6-hydroxy-5-(phenyl/heteroarylsulfonyl)pyrimidin-4(1H)-one as APJ agonists

Patent metadata

Field	Value
Publication number	US-10508104-B2
Application number	US-201716309161-A
Country	US
Kind code	B2
Filing date	Jun 14, 2017
Priority date	Jun 14, 2016
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

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 APJ agonists which may be used as medicaments.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein
ring A is independently selected from C 3-6 cycloalkyl, —(CH 2 ) 0-1 -5- or 6-membered aryl and heterocyclyl comprising carbon atoms and 1-4 heteroatoms selected from N, NR 3a , O, and S, each substituted with 1-3 R 3 and 1-2 R 5 ; provided R 3 and R 5 are not both H;
ring B is independently selected from C 3-6 cycloalkyl, C 3-6 cycloalkenyl, aryl, bicyclic carbocyclyl, 6-membered heteroaryl, 6-membered heterocyclyl, and bicyclic heterocyclyl, each substituted with 1-3 R 1 ;
R 1 is independently selected from H, F, Cl, Br, NO 2 , —(CH 2 ) n OR b , (CH 2 ) n S(O) p R c , —(CH 2 ) n C(═O)R b , —(CH 2 ) n NR a R a , —(CH 2 ) n CN, —(CH 2 ) n C(═O)NR a R a , —(CH 2 ) n NR a C(═O)R b , —(CH 2 ) n NR a C(═O)NR a R a , —(CH 2 ) n NR a C(═O)OR b , —(CH 2 ) n OC(═O)NR a R a , —(CH 2 ) n C(═O)OR b , —(CH 2 ) n S(O) p NR a R a , —(CH 2 ) n NR a S(O) p NR a R a , —(CH 2 ) n NR a S(O) p R c , C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) n —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ;
R 2 is independently selected from C 1-5 alkyl substituted with 0-3 R e ; C 2-5 alkenyl substituted with 0-3 R e , aryl substituted with 0-3 R e , heterocyclyl substituted with 0-3 R e , and C 3-6 cycloalkyl substituted with 0-3 R e ; provided when R 2 is C 1-5 alkyl, the carbon atom except the one attached to the pyrimidine ring may be replaced by O, N, and S;
R 3 is independently selected from H, F, Cl, Br, C 1-5 alkyl substituted with 0-3 R e , —(CH 2 ) n OR b , —(CH 2 ) n NR a R a , —(CH 2 ) n CN, —(CH 2 ) n C(═O)R b , —(CH 2 ) n C(═O)OR b , —(CH 2 ) n C(═O)NR a R a , —(CH 2 ) n NHC(═O)R b , —(CH 2 ) n NHC(═O)NR a R a , —(CH 2 ) n NHC(═O)OR b , —(CH 2 ) n NHS(O) p NR a R a , —(CH 2 ) n NHS(O) p R e —(CH 2 ) n S(O) p R e , —(CH 2 ) n S(O) p NR a R a , and —(CH 2 ) n OC(═O)NR a R a ;
R 3a is independently selected from H, C 1-5 alkyl substituted with 0-3 R e , —S(O) p R c , —C(═O)R b , —C(═O)NR a R a , —C(═O)OR b , S(O) p NR a R a , R 6 , —S(O) p R 6 , —C(═O)R 6 , —C(═O)NR a R 6 , —C(═O)OR 6 , and —S(O) p NR a R 6 ;
R 4 is independently selected from H, C 1-5 alkyl substituted with 0-3 R e , C 2-5 alkenyl substituted with 0-3 R e , (CH 2 ) n —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ;
R 5 is independently selected from H, R 6 , —OR 6 , —S(O) p R 6 , —C(═O)R 6 , —C(═O)OR 6 , —NR a R 6 , —C(═O)NR a R 6 , —NR a C(═O)R 6 , —NR a C(═O)OR 6 , —OC(═O)NR a R 6 , —S(O) p NR a R 6 , —NR a S(O) p NR a R 6 , and —NR a S(O) p R 6 ;
R 6 is independently selected from —(CR 7 R 7 ) n -aryl, —(CR 7 R 7 ) n —C 3-6 cycloalkyl, and —(CR 7 R 7 ) n -heteroaryl, each substituted with 1-6 R 8 ;
R 7 is independently selected from H, C 1-4 alkyl, and (CH 2 ) n —C 3-12 carbocyclyl substituted with 0-3 R e ;
R 8 is independently selected from H, F, Cl, Br, —(CH 2 ) n CN, —(CH 2 ) n OR b , —(CH 2 ) n C(═O)R b , —(CH 2 ) n C(═O)OR b , —(CH 2 ) n C(═O)NR a R a , —(CH 2 ) n NR a R a , —(CH 2 ) n NR a C(═O)R b , —(CH 2 ) n NR a C(═O)OR b , —(CH 2 ) n NR a C(═O)NR a R a , —(CH 2 ) n OC(═O)NR a R a , —(CH 2 ) n S(O) p R c , —(CH 2 ) n S(O) p NR a R a , —(CH 2 ) n NR a S(O) p NR a R a , —(CH 2 ) n NR a S(O) p R e , C 1-4 alkyl substituted with 0-3 R e , (CH 2 ) n —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ;
R a is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;
R b is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-5 R e ;
R e is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;
R e is independently selected from C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n C 4-6 heterocyclyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) n OR f , S(O) p R f , C(═O)NR f R f , NR f C(═O)R f , S(O) p NR f R f , NR f S(O) p R f , NR f C(═O)OR f , OC(═O)NR f R f , and —(CH 2 ) n NR f R f ;
R f is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl (optimally substituted with F, Cl, Br and OH), C 3-6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;
n is independently selected from zero, 1, 2, 3, and 4; and
p is independently selected from zero, 1, and 2.

