# US 12,758,559 B2 · RXFP1 agonists

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- Number: US 12,758,559 B2
- Document ID: US12758559B2
- Status: Granted
- Kind: B2
- Application number: 18/701,276
- Filed: 2022-10-28
- Published: 2025-08-28
- Granted: 2026-10-13
- Earliest claimed: 2021-10-29
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Scott A. Shaw; Adam James Clarke; Todd J. Friends; Arvind Mathur; Michael C. Myers; Jianqing Li; Kumar Balashanmuga Pabbisetty; Shun Su; George O. Tora; Benjamin P. Vokits; Laxman Pasunoori; Nicholas R. Wurtz; Donald J.P. Pinto
- Web page: https://patentgrep.com/patent/US12758559B2

## CPC

- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/351: not condensed with another ring
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/4174: Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- C07C 237/24: having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07C 271/54: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 317/50: at least one of the nitrogen atoms being part of any of the groups [IMAGE cpc-sch-C07C-0976.gif], X being a hetero atom, Y being any atom
- C07D 233/72: Two oxygen atoms, e.g. hydantoin
- C07D 235/26: Oxygen atoms
- C07D 257/06: with nitrogen atoms directly attached to the ring carbon atom
- C07D 295/155: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 305/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
- C07D 307/20: Oxygen atoms
- C07D 309/08: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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).

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, having Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo, C1-4 alkyl substituted with 0-3 halo substituents, or —OC1-4 alkyl substituted with 0-3 halo substituents;
R6 is halo, CN, C1-6 alkyl substituted with 0-3 R6a, C2-6 alkenyl substituted with 0-3 R6a, C2-6 alkynyl substituted with 0-3 R6a, C3-6 cycloalkyl substituted with 0-3 R14, C3-6 cycloalkenyl substituted with 0-3 R14, phenyl substituted with 0-3 R14, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from O, S(═O)p, N, and NR13, and substituted with 0-3 R14;
R7 is H or C1-2 alkyl;
R6a is halo, —OC1-4 alkyl, C1-6 cycloalkyl, or phenyl;
R8 is H, halo, CN, or —OC1-4 alkyl substituted with 0-4 halo, OH, or —OC1-4 alkyl;
R9 is C1-7 alkyl substituted with 0-3 R10 and 0-2 R11, C2-7 alkenyl substituted with 0-2 R10 and 0-2 R11, C2-7 alkynyl substituted with 0-2 R10 and 0-2 R11, C3-9 cycloalkyl substituted with 0-2 R10 and 0-2 R10, or C6-9 spirocycloalkyl substituted with 0-2 R10 and 0-2 R11, —CH2—O—C6-9 carbocyclyl substituted with 0-2 R10 and 0-2 R11, or —O—C3-6 cycloalkyl substituted with 0-2 R10 and 0-2 R11;
R10 is halo, CN, or C1-5 alkyl substituted with 0-4 halo or —OH substituents;
R11 is —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), Rc, —OC(═O)Rb, —OC(═O)NRaRa, —S(═O), Re, —S(═O)pNRaRa, aryl substituted with 0-4 Re, C3-6 cycloalkyl substituted with 0-4 Rc, or 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N and NR12, and substituted with 0-4 Re;
R12 is H, C1-2 alkyl, or phenyl;
R13 is H, C(═O)C1-3 alkyl, or C1-3 alkyl substituted with 0-2 aryl substituted with 0-2 halo substituents;
R14 is halo, CN, C1-4 alkyl substituted with 0-3 halo, —OC1-4 alkyl substituted with 0-3 halo, —(CH2)0-2—NRaRa, —(CH2)0-2-aryl substituted with 0-3 Rc, —O-aryl substituted with 0-3 Re, or —(CH2)0-2-4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-3 Re;
Ra is H, C1-8 alkyl substituted with 0-4 Re, C2-5 alkenyl substituted with 0-4 Re, C2-5 alkynyl substituted with 0-4 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-4 Re, or —(CH2)n-4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-4 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a 4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from 0, S(═O)p, and N, and substituted with 0-4 Rc;
Rb is H, C1-5 alkyl substituted with 0-4 Re, C2-5 alkenyl substituted with 0-4 Re, C2-5 alkynyl substituted with 0-4 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-4 Rc, or —(CH2)n-4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-4 Rc;
Rc is C1-5 alkyl substituted with 0-4 Re, C2-5 alkenyl substituted with 0-4 Re, C2-5 alkynyl substituted with 0-4 Rc, C3-6 carbocyclyl substituted with 0-4 Re, or 4-to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from 0, S(═O)p, and N, and substituted with 0-4 Rc;
Re is halo, CN, ═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—4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-5 Rg, —(CH2)nORf, —C(═O)ORf, S(═O)pRf, C(═O)NRfRf, NRfC(═O)Rf, S(═O)pNRfRf, NRfS(═O)pRf, NRfC(═O)ORf, or —(CH2)NRfRf;
Rf is H, C1-6 alkyl, C3-6 cycloalkyl, or aryl; or Rf and Rf together with the nitrogen atom to which they are both attached form a 4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N;
Rg is halo, CN, OH, C1-4 alkyl, C3-6 cycloalkyl, or aryl,
n is zero, 1, 2, or 3; and
p is zero, 1, or 2.

