Tri-cyclic pyrazolopyridine kinase inhibitors

摘要

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. The compounds of the present invention are represented by the structure of formula I:;
or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

主权项

1. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein:
R1 is —H, halogen, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;R2 is —H, halogen, —CN, —NO2, —OR′, —N(R′)2, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;ring B is a pyrazinyl or pyrimidinyl; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more Jc;Y is —Y1-Q1;Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y1 is optionally and independently substituted with one or more Jd;Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more Jb; wherein at least one of Y1 and Q1 are not absent when ring B is substituted with Y;ring C is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring C is optionally substituted with one Z and independently further optionally and independently substituted with one or more Jb;Z is —Y2-Q2;Y2 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y2 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p—; and Y2 is optionally and independently substituted with one or more Jd;Q2 is absent, C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q2 is optionally and independently substituted with one or more Je; wherein at least one of Y2 and Q2 are not absent when ring C is substituted with Z;each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or more Ja;each Ja is independently halogen, —OR, —N(R)2, —C(O)R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —NRC(O)OR, —CN, —NO2, or oxo;each Jb is independently halogen, —OR, —N(R)2, —C(O)R, —C(O)OR, —C(O)N(R)2, —NRC(O)R, —NRC(O)OR, —CN, —NO2, oxo, or C1-C6 alkyl optionally and independently substituted with one or more Ja; ortwo Jb groups on the same atom can join together to form a C3-8 membered partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally and independently substituted with one or more Ja;each Jc is independently halogen, —OR′, —C(O)R, —C(O)OR′, —C(O)N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO2, or C1-C10 aliphatic optionally and independently substituted with one or more Ja, or C3-C8 cycloaliphatic optionally and independently substituted with one or more Jb;each Jd is independently halogen, —OH, —N(H)2, —C(O)H, —C(O)OH, —C(O)N(H)2, —NHC(O)H, —NHC(O)OH, —CN, or —NO2;each Je is independently halogen, —OH, —N(H)2, —C(O)H, —C(O)OH, —C(O)N(H)2, —NHC(O)H, —NHC(O)OH, —CN, —NO2, oxo, C1-10 aliphatic, wherein up to three methylene units are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O)p— and the aliphatic group is optionally and independently substituted with one or more Jd, or Je is C3-8 cycloaliphatic optionally and independently substituted with one ore more Jb;each R is independently —H or C1-C6 alkyl; andeach p is independently 0, 1, or 2.