IP Library › Granted Patent US 10,696,655

Granted Patent B2

US 10,696,655 · App. 16/198,597 · Granted Jun 30, 2020

Therapeutic compounds and uses thereof

Inventors: Patrick Cyr (South San Francisco, CA); Sarah Bronner (South San Francisco, CA); F. Anthony Romero (South San Francisco, CA); Steven Magnuson (South San Francisco, CA); Vickie Hsiao-Wei Tsui (South San Francisco, CA); John Wai (Shanghai, CN); Kwong Wah Lai (Shanghai, CN); Fei Wang (Shanghai, CN)

Assignees: GENENTECH, INC.; CONSTELLATION PHARMACEUTICALS, INC.

C07D401/14 A61K31/435 A61K31/437 A61K31/4375 A61K31/496 A61K31/4985 A61K31/5025 A61K31/519 A61K31/5377 A61K31/5513 A61K45/06 C07D243/14 C07D267/14 C07D405/14 C07D409/14 C07D413/04 C07D413/10 C07D413/14 C07D417/14 C07D471/04 C07D487/04 C07D487/22

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Quick Facts

Patent No.: US 10,696,655
App. No.: 16/198,597
Granted: Jun 30, 2020
Kind: B2

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Abstract

The present invention relates to compounds of formula (I) and formula (II): and to salts thereof, wherein R 1 -R 4 of formula (I) and R 5 -R 6 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II), or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.

Claims (38)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen, —NR a R b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or a saturated 3-8 membered carbocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and saturated 3-8 membered carbocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, and C 1 -C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R 2 is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —F, —Cl, —Br, —I, —NO 2 , —N(R t ) 2 , —CN, —C(O)—N(R t ) 2 , —O—R t , —O—C(O)—R t , —C(O)—R t , and —C(O)—O—R t , wherein any C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more halo;

R 3 is selected from the group consisting of:

Y is O;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

each R 4 is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —F, —Cl, —Br, —I, —NO 2 , —N(R w ) 2 , —CN, —C(O)—N(R w ) 2 , —O—R w , —O—C(O)—R w , —C(O)—R x , and —C(O)—O—R w , wherein any C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more oxo or halo;

each R a and R b is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or R a and R b are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R t is independently selected from hydrogen, C 1-6 alkyl, C 2-6 -alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R t are taken together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R w is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R w are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

each R x of is independently selected from, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, —F, —Cl, —Br, —I, —NO 2 , —N(R y ) 2 , —CN, —C(O)—N(R y ) 2 , —S(O)—N(R y ) 2 , —S(O) 2 —N(R y ) 2 , —O—R y , —S—R y , —O—C(O)—R y , —O—C(O)—O—R y , —C(O)—R y , —C(O)—O—R y , —S(O)—R y , —S(O) 2 —R y , —O—C(O)—N(R y ) 2 , —N(R y )—C(O)—OR y , —N(R y )—C(O)—N(R y ) 2 , —N(R y )—C(O)—R y , —N(R y )—S(O)—R y , —N(R y )—S(O) 2 —R y , —N(R y )—S(O)—N(R y ) 2 , and —N(R y )—S(O) 2 —N(R y ) 2 , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, is optionally substituted with one or more groups independently selected from oxo, halo, —NO 2 , —N(R y ) 2 , —CN, —C(O)—N(R y ) 2 , —S(O)—N(R y ) 2 , —S(O) 2 —N(R y ) 2 , —O—R y , —S—R y , —O—C(O)—R y , —C(O)—R y , —C(O)—O—R y , —S(O)—R y , —S(O) 2 —R y , —C(O)—N(R y ) 2 , —N(R y )—C(O)—R y , —N(R y )—S(O)—R y , —N(R y )—S(O) 2 —R y , 3-12 membered carbocycle, and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and

each R y is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, and 3-12 membered heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C 1-6 alkoxy, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two R y are taken together with the nitrogen to which they are attached to form a 3-12 membered heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo;

wherein the 3-12 membered heterocyclyl is a monocycle, bicycle, tricycle or spiro ring system, wherein one to five ring atoms is a heteroatom independently selected from nitrogen, sulfur and oxygen, and wherein the 3-12 membered heterocyclyl is saturated, partially unsaturated, or aromatic; and

wherein the 3-12 membered carbocyclyl is a monocycle bicycle or spiro ring system.

2. The compound or pharmaceutically acceptable salt of claim 1 which is a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof.

3. The compound or pharmaceutically acceptable salt of claim 1 wherein R 1 is —NHR b .

4. The compound or pharmaceutically acceptable salt of claim 1 selected from the group consisting of:

or a salt thereof.

5. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in claim 1 and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

6. A method for treating a CBP and/or EP300-mediated disorder in an animal comprising administering a compound or a pharmaceutically acceptable salt thereof as described in claim 1 to the animal, wherein the CBP and/or EP300-mediated disorder is cancer, wherein the cancer is melanoma, NSCLC, renal cancer, ovarian cancer, colon cancer, pancreatic cancer, hepatocellular cancer, or breast cancer.

7. The method of claim 6 further comprising the administration of a cytotoxic agent to the animal.

8. The compound or pharmaceutically acceptable salt of claim 1 wherein R 3 is:

9. The compound or pharmaceutically acceptable salt of claim 1 which is a compound of formula (Ib):

or a pharmaceutically acceptable salt thereof.

10. The compound or pharmaceutically acceptable salt of claim 1 , wherein R b is C 1-6 alkyl.

11. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is methyl or —NH(CH 3 ).

12. The compound or pharmaceutically acceptable salt of claim 1 , wherein n is 0 or 1.

13. The compound or pharmaceutically acceptable salt of claim 1 , wherein each R 4 is independently selected from C 1-6 alkyl.

14. The compound or pharmaceutically acceptable salt of claim 1 , wherein m is 0.

15. The compound or pharmaceutically acceptable salt of claim 1 , wherein m is 1.

16. The compound or pharmaceutically acceptable salt of claim 1 , wherein each R 2 is independently selected from the group consisting of C 1-6 alkyl and —O—R t .

17. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is —O—R t .

18. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is —OMe.

19. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is methyl, —NH(CH 3 ) or ethyl.

20. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is —OMe, ethyl or isopropyl.

Assignments (5)