US 12,758,559 B2 · RXFP1 agonists

Abstract

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).

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
L is —O— or —NH—;
R1 is C1-3 alkyl substituted with 1 aryl or C3-6 cycloalkyl substituent;
R2 is H;
or R1 and R2 are taken together to be ═CR6R7, wherein “═” is a double bond;
or R1 and R2 together with the carbon atom to which they are both attached form a dioxolanyl substituted with 0-1 aryl substituent;
R3 is C1-8 alkyl substituted with 0-5 halo, CN, —OH, or —OC1-3 alkyl substituents, —(CRdRd)n—C3-10-carbocyclyl substituted with 0-5 R4 or —(CRdRd)n-3 to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)P, N, NR4a, and substituted with 0-5 R4;
R4 is halo, CN, —OH, —SF5, —S(═O)pRc, C1-4 alkyl substituted with 0-5 halo, —OH, or —OC1-4 alkyl substituents, or —OC1-4 alkyl substituted with 0-5 halo substituents, —, —(CRdRd)n—C3-10 carbocyclyl substituted with 0-5 Re, or —(CRdRd)n-4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N, and NR4a;
R4a is H, C1-4 alkyl, or —S(═O)2CF3;
R5 is H, halo, OH, C1-4 alkyl substituted with 0-5 halo substituents, or —OC1-4 alkyl substituted with 0-5 halo substituents;
R6 is H, halo, CN, C1-7alkyl substituted with 0-3 R6a, C2-7 alkenyl substituted with 0-3 R6a, C2-7 alkynyl substituted with 0-3 R6a, —C(═O)OR6b, —CONR6bR6b, —(CH2)n—C3-6 carbocyclyl substituted with 0-5 R14, or 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N, or NR13, and substituted with 0-5 R14;
R6a is halo, —OH, —OC1-4 alkyl, C1-4 alkyl, aryl, or C3-6 cycloalkyl substituted with 0-4 halo substituents;
R6b is H, C1-4 alkyl substituted with 0-1 aryl, or C3-6 cycloalkyl substituted with 0-4 halo substituents;
R7 is H or C1-4 alkyl;
R8 is H, halo, CN, —NR7R7 or —OC1-4 alkyl substituted with 0-5 halo, OH, —OC1-4 alkyl, C3-6 cycloalkyl, aryl, or 4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N substituents;
R9 is —C(═O)OR15, —C(═O)NR15R15, —S(═O)pNR15R15, —S(═O)pRc, —NR17R17, C1-8 alkyl substituted with 0-4 R10 and 0-2 R11, C2-8 alkenyl substituted with 0-2 R10 and 0-2 R11, C2-8 alkynyl substituted with 0-2 R10 and 0-2 R11, C3-9 cycloalkyl substituted with 0-2 R10 and 0-2 R11, C3-9cycloalkenyl substituted with 0-2 R10 and 0-2 R11, fused C3-6 cycloalkyl substituted with 0-2 R10 and 0-2 R11, C6-9 spirocycloalkyl substituted with 0-2 R10 and 0-2 R11, A-C3-6 carbocyclyl substituted with 0-2 R10 and 0-2 R11, or A-4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N and NR18, and substituted with 0-2 R10 and 0-2 R11;
A is —O—, —S—, —CH2O—, or —OCH2—;
R10 is halo, CN, or C1-6 alkyl substituted with 0-4 R11;
R11 is halo, —ORb, —NRaRa, —NRaC(═O)Rb, —NRaC(═O)ORb, —NRaC(═O)NRaRa, —NRaS(═O)pRc, —NRaS(═O)pNRaRa, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═O)NRaS(═O)pRc, —OC(═O)Rb, —OC(═O)ORb, —OC(═O)NRaRa, —OC(═O)NRaORb, —S(═O)pRc, —S(═O)pNRaRa, C3-9 carbocyclyl substituted with 0-5 Re, 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N, and NR12, and substituted with 0-5 Re;
R12 is H, C1-4 alkyl substituted with 0-4 halo or ORb substituents, or aryl;
R13 is H, C(═O)C1-4 alkyl, C1-3 alkyl substituted with 0-3 Si(C1-3 alkyl)3, or aryl substituted with 0-2 halo substituents;
R14 is halo, CN, C1-4 alkyl substituted with 0-3 halo substituents, —OC1-4 alkyl substituted with 0-3 halo substituents, —(CH2)nNRaRa, —(CH2)n-aryl substituted with 0-3 Re, —O-aryl substituted with 0-3 Re, or —(CH2)n-3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-3 Re;
R15 is H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alknyl substituted with 0-5 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-5 Re, or —(CH2)n-3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N and NR16, and substituted with 0-5 Re;
or R15 and R15 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, N, and NR16, and substituted with 0-5 Re;
R16 is H, C1-6 alkyl substituted with 0-5 Re, —C(═O)Rf, —C(═O)ORf, —C(═O)NRfRf, —S(═O)pRf, or —S(═O)pNRfRf;
R17 is H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n-C3-10 carbocyclyl substituted with 0-5 Re, or —(CH2)n-4- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N, and NR18, and substituted with 0-5 Re;
R18 is H, C1-4 alkyl substituted with 0-4 halo or —OH substituents, —C(═O)Rb, —C(═O)OR, —C(═O)NRaRa, —S(═O)pRc, —S(═O), NRaRa, aryl substituted with 0-5 Re, C3-6 cycloalkyl substituted with 0-5 Re, or 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-5 Re;
Ra is H, C1-6 alkyl substituted with 0-8 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n-C3-10 carbocyclyl substituted with 0-5 Re, or —(CH2)n-3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-5 Re;
or Ra and Ra 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 Re;
Rb is H, C1-6 alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, or —(CH2)n-3- to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-5 Re;
Rc is C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, C3-6 carbocyclyl substituted with 0-5 Re, or 3-to 12-membered heterocyclyl comprising 1-5 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-5 Re;
Rd is H, C-1-4 alkyl, or C3-6 cycloalkyl;
Re is halo, CN, NO2, ═O, C1-6 alkyl substituted with 0-5 Rg, C2-6 alkenyl substituted with 0-5 Rg, C2-6 alkynyl substituted with 0-5 Rg, —(CH2)n—C3-6 carbocyclyl substituted with 0-5 Rg, —(CH2)n-3- to 12-membered heterocyclyl comprising 1-5 hetero atoms selected from O, S(═O)p, and N, and substituted with 0-5 Rg, —(CH2)nORf, —C(═O)Rf, —C(═O)ORf, —C(═O)NRfRf, —NRfC(═O)Rf, —S(═O)pRf, —S(═O)pNRfRf, —NRfS(═O)pRf, —NRfC(═O)ORf, —OC(═O)NRfRf, or —(CH2)nNRfRf;
Rf is H, C1-6 alkyl, C3-6 cycloalkyl, aryl, or 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N;
or Rf and Rf together with the nitrogen atom to which they arm both attached form a 3- to 12-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N;
Rg is halo, CN, OH, OC1-6alkyl, C1-6alkyl, C3-6 cycloalkyl, or aryl;
n is zero, 1, 2, or 3;
and
p is zero, 1, or 2.

36 more elements

RXFP1 agonists

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RXFP1 agonists

Life of this patent

Abstract

Claims24