Heterocyclic compound

Patent metadata

Field	Value
Publication number	US-10696651-B2
Application number	US-201716323863-A
Country	US
Kind code	B2
Filing date	Aug 9, 2017
Priority date	Aug 10, 2016
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

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.

First claim

The invention claimed is:

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;
the combination of X 1 , X 2 and X 3 (X 1 , X 2 , X 3 ) is (carbon atom, carbon atom, carbon atom) or (carbon atom, carbon atom, nitrogen atom);
R 1 is a (1) a chlorine atom, (2) a bromine atom, (3) methyl, (4) trifluoromethyl, or (5) a hydroxy group substituted by methyl or trifluoromethyl;
R 2 is (1) a halogen atom, (2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxy group, (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, or the formula:

wherein ring C is a 6-membered aromatic ring optionally further substituted by 1 to 3 halogen atoms;
ring D is a 5- to 7-membered non-aromatic heterocycle;
one of X 4 and X 5 is a carbon atom, and the other one is a carbon atom or a nitrogen atom;
X 6 is a hydrogen atom, a fluorine atom, or a chlorine atom;
X 7 is a fluorine atom or a chlorine atom;
ring E is a nitrogen-containing 6-membered aromatic ring optionally further substituted by 1 to 3 C 1-6 alkyl groups;
the combination of X 8 and X 9 (X 8 , X 9 ) is (carbon atom, nitrogen atom), (nitrogen atom, carbon atom) or (nitrogen atom, nitrogen atom); and
X 10 is an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of (1) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (2) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups and (3) a 3- to 14-membered non-aromatic heterocyclic group, or
X 9 and X 10 are bonded to each other to form an unsubstituted 5- to 14-membered aromatic heterocycle,

or a salt thereof.

2. The compound according to claim 1 , wherein ring A is the formula

wherein the combination of X 1 , X 2 and X 3 (X 1 , X 2 , X 3 ) is (carbon atom, carbon atom, carbon atom) or (carbon atom, carbon atom, nitrogen atom);
R 1 is (1) a chlorine atom, (2) a bromine atom, (3) methyl, (4) trifluoromethyl, or (5) a hydroxy group substituted by methyl or trifluoromethyl;
R 2 is (1) a halogen atom, (2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxy group, or (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
ring B is optionally further substituted by 1 to 3 substituents selected from the group consisting of (1) a halogen atom and (2) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups;
X 6 is a hydrogen atom, a fluorine atom, or a chlorine atom;
X 7 is a fluorine atom or a chlorine atom;
the combination of X 8 and X 9 (X 8 , X 9 ) is (carbon atom, nitrogen atom);
ring E is optionally further substituted by 1 to 3 C 1-6 alkyl groups; and
X 10 is an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of (1) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (2) a C 3-10 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.

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

4. 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.

5. 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.

6. A medicament comprising the compound according to claim 1 or a salt thereof, and a pharmacologically acceptable carrier.

7. A method for the treatment of a cancer selected from the group consisting of osteosarcoma, acute lymphocytic leukemia, acute myeloid leukemia, pancreatic cancer, colorectal cancer, melanoma, lung cancer, ovarian cancer, hepatoma, malignant lymphoma and multiple myeloma in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

8. The compound according to claim 1 , wherein ring A is the formula

wherein the combination of X 1 , X 2 and X 3 (X 1 , X 2 , X 3 ) is (carbon atom, carbon atom, carbon atom);
R 1 is (1) a chlorine atom, (2) a bromine atom, (3) methyl, (4) trifluoromethyl, or (5) a hydroxy group substituted by methyl or trifluoromethyl;
R 2 is (1) a halogen atom, (2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxy group, or (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
ring B is further substituted by a substituent selected from the group consisting of (1) a halogen atom and (2) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups;
X 6 is a hydrogen atom, a fluorine atom, or a chlorine atom;
X 7 is a fluorine atom or a chlorine atom;
the combination of X 8 and X 9 (X 8 , X 9 ) is (carbon atom, nitrogen atom);
ring E is optionally further substituted by 1 to 3 C 1-6 alkyl groups; and
X 10 is an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of (1) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (2) a C 3-10 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.

9. The compound according to claim 1 , wherein ring A is the formula

wherein the combination of X 1 , X 2 and X 3 (X 1 , X 2 , X 3 ) is (carbon atom, carbon atom, nitrogen atom);
R 1 is (1) a chlorine atom, (2) a bromine atom, (3) methyl, (4) trifluoromethyl, or (5) a hydroxy group substituted by methyl or trifluoromethyl;
R 2 is (1) a halogen atom, (2) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxy group, or (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
X 6 is a hydrogen atom, a fluorine atom, or a chlorine atom;
X 7 is a fluorine atom or a chlorine atom;
the combination of X 8 and X 9 (X 8 , X 9 ) is (carbon atom, nitrogen atom);
ring E is optionally further substituted by 1 to 3 C 1-6 alkyl groups; and
X 10 is an amino group optionally substituted by 1 to 2 substituents selected from the group consisting of (1) a C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, (2) a C 3-10 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.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Fujimoto Jun
• Liu Xin
• Kurasawa Osamu
• Takagi Terufumi
• Cary Douglas Robert
• Banno Hiroshi
• Asano Yasutomi
• Kojima Takuto

Classifications

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D253/06

  1,2,4-Triazines · CPC title

• C07D239/20

  having two double bonds between ring members or between ring members and non-ring members · CPC title

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title