Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9309250-B2
Application number	US-201213531467-A
Country	US
Kind code	B2
Filing date	Jun 22, 2012
Priority date	Jun 22, 2011
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

The present invention relates to pyrrolopyrazines 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.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof wherein:
R 1 is halo, CN, NO 2 , X, Q 1 , or X-Q 1 ;
X is C 1-10 alkyl wherein up to two methylene units of said C 1-10 alkyl is optionally replaced with —O—, —S—, or —NR*—; and wherein X is optionally substituted with 1-2 occurrences of J X ;
Q 1 is a 3-8 membered monocyclic aromatic or nonaromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and wherein Q 1 is optionally substituted with 0-2 occurrences of J Q1 ;
J X is halo, CN, C 1-3 alkyl, OH, O(C 1-3 alkyl), NH 2 , NH(C 1-3 alkyl), or N(C 1-3 alkyl) 2 ;
J Q1 is C 1-6 alkyl wherein up to one methylene unit of said C 1-6 alkyl is optionally replaced with —O—, —S—, or —NR*—;
Q is a 5-6 membered monocyclic aromatic or nonaromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
J is H, halo, ═O, CN, V 1 , (V) t —R 2 , or

each V and V 1 is independently a C 1-10 aliphatic group wherein up to 3 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 occurrences of halo or CN;
R 2 is a 3-7 membered aromatic or nonaromatic monocyclic ring having 0-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; and wherein R 2 is optionally substituted with 1-3 occurrences of halo, ═O, CN, C 3-6 cycloalkyl, or C 1-10 aliphatic; wherein up to 3 methylene units of said C 1-10 aliphatic are optionally replaced with NR′, O, S, or CO;
J 1 is halo, CN, or C 1-2 aliphatic wherein up to one methylene unit is optionally replaced with O, NR + , or S;
J a is H or C 1-6 alkyl;
J b is C 1-6 alkyl;
or J a and J b join together to form a 3-7 membered monocyclic saturated ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; wherein said monocyclic saturated ring is optionally substituted with 1-2 occurrences of halo or C 1-3 alkyl;
J c is CN or L-Z;
L is C(O), S(O) 2 , or C(O)NR + ;
Z is (U) r -Q 2 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;
Q 2 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 3 is H, halo, CN, or C 1-3 alkyl wherein up to one methylene unit of said C 1-3 alkyl is optionally replaced with O, NH, or S; and wherein said C 1-3 alkyl is optionally and independently substituted with 1-3 occurrences of halo or OH;
q, r, n, and t are each independently 0 or 1;
p is 0, 1, 2, 3, or 4; and
each R, R′, R″, R + , and R* is independently H or C 1-4 alkyl wherein said C 1-4 alkyl is optionally substituted with 1-4 halo.

2. The compound of claim 1 , wherein Q is a 6-membered monocyclic aromatic or nonaromatic ring having 0-1 nitrogen atoms.

3. The compound of claim 2 , wherein Q is phenyl, pyridyl, or pyridinone.

4. The compound of claim 3 , wherein Q is phenyl.

5. The compound of claim 4 , wherein Q is substituted in the para position with J.

6. The compound of claim 5 , wherein J is V 1 or (V) t —R 2 .

7. The compound of claim 6 , wherein V 1 and V are each independently C(O)C 1-9 aliphatic or S(O) 2 C 1-9 aliphatic.

8. The compound of claim 6 , wherein J is S(O) 2 (C 1-6 alkyl).

9. The compound of claim 7 , wherein V 1 and V are each independently S(O) 2 C 1-9 aliphatic.

10. The compound of claim 9 , wherein R 2 is a 3-7 membered monocyclic aromatic or nonaromatic ring having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

11. The compound of claim 3 , wherein Q is pyridyl.

12. The compound of claim 11 , wherein Q is substituted with one occurrence of J and is

13. The compound of claim 12 , wherein J a is H or C 1-4 alkyl; J b is C 1-4 alkyl; and J c is CN.

14. The compound of claim 12 , wherein J a is H, methyl or ethyl; J b is methyl or ethyl; or J a and J b join together to form cyclopropyl, cyclobutyl, cyclopentyl, piperidinyl, or tetrahydropyranyl ring.

15. The compound of claim 3 , wherein Q is substituted with one occurrence of J and is

16. The compound of claim 15 , wherein J 1 is C 1-10 aliphatic, —(C 1-4 alkyl)-CF 3 , —(C 1-4 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.

17. The compound of claim 2 wherein q is 0.

18. The compound of claim 1 , wherein R 1 is X-Q 1 .

19. The compound of claim 18 , wherein X is —NR*—.

20. The compound of claim 19 , wherein Q 1 is a 4-7 membered monocyclic aromatic or nonaromatic ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur.

21. The compound of claim 20 , wherein R 1 is N(CH 3 )piperidinyl, NH—(CH 2 ) 2 (morpholinyl), NH-azetidinyl, or NH-piperidinyl.

22. The compound of claim 1 , wherein R 1 is halo, CN, NO 2 or X.

23. The compound of claim 22 , wherein X is N(R 4 ) 2 , —(C 1-3 alkyl)-N(R 4 ) 2 , OR 4 , —(C 1-3 alkyl)-OR 4 , —O—(C 1-3 alkyl)-N(R 4 ) 2 , or —NR 4 —(C 1-3 alkyl)-N(R 4 ) 2 ; and wherein R 4 is H or C 1-4 alkyl.

24. The compound of claim 22 , wherein R 1 is halo, CN, NO 2 , CH 2 NH 2 , NH 2 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , OCH 2 CH 2 N(CH 3 ) 2 , CH 2 CH 2 OH, NHCH 2 CH 2 N(CH 3 ) 2 , NH—(CH 2 ) 2 NH 2 , or N(CH 3 )(CH 2 ) 3 N(CH 3 ) 2 .

25. The compound of claim 1 , wherein R 1 is Q 1 .

26. The compound of claim 25 , wherein R 1 is a 4-7 membered monocyclic aromatic or nonaromatic ring having 1-2 nitrogen atoms.

27. The compound of claim 25 , wherein R 1 is pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, or homopiperazinyl.

28. The compound of claim 1 , wherein J Q1 is C 1-3 alkyl wherein up to one methylene unit is replaced with —NR*—.

29. The compound of claim 28 , wherein J Q1 is CH 2 NH 2 , NH 2 , or N(CH 3 ) 2 .

30. The compound of claim 1 , wherein R 3 is halo, CN, or C 1-3 alkyl wherein up to one methylene unit of said C 1-3 alkyl is optionally replaced with O, NH, or S; and wherein said C 1-3 alkyl is optionally and independently substituted with 1-3 occurrences of halo or OH.

31. The compound of claim 1 , wherein J is halo, ═O, CN, V 1 , (V) t —R 2 , or

32. The compound of claim 1 , wherein p is 0 or 1.

33. The compound of claim 1 , wherein p is 0.

34. The compound of claim 1 , wherein p is 1.

35. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

Assignees

• Storck Pierre-Henri
• Charrier Jean-Damien
• Rutherford Alistair
• Mortimore Michael Paul
• Maccormick Somhairle
• Knegtel Ronald Marcellus Alphonsus
• Durrant Steven John
• Vertex Pharma

Inventors

• Storck Pierre-Henri
• Charrier Jean-Damien
• Rutherford Alistair
• Mortimore Michael Paul
• Maccormick Somhairle
• Knegtel Ronald Marcellus Alphonsus
• Durrant Steven John

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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