# US 2019/0314360 A1 · Antitumor agent and bromodomain inhibitor

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- Number: US 2019/0314360 A1
- Document ID: US20190314360A1
- Status: Published application
- Kind: A1
- Application number: 16/453,393
- Filed: 2019-06-26
- Published: 2019-10-17
- Earliest claimed: 2016-12-27
- Assignees: FUJIFILM Corporation; FUJIFILM Toyama Chemical Co., Ltd.; National Institute of Advanced Industrial Science and Technology
- Applicants: FUJIFILM Corporation; FUJIFILM Toyama Chemical Co., Ltd.; National Institute of Advanced Industrial Science and Technology
- Inventors: Keiko MAKITA; Kazunori SAEKI; Tadashi TANAKA; Masataka FUJINO; Tohru NATSUME; Kentaro FURUYA
- Web page: https://patentgrep.com/patent/US20190314360A1

## CPC

- A61K 31/4704: 2-Quinolinones, e.g. carbostyril
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/497: containing further heterocyclic rings
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- 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
- 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

It is an object of the present invention to provide an antitumor agent, which is further excellent as a treatment agent used in the prevention and/or therapy of tumor associated with a bromodomain, and also to provide a bromodomain inhibitor, which is useful as a treatment agent for diseases or states associated with a bromodomain. An antitumor agent and a bromodomain inhibitor, comprising a compound represented by the following formula, have an excellent bromodomain inhibitory activity and are useful as treatment agents in the prevention and/or therapy of tumor associated with a bromodomain, and the like: wherein R1 represents a C1-6 alkyl group, etc.; R2 represents a hydrogen atom, etc.; R3 represents a halogen atom, etc.; Z1, Z2 and Z3 each represent CH, etc.; X1 represents CONH, etc.; Ring A represents a phenyl group, etc.; R4 represents a halogen atom, etc.; and m represents an integer from 0 to 5.

## Claims

### Claim 1

A method for treating tumor, comprising administering a therapeutically effective amount of a compound represented by the following formula [1] or a salt thereof:
wherein R1 represents a hydrogen atom or an optionally substituted C1-6 alkyl group;
R2 represents a hydrogen atom, a halogen atom, or an optionally substituted C1-6 alkyl group;
R3 represents a halogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C4-8 cycloalkenyl group, an optionally substituted aryl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C1-6 alkylamino group, an optionally substituted di(C1-6 alkyl)amino group, or an optionally substituted heterocyclic group;
Z1, Z2 and Z3, which are the same or different, each represent a nitrogen atom or a group represented by the formula CR5 (wherein R5 represents a hydrogen atom, a halogen atom or an optionally substituted C1-6 alkyl group);
X1 represents
(1) a group represented by the formula C(═O)N(R6) (wherein the carbon atom binds to Ring A, and R6 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C1-6 alkyl group),
(2) a group represented by the formula N(R7)C(═O) (wherein the nitrogen atom binds to Ring A, and R7 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C1-6 alkyl group; or R7 represents, together with one substituent R4 of Ring A, an optionally substituted C2-4 alkylene group, a group represented by the formula O—Y1 (wherein the oxygen atom binds to Ring A, and Y1 represents an optionally substituted C1-3 alkylene group), a group represented by the formula S(O)n—Y2 (wherein the sulfur atom binds to Ring A, Y2 represents an optionally substituted C1-3 alkylene group, and n represents an integer from 0 to 2), or a group represented by the formula N(R8)—Y3 (wherein the nitrogen atom binds to Ring A, Y3 represents an optionally substituted C1-3 alkylene group, and R8 represents a hydrogen atom, an amino-protecting group, an optionally substituted C1-6 alkyl group, or an optionally substituted aryl group)),
(3) an optionally substituted divalent cyclic hydrocarbon group that is formed by removing each one hydrogen atom on the two adjacent atoms, or
(4) an optionally substituted divalent heterocyclic group that is formed by removing each one hydrogen atom on the two adjacent atoms;
Ring A represents a cyclic hydrocarbon group or a heterocyclic group;
an m number of R4, which are the same or different, each represent a halogen atom, a cyano group, a nitro group, an amino-protecting group, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C4-8 cycloalkenyl group, an optionally substituted aryl group, an optionally substituted C1-6 alkoxy group, an optionally substituted aryloxy group, an optionally substituted C1-6 alkylamino group, an optionally substituted di(C1-6 alkyl)amino group, an optionally substituted arylamino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted C1-6 alkylthio group, an optionally substituted arylthio group, an optionally substituted C1-6 alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted heterocyclic group, an optionally protected amino group, an optionally protected hydroxyl group,
an optionally protected carboxyl group,
an optionally substituted C2-5 alkylene group formed together by the two adjacent R4,
an optionally substituted C2-4 alkylene group formed by one R4 together with R7,
a group represented by the formula O—Y1 (wherein the oxygen atom binds to Ring A, and Y1 represents an optionally substituted C1-3 alkylene group), which is formed by one R4 together with R7,
a group represented by the formula S(O)n—Y2 (wherein the sulfur atom binds to Ring A, Y2 represents an optionally substituted C1-3 alkylene group, and n represents an integer from 0 to 2), which is formed by one R4 together with R7, or
a group represented by the formula N(R8)—Y3 (wherein the nitrogen atom binds to Ring A,
Y3 represents an optionally substituted C1-3 alkylene group, and R8 represents a hydrogen atom,
an amino-protecting group, an optionally substituted C1-6 alkyl group, or an optionally substituted aryl group), which is formed by one R4 together with R7; and
m represents an integer from 0 to 5.

