Compounds useful as inhibitors of ATR kinase
The present invention relates to pyrazine and pyridine 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 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
A is CH or N;
Ring D is isoxazolyl or oxadiazolyl;
J is —C 1-3 alkyl, —O(C 1-3 alkyl), halo, or CN;
q is 0 or 1;
R 1 is H, C 1-6 aliphatic, phenyl, or tetrahydrofuranyl, wherein said C 1-6 aliphatic is optionally substituted with one occurrence of OH and up to two occurrences of F;
R 2 is H or C 1-3 alkyl;
or R 1 and R 2 , together with the nitrogen atom to which they are attached, optionally form a 4-6 membered monocyclic heterocyclyl ring having 1-2 heteroatoms selected from the group consisting of O, N, and S;
R 3 is H or C 1-3 alkyl, wherein said alkyl is optionally substituted with up to three occurrences of F;
R 3′ is H or C 1-3 alkyl;
or R 3 and R 3′ , together with the carbon atom to which they are attached, form a 3-4 membered monocyclic saturated carbocyclic ring;
R 4 is Q, —(C 1-2 alkyl)-Q, or a C 1-10 aliphatic, wherein up to two methylene units of said C 1-10 aliphatic are optionally replaced with O, NR′, S, or CO; and wherein one methylene unit of the C 1-2 alkyl can optionally be replaced with C(═O);
R 4 is optionally substituted with 1-3 occurrences of halo, CN, NRR′, OR, or C 1-3 aliphatic, wherein said C 1-3 aliphatic is optionally substituted with up to 1 occurrence of CN and up to 4 occurrences of F;
Q is 3-6 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; Q is optionally substituted with 1-3 occurrences of halo, CN, NRR′, OR, or C 1-3 aliphatic, wherein said C 1-3 aliphatic is optionally substituted with up to 4 occurrences of F;
R′ is H or C 1-4 alkyl;
R is H or C 1-4 alkyl;
or R and R′, together with the nitrogen to which they are attached, optionally form a 3-6 membered heterocyclic ring having 1-2 heteroatoms selected from the group consisting of O, N, and S;
J 2 is H, C 1-6 aliphatic, halo, phenyl, or CN, wherein said C 1-6 aliphatic is optionally substituted with 1-2 occurrences of halo, OH, CN, or OR.
2. The compound of claim 1 , wherein
R 1 is H, C 1-6 aliphatic, or tetrahydrofuranyl, wherein said C 1-6 aliphatic is optionally substituted with one occurrence of OH and up to two occurrences of F;
R 3′ is H;
R 4 is Q, —(C 1-2 alkyl)-Q, or a C 1-10 aliphatic, wherein up to two methylene units of said C 1-10 aliphatic are optionally replaced with O, NR′, S, or CO;
Q is 3-6 membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; Q is optionally substituted with 1-3 occurrences of halo, CN, NRR′, OR, or C 1-3 aliphatic, wherein said C 1-3 aliphatic is optionally substituted with up to 4 occurrences of F;
J 2 is H.
3. The compound of claim 1 , wherein A is N.
4. The compound of claim 1 , wherein R 2 is H.
5. The compound of claim 4 , wherein Ring D is isoxazolyl.
6. The compound of claim 4 , wherein Ring D is oxadiazolyl.
7. The compound of claim 5 ,
wherein
is bonded at the meta or para position of the phenyl ring as shown in Formula Ia and Ib below:
or a pharmaceutically acceptable salt thereof; or
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 having Formula Ib or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein R 3 is H or methyl.
10. The compound of claim 9 , wherein R 3 is H.
11. The compound of claim 1 , wherein R 1 is C 1-6 aliphatic, phenyl, or tetrahydrofuranyl.
12. The compound of claim 11 wherein R 1 is C 1-6 aliphatic or tetrahydrofuranyl.
13. The compound of claim 12 , wherein R 1 is C 1-4 alkyl or tetrahydrofuranyl.
14. The compound of claim 13 , wherein R 1 is C 1-4 alkyl.
15. The compound of claim 13 , wherein R 1 is methyl, isopropyl, tert-butyl, or tetrahydrofuranyl.
16. The compound of claim 11 , wherein R 1 is C 1-6 aliphatic and wherein R 1 is optionally substituted with one occurrence of OH or 1-2 occurrences of fluoro.
