# US 2020/0399267 A1 · Bicyclic heterocycles as fgfr4 inhibitors

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- Number: US 2020/0399267 A1
- Document ID: US20200399267A1
- Status: Published application
- Kind: A1
- Application number: 16/924,905
- Filed: 2020-07-09
- Published: 2020-12-24
- Earliest claimed: 2015-02-20
- Assignees: Incyte Corporation
- Applicants: Incyte Corporation
- Inventors: Liang Lu; Liangxing Wu; Ding-Quan Qian; Wenqing Yao
- Web page: https://patentgrep.com/patent/US20200399267A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 471/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR4 enzyme and are useful in the treatment of FGFR4-associated diseases such as cancer.

## Claims

### Claim at position 1

1-39. (canceled)

### Claim 40

A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X1 is CR10R11;
X is N or CR6;
R1 is C1-3 alkyl or C1-3 haloalkyl;
R2 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN, or C1-3 alkoxy;
R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN, or C1-3 alkoxy;
R4 is C1-3 alkyl or C1-3 haloalkyl;
R5 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN, or C1-3 alkoxy;
R6 is selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl groups of R6 are each optionally substituted with 1, 2, or 3 substituents independently selected from R10A;
L is —(CR13R14)n—, wherein R13 and R14 are each independently H;
the subscript n is 1 or 2;
R8 is H;
R10 and R11 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, a 5-10 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-10 membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl groups of R10 and R11 are each optionally substituted with 1, 2, 3, or 4 R10A;
R10A, at each occurrence, is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl group of R10A are each optionally substituted with 1, 2, or 3 substituents independently selected from R19;
Ra4, Rb4, Rc4, and Rd4, at each occurrence, are independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl group of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, or 3 substituents independently selected from R19;
alternatively, Rc4 and Rd4 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2 or 3 substituents independently selected from R19;
Re4, at each occurrence, is H or C1-4 alkyl;
alternatively, R10 and R11 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; wherein said 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4 R10A;
R12 is H or C1-4 alkyl which is optionally substituted by R17;
R17, at each occurrence, is independently selected from halo, CN, NO2, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, C(═NRe7)NRc7Rd7, NRc7C(═NRe7)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)ORa7, NRc7C(O)NRc7Rd7, NRc7S(O)Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, S(O)2NRc7Rd7, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl groups of R17 are each optionally substituted with 1, 2, or 3 substituents independently selected from R19;
Ra7, Rb7, Rc7, and Rd7, at each occurrence, are independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S, and a 4-7 membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl groups of Ra7, Rb7, Rc7, and Rd7 are each optionally substituted with 1, 2, or 3 substituents independently selected from R19;
alternatively, Rc7 and Rd7 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2 or 3 substituents independently selected from R19;
Re7, at each occurrence, is independently H or C1-4 alkyl;
R19, at each occurrence, is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9, NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S(O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C1-4 haloalkyl;
Ra9, Rc9, and Rd9, at each occurrence, are independently selected from H and C1-4 alkyl; and
Rb9, at each occurrence, is independently C1-4 alkyl.

### Claim at position 3

41-43. (canceled)

### Claim 44 (depends on 40)

The method of claim 40, wherein R2 is F and R5 is F.

### Claim 45 (depends on 40)

The method of claim 40, wherein the compound has Formula (V):
or a pharmaceutically acceptable salt thereof.

### Claim 46 (depends on 40)

The method of claim 40, wherein R10 is C1-6 alkyl and R11 is C1-6 alkyl.

### Claim 47 (depends on 40)

The method of claim 40, wherein R10 and R11 are each methyl.

### Claim 48 (depends on 40)

The method of claim 40, wherein R10 and R11 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group.

### Claim 49 (depends on 40)

The method of claim 40, wherein R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

### Claim 50 (depends on 40)

The method of claim 40, wherein R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl.

### Claim 51 (depends on 40)

The method of claim 40, wherein R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl group.

### Claim 52 (depends on 40)

The method of claim 40, wherein R10 and R11 together with the carbon atom to which they are attached form 4-, 5-, 6-, or 7-membered heterocycloalkyl group.

### Claim 53 (depends on 40)

The method of claim 40, wherein R10 and R11 together with the carbon atom to which they are attached form a tetrahydropyranyl group.

### Claim 54 (depends on 40)

The method of claim 40, wherein L is —CH2—.

### Claim 55 (depends on 40)

The method of claim 40, wherein R1 and R4 are each C1-3 alkyl.

### Claim 56 (depends on 40)

The method of claim 40, wherein R1 and R4 are methyl.

### Claim 57 (depends on 40)

The method of claim 40, wherein X is CH or N.

### Claim 58 (depends on 40)

The method of claim 40, wherein X is CH.

### Claim 59 (depends on 40)

The method of claim 40, wherein X is N.

### Claim 60 (depends on 40)

The method of claim 40, wherein R12 is H.

### Claim 61 (depends on 40)

The method of claim 40, wherein the compound is selected from the group consisting of
N-{[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]methyl}acrylamide;
N-((6′-(2,6-difluoro-3,5-dimethoxyphenyl)-7′-oxo-6′,7′-dihydro-5′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-2′-yl)methyl)acrylamide;
N-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide;
N-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)methyl)acrylamide; and
N-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′-methyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide;
or a pharmaceutically acceptable salt thereof.

### Claim 62 (depends on 40)

The method of claim 40, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, ovarian cancer, kidney cancer, esophageal cancer, head and neck cancer, rhabdomyosarcoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer.

### Claim 63 (depends on 40)

The method of claim 40, wherein the cancer is hepatocellular carcinoma.

### Claim 64 (depends on 40)

The method of claim 40, wherein the cancer is ovarian cancer.

### Claim 65 (depends on 40)

The method of claim 40, wherein the cancer is kidney cancer.

### Claim 66 (depends on 40)

The method of claim 40, wherein the cancer is esophageal cancer.

### Claim 67 (depends on 40)

The method of claim 40, wherein the cancer is head and neck cancer.

### Claim 68 (depends on 40)

The method of claim 40, wherein the cancer is rhabdomyosarcoma.

### Claim 69 (depends on 40)

The method of claim 40, wherein the cancer is breast cancer.

### Claim 70 (depends on 40)

The method of claim 40, wherein the cancer is lung cancer.

### Claim 71 (depends on 70)

The method of claim 70, wherein the lung cancer is non-small cell lung cancer.

### Claim 72 (depends on 70)

The method of claim 70, wherein the lung cancer is adenocarcinoma, small cell lung cancer, parvicellular carcinoma, non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, or pleuropulmonary blastoma.

### Claim 73 (depends on 40)

The method of claim 40, wherein the cancer is colorectal cancer.

### Claim 74 (depends on 40)

The method of claim 40, wherein the cancer is prostate cancer.