# US 10,370,372 B2 · Fused pyrimidine compound or salt thereof

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- Number: US 10,370,372 B2
- Document ID: US10370372B2
- Status: Granted
- Kind: B2
- Application number: 15/771,487
- Filed: 2016-11-25
- Published: 2018-11-01
- Granted: 2019-08-06
- Earliest claimed: 2015-11-27
- Assignees: Taiho Pharmaceutical Co., Ltd.
- Applicants: Taiho Pharmaceutical Co., Ltd.
- Inventors: Kazuhisa Minamiguchi; Shigeo Okajima; Takahiro Asai; Masanori Asai; Yoshio Ogino
- Web page: https://patentgrep.com/patent/US10370372B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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

To provide a compound having an inhibitory activity for an androgen receptor. A fused pyrimidine compound represented by the following formula (I) or a pharmaceutically acceptable thereof (in the formula, X, Y, Z, R1, and R2 are as defined in the specification).

## Claims

### Claim 1

A fused pyrimidine compound represented by formula (I):
wherein, in the formula,
X represents a cyano group or a nitro group;
Y represents a halogen atom, a halogeno-C1-3 alkyl group, a C1-3 alkoxy group, or a C1-3 alkyl group;
Z represents a hydrogen atom, a halogen atom, or a C1-3 alkyl group;
R1 represents a C6-14 aryl group which is substituted with Ra and may be substituted simultaneously with Rb or a 5- or 6-membered heteroaryl group which is substituted with Ra and may be substituted simultaneously with Rb, wherein the Ra and Rb may be bonded to each other to form a fused ring together with the C6-14 aryl group or the heteroaryl group; and
R2 represents a hydrogen atom, a C1-3 alkyl group, or a cyano group, wherein
Ra represents a phenyl group, a hydroxy-C1-6 alkyl group, a hydroxy-C3-7 cycloalkyl group, a hydroxy-heterocycloalkyl group, a C1-6 alkoxy group which may be substituted with Rc, an amino-C1-6 alkyl group which may be substituted with Rf, a halogeno-C1-3 alkoxy group, a C3-7 cycloalkylaminosulfonyl group, a C1-3 alkylsulfonyl group, a 3- to 7-membered monocyclic heterocycloalkylsulfonyl group, a C1-3 alkoxycarbonylamino group which may be substituted with a halogen, a C1-3 alkylcarbonylamino group which may be substituted with a halogen, a 3- to 7-membered monocyclic heterocycloalkanecarbonyl group substituted with a hydroxy-C1-6 alkyl group, a bicyclic heterocycloalkyl group, or —(CH2)n—C(═O)—NRdRe;
Rb represents a hydrogen atom, a halogen atom, a C1-3 alkyl group which may be substituted with a halogen atom, or a C1-4 alkoxy group which may be y substituted with a halogen atom;
Rc represents a pyrazolyl group, triazolyl group, or tetrazolyl group which may be substituted or a piperazinyl group which may be substituted with Rf;
Rd and Re each independently represent a hydrogen atom, a C1-3 alkyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C3-7 cycloalkyl group, a halogeno-C1-3 alkyl group, a hydroxy-C1-6 alkyl group, a hydroxy-C3-7 cycloalkyl group, a hydroxy-C3-7 cycloalkyl-C1-6 alkyl group, a C1-4 alkoxy group, or a C1-6 alkyl group substituted with Rg, or NRdRe of the —(CH2)n—C(═O)—NRdRe may form a ring;
Rf represents a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkylsulfonyl group, a C1-6 alkoxycarbonyl group, or a C1-6 alkylaminocarbonyl group;
Rg represents a C1-6 alkylpyrazolyl group, a halogeno-C1-3 alkylthiazolyl group, an oxadiazolyl group, a halogeno-C1-3 alkyloxadiazolyl group, or a C1-6 alkoxycarbonylamino group; and
n represents an integer of from 0 to 3,
provided that:
if X is a cyano group, Y is a halogen atom or a halogeno-C1-3 alkyl group, R2 is a hydrogen atom, Z is a hydrogen atom,
R1 is a C6-14 aryl group which is substituted with Ra and may be substituted simultaneously with Rb or a 5- or 6-membered heteroaryl group which is substituted with Ra and may be substituted simultaneously with Rb, and
Rb is a hydrogen atom, a halogen atom, or a C1-3 alkyl group which may be substituted with a halogen atom,
then Ra is
a hydroxy-heterocycloalkyl group,
a C1-6 alkoxy group which may be substituted with Rc, wherein Rc represents a piperazinyl group which may be substituted with C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, or C1-6 alkylaminocarbonyl,
an amino-C1-6 alkyl group which may be substituted with Rf, wherein Rf is as described above,
a halogeno-C1-3 alkoxy group,
a C1-3 alkylsulfonyl group,
a bicyclic cycloheteroalkyl group, or
—(CH2)n—C(═O)—NRdRe, wherein n, Rd, and Re are as described above, provided that if either one of Rd and Re is a halogeno-C1-3 alkyl group, a hydroxy-C1-6 alkyl group, a hydroxy-C3-7 cycloalkyl group, a hydroxy-C3-7 cycloalkyl-C1-6 alkyl group, or a C1-6 alkyl group substituted with C1-6 alkylpyrazolyl, halogeno-C1-3 alkylthiazolyl, oxadiazolyl, or halogeno-C1-3 alkyloxadiazolyl, then the other is not a hydrogen atom,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Z is a hydrogen atom or a fluorine atom.

