US 12,012,373 B2
Cannabinoid derivatives
Siawash Ahmar, Toronto (CA); Krishna Kumar Gnanasekaran, Mississauga (CA); Jeffrey Alan Omeara, Halton Hills (CA); and Ji Sung Park, Milton (CA)
Assigned to CANOPY GROWTH CORPORATION, Smith Falls (CA)
Appl. No. 17/626,519
Filed by CANOPY GROWTH CORPORATION, Smiths Falls (CA)
PCT Filed Jul. 10, 2020, PCT No. PCT/CA2020/050969
§ 371(c)(1), (2) Date Jan. 12, 2022,
PCT Pub. No. WO2021/007663, PCT Pub. Date Jan. 21, 2021.
Claims priority of provisional application 62/873,666, filed on Jul. 12, 2019.
Claims priority of provisional application 62/934,762, filed on Nov. 13, 2019.
Claims priority of provisional application 62/966,407, filed on Jan. 27, 2020.
Prior Publication US 2023/0134776 A1, May 4, 2023
Int. Cl. C07C 311/29 (2006.01); C07C 69/16 (2006.01); C07C 309/42 (2006.01); C07C 311/51 (2006.01); C07C 317/22 (2006.01); C07D 205/06 (2006.01); C07D 205/12 (2006.01); C07D 207/404 (2006.01); C07D 211/54 (2006.01); C07D 213/71 (2006.01); C07D 233/84 (2006.01); C07D 235/16 (2006.01); C07D 239/38 (2006.01); C07D 249/08 (2006.01); C07D 249/10 (2006.01); C07D 263/32 (2006.01); C07D 277/30 (2006.01); C07D 295/26 (2006.01); C07D 305/08 (2006.01); C07D 307/64 (2006.01); C07D 487/10 (2006.01)
CPC C07C 311/29 (2013.01) [C07C 69/16 (2013.01); C07C 309/42 (2013.01); C07C 311/51 (2013.01); C07C 317/22 (2013.01); C07D 205/06 (2013.01); C07D 205/12 (2013.01); C07D 207/404 (2013.01); C07D 211/54 (2013.01); C07D 213/71 (2013.01); C07D 233/84 (2013.01); C07D 235/16 (2013.01); C07D 239/38 (2013.01); C07D 249/08 (2013.01); C07D 249/10 (2013.01); C07D 263/32 (2013.01); C07D 277/30 (2013.01); C07D 295/26 (2013.01); C07D 305/08 (2013.01); C07D 307/64 (2013.01); C07D 487/10 (2013.01)] 19 Claims
 
1. A compound having structural formula:

OG Complex Work Unit Chemistry
or an enantiomer, diastereomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, enantiomer, diastereomer, racemate, or tautomer, wherein
the

OG Complex Work Unit Chemistry
 moiety is

OG Complex Work Unit Chemistry
R1 is hydrogen, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —CO2H, —(C0-C4 alkyl)-C(O)O(C1-C6 alkyl), —(C0-C4 alkyl)-OC(O)O—(C1-C6 alkyl), —OR1a, —(C1-C4 alkyl)OR1a, —SR1a, —(C1-C4 alkyl)SR1a, —NR1bR1c, —(C1-C4 alkyl)NR1bR1c, —(C1-C4 alkyl)C(O)NR1bR1c, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, or oxo when attached to a ring of appropriate saturation, wherein
R1a, R1b, and R1c are independently hydrogen, C1-C4 alkyl, or —C(O)(C1-C4) alkyl;
R2 is hydrogen, halo, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —CO2H, —(C0-C4 alkyl)-C(O)O(C1-C6 alkyl), —(C0-C4 alkyl)-OC(O)O—(C1-C6 alkyl), —OR2a, —(C1-C4 alkyl)OR2a, —SR2a, —(C1-C4 alkyl)SR2a, —NR2bR2c, —(C1-C4 alkyl)NR2bR2c, —(C1-C4 alkyl)C(O)NR2bR2c, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, or oxo when attached to a ring of appropriate saturation, wherein
R2a, R2b, and R2c are independently hydrogen, C1-C4 alkyl, or —C(O)(C1-C4) alkyl;
R3 is C1-C12 alkyl;
R4 is

