CN108929263B - Arylamide Kv2.1 inhibitor and preparation method, pharmaceutical composition and application thereof - Google Patents

Arylamide Kv2.1 inhibitor and preparation method, pharmaceutical composition and application thereof Download PDF

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CN108929263B
CN108929263B CN201810307478.7A CN201810307478A CN108929263B CN 108929263 B CN108929263 B CN 108929263B CN 201810307478 A CN201810307478 A CN 201810307478A CN 108929263 B CN108929263 B CN 108929263B
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CN108929263A (en
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徐柏玲
王晓良
周洁
王伟平
刘冬
郭婷婷
王雪
冯楠
陈华龙
徐少峰
李江
王玲
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Institute of Materia Medica of CAMS
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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Abstract

The invention discloses a novel aromatic amide Kv2.1 inhibitor, a preparation method thereof, a pharmaceutical composition and application thereof. In particular to an aromatic amide derivative shown in a general formula I, a pharmaceutically acceptable salt thereof, a preparation method thereof, a composition containing one or more compounds, and application of the compounds in preparation of medicaments for preventing and/or treating Kv2.1 related diseases.

Description

Arylamide Kv2.1 inhibitor, and preparation method, pharmaceutical composition and application thereof
Technical Field
The invention relates to an aromatic amide Kv2.1 inhibitor with a novel structure shown in formula I, a pharmaceutically acceptable salt thereof, a preparation method thereof, a composition containing one or more compounds, and application of the compounds in inhibiting Kv2.1 and treating kv2.1 related diseases and preparing, preventing and/or treating mental and nervous system diseases, metabolic diseases and cardiovascular and cerebrovascular diseases.
Background
Voltage-gated potassium channels (Kv channels) are widely present on the surface of many excitable cell membranes and can be involved in the regulation of cell electrophysiological activities and endocrine secretion. For example, in excitatory cells, the Kv channel regulates depolarization of action potentials and in non-excitatory cells, it regulates resting potentials of cell membranes, so that the Kv channel is involved in many electrophysiological activities and is an important therapeutic target for immune, metabolic, cardiovascular and neuropsychiatric diseases and even cancer [ Molecular pharmacology,2011,80(6): 959-. Kv channels can be divided into 12 subfamilies by gene coding, such as Kv1, Kv2, Kv3, etc., each of which is divided into several subtypes such as Kv2.1, Kv2.2, Kv4.5, etc. according to different functions [ Pharmacol rev.2005, 57: 473-508]. Kv2.1 is a subtype of voltage-gated potassium ion channel, is distributed in various tissues of mammals, including cerebral neurons, central nervous system neurons, cardiac myocytes, skeletal muscle, cardiovascular smooth muscle, beta islet cells and some cancer cells, and has important effects on regulating neuronal excitability, neuronal apoptosis, insulin secretion and the like. The regulation and control of the target point are beneficial to the research and treatment of a plurality of common difficult and complicated diseases such as senile dementia, epilepsy, diabetes, cerebral apoplexy, depression, tumor and the like, so the research of the action mechanism and the regulation and control of Kv2.1 has very important significance [ pharmaceutical reports.2016, 457-461; brain research.2010, 1359:67-74 ].
The Kv2.1 selective blocking agent discovered in the early days is a plurality of polypeptide compounds which come from venom of animals such as spiders, toads and the like, such as: jingzhao Chilobrachys spider toxin-I, Jingzhao Chilobrachys spider toxin-III and GxTX-1E, etc., but the source of the polypeptides is limited, which limits the application of the polypeptides in pharmacology. Most of Kv2.1 small-molecule blockers reported in the literature at present are found by a common sieve method, and have weak inhibitory activity and poor selectivity such as: SC-791[ Brain research,2010,1359:67-74], propafenone [ Nauyn-Schmiedeberg's archives of pharmacology,2000,362(1):22-31], haloperidol [ Brain research,1997,761(1):42-50], 17 β -estradiol [ Acta Pharm Sin (Proc. Rev., 2004,39(9): 686) 690], bugur furan (AF-5) [ Acta Pharm Sin (Proc. Rev., 2013,48(1):38-44], etc. A study person of Merk corporation reports that benzimidazole RY785 and substituted benzamide RY796 Kv2.1 small molecule blockers obtained by high-throughput screening have stronger inhibitory activity and better selectivity on Kv2.1 in 2011 [ Molecular pharmacology,2011,80(6):959-964 ]. Therefore, the search for high-activity Kv2.1 small molecule blockers with new structures is of great significance, and the blockers not only can be molecular probes for researching Kv2.1 biological functions, but also can be possibly developed into drugs taking Kv2.1 as targets.
The novel aromatic amide Kv2.1 inhibitor is designed and synthesized, and aims to provide a brand new material basis for treating Kv2.1-related diseases.
Disclosure of Invention
The invention aims to provide an aromatic amide derivative and a physiologically acceptable salt shown in a formula I, a preparation method thereof, a pharmaceutical composition, application thereof in preparing Kv2.1 inhibitors and potential drugs thereof, and application thereof in preparing drugs for treating mental and nervous system diseases, metabolic diseases and cardiovascular and cerebrovascular diseases.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides an aromatic amide derivative or a physiologically acceptable salt shown as a general formula I:
Figure BDA0001620885820000021
in the formula I, the compound is shown in the specification,
x is selected from CRxN; y is selected from CRyN; z is selected from CRzN; x, Y, Z can be N alone, two at the same time, and/or three at the same time;
Rx、Ryand RzIs independently selected from the group consisting of atoms or groups or moieties including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl having 3 to 8 membered rings, wherein the substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
R1selected from the group consisting of:
(1) substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl with 3 to 8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl group having 3-to 8-membered ring and the azacycloalkyl group having 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(3)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO 2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、 NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、 Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or mono-substitutedMay be polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R2selected from the group consisting of:
(1)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6CONRf4Rf5、NRe7SO2Rf6wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6And may also be independently selected from the group consisting of substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring Wherein the substituent is selected from C1-5 straight chain or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen-substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 linear chainOr branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2)CONRh1Ri1、COORh2、SO2Rh3、SO2NRh4Ri2Wherein Rh is1、Ri1、Rh2、 Rh3、Rh4、Ri2Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
the Rh1、Ri1、Rh2、Rh3、Rh4、Ri2And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
the Rh1、Ri1、Rh2、Rh3、Rh4、Ri2Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen-substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO 2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、NRa′6COORb′3、 SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、 Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、 Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein said halogenIncluding F, Cl, Br;
(3) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, substituted or unsubstituted 4-8 membered heterocycle (including 4-8 membered ring lactam), wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R3Selected from the group consisting of:
(2) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from
(a) C1-8 straight chain or branched chain alkyl, halogen substituted C1-8 straight chain or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 linear or branched alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered oxacycloalkyl, substituted or unsubstituted 3-8 membered azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered heteroaromatic ring, substituted or unsubstituted five membered heteroaromatic ring, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(b) Substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) Substituted or non-substituted aromatic condensed ring or condensed heterocyclic ring, substituted or non-substituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or non-substituted naphthalene ring, substituted or non-substituted benzo six-membered heterocyclic ring, substituted or non-substituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、 NRs4CORt2、COORs5、CONRs6Rt3、NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、 (CH2)nORs10Wherein said Rs1、Rs2、Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、 Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.
