US 12,227,489 B2
Dichlorophenol HSD17B13 inhibitors and uses thereof
Sampath Kumar Anandan, Fremont, CA (US); Joshua Odingo, Bothell, WA (US); Heather Kay Webb Hsu, Seattle, WA (US); Vincent Florio, Seattle, WA (US); Subramanyam Janardhan Tantry, Bangalore (IN); and Athisayamani Jeyaraj Duraiswamy, Bangalore (IN)
Assigned to INIPHARM, INC., Bellevue, CA (US)
Filed by INIPHARM, INC., Bellevue, WA (US)
Filed on Oct. 2, 2023, as Appl. No. 18/479,578.
Application 18/479,578 is a continuation of application No. 18/315,138, filed on May 10, 2023, granted, now 11,827,619.
Application 18/315,138 is a continuation of application No. PCT/US2021/058978, filed on Nov. 11, 2021.
Claims priority of provisional application 63/225,282, filed on Jul. 23, 2021.
Claims priority of provisional application 63/170,855, filed on Apr. 5, 2021.
Claims priority of provisional application 63/113,557, filed on Nov. 13, 2020.
Claims priority of provisional application 63/113,555, filed on Nov. 13, 2020.
Prior Publication US 2024/0150314 A1, May 9, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/06 (2006.01); C07D 239/91 (2006.01); C07D 401/10 (2006.01); C07D 401/14 (2006.01); C07D 403/06 (2006.01); C07D 403/10 (2006.01); C07D 413/06 (2006.01); C07D 417/06 (2006.01)
CPC C07D 401/06 (2013.01) [C07D 239/91 (2013.01); C07D 401/10 (2013.01); C07D 401/14 (2013.01); C07D 403/06 (2013.01); C07D 403/10 (2013.01); C07D 413/06 (2013.01); C07D 417/06 (2013.01); C07B 2200/05 (2013.01)] 28 Claims
 
1. A method of therapeutically treating a disease that is a liver disease associated with HSD17B13, a metabolic disease associated with HSD17B13, or a cardiovascular disease associated with HSD17B13, the method comprising administering a compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

OG Complex Work Unit Chemistry
wherein:
Y is N or CR1;
each R1 are independently hydrogen, deuterium, halogen, —CN, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;
L is —C(═O) NR3—;
R3 is hydrogen, C1-C6alkyl, C1-C6 haloalkyl, or C1-C6deuteroalkyl;

OG Complex Work Unit Chemistry
R5a, R5b, R5c, and R5d are independently hydrogen, deuterium, halogen, —CN, —OH, —ORa, —SH, —SRa, —NRcRd, C1-C6 alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;
RA is —(C(R12)2)paryl or —(C(R12)2)pheteroaryl; wherein the aryl and heteroaryl is optionally and independently substituted with one or more RAb;
each RAb are independently deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O) NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O) NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)C(═O)Ra, —C(═O)ORb, —C(═O) NRcRd, —C(═O)C(═O) NRcRd, C1-C6alkyl, C1-C6 haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more RAaa:
each RAaa is independently deuterium, halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O) NRcRd, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —NRbC(═O) NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NHS(═O)2Ra, —C(═O)Ra, —C(═O)C(═O)Ra, —C(═O)ORb, —C(═O) NRcRd, —C(═O)C(═O) NRcRd, C1-C6alkyl, C1-C6 haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or two R12 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally substituted with deuterium, halogen, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl;
p is 1;
each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6 heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O) CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O) CH3, —C(═O) OH, —C(═O) OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
each Rb is independently hydrogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O) CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O) CH3, —C(═O) OH, —C(═O) OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6 deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; and
each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O) CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O) CH3, —C(═O) OH, —C(═O) OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6 deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl;
or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O) CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O) CH3, —C(═O) OH, —C(═O) OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6 deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.