according to claim 1 , wherein R 3 and R 4 are each independently U m —V.
8. The compound according to claim 1 , wherein Z is a bond and R is selected from
9. The compound according to claim 1 , wherein said compound is of formula II:
or a pharmaceutically accepted salt thereof, wherein Ring A is Y.
10. The compound according to claim 9 , wherein said compound is of formula III:
or a pharmaceutically accepted salt thereof, wherein R 3 is halogen, C 1-6 aliphatic, C 1-6 alkoxy, N(R 5 ) 2 , CN, NO 2 , or U m —V.
11. The compound according to claim 10 , wherein said compound is of formula IV:
wherein each of Z 1 and Z 2 is CH or N.
12. A compound according to claim 1 selected from any one of
13. A compound according to claim 1 selected from
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14. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
15. A method of treating a cancer selected from colon, breast, gastric, ovarian, prostate, or pancreatic cancer in a patient in need thereof, wherein said method comprises administering to said patient a compound according to claim 1 or a composition comprising said compound.