R9、R10May be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-4 straight chain or branched alkyl, substituted or unsubstituted C2-4 straight chain or branched alkenyl, substituted or unsubstituted C2-4 straight chain or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx 1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-6 cycloalkyl wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3)R9、R10can form a ring, and the size of the ring system is 3-7 membered alicyclic ring;
in formula I, said X, Y, Z is independently selected from CH, N, CF, CCl, CCH3、CC2H5、 COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds and physiologically acceptable salts of the present invention according to formula I of the present invention include, but are not limited to, compounds represented by formula (IA):
Figure BDA0001620885820000091
in the formula IA,
x is selected from CRxN; y is selected from CRyN; z is selected from CRzN; x, Y, Z may be N individually, two at the same time and/or three at the same time;
Rx、Ryand RzIs independently selected from the group consisting of atoms or groups or moieties including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein said Rc1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chainAlkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selectFrom H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
R2selected from the group consisting of:
(1)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6CONRf4Rf5、NRe7SO2Rf6wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
Said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2)CONRh1Ri1、COORh2、SO2Rh3、SO2NRh4Ri2wherein Rh is1、Ri1、Rh2、 Rh3、Rh4、Ri2Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
The Rh1、Ri1、Rh2、Rh3、Rh4、Ri2Can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; oxacycloalkyl of 3-to 8-membered ring and nitrogenThe heterocycloalkyl group may contain 1 heteroatom or a plurality of heteroatoms at the same time;
the Rh1、Ri1、Rh2、Rh3、Rh4、Ri2Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、NRa′6COORb′3、 SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、 Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、 Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(3) Substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, substituted or unsubstituted 4-8 membered heterocycle (including 4-8 membered cyclic lactam), wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R3selected from the group consisting of:
(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from
(a) C1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 linear or branched alkynyl, substituted or unsubstituted 3-7 membered cycloalkane A group, a substituted or unsubstituted oxacycloalkyl group having 3 to 8 membered rings, a substituted or unsubstituted azacycloalkyl group having 3 to 8 membered rings, a substituted or unsubstituted phenyl group, a substituted or unsubstituted six-membered aromatic heterocyclic ring, a substituted or unsubstituted five-membered aromatic heterocyclic ring, wherein the substituent is selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(b) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic Heterocycle, wherein said substituents are selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) substituted or non-substituted aromatic condensed ring or condensed heterocyclic ring, substituted or non-substituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or non-substituted naphthalene ring, substituted or non-substituted benzo six-membered heterocyclic ring, substituted or non-substituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、 NRs4CORt2、COORs5、CONRs6Rt3、NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、 (CH2)nORs10Wherein said Rs1、Rs2、Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、 Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independent of each otherIs selected from H, C1-4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.
R4Selected from the group consisting of:
(1) selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) can be selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Is independently selected from H, C1-4 linear or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(3) can be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched chain alkyl, halogen-substituted C1-4 straight chain or branched chain alkyl, F, Cl, Br, NO 2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R9、R10may be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-4 straight or branched chain alkyl, substituted or unsubstituted C2-4 straight or branched chain alkenyl, substituted or unsubstituted C2-4 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-6 cycloalkyl, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3)R9、R10Can form a ring, and the size of the ring system is 3-7 membered alicyclic ring;
in formula IA, said X, Y, Z is independently selected from CH, N, CF, CCl, CCH3、CC2H5、 COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IA-1:
Figure BDA0001620885820000161
in the formula IA-1, the compound of formula,
x is selected from CRxN; y is selected from CRyN; z is selected from CRzN; x, Y, Z can be N alone, two at the same time, and/or three at the same time;
Rx、Ryand RzIs independently selected from the group consisting of atoms or groups or moieties, including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein R isa1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
R3Selected from the group consisting of:
(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from
(a) C1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 linear or branched alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered oxacycloalkyl, substituted or unsubstituted 3-8 membered azacycloalkyl, substituted or unsubstitutedPhenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(b) Substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) Substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、 NRs4CORt2、COORs5、CONRs6Rt3、NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、 (CH2)nORs10Wherein said Rs1、Rs2、Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、 Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein said naphthalene ring, benzo-hexaThe heterocyclic ring or benzo five-membered heterocyclic ring can be mono-substituted or poly-substituted; the benzo six-membered heterocycle or benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.
