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 B is a 5-6 membered monocyclic aryl or heteroaryl ring, wherein said heteroaryl ring has 1 heteroatom selected from the group consisting of oxygen, nitrogen, and 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 3-7 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;
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;
each m, n, and u is independently 0 or 1;
q is 0, 1, or 2;
Q is phenyl, pyridyl, or an N-alkylated pyridone;
J 2 is halo; CN; phenyl; oxazolyl; or a C 1-6 aliphatic group wherein up to 2 methylene units are optionally replaced with O, NR″, C(O), S, S(O), or S(O) 2 ; said C 1-6 aliphatic group is optionally substituted with 1-3 fluoro or CN;
R″ is H or C 1-6 alkyl.
2. The compound of claim 1 , wherein Ring B is phenyl, thienyl, or morpholinyl.
3. The compound of claim 2 , wherein Ring B is phenyl.
4. The compound of claim 1 , wherein J 1 is H, CH 3 , OH, OCH 3 , CH 2 OH, CH 2 NHCH 3 , CH 2 NH-cyclopropyl, CH(CH 2 F)NH 2 , CH(CH 3 )NH 2 , CH 2 NH-(tetrahydrofuranyl), CH 2 NH-(oxetanyl), or piperazinyl.
5. The compound of claim 1 , wherein Q is phenyl.
6. The compound of claim 5 , wherein q is 1; and J 2 is a C 1-4 aliphatic group wherein one methylene unit is replaced with S(O) 2 .
7. The compound claim 6 , wherein J 2 is —SO 2 CH(CH 3 ) 2 .
8. The compound of claim 1 , wherein Q is
J 2 is H or C 1-6 alkyl;
J 3 is H or C 1-6 alkyl;
or J 2 and J 3 join together to form a 3-7 membered monocyclic saturated ring having 0-2 heteroatoms selected form the group consisting of oxygen, nitrogen, and sulfur; wherein said monocyclic ring is optionally substituted with 1-2 occurrences of halo or C 1-3 alkyl;
J 4 is CN, OH, or L-Z;
L is C(O), S(O) 2 , or C(O)NR;
Z is (U) t- Q 1 or C 1-6 alkyl wherein 0-2 methylene units of said C 1-6 alkyl are replaced with O or NR;
U is C 1-2 alkyl;
t is 0 or 1;
Q 1 is C 3-6 cycloalkyl or 4-6 membered saturated or partially saturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R is H or C 1-4 alkyl.
9. The compound of claim 8 , wherein J 2 is H, C 1-4 alkyl; and J 3 is C 1-4 alkyl.
10. The compound of claim 8 , J 2 and J 3 join together to form a 3-6 membered fully saturated monocyclic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
11. The compound of claim 8 , wherein J 2 is hydrogen, methyl or ethyl; J 3 is methyl or ethyl; or J 2 and J 3 join together to form cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, or tetrahydropyranyl.
12. The compound of claim 8 , wherein
Ring B is phenyl or thienyl;
J 2 is methyl and J 3 is methyl;
J 4 is CN; and
q is 1.
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.