### Claim 3 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or C1-3 alkyl substituted with 0-3 halo substituents;
R6 is C1-5 alkyl substituted with 0-3 R6a, C3-6 cycloalkyl substituted with 0-3 R14, or 5- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from 0, S(═O)p, N, and NR13, and substituted with 0-3 R14;
R6a is halo, —OC1-4 alkyl, or C3-6 cycloalkyl
R7 is H;
R is —OC1-3 alkyl substituted with 0-2 halo or OH substituents;
R9 is C1-7 alkyl substituted with 0-3 R10 and 0-2 R14;
R10 is halo, CN or C1-4 alkyl substituted with 0-4 halo substituents;
R11 is —ORb, —NRaRa, —NRaC(═O)Rb, —NRaC(═O)ORb, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —OC(═O)NRaRa, aryl substituted with 0-3 Rr, C3-6 cycloalkyl substituted with 0-3 Re, or 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N and NR12, and substituted with 0-3 Re;
R12 is H, C1-2 alkyl, or phenyl;
R14 is halo, CN, C1-4 alkyl substituted with 0-3 halo substituents, —OC1-4 alkyl substituted with 0-3 halo substituents, —(CH2)0-2—NRaRa, —(CH2)0-2-aryl substituted with 0-3 Re, —O-aryl substituted with 0-3 Re, or —(CH2)0-2-4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-3 Re;
Ra is H, C1-8 alkyl substituted with 0-4 R1, C2-5 alkenyl substituted with 0-4 Re, C2-5 alkynyl substituted with 0-4 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-4 Rb, or —(CH2)n—4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-4 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a 4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from 0, S(═O)p, and N, and substituted with 0-4 Re;
Rb is H, C1-4 alkyl substituted with 0-4 Re, C2-4 alkenyl substituted with 0-4 Re, C2-5 alkynyl substituted with 0-4 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-3 Rc, or —(CH2)n—4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-3 Re;
Rc is halo, CN, ═O, C1-5 alkyl substituted with 0-5 Rg, C2-5 alkenyl substituted with 0-4 Rg, C2-5 alkynyl substituted with 0-4 Rg, —(CH2)n—C3-6 cycloalkyl substituted with 0-4 Rg, —(CH2)n—4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-4 Rf, —(CH2)n-aryl substituted with 0-4 Rg, —(CH2)nORf, —C(═O)ORf, S(═O)pRf, C(═O)NRfRf, NRfC(═O)Rf, or —(CH2)NRfRf;
Rf is H, C1-5 alkyl substituted with 0-3 Rg, C3-6 cycloalkyl, or aryl; or Rf and Rf together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N;
Rg is halo, CN, OH, OC1-4 alkyl, C1-4 alkyl, C3-6 cycloalkyl, or aryl;
n is zero, 1, 2, or 3; and
p is zero, 1, or 2.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or CF3;
R6 is C1-3 alkyl substituted with 0-3 halo or OC1-3 alkyl substituents, C3-6 cycloalkyl substituted with 0-2 halo, or heterocyclyl selected from
R8 is —OC1-3 alkyl substituted with 0-1 —OH substituents;
R9 is C1-7 alkyl substituted with 0-3 halo, —OH, or CN substituents; and
R14 is halo, CN, or C1-3 alkyl substituted with 0-3 halo substituents.