R4Selected from the group consisting of:
(1) selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, and substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) can be selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; in oxacycloalkyl and azacycloalkyl radicals of 3-to 8-membered ringsMay contain 1 or more heteroatoms at the same time;
(3) can be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen-substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R7、R8May be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl, substituted or unsubstituted C2-8 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl with 3 to 8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl group having 3 to 8 membered ring and the azacycloalkyl group having 3 to 8 membered ring may contain 1 or more heteroatoms;
(3)CORf′1、COORf′2、SO2Rf′3、CONRf′4Rf′5wherein Rf'1、Rf′2、Rf′3、Rf′4、 Rf′5Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
rf'1、Rf′2、Rf′3、Rf′4、Rf′5And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、 COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms; rf'1、Rf′2、Rf′3、Rf′4、Rf′5Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、NRa′6COORb′3、 SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、 Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、 Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R9、R10May be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-4 straight or branched chain alkyl, substituted or unsubstituted C2-4 straight or branched chain alkenyl, substituted or unsubstituted C2-4 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-6 cycloalkyl wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3)R9、R10can form a ring, and the size of the ring system is 3-7 membered alicyclic ring;
in formula IA-1, said X, Y, Z is independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、 COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA-1 of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IA-1 a:
Figure BDA0001620885820000211
in the formula IA-1a,
X、Y、Z、R4、R7、R8、R9、R10is as defined for formula IA-1;
R11selected from the group consisting of:
(1) c1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO 2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10In whichThe Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered aromatic heterocycle, substituted or unsubstituted five membered aromatic heterocycle, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(c) Substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
a is selected from CRaN; b is selected from CRbN; c is selected from CRcN; d is selected from CRdN; A. b, C, D may be N individually, two at the same time and/or three at the same time;
Ra、Rb、Rcand RdIs independently selected from the group consisting of atoms or groups or moieties including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-5 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl, substituted or unsubstituted C2-6 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4And can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independent of each otherIs selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
in formula IA-1a, said X, Y, Z, A, B, C, D is independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA-1a of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IA-1 a-1:
Figure BDA0001620885820000241
in the formula IA-1a-1,
R4、R7、R8、R9、R10and R11Has the same definition as formula IA-1 a;
a 'is selected from CR'aN; b 'is selected from CR'bN; c 'is selected from CR'cN; d 'is selected from CR'dN; x 'is selected from CR'xN; y 'is selected from CR'yN; z 'is selected from CR'zN; a ', B ', C ', D ', X ', Y ' and Z ' can be N independently or N simultaneously;
R'a、R'b、R'c、R'd、R'x、R'y、R'zindependently selected from the group consisting of atoms or groups or moieties comprising (1) H, F, Cl, Br, CN, NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
(2) A substituted or unsubstituted C1-4 straight or branched chain alkyl group, wherein the substituents are selected from the group consisting of F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3-6 membered ring, substituted or unsubstituted azacycloalkyl having 3-6 membered ring, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-3 straight chain or branched chain alkyl, substituted or unsubstitutedThe C2-4 linear or branched alkenyl group, the substituted or unsubstituted C2-4 linear or branched alkynyl group, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
in formula IA-1a-1, X ', Y ', Z ', A ', B ', C ', D ' are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA-1a-1 of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IA-1a-1 a:
Figure BDA0001620885820000251
in formula IA-1a-1a,
R4、R9、R10the definitions of A ', B ', C ', D ', X ', Y ' and Z ' are the same as the general formula IA-1 a-1;
a 'is selected from CR'aN; b 'is selected from CR'bN; c 'is selected from CR'cN; d 'is selected from CR'dN; x 'is selected from CR'xN; y 'is selected from CR'yN; z 'is selected from CR'zN; a ', B ', C ', D ', X ', Y ' and Z ' can be N independently or N simultaneously;
R'a、R'b、R'c、R'd、R'x、R'y、R'zindependently selected from the group consisting of atoms or groups or moieties including (1) H, F, Cl, Br, CN, NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
(2) a substituted or unsubstituted C1-4 straight or branched chain alkyl group, wherein the substituents are selected from the group consisting of F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-3 linear or branched alkyl, substituted or unsubstituted C2-4 linear or branched alkenyl, substituted or unsubstituted C2-4 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
R'7、R'8may be independently selected from the following groups or structural fragments:
hydrogen, methyl, ethyl, propyl, CORf'1、COORf′2、SO2Rf′3、CONRf′4Rf′5Wherein Rf'1、Rf′2、Rf′3、Rf′4、Rf′5Independently selected from H, substituted or unsubstituted C1-6 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl, substituted or unsubstituted C2-6 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
rf'1、Rf′2、Rf′3、Rf′4、Rf′5And can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from C1-3 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、 COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-3 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time; rf' 1、Rf′2、Rf′3、Rf′4、Rf′5Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、NRa′6COORb′3、 SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、 Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、 Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R'11selected from the group consisting of:
(1) c1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 straight or branched alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered oxacycloalkyl, substituted or unsubstituted 3-8 membered azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered aromatic heterocycle, substituted or unsubstituted five membered aromatic heterocycle, wherein the substituents are selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
In the general formula IA-1a-1a, the X' and Y are', Z', A ', B', C ', D' are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA-1a-1 of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IA-1a-1 b:
Figure BDA0001620885820000281
in formula IA-1a-1b,
R4、R9、R10the definitions of A ', B ', C ', D ', X ', Y ' and Z ' are the same as the general formula IA-1a-1 a;
a 'is selected from CR'aN; b 'is selected from CR'bN; c 'is selected from CR'cN; d 'is selected from CR'dN; x 'is selected from CR'xN; y 'is selected from CR'yN; z 'is selected from CR'zN; a ', B ', C ', D ', X ', Y ' and Z ' can be N independently or N simultaneously;
R'a、R'b、R'c、R'd、R'x、R'y、R'zindependently selected from the group consisting of atoms or groups or moieties including (1) H, F, Cl, Br, CN, NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
(2) a substituted or unsubstituted C1-4 straight or branched chain alkyl group, wherein the substituents are selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-3 linear or branched alkyl, substituted or unsubstituted C2-4 linear or branched alkenyl, substituted or unsubstituted C2-4 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4And can also be independently selected from the group consisting of substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
R'7、R'8may be independently selected from the following groups or structural fragments:
Hydrogen, methyl, ethyl, propyl and CORf'1、COORf′2、SO2Rf′3、CONRf′4Rf′5Wherein Rf'1、Rf′2、Rf′3、Rf′4、Rf′5Independently selected from H, substituted or unsubstituted C1-6 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenylSubstituted or unsubstituted C2-6 straight or branched alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
rf'1、Rf′2、Rf′3、Rf′4、Rf′5Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from C1-3 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、 COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-3 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms; rf'1、Rf′2、Rf′3、Rf′4、Rf′5Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen-substituted C1 -4 straight or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、NRa′6COORb′3、 SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、 Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、 Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
Ar'2may be independently selected from the following groups or structural fragments:
(1) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight chain or branched chain alkyl, cyclopropyl,Cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) Substituted or non-substituted aromatic condensed ring or condensed heterocyclic ring, substituted or non-substituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or non-substituted naphthalene ring, substituted or non-substituted benzo six-membered heterocyclic ring, substituted or non-substituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、 NRs4CORt2、COORs5、CONRs6Rt3、NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、 (CH2)nORs10Wherein said Rs1、Rs2、Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、 Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.
