Compound for preventing or treating lipid metabolism-related diseases

A compound or a pharmaceutically acceptable salt, stereoisomer,

• solvate, polymorph, tautomer, isotopic compound, metabolite, or prodrug thereof, wherein the compound has a structure comprising formula (I)
• LCM-L-TM (I)
• wherein:
• LCM is a LC3 binding moiety, which is a moiety with affinity to LC3 protein;
• L is a linker moiety;
• TM is a lipid droplet binding moiety, which interacts non-covalently with the lipid droplet;
• wherein the formula (I) has a structure of formula (xv):
• wherein:
• L has a structure of formula (a), or a pharmaceutically acceptable salt thereof:
• -Dy- (a)
• wherein y is an integer greater than 1;
• and
• y is an integer less than or equal to 30, preferably less than or equal to 20, more preferably less than or equal to 16, further preferably less than or equal to 12;
• each D is independently selected from the group consisting of:
• bond, —CRL1RL2—, —O—, —S—, —S(═O)—, S(═O)2—, —NRL3—, —S(═O)2NRL3—, —S(═O)NRL3—, —C(═O)NRL3—, —NRL3C(═O)NRL4—, —NRL3S(═O)2NRL4—, —C(═O)—, —CRL1═CRL2—, —C≡C—, —SiRL1RL2—, —P(═O)RL1—, —P(═O)ORL1—, C3-6cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, 3- to 7-membered heterocyclyl optionally substituted with 0-6 RL1 and/or RL2 groups, aryl optionally substituted with 0-6 RL1 and/or RL2 groups, and heteroaryl optionally substituted with 0-6 RL1 and/or RL2 groups;
• wherein
• RL1, RL2, RL3, RL4 and RL5 are each independently selected from the group consisting of:
• H, halo, C1-6alkyl, —O(C1-6alkyl), —S(C1-6alkyl), —NH(C1-6alkyl), —N(C1-6alkyl)2, C3-6cycloalkyl, C6-10aryl, 5- to 7-membered heteroaryl, 3- to 7-membered heterocyclyl, —O(C3-6cycloalkyl), —S(C3-6cycloalkyl), —NH(C3-6cycloalkyl), —N(C3-6cycloalkyl)2, —N(C3-6cycloalkyl)(C1-6alkyl), —OH, —NH2, —SH, —S(═O)2(C1-6alkyl), —P(═O)(OC1-6alkyl)(C1-6alkyl), —P(═O)(OC1-6alkyl)2, —C≡C—C1-6alkyl, —C≡CH, —CH═CH(C1-6alkyl), —C(C1-6alkyl)=CH(C1-6alkyl), —C(C1-6alkyl)=C(C1-6alkyl)2, —Si(OH)3, —Si(C1-6alkyl)3, —Si(OH)(C1-6alkyl)2, —C(═O) (C1-6alkyl), —COOH, halogen, —CN, —CF3, —CHF2, —CH2F, —NO2, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —S(═O)NH(C1-6alkyl), —S(═O)N(C1-6alkyl)2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —N(C1-6alkyl)C(═O)NH(C1-6alkyl), —N(C1-6alkyl)C(═O)N(C1-6alkyl)2, —NHC(═O)NH(C1-6alkyl), —NHC(═O)N(C1-6alkyl)2, —NHC(═O)NH2, —N(C1-6alkyl)S(═O)2NH(C1-6alkyl), —N(C1-6alkyl)S(═O)2N(C1-6alkyl)2, —NHS(═O)2NH(C1-6alkyl), —NHS(═O)2N(C1-6alkyl)2 and NHS(═O)2NH2;
• RL1 or RL2 is each independently linked to another D group to form cycloalkyl and/or heterocyclyl moiety which is optionally substituted with 0-4 RL5 groups;
• ring E and ring F are each independently selected from the group consisting of benzene ring and naphthalene ring;
• wherein the ring E is optionally substituted with one or more RE, the ring F is optionally substituted with one or more;
• ring G is absent, or is selected from the group consisting of benzene ring and naphthalene ring, and the ring G is optionally substituted with one or more RG;
• Z1 is azo group;
• Z2 is absent, or is azo group;