2. The compound of claim 1 , having Formula (II):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein
ring A is independently selected from

ring B is independently selected from

R 1 is independently selected from H, F, Cl, Br, —OR b , CN, C 1-4 alkyl substituted with 0-3 R e and C 3-6 cycloalkyl substituted with 0-3 R e ;
R 2 is independently selected from C 1-5 alkyl substituted with 0-3 R e ; C 2-5 alkenyl, aryl substituted with 0-3 R e , heterocyclyl substituted with 0-3 R e , and C 3-6 cycloalkyl; provided when R 2 is C 1-5 alkyl, the carbon atom except the one attached to the pyrimidine ring may be replaced by O, N, and S;
R 3 is independently selected from H, F, Cl, Br, C 1-5 alkyl substituted with 0-3 R e , —OR b , —NR a R a , —CN, —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —NHC(═O)R b , —NHC(═O)NR a R a , —NHC(═O)OR b , —NHS(O) p R e —S(O) p R c , —S(O) p NR a R a , and —OC(═O)NR a R a ;
R 3a is independently selected from H, C 1-5 alkyl substituted with 0-3 R e , —C(═O)R b , —C(═O)NR a R a , —C(═O)OR b , R 6 , —S(O) p R 6 , —C(═O)R 6 , —C(═O)NR a R 6 , —C(═O)OR 6 , and —S(O) p NR a R 6 ;
R 4 is independently selected from H, C 1-5 alkyl substituted with 0-3 R e , C 2-5 alkenyl substituted with 0-3 R e , —(CH 2 ) n —C 3-6 cycloalkyl substituted with 0-3 R e , and —(CH 2 ) n -heterocyclyl substituted with 0-3 R e ;
R 5 is independently selected from H, R 6 , —OR 6 , —S(O) p R 6 , —C(═O)R 6 , —C(═O)OR 6 , —NR a R 6 , —C(═O)NR a R 6 , —NR a C(═O)R 6 , —NR a C(═O)OR 6 , —OC(═O)NR a R 6 , —S(O) p NR a R 6 , —NWS(O) p NR a R 6 , and —NR a S(O) p R 6 ;
R 6 is independently selected from —(CR 7 R 7 ) n -aryl, —(CR 7 R 7 ) n —C 3-6 cycloalkyl, and —(CR 7 R 7 ) n -heteroaryl, each substituted with 1-4 R 8 ;
R 7 is independently selected from H and C 1-4 alkyl;
R 8 is independently selected from H, F, Cl, Br, CN, —OR b , —(CH 2 ) n C(═O)R b , —(CH 2 ) n C(═O)OR b

Assignees

• Bristol Myers Squibb Co

Inventors

• Tora George O
• Finlay Heather
• Jiang Wen
• Meng Wei
• Zhang Xiaojun

Classifications

• C07D239/60 Primary

  Three or more oxygen or sulfur atoms · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title