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.

1 . 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;   R 7  is selected from -H, -F, —CH 3  and -OCH 3 ;   each R 8  is independently selected from C 1-4  alkyl substituted with 0-3 —F substituents; C 1-4  alkoxy; —OH; -F; and -COO(C 1-4  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 R 9  is independently selected from C 1-4  alkyl, C 1-4  alkoxy, -halo and —OH;   q is 0, 1 or 2;   R 1  is selected from —COOH, —CONH 2 , —CONHMe, —CONMe 2 , —C(CH 2 OH) 2 NH 2 , —C(NH)NH 2 , —SO 2 NH 2 , —NHSO 2 Me,
                     
                     
                     
                     
                     
   X is selected from a bond, —CH 2 —, —O—, -S-, —CH 2 O— and —OCH 2 -;   Y is selected from C 2-6  alkylene substituted with 0-2 R 14  substituents; C 3-8  cycloalkylene substituted with 0-2 R 14  substituents; C 5-8  cycloalkenylene substituted with 0-2 R 14  substituents; 5- to 8-membered heterocycloalkylene having 1-3 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R 14  substituents; phenylene substituted with 0-2 R 14  substituents; 5- or 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and substituted with 0-2 R 14  substituents; and
                     
   R 14  is selected from C 1-3  alkyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; C 1-3  alkoxy substituted with 0-3 —F substituents; cyclopropyl substituted with 0-3 substituents selected from —OH, —OMe, —F and —CN; -F; —OH; ═O; —CN; —NH 2 ; -NHMe; and —NMe 2 ;   Z is selected from a bond; C 1-3  alkylene substituted with 0-2 substituents selected from —Me, —NH 2 , —NHMe and —NMe 2 ; C 2-4  heteroalkylene having one heteroatom selected from nitrogen and oxygen and substituted with 0-2 substituents selected from —Me, —NH 2 , -NHMe and —NMe 2 ; C 3-4  cycloalkylene; and —CH═CH—;   R 5  is selected from -H, —Me and -F;   R 6  is -(CR 10 R 11 ) n R 12 ;   n is 0, 1 or 2; R 10  and R 11  are each independently selected from —H, —Me and -F, or R 10  and R 11  together with the carbon to which they are attached form cyclopropyl; R 12  is selected from C 3-8  alkyl substituted with 0-5 substituents selected from —OH, -F, CN, and C 1-4  alkoxy; C 3-10  cycloalkyl substituted with 0-4 R 13  substituents; 5- to 10-membered heterocycloalkyl having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-4 R 13  substituents; phenyl substituted with 0-3 substituents selected from -halo, C 1-4  alkyl substituted with 0-3 —F substituents, C 3-5  cycloalkyl, —CN, —SF 5 , OMe,OCH 2 F, —OCHF 2 , —OCF 3  and —SO 2 CF 3 ; 6-membered heteroaryl having 1-2 nitrogen heteroatoms and substituted with 1-3 substituents selected from -halo, —SF 5 , —CF 3 , —OCF 3  and SO 2 CF 3 ;
                     
                     
   each R 13  is independently selected from —OH; -F; —CN; C 1-4  alkoxy substituted with 0-3 substituents selected from -F, —OH, —OMe and —OEt; and C 1-4  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, R 2  is absent; when V is N, R 3  is absent; and when W is N, R 4  is absent; and wherein 
 (i) R 2 , R 3  and R 4  are each independently selected from —H, -halo, —CN, C 1-4  alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4  alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4  cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4  cycloalkoxy substituted with 0-3 substituents selected from —F and —Me; or 
 (ii) U and V are each C; 
   R 2  and R 3 , 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   R 4  is selected from —H, -halo, —CN, C 1-4  alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4  alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4  cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4  cycloalkoxy substituted with 0-3 substituents selected from —F and —Me; or   (iii) V and W are each C;   R 3  and R 4 , 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   R 2  is selected from —H, -halo, —CN, C 1-4  alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4  alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4  cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4  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. 
   
     
     
         2 - 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein Ring B is bicyclo[2.2.1]heptanyl. 
     
     
         7 . The compound of  claim 1 , wherein each R 8  is independently selected from C 1-2  alkyl substituted with 0-3 -F substituents; C 1-2  alkoxy; —OH; and -F. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein R 7  is —H. 
     
     
         11 . The compound of  claim 1 , wherein Ring C is phenyl; a monocyclic 5- or 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a monocyclic 4- to 7-membered cycloalkenyl optionally bridged with C 1-3  alkylene; or a monocyclic 4- to 7-membered heterocycloalkenyl having 1-2 heteroatoms independently selected from nitrogen and oxygen and optionally bridged with C 1-3  alkylene. 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein each R 9  is independently selected from C 1-2  alkyl, C 1-2  alkoxy, -halo and —OH. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein A is
                                             .   
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein A is selected from
                                                                                         .   
     
     
         20 - 22 . (canceled) 
     
     
         23 . The compound of  claim 11 , wherein A is
                       .   
     
     
         24 . The compound of  claim 1 , wherein R 1  is -COOH. 
     
     
         25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein X is —O—. 
     
     
         27 . The compound of  claim 1 , wherein Y is selected from C 2-4  alkylene substituted with 0-2 R 14  substituents; C 3-8  cycloalkylene substituted with 0-2 R 14  substituents; and 5- to 8-membered heterocycloalkylene having 1-2 heteroatoms independently selected from oxygen and sulfur and substituted with 0-2 R 14  substituents. 
     
     
         28 . (canceled) 
     
     
         29 . The compound of  claim 1 , 
       wherein Y is
                     
 . 
 
     
     
         30 - 32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein R 14  is —Me. 
     
     
         34 . (canceled) 
     
     
         35 . The compound of  claim 1 , wherein Z is a bond. 
     
     
         36 - 40 . (canceled) 
     
     
         41 . The compound of  claim 1 , wherein R 12  is selected from
                     
                     
                     
                     
 each substituted with 0-1 substituents selected from -halo, —Me, —CF 
 3  and —CN. 
     
     
         42 - 46 . (canceled) 
     
     
         47 . The compound of  claim 1 , wherein R 6  is selected from
                     
                     
                     
 . 
 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . The compound of  claim 1 , wherein U, V and W are each C. 
     
     
         51 . The compound of  claim 1 , wherein R 2 , R 3  and R 4  are each independently selected from —H, -halo, —CN, C 1-4  alkyl substituted with 0-3 substituents selected from —F and —OMe, C 1-4  alkoxy substituted with 0-3 substituents selected from —F and —OMe, C 3-4  cycloalkyl substituted with 0-3 substituents selected from —F and —OMe, and C 3-4  cycloalkoxy substituted with 0-3 substituents selected from —F and —Me. 
     
     
         52 - 55 . (canceled) 
     
     
         56 . The compound of  claim 1 , wherein R 4  is selected from —F and C 1-4  alkoxy substituted with 0-3 substituents selected from F andOMe. 
     
     
         57 - 59 . (canceled) 
     
     
         60 . The compound of  claim 1 , wherein the compound is of Formula (IIa) or Formula (IIb):
                                             or a pharmaceutically acceptable salt thereof.   
     
     
         61 . (canceled) 
     
     
         62 . (canceled) 
     
     
         63 . The compound of  claim 60 , wherein R 2  is —F or —CN; and R 6  is selected from
                     
                     
                     
 . 
 
     
     
         64 - 75 . (canceled) 
     
     
         76 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         77 - 98 . (canceled)