In formula IA-1a-1B, X ', Y ', Z ', A ', B ', C ', D ' are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA of the present invention, and physiologically acceptable salts thereof, include, but are not limited to, compounds of formula IA-2:
Figure BDA0001620885820000311
In the case of the formula IA-2,
x is selected from CRxN; y is selected from CRyN; z is selected from CRzN; x, Y, Z can be N alone, two at the same time, and/or three at the same time;
Rx、Ryand RzIs independently selected from the group consisting of atoms or groups or moieties including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straightChain or branched alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
Ar1selected from the group consisting of:
substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, substituted or unsubstituted 4-8 membered heterocycle (including 4-8 membered ring lactam), wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight chain or branched chain alkyl, cyclopropyl,Cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R3selected from the group consisting of:
(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from
(a) C1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 linear or branched alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered oxacycloalkyl, substituted or unsubstituted 3-8 membered azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered heteroaromatic ring, substituted or unsubstituted five membered heteroaromatic ring, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(b) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl having 3 to 8 membered rings, wherein the substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) Substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、 NRs4CORt2、COORs5、CONRs6Rt3、NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、 (CH2)nORs10Wherein said Rs1、Rs2、Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、 Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or polysubstituted; the benzo six-membered heterocycle or benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R4selected from the group consisting of:
(1) selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, and substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) can be selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
(3) can be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or C1-4 straight chainBranched alkyl, halogen-substituted C1-4 straight or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R9、R10May be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-4 straight or branched chain alkyl, substituted or unsubstituted C2-4 straight or branched chain alkenyl, substituted or unsubstituted C2-4 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-6 cycloalkyl wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3)R9、R10can form a ring, and the size of the ring system is 3-7 membered alicyclic ring;
in formula IA-2, said X, Y, Z is independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、 COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA-2 of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IA-2 a:
Figure BDA0001620885820000361
in the case of the formula IA-2a,
X、Y、Z、R4、Ar1、R9、R10has the same definition as in formula IA-2;
R11selected from the group consisting of:
(1) c1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO 2CN, methylenedioxyRadicals, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered aromatic heterocycle, substituted or unsubstituted five membered aromatic heterocycle, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl having 3 to 8 membered rings, wherein the substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(c) Substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
a is selected from CRaN; b is selected from CRbN; c is selected from CRcN; d is selected from CRdN; A. b, C, D may be N individually, two at the same time and/or three at the same time;
Ra、Rb、Rcand RdIs independently selected from the group consisting of atoms or groups or moieties including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein said Rc1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-5 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl, substituted or unsubstituted C2-6 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
in formula IA-2a, said X, Y, Z, A, B, C, D is independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IA-2a of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IA-2 a-1:
Figure BDA0001620885820000391
in the formula IA-2a-1,
R4、Ar1、R9、R10has the same definition as in formula IA-2 a;
R11selected from the group consisting of:
(1) c1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 linear or branched alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered oxacycloalkyl, substituted or unsubstituted 3-8 membered azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered heteroaromatic ring, substituted or unsubstituted five membered heteroaromatic ring, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl having 3 to 8 membered rings, wherein the substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
A 'is selected from CR'aN; b 'is selected from CR'bN; c 'is selected from CR'cN; d 'is selected from CR'dN; x 'is selected from CR'xN; y 'is selected from CR'yN; z 'is selected from CR'zN; a ', B ', C ', D ', X ', Y ' and Z ' can be N independently or N simultaneously;
R'a、R'b、R'c、R'd、R'x、R'y、R'zindependently selected from the group consisting of atoms or groups or moieties including (1) H, F, Cl, Br, CN, NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
(2) a substituted or unsubstituted C1-4 straight or branched chain alkyl group, wherein the substituents are selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3-6 membered ring, substituted or unsubstituted azacycloalkyl having 3-6 membered ring, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-3 straight chain or branched chain alkyl, substituted or unsubstituted C2-4 straight chain or branched chain alkenyl, substituted or unsubstituted C2-4 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; 3-6 membered ring oxacycloalkyl and azacycloalkanesThe group may contain 1 heteroatom or a plurality of heteroatoms at the same time;
in formula IA-2a-1, X ', Y ', Z ', A ', B ', C ', D ' are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the invention according to formula I of the present invention and their physiologically acceptable salts include, but are not limited to, compounds of formula IB:
Figure BDA0001620885820000411
In the formula IB, the compound represented by the formula IB,
x is selected from CRxN; y is selected from CRyN; z is selected from CRzN; x, Y, Z can be N alone, two at the same time, and/or three at the same time;
Rx、Ryand RzIs independently selected from the group consisting of atoms or groups or moieties including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein said Rc1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
R2selected from the group consisting of:
(1)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6CONRf4Rf5、NRe7SO2Rf6wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Independently selectFrom H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4、Re7、Rf5、Rf6Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen-substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2)CONRh1Ri1、COORh2、SO2Rh3、SO2NRh4Ri2Wherein Rh is1、Ri1、Rh2、 Rh3、Rh4、Ri2Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 linear or branched alkyneWherein said substituents are selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
the Rh1、Ri1、Rh2、Rh3、Rh4、Ri2Can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
the Rh1、Ri1、Rh2、Rh3、Rh4、Ri2Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched alkyl, halogen substituted C1-4 straight chain Chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、NRa′6COORb′3、 SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、 Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、 Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(3) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, substituted or unsubstituted 4-8 membered heterocycle (including 4-8 membered ring lactam), wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl,A cyclohexyl group;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R3Selected from the group consisting of:
(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from
(a) C1-8 straight chain or branched alkyl, halogen substituted C1-8 straight chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered aromatic heterocycle, substituted or unsubstituted five membered aromatic heterocycle, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(b) Substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl having 3 to 8 membered rings, wherein the substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) Substituted or non-substituted aromatic condensed ring or condensed heterocyclic ring, substituted or non-substituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or non-substituted naphthalene ring, substituted or non-substituted benzo six-membered heterocyclic ring, substituted or non-substituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、 NRs4CORt2、COORs5、CONRs6Rt3、NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、 (CH2)nORs10Wherein said Rs1、Rs2、Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、 Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or polysubstituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.
