US 12,325,709 B2
Cannabinoid derivatives
Siawash Ahmar, Toronto (CA); Jung Yun Kim, Mississauga (CA); Ping Shan Lai, North York (CA); Jeffrey Alan Omeara, Halton Hills (CA); Quang Huy To, Hamilton (CA); and Peter Martin Dove, Smiths Falls (CA)
Assigned to CANOPY GROWTH CORPORATION, Smiths Falls (CA)
Appl. No. 17/765,856
Filed by CANOPY GROWTH CORPORATION, Smiths Falls (CA)
PCT Filed Oct. 2, 2020, PCT No. PCT/CA2020/051330
§ 371(c)(1), (2) Date Apr. 1, 2022,
PCT Pub. No. WO2021/062559, PCT Pub. Date Apr. 8, 2021.
Claims priority of provisional application 62/909,363, filed on Oct. 2, 2019.
Claims priority of provisional application 62/966,418, filed on Jan. 27, 2020.
Prior Publication US 2022/0348586 A1, Nov. 3, 2022
Int. Cl. C07D 487/04 (2006.01); C07C 233/18 (2006.01); C07C 233/60 (2006.01); C07C 235/58 (2006.01); C07C 235/60 (2006.01); C07C 235/62 (2006.01); C07C 235/64 (2006.01); C07C 235/88 (2006.01); C07C 255/29 (2006.01); C07C 271/16 (2006.01); C07C 271/24 (2006.01); C07C 271/34 (2006.01); C07C 271/48 (2006.01); C07D 203/18 (2006.01); C07D 205/04 (2006.01); C07D 207/16 (2006.01); C07D 207/24 (2006.01); C07D 209/08 (2006.01); C07D 209/44 (2006.01); C07D 213/40 (2006.01); C07D 233/64 (2006.01); C07D 239/26 (2006.01); C07D 257/04 (2006.01); C07D 261/08 (2006.01); C07D 261/14 (2006.01); C07D 263/32 (2006.01); C07D 271/10 (2006.01); C07D 295/192 (2006.01); C07D 295/26 (2006.01)
CPC C07D 487/04 (2013.01) [C07C 233/18 (2013.01); C07C 233/60 (2013.01); C07C 235/58 (2013.01); C07C 235/60 (2013.01); C07C 235/62 (2013.01); C07C 235/64 (2013.01); C07C 235/88 (2013.01); C07C 255/29 (2013.01); C07C 271/16 (2013.01); C07C 271/24 (2013.01); C07C 271/34 (2013.01); C07C 271/48 (2013.01); C07D 203/18 (2013.01); C07D 205/04 (2013.01); C07D 207/16 (2013.01); C07D 207/24 (2013.01); C07D 209/08 (2013.01); C07D 209/44 (2013.01); C07D 213/40 (2013.01); C07D 233/64 (2013.01); C07D 239/26 (2013.01); C07D 257/04 (2013.01); C07D 261/08 (2013.01); C07D 261/14 (2013.01); C07D 263/32 (2013.01); C07D 271/10 (2013.01); C07D 295/192 (2013.01); C07D 295/26 (2013.01)] 20 Claims
 
1. A compound having structural formula:

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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

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 moiety is

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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, C2-C12 alkenyl, C2-C12 alkynyl, —(OCH2CH2)0-6O(C1-C8 alkyl), —(C0-C4 alkyl)-NR3aR3b, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl or —(C0-C4 alkyl)-heterocycloalkyl, wherein R3a and R3b are each independently hydrogen or C1-C6 alkyl;
R4 is hydrogen,

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 wherein
Q1 is O or S;
R4a is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR4c, —(C1, C2 or C4 alkyl)OR4c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R4c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)3-6(NR4cR4d), (—C1, C2 or C4 alkyl)NR4cR4d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0, C1 or C4 alkyl)-heterocycloalkyl,
R4b is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR4c, —(C1, C2 or C4 alkyl)OR4c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R4c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)3-6(NR4cR4d), —(C1, C2 or C4 alkyl)NR4cR4d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0, C1 or C4 alkyl)-heterocycloalkyl,
wherein R4c and R4d are hydrogen or C1-C6 alkyl,
or R4a and R4b together with a nitrogen to which they are attached form a heterocycloalkyl or heteroaryl ring,
R4c is hydrogen, C1-C8 alkyl, cycloalkyl or aryl,
R4f is —OR4g, C1-C8 alkyl, cycloalkyl or NR4hR4i,
wherein R49 is C1-C8 alkyl, cycloalkyl, or aryl, and
wherein R4h and R4i are C1-C8 alkyl, or R4h and R4i together with a nitrogen to which they are attached form a heterocyloalkyl ring or heteroaryl ring, and
R4j and R4k are each independently hydrogen or C1-C8 alkyl;
R5 is hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)-O—(C1-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);
R6 is —OR6a, wherein R6a is hydrogen, —(C1-C4 alkyl)-O—(C1-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
R7 is hydrogen,

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 provided R7 is not hydrogen when R4 is hydrogen, wherein
Q2 is O or S;
R7a is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR7c, —(C1-C4 alkyl)OR7c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R7c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)3-6(NR7cR7d), —(C1, C2 or C4 alkyl)NR7cR7d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0, C1 or C4 alkyl)-heterocycloalkyl,
R7b is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —OR7c, —(C1-C4 alkyl)OR7c, —(C0-C4 alkyl)-C(O)(C1-C4 alkyl), —(C0-C4 alkyl)-C(O)O(R7c), —(C0-C4 alkyl)CN, —(CH2CH2O)0-6(C1-C8 alkyl), —(CH2CH2O)3-6(NR7cR7d), —(C1, C2 or C4 alkyl)NR7cR7d, —(C0-C4 alkyl)-aryl, —(C0-C4 alkyl)-heteroaryl, —(C0-C4 alkyl)-cycloalkyl, or —(C0, C1 or C4 alkyl)-heterocycloalkyl,
wherein R70 and R7d are hydrogen or C1-C6 alkyl,
or R7a and R7h together with a nitrogen to which they are attached form a heterocycloalkyl or heteroaryl ring,
R7e is H, C1-C8 alkyl, cycloalkyl, or aryl,
R7f is —OR7g, C1-C8 alkyl, cycloalkyl, or NR7hR7i,
wherein R7g is C1-C8 alkyl, cycloalkyl, or aryl, and
wherein R7h and R7i are C1-C8 alkyl, or R7h and R7i together with a nitrogen to which they are attached form a heterocyloalkyl ring or heteroaryl ring, and
R7j and R7k are each independently hydrogen or C1-C8 alkyl;
wherein
each alkyl, alkenyl and alkynyl is unsubstituted, halogenated, substituted with one hydroxyl group, one or two C1-C6 alkoxy groups, one or two —C(O)O(C1-C4 alkyl) groups, or 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 R8;
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 R8;
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 R9;
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 R9,
in which
each R8 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 R9 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),
wherein the compound is not

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