### Claim 5 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or CF3;
R6 is C1-3 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl;
R9 is C1-3 alkyl substituted with 0-1 R10 and 0-1 R11;
R10 is halo or C1-4 alkyl substituted with 0-4 halo substituents;
R11 is —ORb;
Rb is C1-4 alkyl substituted with 0-4 Rc, —(CH2)0-1—C3-6 cycloalkyl substituted with 0-4 Re, —(CH2)0-1-phenyl substituted with 0-4 Re, or —(CH2)0-1-heterocyclyl wherein the heterocyclyl is
Rc is halo, CN, C1-5 alkyl substituted with 0-5 Rg, —(CH2)nORf, —C(═O)ORf, or C(═O)NRfRf;
Rf is H, C1-4 alkyl substituted with 0-3 Rg;
Rg is halo, CN, OH, C1-6 alkyl, C3-6 cycloalkyl, or aryl; and
n is zero or 1.

### Claim 6 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or CF3;
R6 is C1-3 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl;
R9 is C1-3 alkyl substituted with 0-1 R10 and 0-1 R11;
R10 is halo or C1-4 alkyl substituted with 0-4 halo substituents;
R11 is —NRaRa;
Ra is H or C1-4 alkyl substituted with 0-4 Re, C3-6 cycloalkyl substituted with 0-4 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclyl selected from
Rc is halo, CN, ═O, C1-4 alkyl substituted with 0-5 Rg, —(CH2)n—C3-6 cycloalkyl, —(CH2)n-4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, —(CH2)n-aryl, —(CH2)nORf, —C(═O)ORf, S(═O)pRf, C(═O)NRfRf, or —(CH2)nNRfRf;
Rf is H or C1-4 alkyl; and
Rg is halo, CN, OH, OC1-4 alkyl, C1-4 alkyl, C3-6 cycloalkyl, or aryl.

### Claim 7 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or CF3;
R6 is C1-3 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl;
R9 is C1-3 alkyl substituted with 0-1 R10 and 0-1 R11;
R10 is halo or C1-4 alkyl substituted with 0-4 halo;
R11 is —OC(═O)NRaRa;
Ra is H, C1-4 alkyl substituted with 0-4 R*, C3-6cycloalkyl substituted with 0-4 Re, or phenyl substituted with 0-4 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclyl selected from
Re is halo, CN, ═O, C1-4 alkyl substituted with 0-3 Rg, —(CH2)nORf, —C(═O)ORf, S(═O)pRf, C(═O)NRfRf, NRfC(═O)Rf, or —(CH2)mNRfRf,
Rf is H or C1-4 alkyl;
Rg is halo, CN, OH, C1-4 alkyl, C3-6 cycloalkyl, or aryl;
n is zero or 1; and
p is 2.

### Claim 8 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or CF3;
R6 is C1-3 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl;
R9 is C1-3 alkyl substituted with 0-1 R10 and 0-1 R11;
R10 is halo or C1-4 alkyl substituted with 0-4 halo substituents;
R11 is —NHC(═O)Rb or —NRaC(═O)ORb;
Ra is H or C1-3 alkyl;
Rb is C1-4 alkyl substituted with 0-3 Re, C3-6cycloalkyl substituted with 0-3 Re, phenyl substituted with 0-3 Re, heterocyclyl selected from
Rc is halo, CN, C1-4 alkyl substituted with 0-4 Rg, —OR, —C(═O)ORf, C(═O)NRfRf,
Rf is H or C1-4 alkyl; and
Rg is halo, CN, OH, C1-4 alkyl, C3-4 cycloalkyl, or aryl.