• RE, RF and RG, on each occurrence, are each independently selected from the group consisting of H, halogen, —NO2, —CN, ═O, ═S, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, —OH, —O(C1-6alkyl), —O(C3-6cyclohydrocarbyl), —O(C1-4alkylene-C3-6cyclohydrocarbyl), —O(3- to 7-membered heterocyclyl), —O(C1-4alkylene)-(3- to 7-membered heterocyclyl), —O(C═O)(C1-6alkyl), —O(C═O)(C3-6cyclohydrocarbyl), —O(C═O)(C1-4alkylene-C3-6cyclohydrocarbyl), —O(C═O)(3- to 7-membered heterocyclyl), —O(C═O)(C1-4alkylene)-(3- to 7-membered heterocyclyl), —SH, —S(C1-6alkyl), —S(C3-6cyclohydrocarbyl), —S(C1-4alkylene-C3-6cyclohydrocarbyl), —S(3- to 7-membered heterocyclyl), —S(C1-4alkylene)-(3- to 7-membered heterocyclyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH(C3-6cyclohydrocarbyl), —N(C3-6cyclohydrocarbyl)2, —NH(C1-4alkylene-C3-6cyclohydrocarbyl), —N(C1-4alkylene-C3-6cyclohydrocarbyl)2, —NH(3- to 7-membered heterocyclyl), —N(3- to 7-membered heterocyclyl)2, —NH(C1-4alkylene- 3- to 7-membered heterocyclyl), —N(C1-4alkylene- 3- to 7-membered heterocyclyl)2, —NH(C═O)(C1-6alkyl), —N(C1-6alkyl)-(C═O)(C1-6alkyl), —NH(C═O)(C3-6cyclohydrocarbyl), —N(C1-6alkyl)-(C═O)(C3-6cyclohydrocarbyl), —NH(C═O)(C1-4alkylene-C3-6cyclohydrocarbyl), —N(C1-6alkyl)-(C═O)(C1-4alkylene-C3-6cyclohydrocarbyl), —NH(C═O)(3- to 7-membered heterocyclyl), —N(C1-6alkyl)-(C═O)(3- to 7-membered heterocyclyl), —COOH, —C(═O)(C1-6alkyl), —C(═O)O(C1-6alkyl), —C(═O)O(C3-6cyclohydrocarbyl), —C(═O)O(C1-4alkylene-C3-6cyclohydrocarbyl), —C(═O)O(3- to 7-membered heterocyclyl), —C(═O)O(C1-4alkylene)-(3- to 7-membered heterocyclyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —C(═O)NH(C1-4alkylene-C3-6cyclohydrocarbyl), —C(═O)N(C1-4alkylene-C3-6cyclohydrocarbyl)2, —C(═O)NH(3- to 7-membered heterocyclyl), —C(═O)N(3- to 7-membered heterocyclyl)2, —C(═O)NH(C1-4alkylene- 3- to 7-membered heterocyclyl), —C(═O)N(C1-4alkylene- 3- to 7-membered heterocyclyl)2, —S(═O)2OH, —S(═O)2NH(C1-6alkyl), —S(═O)2N(C1-6alkyl)2, —S(═O)NH(C1-6alkyl), —S(═O)N(C1-6alkyl)2, wherein the alkyl, alkylene, alkenyl, alkynyl, cyclohydrocarbyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —COOH, —C(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —S(═O)2OH, —S(═O)2NH(C1-6alkyl), and —S(═O)2N(C1-6alkyl)2;
• or
• two RE, two RF or two RG are bonded each other, together with the atom(s) attached thereto to form C3-10hydrocarbyl ring or 3- to 7-membered heterocyclic ring, wherein the hydrocarbyl ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, cyano, —OH, —O(C1-6alkyl), —SH, —S(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —COOH, —C(═O)(C1-6alkyl), —C(═O)NH2, —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —S(═O)2OH, —S(═O)2NH(C1-6alkyl), and —S(═O)2N(C1-6alkyl)2;
• wherein the LCM moiety has a structure of formula (2):
• wherein:
• Y is O or S;
• ring C is selected from the group consisting of C6-10aryl and 5- to 7-membered heteroaryl, the aryl or heteroaryl is optionally substituted with one or more RX1;
• R2 is selected from the group consisting of H and C1-8alkyl;
• L1 is bond, or is C1-C6 hydrocarbyl chain;
• R3, R4, R5, R6 are each independently selected from the group consisting of H and RX2;
