Compounds useful as inhibitors of ATR kinase
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: wherein the variables are as defined herein.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof; wherein
Ring A is a partially unsaturated 5-membered ring;
Ring B is a 5-6 membered aromatic or nonaromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
J is halo, C 1-4 alkyl, or C 1-4 alkoxy;
J 1 is —(X 1 ) u —Y;
X 1 is C 1-6 alkyl wherein 0-2 methylene units of said C 1-6 alkyl are replaced with NH, O, or S; X 1 is optionally substituted with 1-2 occurrences of C 1-3 alkyl or halo;
Y is hydrogen, C 1-4 alkyl, or a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein the heterocyclyl is optionally substituted with 1 occurrence of halo or C 1-3 alkyl;
or J and J 1 join together to form a 5-7 heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein the heterocyclyl is optionally substituted with 1 occurrence of halo or C 1-3 alkyl;
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;
L is a C 1-4 alkyl chain wherein up to two methylene units of the alkyl chain are optionally replaced with O, NR 6 , S, —C(O)—, —SO—, or —SO 2 —;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H, C 1 -C 6 alkyl, —(C 2 -C 6 alkyl)—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 J Z ;
or R 1 and R 2 , 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 J Z1 ;
J Z1 is halo, CN, C 1 -C 8 aliphatic, —(X 2 ) t —CN, or —(X 3 ) r —Z; wherein said up to two methylene units of said C 1 -C 8 aliphatic can be optionally replaced with O, NR, S, P(O), C(O), S(O), or S(O) 2 ; wherein said C 1 -C 8 aliphatic is optionally substituted with halo, CN, or NO 2 ;
R is H or C 1-6 alkyl;
each X 2 and X 3 is C 1 -C 4 alkyl;
Z is —NR 3 R 4 ;
R 3 is H or C 1 -C 2 alkyl;
R 4 is H or C 1 -C 6 alkyl;
or R 3 and R 4 , 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 J Z ;
R 6 is H, or C 1 -C 6 alkyl;
J Z is independently NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO(C 1-4 aliphatic), CO 2 (C 1-4 aliphatic), O(haloC 1-4 aliphatic), or haloC 1-4 aliphatic;
J 2 is halo; CN; a 5-6 membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or a C 1-10 aliphatic group wherein up to 2 methylene units are optionally replaced with O, NR″, C(O), S, S(O), or S(O) 2 ; wherein said C 1-10 aliphatic 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 C 3-6 cycloalkyl; a 3-7 membered heterocyclyl containing 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; or a C 1-4 alkyl wherein up to one methylene unit of the alkyl chain is optionally replaced with O, NR″, or S; and wherein said C 1-4 alkyl is optionally substituted with 1-3 halo;
each p, r, t, u, m, and n is independently 0 or 1;
q is 0, 1, or 2;
R″ is H, C 1-4 alkyl, or is absent; wherein said C 1-4 alkyl is optionally substituted with 1-4 halo.
2. The compound of claim 1 , wherein Ring A is
3. The compound of claim 1 , wherein Q is phenyl.
4. The compound of claim 2 , wherein p is 0; q is 1; and J 2 is a C 1-4 aliphatic group wherein one methylene unit is replaced with S(O) 2 .
5. The compound of claim 4 , wherein J 2 is —SO 2 CH(CH 3 ) 2 .
6. The compound of claim 1 , wherein Ring B is phenyl.
7. The compound of claim 1 , wherein m is 0 and n is 1.
8. The compound of claim 7 , wherein
X 1 is C 1-6 alkyl wherein 0-2 methylene units of said C 1-6 alkyl are replaced with NH or O;
Y is hydrogen, C 1-4 alkyl, or a 3-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein the heterocyclyl is optionally substituted with 1 occurrence of halo or C 1-3 alkyl;
q is 0 or 1.
9. The compound of claim 8 , wherein J 1 is —C 1-4 alkyl, —OH, —OCH 3 , —CH 2 NHCH 3 , —CH 2 OH, —OCH 2 CH 2 OH, —CH 2 NH—(morpholinyl), or morpholinyl.
10. The compound of claim 1 , wherein m is 1 and n is 0.
11. The compound of claim 9 , wherein J is halo.
12. The compound of claim 1 , wherein n and m are both 0.
13. The compound of claim 1 , wherein the compound is selected from the following:
14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.