Biarylmethyl heterocycles

Patent metadata

Field	Value
Publication number	US-12037324-B2
Application number	US-202217861809-A
Country	US
Kind code	B2
Filing date	Jul 11, 2022
Priority date	Jun 29, 2016
Publication date	Jul 16, 2024
Grant date	Jul 16, 2024

Abstract

The present invention provides compounds of Formula (I):

wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are biased agonists, or β-Arrestin agonists of the angiotensin II receptor, which may be used as medicaments.

First claim

What is claimed is:

1. A compound of formula (I), or salt thereof:

wherein
ring A is

W is N, or CR 16
W′, at each occurrence, is independently selected from N, O, S and CR 16 where at least one W′ is not CR 16 , and at most only one W′ is selected as O or S;
R 1 and R 2 are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyalkyl, and C 3 -C 6 cycloalkyl;
alternatively, R 1 and R 2 , together with the atom to which they are attached, join together to form a C 3 -C 6 cycloalkyl, or a 4 to 6 membered heterocycle having 1-2 heteroatoms, the cycloalkyl or heterocycle is substituted with 0-4 F and 0-1 OH;
R 16 , at each occurrence, is independently selected from H, F, Cl, Br, I, CN, OH, N(R a ) 2 , C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 4 -hydroxyalkyl, C 1 -C 3 -haloalkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -halocycloalkyl
R a is, at each occurrence, independently selected from H, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -hydroxyalkyl, and C 3 -C 6 -cycloalkyl;
or two R a , along with the nitrogen atom to which they are attached, join to form a 5 to 6 membered heterocycle containing 0-2 additional heteroatoms selected from N, O and S;
Y is 5-tetrazolyl, SO 3 H, PO 2 H 2 , PO 3 H 2 , COOR,

R, at each occurrence, is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkyl, C 3 -C 7 cycloalkyl, C 6 aryl-C 1 -C 6 alkyl heterocycle-C 1 -C 6 alkyl, wherein said heterocycle is a 4-10 membered group having 1-3 heteroatoms selected from N, O, or S, said aryl and heterocycle are each substituted with 0-3 groups chosen from C 1 -C 3 alkyl, halo, OH, or C 1 -C 3 fluoroalkyl;
R 8 at each occurrence, is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 3 alkyl, C 6-10 aryl, C 6-10 -aryl-C 1 -C 6 -alkyl, heteroaryl, heteroaryl-C 1 -C 6 -alkyl, heterocyclyl, heterocycle-C 1 -C 6 -alkyl, wherein the heteroaryl and heterocycle are each a 4-10 membered group having 1-3 heteroatoms selected from N, O, or S;
Z, at each occurrence, is independently selected from a bond, O, S, N(R z ), C(R z ) 2 , C═O, C(═O)N(R z ), N(R z )C(═O), C(R z ) 2 C(R z ) 2 , OC(R z ) 2 , SC(R z ) 2 , N(R z )C(R z ) 2 , C(R z ) 2 O, C(R z ) 2 S, C(R z ) 2 N(R z );
R z is at each occurrence independently selected from H, C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl or, alternatively, two R z groups either on the same atom or on adjacent atoms can join to form a C 3 -C 6 -cycloalkyl or a 4 to 7 membered heterocycle containing 1-2 heteroatoms selected from N, O and S;
G is selected from a 4 to 11 membered heterocycle having 1-4 atoms selected from N, O, and S, a C 3 -C8-cycloalkyl, C 6 -C 10 -aryl or a 5 to 10 membered heteroaryl having 1-4 atoms selected from N, O, and S; wherein the heterocycle, cycloalkyl, aryl and heteroaryl are substituted with 0-3 substituents independently selected from the group consisting of ═O, F, Cl, Br, I, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkyl, OH, OR x , SR x , N(R x ) 2 , CO(R x ), CON(R x ) 2 , CO 2 R x , N(R x )CO 2 (R x ), N(R x )CO(R x ), N(R x )CON(R x ) 2 , S(O) 2 (R x ), S(O) 2 N(R x ) 2 , or N(R x )S(O) 2 (R x );
R x is H, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, phenyl, CH 2 -phenyl; ring B is

Group C is

R 5 is C 1-6 alkyl, C 1-6 haloalkyl C 1-6 alkoxyalkyl, C 3-6 -cycloalkylC 0-4 -alkyl which may be substituted with 1-3 halogens or a C 1-3 -alkoxy group;
R 6 is H, F, Cl, Br, CF 3 , CN, N(R z ) 2 , CON(R z ) 2 , C 1-4 alkyl, C 1-4 haloalkyl C 1-4 alkoxyalkyl, C 1-4 hydroxyalkyl, C 3-6 -cycloalkyl, C 3-6 -halocycloalkyl, C 3-6 -alkoxycycloalkyl, or C 3-6 -hydroxycycloalkyl;
R 9 is COOR, CON(R z ) 2 ; and
r is 0 to 3;
provided that the compounds of Formula (I) are not

2. A compound of claim 1 , or salt thereof, wherein R 5 is C 1-6 alkyl or C 3-6 cycloalkyl;
R 9 is CO 2 H, CO 2 -C 1-6 -alkyl; and
R 6 is hydrogen, or C 1-4 alkyl.

3. A compound of claim 1 , or salt thereof, wherein
G is selected from a 5 to 10 membered heterocycle having 1-3 atoms selected from N, O, and S, phenyl or a C 6 -C 10 -heteroaryl having 1-3 atoms selected from N, O, and S; wherein the heterocycle, phenyl and heteroaryl are substituted with 0-3 substituents independently selected from the group consisting of ═O, Cl, Br, I, F, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkylthio, C 1 -C 6 -hydroxyalkyl, OH, OR x , N(R x ) 2 , CO(R x ), CON(R x ) 2 , CO 2 R x , N(R x )CO 2 (R x ), N(R x )CO(R x ), N(R x )CON(R x ) 2 , S(O) 2 (R x ), S(O) 2 N(R x ) 2 , or N(R x )S(O) 2 R x ;
R x is H, C 1-6 alkyl, CF 3 , phenyl, CH 2 -phenyl.

4. A compound of claim 1 , or salt thereof, wherein Ring B is

any of which are optionally substituted with 0-2 F.

5. A compound of claim 1 , or salt thereof, wherein Ring B is

any of which are optionally substituted with 0-2 F, Y is COOH, COOMe, COOEt,

5-tetrazolyl, SO 3 H,

6. A compound of claim 1 , or salt thereof, wherein wherein Y is COOH, 5-tetrazolyl, SO 3 H,

R=C 1-6 alkyl, C 6-10 -aryl-C 1 -C 6 -alkyl, or (CH 2

Assignees

• Univ Montreal
• Bristol Myers Squibb Co

Inventors

• Priestley Eldon Scott
• Reznik Samuel Kaye
• Ruediger Edward H
• Gillard James R
• Halpern Oz Scott
• Jiang Wen
• Richter Jeremy
• Ruel Rejean
• Tripathy Sasmita
• Yang Wu
• Zhang Xiaojun

Classifications

• C07D271/07

  with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical · CPC title

• C07D239/20

  having two double bonds between ring members or between ring members and non-ring members · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title