RXFP1 agonists
The disclosure relates to compounds of Formula (I), which are RXFP1 receptor agonists, compositions containing them, and methods of using them, for example, in the treatment of heart failure, fibrotic diseases, and related diseases such as lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease), or hepatic disease (e.g., non-alcoholic steatohepatitis and portal hypertension).
1 . A compound having Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, CN, C 1-7 alkyl substituted with 0-3 R 6 , C 2-7 alkenyl substituted with 0-3 R 6 , C 2-7 alkynyl substituted with 0-3 R 6 , C 3-6 cycloalkyl substituted with 0-3 R 14 , C 3-6 cycloalkenyl substituted with 0-3 R 14 , aryl substituted with 0-3 R 14 , or a 4- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S(═O) p , N, and NR 14a and substituted with 0-3 R 14 ;
R 2 is H or C 1-3 alkyl;
R 3 is —NR a C(═O)R 5 , —NR a C(═O)(CR d R d ) 1-2 R 7 , or —NR a C(═O)NR a R 7 ;
R 4 is halo, CN, C 1-4 alkyl substituted with 0-5 halo substituents, —OH, —OC 1-4 alkyl substituted with 0-5 halo substituents, —S(═O) p R c , or aryl;
R 5 is C 1-8 alkyl substituted with 0-4 R 11 or C 3-6 cycloalkyl substituted with 0-4 R 8 and 0-2 R 9 ,
R 6 is halo, OH, C 3-6 cycloalkyl, or aryl;
R 7 is aryl substituted with 0-4 R 8 and 0-2 R 9 ;
R 8 is —OR b ;
R 9 is halo, CN, phenyl substituted with 0-3 R 10 and 0-2 R 11 , or 3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(═O) p , N, and NR 11a , and substituted with 0-3 R 10 and 0-2 R 11 ;
R 10 is halo, CN, or C 1-4 alkyl;
R 11 is C 1-3 alkyl substituted with 0-1 R 13 and 0-1 R 13 , —OR b , —NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —NR a C(═O)NR a R a , —NR a S(═O) p R c , —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═O)NR a S(═O) p R c , —OC(═O)R b , —S(═O) p R c , —S(═O) p NR a R a , C 3-10 carbocyclyl substituted with 0-5 R e , 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , N and NR 15 , and substituted with 0-5 R e ;
R 11a is H, or C 1-4 alkyl substituted with 0-2 R e ;
R 12 is halo, —C(═O)OR b , —C(═O)NHR a , —C(═O)NHOR b , or C 1-4 alkyl substituted with 0-3 halo or OH substituents;
R 13 is —OR b , —NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —NR a S(═O) p R c , —NR a S(O) p NR a R a , —OC(═O)NR a R a , —OC(═O)NR a OR b , —S(═O) p NR a R a , or —S(O) p R c ;
R 14 is halo, CN, C 1-4 alkyl substituted with 0-3 halo substituents, —OC 1-4 alkyl substituted with 0-3 halo substituents, —(CH 2 ) 0-3 —NR a R a , —(CH 2 ) 0-3 -aryl substituted with 0-3 R e , —O-aryl substituted with 0-3 R c , or —(CH 2 ) 0-3 -3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , and N, and substituted with 0-3 R e ;
R 14a is H, C(═O)C 1-4 alkyl, or C 1-3 alkyl substituted with 0-3 aryl substituents substituted with 0-2 halo substituents;
R 15 is H, C 1-3 alkyl, or aryl;
R 16 is C 1-3 alkyl substituted with 0-1 R e , —C(═O)R b , —C(═O)OR b , —C(═O)NR a R a , —C(═O)NR a S(═O) p R c , —OC(═O)R b , —S(═O) p R c , or —S(═O) p NR a R a ;
R a is H, C 1-5 alkyl substituted with 0-5 R e , C 2-5 alkenyl substituted with 0-5 R e , C 2-5 alkynyl substituted with 0-5 R e , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R e , or —(CH 2 ) n -3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , and N, and 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 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , and N, and substituted with 0-5 R e ;
