# US 10,308,643 B2 · Heterocyclic compound

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- Number: US 10,308,643 B2
- Document ID: US10308643B2
- Status: Granted
- Kind: B2
- Application number: 15/210,965
- Filed: 2016-07-15
- Published: 2017-01-19
- Granted: 2019-06-04
- Earliest claimed: 2015-07-17
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Akira Kaieda; Masashi Toyofuku; Masaki Daini; Hiroshi Nara; Masato Yoshikawa; Naoki Ishii; Kousuke Hidaka
- Web page: https://patentgrep.com/patent/US10308643B2

## CPC

- C07D 413/14: containing three or more hetero rings
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/02: for peripheral neuropathies
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 491/08: Bridged systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 498/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provide a heterocyclic compound having a HDAC inhibitory action, and useful for the treatment of autoimmune diseases and/or inflammatory diseases, graft versus host disease, cancers, central nervous diseases including neurodegenerative diseases, Charcot-Marie-Tooth disease and the like, and a pharmaceutical composition comprising the compound. The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.

## Claims

### Claim 1

A compound represented by the formula:
wherein
X is CH or N,
one of Y and Z is C(O), and the other is C(R2)(R3),
R2 and R3 are both hydrogen atoms;
the atom on R1 bonded to N of the Y—N—Z is C; and
R1 is
(1) a C3-6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a C6-14 aryl group,
(c) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups,
(d) a C1-6 alkyl-carbonylamino group optionally substituted by 1 to 3 hydroxy groups,
(e) a C1-6 alkoxy-carbonylamino group,
(f) a C3-6 cycloalkyl-carbonylamino group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a cyano group,
(iii) a hydroxy group,
(iv) a C1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and
(v) a C1-6 alkoxy group,
(g) a C6-14 aryl-carbonylamino group,
(h) a 4- to 10-membered non-aromatic heterocyclylcarbonylamino group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom,
(ii) a C1-6 alkyl group, and
(iii) a C6-14 aryl group,
(i) a mono- or di-C1-6 alkyl-carbamoylamino group,
(j) a C3-6 cycloalkyl-carbamoylamino group,
(k) a (C1-6 alkyl)(C3-6 cycloalkyl)carbamoylamino group,
(1) a 3- to 8-membered non-aromatic heterocyclylcarbamoylamino group, and
(m) a C3-6 cycloalkylsulfonylamino group, or
(2) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(a) a C6-14 aryl group,
(b) a C1-6 alkyl-carbonyl group,
(c) a C1-6 alkoxy-carbonyl group,
(d) a C3-6 cycloalkyl-carbonyl group,
(e) a C6-14 aryl-carbonyl group,
(f) a carbamoyl group,
(g) a C1-6 alkyl-carbamoyl group,
(h) a C1-6 alkoxy-carbonylamino group,
(i) a C3-6 cycloalkyl-carbonylamino group optionally substituted by 1 to 3 halogen atoms,
(j) a 3- to 8-membered non-aromatic heterocyclylcarbonylamino group optionally substituted by 1 to 3 C1-6 alkyl groups, and
(k) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups or a salt thereof.

### Claim 2 (depends on 1)

The compound or salt according to claim 1, wherein
Y is C(O); and
Z is C(R2)(R3).

### Claim 3 (depends on 1)

The compound or salt according to claim 1, wherein
X is CH;
Y is C(O); and
Z is (R2)(R3).

### Claim 4

3-Methyl-N-((1R,2R)-2-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)oxetane-3-carboxamide, or a salt thereof.

### Claim 5

(2S)-N-((1R,2R)-2-(1-Oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)tetrahydrofuran-2-carboxamide, or a salt thereof.

### Claim 6

2-Hydroxy-2-methyl-N-((1R,2R)-2-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)propanamide, or a salt thereof.

### Claim 7

(1S)-2,2-Difluoro-N-((3S,4R)-4-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-2H-pyran-3-yl)cyclopropanecarboxamide, or a salt thereof.

### Claim 8

(1S)-2,2-Difluoro-N-((3S,4R)-3-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-2H-pyran-4-yl)cyclopropanecarboxamide, or a salt thereof.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

A method of inhibiting histone deacetylase in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

### Claim 11 (depends on 1)

A method for the prophylaxis or treatment of neurodegenerative diseases in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

### Claim 12 (depends on 1)

A method for the prophylaxis or treatment of Charcot-Marie-Tooth disease in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.