• RX1 and RX2, on each occurrence, are each independently selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —OR7, —SR7, —NR7R8, —C(═O)OR7, —C(═O)NR7R8, —OC(═O)R7, —NC(═O)R7R8, —C(═O)R7, —S(═O)2OR7, —S(═O)2R7, —S(═O)2NR7R8, —OS(═O)2R7, —NS(═O)2R7R8, —S(═O)R7, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —O(C1-6alkyl), —O(C3-6cyclohydrocarbyl), —O(C1-4alkylene-C3-6cyclohydrocarbyl), —O(3- to 7-membered heterocyclyl), —O(C1-4alkylene)-(3- to 7-membered heterocyclyl), —SH, —S(C1-6alkyl), —S(C3-6cyclohydrocarbyl), —S(C1-4alkylene-C3-6cyclohydrocarbyl), —S(3- to 7-membered heterocyclyl), —S(C1-4alkylene)-(3- to 7-membered heterocyclyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH(C3-6cyclohydrocarbyl), —N(C3-6cyclohydrocarbyl)2, —NH(C1-4alkylene-C3-6cyclohydrocarbyl), —N(C1-4alkylene-C3-6cyclohydrocarbyl)2, —NH(3- to 7-membered heterocyclyl), —N(3- to 7-membered heterocyclyl)2, —NH(C1-4alkylene- 3- to 7-membered heterocyclyl), —N(C1-4alkylene- 3- to 7-membered heterocyclyl)2, ═O, —COOH and C1-6alkyl;
• R7, R8, on each occurrence, are each independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, and C6-10aryl-C1-4alkyl, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl, heterocyclyl or aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —COOH, —C(═O)O(C1-6alkyl), —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —OC(═O)(C1-6alkyl), —NHC(═O)(C1-6alkyl), —C(═O)(C1-6alkyl);
• or
• wherein the LCM moiety has a structure of formula (5):
• Y is O or S;
• R9 is selected from the group consisting of H, halogen, C1-6alkyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, —ORa1, —SRa1, —NRa1Rb1, —C(═O)ORa1, —C(═O)NRa1Rb1, —C(═O)Ra1, —S(═O)2ORa1, —S(═O)2Ra1, —S(═O)2NRa1Rb1, —S(═O)Ra1, wherein the alkyl, cyclohydrocarbyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, —ORa2, —SRa2, —NRa2Rb2, —C(═O)ORa2, —C(═O)NRa2Rb2, —C(═O)Ra2, —S(═O)2ORa2, —S(═O)2Ra2, —S(═O)2NRa2Rb2 and —S(═O)Ra2;
• R10 is selected from the group consisting of H, halogen, C1-6alkyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, and 3- to 7-membered heterocyclyl-C1-4alkyl;
• R3 is selected from the group consisting of H, halogen, C1-6alkyl, —OH, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2:
• R4 is selected from the group consisting of H, halogen, —NO2, —CN, C1-6alkyl, —OR7, —SR7, —NR7R8;
• R7, R8, on each occurrence, are each independently selected from the group consisting of H and C1-6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —COOH, —C(═O)O(C1-6alkyl), —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —OC(═O)(C1-6alkyl), —NHC(═O)(C1-6alkyl), and —C(═O)(C1-6alkyl);
• R5 is selected from the group consisting of H, halogen, —NO2, —CN, C1-6alkyl, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C(═O)O(C1-6alkyl), —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —OC(═O)(C1-6alkyl), —NHC(═O)(C1-6alkyl), and —C(═O)(C1-6alkyl), wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C(═O)O(C1-6alkyl), —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —OC(═O)(C1-6alkyl), —NHC(═O)(C1-6alkyl), and —C(═O)(C1-6alkyl);
• R6 is selected from the group consisting of H, halogen, —NO2, —CN, C1-6alkyl, —OH, —O(C1-6alkyl), —O(benzyl), —SH, —S(C1-6alkyl), —S(benzyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, and —NH(benzyl), wherein the alkyl or benzyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2;
• Ra1, Rb1, Ra2, Rb2, on each occurrence, are each independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C1-4alkyl, —ORY1, —SRY1, —NRY1RY2, —C(═O)ORY1, —C(═O)NRY1RY2, —C(═O)RY1, —S(═O)2ORY1, —S(═O)2RY1, —S(═O)2NRY1RY2, and —S(═O)RY1, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, —ORY3, —SRY3, —NRY3RY4, —C(═O)RY3, —C(═O)ORY3 and —C(═O)NRY3RY4;