R b is H, C 1-5 alkyl substituted with 0-5 R e , C 2-3 alkenyl substituted with 0-5 R e , C 2-5 alkynyl substituted with 0-5 R e , —(CH 2 ), —C 3-10 carbocyclyl substituted with 0-5 R e , or —(CH 2 ) n -3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , and N, and substituted with 0-5 R e ;
R c is C 1-5 alkyl substituted with 0-5 R e , C 2-5 alkenyl substituted with 0-5 R e , C 2-5 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, or 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , and N;
R d is H, —OR b , or C 1-5 alkyl substituted with 0-5 R e ;
R e is halo, CN, ═O, C 1-6 alkyl substituted with 0-5 R g , C 2-6 alkenyl substituted with 0-5 R g , C 2-6 alkynyl substituted with 0-5 R g , —(CH 2 ) n —C 3-10 carbocyclyl substituted with 0-5 R g , —(CH 2 ) n -3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , and N, and substituted with 0-5 R g , —(CH 2 ) n OR f , —C(═O)OR f , —C(═O)NR f R f , —NR f C(═O)R f , —S(═O) p R f , —NR f C(═O)OR f , —OC(═O)NR f R f , or —(CH 2 ) n NR f R f ;
R f is H, C 1-5 alkyl, C 3-6 , cycloalkyl, or aryl; or R f and R f together with the nitrogen atom to which they are both attached form a 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O) p , and N;
R g is halo, CN, OH, C 1-6 alkyl, C 3-6 cycloalkyl, or aryl;
n is zero, 1, 2, or 3; and
p is zero, 1, or 2.
2 . The compound of claim 1 , having Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, C 1-4 alkyl substituted with 0-4 halo, C 3-6 cycloalkyl, or phenyl;
R 2 is H;
R 4 is halo or C 1-4 alkyl substituted with 0-4 halo substituents;
R 5 is C 3-6 cycloalkyl substituted with 0-1 R 9 ;
R 9 is halo, CN, or phenyl substituted with 0-1 R 10 and 0-1 R 11 ,
R 10 is halo, CN, or C 1-4 alkyl;
R 11 is —OH, —OC 1-4 alkyl, or —C(═O)OR b ;
R 11a is H or C 1-3 alkyl;
R a is H or C 1-4 alkyl; and
R b is H or C 1 alkyl.
3 . The compound of claim 1 , having Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, C 1-4 alkyl substituted with 0-4 halo substituents, C 3-6 cycloalkyl, or phenyl;
R 2 is H;
R 4 is halo or C 1-4 alkyl substituted with 0-4 halo substituents;
R 5 is C 1-7 alkyl substituted with 0-1 R 11 ;
R 11 is —OR b , —C(═O)R b , —C(═O)OR b , or —C(═O)NR a R a ;
R a is H or C 1-4 alkyl; and
R b is H or C 1-4 alkyl.
4 . The compound of claim 1 , having Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, C 1-4 alkyl substituted with 0-4 halo substituents, C 3-6 cycloalkyl, or phenyl;
R 2 is H;
R 4 is halo or C 1-4 alkyl substituted with 0-4 halo substituents;
R 7 is aryl substituted with 0-1 R g and 0-1 R 9 ;
R 8 is —OR b ;
R 9 is halo, CN, or phenyl substituted with 0-3 R 10 and 0-2 R 11 ;
R 10 is halo, CN, C 1-4 alkyl, —OH, or —OC 1-4 alkyl;
R 11 is —OR 1 or —C(═O)OR b ;
R a is H or C 1-4 alkyl;
R b is H, C 1-4 alkyl, or phenyl; and
R d is —OH or —OC 1-4 alkyl.
5 . The compound of claim 2 , having Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is halo, C 1-4 alkyl substituted with 0-4 halo substituents, C 3-6 , cycloalkyl, or phenyl;
R 2 is H;
R 4 is halo or C 1-4 alkyl substituted with 0-4 halo substituents;
R 7 is aryl substituted with 0-1R 8 and 0-1 R 9 ;
R 8 is —OC 1-4 alkyl substituted with 0-5 halo or OH substituents;
R 9 is halo, CN, or phenyl substituted with 0-3 R 10 and 0-2 R 11 ;
R 10 is halo, CN, C 1-4 alkyl, —OH, or —OC 1-4 alkyl;
R 11 is —OR 1 or —C(═O)OR b ;
R a is H or C 1-4 alkyl; and
R b is H, C 1-4 alkyl, or phenyl.
6 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.