US 8,410,112 B2 · Compounds useful as inhibitors of ATR kinase

Abstract

The present disclosure relates to pyrazine compounds of formula I: wherein L, n, R1, and R2 are as described in the specification. These compounds are useful as inhibitors of ATR protein kinase. The disclosure also relates to pharmaceutically acceptable compositions comprising the compounds of the disclosure; methods of treating of various diseases, disorders, and conditions using the compounds of the disclosure; processes for preparing the compounds of the disclosure; intermediates for the preparation of the compounds of the disclosure; 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.

A compound of formula I:

or a pharmaceutically acceptable salt thereof wherein:
R1 is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
wherein said monocyclic aryl or heteroaryl ring is optionally fused to another ring to form a 8-10 membered bicyclic aryl or heteroaryl ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R1 is optionally substituted with 1-5 J1 groups;
C2, C3 and C5 are carbon;
R2 is -Q or -Q-Q1;
Q is a 3-7 membered monocyclic saturated or unsaturated non-aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Q is independently and optionally substituted with 1-4 JQ groups;
Q is substituted with zero to two occurrences of J;
Q is optionally fused to Q1 to form a fused bicyclic ring Q-Q1;
or Q and Q1 are optionally joined together at a carbon atom to form a spirocyclic bicyclic ring Q-Q1;
or Q and Q1, taken together, form a bridged bicyclic ring Q-Q1 wherein said bridge is 1-3 atoms long;
Q-Q1 can be optionally substituted with 1-2 J groups;
wherein J can be bonded to either Q or Q1;
Q1 is a 3-8 membered monocyclic saturated or unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Q1 is independently and optionally substituted with 1-4 JQ1 groups;
J is halo, oxo, —CN, —NO2, V1—R″, or —(V)m—R*;
R″ is H or 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 R″ is optionally substituted with 1-5 J′;
L is —C(O)NH—or —C(O)N(C1-6alkyl)-;
n is 0 or 1;
each JQ and JQ1 is independently halo, oxo, —CN, —NO2, V—R, or —(V)m-Q2;
J1 is halo, —CN, —NO2, V—R, or —(V2)m-Q3;
V is a C1-10aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, nitrogen, sulfur, C(O), S(O), or S(O)2;
V is optionally substituted with 1-6 occurrences of JV;
V1 is a C1-10aliphatic chain wherein 0-3 methylene units are optionally replaced with —NR′—, —O—, —S—, C(O), S(O), or S(O)2;
V1 is optionally substituted with 1-6 occurrences of JV1;
m is 0 or 1;
V2 is a C1-10aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, nitrogen, sulfur, C(O), S(O), or S(O)2;
V is optionally substituted with 1-6 occurrences of JV2;
m is 0 or 1;
Q2 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 Q2 is optionally substituted with 1-5 JQ2;
Q3 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 Q3 is optionally substituted with 1-5 JQ3;
each JV, JV1, and JV2 is independently halogen, CN, NH2, NO2, C1-4aliphatic, NH(C1-4aliphatic) N(C1-4aliphatic)2, OH, O(C1-4aliphatic), CO2H, CO2(C1-4aliphatic), C(O)NH2, C(O)NH(C1-4aliphatic), C(O)N(C1-4aliphatic)2,NHCO(C1-4aliphatic), N(C1-4aliphatic)CO(C1-4aliphatic), SO2(C1-4aliphatic), NHSO2(C1-4aliphatic), or N(C1-4aliphatic)SO2(C1-4aliphatic), wherein said C1-4aliphatic is optionally substituted with halo;
each JQ2 and JQ3 is independently halo, oxo, CN, NO2, X—R, or —(X)p-Q4,
p is 0 or 1;
X is C1-10aliphatic;
wherein 1-3 methylene units of said C1-6aliphatic are optionally replaced with —NR, —O—, —S—, C(O), S(O)2, or S(O);
wherein X 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, N, S, C(O), S(O), or S(O)2;
each R*, R′, and R is independently H or C1-4alkyl wherein said C1-4alkyl is optionally substituted with 1-4 halo.

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Compounds useful as inhibitors of ATR kinase

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Compounds useful as inhibitors of ATR kinase

Life of this patent

Abstract

Claims71