R5、R6May be independently selected from the following groups or structural fragments:
(1) selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, and substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) can be selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(3) can be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight chain or branched chain alkylHalogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R9、R10May be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-4 straight chain or branched alkyl, substituted or unsubstituted C2-4 straight chain or branched alkenyl, substituted or unsubstituted C2-4 straight chain or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-6 cycloalkyl, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3)R9、R10can form a ring, and the size of the ring system is 3-7 membered alicyclic ring;
in formula IB, said X, Y, Z are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、 COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention and physiologically acceptable salts thereof according to formula IB of the present invention include, but are not limited to, compounds represented by formula IB-1:
Figure BDA0001620885820000481
in the formula IB-1, the compound represented by the formula,
x, Y, Z, R3, R5, R6, R9 and R10 are as defined in formula IB;
R7、R8may be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl, substituted or unsubstituted C2-8 straight or branched chain alkynyl, wherein The substituent is selected from F, Cl, Br, CN and ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl with 3 to 8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl group having 3 to 8 membered ring and the azacycloalkyl group having 3 to 8 membered ring may contain 1 or more heteroatoms;
(3)CORf′1、COORf′2、SO2Rf′3、CONRf′4Rf′5wherein Rf'1、Rf′2、Rf′3、Rf′4、 Rf′5Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, C,ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
rf'1、Rf′2、Rf′3、Rf′4、Rf′5And can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, and substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、 COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms; rf'1、Rf′2、Rf′3、Rf′4、Rf′5Can also be independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、CONRa′5Rb′2、NRa′6COORb′3、 SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、(CH2)nORa′10Wherein Ra'1、 Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、 Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
in formula IB-1, said X, Y, Z are independently preferably selected from CH, N, CF, CCl, CCH 3、CC2H5、 COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IB-1 of the present invention, and physiologically acceptable salts thereof, include, but are not limited to, compounds represented by formula IB-1 a:
Figure BDA0001620885820000491
in the formula IB-1a,
x, Y, Z, R5, R6, R7, R8, R9, R10 are as defined for formula IB-1;
R11selected from the group consisting of:
(1) c1-8 straight or branched chain alkaneAlkyl, halogen substituted C1-8 straight chain or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered aromatic heterocycle, substituted or unsubstituted five membered aromatic heterocycle, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(2) Substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3-to 8-membered ring, substituted or unsubstituted azacycloalkane having 3-to 8-membered ringWherein said substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
A is selected from CRaN; b is selected from CRbN; c is selected from CRcN; d is selected from CRdN; A. b, C, D can be N alone, two at the same time, and/or three at the same time;
Ra、Rb、Rcand RdIs independently selected from the group consisting of atoms or groups or moieties, including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-5 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl, substituted or unsubstituted C2-6 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
in formula IB-1a, said X, Y, Z, A, B, C, D are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IB-1a of the present invention, and physiologically acceptable salts thereof, include, but are not limited to, compounds represented by formula IB-1 a-1:
Figure BDA0001620885820000521
In the formula IB-1a-1,
r5, R6, R7, R8, R9, R10 and R11 are as defined for formula IB-1;
a 'is selected from CR'aN; b 'is selected from CR'bN; c 'is selected from CR'cN; d 'is selected from CR'dN; x 'is selected from CR'xN; y 'is selected from CR'yN; z 'is selected from CR'zN; a ', B ', C ', D ', X ', Y ' and Z ' can be N independently or N simultaneously;
R'a、R'b、R'c、R'd、R'x、R'y、R'zindependently selected from the group consisting of atoms or groups or moieties comprising (1) H, F, Cl, Br, CN, NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
(2) a substituted or unsubstituted C1-4 straight or branched chain alkyl group, wherein the substituents are selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-3 straight chain or branched chain alkyl, substituted or unsubstituted C2-4 straight chain or branched chain alkenyl, substituted or unsubstituted C2-4 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
in formula IB-1a-1, said X ', Y ', Z ', A ', B ', C ', D ' are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention and physiologically acceptable salts thereof according to formula IB of the present invention include, but are not limited to, compounds represented by formula IB-2:
Figure BDA0001620885820000531
In the formula IB-2, the compound of formula I,
x is selected from CRxN; y is selected from CRyN; z is selected from CRzN; x, Y, Z can be N alone, two at the same time, and/or three at the same time;
Rx、Ryand RzIs independently selected from the group consisting of atoms or groups or moieties, including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein said Rc1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
Ar1selected from the group consisting of:
substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, substituted or unsubstituted 4-8 membered heterocycle (including 4-8 membered ring lactam), wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R3selected from the group consisting of:
(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from
(a) C1-8 straight chain or branched chain alkyl, halogen substituted C1-8 straight chain or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 linear or branched alkyl, substituted or unsubstituted C2-8 linear or branched alkenyl, substituted or unsubstituted C2-8 linear or branched alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted Substituted 3-8 membered ring azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered aromatic heterocycle, substituted or unsubstituted five membered aromatic heterocycle, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(b) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa 1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
(2) substituted or non-substituted aromatic condensed ring or condensed heterocyclic ring, substituted or non-substituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or non-substituted naphthalene ring, substituted or non-substituted benzo six-membered heterocyclic ring, substituted or non-substituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、 NRs4CORt2、COORs5、CONRs6Rt3、NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、 (CH2)nORs10Wherein said Rs1、Rs2、Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、 Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cycloButyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or polysubstituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.
