Substituted pyrazines as ATR kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9701674-B2
Application number	US-201414467175-A
Country	US
Kind code	B2
Filing date	Aug 25, 2014
Priority date	Dec 19, 2008
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

The present invention relates to pyrazine 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.
Certain compounds of this invention are of formula II, V, and/or VII:

wherein the variables are as defined herein.

First claim

We claim:

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl;
L is C(O);
R 1 is C 1 -C 6 alkyl;
R 2 is —(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 nitrogen atoms, wherein said heterocyclic ring is optionally substituted with one occurrence of J Z1 ;
J Z1 is —(X) t —CN, C 1 -C 6 alkyl, or —(X) r —Z;
X is C 1 -C 4 alkylene;
each t, p, and r is independently 0 or 1;
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 nitrogen atoms, wherein said ring is optionally substituted with one occurrence of J Z ;
each of J Z and J 1 is, independently, NH 2 , NH(C 1 -C 4 aliphatic), N(C 1 -C 4 aliphatic) 2 , halogen, C 1 -C 4 aliphatic, OH, O(C 1 -C 4 aliphatic), NO 2 , CN, CO 2 H, CO(C 1 -C 4 aliphatic), CO 2 (C 1 -C 4 aliphatic), O(haloC 1 -C 4 aliphatic), or haloC 1 -C 4 aliphatic;
J 2 is halo, C 1 -C 2 alkyl optionally substituted with 1-3 fluoro, or CN; and
q is 0, 1, or 2.

2. The compound of claim 1 , wherein 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 nitrogen atoms.

3. The compound of claim 2 , wherein t is 1.

4. The compound of claim 2 , wherein t is 0.

5. The compound of claim 2 , wherein the heterocyclic ring formed by R 1 and R 2 is pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1,4-diazepanyl.

6. The compound of claim 5 , wherein the heterocyclic ring formed by R 1 and R 2 is

7. The compound of claim 6 , wherein the ring formed by R 1 and R 2 is optionally substituted with CH 2 pyrrolidinyl, C 1 -C 4 alkyl, N(C 1 -C 2 alkyl) 2 , or CH 2 CH 2 CN.

8. The compound of claim 7 , wherein R 3 and R 4 are both C 1 -C 2 alkyl.

9. The compound of claim 7 , wherein R 3 and R 4 , taken together with the atom to which they are bound, form a ring selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, and 1,4-diazepanyl.

10. The compound of claim 9 , wherein said ring is pyrrolidinyl or piperidinyl.

11. The compound of claim 1 , wherein R 2 is —(C 2 -C 6 alkyl)-Z.

12. The compound of claim 1 , wherein p is 0, q is 0, and -L-NR 1 R 2 is C(O)-pyrrolidinyl, C(O)-piperidinyl, C(O)-piperazinyl, C(O)-azepanyl, C(O)-1,4-diazepanyl, or C(O)—N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , wherein said pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1,4-diazepanyl is optionally substituted with CH 2 pyrrolidinyl, C 1 -C 4 alkyl, N(C 1 -C 2 alkyl) 2 , or CH- 2 CH 2 CN.

13. The compound of claim 1 , the compound is:

or a pharmaceutically acceptable salt thereof.

14. A method if inhibiting ATR in a biological sample, comprising the step of contacting a compound of claim 1 with said biological sample.

15. The method of claim 14 , wherein said biological sample is a cell.

16. A pharmaceutical composition comprising a compound of formula II,

or a pharmaceutically acceptable salt thereof; wherein
Ring A is phenyl;
L is —C(O)—;
R 1 is C 1 -C 6 alkyl;
R 2 is —(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 nitrogen atoms, wherein said heterocyclic ring is optionally substituted with one occurrence of J Z1 ;
J z1 is (X) t —CN, C 1 -C 6 alkyl, or —(X) t —Z;
X is C 1 -C 4 alkylene;
each t, p, and r is independently 0 or 1;
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 nitrogen atoms, wherein said ring is optionally substituted with one occurrence of J z ;
each J z and J 1 is independently NH 2 , NH(C 1 -C 4 aliphatic), N(C 1 -C 4 aliphatic) 2 , halogen, C 1 -C 4 aliphatic, OH, O(C 1 -C 4 aliphatic), NO 2 , CN, CO 2 H, CO(C 1-4 aliphatic), CO 2 (C 1 -C 4 aliphatic), O(haloC 1 -C 4 aliphatic), or haloC 1 -C 4 aliphatic;
J 2 is halo, C 1 -C 2 alkyl optionally substituted with 1-3 fluoro, or CN; and
q is 0, 1, or 2;
and a pharmaceutically acceptable carrier.

17. A method of promoting cell death in cancer cells of a patient comprising administering to the patient a compound of formula II,

or a pharmaceutically acceptable salt thereof; wherein
Ring A is phenyl;
L is —C(O)—;
R 1 is C 1 -C 6 alkyl;
R 2 is —(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 nitrogen atoms, wherein said heterocyclic ring is optionally substituted with one occurrence of J Z1 ;
j Z1 is (X) t —CN, C 1 -C 6 alkyl, or —(X) t —Z;
X is C 1 -C 4 alkylene;
each t, p, and r is independently 0 or 1;
Z is —NR3R4;
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 nitrogen atoms, wherein said ring is optionally substituted with one occurrence of J Z ;
each J Z and J 1 is independently NH 2 , NH(C 1 -C 4 aliphatic), N(C 1 -C 4 aliphatic) 2 , halogen, C 1 -C 4 aliphatic, OH, O(C 1 -C 4 aliphatic), NO 2 , CN, CO 2 H, CO(C 1 -C 4 aliphatic), CO 2 (C 1 -C 4 aliphatic), O(haloC 1 -C 4 aliphatic), or haloC 1 -C 4 aliphatic;
J 2 is halo, C 1 -C 2 alkyl optionally substituted with 1-3 fluoro, or CN; and
q is 0, 1, or 2.

18. A method of preventing cell repair from DNA damage in a patient comprising administering to the patient a compound of formula II,

or a pharmaceutically acceptable salt thereof; wherein
Ring A is phenyl;
L is —C(O)—;
R 1 is C 1 -C 6 alkyl;
R 2 is —(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 nitro

Assignees

• Vertex Pharma

Inventors

• Charrier Jean-Damien
• Durrant Steven
• Kay David
• Knegtel Ronald
• Maccormick Somhairle
• Mortimore Michael
• O'Donnell Michael
• Pinder Joanne
• Rutherford Alistair
• Virani Anisa Nizarali
• Young Stephen
• Reaper Philip Michael

Classifications

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title