Preparation Method for Amide Compounds and Use Thereof in Medical Field

A compound represented by formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture thereof, a pharmaceutically acceptable salt, a polymorph, a solvate, a prodrug, a metabolite or an isotope derivative thereof,

• wherein, R1 is H or halogen, R2 is phenyl, 5- to 6-membered heteroaryl, 8- to 11-membered bicyclic group, or 11- to 16-membered tricyclic group;
• wherein rings in the bicyclic or tricyclic group are fused connected, or are bridged by a carbon atom into a spiro compound;
• wherein at least one ring in the bicyclic or tricyclic group is an aromatic ring, in case that one ring in the bicyclic or tricyclic group is a heterocyclic ring containing a nitrogen atom, the nitrogen atom is not substituted or is substituted by Re;
• a methylene on rings in the bicyclic or tricyclic group is not substituted, or substituted by oxygen to form a ketone, or substituted by one Rf, or substituted by both Rf and Rg, the phenyl or 5- to 6-membered heteroaryl is substituted by Rj, the aromatic ring in the bicyclic or tricyclic group is not substituted or substituted by one Re;
• Re is —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, —C2-4 alkyl substituted by —OH, —C1-4 alkylene-OH, -T0, —C1-3 alkylene-T0, —(CH2)n—CF3, —(CH2)n—CF2—CF3, —(CH2)n—CHF2, —(CH2)n—CH2F, —(CH2)n—O—C1-3 alkyl, —C(O)—C1-3 alkyl, —(CH2)n—C(O)—C1-3 alkyl, —C(O)—C2-4 alkenyl, —C(O)—CF3, —C(O)—(CH2)n—CF3, —C(O)—(CH2)n—CF2—CF3, —C(O)—(CH2)n—CHF2, —C(O)—(CH2)n—CH2F, —C(O)-T0, —C(O)—C1-3 alkylene-T0, tert-butoxycarbonyl, —C(O)—O—C1-3 alkyl, —C(O)—O—(CH2)n—CF3, —C(O)—O—(CH2)n—CHF2, —C(O)—O—(CH2)n—CH2F, —C(O)—O-T0, —C(O)—O—C1-3 alkylene-T0, —S(O)2—C1-3 alkyl, —S(O)2—(CH2)n—CF3, —S(O)2—(CH2)n—CHF2, —S(O)2—(CH2)n—CH2F, —S(O)2-T0 or —S(O)2—C1-3 alkylene-T0;
• Rf and Rg are each independently halogen, —OH, —C1-4 alkylene-OH, —CF3, —CHF2, —CH2F, —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, —(CH2)n—CF3, —(CH2)n—CHF2, —(CH2)n—CH2F, -T0, —C1-3 alkylene-T0, —NRaRb, —C1-3 alkylene-NRaRb, —O—C1-4 alkyl, —O—C2-4 alkenyl, —O—C1-4 alkylene-OH, —O—(CH2)n—CF3, —O—(CH2)n—CHF2, —O—(CH2)n—CH2F, —O-T0, —O—C1-3 alkylene-T0, —NH—C(O)—C2-4 alkenyl, —C(O)—C1-3 alkyl, —(CH2)n—C(O)—C1-3 alkyl, —C(O)—C2-4 alkenyl, —C(O)—(CH2)n—CF3, —C(O)—(CH2)n—CHF2, —C(O)—(CH2)n—CH2F, —C(O)-T0, —C(O)—C1-3 alkylene-T0, tert-butoxycarbonyl, —C(O)—O—C1-3 alkyl, —C(O)—O—(CH2)n—CF3, —C(O)—O—(CH2)n—CHF2, —C(O)—O—(CH2)n—CH2F, —C(O)—O-T0, —C(O)—O—C1-3 alkylene-T0, —S(O)2—C1-3 alkyl, —S(O)2—(CH2)n—CF3, —S(O)2—(CH2)n—CHF2, —S(O)2—(CH2)n—CH2F, —S(O)2-T0 or —S(O)2—C1-3 alkylene-T0;
• when the methylene on rings in the bicyclic or tricyclic group is substituted by both Rf and Rg, Rf and Rg are each independently halogen, —OH or —C1-3 alkyl;
• Rj is
• Rj1 is —CN, —COOH, —C(O)O—C1-3 alkyl, —(CH2)n—OH or —(CH2)n—O—C1-3 alkyl;
• Ra and Rb are each independently —H, —C1-3 alkyl, —C1-4 alkylene-OH, -T0, —C1-3 alkylene-T0, —(CH2)n—CF3, —(CH2)n—CHF2, —(CH2)n—CH2F, —C(O)—C1-3 alkyl, —C(O)—C2-4 alkenyl, —C(O)—(CH2)n—CF3, —C(O)—(CH2)n—CHF2, —C(O)—(CH2)n—CH2F, —C(O)-T0, —C(O)—C1-3 alkylene-T0, —C2-4 alkylene-OCH3 or —C2-6 alkylene-CH3, wherein the C2-6 alkylene is optionally inserted by 0 and/or optionally substituted by one or more —C1-3 alkyl;
