IP Library › Granted Patent US 12,264,155
Granted Patent B2
US 12,264,155 · App. 17/245,574 · Granted Apr 1, 2025

Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use as ATR kinase inhibitors

Inventors: Sheldon N. Crane (Pincourt, CA); Vouy Linh Truong (Pierrefonds, CA); Abbas Abdoli (Montreal, CA); Jean-François Truchon (Saint-Laurent, CA); Cameron Black (St-Laurent, CA); Stéphane Dorich (Pointe-Claire, CA); Lee Fader (Hawkesbury, CA); Stéphanie Lanoix (Mansfield, CA); Paul Jones (Verdun, CA); Miguel St-Onge (Vaudreuil-Dorion, CA); Audrey Picard (Mirabel, CA); Cyrus M. Lacbay (Montreal, CA)
Assignee: Repare Therapeutics Inc.
C07D471/04C07D519/00C07B2200/05
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Quick Facts
Patent No.
US 12,264,155
App. No.
17/245,574
Granted
Apr 1, 2025
Kind
B2
Abstract

Disclosed are compounds and pharmaceutically acceptable salts thereof that may be used in the treatment of subjects in need thereof. The compounds disclosed herein may be inhibitors of Ataxia-telangiectasia and RAD-3-related protein kinase (ATR). Also disclosed are pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and methods of their preparation and use.

Claims (57)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

is a double bond, and each Y is independently N or CR 4 ; or is a single bond, and each Y is independently NR Y , carbonyl, or C (R Y ) 2 ; wherein each R Y is independently H or optionally substituted C 1-6 alkyl;

R 1 is optionally substituted C 1-6 alkyl or H;

R 2 is optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 heterocyclyl C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 alkyl, halogen, —N(R 5 ) 2 , —OR 5 , —CON(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —SO 2 R 5A , or -Q-R 5B ;

R 3 is optionally substituted C 1-9 heteroaryl;

each R 4 is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

each R 5 is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, or —SO 2 R 5A ; or both R 5 , together with the atom to which they are attached, combine to form an optionally substituted C 2-9 heterocyclyl;

each R 5A is independently optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 6-10 aryl;

R 5B is hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, —N(R 5 ) 2 , —CON(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —SO 2 R 5A , or optionally substituted alkoxy;

each R 6 is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkoxyalkyl, optionally substituted C 6-10 aryl C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-9 heteroaryl; or both R 6 , together with the atom to which they are attached, combine to form an optionally substituted C 2-9 heterocyclyl;

Q is optionally substituted C 2-9 heterocyclylene, optionally substituted C 3-8 cycloalkylene, optionally substituted C 1-9 heteroarylene, or optionally substituted C 6-10 arylene; and

X is hydrogen or halogen.

2. The compound of claim 1 , wherein the compound is a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

each Y is independently N or CR 4 ;

R 1 is optionally substituted C 1-6 alkyl or H;

R 2 is optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 2-9 heterocyclyl C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 alkyl, halogen, —N(R 5 ) 2 , —OR 5 , —CON(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —SO 2 R 5A , or -Q-R 5B ;

R 3 is optionally substituted C 1-9 heteroaryl;

each R 4 is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

each R 5 is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, or —SO 2 R 5A ; or both R 5 , together with the atom to which they are attached, combine to form an optionally substituted C 2-9 heterocyclyl;

each R 5A is independently optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 6-10 aryl;

R 5B is hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 1-9 heteroaryl, —N(R 5 ) 2 , —CON(R 6 ) 2 , —SO 2 N(R 6 ) 2 , —SO 2 R 5A , or optionally substituted alkoxy;

each R 6 is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkoxyalkyl, optionally substituted C 6-10 aryl C 1-6 alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-9 heteroaryl; or both R 6 , together with the atom to which they are attached, combine to form an optionally substituted C 2-9 heterocyclyl;

Q is optionally substituted C 2-9 heterocyclylene, optionally substituted C 3-8 cycloalkylene, optionally substituted C 1-9 heteroarylene, or optionally substituted C 6-10 arylene; and

X is hydrogen or halogen.

3. The compound of claim 1 , wherein the compound is a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is a compound of formula (IB-a):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is a compound of formula (I-a):

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is a compound of formula (IA-a):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is a compound of formula (IC):

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the compound is a compound of formula (IC-a):

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein R 1 is methyl.

11. The compound of claim 1 , wherein R 2 is optionally substituted C 2-9 heterocyclyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 6-10 aryl, optionally substituted C 1.9 heteroaryl, optionally substituted C 1-9 heteroaryl C 1-6 alkyl, —N(R 5 ) 2 , —CON(R 6 ) 2 , —SO 2 N (R 6 ) 2 , or —SO 2 R 5A .

12. The compound of claim 1 , wherein each R 5A is independently optionally substituted C 1-6 alkyl or optionally substituted C 3-8 cycloalkyl.

13. The compound of claim 1 , wherein each R 6 is independently hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl C 1-6 alkyl, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 heteroaryl; or both R 6 , together with the atom to which they are attached, combine to form an optionally substituted C 2-9 heterocyclyl.

14. The compound of claim 1 , wherein R 2 is:

15. The compound of claim 1 , wherein R 3 is optionally substituted, monocyclic C 1-9 heteroaryl comprising at least one nitrogen atom.

16. The compound of claim 1 , wherein R 3 is:

17. The compound of claim 1 , wherein R 4 is hydrogen.

18. The compound of claim 1 , wherein X is hydrogen.

19. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.

20. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

21. A method of inhibiting ATR kinase in a cell expressing ATR kinase, the method comprising contacting the cell with the compound of claim 1 .

22. The method of claim 21 , wherein the cell is in a subject.

23. A method of treating a subject in need of a treatment for cancer comprising administering to the subject the compound of claim 1 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 3, 2021
From: CRANE, SHELDON N.; TRUONG, VOUY LINH; ABDOLI, ABBAS; TRUCHON, JEAN-FRANÇOIS; BLACK, CAMERON; DORICH, STÉPHANE; FADER, LEE; LANOIX, STÉPHANIE; JONES, PAUL; ST-ONGE, MIGUEL; PICARD, AUDREY; LACBAY, CYRUS M.
To: REPARE THERAPEUTICS INC.
Reel/Frame 056113/0226 →
Continuity (4)
Continuation PCTCA2019051539 · Oct 30, 2019
Provisional Application 62877177 · Jul 22, 2019
Provisional Application 62752873 · Oct 30, 2018
Related Publication 20210277002A1 · Sep 9, 2021
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