### Claim 2 (depends on 1)

The method according to claim 1, wherein
R2 represents a hydrogen atom or a C1-6 alkyl group; and
Z1, Z2 and Z3 each represent CH.

### Claim 3 (depends on 1)

The method according to claim 1, wherein
R3 represents an optionally substituted C3-8 cycloalkyl group or an optionally substituted heterocyclic group.

### Claim 4 (depends on 1)

The method according to claim 1, wherein
R3 represents any one of the following heterocyclic groups:
wherein R9 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C1-6 alkyl group, and * represents a binding site.

### Claim 5 (depends on 1)

The method according to claim 1, wherein Ring A represents a cyclic hydrocarbon group.

### Claim 6 (depends on 1)

The method according to claim 1, wherein
X1 represents
(2) a group represented by the formula N(R7)C(═O) (wherein the nitrogen atom binds to Ring A, and R7 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C1-6 alkyl group; or R7 represents, together with one substituent R4 of Ring A, an optionally substituted C2-4 alkylene group, a group represented by the formula O—Y1 (wherein the oxygen atom binds to Ring A, and Y1 represents an optionally substituted C1-3 alkylene group), a group represented by the formula S(O)n—Y2 (wherein the sulfur atom binds to Ring A, Y2 represents an optionally substituted C1-3 alkylene group, and n represents an integer from 0 to 2), or a group represented by the formula N(R8)—Y3 (wherein the nitrogen atom binds to Ring A, Y3 represents an optionally substituted C1-3 alkylene group, and R8 represents a hydrogen atom, an amino-protecting group, an optionally substituted C1-6 alkyl group, or an optionally substituted aryl group)), or
(4) an optionally substituted divalent heterocyclic group that is formed by removing each one hydrogen atom on the two adjacent atoms.

