US 11,753,410 B2
Hormone receptor modulators for treating metabolic mutagenic and fibrotic conditions and disorders
Jianhua Chao, Fremont, CA (US)
Assigned to Ardelyx, Inc., Fremont, CA (US)
Appl. No. 16/647,385
Filed by Ardelyx, Inc., Fremont, CA (US)
PCT Filed Sep. 18, 2018, PCT No. PCT/US2018/051122
§ 371(c)(1), (2) Date Mar. 13, 2020,
PCT Pub. No. WO2019/055808, PCT Pub. Date Mar. 21, 2019.
Claims priority of provisional application 62/558,858, filed on Sep. 14, 2017.
Prior Publication US 2021/0380585 A1, Dec. 9, 2021
Int. Cl. C07D 403/12 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01); C07D 403/04 (2006.01); C07D 403/14 (2006.01); A61K 31/439 (2006.01); A61P 35/00 (2006.01); C07D 471/08 (2006.01)
CPC C07D 471/08 (2013.01) 19 Claims
 
1. A compound of the Formula (IIb), (IIc) or (IId):

OG Complex Work Unit Chemistry
or a salt thereof,
wherein:
one of X1 or X2 is NRx or N+(O−)Rx and the other is CHRy or C(O);
Rx is

OG Complex Work Unit Chemistry
Ry is H, alkyl, cycloalkyl or cycloalkylalkyl wherein said alkyl, cycloalkyl and cycloalkylalkyl are optionally substituted with halogen or alkoxy;
L1 is —(CH2)m(C═O)— or —(CH2)p—;
L2 is a bond or —S(O)2—;
A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R7;
B is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R5;
R1 and R2 are each independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, wherein the cycloalkyl is optionally substituted with one or more R9;
or when A is cycloalkyl or heterocycloalkyl, R1 and R2 together when attached to the same carbon atom form a spirocycloalkyl ring optionally substituted with one or more R8; or when A is cycloalkyl or heterocycloalkyl, R1 and R2 together when attached to the same atom form a spiroheterocycloalkyl ring optionally substituted with one or more R8; or R1 and R2 when on adjacent atoms together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R8; or R1 and R2 when on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R8; or R1 and R2 when on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R8; or R1 and R2 when on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R8; or when A is cycloalkyl or heterocycloalkyl, R1 and R2 when on non-adjacent atoms, together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R8; or when cycloalkyl or heterocycloalkyl, R1 and R2 when on non-adjacent atoms, together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R8; cycloalkyl ring optionally substituted with one or more R8; or when cycloalkyl or heterocycloalkyl, R1 and R2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R8;
R3 is alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, or cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, and —OH;
R4 is COOR6a, —(CH2)n—COOR6a, CONR6bOH, CONR6bR6c, CONH(CH2)nCOOR6a, CONH(CH2)nR6a, —(CH2)nCONH(CH2)nR6a, CONR6bSO2R6d, CONR6bSO2(CH2)nR6d, —(CH2)n—CONR6bSO2R6d, CONR6bSO2(CH2)nN(CO)R6d CONH(CH2)nSO2R6e, COR6f, (CH2)nPO(OR6g)2, CONR6b(CH2)nPO(OR6g)2, CONR6bSO2(CH2)nN+(R6f)3, COO(CH2)nPO(OR6g)2, SO2NR6b(CH2)nCOOR6a, SO2R6e, CN, —(CH2)n—NR6bC(O)R6c, —(CH2)n—N(OH)—C(O)R6c, oxo, alkyl, cycloalkyl, —(CH2)n-cycloalkyl, heterocycloalkyl, —(CH2)n-heterocycloalkyl, heteroaryl or —(CH2)n-heteroaryl; wherein said alkyl, cycloalkyl, —(CH2)n-cycloalkyl, heterocycloalkyl, —(CH2)n-heterocycloalkyl, heteroaryl and —(CH2)n-heteroaryl are optionally substituted with COOR6a, —(CH2)n—COOR6a, CONR6bOH, CONR6bR6c, CONH(CH2)nCOOR6a, CONH(CH2)nR6a, —(CH2)nCONH(CH2)nR6a, CONR6bSO2R6d, CONR6bSO2(CH2)nR6d, —(CH2)n—CONR6bSO2R6d, CONR6bSO2(CH2)nN(CO)R6d CONH(CH2)nSO2R6e, COR6f, (CH2)nPO(OR6g)2, COO(CH2)nPO(OR6g)2, SO2NR6b(CH2)nCOOR6a, SO2R6e, CN, —(CH2)n—NR6bC(O)R6c, or —(CH2)n—N(OH)—C(O)R6c;
each R5 is independently at each occurrence halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, spiroheterocycloalkyl, —O-cycloalkyl, —O-heterocycloalkyl, aryl, heterocycloalkyl, or heteroaryl wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;
R6a is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, NR6bR6c, SO2NR6bR6c, and —OH;
R6b and R6c are each independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and —OH;
R6d is alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, COOH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, —O—CO-alkyl, —O—COcycloalkyl, —O—CO-alkyl-COOH, NR6bR6c, NR6fCO-alkyl, NR6fCO-alkoxy, cycloalkyl, heterocycloalkyl and —OH;
R6e is —OH, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and —OH;
R6f is alkyl or haloalkyl;
R6g is H or alkyl optionally substituted with —O—CO-alkyl;
each R7 is independently at each occurrence OH, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN;
each R8 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or —OH;
each R9 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or —OH;
m is 0, 1, or 2;
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and
p is 1 or 2.