### Claim 9 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or C1-4 alkyl substituted with 0-3 halo substituents;
R6 is C1-3 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl;
R8 is —OC1-3 alkyl;
R9 is C2-4 alkenyl substituted with 0-2 R10 or 0-2 R11;
R10 is C1-2 alkyl substituted with 0-4 halo or OH substituents;
R11 is —C(═O)Rb, —C(═O)ORb, or —C(═O)NRaRa;
Ra is H, C1-4 alkyl substituted with 0-4 Re, C3-6cycloalkyl substituted with 0-4 Re, or phenyl substituted with 0-4 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a 4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)P, and N, and substituted with 0-4 Rc;
Rb is H or C1-4 alkyl;
Re is halo, C1-6 alkyl substituted with 0-5 Rg, —(CH2)0-1ORf, or —C(═O)ORf;
Rf H or C1-4 alkyl; and
Rg is C1-4 alkyl.

### Claim 10 (depends on 9)

The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or CF3;
R6 is CF3 or cyclopropyl;
R8 is —OC1-3 alkyl;
R9 is C2-3 alkenyl substituted with 0-1 R11;
R11 is —C(═O)NRaRa;
Ra is H or C1-4 alkyl substituted with 0-4 Re, C3-6 cycloalkyl substituted with 0-4 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a heterocyclyl selected from
Re is halo, CN, C1-4 alkyl substituted with 0-4 Rg, —(CH2)0-1ORf, —C(═O)ORf; and
Rf is H or C1-4 alkyl; and
Rg is C1-3 alkyl.

### Claim 11 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or C1-4 alkyl substituted with 0-3 halo substituents;
R6 is C1-3 alkyl substituted with 0-3 halo or C3-6 cycloalkyl;
R8 is —OC1-3 alkyl substituted with 0-2 halo or OH substituents;
R9 is C2-6 alkynyl substituted with 0-2 R11;
R11 is —ORb or —OC(═O)NRaRa;
Ra is H, C1-4 alkyl substituted with 0-4 Re, C3-6cycloalkyl substituted with 0-4 Re, or phenyl substituted with 0-4 Re;
Rb is H or C1-4 alkyl; and
Rc is halo or C1-4 alkyl.

### Claim 12 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or C1-4 alkyl substituted with 0-3 halo substituents;
R6 is C1-2 alkyl substituted with 0-3 F substituents or C3-6 cycloalkyl;
R8 is —OC1-3 alkyl;
R9 is C3-9 cycloalkyl, —O—C3-9 cycloalkyl, or fused C3-6 cycloalkyl, each substituted with 0-2 R10 and 0-2 R11,
R10 is halo, CN, or C1-4 alkyl substituted with 0-4 halo or —OH substituents;
R11 is —OR, —NRaRa, —NRaC(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, or —OC(═O)NRaRa;
Ra is H, C1-4 alkyl substituted with 0-4 Rc, C3-6cycloalkyl substituted with 0-4 Rc, or phenyl substituted with 0-4 Re; or Ra and Ra together with the nitrogen atom to which they are both attached form a 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-4 Re; and
Rb is H, C1-4 alkyl, or 4- to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N;
Rc is halo, —(CH2—)nORf or —C(═O)ORf; and
Rf is H or C1-3 alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein:
R4 is F or CF3;
R6 is CF3, cyclopropyl, cyclobutyl, or cyclopentyl;
R8 is —OC1-3 alkyl;
R9 is cyclobutyl, cyclopentyl, or cyclohexyl, bicycle[2,2,2]octanyl, each substituted with 0-2 R10 and 0-2 R11;
R10 is F, CN, CH2OH, C(CH3)2OH, or CHC(CH3)2OH;
R11 is —OH, —NHC(═O)Rb, —C(═O)ORb, or —OC(═O)NRaRa;
Ra is H, C1-4 alkyl substituted with 0-3 Rc, C3-6 cycloalkyl substituted with 0-3 Re, or phenyl substituted with 0-3 Rc;
Rb is H, C1-4 alkyl,
Rc is halo, —(CH2)0-1ORf or —C(═O)ORf; and
Rf is H or C1-3 alkyl.