17. The compound of claim 1 , wherein q is 1.
18. The compound of claim 17 , wherein J is bonded at the ortho position of the phenyl ring as shown in Formula Ic:
Ic or a pharmaceutically acceptable salt thereof.
19. The compound of claim 18 , wherein J is fluoro, C 1-3 alkyl, O(C 1-3 alkyl), or CN.
20. The compound of claim 19 , wherein J is methyl or isopropyl.
21. The compound of claim 18 , wherein J is fluoro, CH 3 , OCH 3 , or CN.
22. The compound of claim 1 , wherein q is 0.
23. The compound according to claim 1 , wherein R 4 is Q, —(C 1-2 alkyl)-Q, or C 1-10 aliphatic, wherein up to two methylene units of said C 1-10 aliphatic are optionally replaced with O, NR′, or CO; and wherein one methylene unit of the C 1-2 alkyl can optionally be replaced with C(═O).
24. The compound of claim 23 , wherein Q is a 5 membered heteroaryl having 1-2 heteroatoms selected from the group consisting of O, N, and S; 4-6 membered heterocyclyl having 1 heteroatoms selected from the group consisting of O and N; or a 3-6 membered cycloalkyl.
25. The compound of claim 24 , wherein Q is furanyl, thiazoyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 3-6 membered cycloalkyl.
26. The compound of claim 23 , wherein R 4 is C 1-10 aliphatic, —(C 1-4 alkyl)-CF 3 , —(C 1-2 alkyl)-(C 3 -C 6 cycloaliphatic), —(C 1-4 alkyl)-N(C 1-3 alkyl) 2 , —(C 1-4 alkyl)-O(C 1-3 alkyl), C 3 -C 6 cycloaliphatic, or tetrahydrofuranyl, wherein said alkyl group is optionally substituted.
27. The compound of claim 26 , wherein R 4 is C 1-6 alkyl, —(C 1-4 alkyl)-CF 3 , —(C 1-2 alkyl)-(C 3 -C 6 cycloaliphatic), C 3 -C 6 cycloaliphatic, or tetrahydrofuranyl.
28. The compound of claim 1 , wherein R 4 is methyl, ethyl, isopropyl, sec-butyl, isobutyl, CH(CH 3 )C≡CCH 3 , CH(CH 3 )COOH, CH 2 CONH 2 , CH(CH 3 )CONH 2 , CH(CH 3 )CONHCH 3 , CH(CH 3 )CON(CH 2 CH 3 ) 2 , cyclobutyl, cyclopentyl, methylcyclopentyl, CH(CH 3 )(cyclopropyl), CH 2 (cyclopropyl), CH 2 CH 2 (cyclopropyl), CH 2 CH 2 (cyclopentyl), CH(CH 3 )CH 2 F, CH(CH 3 )CF 3 , CH 2 CF 3 , C(CH 3 ) 2 CN, C(CH 2 CH 3 ) 2 CN, CH(CH 3 )CN, CH 2 CN, CH 2 CH(CH 3 )CH 2 CH 3 , CH(CH 2 CH 3 ) 2 CH(CH 2 OH) 2 CH(CH 3 )CH 2 OH, CH(CH 3 )CH 2 OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 CH 2 NH 2 , tetrahydrofuranyl, tetrahydropyranyl, CH 2 (furanyl), CH 2 (thiazolyl), CH 2 (imidazolyl), CH 2 CH 2 CN, CH 2 CH(OCH 3 )CH 2 CH 3 , CH 2 CH 2 CH(CH 3 )CH 2 CH 3 ,
29. The compound of claim 26 , wherein R 4 is methyl, ethyl, isopropyl, sec-butyl, isobutyl, CH(CH 3 )C≡CCH 3 , CH(CH 3 )COOH, cyclobutyl, cyclopentyl, CH(CH 3 )(cyclopropyl), CH(CH 3 )CH 2 F, CH(CH 3 )CF 3 , CH 2 CF 3 , CH(CH 3 )CN, CH 2 CN, CH(CH 3 )CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 CH 2 NH 2 , CH(CH 3 )CH 2 OCH 3 , or tetrahydrofuranyl.
