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 have formula I:;;or a pharmaceutically acceptable salt, wherein the variables are as defined herein.

主权项

1. A compound of formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1 and R2 are independently selected from H; halo; —C(J1)2CN; —CN; W; or M; J1 is independently selected from 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 is a C1-8aliphatic wherein up to three methylene units are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)z—, each M is optionally substituted with 0-3 occurrences of R2a; R2a is independently selected from halo; —CF3; —CN; 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 a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; W is independently selected from a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or an 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein W is optionally substituted with 0-5 occurrences of JW; JW is independently selected from —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 oxygen, nitrogen, or sulfur; 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 oxygen, nitrogen, or sulfur; or two occurrences of JW, together with W, form a 6-10 membered saturated or partially unsaturated bridged ring system; A is independently selected from: p is 0, 1, or 2; R3 is independently selected from -(L)n-Q1 or T; L and T are each independently a C1-10aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S(O)z—, or —C(O)—; each L and T is independently substituted with 0-5 occurrences of JLT; JLT is independently selected from 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—; n is 0 or 1; Q1 is independently selected from a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or an 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Q1 is independently substituted with 0-5 occurrences of JQ; JQ is independently selected from 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 oxygen, nitrogen, or 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 oxygen, nitrogen, or sulfur; JR is independently selected from halo; —CN; ═O; →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 oxygen, nitrogen, or 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 oxygen, nitrogen, or sulfur; a 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur; JX is independently selected from 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 selected from 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 oxygen, nitrogen, or sulfur; each JP is optionally substituted with 0-3 occurrences of 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 oxygen, nitrogen, or sulfur; or two occurrences of JP, together with Q3, form a 6-10 membered saturated or partially unsaturated bridged ring system; R4 is independently selected from H, halo, a C3-4 membered cycloalkyl, 3-4 membered heterocyclyl, or 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—; JM is independently selected from halo or C1-6aliphatic; z is 0, 1, or 2; and R is independently selected from H or C1-4aliphatic.