# US 2019/0169166 A1 · Heterocyclic compound

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- Number: US 2019/0169166 A1
- Document ID: US20190169166A1
- Status: Published application
- Kind: A1
- Application number: 16/323,863
- Filed: 2017-08-09
- Published: 2019-06-06
- Earliest claimed: 2016-08-10
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Jun FUJIMOTO; Xin LIU; Osamu KURASAWA; Terufumi TAKAGI; Douglas Robert CARY; Hiroshi BANNO; Yasutomi ASANO; Takuto KOJIMA
- Web page: https://patentgrep.com/patent/US20190169166A1

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- 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 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/42: having hetero atoms attached to the substituent nitrogen atom (nitro radicals C07D213/26)
- C07D 213/65: attached in position 3 or 5
- C07D 213/68: attached in position 4
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 239/20: having two double bonds between ring members or between ring members and non-ring members
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 241/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 253/06: 1,2,4-Triazines
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/30: Halogen atoms or nitro radicals
- C07D 239/34: One oxygen atom
- C07D 239/48: Two nitrogen atoms
- C07D 253/07: with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 487/04: Ortho-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

Provided is a heterocyclic compound that may have a GCN2 inhibitory action, and is expected to be useful for the prophylaxis or treatment of GCN2 associated diseases including cancer and the like. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof.

## Claims

### Claim 1

A compound represented by the formula (I):
wherein
ring A is the formula:
wherein ring B is an optionally further substituted 6-membered aromatic ring;
two of X1, X2 and X3 are carbon atoms and the remaining one is a carbon atom or a nitrogen atom;
R1 is a halogen atom, optionally halogenated methyl, or a hydroxy group optionally substituted by optionally halogenated methyl;
R2 is a substituent, or the formula:
wherein ring C is an optionally further substituted 6-membered aromatic ring;
ring D is an optionally further substituted 5- to 7-membered ring;
one of X4 and X5 is a carbon atom, and the other one is a carbon atom or a nitrogen atom;
X6 is a hydrogen atom or a halogen atom;
X7 is a halogen atom;
ring E is an optionally further substituted nitrogen-containing 6-membered aromatic ring;
X8 is a carbon atom or a nitrogen atom;
X9 is a carbon atom or a nitrogen atom; and
X10 is a hydrogen atom or an optionally substituted amino group, or
X9 and X10 are bonded to each other to form an optionally substituted ring,
or a salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein ring A is (1) the formula:
wherein the combination of X1, X2 and X3 (X1, X2, X3) is (carbon atom, carbon atom, carbon atom) or (carbon atom, carbon atom, nitrogen atom);
R1 is (1) a fluorine atom, a chlorine atom, a bromine atom, (2) methyl, trifluoromethyl, or (3) a hydroxy group optionally substituted by methyl, difluoromethyl or trifluoromethyl;
R2 is (1) a halogen atom, (2) a cyano group, (3) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a hydroxy group, (4) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms or (5) a mono- or di-C1-6 alkylamino group; and
ring B is optionally further substituted by 1 to 3 substituents selected from (1) a halogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups and (3) a C1-6 alkoxy group, or (2) the formula:
wherein the combination of X4 and X5 (X4, X5) is (carbon atom, carbon atom);
ring C is optionally further substituted by 1 to 3 halogen atoms;
ring D is a 5- to 7-membered aromatic heterocycle or a 5- to 7-membered non-aromatic heterocycle;
ring D is optionally further substituted by 1 to 3 substituents selected from (1) a halogen atom and (2) a hydroxy group;
X6 is a hydrogen atom, a fluorine atom or a chlorine atom;
X7 is a fluorine atom or a chlorine atom;
the combination of X8 and X9 (X8, X9) is (carbon atom, nitrogen atom), (nitrogen atom, carbon atom) or (nitrogen atom, nitrogen atom);
ring E is optionally further substituted by 1 to 3 substituents selected from (1) a C1-6 alkyl group and (2) an amino group; and
X10 is an amino group optionally substituted by 1-2 substituents selected from (1) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a 3- to 14-membered non-aromatic heterocyclic group, (2) a C3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, (3) a 3- to 14-membered non-aromatic heterocyclic group and (4) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C1-6 alkyl groups; or
X9 and X10 are bonded to each other to form a 5- to 14-membered aromatic heterocycle,
or a salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein ring A is (1) the formula:
wherein the combination of X1, X2 and X3 (X1, X2, X3) is (carbon atom, carbon atom, carbon atom) or (carbon atom, carbon atom, nitrogen atom);
R1 is (1) a chlorine atom, a bromine atom, (2) methyl, trifluoromethyl, or (3) a hydroxy group substituted by methyl or trifluoromethyl;
R2 is (1) a halogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a hydroxy group or (3) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
ring B is optionally further substituted by 1 to 3 substituents selected from (1) a halogen atom and (2) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, or (2) the formula:
wherein the combination of X4 and X5 (X4, X5) is (carbon atom, carbon atom);
ring C is optionally further substituted by 1 to 3 halogen atoms;
ring D is a 5- to 7-membered non-aromatic heterocycle;
X6 is a hydrogen atom, a fluorine atom or a chlorine atom;
X7 is a fluorine atom or a chlorine atom;
the combination of X8 and X9 (X8, X9) is (carbon atom, nitrogen atom), (nitrogen atom, carbon atom) or (nitrogen atom, nitrogen atom);
ring E is optionally further substituted by 1 to 3 C1-6 alkyl groups; and
X10 is an amino group optionally substituted by 1-2 substituents selected from (1) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (2) a C3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups and (3) a 3- to 14-membered non-aromatic heterocyclic group; or
X9 and X10 are bonded to each other to form a 5- to 14-membered aromatic heterocycle,
or a salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein ring A is the formula
wherein the combination of X1, X2 and X3 (X1, X2, X3) is (carbon atom, carbon atom, carbon atom) or (carbon atom, carbon atom, nitrogen atom);
R1 is (1) a chlorine atom, a bromine atom, (2) methyl, trifluoromethyl, or (3) a hydroxy group substituted by methyl or trifluoromethyl;
R2 is (1) a halogen atom, (2) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a hydroxy group or (3) a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
ring B is optionally further substituted by 1 to 3 substituents selected from (1) a halogen atom and (2) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups;
X6 is a hydrogen atom, a fluorine atom or a chlorine atom;
X7 is a fluorine atom or a chlorine atom;
the combination of X8 and X9 (X8, X9) is (carbon atom, nitrogen atom);
ring E is optionally further substituted by 1 to 3 C1-6 alkyl groups; and
X10 is an amino group optionally substituted by 1-2 substituents selected from (1) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (2) a C3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups and (3) a 3- to 14-membered non-aromatic heterocyclic group, or a salt thereof.

