# US 10,308,614 B2 · Therapeutic compounds and uses thereof

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- Number: US 10,308,614 B2
- Document ID: US10308614B2
- Status: Granted
- Kind: B2
- Application number: 15/686,028
- Filed: 2017-08-24
- Published: 2018-03-29
- Granted: 2019-06-04
- Earliest claimed: 2015-02-25
- Assignees: Genentech, Inc.; Constellation Pharmaceuticals, Inc.
- Applicants: Genentech, Inc.; Constellation Pharmaceuticals, Inc.
- Inventors: Brian K. Albrecht; Alexandre Cote; Terry Crawford; Martin Duplessis; Andrew Charles Good; Yves LeBlanc; Steven R. Magnuson; Christopher G. Nasveschuk; F. Anthony Romero; Yong Tang; Alexander M. Taylor
- Web page: https://patentgrep.com/patent/US10308614B2

## CPC

- C07D 237/20: Nitrogen atoms (nitro radicals C07D237/12)
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 237/22: Nitrogen and oxygen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 451/02: containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/08: Bridged systems
- C07D 498/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of formula (I): and salts thereof, wherein: R1-R4 have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of BRG1, BRM and/or PB1. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various BRG1-mediated disorders, BRM-mediated disorders and/or PB1-mediated disorders.

## Claims

### Claim 1

A compound of formula (I):
or a salt thereof, wherein:
R1 is 2-hydroxy phenyl that is optionally substituted with one or more groups independently selected from the group consisting of halo;
R2 is H;
R3 is H;
R4 is selected from the group consisting of, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, 3-15 membered heterocyclyl —O—Rb, —N(Rb)2, —S(O)2Rb, and —C(O)—N(Rb)2, wherein each C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc;
each Rb is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc;
each Rc is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from Rd; or two Rc 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 the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
each Rd is independently selected from the group consisting of oxo, halo, —NO2, —N(Re)2, —CN, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —C(O)—Re, —C(O)—ORe, —S(O)—Re, —S(O)2—Re, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—C(O)—N(Re)2, —N(Re)—S(O)2—Re, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Re, oxo, halo, —NO2, —N(Re)2, —CN, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —C(O)—Re, —C(O)—ORe, —S(O)—Re, —S(O)2—Re, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—C(O)—N(Re)2, and —N(Re)—S(O)2—Re; and
each Re is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and carbocyclyl(C1-3alkyl)-.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R4 is a 3-15 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of:

### Claim 4 (depends on 1)

The compound of claim 1 wherein R4 is an N-linked 3-15 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc.

### Claim 5 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of:

### Claim 6 (depends on 1)

The compound of claim 1 wherein R4 is —O—Rb.

### Claim 7 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of:

### Claim 8 (depends on 1)

The compound of claim 1 wherein R4 is —N(Rb)2.

### Claim 9 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of:

### Claim 10 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, 3-15 membered heterocyclyl, and —C(O)—N(Rb)2, wherein each C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc.

### Claim 11 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of:

### Claim 12 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of:

### Claim 13 (depends on 1)

The compound of claim 1 wherein R4 is selected from the group consisting of:

### Claim 14

A compound of selected from the group consisting of:
or a salt thereof.

### Claim 15

The compound:
or a salt thereof.

### Claim 16 (depends on 1)

A composition comprising a compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

### Claim 17

A compound of formula (I):
or a salt thereof, wherein:
R1 is phenyl that is substituted with hydroxy and that is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, trifluoromethyl, trifluoromethoxy, C1-3alkyl, and C1-3alkoxy;
R2 is H, C1-6alkyl, or —C(═O)—C1-6alkyl;
R3 is H or C1-6alkyl;
R4 is selected from the group consisting of —O—Rb, —N(Rb)2, —S(O)2Rb, —C(O)—N(Rb)2, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein each C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc;
each Rb is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc;
each R is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from Rd; or two Rc 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 the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
each Rd is independently selected from the group consisting of oxo, halo, —NO2, —N(Re)2, —CN, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —C(O)—Re, —C(O)—ORe, —S(O)—Re, —S(O)2—Re, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—C(O)—N(Re)2, —N(Re)—S(O)2—Re, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Re, oxo, halo, —NO2, —N(Re)2, —CN, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —C(O)—Re, —C(O)—ORe, —S(O)—Re, —S(O)2—Re, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—C(O)—N(Re)2, and —N(Re)—S(O)2—Re; and
each Re is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and carbocyclyl(C1-3alkyl)-.

### Claim 18 (depends on 17)

A composition comprising a compound of formula (I) as described in claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

### Claim 19 (depends on 14)

A composition comprising a compound of formula (I) as described in claim 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

### Claim 20

A compound of formula (I):
or a salt thereof, wherein:
R1 is 2-hydroxy phenyl that is optionally substituted with one or more groups independently selected from the group consisting of halo;
R2 is H;
R3 is H;
R4 is selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, 3-15 membered heterocyclyl —O—Rb, —N(Rb)2, —S(O)2Rb, and —C(O)—N(Rb)2, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl of R4 is substituted with one or more groups independently selected from the group consisting of C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-15 membered carbocyclyl, 3-15 membered heterocyclyl, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc;
each Rb is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Re, —O—C(O)—Rc, —C(O)—Rc, —C(O)—ORc, —S(O)—Rc, —S(O)2—Rc, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—C(O)—N(Rc)2, and —N(Rc)—S(O)2—Rc;
each Rc is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from Rd; or two Rc 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 the group consisting of oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;
each Rd is independently selected from the group consisting of oxo, halo, —NO2, —N(Re)2, —CN, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —C(O)—Re, —C(O)—ORe, —S(O)—Re, —S(O)2—Re, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—C(O)—N(Re)2, —N(Re)—S(O)2—Re, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Re, oxo, halo, —NO2, —N(Re)2, —CN, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —C(O)—Re, —C(O)—ORe, —S(O)—Re, —S(O)2—Re, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—C(O)—N(Re)2, and —N(Re)—S(O)2—Re; and
each Re is independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and carbocyclyl(C1-3alkyl)-.

### Claim 21 (depends on 20)

A composition comprising a compound of formula (I) as described in claim 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.