### Claim 7 (depends on 1)

The method according to claim 1, wherein
the compound is represented by the following formula [1-1]:
wherein R1 represents a hydrogen atom or an optionally substituted C1-6 alkyl group;
R3a represents an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, or an optionally substituted heterocyclic group;
Ring A1 represents a cyclic hydrocarbon group;
R7a represents an amino-protecting group or an optionally substituted C1-6 alkyl group; or
R7a represents, together with one substituent R4a of Ring A1, an optionally substituted C2-3 alkylene group, a group represented by the formula O—Ya (wherein the oxygen atom binds to Ring A1, and Y1a represents an optionally substituted C1-3 alkylene group), a group represented by the formula S(O)n—Y2a (wherein the sulfur atom binds to Ring A1, Y2a represents an optionally substituted C1-3 alkylene group, and n represents an integer from 0 to 2), or a group represented by the formula N(R8a)—Y3a (wherein the nitrogen atom binds to Ring A1, Y3a represents an optionally substituted C1-3 alkylene group, and R8a represents a hydrogen atom or an optionally substituted C1-6 alkyl group),
an m1 number of R4a, which are the same or different, each represent a halogen atom, a cyano group, an optionally substituted C1-3 alkyl group, an optionally substituted carbamoyl group, an optionally substituted C1-3 alkylsulfonyl group, an optionally protected carboxyl group, an optionally substituted C2-5 alkylene group formed together by the two adjacent R4a an optionally substituted C2-3 alkylene group formed by one R4a together with R7a, a group represented by the formula O—Ya (wherein the oxygen atom binds to Ring A1, and Y1a represents an optionally substituted C1-3 alkylene group), which is formed by one R4a together with R7aa group represented by the formula S(O)n—Y2a (wherein the sulfur atom binds to Ring A1, Y2a represents an optionally substituted C1-3 alkylene group, and n represents an integer from 0 to 2), which is formed by one R4a together with R7a, or
a group represented by the formula N(R8a)—Y3a (wherein the nitrogen atom binds to Ring A1, Y3a represents an optionally substituted C1-3 alkylene group, and R8a represents a hydrogen atom or an optionally substituted C1-6 alkyl group), which is formed by one R4a together with R7a; and
m1 represents an integer from 0 to 2.

### Claim 8 (depends on 1)

The method according to claim 1, wherein
X1 represents an optionally substituted dihydrooxoimidazole-1,5-diyl group, an optionally substituted imidazole-1,2-diyl group, an optionally substituted imidazole-4,5-diyl group, an optionally substituted 1,2,4-triazole-1,5-diyl group, an optionally substituted 1H-pyrazole-4,5-dihyl group, an optionally substituted oxopyrrolidine-1,2-diyl group, an optionally substituted dioxotriazolidine-1,2-diyl group, an optionally substituted dioxopyrazolidine-1,2-diyl group, an optionally substituted oxopyrazoline-1,2-diyl group, an optionally substituted pyridine-2,3-diyl group, or an optionally substituted pyrazine-2,3-diyl group.

### Claim 9 (depends on 1)

The method according to claim 1, wherein
the compound is represented by the formula [1-2]:
wherein R1 represents a hydrogen atom or an optionally substituted C1-6 alkyl group;
R3b represents an optionally substituted C1-6 alkyl group, an optionally substituted C3-8 cycloalkyl group, or an optionally substituted heterocyclic group;
X1b represents an optionally substituted dihydrooxoimidazole-1,5-diyl group;
Ring A2 represents a cyclic hydrocarbon group;
an m2 number of R4b, which are the same or different, each represent a halogen atom or an optionally substituted C1-6 alkyl group; and
m2 represents an integer from 0 to 2.

### Claim 10 (depends on 1)

The method according to claim 1, wherein
the compound is at least one selected from the group consisting of:
N-(4-cyclopropyl-1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl)-N-methylbenzamide, 1-ethyl-4-(1-ethylpiperidin-4-yl)-N-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-6-carboxamide,
6-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-1-ethyl-4-(1-methylpiperidin-4-yl)quinolin-2(1H)-one,
1-ethyl-N-methyl-N-(4-methylphenyl)-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
N-(2,3-dihydro-1H-inden-5-yl)-1-ethyl-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
6-(5-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-ethyl-4-(morpholin-4-yl)quinolin-2(1H)-one,
6-(5-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-ethyl-4-(morpholin-4-yl)quinolin-2(1H)-one,
1-ethyl-4-(morpholin-4-yl)-6-(2-oxo-5-phenyl-3-(propan-2-yl)-2,3-dihydro-1H-imidazol-1-yl)quinolin-2(1H)-one,
1-(4-cyclopropyl-1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-phenyl-1,2,4-triazolidine-3,5-dione,
4-chloro-N-(1-ethyl-4-(morpholin-4-yl)-2-oxo-1,2-dihydroquinolin-6-yl)-N-methylbenzamide,
4-(1-acetylpiperidin-4-yl)-1-ethyl-N-methyl-N-(4-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
1-ethyl-N-(3-fluoro-4-methylphenyl)-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
N-(3-chloro-4-methylphenyl)-1-ethyl-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide, and N-(3,4-dimethylphenyl)-1-ethyl-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide.

