Piperidinyl-3-(aryloxy)propanamides and propanoates

Patent metadata

Field	Value
Publication number	US-11045457-B2
Application number	US-201916289311-A
Country	US
Kind code	B2
Filing date	Feb 28, 2019
Priority date	Mar 1, 2018
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

Disclosed are compounds of Formula 1,

stereoisomers thereof, and pharmaceutically acceptable salts thereof, wherein L, r, s, R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , X 1 , X 2 , X 3 , X 4 , X 13 , and X 14 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with SSTR4.

First claim

What is claimed is:

1. A compound of Formula 1,

or a pharmaceutically acceptable salt thereof in which:
X 1 is selected from N and CR 1 ;
X 2 is selected from N and CR 2 ;
X 3 is selected from N and CR 3 ; and
X 4 is selected from N and CR 4 , provided no more than two of X 1 , X 2 , X 3 , and X 4 are N;
X 13 is NR 13 and X 14 is CR 15 R 16 or X 13 is CH 2 and X 14 is NR 14 ;
L is selected from NR 8 and O;
r is selected from 0 and 1;
s is selected from 0 and 1;
R 1 , R 2 , and R 3 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

R 4 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo;

R 5 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo, oxo, and phenyl which is substituted with 0 to 3 optional substituents independently selected from halo; or

R 4 and R 5 , together with the carbon atoms to which they are attached, form a cyclopent-1-en-1,2-diyl or a furan-2,3-diyl;
R 6 and R 7 are each independently selected from halo and C 1-3 alkyl, or R 6 and IC, together with the carbon atom to which they are attached, form a C 3-4 cycloalkan-1,1-diyl;
R 8 is selected from H and C 1-4 alkyl;
R 9 and R 10 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano;
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and
(c) phenyl and C 1-5 heteroaryl, each substituted with 0 to 3 optional substituents independently selected from halo, C 1-4 alkyl, and C 1-4 alkoxy, wherein the C 1-5 heteroaryl substituent is a monocyclic ring with 5 to 6 ring members in which 1 to 4 ring members are heteroatoms, each of the heteroatoms independently selected from N, O, and S, provided no more than one of the ring members is O or S, and wherein the C 1-4 alkyl and C 1-4 alkoxy optional substituents on phenyl and C 1-5 heteroaryl are each independently substituted with 0 to 3 optional substituents independently selected from halo; or

R 9 and R 10 , together with the carbon atom to which they are attached, form a C 3-4 cycloalkan-1,1-diyl;
R 11 and R 12 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or

R 11 and R 12 , together with the carbon atom to which they are attached, form a C 3-4 cycloalkan-1,1-diyl;
R 13 and R 14 are each independently selected from
(a) hydrogen; and
(b) C 1-4 alkyl, which is substituted with an optional substituent selected from cyano and oxo; and

R 15 and R 16 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; or

R 15 and R 16 , together with the carbon atom to which they are attached, form a C 3-4 cycloalkan-1,1-diyl.

2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , and X 4 is CR 4 .

3. The compound or pharmaceutically acceptable salt according to claim 2 , wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from
(a) hydrogen, halo, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein X 1 is N, X 2 is CR 2 , X 3 is CR 3 , and X 4 is CR 4 .

5. The compound or pharmaceutically acceptable salt according to claim 4 , wherein R 2 , R 3 , and R 4 are each independently selected from
(a) hydrogen, halo, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

6. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo, oxo, and phenyl which is substituted with 0 to 3 optional substituents independently selected from halo.

7. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 6 and R 7 are each independently selected from fluoro and methyl or together with the carbon atom to which they are attached form a cyclopropan-1,1-diyl or a cyclobutan-1,1-diyl.

8. The compound or pharmaceutically acceptable salt according to claim 1 , wherein each of R 6 and R 7 is methyl.

9. The compound or pharmaceutically acceptable salt according to claim 1 , wherein L is NR 8 .

10. The compound or pharmaceutically acceptable salt according to claim 9 , wherein R 8 is hydrogen.

11. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 9 and R 10 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano;
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo; and
(c) phenyl and C 1-5 heteroaryl, each substituted with 0 to 3 optional substituents independently selected from halo, C 1-4 alkyl, and C 1-4 alkoxy, wherein the C 1-5 heteroaryl substituent is a monocyclic ring with 5 to 6 ring members in which 1 to 4 ring members are heteroatoms, each of the heteroatoms independently selected from N, O, and S, provided no more than one of the ring members is 0 or S, and wherein the C 1-4 alkyl and C 1-4 alkoxy optional substituents on phenyl and C 1-5 heteroaryl are each independently substituted with 0 to 3 optional substituents independently selected from halo.

12. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 11 and R 12 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

13. The compound or pharmaceutically acceptable salt according to claim 1 , wherein X 13 is NR 13 and X 14 is CR 15 R 16 .

14. The compound or pharmaceutically acceptable salt according to claim 13 , wherein R 13 is selected from
(a) hydrogen; and
(b) C 1-4 alkyl, which is substituted with and optional substituent selected from cyano and oxo.

15. The compound or pharmaceutically acceptable salt according to claim 13 , wherein R 15 and R 16 are each independently selected from
(a) hydrogen, halo, hydroxy, and cyano; and
(b) C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy, each substituted with 0 to 3 optional substituents independently selected from halo.

16. The comp

Assignees

• Takeda Pharmaceuticals Co
• Cheruvallath Zacharia
• Green Jason
• Johnson Ben
• Schleicher Kristin
• Sun Huikai
• Tang Mingnam

Inventors

• Cheruvallath Zacharia
• Green Jason
• Johnson Ben
• Schleicher Kristin
• Sun Huikai
• Tang Mingnam

Classifications

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/24

  Antidepressants · 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