R5、R6May be independently selected from the following groups or structural fragments:
(1) selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) can be selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropyleneMethyl, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(3) can be selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkyl, halogen-substituted C1-4 straight-chain or branched-chain alkyl, F, Cl, Br, NO 2CN, methylenedioxy, ORa'1、SRa′2、NRa′3Rb′1、COORa′4、 CONRa′5Rb′2、NRa′6COORb′3、SO2NRa′7Rb′4、NRa′8CORb′5、(CH2)nNRa′9Rb′6、 (CH2)nORa′10Wherein Ra'1、Ra′2、Ra′3、Rb′1、Ra′4、Ra′5、Rb′2、Ra′6、Rb′3、 Ra′7、Rb′4、Ra′8、Rb′5、Ra′9、Rb′6、Ra′10Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocycle may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
R9、R10may be independently selected from the following groups or structural fragments:
(1) hydrogen, substituted or unsubstituted C1-4 straight chain or branched alkyl, substituted or unsubstituted C2-4 straight chain or branched alkenyl, substituted or unsubstituted C2-4 straight chain or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、NRx7COORy4、 SO2NRx8Ry5Said Rx being1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、Ry3、Rx7、Ry4、 Rx8、Ry5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C3-6 cycloalkyl, wherein the substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORx1、SRx2、NRx3Ry1、NRx4CORy2、COORx5、CONRx6Ry3、 NRx7COORy4、SO2NRx8Ry5Said Rx1、Rx2、Rx3、Ry1、Rx4、Ry2、Rx5、Rx6、 Ry3、Rx7、Ry4、Rx8、Ry5Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3)R9、R10Can form a ring, and the size of the ring system is 3-7 membered alicyclic ring;
in formula IB-2, said X, Y, Z are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、 COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the present invention according to formula IB-2 of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula IB-2 a:
Figure BDA0001620885820000581
in the formula IB-2a,
X、Y、Z、R5、R6、Ar1、R9、R10is as defined for formula IB-2;
R11selected from the group consisting of:
(1) c1-8 straight chain or branched chain alkyl, halogen substituted C1-8 straight chain or branched chain alkyl, F, Cl, Br, NO2CN, methylenedioxy, ORs1、SRs2、NRs3Rt1、NRs4CORt2、COORs5、CONRs6Rt3、 NRs7COORt4、SO2NRs8Rt5、(CH2)nNRs9Rt6、(CH2)nORs10Wherein said Rs1、Rs2、 Rs3、Rt1、Rs4、Rt2、Rs5、Rs6、Rt3、Rs7、Rt4、Rs8、Rt5、Rs9、Rt6、Rs10Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-8 membered ring oxacycloalkyl, substituted or unsubstituted 3-8 membered ring azacycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted six membered aromatic heterocycle, substituted or unsubstituted five membered aromatic heterocycle, wherein the substituents are selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、 NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、 Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl; oxacycloalkyl of 3-to 8-membered rings or The azacycloalkyl group may contain 1 heteroatom or a plurality of heteroatoms at the same time;
(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having a 3-to 8-membered ring may contain 1 or more heteroatoms;
(c) substituted or unsubstituted phenyl, substituted or unsubstituted six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, cyclohexyl;
the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;
A is selected from CRaN; b is selected from CRbN; c is selected from CRcN; d is selected from CRdN; A. b, C, D can be N alone, two at the same time, and/or three at the same time;
Ra、Rb、Rcand RdIs independently selected from the group consisting of atoms or groups or moieties including
(1)H、F、Cl、Br、CN、NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、 CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、 Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 8 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-5 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl, substituted or unsubstituted C2-6 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein Ra is as defined above1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or substitutedUnsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl having 3 to 6 membered rings, substituted or unsubstituted azacycloalkyl having 3 to 6 membered rings, wherein the substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
in formula IB-2a, said X, Y, Z, A, B, C, D are independently preferably selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
Preferred compounds of the invention according to formula IB-2a of the invention, and physiologically acceptable salts thereof, include, but are not limited to, compounds represented by formula IB-2 a-1:
Figure BDA0001620885820000601
In the formula IB-2a-1,
R5、R6、Ar1、R9、R10、R11is as defined for formula IB-2 a;
a 'is selected from CR'aN; b 'is selected from CR'bN; c 'is selected from CR'cN; d 'is selected from CR'dN; x 'is selected from CR'xN; y 'is selected from CR'yN; z 'is selected from CR'zN; a ', B ', C ', D ', X ', Y ' and Z ' can be independentlyN, or a plurality of N at the same time;
R'a、R'b、R'c、R'd、R'x、R'y、R'zindependently selected from the group consisting of atoms or groups or moieties including (1) H, F, Cl, Br, CN, NO2、NH2、CONRc1Rd1、COORc2、SO2Rc3、SO2NRc4Rd2Wherein Rc is1、Rc2、Rc3、Rc4、Rd1、Rd2Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;
(2) a substituted or unsubstituted C1-4 straight or branched chain alkyl group, wherein the substituents are selected from the group consisting of F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、 SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、 Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
(4)ORe1、NRe2Rf1、SRe3、NRe4CORf2、NRe5COORf3、NRe6SO2Rf4Wherein said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Independently selected from H, substituted or unsubstituted C1-3 linear or branched alkyl, substituted or unsubstituted C2-4 linear or branched alkenyl, substituted or unsubstituted C2-4 linear or branched alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa1、SRa2、 NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene;
said Re1、Re2、Rf1、Re3、Re4、Rf2、Re5、Rf3、Re6、Rf4Can also be independently selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, F, Cl, Br, CN, ORa1、SRa2、NRa3Rb1、COORa4、CONRa5Rb2、NRa6COORb3、SO2NRa7Rb4、 NRa8CORb5Wherein said Ra1、Ra2、Ra3、Rb1、Ra4、Ra5、Rb2、Ra6、Rb3、Ra7、 Rb4、Ra8、Rb5Independently selected from H, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethylene; the oxacycloalkyl and azacycloalkyl groups having 3 to 6 membered rings may contain 1 or more heteroatoms;
in the general formula IB-2a-1, the X ', Y ', Z ', A ', B ', C ', D ' are independently selected from CH, N, CF, CCl, CCH3、CC2H5、COCH3、COC2H5、CNHCH3、CNHC2H5。
For the purposes of the present invention, preferred compounds include, but are not limited to:
Figure BDA0001620885820000621
Figure BDA0001620885820000631
Figure BDA0001620885820000641
Figure BDA0001620885820000651
Figure BDA0001620885820000661
Figure BDA0001620885820000671
in a second aspect of the present invention, there is provided a process for the preparation of a compound of the first aspect, which comprises the steps of:
The synthesis of the target compound (shown in the general formula I) of the aryl formamide is carried out by carrying out condensation reaction on acid and substituted primary amine which are differently substituted at 2-position and 5-position; wherein the key acid intermediate is prepared by esterification reaction of 2-hydroxy-5-nitro aromatic (hetero) acid and 2-hydroxy-5-bromo aromatic (hetero) acid under the action of thionyl chloride, and then substitution reaction and hydrolysis reaction, or nucleophilic substitution reaction of 2-chloro-5-nitro aromatic (hetero) acid and amine; another key intermediate amine 10 is prepared by starting from a bromo-aryl (hetero) acyl compound 7a, sequentially performing a coupling reaction, a condensation reaction with hydroxylamine and a reduction reaction; or the compound is prepared by the different substituted aryl (hetero) amide compounds 7b through the addition elimination reaction, the hydroxylamine reaction and the reduction reaction in turn; or starting from a differently substituted cyano compound 7c, the subsequent addition elimination reaction, reaction with hydroxylamine and reduction reaction. The alpha-disubstituted amine 11 is prepared by the addition reaction of different substituted cyano compounds; the resulting acid is subjected to a condensation reaction with an amine to give compounds 12, 15, 17, 20, 23 and 26, and then compounds 12, 17, 23 and 26 are subjected to a reduction reaction, an acylation reaction or a reductive amination reaction to prepare the objective compounds. The target compound is prepared from the compounds 15 and 20 through a coupling reaction.
