Substituted heterocyclic amide compound and preparation method therefor and pharmaceutical use thereof

A compound or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the compound has a structure as represented by formula (I):

• wherein,
• R0 is a substituted or unsubstituted C6-14 aryl or a substituted or unsubstituted C5-14 heteroaryl;
• R1, R2, R3 are each independently hydrogen, hydroxy, halo, nitro, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy, substituted or unsubstituted C3-20 cycloalkyl, —(CH2)u—C3-6 monocyclic heterocyclyl, —(CH2)u-phenyl, —(CH2)u-5- or 6-membered monoheteroaryl, —(CH2)u—C3-8 monocyclic cycloalkyl, —SO2C1-6 alkyl, —(CH2)u—NRa0Rb0, —(CH2)u—C(O)NRa0Rb0, —C(O)C1-6 alkyl, —C(O)OC1-6 alkyl;
• wherein the phenyl, C3-8 monocyclic cycloalkyl, C3-6 monocyclic heterocyclyl, 5- or 6-membered monoheteroaryl is optionally substituted by 1, 2 or 3 substituent(s) selected from the group consisting of halo, cyano, C1-3 alkyl, C1-3 alkoxy and C3-6 monocyclic cycloalkyl;
• u is 0, 1, 2, 3 or 4;
• Ra0, Rb0 are each independently hydrogen or C1-3 alkyl, or Ra0 and Rb0 together with the nitrogen atom attached thereto form a C3-8 monocyclic heterocyclyl, the C3-8 monocyclic heterocyclyl is optionally substituted by 1, 2 or 3 substituent(s) selected from the group consisting of halo or C1-3 alkyl;
• A has a structure as represented by formula (a) or formula (b)
• wherein Z1, Z2 and “” are selected from the group consisting of:
• (a1) Z1 is CRb, Z2 is N, and “” is a double bond;
• wherein Rb is hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• (b1) Z1 is C(O), Z2 is NRc, and “” is a single bond;
• wherein Rc is hydrogen or substituted or unsubstituted C1-10 alkyl;
• (c1) Z1 is CRb, Z2 is CRc, and “” is a single bond or a double bond;
• wherein Rb, Rc together with the ring attached thereto form a substituted or unsubstituted 9- or 10-membered biheteroaryl fused ring;
• (d1) Z1 is NRb, Z2 is CRc, and “” is a single bond;
• wherein Rb, Rc together with the ring attached thereto form a substituted or unsubstituted 9- or 10-membered biheteroaryl fused ring;
• (e1) Z1 is CRb, Z2 is NRc, and “” is a single bond;
• wherein Rb, Rc together with the ring attached thereto form a substituted or unsubstituted 9- or 10-membered biheteroaryl fused ring;
• Ra, Rd are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R01, R02 are each independently hydrogen, —C(O)C1-6 alkyl or —C(O)C3-8 monocyclic cycloalkyl;
• L is a bond, —(CR11R12)t)—(CR21R22)t2—(CR31R32)6—(CR41R42)t4—(O)t5 or —(CR11R12)t1—(CR21R22)t2—(NR31)t3—(CR41R42)t4—(O)ts;
• wherein t1, t2, t3, t4, t5 are each independently 0 or 1;
• Rd′, R03, R11, R12, R21, R22, R31, R32, R41, R42 are selected from the combination selected from the group consisting of:
• (a2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• (b2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22 together with the carbon atom attached thereto form a substituted or unsubstituted C3-8 monocyclic cycloalkyl or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• (c2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted
