COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE

摘要

The present invention relates to 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 are represented by formula I-A and formula I-B:;;or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

主权项

1. A compound of Formula I-B: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are independently H, —C(J1)2CN, halo, -(L1)n-W, or M; or R1 and R2, taken together with the atoms to which they are bound, form a 5-6 membered aromatic or non-aromatic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; the ring formed by R1 and R2 is optionally substituted with 0-3 occurrences of JZ; JZ is independently a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or a C1-6aliphatic chain, wherein up to three methylene units are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; JZ is optionally substituted with 0-3 occurrences of JX; J1 is independently H or C1-2alkyl; or two occurrences of J1, together with the carbon atom to which they are attached, form an optionally substituted 3-4 membered carbocyclic ring; M and L1 independently are C1-8aliphatic, wherein up to three methylene units are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—, each L1 and M are optionally substituted with 0-3 occurrences of JLM; JLM is independently halo, —CN, or a C1-4aliphatic chain, wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; or n is 0 or 1; W is a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or an 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein W is optionally substituted with 0-5 occurrences of JW; JW is independently —CN; halo; —CF3; a C1-4aliphatic wherein up to two methylene units are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or two occurrences of JW on the same atom, together with atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or two occurrences of JW, together with W, form a 6-10 membered saturated or partially unsaturated bridged ring system; Ring A is: R3 is -(L2)k-Q1 or T; L2 and T are each independently a Cl1-10aliphatic chain, wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S(O)z—, or —C(O)—; each L2 and T is independently substituted with 0-5 occurrences of JLT; JLT is independently halo, —CN, or a C1-4aliphatic chain, wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; k is 0 or 1; Q1 is a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or an 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein Q1 is independently substituted with 0-5 occurrences of JQ; JQ is independently halo; —CN; ═O; Q2; or a C1-8aliphatic chain, wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; each occurrence of JQ is optionally substituted by 0-3 occurrences of JR; or two occurrences of JQ on the same atom, taken together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein the ring formed by two occurrences of JQ is optionally substituted with 0-3 occurrences of JX; or two occurrences of JQ, together with Q1, form a 6-10 membered saturated or partially unsaturated bridged ring system; Q2 is independently a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; JR is independently halo; —CN; ═O; Q3; or a C1-6aliphatic chain, wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; each JR is optionally substituted with 0-3 occurrences of JP; or two occurrences of JR on the same atom, together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein the ring formed by two occurrences of JR is optionally substituted with 0-3 occurrences of JX; or two occurrences of JR, together with Q2, form a 6-10 membered saturated or partially unsaturated bridged ring system; Q3 is a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; a 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; JX is independently halo or a C1-4aliphatic chain, wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; or JP is independently halo; —CN; ═O; a C1-6aliphatic chain, wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; each JP is optionally substituted with 0-3 JM; or two occurrences of JP on the same atom, together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; two occurrences of JP, together with Q3, form a 6-10 membered saturated or partially unsaturated bridged ring system; R4 is independently H; halo; —CN; a C1-2alkyl optionally substituted with 0-3 occurrences of fluoro; a C3-6cycloalkyl; a 3-4 membered heterocyclyl; or a C1-3aliphatic chain, wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—; JM is independently halo or C1-6aliphatic; z is 0, 1, or 2; p is 0, 1, or 2; and R is independently H or C1-4aliphatic.