Biarylmethyl heterocycles

Patent metadata

Field	Value
Publication number	US-2019202808-A1
Application number	US-201716311835-A
Country	US
Kind code	A1
Filing date	Jun 28, 2017
Priority date	Jun 29, 2016
Publication date	Jul 4, 2019
Grant date	—

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

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

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate 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 , wherein 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, 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 6-10 -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 having 1-3 heteroatoms selected from N, O, or S;
R s 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 is a 5-10 membered group and the heterocycle is a 4-10 membered each 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 -C 8 -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 3 is C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-6 -hydroxycycloalkyl, C 1-6 -halocycloalkyl, COOR, CON(R z ) 2 , or

R 4 is H, F, Cl, Br, CF 3 , CN, N(R z ) 2 , CON(R x ) 2 , C 1-4 alkyl, C 1-4 haloalkyl C 1-4 alkoxyalkyl, C 1-4 hydroxyalkyl, C 1-6 -cycloalkyl, C 1-6 -halocycloalkyl, C 1-6 -alkoxycycloalkyl, or C 1-6 -hydroxycycloalkyl;
R 5 is C 1-6 alkyl, C 1-6 haloalkyl; C 1-6 alkoxyalkyl, C 1-6 -cycloalkyl-C 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 x ) 2 , C 1-4 -alkyl, C 1-4 -haloalkyl, C 1-4 -alkoxyalkyl, C 1-4 hydroxyalkyl, C 1-6 -cycloalkyl, C 1-6 -halocycloalkyl, C 1-6 -alkoxycycloalkyl, or C 1-6 -hydroxycycloalkyl; and
R 7 and R 8 , are 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, R 7 and R 8 , along with the atom to which they are attached, can join to form a C 3 -C 6 -cycloalkyl, a C 3 -C 6 -halocycloalkyl, a C 3 -C 6 -hydroxycycloalkyl or a 4 to 7 membered heterocycle having 1-2 heteroatoms selected from N, O, or S and the potential for further substitution with 1-4 F, OH, C 1-4 -alkyl, C 1-4 -haloalkyl C 1-4 -alkoxyalkyl, C 1-4 -hydroxyalkyl,
provided the compounds of Formula (I) are not

2 . A compound of claim 1 , or salt thereof, wherein Group C is

3 . A compound of claim 1 , or salt thereof, wherein
R 1 and R 2 are H; R 3 is H, C 1-2 hydroxyalkyl, CO 2 H, CO 2 —C 1-6 -alkyl, CONH 2 , CONH(C 1-6 -alkyl), CON(C 1-6 -alkyl) 2 , or

R 4 is H, F, Cl, Br, CF 3 , CN, C 1-3 alkyl, C 1-3 haloalkyl, or C 1-2 hydroxyalkyl;
R 5 is C 1-6 alkyl, C 3-6 cycloalkyl or O(C 1-6 alkyl);
R 6 is hydrogen, or C 1-4 alkyl;
R 7 and R 8 are H, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-3 hydroxyalkyl
alternatively, R 7 and R 8 , along with the atom to which they are attached, join to form a C 3 -C 6 -cycloalkyl or a C 4 -C 7 -heterocycle; and
R is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or

4 . A compound of claim 1 , or salt thereof, wherein:
Group C is

R 1 and R 2 are H;
R 3 is hydroxyalkyl, CO 2 H, or

R 4 is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 hydroxyalkyl; and
R 5 is ethyl, n-propyl, or n-butyl.

5 . 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 -heteroa

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

• C07D257/04

  Five-membered rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D239/20

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