• alternatively, Ra and Rb together with a nitrogen atom to which they attach, form an unsubstituted or substituted 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl is a heterocycloalkyl in which the heteroatom(s) is/are one N, two N, or one N and one O;
• T0 is unsubstituted or T1-substituted —C3-8 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, in case that T0 is 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl, if the heteroatom is N, then the N is unsubstituted or T2-substituted;
• T1 is halogen, —C1-6 alkyl, —C1-3 alkoxy, —C1-6 alkyl substituted by —C1-3 alkyl, or —NRcRd;
• T2 is —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, —C1-4 alkylene-OH, —C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, —(CH2)n—CF3, —(CH2)n—CHF2, —(CH2)n—CH2F, —C(O)—C1-3 alkyl, —C(O)—C2-4 alkenyl, —C(O)—(CH2)n—CF3, —C(O)—(CH2)n—CHF2, —C(O)—(CH2)n—CH2F, tert-butoxycarbonyl, —S(O)2—C1-3 alkyl, —S(O)2—(CH2)n—CF3 or —S(O)2—(CH2)n—CHF2;
• n is 1, 2, 3 or 4;
• R3 is —H, —C1-4 alkyl or substituted —C1-4 alkyl, wherein the substituted —C1-4 alkyl is optionally substituted by one or more following substituents:
• hydroxyl, carboxyl or —C(O)O—R′;
• R′ is —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-8 cycloalkyl or —C4-10 heterocycloalkyl;
• R4 and R5 are each independently —C1-6 alkyl;
• R5a is —C1-6 alkyl or —C1-6 alkoxy;
• R6 is —C1-6 alkyl, 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl or bicyclic group with 8 to 10 carbon atoms, wherein a heteroatom of the 5- to 6-membered heterocycloalkyl is selected from the group consisting of N, S and O, rings in the bicyclic group are fused connected, each ring in the bicyclic group is saturated, unsaturated or aromatic, the cycloalkyl, heterocycloalkyl or bicyclic group with 8 to 10 carbon atoms are unsubstituted or substituted by one or more R6a, in which R6a is halogen, hydroxy, —C1-3 alkyl, —C1-3 alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, —NRhRk, —C(O)—C1-3 alkyl, —C(O)—C3-6 cycloalkyl, —S(O)2—C1-3 alkyl, —(CH2)n—CF3 or —S(O)2—C3-6 cycloalkyl;
• when R6 is a heterocyclic group containing one sulfur atom, the sulfur atom is not oxidized, or oxidized by two oxygen atoms to form a sulfonyl;
• when R6 is a heterocyclic group containing one nitrogen atom, the nitrogen atom is unsubstituted or substituted by R6b, in which R6b is —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, —C1-4 alkylene-OH, —C3-8 cycloalkyl, 4- to 6-membered heterocycloalkyl, —C(O)—C1-3 alkyl, —C(O)—C3-6 cycloalkyl, —(CH2)n—CF3, —S(O)2—C1-3 alkyl or —S(O)2—C3-6 cycloalkyl;
• Rh and Rk are each independently —H, —C1-3 alkyl, —C1-4 alkylene-OH, -T0, —C1-3 alkylene-T0, —(CH2)n—CF3, —(CH2)n—CHF2, —(CH2)n—CH2F, —C(O)—C1-3 alkyl, —C(O)—C2-4 alkenyl, —C(O)—(CH2)n—CF3, —C(O)—(CH2)n—CHF2, —C(O)—(CH2)n—CH2F, —C(O)-T0, —C(O)—C1-3 alkylene-T0, —C2-4 alkylene-OCH3 or —C2-6 alkylene-CH3, wherein the —C2-6 alkylene is optionally inserted by O and/or optionally substituted by one or more —C1-3 alkyl,
• Rh and Rk, optionally together with a nitrogen atom to which they attach, form a unsubstituted 4- to 6-membered heterocycloalkyl, or a 4- to 6-membered heterocycloalkyl substituted by one or two T groups, wherein T is halogen, —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, or —NRcRd, wherein the Rc and Rd are each independently —H, —C1-3 alkyl, —C1-4 alkylene-OH, —C2-4 alkylene-OCH3 or —C2-6 alkylene-CH3, and wherein —C2-6 alkylene is optionally inserted by O and/or optionally substituted by one or more —C1-3 alkyl.