• C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen, or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R31, R32 together with the carbon atom attached thereto form a substituted or unsubstituted C3-8 monocyclic cycloalkyl or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• (d2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen, or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R22, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R31 together with the carbon atom attached thereto form a substituted or unsubstituted C3-8 monocyclic cycloalkyl or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• (e2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R03 and R31 are linked together to form a substituted or unsubstituted C3-8 monocyclic heterocyclyl;
• (f2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R22, R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R03 and R21 are linked together to form a substituted or unsubstituted C3-8 monocyclic heterocyclyl;
• (g2) R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• Rd′ and R03 are linked together to form a substituted or unsubstituted 4- to 7-membered oxo-substituted heterocyclyl;
• (h2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen or substituted or unsubstituted C1-10 alkyl;
• R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R11 and R31 are linked together to form a substituted or unsubstituted C3-8 monocyclic cycloalkyl, or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• in the above groups, the “substituted” means that 1, 2, 3 or 4 hydrogen atom(s) in the group are substituted by a substituent independently selected from the group S consisting of:
• hydroxy, halo, nitro, oxo, C1-6 alkyl, hydroxy-substituted C1-6 alkyl, benzyl, —S—C1-6 alkyl, —S-halo C1-6 alkyl, —(CRa1Rb1)u-cyano, —(CRa1Rb1)u—C1-6 alkoxy, —(CRa1Rb1)u-halo C1-6 alkoxy, —(CRa1Rb1)u-halo C1-6 alkyl, —(CRa1Rb1)u—C3-6 monocyclic heterocyclyl, —(CRa1Rb1)u—C3-8 monocyclic cycloalkyl, —(CRa1Rb1)u-phenyl, —(CRa1Rb1)u-5- or 6-membered monoheteroaryl, —(CRa1Rb1)u—O—(CRa2Rb2)v-halo C1-6 alkyl, —(CRa1Rb1)u—O—(CRa2Rb2)v—C3-8 monocyclic cycloalkyl, —(CRa1Rb1)u—O—(CRa2Rb2)v—C3-6 monocyclic heterocyclyl, —(CRa1Rb1)u—O—(CRa2Rb2)v-phenyl, —(CRa1Rb1)u—O—(CRa2Rb2)v-5- or 6-membered monoheteroaryl, —(CRa1Rb1)u—S—(CRa2Rb2)v-phenyl, —(CRa1Rb1)u—SO2—(CRa2Rb2)v-phenyl, —(CRa1Rb1)u—O—C(O)NRa0Rb0, —(CRa1Rb1)u—O—(CRa2Rb2)v— C1-6 alkoxy, —(CRa1Rb1)u—O—(CRa2Rb2)vOH, —(CRa1Rb1)u—SO2C1-6alkyl, —(CRa1Rb1)u—SO2NRa0Rb0, —(CRa1Rb1)u—C(O)NRa0Rb0, —(CRa1Rb1)u—NRa0Rb0, —(CRa1Rb1)u—C(O)C1-6 alkyl, —C(O)OC1-6alkyl, NRa0C(O)—(CRa1Rb1)u—NRa0Rb0, NRa0C(O)—(CRa1Rb1)uOH, NRa0C(O)-halo C1-6alkyl;
• wherein the C3-8 monocyclic cycloalkyl, C3-6 monocyclic heterocyclyl, phenyl, 5- or 6-membered monoheteroaryl is optionally substituted by 1, 2 or 3 substituent(s) selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, halo, cyano, cyanomethyl, cyanoethyl, C1-3 alkyl, C1-3 alkoxy and C3-6 monocyclic cycloalkyl;
• u, v are each independently 0, 1, 2, 3 or 4;
• Ra0, Rb0 are each independently hydrogen or C1-3 alkyl;
• or Ra0, Rb0 together with the nitrogen atom attached thereto form a C3-8 monocyclic heterocyclyl, the C3-8 monocyclic heterocyclyl is optionally substituted by 1, 2 or 3 halo or C1-3 alkyl;
• Ra1, Rb1, Ra0, Rb2 are the same or different, and are each independently hydrogen, hydroxyl or C1-3-alkyl.

