Pyrazole and imidazole derivatives useful as orexin antagonists

Patent metadata

Field	Value
Publication number	US-9303023-B2
Application number	US-201214000172-A
Country	US
Kind code	B2
Filing date	Feb 17, 2012
Priority date	Feb 18, 2011
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The present invention relates to pyrazole and imidazole derivatives of formula (I)

wherein U, V, L, X, Y, R 1 , (R 2 ) n and (R 3 ) m and ring A are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as orexin receptor antagonists.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 represents aryl or 5- to 10-membered heteroaryl, wherein the aryl or 5- to 10-membered heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of:
(C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy; and
—NR 4 R 5 , wherein R 4 and R 5 are independently hydrogen or (C 1-4 )alkyl; or R 4 and R 5 together with the nitrogen atom to which they are attached to form a saturated 5- to 7-membered ring optionally containing an oxygen atom; and
phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy;
wherein at maximum one substituent selected from —NR 4 R 5 and phenyl or 5- or 6-membered heteroaryl is present;

U represents CH, and V represents N; or U represents N and V represents CH;
(R 2 ) n represents one or two optional substituents, wherein each R 2 independently is (C 1-3 )alkyl; and
Y represents O or S; and
ring A represents aryl or 5- to 10-membered heteroaryl, wherein said aryl or 5- to 10-membered heteroaryl independently is optionally substituted with (R 3 ) m ; wherein
(R 3 ) m represents one, two or three optional substituents, wherein each R 3 independently is selected from the group consisting of:
(C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy; and
phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy;

wherein at maximum one phenyl or 5- or 6-membered heteroaryl substituent is present;

or (R 3 ) m represents two substituents which form a non-aromatic 5- or 6-membered ring fused to ring A, wherein said 5- or 6-membered ring optionally contains one or two oxygen atoms;
L represents a group —(CH 2 ) m —, wherein m represents the integer 2 or 3; wherein said group L is optionally substituted with R 6 ; wherein R 6 , if present, represents (C 1-3 )alkyl; and
X represents a direct bond, O, S or NR 7 ;
wherein, in case X represents NR 7 ,
R 7 represents hydrogen or (C 1-3 )alkyl; or, additionally,
R 7 and R 6 may form a 5- to 7-membered saturated ring including the nitrogen to which R 7 is attached to; or
R 7 together with one of the substituents R 3 may form a non-aromatic 5- to 7-membered ring including the nitrogen to which R 7 is attached to, which ring is fused to ring A; wherein R 6 is absent; and the remaining of said substituents R 3 , if present, independently are selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;

or a salt thereof.

2. A compound according to claim 1 ; wherein R 1 represents phenyl which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy;
or a salt thereof.

3. A compound according to claim 1 ; wherein U represents CH, and V represents N;
or a salt thereof.

4. A compound according to claim 1 ; wherein Y represents O;
or a salt thereof.

5. A compound according to claim 1 ; wherein L represents a group —(CH 2 ) m —, wherein m represents the integer 2 or 3; wherein, in case m represents the integer 2, said group L is optionally substituted at the carbon atom which is adjacent to X with R 6 ; wherein R 6 , if present, represents methyl; or, in case X represents NR 7 , R 7 and R 6 additionally may form a piperidine or a pyrrolidine ring including the nitrogen to which R 7 is attached to;
or a salt thereof.

6. A compound according to claim 1 ; wherein ring A represents aryl or 5- to 10-membered heteroaryl, wherein said aryl or 5- to 10-membered heteroaryl independently is optionally substituted with (R 3 ) m ; wherein
(R 3 ) m represents one, two or three optional substituents, wherein each R 3 independently is selected from the group consisting of:
(C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy; and phenyl
wherein at maximum one phenyl substituent is present;

or (R 3 ) m represents two substituents which form a fragment —O—(CH 2 ) q —O—, wherein q represents the integer 1 or 2;
or, in case X represents NR 7 , (R 3 ) m additionally may represent one substituent, wherein R 7 together with said substituent R 3 forms a non-aromatic 5- to 7-membered ring including the nitrogen to which R 7 is attached to, which ring is fused to ring A;

or a salt thereof.

7. A compound according to claim 1 ; wherein X represents a direct bond, O or NR 7 ;
or a salt thereof.

8. A compound according to claim 1 ; wherein, in case X represents NR 7 ,
R 7 represents hydrogen or (C 1-3 )alkyl; or, additionally,
R 7 and R 6 may form a piperidine or a pyrrolidine ring including the nitrogen to which R 7 is attached to; or
X being NR 7 together with (R 3 ) m and ring A represents 2,3-dihydro-indol-1-yl;

or a salt thereof.

9. A compound according to claim 1 ; wherein
L represents a group —(CH 2 ) m —, wherein m represents the integer 2 or 3;
X represents a direct bond; and
ring A represents a group selected from the group consisting of pyrrol-1-yl, imidazol-1-yl, pyrazol-1-yl, triazol-1-yl, indol-1-yl, isoindol-2-yl, indazol-1-yl, benzimidazol-1-yl, benzotriazol-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, 1H-pyrrolo[2,3-b]pyridin-1-yl, 1H-pyrrolo[3,2-c]pyridin-1-yl, 1H-pyrrolo[2,3-c]pyridin-1-yl, 7H-pyrrolo[2,3-d]pyrimidin-7-yl, 5H-pyrrolo[3,2-d]pyrimidin-5-yl, 4H-furo[3,2-b]pyrrol-4-yl, 7H-purin-7-yl, and 9H-purin-9-yl; wherein each of said groups independently is optionally substituted with (R 3 ) m ; wherein (R 3 ) m represents one, or two optional substituents, wherein each R 3 independently is selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen; or
L represents a group —(CH 2 ) m —, wherein m represents the integer 2 or 3;
X represents a direct bond; and
ring A represents a group selected from the group consisting of pyrimidin-2-yl, indol-3-yl, and 1H-pyrrolo[3,2-b]pyridin-3-yl; wherein each of said groups independently is optionally substituted with (R 3 ) m ; wherein (R 3 ) m represents one, or two optional substituents, wherein each R 3 independently is selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen; or
L represents a group —(CH 2 ) m —, wherein m represents the integer 2 or 3;
X represents a O or NR 7 ;
R 7 represents hydrogen or (C 1-3 )alkyl; and
ring A represents a group selected from the group consisting of oxazol-2-yl, thiazol-2-yl, imidazol-2-yl, pyrazol-3-yl, pyridin-2-yl, pyrimid-2-yl, pyrimid-4-yl, pyridazin-3-yl, pyrazin-2-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl, quinolin-2-yl, quinazolin-2-yl, and quinoxalin-2-yl; wherein each of said groups independently is optionally substituted with (R 3 ) m ; wherein (R 3 ) m represents one, or two optional substituents, wherein each R 3

Assignees

• Bolli Martin
• Boss Christoph
• Brotschi Christine
• Gude Markus
• Heidmann Bibia
• Sifferlen Thierry
• Williams Jodi T
• Actelion Pharmaceuticals Ltd

Inventors

• Bolli Martin
• Boss Christoph
• Brotschi Christine
• Gude Markus
• Heidmann Bibia
• Sifferlen Thierry
• Williams Jodi T

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  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 · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P1/14

  Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents · CPC title