### Claim 11 (depends on 1)

The method according to claim 1, wherein
the tumor is blood cancer, thymoma, myeloma, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colon cancer, breast cancer, skin cancer, or epithelial cell cancer.

### Claim 12

A method for treating disease associated with a bromodomain comprising administering a therapeutically effective amount of a compound represented by the formula [1] or a salt thereof:
wherein R1 represents a hydrogen atom or an optionally substituted C1-6 alkyl group;
R2 represents a hydrogen atom, a halogen atom, or an optionally substituted C1-6 alkyl group;
R3 represents a halogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C4-8 cycloalkenyl group, an optionally substituted aryl group, an optionally substituted C1-6 alkoxy group, an optionally substituted C1-6 alkylamino group, an optionally substituted di(C1-6 alkyl)amino group, or an optionally substituted heterocyclic group;
Z1, Z2 and Z3, which are the same or different, each represent a nitrogen atom or a group represented by the formula CR5 (wherein R5 represents a hydrogen atom, a halogen atom or an optionally substituted C1-6 alkyl group);
X1 represents
(1) a group represented by the formula C(═O)N(R6) (wherein the carbon atom binds to Ring A, and R6 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C1-6 alkyl group,
(2) a group represented by the formula N(R7)C(═O) (wherein the nitrogen atom binds to Ring A, and R7 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C1-6 alkyl group; or R7 represents, together with one substituent R4 of Ring A, an optionally substituted C2-4 alkylene group, a group represented by the formula O—Y1 (wherein the oxygen atom binds to Ring A, and Y1 represents an optionally substituted C1-3 alkylene group), a group represented by the formula S(O)n—Y2 (wherein the sulfur atom binds to Ring A, Y2 represents an optionally substituted C1-3 alkylene group, and n represents an integer from 0 to 2), or a group represented by the formula N(R8)—Y3 (wherein the nitrogen atom binds to Ring A, Y3 represents an optionally substituted C1-3 alkylene group, and R8 represents a hydrogen atom, an amino-protecting group, an optionally substituted C1-6 alkyl group, or an optionally substituted aryl group)),
(3) an optionally substituted divalent cyclic hydrocarbon group that is formed by removing each one hydrogen atom on the two adjacent atoms, or
(4) an optionally substituted divalent heterocyclic group that is formed by removing each one hydrogen atom on the two adjacent atoms;
Ring A represents a cyclic hydrocarbon group or a heterocyclic group;
an m number of R4, which are the same or different, each represent a halogen atom, a cyano group, a nitro group, an amino-protecting group, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C4-8 cycloalkenyl group, an optionally substituted aryl group, an optionally substituted C1-6 alkoxy group, an optionally substituted aryloxy group, an optionally substituted C1-6 alkylamino group, an optionally substituted di(C1-6 alkyl)amino group, an optionally substituted arylamino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted C1-6 alkylthio group, an optionally substituted arylthio group, an optionally substituted C1-6 alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted heterocyclic group, an optionally protected amino group, an optionally protected hydroxyl group, an optionally protected carboxyl group,
an optionally substituted C2-5 alkylene group formed together by the two adjacent R4,
an optionally substituted C2-4 alkylene group formed by one R4 together with R7,
a group represented by the formula O—Y1 (wherein the oxygen atom binds to Ring A, and Y1 represents an optionally substituted C1-3 alkylene group), which is formed by one R4 together with R7,
a group represented by the formula S(O)n—Y2 (wherein the sulfur atom binds to Ring A, Y2 represents an optionally substituted C1-3 alkylene group, and n represents an integer from 0 to 2), which is formed by one R4 together with R7, or
a group represented by the formula N(R8)—Y3 (wherein the nitrogen atom binds to Ring A,
Y3 represents an optionally substituted C1-3 alkylene group, and R8 represents a hydrogen atom, an amino-protecting group, an optionally substituted C1-6 alkyl group, or an optionally substituted aryl group), which is formed by one R4 together with R7; and
m represents an integer from 0 to 5.

### Claim 13 (depends on 12)

The method according to claim 12, which inhibits the binding of bromodomain to acetylated histone.

### Claim 14 (depends on 12)

The method according to claim 12, wherein the bromodomain is a protein domain comprised in a BET family protein.