### Claim 3 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is a hydrogen atom, a methyl group, or a cyano group.

### Claim 4 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Y is a chlorine atom, a bromine atom, a trifluoromethyl group, a methoxy group, an isopropoxy group, or a methyl group.

### Claim 5 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein n is 0.

### Claim 6 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is a phenyl group substituted with the Ra and the Rb, a pyridinyl group substituted with the Ra and the Rb, or a pyridazinyl group substituted with the Ra and the Rb.

### Claim 7 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein Ra represents a phenyl group, a hydroxy-ethyl group, a hydroxy-isopropyl group, a hydroxy-oxetanyl group, a methoxy group, a trifluoromethoxy group, a 2-oxa-6-azaspiro[3.3]heptyl group, —(CH2)n—C(═O)—NRdRe, or an n-propoxy group substituted with a piperazinyl group which may be substituted with acetyl, mesyl, tert-butoxycarbonyl, or methyl.

### Claim 8 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is selected from the group consisting of the following groups:
wherein, in the formula, Ra represents a phenyl group, a C1-6 alkoxy group which may be substituted with the Rc, an amino-C1-6 alkyl group which may be substituted with the Rf, a halogeno-C1-3 alkoxy group, or a bicyclic heterocycloalkyl group, and Rb represents a hydrogen atom, a halogen atom, a C1-3 alkyl group which may be substituted with a halogen atom, or a C1-4 alkoxy group which may be substituted with a halogen atom:
or Ra is an amino-C1-6 alkyl group which may be substituted with the Rf, and Rb is a C1-3 alkyl group, and the Ra and Rb are bonded to each other to form a fused ring together with the ring on which they are substituted;
wherein, in the formula,
Ra represents a hydroxy-C1-6 alkyl group, a hydroxy-heterocycloalkyl group, or —(CH2)n—C(═O)—NRdRe, and
Rb represents a hydrogen atom or a halogen atom; and
wherein, in the formula,
Ra represents —(CH2)n—C(═O)—NRdRe, and
Rb represents a hydrogen atom.

### Claim 9 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein
X represents a cyano group or a nitro group;
Y represents a halogen atom, a halogeno-C1-3 alkyl group, a C1-3 alkoxy group, or a C1-3 alkyl group;
Z represents a hydrogen atom or a halogen atom;
R1 is a substituent selected from the group consisting of the following groups:
R2 represents a hydrogen atom, a C1-3 alkyl group, or a cyano group;
wherein:
Ra represents a phenyl group, a hydroxy-C1-6 alkyl group, a hydroxy-heterocycloalkyl group, a C1-6 alkoxy group which may be substituted with Rc, an amino-C1-6 alkyl group which may be substituted with Rf, a halogeno-C1-3 alkoxy group, a bicyclic heterocycloalkyl group, or —(CH2)n—C(═O)—NRdRe;
Rb represents a hydrogen atom, a halogen atom, a C1-3 alkyl group which may be substituted with a halogen atom, or a C1-4 alkoxy group which may be substituted with a halogen atom;
or Ra and Rb are bonded to each other to form a fused ring together with the ring on which they are substituted;
Rc represents a piperazinyl group which may be substituted with Rf;
Rd and Re each independently represent a hydrogen atom, a C1-3 alkyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C3-7 cycloalkyl group, a halogeno-C1-3 alkyl group, or a C1-6 alkyl group substituted with Rg;
or NRdRe forms a 3- to 7-membered nitrogen-containing heterocyclic ring;
Rf represents a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkylsulfonyl group, a C1-6 alkoxycarbonyl group, or a C1-6 alkylaminocarbonyl group;
Rg represents a C1-6 alkoxycarbonylamino group; and
n represents an integer of 0 or 1.

### Claim 10 (depends on 9)

The compound or pharmaceutically acceptable salt thereof according to claim 9, wherein
X represents a cyano group or a nitro group;
Y represents a chlorine atom, a bromine atom, a trifluoromethyl group, a methoxy group, an isopropoxy group, or a methyl group;
Z represents a hydrogen atom or a fluorine atom;
R1 is a substituent selected from the group consisting of the followings:
R2 represents a hydrogen atom, a methyl group, or a cyano group;
Ra represents a phenyl group, a hydroxy-ethyl group, a hydroxy-isopropyl group, a hydroxy-oxetanyl group, a methoxy group, a trifluoromethoxy group, a 2-oxa-6-azaspiro[3.3]heptyl group, —(CH2)n—C(═O)—NRdRe, or an n-propoxy group substituted with a piperazinyl group which may be substituted with acetyl, tert-butoxycarbonyl, mesyl, or methyl;
Rb represents a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, or a methoxy group;
or Ra and Rb are bonded to each other to form a substituted or unsubstituted tetrahydroisoquinolinyl group or isoindolinyl group together with the ring on which they are substituted;
either one of Rd and Re represents a methyl group, an ethyl group, a propynyl group, a cyclopropyl group, a trifluoroethyl group, a tert-butoxy group, or an ethyl group substituted with tert-butoxycarbonylamino, and the other represents a hydrogen atom or a methyl group;
or NRdRe forms azepane; and
n is 0.