30. The compound of claim 28 , wherein R 4 is methyl, ethyl, isopropyl, sec-butyl, isobutyl, CH(CH 3 )C≡CCH 3 , cyclobutyl, cyclopentyl, CH(CH 3 )(cyclopropyl), CH(CH 3 )CH 2 F, CH(CH 3 )CF 3 , CH 2 CF 3 , CH(CH 3 )CN, CH 2 CN, or tetrahydrofuranyl.
31. The compound of claim 1 , wherein J 2 is H, CN, F, Cl, Br, CH═CH 2 , methyl, ethyl, isopropyl, CH 2 OH, CH(CH 2 CH 3 )CH 2 CH 2 CH 3 , CH(CH 2 CH 3 ) 2 , cyclopentyl, cyclohexyl, cyclohexenyl, or phenyl.
32. The compound of claim 1 , wherein
A is N;
J 2 is H;
R 1 is methyl;
R 2 is H;
R 3 is H; and
R 4 is C 1-10 aliphatic, —(C 1-4 alkyl)-CF 3 , —(C 1-2 alkyl)-(C 3 -C 6 cycloaliphatic), —(C 1-4 alkyl)-N(C 1-3 alkyl) 2 , —(C 1-4 alkyl)-O(C 1-3 alkyl), C 3 -C 6 cycloaliphatic, or tetrahydrofuranyl, wherein said alkyl group is optionally substituted.
33. The compound of claim 32 , wherein R 4 is C 1-10 aliphatic, —(C 1-4 alkyl)-CF 3 , —(C 1-2 alkyl)-(C 3 -C 6 cycloaliphatic), C 3 -C 6 cycloaliphatic, or tetrahydrofuranyl.
34. The compound of claim 33 , wherein said alkyl group of R 4 is optionally substituted with CH 3 , OH, OCH 3 , NH 2 , CN, or tetrahydrofuranyl.
35. A compound selected from the group consisting of:
and a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein
A is CH or N;
Ring D is isoxazolyl or oxadiazolyl;
J is —C 1-3 alkyl, —O(C 1-3 alkyl), halo, or CN;
q is 0 or 1;
R 1 is H, C 1-6 aliphatic, phenyl, or tetrahydrofuranyl, wherein said C 1-6 aliphatic is optionally substituted with one occurrence of OH and up to two occurrences of F;
R 2 is H or C 1-3 alkyl;
or R 1 and R 2 , together with the nitrogen atom to which they are attached, optionally form a 4-6 membered monocyclic heterocyclyl ring having 1-2 heteroatoms selected from the group consisting of O, N, and S;
R 3 is H or C 1-3 alkyl, wherein said alkyl is optionally substituted with up to three occurrences of F;
R 3′ is H or C 1-3 alkyl;
or R 3 and R 3′ , together with the carbon atom to which they are attached, form a 3-4 membered monocyclic saturated carbocyclic ring;
R 4 is Q, —(C 1-2 alkyl)-Q, or a C 1-10 aliphatic, wherein up to two methylene units of said C 1-10 aliphatic are optionally replaced with O, NR′, S, or CO; and wherein one methylene unit of the C 1-2 alkyl can optionally be replaced with C(═O);
R 4 is optionally substituted with 1-3 occurrences of halo, CN, NRR′, OR, or C 1-3 aliphatic, wherein said C 1-3 aliphatic is optionally substituted with up to 1 occurrence of CN and up to 4 occurrences of F;
Q is 3-6 membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; Q is optionally substituted with 1-3 occurrences of halo, CN, NRR′, OR, or C 1-3 aliphatic, wherein said C 1-3 aliphatic is optionally substituted with up to 4 occurrences of F;
R′ is H or C 1-4 alkyl;
R is H or C 1-4 alkyl;
or R and R′, together with the nitrogen to which they are attached, optionally form a 3-6 membered heterocyclic ring having 1-2 heteroatoms selected from the group consisting of O, N, and S;
J 2 is H, C 1-6 aliphatic, halo, phenyl, or CN, wherein said C 1-6 aliphatic is optionally substituted with 1-2 occurrences of halo, OH, CN, or OR;
and a pharmaceutically acceptable carrier.