Heterocyclic compound
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.
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(R 2 )(R 3 ),
R 2 and R 3 are both hydrogen atoms;
the atom on R 1 bonded to N of the Y—N—Z is C; and
R 1 is
(1) a C 3-6 cycloalkyl group optionally substituted by 1 to 3 substituents selected from
(a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 oxo groups,
(d) a C 1-6 alkyl-carbonylamino group optionally substituted by 1 to 3 hydroxy groups,
(e) a C 1-6 alkoxy-carbonylamino group,
(f) a C 3-6 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 C 1-6 alkyl group optionally substituted by 1 to 3 hydroxy groups, and
(v) a C 1-6 alkoxy group,
(g) a C 6-14 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 C 1-6 alkyl group, and
(iii) a C 6-14 aryl group,
(i) a mono- or di-C 1-6 alkyl-carbamoylamino group,
(j) a C 3-6 cycloalkyl-carbamoylamino group,
(k) a (C 1-6 alkyl)(C 3-6 cycloalkyl)carbamoylamino group,
(1) a 3- to 8-membered non-aromatic heterocyclylcarbamoylamino group, and
(m) a C 3-6 cycloalkylsulfonylamino group, or
(2) a 3- to 8-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from
(a) a C 6-14 aryl group,
(b) a C 1-6 alkyl-carbonyl group,
(c) a C 1-6 alkoxy-carbonyl group,
(d) a C 3-6 cycloalkyl-carbonyl group,
(e) a C 6-14 aryl-carbonyl group,
(f) a carbamoyl group,
(g) a C 1-6 alkyl-carbamoyl group,
(h) a C 1-6 alkoxy-carbonylamino group,
(i) a C 3-6 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 C 1-6 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.
2. The compound or salt according to claim 1 , wherein
Y is C(O); and
Z is C(R 2 )(R 3 ).
3. The compound or salt according to claim 1 , wherein
X is CH;
Y is C(O); and
Z is (R 2 )(R 3 ).
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.
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.
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.
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.
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.
9. A medicament comprising the compound or salt according to claim 1 .
10. 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.
11. 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.
12. 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.