### Claim 11 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of the following compounds (1) to (48):
(1) 6-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-ethyl-2-fluoronicotinamide;
(2) 6-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2-fluoro-N-methylnicotinamide;
(3) 6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2-fluoro-N-methylnicotinamide;
(4) 6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-ethyl-2-fluoronicotinamide;
(5) 6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-ethylnicotinamide;
(6) 4-(4-((5-(azepane-1-carbonyl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;
(7) N-(tert-butoxy)-6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinamide;
(8) tert-butyl (2-(6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridazine-3-carboxamido)ethyl)carbamate;
(9) 6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-cyclopropylpyridazine-3-carboxamide;
(10) 6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-ethylpyridazine-3-carboxamide;
(11) 6-((7-(4-cyano-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(prop-2-yn-1-yl)pyridazine-3-carboxamide;
(12) N-ethyl-2-fluoro-6-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)nicotinamide;
(13) 2-(6-((7-(3-chloro-4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol;
(14) 2-(6-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol;
(15) 2-(6-((7-(3-methoxy-4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol;
(16) 2-(6-((7-(3-methyl-4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol;
(17) 2-(6-((7-(3-bromo-4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol;
(18) 2-(6-((7-(3-chloro-2-fluoro-4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol;
(19) 2-(6-((7-(3-isopropoxy-4-nitrophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)pyridin-3-yl)propan-2-ol;
(20) 4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-methylbenzonitrile;
(21) N-(3-fluoro-4-methoxyphenyl)-7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(22) 7-(3-chloro-4-nitrophenyl)-N-(3-fluoro-4-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(23) 4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-methoxybenzonitrile;
(24) 6-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-N-(2,2,2-trifluoroethyl)pyridazine-3-carboxamide;
(25) N-(6-methoxypyridin-3-yl)-7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(26) 4-(4-((3,4-dimethoxyphenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;
(27) 4-(4-((4-(trifluoromethoxy)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;
(28) 4-(4-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-chlorobenzonitrile;
(29) tert-butyl 5-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)isoindoline-2-carboxylate;
(30) tert-butyl 4-(3-(2-chloro-4-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)propyl)piperazine-1-carboxylate;
(31) N-(3,4-dimethoxyphenyl)-7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(32) tert-butyl 7-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate;
(33) N-(3-methyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(34) N-([1,1′-biphenyl]-3-yl)-7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(35) 2-chloro-4-(4-((6-fluoro-5-(3-hydroxyoxetan-3-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile;
(36) tert-butyl 7-((7-(3-chloro-4-cyanophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-3,4-dihydroisoquinolin-2 (1H)-carboxylate;
(37) 2-chloro-4-(4-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile;
(38) 2-chloro-4-(4-((4-(3-(piperazin-1-yl)propoxy)-3-(trifluoromethyl)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile;
(39) 1-(4-(3-(2-chloro-4-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)propyl)piperazin-1-yl)ethanone;
(40) N-(3-chloro-4-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)phenyl)-7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(41) N-(3-chloro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine;
(42) 4-(4-((4-(3-(4-acetylpiperazin-1-yl)propoxy)-3-chlorophenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-chlorobenzonitrile;
(43) 4-(4-((4-(3-(4-acetylpiperazin-1-yl)propoxy)-3-(trifluoromethyl)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-chlorobenzonitrile;
(44) 4-(4-((4-(3-(4-acetylpiperazin-1-yl)propoxy)-2-(trifluoromethyl)phenyl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile;
(45) 1-(4-(3-(4-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2-(trifluoromethyl)phenoxy)propyl)piperazin-1-yl)ethanone;
(46) 1-(4-(3-(4-((7-(4-nitro-3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)phenoxy)propyl)piperazin-1-yl)ethanone;
(47) 7-(4-cyano-3-(trifluoromethyl)phenyl)-4-((4-methoxyphenyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2-carbonitrile; and
(48) 4-(4-((4-methoxyphenyl)amino)-2-methyl-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising the fused pyrimidine compound or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 1)

A method for inhibiting androgen activity, comprising administering an effective amount of the fused pyrimidine compound or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need of treatment for prostate cancer.

### Claim 14 (depends on 1)

A method for treating prostate cancer, comprising administering an effective amount of the fused pyrimidine compound or pharmaceutically acceptable salt thereof according to claim 1 to a subject in need thereof.