• RY1, RY2, RY3, RY4, on each occurrence, are each independently selected from the group consisting of H, C1-8alkyl, C3-10cyclohydrocarbyl, C3-10cyclohydrocarbyl-C1-4alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroaryl-C1-4alkyl, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, —OH, —SH, —NH2, ═O and —COOH;
• or
• wherein the LCM moiety has a structure of formula (8):
• wherein:
• Y is O or S;
• ring C is
• wherein R14, R15, R16, R17, R18 are each independently selected from the group consisting of H, halogen, —NO2, —CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —OR7, —SR7, —NR7R8, —C(═O)OR7, —C(═O)NR7R8, —OC(═O)R7, —NC(═O)R7R8, —C(═O)R7, —S(═O)2OR7, —S(═O)2R7, —S(═O)2NR7R8, —OS(═O)2R7, —NS(═O)2R7R8, and —S(═O)R7;
• wherein R7, R8, on each occurrence, are each independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, and C6-10aryl-C1-4alkyl, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl, heterocyclyl or aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —COOH, —C(═O)O(C1-6alkyl), —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —OC(═O)(C1-6alkyl), —NHC(═O)(C1-6alkyl), and —C(═O)(C1-6alkyl);
• preferably, R14, R15, R17, R18 are each independently selected from the group consisting of H, halogen, —NO2, —CN, C1-6alkyl, —OH, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH(C═O)(C1-6alkyl), and R16 is H or —OCH3
• R2 is selected from the group consisting of H, halogen, C1-6alkyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, and 3- to 7-membered heterocyclyl-C1-4alkyl, wherein the alkyl, cyclohydrocarbyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, —ORa2, —SRa2, —NRa2Rb2, —C(═O)ORa2, —C(═O)NRa2Rb2, —C(═O)Ra2, —S(═O)2ORa2, —S(═O)2Ra2, —S(═O)2NRa2Rb2 and —S(═O)Ra2;
• wherein Ra2, Rb2, on each occurrence, are each independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C1-4alkyl, —ORY1, —SRY1, —NRY1RY2, —C(═O)ORY1, —C(═O)NRY1RY2, —C(═O)RY1, —S(═O)2ORY1, —S(═O)2RY1, —S(═O)2NRY1RY2 and —S(═O)RY1, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, —ORY3, —SRY3, —NRY3RY4, —C(═O)RY3, —C(═O)ORY3 and —C(═O)NRY3RY4;
• preferably, R2 is selected from the group consisting of H, halogen, C1-6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —NH2 and —COOH;
• R3 is selected from the group consisting of H, —OH, and C1-6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —SH, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH(C3-6cyclohydrocarbyl), —N(C3-6cyclohydrocarbyl)2, —NH(C1-4alkylene-C3-6cyclohydrocarbyl), —N(C1-4alkylene-C3-6cyclohydrocarbyl)2, —NH(3- to 7-membered heterocyclyl), —N(3- to 7-membered heterocyclyl)2, —NH(C1-4alkylene- 3- to 7-membered heterocyclyl), —N(C1-4alkylene-3- to 7-membered heterocyclyl)2 and —COOH;
• R4 is selected from the group consisting of H, —OR7, —SR7, and —NR7R8;
• R7, R8, on each occurrence, are each independently selected from the group consisting of H and C1-6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C1-6alkyl, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —COOH, —C(═O)O(C1-6alkyl), —C(═O)NH(C1-6alkyl), and —C(═O)N(C1-6alkyl)2;
