# US 12,595,267 B2 · Preparation method for amide compound and application thereof in field of medicine

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- Number: US 12,595,267 B2
- Document ID: US12595267B2
- Status: Granted
- Kind: B2
- Application number: 17/442,899
- Filed: 2020-03-24
- Published: 2022-03-31
- Granted: 2026-04-07
- Earliest claimed: 2019-03-25
- Assignees: Shanghai Synergy Pharmaceutical Sciences Co., Ltd; Zhejiang Huahai Pharmaceutical Co., Ltd.
- Applicants: Shanghai Synergy Pharmaceutical Sciences Co., Ltd.; Zhejiang Huahai Pharmaceutical Co., Ltd.
- Inventors: Xin Xu; Jia Chen; Zhen Zhang; Liming Zhang; Qimei Wu; Qingyun Jiang; Fengying Guo; Yuyun Zhang; Hao Yu; Ying Wang; Kang Sun; Chengxu Zang; Chenggang Qin; Xiaobo Zhou; Xiaojuan Zhang; Yijin Wang; Xiaoer Xia; Yunfei Li; Jian Ge
- Web page: https://patentgrep.com/patent/US12595267B2

## CPC

- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 495/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a preparation method for an amide compound and an application thereof in the field of medicine. Specifically, provided by the present invention is an amide small molecule compound which is an inhibitor of Zeste gene enhancer homolog 2 (EZH2) and which may be used to prevent and/or treat EZH2-mediated related diseases, comprising tumors, myeloproliferative diseases or autoimmune diseases.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound represented by general formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable salt, polymorph, solvate or isotopic derivative thereof according to claim 1, wherein R4 and R5 are each independently —C1-3 alkyl;
R3 is hydrogen or —C1-4 alkyl;
R5a is —C1-2 alkyl or —C1-2 alkoxyl;
R6 is selected from the group consisting of methyl, ethyl, propyl,
R6b is selected from the group consisting of —C1-3 alkyl, —C2-3 alkyl substituted by —C1-2 alkyl, —C3-6 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, wherein the heteroatom in the 4-6 membered heterocycloalkyl group is nitrogen or oxygen;
Rh and Rk are each independently selected from the group consisting of hydrogen, —C1-3 alkyl, —C2-3 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.

### Claim 3 (depends on 1)

The compound represented by general formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable salt, polymorph, solvate or isotopic derivative thereof according to claim 1, wherein T0 is —C3-6 cycloalkyl or 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl contains 1 or 2 heteroatoms each independently chosen from nitrogen and oxygen;
T1 is selected from the group consisting of fluorine, methyl, ethyl, propyl, —C1-3 alkoxyl, —C2-3 alkyl substituted by —C1-2 alkyl, and —NRcRd;
Re is selected from the group consisting of methyl, ethyl, propyl, —C2-4 alkyl substituted by —C1-2 alkyl, —C2-4 alkyl substituted by hydroxyl, —CH(CH3)—CH3, —CH(CH3)—(CH2)—CH3, —CH(CH3)—CH(CH3)2, —CH2—C(CH3)3, -T0, —C1-3alkylene-T0, —(CH2)n—CF3, —(CH2)n—CF2—CF3, —(CH2)n—O—C1-3 alkyl, —CH2—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)-T0, tert-butoxycarbonyl, —C(O)—O—C1-3 alkyl, —C(O)—O-T0, —S(O)2—C1-3 alkyl and —S(O)2-T0;
Rf and Rg are each independently selected from the group consisting of fluorine, —OH, —CF3, methyl, ethyl, propyl, —C2-3 alkyl substituted by —C1-2 alkyl, —(CH2)n—CF3, -T0, —C1-3 alkylene-T0, —NRaRb, —C1-3 alkylene-NRaRb, —O—C1-4 alkyl, —O—C2-4 alkenyl, —O-T0, —NH—C(O)—C2-4 alkenyl, —C(O)—C1-3 alkyl, —C(O)—C2-4 alkenyl, —C(O)—(CH2)n—CF3, —C(O)-T0, tert-butoxycarbonyl, —C(O)—O—C1-3 alkyl, and —C(O)—O-T0;
Ra and Rb are each independently selected from the group consisting of methyl, ethyl, propyl, —C1-4 alkylene-OH, —C2-4 alkylene-OCH3 and
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.

### Claim 4 (depends on 1)

The compound represented by general formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable salt, polymorph, solvate or isotopic derivative thereof according to claim 1, wherein
R6 is selected from the group consisting of methyl, ethyl, propyl,
Re is selected from the group consisting of methyl, ethyl, propyl, —CH(CH3)—CH3, —CH(CH3)—(CH2) CH3, —CH(CH3)—CH(CH3)2, —CH2—C(CH3)3, T0, —(CH2)n-T0, —(CH2)n—CF3, —CH2—CH(OH)—CH3, —(CH2)n—CF2—CF3, —(CH2)2—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)-morpholinyl, —C(O)C3-6 cycloalkyl, tert-butoxycarbonyl, —C(O)—O—C1-3 alkyl and —S(O)2—C1-3 alkyl;
Rf is selected from the group consisting of methyl, ethyl, propyl, —F, —Cl, —OH, T0, and —C1-3 alkylene-T0;
Rg is selected from the group consisting of T0, —C1-3 alkylene-T0, —NH—C(O)—C2-3 alkenyl, —NRaRb and —F;
Ra and Rb are each independently selected from the group consisting of methyl, ethyl, propyl and
and
T0 is selected from the group consisting of