A compound or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the compound has a structure as represented by formula (II):

• wherein,
• R0 is a substituted or unsubstituted C6-14 aryl, or a substituted or unsubstituted C5-14 heteroaryl;
• R1, R2, R3 are each independently hydrogen, hydroxy, halo, nitro, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy, substituted or unsubstituted C3-20 cycloalkyl, —(CH2)u—C3-6 monocyclic heterocyclyl, —(CH2)u-phenyl, —(CH2)u-5- or 6-membered monoheteroaryl, —(CH2)u—C3-8 monocyclic cycloalkyl, —SO2C1-6 alkyl, —(CH2)u—NRa0Rb0, —(CH2)u—C(O)NRa0Rb0, —C(O)C1-6 alkyl, —C(O)OC1-6 alkyl;
• wherein the phenyl, C3-8 monocyclic cycloalkyl, C3-6 monocyclic heterocyclyl, 5- or 6-membered monoheteroaryl is optionally substituted by 1, 2 or 3 substituent(s) selected from the group consisting of halo, cyano, C1-3 alkyl, C1-3 alkoxy and C3-6 monocyclic cycloalkyl;
• u is 0, 1, 2, 3 or 4;
• Ra0, Rb0 are each independently hydrogen or C1-3 alkyl, or Ra0 and Rb0 together with the nitrogen atom attached thereto form a C3-8 monocyclic heterocyclyl, the C3-8 monocyclic heterocyclyl is optionally substituted by 1, 2 or 3 substituent(s) selected from the group consisting of halo or C1-3 alkyl;
• B has a structure as represented by formula (II-a) or formula (II-b):
• wherein W1, W2 and “” are selected from the group consisting of:
• (a1) W1 is C(O), W2 is NRc, and “” is a single bond;
• wherein Rc is hydrogen or substituted or unsubstituted C1-10 alkyl;
• (b1) W1 is CRb, W2 is CRc, and “” is a single bond or a double bond;
• wherein Rb, Rc together with the ring attached thereto form a substituted or unsubstituted 9- or 10-membered biheteroaryl fused ring;
• (c1) W1 is NRb, W2 is CRc, and “” is a single bond;
• wherein Rb, Rc together with the ring attached thereto form a substituted or unsubstituted 9- or 10-membered biheteroaryl fused ring;
• (d1) W1 is CRb, W2 is NRc, and “” is a single bond;
• wherein Rb, Rc together with the ring attached thereto form a substituted or unsubstituted 9- or 10-membered biheteroaryl fused ring;
• Ra, Rd are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R01, R02 are each independently hydrogen, —C(O)C1-6 alkyl or —C(O)C3-8 monocyclic cycloalkyl;
• L is a bond, —(CR11R12)t1—(CR21R22)t2—(CR31R32)t3—(CR41R42)t4—(O)t5 or —(CR11R12)t1—(CR21R22)t2—(NR31)t3—(CR41R42)t4—(O)ts;
• wherein t1, t2, t3, t4 and t5 are each independently 0 or 1;
• Rd′, R03, R11, R12, R21, R22, R31, R32, R41, R42 are selected from the combination selected from the group consisting of:
• (a2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• (b2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22 together with the carbon atom attached thereto form a substituted or unsubstituted C3-8 monocyclic cycloalkyl, or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• (c2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R31, R32 together with the carbon atom attached thereto form a substituted or unsubstituted C3-8 monocyclic cycloalkyl, or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• (d2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen, or substituted or unsubstituted C1-10 alkyl;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R22, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R31 together with the carbon atom attached thereto form a substituted or unsubstituted C3-8 monocyclic cycloalkyl, or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• (e2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R03 and R31 are linked together to form a substituted or unsubstituted C3-8 monocyclic heterocyclyl;