Figure BDA0001620885820000681
Figure BDA0001620885820000691
Reagents and reaction conditions: (a) o-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), 1-Hydroxybenzotriazole (HOBT), Diisopropylethylamine (DIEA), N-Dimethylformamide (DMF), room temperature; or 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC), 1-hydroxybenzotriazole, diisopropylethylamine, N, N-dimethylformamide, at room temperature; (b) thionyl chloride (SOCl)2)，Anhydrous methanol (Anhydrous MeOH), 60 ℃; (c) R-I or R-Br, potassium carbonate (K)2CO3) Anhydrous N, N-dimethylformamide (Anhydrous DMF), 60 ℃; (d) sodium hydroxide (NaOH), tetrahydrofuran/water (THF/H)2O), room temperature; (e) tetratriphenylpalladium phosphide (Pd (PPh)3)4) Sodium carbonate (Na)2CO3) R-Br, 1,4-dioxane (1,4-dioxane), water, argon, 110 ℃; or tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) (±) -2,2 '-bis- (diphenylphosphino) -1,1' -Binaphthyl (BINAP), sodium tert-butoxide, Toluene (Toluene), argon, 100 ℃; (f) methyl magnesium bromide (CH)3MgBr), anhydrous tetrahydrofuran, argon, 0 ℃; (g) methyllithium (CH)3Li), anhydrous tetrahydrofuran, argon, -66 ℃; (h) 50% aqueous hydroxylamine, ethanol (EtOH), water, 60 ℃; (i) zinc powder (Zn), hydrochloric acid, ethanol, water, room temperature; or 10% palladium on carbon (10% Pd/C), ammonium formate, methanol, reflux; (j) cerium trichloride (CeCl) 3) Methyllithium, argon, -66 ℃; (k) 10% Palladium on carbon, Hydrogen (H)2) Ethanol, room temperature; or iron powder (Fe), ammonium chloride (NH)4Cl), ethanol, water, reflux; (l) R-COCl, triethylamine (Et)3N), Dichloromethane (DCM), 0 ℃; or RR' CO, sodium triacetoxyborohydride (NaBH (OAc))3) Dichloromethane, room temperature; (m) tris (dibenzylideneacetone) dipalladium, (±) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, sodium tert-butoxide, toluene, argon, 100 ℃; or palladium tetrakistriphenylphosphine, sodium carbonate, 1, 4-dioxane, water, argon, 110 ℃ or 1, 10-phenanthroline, potassium carbonate, copper iodide (CuI), N, N-dimethylformamide, argon, 120 ℃; or iron (III) acetylacetonate, cesium carbonate (Cs)2CO3) Copper oxide (CuO), N-dimethylformamide, 120 ℃; (n) R5R6-NH, acetonitrile, diisopropylethylamine, 65 ℃;
wherein said X, Y, Z, A, B, C, D, Ar1、R1、R2、R3、R4、R5、R6、R7、R8、 R9、R10And R11As defined in the inventionIn one aspect.
In addition, the starting materials and intermediates in the above reactions are readily available, and the reactions of each step can be readily synthesized according to reported literature or by conventional methods in organic synthesis to those skilled in the art. The compounds of formula I may exist in the form of solvates or non-solvates, and crystallization using different solvents may give different solvates. Pharmaceutically acceptable salts of formula I include salts of various acids, such as the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycic acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. The pharmaceutically acceptable salts of formula I also include salts of various alkali metal (lithium, sodium, potassium), alkaline earth metal (calcium, magnesium) and ammonium salts, and salts with organic bases that provide physiologically acceptable cations, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris (2-hydroxyethyl) amine. All such salts within the scope of the present invention may be prepared by conventional methods.
In a third aspect of the present invention, there is provided a pharmaceutical composition, which comprises the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The composition comprises at least one compound of the invention and a pharmaceutically acceptable carrier. The medicine composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle administration systems. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal and the like.
The dosage form for administration may be a liquid, solid or semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, for example starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, for example water, ethanol, propylene glycol, vegetable oils, for example corn oil, peanut oil, olive oil and the like. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.
For tableting the compounds of the present invention, a wide variety of excipients well known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For the encapsulation of the administration units, the active ingredient compounds according to the invention can be mixed with diluents, glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or the mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, in the preparation of lyophilized powder for injection, mannitol and glucose can also be added as proppant.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage of the compound of the invention is in the range of 0.1 to 1000mg/Kg body weight, preferably 1 to 500mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The fourth aspect of the technical scheme of the invention provides an application of the compound and the pharmaceutical salt thereof in the first aspect of the invention in preparing a Kv2.1 inhibitor, an application in preparing a medicament for preventing and/or treating diseases related to Kv2.1, an application in preparing a medicament for treating diseases related to Kv2.1, which are selected from mental and nervous system diseases, metabolic diseases and cardiovascular and cerebrovascular diseases, and an effect in preparing a medicament related to diseases such as Alzheimer's disease, depression, diabetes, atherosclerosis and cerebral apoplexy.
The beneficial technical effects are as follows:
the aromatic amide Kv2.1 inhibitor has very strong inhibitory activity; compared with other ion channels, the compounds have very good selectivity on Kv2.1; the in vivo activity shows that the medicine has the functions of treating cerebral apoplexy, resisting depression activity, reducing blood fat activity and improving learning and memory functions.
Drawings
FIG. 1. Effect of example 61 on rat jump error time in jump experiment
n-14-16. # # p <0.01vs. control, p <0.05, p <0.01vs. model.
Figure 2. effect of example 61 on immobility time in rat tail suspension experiments, n 15. p <0.05vs model group
Figure 3. effect of example 61 on acute hypoxia (decapitation), p <0.01vs. control.
Figure 4. effect of example 61 on brain hypoxia (cupping), p <0.01vs. control.
Detailed Description
The present invention will be further illustrated with reference to the following examples, but the scope of the present invention is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or High Resolution Mass Spectrometry (HRMS). NMR was measured using a Varian mercure 300 or Varian mercure 400 solvent as CDCl3、DMSO-d6、 acetone-d6、CD3OD, internal standard TMS, chemical shifts are given in ppm. m.p. is the melting point given in ° c, the temperature is uncorrected. The silica gel column chromatography generally uses 200-300 mesh silica gel as a carrier.
