Bicyclic heterocyclic compound

Patent metadata

Field	Value
Publication number	US-10793582-B2
Application number	US-201615769835-A
Country	US
Kind code	B2
Filing date	Oct 21, 2016
Priority date	Oct 22, 2015
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

Abstract

Provided are a novel compound having a superior inhibitory action on KAT-II, a production method thereof, use thereof, and a pharmaceutical composition containing the aforementioned compound and the like.
A compound represented by the formula (I) or a pharmacologically acceptable salt thereof.

wherein each symbol is as defined in the DESCRIPTION.

First claim

The invention claimed is:

1. A compound represented by the formula (I):

wherein
ring A is an optionally substituted aromatic group,
X 1 is CR 1 or a nitrogen atom,
a part represented by the following formula in the formula (I):

is the following A) or B),
A)
is a double bond,
X 2 is a nitrogen atom or CR 2 , and
X 3 is a nitrogen atom or CR 3 ;

B)
is a single bond,
X 2 is NR 2 , and
X 3 is carbonyl;
X 4 is sulfur atom, an oxygen atom or —CH═CH—,
Z 1 is an oxygen atom, —C(R 6 )(R 7 )—, —NH—, —C(R 6 )(R 7 )—NH—, —NH—C(R 6 )(R 7 )—, —C(R 6 )(R 7 )—O—, —O—C(R 6 )(R 7 )— or a single bond (where the left end shows a bond to ring A, and the right end shows a bond to the adjacent carbonyl),
one of Z 2 and Z 3 is CH and the other is a nitrogen atom, or both are nitrogen atoms,
R 1 is a group represented by the following formula (i-a), (i-b) or (i-c):

R 2 is a group represented by the following formula (ii-a), (ii-b) or (ii-c):

R 3 is a group represented by the following formula (iii-a), (iii-b) or (iii-c):

R 4 and R 5 are each independently optionally substituted alkyl or optionally substituted cycloalkyl, or
R 4 and R 5 are bonded to each other to form, together with the adjacent Z 2 and Z 3 , an optionally substituted nitrogen-containing non-aromatic heterocycle,
R 6 and R 7 are each independently a hydrogen atom, optionally substituted alkyl, or optionally substituted cycloalkyl, or R 6 and R 7 are bonded to each other to form, together with the adjacent carbon atom, an optionally substituted cycloalkane,
R 1a , R 1b , R 1c , R ld , R 2a , R 2b , R 2c , R 2d d R 3a , R 3b and R 3d are each independently a hydrogen atom, optionally substituted alkyl, cyano, a halogen atom, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted non-aromatic heterocyclic group or optionally substituted heteroaryl,
R 3c is optionally substituted alkyl, cyano, optionally substituted alkoxy, a halogen atom, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted non-aromatic heterocyclic group or optionally substituted heteroaryl, and
n is 0 or 1, or a pharmacologically acceptable salt thereof, excluding 2-oxazolo[4,5-b]pyridin-2-yl-pyrrolidine-1-carboxylic acid benzyl ester or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1 , wherein X 4 is a sulfur atom, or a pharmacologically acceptable salt thereof.

3. The compound according to claim 1 , wherein X 4 is —CH═CH—, or a pharmacologically acceptable salt thereof.

4. The compound according to claim 1 , wherein, in the formula (I), a part represented by the following formula:

is a group represented by the formula (iv-a), (iv-b), (iv-c), (iv-d) or (iv-e):

or a pharmacologically acceptable salt thereof.

5. The compound according to claim 4 , wherein, in the formula (I), a part represented by the following formula:

is a group represented by the formula (iv-al), (iv-b) or (iv-c):

or a pharmacologically acceptable salt thereof.

6. The compound according to claim 1 , wherein, in the formula (I), a part represented by the following formula:

is a group represented by the formula (v-a):

or a pharmacologically acceptable salt thereof.

7. The compound according to claim 6 , wherein R 4 and R 5 are each independently (a) alkyl optionally substituted by 1, 2 or 3 groups selected from the group consisting of C 1 -C 6 alkoxy and monocyclic heteroaryl; or (b) C 3 -C 8 cycloalkyl, or a pharmacologically acceptable salt thereof.

8. The compound according to claim 4 , wherein, in the formula (I), a part represented by the following formula:

is a group represented by the formula (v-al):

wherein Z 4 is CH 2 , CF 2 or a sulfur atom, or a pharmacologically acceptable salt thereof.

9. The compound according to claim 8 , wherein Z 1 is —C(R 6 )(R 7 )—NH—, or a pharmacologically acceptable salt thereof.

10. The compound according to claim 1 , wherein, in the formula (I), a part represented by the following formula:

is a part represented by the formula (v-b):

or a pharmacologically acceptable salt thereof.

11. The compound according to claim 10 , wherein R 4 and R 5 are bonded to each other to form, together with the adjacent nitrogen atom and carbon atom, optionally substituted pyrrolidine, or a pharmacologically acceptable salt thereof.

12. The compound according to claim 1 , 4 or 8 , wherein ring A is a group represented by the formula (vi):

wherein ring A-1 is C6-C 11 monocyclic or bicyclic aryl,
R 8 is a hydrogen atom, C 1 -C 6 alkyl, C 1 -C 6 halogenoalkyl, cyano or a halogen atom,
R 1 is a group represented by the following formula (i-a), (i-b) or (i-c):

R 1a is (a) a hydrogen atom; (b) C 1 -C 6 alkyl optionally substituted by 1, 2 or 3 groups selected from the group consisting of amino (optionally substituted by 1 or 2 C 1 -C 6 alkyls), hydroxy, C 1 -C 6 alkoxy, monocyclic non-aromatic heterocyclyloxy, a halogen atom, and a monocyclic nonaromatic heterocyclic group; (c) a halogen atom; (d) C 3 -C 5 cycloalkyl; (e) phenyl optionally substituted by 1, 2 or 3 halogen atoms; (f) a monocyclic nonaromatic heterocyclic group; or (g) monocyclic heteroaryl optionally substituted by 1, 2 or 3 C 1 -C 6 alkyls,
R 1b is C 1 -C 6 alkyl,
R 1c is C 1 -C 6 alkyl,
R 1d is (a) C 1 -C 6 alkyl or (b) a monocyclic nonaromatic heterocyclic group,
R 2 is a group represented by the following formula (ii-a), (ii-b) or (ii-c):

R 2a is (a) a hydrogen atom; (b) C 1 -C 6 alkyl optionally substituted by 1, 2 or 3 gro

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

• Okuyama Masahiro
• Fukunaga Kenji
• Usui Kenji
• Hayashi Norimitsu
• Iijima Daisuke
• Horiuchi Hideki
• Fujimoto Nobuaki

Classifications

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title