Quinolinyl glucagon receptor modulators

Patent metadata

Field	Value
Publication number	US-8927577-B2
Application number	US-201214232379-A
Country	US
Kind code	B2
Filing date	Jul 12, 2012
Priority date	Jul 22, 2011
Publication date	Jan 6, 2015
Grant date	Jan 6, 2015

Abstract

The present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , B 1 , B 2 , B 3 and B 4 are as defined herein. The compounds of Formula I have been found to act as glucagon antagonists or inverse agonists. Consequently, the compounds of Formula I and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucagon.

First claim

We claim:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein
R 1 is (C 1 -C 6 )alkyl which is optionally substituted with one to three fluoro, hydroxy or methoxy; (C 3 -C 7 )cycloalkyl which is optionally substituted with one to two fluoro or one to two (C 1 -C 3 )alkyl which are each optionally substituted with one to three fluoro and wherein one carbon of the (C 3 -C 7 )cycloalkyl can be replaced with an O; or (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl wherein the (C 3 -C 7 )cycloalkyl group of said (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl is optionally substituted with one to two (C 1 -C 3 )alkyl which are each optionally substituted with one to three fluoro;
R 2 is hydrogen or (C 1 -C 3 )alkyl;
R 3 is tetrazolyl, —CH 2 -tetrazolyl, —(CH 2 ) 2 SO 3 H, —(CH 2 ) 2 CO 2 H, —CH 2 CHFCO 2 H or —CH 2 CH(OH)CO 2 H;
One of A 1 , A 2 and A 3 is N and the remaining two of A 1 , A 2 and A 3 are CR 4 ;
R 4 at each occurrence is independently hydrogen, halo, cyano, (C 1 -C 3 )alkyl optionally substituted with one to three fluoro, (C 1 -C 3 )alkoxy optionally substituted with one to three fluoro, or (C 3 -C 5 )cycloalkyl;
B 1 , B 2 , B 3 and B 4 are each independently CR 5 ; and
R 5 at each occurrence is independently hydrogen, halo, cyano, (C 1 -C 3 )alkyl optionally substituted with one to three fluoro, or (C 1 -C 3 )alkoxy optionally substituted with one to three fluoro, or (C 3 -C 5 )cycloalkyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen and R 3 is —(CH 2 ) 2 CO 2 H.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl each optionally substituted with 1 to 3 fluoro and wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1 to 2 methyl.

4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein
A 1 and A 2 are each CR 4 and A 3 is N;
R 4 at each occurrence is independently hydrogen, fluoro, chloro, methyl or ethyl; and
R 5 at each occurrence is independently hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy.

5. The compound according to claim 1 selected from the group consisting of
(+/−)-3-(4-(1-(3-methylquinolin-2-ylamino)butyl)benzamido)propanoic acid;
(+/−)-3-{4-[3-methyl-1-(quinolin-3-ylamino)-butyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[3-methyl-1-(quinolin-2-ylamino)-butyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[1-(8-methoxy-quinolin-2-ylamino)-3-methyl-butyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[3-methyl-1-(4-methyl-quinolin-2-ylamino)-butyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[3-methyl-1-(3-methyl-quinolin-2-ylamino)-butyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[1-(7-fluoro-4-methyl-quinolin-2-ylamino)-3-methyl-butyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[1-(8-chloro-quinolin-2-ylamino)-3-methyl-butyl]-benzoylamino}-propionic acid;
(+/−)3-(4-(3-methyl-1-(7-(trifluoromethyl)quinolin-2-ylamino)butyl)benzamido)propanoic acid;
(+/−)-3-(4-(3-methyl-1-(6-(trifluoromethyl)quinolin-2-ylamino)butyl)benzamido)propanoic acid;
(+\−)-3-(4-(3-methyl-1-(2-methylquinolin-3-ylamino)butyl)benzamido)propanoic acid;
(+\−)-3-(4-(3-methyl-1-(4-methylquinolin-3-ylamino)butyl)benzamido)propanoic acid;
(+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid;
(+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(7-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid;
(+/−)3-(4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzamido)propanoic acid;
(+/−)-3-(4-((3,3-di methylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzamido)propanoic acid;
(+/−)-3-(4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzamido)propanoic acid;
(+/−)-3-(4-((6,7-difluoroquinolin-3-ylamino)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoic acid;
(+/−)-3-(4-(3-methyl-1-(7-methylquinolin-3-ylamino)butyl)benzamido)propanoic acid;
(+/−)-3-(4-(3-methyl-1-(8-methylquinolin-3-ylamino)butyl)benzamido)propanoic acid;
(+/−)-3-(4-(3-methyl-1-(6-methylquinolin-3-ylamino)butyl)benzamido)propanoic acid; and
(+/−)-3-(4-(3-methyl-1-(5-methylquinolin-3-ylamino)butyl)benzamido)propanoic acid;
or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 selected from the group consisting of
(+)-3-(4-(1-(3-methylquinolin-2-ylamino)butyl)benzamido)propanoic acid;
(−)-3-(4-(1-(3-methylquinolin-2-ylamino)butyl)benzamido)propanoic acid;
(+)-3-(4-(3-methyl-1-(3-methylquinolin-2-ylamino)butyl)benzamido)propanoic acid; and
(−)-3-(4-(3-methyl-1-(3-methylquinolin-2-ylamino)butyl)benzamido)propanoic acid;
or a pharmaceutically acceptable salt thereof.

7. (R)3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid or a pharmaceutically acceptable salt thereof.

8. (S)3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid or a pharmaceutically acceptable salt thereof.

9. (R)3-{4-[(3,3-dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid or a pharmaceutically acceptable salt thereof.

10. (S)3-{4-[(3,3-dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising (i) a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable excipient, diluent, or carrier.

12. A method for treating obesity in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13. A method for treating or delaying the progression or onset of type 2 diabetes in a human comprising administering to the human in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignees

• Didiuk Mary
• Filipski Kevin J
• Guzman-Perez Angel
• Lee Esther C
• Pfefferkorn Jeffrey A
• Stevens Benjamin
• Tu Meihua
• Pfizer

Inventors

• Didiuk Mary
• Filipski Kevin J
• Guzman-Perez Angel
• Lee Esther C
• Pfefferkorn Jeffrey A
• Stevens Benjamin
• Tu Meihua

Classifications

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D239/84 Primary

  Nitrogen atoms · CPC title

• C07D217/22

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D241/44 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title