US 12,168,648 B2
Opioid receptor modulators
Julio Cesar Medina, South San Francisco, CA (US); Alok Nerurkar, San Diego, CA (US); Corinne Sadlowski, London (GB); Frederick Seidl, San Mateo, CA (US); Heng Cheng, Fremont, CA (US); Jason Duquette, Millbrae, CA (US); John Lee, Pacifica, CA (US); Martin Holan, Stamford, CT (US); Pingyu Ding, Foster City, CA (US); Xiaodong Wang, South San Francisco, CA (US); Tien Widjaja, Lafayette, CO (US); Thomas Nguyen, Newbury Park, CA (US); Ulhas Bhatt, Fremont, CA (US); Yihong Li, South San Francisco, CA (US); and Zhi-liang Wei, Foster City, CA (US)
Assigned to EPIODYNE, INC., San Francisco, CA (US)
Filed by Epiodyne, Inc., San Francisco, CA (US)
Filed on Feb. 13, 2023, as Appl. No. 18/168,155.
Application 18/168,155 is a division of application No. 17/714,030, filed on Apr. 5, 2022, granted, now 11,634,396.
Claims priority of provisional application 63/318,486, filed on Mar. 10, 2022.
Claims priority of provisional application 63/171,008, filed on Apr. 5, 2021.
Prior Publication US 2024/0092746 A1, Mar. 21, 2024
Int. Cl. C07D 277/30 (2006.01); C07C 233/65 (2006.01); C07D 213/56 (2006.01); C07D 239/26 (2006.01); C07D 263/58 (2006.01); C07D 295/155 (2006.01); C07D 307/54 (2006.01); C07D 333/24 (2006.01); C07D 401/12 (2006.01); C07D 413/12 (2006.01)
CPC C07D 277/30 (2013.01) [C07C 233/65 (2013.01); C07D 213/56 (2013.01); C07D 239/26 (2013.01); C07D 263/58 (2013.01); C07D 295/155 (2013.01); C07D 307/54 (2013.01); C07D 333/24 (2013.01); C07D 401/12 (2013.01); C07D 413/12 (2013.01)] 20 Claims
 
1. A method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1 is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, three, four, or five R7;
R2 is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with one, two, three, four, or five R8;
R3 is —X-R3a,
X is a bond;
R3a is C3-8cycloalkyl substituted with one, two, three, four, or five R9;
R4 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;
R5 and R6 are each independently selected from hydrogen, C1-C6alkyl, and C1-C6haloalkyl; or R5 and R6 are combined to form an azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl ring;
each R7 is independently selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)R13, —N(R12)C(O)OR13, —N(R12)S(O); R13, —C(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —S(O)R13, —S(O)2R13, and —S(O); N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR14, —SR14, —C(O)OR14, —OC(O)N(R14)(R15), —N(R16)C(O)N(R14)(R15), —N(R16)C(O)R17, —N(R16)C(O)OR17, —N(R16)S(O)2R17, —C(O)R17, —OC(O)R17, —C(O)N(R14)(R15), —C(O)C(O)N(R14)(R15), —S(O)R17, —S(O)2R17, and —S(O)2N(R14)(R15); or two R7 are combined to form a heterocycloalkyl ring optionally substituted with oxo; or R7 and R6 are combined to form a heterocycloalkyl ring;
each R8 and each R9 are each independently selected from halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)R13, —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —S(O)R13, —S(O), R13, and —S(O)2N(R10)(R11), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, C1-6alkyl, C1-9haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR14, —SR14, —C(O)OR14, —OC(O)N(R14)(R15), —N(R16)C(O)N(R14)(R15), —N(R16)C(O)R17, —N(R16)C(O)OR17, —N(R16)S(O); R17, —C(O)R17, —OC(O)R17, —C(O)N(R14)(R15), —C(O)C(O)N(R14)(R15), —S(O)R17, —S(O)2R17, and —S(O)2N(R14)(R15);
each R10 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R14 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
each R15 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
each R16 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and
each R17 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
wherein the disease or condition is pain, opioid overdose, depression, obsessive compulsive disorder, opioid use disorder, addiction, or a combination thereof.