OG Complex Work Unit Chemistry
wherein
R4a is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR4c, —(C1-C4 alkyl)OR4c, —(C1-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, —NR4dR4e, or —(C1-C4 alkyl)NR4dR4e, and
R4b is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —CH2—(OCH2CH2)0-6O(C1-C8 alkyl), —(C1-C4 alkyl)OR4e, —(C1-C4 alkyl)-C(O)(C1-C4 alkyl), —(C1-C4 alkyl)-C(O)O(R4e), —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, —(C0-C4 alkyl)-heterocycloalkyl, or —(C1-C4 alkyl)NR4dR4e, wherein
R4d is hydrogen, C1-C6 alkyl, —(C1-C4 alkyl)-C(O)(C1-C4 alkyl), —(C1-C4 alkyl)-C(O)O(R4e), —(C1-C4 alkyl)-OC(O)(R4e), —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0-C4 alkyl)-heterocycloalkyl,
R4e is hydrogen or C1-C4 alkyl, and
R4c is hydrogen or C1-C4 alkyl;
R5 is hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)-O—(C0-C4 alkyl), —C(O)(C1-C4 alkyl), —C(O)O(C1-C4 alkyl), —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, —(C1-C4 alkyl)C(O)O(C1-C4 alkyl), or —(C1-C4 alkyl)OC(O)(C1-C4 alkyl); and
R6 is hydrogen or —OR6a, wherein R6a is hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)-O—(C0-C4 alkyl), —C(O)(C1-C4 alkyl), —C(O)O(C1-C4 alkyl), —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, —(C1-C4 alkyl)C(O)O(C1-C4 alkyl), or —(C1-C4 alkyl)OC(O)(C1-C4 alkyl); wherein
each alkyl, alkenyl and alkynyl is unsubstituted, halogenated, substituted with one or two hydroxyl or C1-C6 alkoxy groups, or substituted with one or two oxo groups;
each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused ring having 3-8 ring members, and is substituted with 0-6 R7;
each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms where each is independently nitrogen, oxygen or sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each having 3-8 ring members, and is substituted with 0-6 R7;
each aryl is a phenyl or a naphthyl, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R8;
each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms, where each is independently nitrogen, oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms where each is independently nitrogen, oxygen or sulfur, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R8,
in which
each R7 is independently oxo, C1-C4 alkyl, —Cl, —F, —Br, —CN, —SF5, —N3, nitro, —SRA, —S(O)1-2RA, —ORA, —(C0-C3 alkyl)—ORB, —NRBRA, —C(O)RA, —C(O)NRBRA, —NRBC(O)RA, —C(S)NRBRA, —NRBC(S)RA, —CO2RA, —OC(O)RA, —C(O)SRA, —SC(O)RA, —C(S)ORA, —OC(S)RA, —C(S)SRA, —SC(S)RA, —S(O)1-2ORA, —OS(O)1-2RA, —S(O)1-2NRBRA, —NRBS(O)1-2RA, —OCO2RA, —OC(O)NRBRA, —NRBCO2RA, —NRBC(O)NRBRA, —SCO2RA, —OC(O)SRA, —SC(O)SRA, —SC(O)NRBRA, —NRBC(O)SRA, —OC(S)ORA, —OC(S)NRBRA, —NRBC(S)ORA, —NRBC(S)NRBRA, —SC(S)ORA, —OC(S)SRA, —SC(S)SRA, —SC(S)NRBRA, —NRBC(S)SRA, —NRBC(NRB)NRBRA, —NRBS(O)1-2NRBRA, phenyl, C3-C8 cycloalkyl, a five to six-membered heteroaryl, or a five to six-membered heterocycloalkyl; and
each R8 is independently optionally-substituted C1-C4 alkyl, —Cl, —F, —Br, —CN, —SF5, —N3, nitro, —SRA, —S(O)1-2RA, —ORA, —(C0-C3 alkyl)-ORB, —NRBRA, —C(O)RA, —C(O)NRBRA, —NRBC(O)RA, —C(S)NRBRA, —NRBC(S)RA, —CO2RA, —OC(O)RA, —SO3H,—C(O)SRA, —SC(O)RA, —C(S)ORA, —OC(S)RA, —C(S)SRA, —SC(S)RA, —S(O)1-2ORA, —OS(O)1-2RA, —S(O)1-2NRBRA, —NRBS(O)1-2RA, —OCO2RA, —OC(O)NRBRA, —NRBCO2RA, —NRBC(O)NRBRA, —SCO2RA, —OC(O)SRA, —SC(O)SRA, —SC(O)NRBRA, —NRBC(O)SRA, —OC(S)ORA, —OC(S)NRBRA, —NRBC(S)ORA, —NRBC(S)NRBRA, —SC(S)ORA, —OC(S)SRA, —SC(S)SRA, —SC(S)NRBRA, —NRBC(S)SRA, —NRBC(NRB)NRBRA, —NRBS(O)1-2NRBRA; phenyl, C3-C8 cycloalkyl, a five to six-membered heteroaryl, or a five to six-membered heterocycloalkyl;
wherein each RA is independently H or C1-C3 alkyl, and each RB is independently H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, —S(O)1-2(C1-C3 alkyl), —C(O)(C1-C3 alkyl) or —CO2(C1-C3 alkyl).