### Claim 5

N-(3-((2-Aminopyrimidin-5-yl)ethynyl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide or a salt thereof.

### Claim 6

5-Chloro-N-(2,4-difluoro-3-((2-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)ethynyl)phenyl)-2-methoxypyridine-3-sulfonamide or a salt thereof.

### Claim 7

2,5-Dichloro-N-(2,4-difluoro-3-((2-(((2R)-1-hydroxypropan-2-yl)amino)pyrimidin-5-yl)ethynyl)phenyl)-3-(hydroxymethyl)benzenesulfonamide or a salt thereof.

### Claim 8 (depends on 1)

A medicament comprising the compound according to claim 1 or a salt thereof.

### Claim 9 (depends on 8)

The medicament according to claim 8 which is a prophylactic or therapeutic agent for cancer.

### Claim 10 (depends on 8)

The medicament according to claim 8 which is a GCN2 inhibitor.

### Claim 11 (depends on 1)

A method for inhibiting GCN2 in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

### Claim 12 (depends on 1)

A method for the prophylaxis or treatment of cancer in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

### Claim 13 (depends on 1)

Use of the compound according to claim 1 or a salt thereof for producing a prophylactic or therapeutic agent for cancer.

### Claim 14 (depends on 1)

The compound according to claim 1 or a salt thereof which is used for the prophylaxis or treatment of cancer.