Compounds useful as inhibitors of ATR kinase

Patent metadata

Field	Value
Publication number	US-9630956-B2
Application number	US-201113106476-A
Country	US
Kind code	B2
Filing date	May 12, 2011
Priority date	May 12, 2010
Publication date	Apr 25, 2017
Grant date	Apr 25, 2017

Abstract

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.

First claim

The invention claimed is:

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

Assignees

• Charrier Jean-Damien
• Binch Hayley Marie
• Hurley Dennis James
• Cleveland Thomas
• Joshi Pramod
• Fanning Lev Tyler Dewey
• Pinder Joanne
• O'Donnell Michael
• Nizarali Virani Anisa
• Knegtel Ronald Marcellus Alphonsus
• Durrant Steven John
• Young Stephen Clinton
• Storck Pierre-Henri
• Kay David
• Reaper Philip Michael
• Grote Matthew Paul
• Vertex Pharma

Inventors

• Charrier Jean-Damien
• Binch Hayley Marie
• Hurley Dennis James
• Cleveland Thomas
• Joshi Pramod
• Fanning Lev Tyler Dewey
• Pinder Joanne
• O'Donnell Michael
• Nizarali Virani Anisa
• Knegtel Ronald Marcellus Alphonsus
• Durrant Steven John
• Young Stephen Clinton
• Storck Pierre-Henri
• Kay David
• Reaper Philip Michael
• Grote Matthew Paul

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title