COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE

摘要

The present invention relates to pyrazine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.;The compounds of this invention have formula I:;;wherein the variables are as defined herein.

主权项

1. A compound of formula IA: or a pharmaceutically acceptable salt thereof; wherein Y is a C1-C10aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with O, NR0, S, C(O) or S(O)2; Ring A is a 5 membered heteroaryl ring selected from J3 is H or C1-4alkyl wherein 1 methylene unit of the alkyl group can optionally be replaced with O, NH, N(C1-4alkyl), or S and optionally substituted with 1-3 halo; Q is a 5-6 membered monocyclic aromatic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic aromatic ring containing 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R5 is H; a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an 8-10 membered bicyclic fully saturated, partially unsaturated, or aromatic ring containing 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R5 is optionally substituted with 1-5 J5 groups; L is a C1-4alkyl chain wherein up to two methylene units of the alkyl chain are optionally replaced with O, NR6, S, —C(O)—, —SO—, or —SO2—; R0 is H or C1-C6alkyl wherein one methylene unit of the alkyl chain can be optionally replaced with O, NH, N(C1-4alkyl), or S; R1 is H or C1-C6alkyl; R2 is H, C1-C6alkyl, —(C2-C6alkyl)-Z or a 4-8 membered cyclic ring containing 0-2 nitrogen atoms; wherein said ring is bonded via a carbon atom and is optionally substituted with one occurrence of JZ; or R1 and R2, taken together with the atom to which they are bound, form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said heterocyclic ring is optionally substituted with one occurrence of JZ1; JZ1 is halo, CN, C1-C8aliphatic, —(X)t—CN, or —(X)r—Z; wherein said up to two methylene units of said C1-C8aliphatic can be optionally replaced with O, NR, S, P(O), C(O), S(O), or S(O)2; wherein said C1-C8aliphatic is optionally substituted with halo, CN, or NO2; X is C1-C4alkyl; each t, r and m is independently 0 or 1; Z is —NR3R4; R3 is H or C1-C2alkyl; R4 is H or C1-C6alkyl; or R3 and R4, taken together with the atom to which they are bound, form a 4-8 membered heterocyclic ring containing 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein said ring is optionally substituted with one occurrence of JZ; R6 is H, or C1-C6alkyl; JZ is independently NH2, NH(C1-4aliphatic), N(C1-4aliphatic)2, halogen, C1-4aliphatic, OH, O(C1-4aliphatic), NO2, CN, CO2H, CO(C1-4aliphatic), CO2(C1-4aliphatic), O(haloC1-4aliphatic), or haloC1-4aliphatic; J5 is halo, oxo, CN, NO2, X1—R, or —(X1)p-Q4; X1 is C1-10aliphatic; wherein 1-3 methylene units of said C1-10aliphatic are optionally replaced with —NR′—, —O—, —S—, C(═NR′), C(O), S(O)2, or S(O); wherein X1 is optionally and independently substituted with 1-4 occurrences of NH2, NH(C1-4aliphatic), N(C1-4aliphatic)2, halogen, C1-4aliphatic, OH, O(C1-4aliphatic), NO2, CN, CO2H, CO2(C1-4aliphatic), C(O)NH2, C(O)NH(C1-4aliphatic), C(O)N(C1-4aliphatic)2, SO(C1-4aliphatic), SO2(C1-4aliphatic), SO2NH(C1-4aliphatic), SO2NH(C1-4aliphatic), NHC(O)(C1-4aliphatic), N(C1-4aliphatic)C(O)(C1-4aliphatic), wherein said C1-4aliphatic is optionally substituted with 1-3 occurrences of halo; Q4 is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q4 is optionally substituted with 1-5 JQ4; JQ4 is halo, CN, or C1-4alkyl wherein up to 2 methylene units are optionally replaced with O, NR*, S, C(O), S(O), or S(O)2; R is H or C1-4alkyl wherein said C1-4alkyl is optionally substituted with 1-4 halo; J2 is halo; CN; a 5-6 membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or a C1-10aliphatic group wherein up to 2 methylene units are optionally replaced with O, NR″, C(O), S, S(O), or S(O)2; wherein said C1-10aliphatic group is optionally substituted with 1-3 halo or CN; and said monocyclic ring is optionally substituted with 1-3 occurences of halo; CN; a C3-6cycloalkyl; a 3-7 membered heterocyclyl containing 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; or a C1-4alkyl wherein up to one methylene unit of the alkyl chain is optionally replaced with O, NR″, or S; and wherein said C1-4alkyl is optionally substituted with 1-3 halo; q is 0, 1, or 2; p is 0 or 1; R′, R″, and R* are each independently H, C1-4alkyl, or is absent; wherein said C1-4alkyl is optionally substituted with 1-4 halo.