Pyrrolidine derived beta 3 adrenergic receptor agonists

Patent metadata

Field	Value
Publication number	US-9486448-B2
Application number	US-201415026267-A
Country	US
Kind code	B2
Filing date	Sep 29, 2014
Priority date	Oct 3, 2013
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention provides compounds of Formula (I), pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of β3-adrenoceptor.

First claim

What is claimed is:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:

wherein:
n is 0, 1, 2, 3, or 4;
X is selected from:
(1) a bond, and
(2) C 1 -C 6 alkanediyl optionally substituted with 1 to 5 groups independently selected from:
(a) halogen,
(b) —OR a ,
(c) aryl, and
(d) heteroaryl;

Z is selected from:
(1) a bond,
(2) 5 to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(3) benzene ring fused to a C 5 -C 10 carbocyclic ring,
(4) 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C 5 -C 10 carbocyclic ring, and
(5) 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

R 1 is selected from:
(1) C 1 -C 6 alkyl,
(2) —(C 1-10 alkyl)OH,
(3) —(C 1-10 alkyl)oxy(C 1-10 alkyl),
(4) hydroxy, and
(5) —O(C 1-10 alkyl);

each occurrence of R 2 is independently selected from:
(1) C 1 -C 6 alkyl optionally substituted with 1 to 5 halogen atoms,
(2) C 3 -C 6 cycloalkyl, optionally substituted with 1 to 5 halogen atoms,
(3) oxo,
(4) halogen,
(5) cyano,
(6) —OH,
(7) —C 0 -C 6 alkyloxyC 1 -C 6 alkyl,
(8) —CO 2 R a ,
(9) —(C═O) C 1 -C 6 alkyl,
(10) 5 to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,

wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 0 -C 6 alkyloxyC 1 -C 6 alkyl, and —(C═O) C 1 -C 6 alkyl groups of R 2 are optionally substituted with 0, 1, 2, or 3 R 3 substituents selected from:
(1) C 1 -C 6 alkyl optionally substituted with 1 to 5 halogens,
(2) halogen,
(3) —OH, and
(4) —CO 2 H;

each occurrence of R a is independently selected from:
(1) hydrogen,
(2) C 3 -C 6 cycloalkyl;
(3) C 1 -C 6 alkyl optionally substituted with 1 to 5 groups independently selected from:
(a) halogen,
(b) hydroxy,
(c) —CO(C 1 -C 6 alkyl),
(d) —CO 2 (C 1 -C 6 alkyl), and
(e) —CO 2 H, and

provided that when n is 1, X is —CH 2 —, R 1 is —CH 3 , and R 2 is —CH 3 or F, then Z is other than pyridinyl, pyrazolyl, or [1,2,4]triazolo[4,3-a]pyridinyl.

2. The compound of claim 1 , wherein n is 0, 1, 2, or 3.

3. The compound of claim 1 , wherein X is a bond, —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —CH(CH(CH 3 ) 2 )—, —CH 2 CHCH 3 —, —CH(CH 2 CH 3 )—, —CH 2 CHCH 3 —, —CH 2 CH(CH 3 ) 2 —, or —CH(CH 3 )CH 2 — and X is optionally substituted with one to three groups selected from —OR a , and aryl.

4. The compound of claim 3 , wherein X is optionally substituted with one to three groups selected from —OCH 3 , —OCHCH 3 , —OCH(CH 3 ) 2 and phenyl.

5. The compound of claim 4 wherein Z is thiazolyl, oxazolyl, pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, pyridinyl, dihydropyridinyl, dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, 2,3-dihydro-1,3,4-oxadiazolyl, oxadiazolyl, dihydro-oxadiazolyl, 4,5-dihydro-1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,

6. The compound of claim 5 wherein R 1 is selected from: C 1 -C 6 alkyl, —(C 1-10 alkyl)OH, —(C 1-10 alkyl)oxy(C 1-10 alkyl), hydroxy, and —O(C 1-10 alkyl).

7. The compound of claim 5 wherein Z is selected from dihydropyrazinyl, pyrazolyl,

dihydro-oxadiazolyl, 4,5-dihydro-1,3,4-oxadiazolyl, dihydropyridinyl, pyridinyl, pyrazinyl, and pyridazinyl.

8. The compound of claim 7 , wherein R 1 is selected from: —C 1 -C 4 alkyl, —(C 1-4 alkyl)OH, —(C 1-4 alkyl)oxy(C 1-4 alkyl), hydroxy, and —O(C 1-4 alkyl).

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, selected from:
4-(((2S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(2-methoxyethyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(2-methoxypropyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(2-methoxy-2-(6-oxo-1,6-dihydropyridin-2-yl)ethyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)propyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)-2-phenylethyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-isopropyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-cyclopropyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-(methoxymethyl)-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;
4-(((2 S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-ethoxy-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-ethyl-4-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)benzamide;
4-(((2 S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((4-hydroxy-5-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((4-methoxy-5-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;
N-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N—((R)-1-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(-2-methyl-1-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl) benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((6-oxo-1,6-dihydropyridin-2-yl)methyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(pyridin-3-ylmethyl)benzamide,
4-(((2 S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-ethyl-N-(pyridin-3-ylmethyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(pyridin-3-yl)ethyl)benzamide;
4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-N-methylbenzamide;
4-(((2S,5R)-5-((R)-(6-chlor

Assignees

• Barr Kenneth Jay
• Scott Mark E
• Thompson Christopher F
• Anthony Neville
• Cammarano Carolyn Michele
• Bakshi Raman Kumar
• Mohanty Subhendu Kumar
• Korapala Chandra Sekhar
• Latthe Prashant R
• Kambam Vyjayanthi N
• Sarkar Sujit Kumar
• Thatai Jayanth Thiruvellore
• Merck Sharp & Dohme

Inventors

• Barr Kenneth Jay
• Scott Mark E
• Thompson Christopher F
• Anthony Neville
• Cammarano Carolyn Michele
• Bakshi Raman Kumar
• Mohanty Subhendu Kumar
• Korapala Chandra Sekhar
• Latthe Prashant R
• Kambam Vyjayanthi N
• Sarkar Sujit Kumar
• Thatai Jayanth Thiruvellore

Classifications

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title