• R5 is selected from the group consisting of H and C1-6alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —O(C1-6alkyl), —O(C3-6cyclohydrocarbyl), —O(C1-4alkylene-C3-6cyclohydrocarbyl), —O(3- to 7-membered heterocyclyl), —O(C1-4alkylene)-(3- to 7-membered heterocyclyl), —SH, —S(C1-6alkyl), —S(C3-6cyclohydrocarbyl), —S(C1-4alkylene-C3-6cyclohydrocarbyl), —S(3- to 7-membered heterocyclyl), —S(C1-4alkylene)-(3- to 7-membered heterocyclyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH(C3-6cyclohydrocarbyl), —N(C3-6cyclohydrocarbyl)2, —NH(C1-4alkylene-C3-6cyclohydrocarbyl), —N(C1-4alkylene-C3-6cyclohydrocarbyl)2, —NH(3- to 7-membered heterocyclyl), —N(3- to 7-membered heterocyclyl)2, —NH(C1-4alkylene- 3- to 7-membered heterocyclyl), —N(C1-4alkylene- 3- to 7-membered heterocyclyl)2 and —COOH;
• and
• R6 is selected from the group consisting of H, halogen, C1-6alkyl, —OH, and —NH2, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, and —NH2;
• or
• wherein the LCM moiety has a structure of formula (9):
• wherein:
• R2 is selected from the group consisting of H, halogen, —NO2, —CN, C1-6alkyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, —ORa1, —SRa1, —NRa1Rb1, —C(═O)ORa1, —C(═O)NRa1Rb1, —C(═O)Ra1, —S(═O)2ORa1, —S(═O)2Ra1, —S(═O)2NRa1Rb1, and —S(═O)Ra1, wherein the alkyl, cyclohydrocarbyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, —ORa2, —SRa2, —NRa2Rb2, —C(═O)ORa2, —C(═O)NRa2Rb2, and —C(═O)Ra2;
• R19, on each occurrence, is each independently selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, —OR7, —SR7, —NR7R8, —C(═O)OR7, —C(═O)NR7R8, —OC(═O)R7, —NC(═O)R7R8, —C(═O)R7, —S(═O)2OR7, —S(═O)2R7, —S(═O)2NR7R8, —OS(═O)2R7, —NS(═O)2R7R8, and —S(═O)R7, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, and —COOH;
• m is 0, 1, 2, 3, 4 or 5;
• R3, R4, R5, R6 are each independently selected from the group consisting of H and RX2;
• RX2, on each occurrence, is each independently selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —OR7, —SR7, —NR7R8, —C(═O)OR7, —C(═O)NR7R8, —OC(═O)R7, —NC(═O)R7R8, —C(═O)R7, —S(═O)2OR7, —S(═O)2R7, —S(═O)2NR7R8, —OS(═O)2R7, —NS(═O)2R7R8, and —S(═O)R7, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, —OH, —O(C1-6alkyl), —O(C3-6cyclohydrocarbyl), —O(C1-4alkylene-C3-6cyclohydrocarbyl), —O(3- to 7-membered heterocyclyl), —O(C1-4alkylene)-(3- to 7-membered heterocyclyl), —SH, —S(C1-6alkyl), —S(C3-6cyclohydrocarbyl), —S(C1-4alkylene-C3-6cyclohydrocarbyl), —S(3- to 7-membered heterocyclyl), —S(C1-4alkylene)-(3- to 7-membered heterocyclyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH(C3-6cyclohydrocarbyl), —N(C3-6cyclohydrocarbyl)2, —NH(C1-4alkylene-C3-6cyclohydrocarbyl), —N(C1-4alkylene-C3-6cyclohydrocarbyl)2, —NH(3- to 7-membered heterocyclyl), —N(3- to 7-membered heterocyclyl)2, —NH(C1-4alkylene- 3- to 7-membered heterocyclyl), —N(C1-4alkylene- 3- to 7-membered heterocyclyl)2, ═O, —COOH and C1-6alkyl;
• R7, R8, on each occurrence, are each independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, and 3- to 7-membered heterocyclyl-C1-4alkyl, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-6alkyl, —OH, —O(C1-6alkyl), —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —COOH, —C(═O)O(C1-6alkyl), —C(═O)NH(C1-6alkyl), —C(═O)N(C1-6alkyl)2, —OC(═O)(C1-6alkyl), —NHC(═O)(C1-6alkyl), and —C(═O)(C1-6alkyl);
• Ra1, Rb1, Ra2, Rb2, on each occurrence, are each independently selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cyclohydrocarbyl, C3-6cyclohydrocarbyl-C1-4alkyl, 3- to 7-membered heterocyclyl, 3- to 7-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C1-4alkyl, —ORY1, —SRY1, —NRY1RY2, —C(═O)ORY1, —C(═O)NRY1RY2, —C(═O)RY1, —S(═O)2ORY1, —S(═O)2RY1, —S(═O)2NRY1RY2, and —S(═O)RY1, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, ═O, ═S, —ORY3, —SRY3, —NRY3RY4, —C(═O)RY3, —C(═O)ORY3 and —C(═O)NRY3RY4;
