Preparation method for amide compound and application thereof in field of medicine

A compound represented by general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, a pharmaceutically acceptable salt, a polymorph, a solvate or an isotopic derivative thereof,

• wherein,
• R1 is hydrogen, —F or —Cl;
• R2 is selected from the group consisting of
• Re is selected from the group consisting of —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, —C2-4 alkyl substituted by hydroxyl, —C1-4 alkylene-OH, -T0, —C1-4 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, and —S(O)2—C1-3 alkylene-T0;
• Rf and Rg are each independently selected from the group consisting of 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, and —S(O)2—C1-3 alkylene-T0;
• 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 selected from the group consisting of hydrogen, —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 and —C2-6 alkylene-CH3, wherein the C2-6 alkylene is optionally interrupted by an oxygen atom and/or is optionally substituted by one or more C1-3 alkyl;
• or Ra and Rb together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is a heterocycloalkane with one nitrogen as heteroatom, a heterocycloalkane with two nitrogens as heteroatoms, or a heterocycloalkane with one nitrogen and one oxygen as heteroatoms;
• T0 is —C3-8 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl unsubstituted or substituted by T1;
• when the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl comprising a nitrogen as a heteroatom, the nitrogen atom is not substituted or substituted by T2;
• T1 is selected from the group consisting of halogen, —C1-6 alkyl, —C1-3 alkoxyl, —C1-6 alkyl substituted by —C1-3 alkyl, and —NRcRd;
• T2 is selected from the group consisting of —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, —C1-4 alkylene-OH, —C3-6 cycloalkyl, 4-6 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, and —S(O)2—(CH2)n—CHF2;
• n is 1, 2, 3, or 4;
• R3 is hydrogen, —C1-4 alkyl or substituted —C1-4 alkyl, wherein the substituted —C1-4 alkyl is optionally substituted by one or more of the following substituents:
• hydroxyl, carboxy or —C(O)O—R′;
• R′ is selected from the group consisting of —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-8 cycloalkyl and —C4-10 heterocycloalkyl;
• R4 and R5 are each independently —C1-6 alkyl;
• R5a is —C1-6 alkyl or —C1-6 alkoxyl;
• R6 is selected from the group consisting of —C1-6 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl and a bicyclic ring having 8 to 10 carbon atoms;
• in the 4-6 membered heterocycloalkyl, the heteroatom is nitrogen, sulfur or oxygen;
• both rings in the bicyclic ring are connected by fusion, and any ring of the bicyclic ring is saturated, unsaturated or aromatic;
• the cycloalkyl, heterocycloalkyl or bicyclic ring with 8 to 10 carbon atoms is unsubstituted or substituted by one or more R6a, wherein R6a is selected from the group consisting of halogen, hydroxyl, —C1-3 alkyl, —C1-3 alkoxyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclic group, —NRhRk, —C(O)—C1-3 alkyl, —C(O)—C3-6 cycloalkyl, —S(O)2—C1-3 alkyl, —(CH2)n—CF3, and —S(O)2—C3-6 cycloalkyl;
• when R6 is a 4-6 membered heterocycloalkyl containing one sulfur atom, the sulfur heteroatom is not oxidized or is oxidized by two oxy groups to form a sulfone group;
• or
• when R6 is a 4-6 membered heterocycloalkyl containing one nitrogen atom, the nitrogen atom is unsubstituted or substituted by R6b, wherein R6b is selected from the group consisting of —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl, —C1-4 alkylene-OH, —C3-8 cycloalkyl, 4-6 membered heterocycloalkyl, —C(O)—C1-3 alkyl, —C(O)—C3-6 cycloalkyl, —(CH2)n—CF3, —S(O)2—C1-3 alkyl, and —S(O)2—C3-6 cycloalkyl;
• Rh and Rk are each independently selected from the group consisting of hydrogen, —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 and —C2-6 alkylene-CH3, wherein the C2-6 alkylene is optionally interrupted by an oxygen atom and/or is optionally substituted by one or more C1-3 alkyl;
• or Rh and Rk together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl which is unsubstituted or substituted with one or two T groups, wherein T is selected from the group consisting of halogen, —C1-4 alkyl, —C2-4 alkyl substituted by —C1-3 alkyl and —NRcRd;
• and
• Rc and Rd are each independently selected from the group consisting of hydrogen, —C1-3 alkyl, —C1-4 alkylene-OH, —C2-4 alkylene-OCH3 and —C2-6 alkylene-CH3, wherein the C2-6 alkylene is optionally interrupted by an oxygen atom and/or is optionally substituted by one or more C1-3 alkyl.