• (f2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R22, R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R03 and R21 are linked together to form a substituted or unsubstituted C3-8 monocyclic heterocyclyl;
• (g2) R11, R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R31, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• Rd′ and R03 are linked together to form a substituted or unsubstituted 4- to 7-membered oxo-substituted heterocyclyl;
• (h2) Rd′ are each independently hydrogen, halo, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted C1-10 alkoxy or NRa0Rb0;
• R03 is hydrogen or substituted or unsubstituted C1-10 alkyl;
• R12, R41, R42 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R21, R22, R32 are each independently hydrogen, halo, hydroxy, hydroxymethyl, hydroxyethyl or C1-3 alkyl;
• R11 and R31 are linked together to form a substituted or unsubstituted C3-8 monocyclic cycloalkyl or substituted or unsubstituted C3-6 monocyclic heterocyclyl;
• in the above groups, the “substituted” means that 1, 2, 3 or 4 hydrogen atom(s) in the group are substituted by a substituent independently selected from the group S consisting of:
• hydroxy, halo, nitro, oxo, C1-6 alkyl, hydroxy-substituted C1-6 alkyl, benzyl, —S—C1-6 alkyl, —S-halo C1-6 alkyl, —(CRa1Rb1)u-cyano, —(CRa1Rb1)u—C1-6 alkoxy, —(CRa1Rb1)u-halo C1-6 alkoxy, —(CRa1Rb1)u-halo C1-6 alkyl, —(CRa1Rb1)u—C3-6 monocyclic heterocyclyl, —(CRa1Rb1)u—C3-8 monocyclic cycloalkyl, —(CRa1Rb1)u-phenyl, —(CRa1Rb1)u-5- or 6-membered monoheteroaryl, —(CRa1Rb1)u—O—(CRa2Rb2)v-halo C1-6 alkyl, —(CRa1Rb1)u—O—(CRa2Rb2)v— C3-8 monocyclic cycloalkyl, —(CRa1Rb1)u—O—(CRa2Rb2)v—C3-6 monocyclic heterocyclyl, —(CRa1Rb1)u—O—(CRa2Rb2)v-phenyl, —(CRa1Rb1)u— O—(CRa2Rb2)v-5- or 6-membered monoheteroaryl, —(CRa1Rb1)u—S—(CRa2Rb2)v-phenyl, —(CRa1Rb1)u—SO2—(CRa2Rb2)v-phenyl, —(CRa1Rb1)u—O—C(O)NRa0Rb0, —(CRa1Rb1)6—O—(CRa2Rb2)v—C1-6 alkoxy, —(CRa1Rb1)u—O—(CRa2Rb2)vOH, —(CRa1Rb1)u—SO2C1-6 alkyl, —(CRa1Rb1)u—SO2NRa0Rb0, —(CRa1Rb1)u—C(O)NRa0Rb0, —(CRa1Rb1)u—NRa0Rb0, —(CRa1Rb1)u—C(O)C1-6 alkyl, —C(O)OC1-6 alkyl, NRa0C(O)—(CRa1Rb1)u—NRa0Rb0, NRa0C(O)—(CRa1Rb1)u0H, NRa0C(O)-halo C1-6 alkyl;
• wherein the C3-8 monocyclic cycloalkyl, C3-6 monocyclic heterocyclyl, phenyl, 5- or 6-membered monoheteroaryl is optionally substituted by 1, 2 or 3 substituent(s) selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, halo, cyano, cyanomethyl, cyanoethyl, C1-3 alkyl, C1-3 alkoxy and C3-6 monocyclic cycloalkyl;
• u, v are each independently 0, 1, 2, 3 or 4;
• Ra0, Rb0 are each independently hydrogen or C1-3 alkyl;
• or Ra0, Rb0 together with the nitrogen atom attached thereto form a C3-8 monocyclic heterocyclyl, the C3-8 monocyclic heterocyclyl is optionally substituted by 1, 2 or 3 halo or C1-3 alkyl;
• Ra1, Rb1, Ra0, Rb2 are the same or different, and are each independently hydrogen, hydroxyl or C1-3-alkyl.