### Claim 14 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:
R4 is halo or C1-4 alkyl substituted with 0-3 halo;
R6 is C1-t alkyl substituted with 0-3 F substituents or C3-6 cycloalkyl;
R8 is —OC1-3 alkyl;
R9 is C6-9 spirocycloalkyl substituted with 0-2 R11;
R11 is —ORb, —NRaRa, or C(═O)ORb;
Ra is H or C1-4 alkyl; and
Rb is H or C1-4 alkyl.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
L is —NH;
R4 is halo or C1-4 alkyl substituted with 0-4 halosubstituents;
R6 is C1-4 alkyl substituted with 0-3 halo or C3-6 cycloalkyl;
R7 is H;
R8 is halo or —OC1-4 alkyl substituted with 0-5 halo substituents;
R9 is —S(═O)pRc or —S(═O)pNR15R15;
R15 is H, C1-5 alkyl substituted with 0-5 Re, C3-10carbocyclyl substituted with 0-5 Re, or 4- to 9-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 4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N and NR16, and substituted with 0-4 Re;
R16 is H, C1-4 alkyl substituted with 0-5 Re, —C(═O)R, —C(═O)ORf, —C(═O)NRfRf, —S(═O)pRf, or —S(═O)PNRfRf,
Rc is C1-3 alkyl substituted with 0-3 Re;
Re is halo, —(CH2)nORf, C(═O)ORf, or C1-6 alkyl;
Rf is H or C1-3 alkyl; and
n is zero, 1 or 2.

### Claim 16 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein:
R4 is F or CF3;
R6 is CF3 or C3-6 cycloalkyl;
Ra is F or —OC1-2 alky;
R9 is —S(═O)2NR15R15;
R15 is H, C1-5 alkyl substituted with 0-5 Re, phenyl substituted with 0-5 R, or heterocyclyl selected from
or R15 and R15 together with the nitrogen atom to which they are both attached form a heterocyclyl selected from
R16 is H, C1-3 alkyl substituted with 0-5 Re, —C(═O)Rf, —C(═O)ORf, —C(═O)NRfRf, —S(═O)pRf, or —S(═O)pNRfRf;
Re is halo, ═O, —(CH2)0-1ORf, or C1-5 alkyl; and
Rf is H or C1-3 alkyl.

### Claim 17 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
L is —NH;
R3 is phenyl substituted with 2 R4;
R4 is F or CF3;
R5 is H;
R6 is CF3 or C3-6 cycloalkyl;
R7 is H;
R8 is —OC1-2 alkyl;
R9 is —NR17R17;
R17 is H or —(CH2)n-phenyl substituted with 0-4 Re;
Rc is halo, —OH, or C1-6 alkyl; and
n is zero or 1.

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
L is —NH;
R3 is phenyl substituted with 2 R4;
R4 is halo or C1-4 alkyl substituted with 0-4 halo substituents;
R5 is H;
R6 is C1-4 alkyl substituted with 0-3 halo substituents or C3-6 cycloalkyl;
R7 is H;
R8 is halo or —OC1-4 alkyl substituted with 0-5 halo substituents;
R9 is —C(═O)OR15 or —C(═O)NR15R15;
R15 is H, C1-5 alkyl substituted with 0-5 Re, —(CH2)n—C3-6 cycloalkyl substituted with 0-5 Rc, phenyl substituted with 0-5 Re, or 4- to 9-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 4- to 9-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)R, —C(═O)OR, —C(═O)NRfRf, —S(═O)pRf, or —S(═O)pNRfRf;
Rc is C1-5 alkyl substituted with 0-5 Re;
Re is halo, ═O, C1-6 alkyl substituted with 0-2 OH substituents, —(CH2)nORf, —C(═O)Rf, —C(═O)ORf, —C(═O)NRfRf, —NRfC(═O)Rf, —S(═O)p Rf, or —S(═O)pNRfRf;
Rf is H or C1-3 alkyl; and
n is zero, 1 or 2.

