Cannabidiol derivatives, preparation method thereof and use thereof

A compound represented by general formula (I), or stereoisomer, solvate, metabolite, pharmaceutically acceptable salt or cocrystal thereof:

• wherein:
• X is selected from the group consisting of hydrogen, hydroxyl, C1-6 alkyl and halogen;
• Y is selected from the group consisting of hydrogen, carboxylic acid, C1-6 alkyl and halogen;
• r is selected from the group consisting of 0, 1, 2 and 3;
• n is selected from the group consisting of 0, 1 and 2;
• R0 is selected from the group consisting of methyl, C3-8 carbocyclic group, —CH2OH, —C(═O)OC1-6 alkyl, —C(═O)NRb1Rb2 and carboxyl;
• R1 is selected from the group consisting of C1-6 alkyl optionally further substituted with 0 to 3 halogen atoms;
• R2 is
• Ra is selected from the group consisting of H and C1-6 alkyl;
• Rb and Rc are each independently selected from the group consisting of H, C1-6 alkyl, amino acid side chain, —C1-6 alkylene-C3-12 carbocyclic ring and —C1-6 alkylene-C3-12 heterocyclic ring;
• wherein, the C3-12 heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S;
• the C1-6 alkylene, the C1-6 alkyl, the C3-12 carbocyclic ring or the C3-12 heterocyclic ring is optionally substituted with 0 to 3 substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, ═O, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, —NRb1Rb2, —C(═O)OC1-6 alkyl, —C(═O)NRb1Rb2, C3-12 cycloalkyl, C3-12 heterocylcloalkyl, C6-12 aryl and C5-12 heteroaryl;
• and as substituents, the C1-6 alkyl, the C1-6 heteroalkyl, the C2-6 alkenyl or the C2-6 alkynyl is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, carboxyl, cyano, halogen, —O—Rb1, —NRb1Rb2, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C6-12 aryl and C5-12 heteroaryl;
• when the amino acid side chain contains hydroxyl, mercapto or carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified;
• Rb1 and Rb2 are each independently selected from the group consisting of H, C1-6 alkyl, —C(═O)Rb3 and —C(═O)NRb4Rb5, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C1-6 alkyl, C1-6 alkoxy, C6-12 aryl, C5-12 heteroaryl, C3-12 cycloalkyl and C3-12 heterocycloalkyl;
• Rb3 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and C6-12 aryl;
• Rb4 and Rb5 are each independently selected from the group consisting of H and C1-6 alkyl;
• or Rb4 and Rb5 together with N atom form a 3 to 12 membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of N, O and S;
• or, Rb and Rc together with the atom to which they are attached form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, wherein the 3 to 6 membered carbocyclic ring or the 3 to 6 membered heterocyclic ring is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, carboxyl and amino, wherein the 3 to 6 membered heterocyclic ring contains 1 to 4 heteroatoms selected from the group consisting of N, O and S;
• Rd is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclic ring, 3 to 10 membered heterocyclic ring, —C1-6 alkylene-C3-10 carbocyclic ring,
• —C1-6 alkylene-3 to 10 membered carbocyclic ring, —C1-6 alkylene-O—C1-6 alkylene-C3-10 carbocyclic ring, —C1-6 alkylene-O—C1-6 alkylene-3 to 10 membered heterocyclic ring and —C1-6 alkylene-O—C1-4 alkyl, wherein the C1-6 alkylene, the C2-6 alkenyl, the C2-6 alkynyl, the C1-6 alkyl, the C3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, amino, 1-cyclopropyl ethyl, C1-4 alkyl, C1-4 alkoxy, —OC(═O)ORd1 and —OC(═O)ORd2, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S;
• Rd1 and Rd2 are each independently selected from the group consisting of C1-4 alkyl, C3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, wherein the C1-4 alkyl, the C3-10 carbocyclic ring or the 3 to 10 membered heterocyclic ring is optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, hydroxyl, carboxyl, C1-4 alkyl, C1-4 alkoxy, C3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, wherein the 3 to 10 membered heterocyclic ring contains 1 to 6 heteroatoms selected from the group consisting of N, O and S;
• R3 is selected from the group consisting of C1-6 alkyl, C3-8 carbocyclic group and C2-6 alkenyl, wherein the C1-6 alkyl, the C2-6 alkenyl or the C3-8 carbocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of halogen, C3-8 carbocyclic group and hydroxyl and C1-6 alkyl;
• R4 is selected from the group consisting of H, hydroxyl, C1-6 alkoxy, —C(═O)ORd1,
• —C(═O)Rd1, —C(═O)C(NH2)—R and
• wherein the amino in —C(═O)CH(NH2)—R optionally forms a polypeptide chain with an amino acid;
• R is selected from the group consisting of amino acid side chain;
• when the amino acid side chain contains hydroxyl, mercapto and carboxyl, the hydroxyl, the mercapto or the carboxyl is optionally esterified;
• R5 is selected from the group consisting of C1-12 alkyl, C1-12 heteroalkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 carbocyclic group, C3-12 heterocyclic group, —C1-6 alkylene-C3-12 carbocyclic group, —C1-6 alkylene-C3-12 heterocyclic group, —NRb1Rb2, —C1-6 alkylene-C(═O) OC1-6 alkyl and —C1-6 alkylene-C(═O)NRb1Rb2, wherein the C1-12 alkyl, the C1-12 heteroalkyl, the C2-12 alkenyl, the C2-12 alkynyl, the C1-6 alkylene, the C3-12 carbocyclic group or the C3-12 heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, carboxyl, halogen, cyano, ═O, C1-6 alkyl, —NRb1Rb2, C3-12 carbocyclic group, C3-12 heterocyclic group, C2-6 alkenyl, C2-6 alkynyl, —C(═O) OC1-6 alkyl, —C(═O) C1-6 alkyl, —C(═O)NRb1Rb2, —S(═O) C1-6 alkyl and —S(═O)2C1-6 alkyl, wherein as substituents, the C1-6 alkyl, the C3-12 carbocyclic group or the C3-12 heterocyclic group is further substituted with one or more substituents selected from the group consisting of ═O, hydroxyl, carboxyl, halogen, cyano, —C(═O)OC1-6 alkyl and —C(═O)C1-6 alkyl;
• is a single bond or a double bond;
• and;
• the general formula (I) is optionally substituted with one or more D atoms.