US 12,258,324 B2
Fatty acid analogues and methods of use
Yu-Hsin Tom Lin, San Diego, CA (US); Cheng-Chi Irene Wang, San Diego, CA (US); and Jason Olejniczak, San Diego, CA (US)
Appl. No. 17/055,550
Filed by LIN BIOSCIENCE PTY LTD., San Diego, CA (US)
PCT Filed May 15, 2019, PCT No. PCT/US2019/032506
§ 371(c)(1), (2) Date Nov. 13, 2020,
PCT Pub. No. WO2019/222414, PCT Pub. Date Nov. 21, 2019.
Claims priority of provisional application 62/672,414, filed on May 16, 2018.
Prior Publication US 2021/0221781 A1, Jul. 22, 2021
Int. Cl. C07D 295/215 (2006.01); A61K 9/00 (2006.01); A61K 31/4725 (2006.01); A61K 31/573 (2006.01); A61K 38/13 (2006.01); A61P 27/04 (2006.01); C07C 275/26 (2006.01); C07C 275/30 (2006.01); C07C 311/32 (2006.01); C07D 211/38 (2006.01); C07D 211/48 (2006.01); C07D 213/40 (2006.01); C07D 237/20 (2006.01); C07D 249/06 (2006.01); C07D 257/04 (2006.01); C07D 309/14 (2006.01); C07D 487/04 (2006.01)
CPC C07D 295/215 (2013.01) [A61K 9/0048 (2013.01); A61K 9/0053 (2013.01); A61K 31/4725 (2013.01); A61K 31/573 (2013.01); A61K 38/13 (2013.01); A61P 27/04 (2018.01); C07C 275/26 (2013.01); C07C 275/30 (2013.01); C07C 311/32 (2013.01); C07D 211/38 (2013.01); C07D 211/48 (2013.01); C07D 213/40 (2013.01); C07D 237/20 (2013.01); C07D 249/06 (2013.01); C07D 257/04 (2013.01); C07D 309/14 (2013.01); C07D 487/04 (2013.01)] 15 Claims
 
1. A compound of Formula (Ia-1) or (Ia-2), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

OG Complex Work Unit Chemistry
wherein:
D is —CO2H or —C(═O) NR7R9;
W is —(CH2)p-(L)n-(CH2)q;
tis 0-2;
each L is independently —(CR1R2)—, —O-alkylene-, —NR7-alkylene-, —S-alkylene-, —S(═O)-alkylene, or —S(═O)2-alkylene wherein R1 and R2 are not both alkyl when the compound is of the Formula (Ia-1);
Ring A is substituted aryl, substituted heteroaryl, or substituted C2-C8 heterocycloalkyl wherein each of the substituents of the substituted aryl, substituted heteroaryl, or substituted C2-C8 heterocycloakyl is itself unsubstituted; wherein if Ring A is heteroaryl or C2-C8 heterocycloakyl then at least one substituent of the substituted heteroaryl or the substituted C2-C8 heterocycloakyl is CF3; and wherein if Ring A is substituted aryl then at least two substituent of the substituted aryl is each CF3;
each R1 or R2 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O) NRcRd, —OC(═O) NRcRd, —NRaC(═O) NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
Ra is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
Rb is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
R3 is hydrogen, —S(═O)Rb, —S(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —CO2Ra, —C(═O) NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
R4 is hydrogen, —S(═O)Rb, —S(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —CO2Ra, —C(═O) NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
R7 and R9 are independently hydrogen;
each R8 is independently hydrogen, —S(═O)Rb, —S(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —CO2Ra, —C(═O) NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl;
wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd, wherein Ra, Rb, Rc and Rd each is not C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl;
m is 1-5;
n is 0-3;
p is 0-9;
q is 0-5; and
the atom chain connecting D and —NR3C (—O) NR4— or —NR3C(═O)— is 11, 12, 13, or 14 atoms.