### Claim 19 (depends on 18)

The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein:
R4 is F or CF3;
R6 is CF3 or C3-4 cycloalkyl;
R8 is halo or —OC1-2 alkyl;
R9 is —C(═O)NR15R15;
R15 is H, C1-5 alkyl substituted with 0-5 Re, —CH2—C3-6 cycloalkyl substituted with 0-5 Re, phenyl substituted with 0-5 Re, or heterocyclyl selected from
or R15 and R15 together with the nitrogen atom to which they are both attached form a heterocyclyl selected from
R16 is H or C1-5 alkyl substituted with 0-5 Re;
Re is halo, ═O, C1-6 alkyl substituted with 0-1 OH, —(CH2)0-1ORf, —C(═O)Rf, —C(═O)ORf, —C(═O)NRfRf, —NRfC(═O)Rf, —S(═O)pRf, or —S(═O)pNRfRf; and
Rf is H or C1-3 alkyl.

### Claim 20 (depends on 1)

The compound of claim 1, having Formula (III);
or a pharmaceutically acceptable salt thereof, wherein:
R3 is —CHRd—C3-6-cycloalkyl substituted with 0-5 R4 or phenyl substituted with 0-5 R4;
R4 is halo, CN, or C1-4 alkyl substituted with 0-5 halo substituents;
R5 is H;
R6 is C1-3 alkyl substituted with 0-3 R6a, C3-6 cycloalkyl substituted with 0-5 R14, or 3-to 6-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N, and substituted with 0-5 R14;
R7 is H;
R6a is halo;
R8 is —OC1-3 alkyl;
R9 is —C(═O)NR15R15, —CH2—O-phenyl substituted with 0-2 R10 and 0-2 R11, C3-9 cycloalkyl substituted with 0-2 R10 and 0-2 R11, or —C3-6 cycloalkyl substituted with 0-2 R10 and 0-2 R11;
R10 is halo, CN, or C1-4 alkyl substituted with 0-4 halo or —OH substituents;
R11 is —ORb, —OC(═O)NRaRa, or —C(═O)ORb;
R14 is halo, CN, or C1-4 alkyl substituted with 0-3 halo substituents;
R15 is H, C1-5 alkyl substituted with 0-3 Re, —(CH2)n—C3-10 carbocyclyl substituted with 0-3 Re; or R15 and R15 together with the nitrogen atom to which they are both attached form a 4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, N and NR16, and substituted with 0-3 Re;
R16 is H or C1-4 alkyl substituted with 0-5 Re;
Ra is H, C1-4 alkyl substituted with 0-5 Re, C3-6 carbocyclyl or —(CH2)n-4- to 9-membered heterocyclyl comprising 1-4 heteroatoms selected from O, S(═O)p, and N, and substituted with 0-5 Re;
Rb is H or C1-4 alkyl;
Rd is H or C1-3 alkyl;
Re is halo, C1-4 alkyl substituted with 0-3 Rf, ORf, or —S(═O)2C1-4 alkyl;
Rf is H or C1-4 alkyl;
Rg is halo or —OH;
n is zero or 1, 2, or 3; and
p is zero, 1, or 2.

### Claim 21 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 22 (depends on 21)

A method for treating a disease associated with relaxin, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 21 to a patient in need thereof.

### Claim 23 (depends on 22)

The method of claim 22 wherein the disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage.

### Claim 24 (depends on 23)

The method of claim 23 wherein the disease is heart failure.