US 2023/0348363 A1 · COMPOUNDS AND THEIR USE

Abstract

The specification generally relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, where A, U, V, W, X, Y, Z, R1, R2, R3, R4 and R5 have the meanings defined herein. Such compounds are modulators of RXFP1 and may be useful as therapeutic agents. The specification also relates to the use of such compounds to treat or prevent diseases and conditions including heart failure, heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, heart failure with reduced ejection fraction, chronic kidney disease and acute kidney injury. The specification further relates to compositions comprising such compounds, intermediates useful in processes for preparing such compounds, and processes for preparing such compounds using such intermediates.

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
A is
Ring B is a 4- to 10-membered cycloalkyl;
a 4- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen and oxygen;
a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen;
or a 4- to 10-membered cycloalkenyl;
R7 is selected from -H, -F, —CH3 and -OCH3;
each R8 is independently selected from C1-4 alkyl substituted with 0-3 —F substituents;
C1-4 alkoxy;
—OH;
-F;
and -COO(C1-4 alkyl);
p is 0, 1 or 2;
Ring C is a 6- to 10-membered aryl;
a 5- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
a 4- to 10-membered cycloalkenyl;
or a 4- to 10-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen;
each R9 is independently selected from C1-4 alkyl, C1-4 alkoxy, -halo and —OH;
q is 0, 1 or 2;
R1 is selected from —COOH, —CONH2, —CONHMe, —CONMe2, —C(CH2OH)2NH2, —C(NH)NH2, —SO2NH2, —NHSO2Me,
X is selected from a bond, —CH2—, —O—, -S-, —CH2O— and —OCH2-;
Y is selected from C2-6 alkylene substituted with 0-2 R14 substituents;
C3-8 cycloalkylene substituted with 0-2 R14 substituents;
C5-8 cycloalkenylene substituted with 0-2 R14 substituents;
5- to 8-membered heterocycloalkylene having 1-3 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R14 substituents;
phenylene substituted with 0-2 R14 substituents;
5- or 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-2 R14 substituents;
and
R14 is selected from C1-3 alkyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN;
C1-3 alkoxy substituted with 0-3 —F substituents;
cyclopropyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN;
-F;
—OH;
═O;
—CN;
—NH2;
-NHMe;
and —NMe2;
Z is selected from a bond;
C1-3 alkylene substituted with 0-2 substituents selected from —Me, —NH2, —NHMe and —NMe2;
C2-4 heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-2 substituents selected from —Me, —NH2, -NHMe and —NMe2;
C3-4 cycloalkylene;
and —CH═CH—;
R5 is selected from -H, —Me and -F;
R6 is -(CR10R11)nR12;
n is 0, 1 or 2;
R10 and R11 are each independently selected from —H, —Me and -F, or R10 and R11 together with the carbon to which they are attached form cyclopropyl;
R12 is selected from C3-8 alkyl substituted with 0-5 substituents selected from —OH, -F, CN, and C1-4 alkoxy;
C3-10 cycloalkyl substituted with 0-4 R13 substituents;
5- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-4 R13 substituents;
phenyl substituted with 0-3 substituents selected from -halo, C1-4 alkyl substituted with 0-3 —F substituents, C3-5 cycloalkyl, —CN, —SF5, OMe,OCH2F, —OCHF2, —OCF3 and —SO2CF3;
6-membered heteroaryl having 1-2 nitrogen heteroatoms and substituted with 1-3 substituents selected from -halo, —SF5, —CF3, —OCF3 and SO2CF3;
each R13 is independently selected from —OH;
-F;
—CN;
C1-4 alkoxy substituted with 0-3 substituents selected from -F, —OH, —OMe and —OEt;
and C1-4 alkyl substituted with 0-3 substituents selected from -F, —OH, —OMe and —OEt;
U, V and W are each independently selected from C and N;
provided that when U is N, R2 is absent;
when V is N, R3 is absent;
and when W is N, R4 is absent;
and wherein
(i) R2, R3 and R4 are each independently selected from —H, -halo, —CN, C1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and —Me;
or
(ii) U and V are each C;
R2 and R3, together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 —Me substituents;
and
R4 is selected from —H, -halo, —CN, C1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and —Me;
or
(iii) V and W are each C;
R3 and R4, together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-3 —Me substituents;
and
R2 is selected from —H, -halo, —CN, C1-4 alkyl substituted with 0-3 substituents selected from —F and —OMe, C1-4 alkoxy substituted with 0-3 substituents selected from —F and —OMe, C3-4 cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C3-4 cycloalkoxy substituted with 0-3 substituents selected from —F and —Me;
wherein
cycloalkyl is a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms;
cycloalkoxy is a cycloalkyl group attached through an oxygen linking atom;
cycloalkenyl is a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic unsaturated aliphatic hydrocarbon group having the specified number of carbon atoms;
heterocycloalkyl is a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic saturated group containing carbon atoms and the specified number of heteroatoms in the ring structure, and having the specified total number of atoms in the ring structure;
heterocycloalkenyl is a monocyclic, bicyclic, polycyclic, fused, bridged, or spirocyclic unsaturated group containing carbon atoms and the specified number of heteroatoms in the ring structure, and having the specified total number of carbon atoms and heteroatoms in the ring structure;
heteroalkyl is an alkyl group in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur, and the specified number of members in the heteroalkyl group refers to the total number of carbon atoms and heteroatoms in the chain.

77 more elements

Compounds and their use

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Compounds and their use

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Abstract

Claims46