• RY1, RY2, RY3, RY4, on each occurrence, are each independently selected from the group consisting of H, C1-8alkyl, C3-10cyclohydrocarbyl, C3-10cyclohydrocarbyl-C1-4alkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered heterocyclyl-C1-4alkyl, C6-10aryl, C6-10aryl-C1-4alkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heteroaryl-C1-4alkyl, wherein the alkyl, alkenyl, alkynyl, cyclohydrocarbyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, —OH, —SH, —NH2, ═O and —COOH;
• or
• wherein the LCM moiety has a structure of formula (10):
• wherein, R20 is bicyclic heteroaryl, having 9-10 ring atoms, the ring atoms comprising 1-3 heteroatoms each independently selected from the group consisting of O, S, and N, the remaining atoms being C:
• the heteroaryl is unsubstituted or substituted with at least one RX3;
• R21 is C1-8alkyl;
• R22 is RX3;
• R23 is phenyl, which is unsubstituted or substituted with at least one RX3;
• RX3, on each occurrence, is each independently selected from the group consisting of C1-8alkyl, C1-8alkenyl, halogen, —CN, —CF3, —CHF2, —CH2F, —NO2, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, —COOH, —C(═O)O(C1-8alkyl), —C(═O)NH(C1-8alkyl), —C(═O)N(C1-8alkyl)2, —S(═O)2OH, —S(═O)2(OC1-8alkyl), —S(═O)2NH2, —S(═O)2NH(C1-8alkyl), and —S(═O)2N(C1-8alkyl)2;
• wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, ═O and —COOH:
• p is 0, 1 or 2;
• or
• wherein LCM moiety has a structure of formula (11):
• wherein, R24 is 3- to 7-membered heterocyclyl;
• the heterocyclyl is unsubstituted or substituted with at least one RX3;
• L3 is selected from the group consisting of a C1-8alkylene and a C3-6cycloalkylene;
• R25 is selected from the group consisting of H and C1-8alkyl;
• R26 is selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), and —N(C1-8alkyl)2;
• L4 is selected from the group consisting of C1-8alkylene and C1-8alkoxylene;
• R27 is phenyl, which is unsubstituted or substituted with at least one RX3;
• q is 0, 1 or 2;
• RX3, on each occurrence, is each independently selected from the group consisting of C1-8alkyl, C1-8alkenyl, halogen, —CN, —CF3, —CHF2, —CH2F, —NO2, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, —COOH, —C(═O)O(C1-8alkyl), —C(═O)NH(C1-8alkyl), —C(═O)N(C1-8alkyl)2, —S(═O)2OH, —S(═O)2(OC1-8alkyl), —S(═O)2NH2, —S(═O)2NH(C1-8alkyl), and —S(═O)2N(C1-8alkyl)2;
• wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, ═O and —COOH;
• or
• wherein the LCM moiety has a structure of formula (12):
• wherein, R28 is C1-8alkenyl;
• the alkenyl is substituted with at least one C1-8alkyl, the alkyl is optionally substituted with one or more RX4:
• R29 is selected from the group consisting of H and C1-8alkyl;
• R30 is selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), and —N(C1-8alkyl)2:
• L5 is selected from the group consisting of —O—, C1-8alkylene and C1-8alkoxylene:
• R31 is 6-membered heteroaryl, having 6 ring atoms, the ring atoms comprising 1-2 heteroatoms each independently selected from the group consisting of O, S, and N, the remaining atoms being C, the heteroaryl is unsubstituted or substituted with at least one RX3;
• r is 0, 1, 2, 3 or 4:
• s is 0, 1, 2, 3 or 4:
• RX4, on each occurrence, is each independently selected from the group consisting of C1-8alkyl, C1-8alkenyl, halogen, —CN, —CF3, —CHF2, —CH2F, —NO2, —O(C1-8alkyl), —S(C1-8alkyl), —NH(C1-8alkyl), —N(C1-8alkyl)2, —OC(═O)(C1-8alkyl), —NHC(═O)(C1-8alkyl), —NC(═O)(C1-8alkyl)2, —OS(═O)2(C1-6alkyl), —NHS(═O)2(C1-8alkyl), and —N(C1-8alkyl)S(═O)2(C1-8alkyl);
• wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, ═O and —COOH;
• RX3, on each occurrence, is each independently selected from the group consisting of C1-8alkyl, C1-8alkenyl, halogen, —CN, —CF3, —CHF2, —CH2F, —NO2, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, —COOH, —C(═O)O(C1-8alkyl), —C(═O)NH(C1-8alkyl), —C(═O)N(C1-8alkyl)2, —S(═O)2OH, —S(═O)2(OC1-8alkyl), —S(═O)2NH2, —S(═O)2NH(C1-8alkyl), and —S(═O)2N(C1-8alkyl)2;
• wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, ═O and —COOH;
• or
• wherein the LCM moiety has a structure of formula (13):
• wherein, R32 is 3- to 7-membered heterocyclyl;
• the heterocyclyl is unsubstituted or substituted with at least one RX3;
• L6 is selected from the group consisting of —O—, C1-8alkylene and C1-8alkoxylene;
• R33, R34 are selected from the group consisting of halogen and C1-8alkyl;
• R35 is selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), and —N(C1-8alkyl)2;
• R36 is 5-membered heteroaryl, having 5 ring atoms, the ring atoms comprising 1-3 heteroatoms each independently selected from the group consisting of O, S, and N, the remaining atoms being C, the heteroaryl is unsubstituted or substituted with at least one RX3;
• t is 0, 1, 2 or 3;
• u is 0, 1, 2, 3 or 4;
• RX3, on each occurrence, is each independently selected from the group consisting of C1-8alkyl, C1-8alkenyl, halogen, —CN, —CF3, —CHF2, —CH2F, —NO2, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, —COOH, —C(═O)O(C1-8alkyl), —C(═O)NH(C1-8alkyl), —C(═O)N(C1-8alkyl)2, —S(═O)2OH, —S(═O)2(OC1-8alkyl), —S(═O)2NH2, —S(═O)2NH(C1-8alkyl), and —S(═O)2N(C1-8alkyl)2;
• wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, ═O and —COOH;
• or
• wherein the LCM moiety has a structure of formula (14):
• wherein, R37 is 6-membered heteroaryl, having 6 ring atoms, the ring atoms comprising 1-2 heteroatoms each independently selected from the group consisting of O, S, and N, the remaining atoms being C, the heteroaryl is unsubstituted or substituted with at least one group selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), and —N(C1-8alkyl)2;
• R38, R39, R40 are each independently RX3;
• R41 is 5-membered heteroaryl, having 5 ring atoms,
• the ring atoms comprising 1-3 heteroatoms each independently selected from the group consisting of O, S, and N, the remaining atoms being C, the heteroaryl is unsubstituted or substituted with at least one RX3;
• v is 0, 1, 2 or 3;
• w is 0, 1, 2, 3 or 4;
• x is 0, 1, 2, 3 or 4;
• RX3, on each occurrence, is each independently selected from the group consisting of C1-8alkyl, C1-8alkenyl, halogen, —CN, —CF3, —CHF2, —CH2F, —NO2, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, —COOH, —C(═O)O(C1-8alkyl), —C(═O)NH(C1-8alkyl), —C(═O)N(C1-8alkyl)2, —S(═O)2OH, —S(═O)2(OC1-8alkyl), —S(═O)2NH2, —S(═O)2NH(C1-8alkyl), and —S(═O)2N(C1-8alkyl)2;
• wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, —NO2, —CN, C1-8alkyl, —OH, —O(C1-8alkyl), —SH, —S(C1-8alkyl), —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, ═O and —COOH.