### Claim 5

A compound, 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 the compound is selected from the group consisting of:

### Claim 6 (depends on 1)

A method for preparing the compound represented by general formula (I) according to claim 1, wherein the compound represented by general formula (I) is prepared by the following scheme,
the compound of general formula I-1 and a ketone compound K1 undergoing a reductive amination reaction to obtain the compound of general formula I-2, wherein K1 is selected from the group consisting of —C(O)—C1-6 alkyl, oxo substituted 4-6 membered cycloalkyl, oxo substituted 4-6 membered heterocycloalkyl and oxo substituted 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 is connected by fusion, and any one ring in the bicyclic ring is saturated, unsaturated or aromatic; the oxo substituted cycloalkyl, oxo substituted heterocycloalkyl or oxo substituted 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;
the compound of general formula I-2 undergoing a reductive amination reaction with an aldehyde compound R7—CHO at the presence of a reducing agent to obtain the compound of general formula I-3, wherein R7 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′; the reducing agent is optionally sodium triacetoxyborohydride;
the compound of general formula I-3 reacting with a pinacol diborate compound under heating and alkaline condition, and the presence of a catalyst to obtain the compound of the general formula I-4, wherein a reagent that provides alkaline condition is optionally potassium acetate, and the catalyst is optionally [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride;
the compound of general formula I-4 reacting with a corresponding halogenated aryl group R2—Z under heating and alkaline condition, and the presence of a catalyst to obtain the compound of general formula I-5, wherein a reagent that provides alkaline condition is optionally selected from the group consisting of potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and cesium fluoride; the catalyst is optionally selected from the group consisting of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, and tris(dibenzylideneacetone)dipalladium, wherein Z is halogen;
hydrolyzing the compound of general formula I-5 under alkaline condition to obtain a compound of general formula I-6, wherein a reagent that provides alkaline condition is optionally sodium hydroxide;
the compound of general formula I-6 undergoing a condensation reaction with a corresponding amine
to obtain the compound of general formula (I); or
the compound of general formula I-3 undergoing a hydrolysis reaction under heating and alkaline conditions to obtain a compound of general formula II-1, wherein a reagent that provides alkaline condition is optionally selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and cesium carbonate; the compound of general formula II-2 is obtained by the condensation reaction of the compound of general formula II-1 with a corresponding amine
the compound of the general formula II-2 reacting with a pinacol diborate compound under heating and alkaline conditions, and the presence of a catalyst to obtain the compound of general formula II-3, wherein a reagent that provides alkaline condition is optionally potassium acetate, and the catalyst is optionally [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride;
the compound of general formula II-3 reacting with a corresponding halogenated aryl group R2—Z under heating and alkaline conditions, and the presence of a catalyst to obtain the compound of general formula (I), wherein a reagent that provides alkaline condition is optionally selected from the group consisting of potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and cesium fluoride; the catalyst is optionally selected from the group consisting of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, and tris(dibenzylideneacetone)dipalladium, wherein Z is halogen; or
the compound of general formula II-2 reacting with a corresponding aryl boronic ester
under conditions of heating, alkalinity, and the presence of a catalyst to obtain the compound of general formula (I); wherein a reagent that provides alkaline condition is optionally selected from the group consisting of potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and cesium fluoride; the catalyst is optionally selected from the group consisting of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium acetate, tetrakistriphenylphosphine palladium, and tris(dibenzylideneacetone)dipalladium.

### Claim 7 (depends on 6)

The method according to claim 6, wherein K1 is selected from the group consisting of
and
R7 is hydrogen or —C1-3 alkyl.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound represented by general formula (I) or the tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable salt, polymorph, solvate or isotopic derivative thereof according to claim 1 and optionally one or more pharmaceutically acceptable carriers and/or diluents.

### Claim 9 (depends on 1)

A method for preventing and/or treating EZH2-mediated diseases, wherein the EZH2-mediated diseases are selected from the group consisting of tumors, myeloproliferative diseases and autoimmune diseases, and wherein the method comprises administering the compound represented by general formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable salt, polymorph, solvate or isotopic derivative thereof according to claim 1.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the tumor is prostate cancer, breast cancer, bladder cancer, lung cancer, rectal cancer, lymphoma or leukemia, and the autoimmune disease is inflammatory enteritis, autoimmune encephalomyelitis or multiple sclerosis.

### Claim 11 (depends on 1)

A method for preventing and/or treating tumors, myeloproliferative diseases, inflammatory bowel disease, autoimmune encephalomyelitis or multiple sclerosis, wherein the method comprises administering a therapeutically effective amount of the compound represented by general formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, pharmaceutically acceptable salt, polymorph, solvate or isotopic derivative thereof according to claim 1 to a subject in need.