List of abbreviations:
TLC, thin layer chromatography;
DIEA: diisopropylethylamine; TFA: trifluoroacetic acid; TEA: triethylamine
DMF: n, N-dimethylformamide; THF: tetrahydrofuran; PE: petroleum ether; EA: ethyl acetate
DCM: dichloromethane; min: the method comprises the following steps of (1) taking minutes; r.t. room temperature; h: hours;
EDC or EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride
HBTU: o-benzotriazole-tetramethylurea hexafluorophosphate
HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
HOBt: 1-hydroxybenzotriazole; TFA: trifluoroacetic acid;
Pd2(dba)3: tris (dibenzylideneacetone) dipalladium; pd (PPh)3)4: tetratriphenylphosphine palladium
Xantphos: 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene
The BINAP: (±) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl
K3PO4: potassium phosphate; CS2CO3: cesium carbonate; PPh3: triphenylphosphine and its use
DDQ: 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone; zn: zinc powder; NaH: sodium hydride;
CDCl3: deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide;
preparation of intermediates
2- (dimethylamino) -5-nitrobenzoic acid
Figure BDA0001620885820000731
Taking 2-chloro-5-nitrobenzoic acid (2.0g,10.00mmol), adding dimethylamine (40% aqueous solution) (20mL), heating to 65 ℃, after 8h, completely reacting the raw materials, dropwise adding dilute acetic acid solution, adjusting the pH value to acidity, performing EA extraction (30mL multiplied by 5), combining, concentrating and drying to obtain yellow solid 1.6g, 76.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.92(d,J＝2.8Hz,1H),8.33(dd,J＝9.2,2.8Hz, 1H),7.36(d,J＝9.2Hz,1H),2.96(s,6H)；ESI-MS m/z:209.06[M-H]-。
Preparation of (di) 2-ethoxy-5-benzoic acid
Figure BDA0001620885820000741
a) 2-hydroxy-5-nitrobenzoic acid methyl ester
Figure BDA0001620885820000742
2-hydroxy-5-nitrobenzoic acid (6g, 32.7mmol) was dissolved in anhydrous methanol (50mL) and SOCl was added slowly with stirring2The solution reacts for 10 hours at 60 ℃, and then is cooled, filtered and filter cake is washed by ice methanol to obtain 5.585g of white solid with 86 percent of yield.
1H NMR(400MHZ,CDCl3)δ(ppm):8.44(s,1H),8.79(d,J＝2.8Hz,1H),8.34(dd, J1＝2.8Hz,J2＝9.2Hz,1H),7.09(d,J＝9.2Hz,1H),4.04(s,3H).m.p.115-117.
b) 2-ethoxy-5-nitrobenzoic acid methyl ester
Figure BDA0001620885820000743
Methyl 2-hydroxy-5-nitrophenyl-carboxylate (5g, 25.3mmol) was dissolved in anhydrous DMF (40mL) and K was added2CO3(6.982g, 50.6mmol), C was added2H5I (11.84g, 75.9mmol), was reacted by heating to 70 ℃. After the raw material disappeared, it was cooled, water was added to precipitate off-white solid, filtered, and the filter cake was washed with water to obtain 5.5g of off-white solid with a yield of 96%. m.p.121-123 deg.C
1H NMR(400MHZ,CDCl3)δ(ppm):8.69(d,J＝2.8Hz,1H),8.34(dd,J1＝2.8Hz, J2＝9.2Hz,1H),7.04(d,J＝9.2Hz,1H),4.24(q,J＝6.8Hz,2H).3.93(s,3H),1.52(t, J＝6.8Hz,3H).
The following intermediates were prepared according to the general procedure described above
Figure BDA0001620885820000744
Figure BDA0001620885820000751
Figure BDA0001620885820000761
c) 2-ethoxy-5-nitrobenzoic acid
Figure BDA0001620885820000762
Methyl 2-ethoxy-5-nitrobenzoate (4.1g, 18.2mmol) was dissolved in THF (60mL)/(30mL), NaOH (3.64g, 91mmol) was added with stirring, the reaction was allowed overnight at room temperature, concentrated, the aqueous layer was washed with diethyl ether, the pH was adjusted to 2 with concentrated hydrochloric acid, and 3.75g of a white solid was precipitated, and the yield was 97%.
1H NMR(500MHZ，CDCl3)δ(ppm):9.03(d,J＝2.5Hz,1H),8.43(dd,J1＝2.5Hz, J2＝9.0Hz,1H),7.16(d,J＝9.0Hz,1H),4.44(q,J＝7.0Hz,2H),1.63(t,J＝7.0Hz, 3H).m.p.80-82℃.
The following intermediates were prepared according to the general procedure described above
Figure BDA0001620885820000763
Figure BDA0001620885820000771
Figure BDA0001620885820000781
2-ethoxy-5-isobutyrylaminobenzoic acid
Figure BDA0001620885820000782
(a) 5-amino-2-ethoxybenzoic acid methyl ester
Methyl 2-ethoxy-5-nitrobenzoate (1g,4.44mmol) was dissolved in THF (15mL), Pd/C100 mg was added, hydrogen was bubbled in at room temperature, reaction was overnight, filtration was performed, filtrate was concentrated to give 859mg of a yellowish green oil with a yield of 99.2%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.19-7.08(m,1H),6.84-6.80(m,2H),4.02(q,J ＝7.2Hz,2H),3.87(s,3H),3.09(s,2H),1.40(t,J＝7.2Hz,3H)；ESI-MS m/z:196.10 [M+H]+。
(b) 2-ethoxy-5-isobutyrylaminobenzoic acid methyl ester
Methyl 5-amino-2-ethoxybenzoate (294mg,1.5mmol), DMF (20mL), EDC (576 mg,3mmol), HOBt (405mg,3mmol), DIEA (0.52mL,3mmol) and isobutyric acid (0.14mL, 1.5mmol) were added, the reaction was stirred at room temperature, stopped the next day, water was added, ethyl acetate (50 mL × 2), the combined organic layers were washed with a saturated NaCl solution (30 mL × 2), dried over anhydrous magnesium sulfate, and column chromatography (E: P ═ 1:5, E: P ═ 1:3) gave 306mg of a white solid in 77% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.75-7.80(m,2H),7.44(brs,0.5H),7.27(brs, 0.5H),6.89-6.93(m,1H),4.05-4.10(m,2H),3.86(d,J＝5.2Hz,3H),2.46-2.54(m, 1H),1.40-1.45(m,3H),1.22-1.25(m,6H).
(c) 2-ethoxy-5-isobutyrylaminobenzoic acid
Placing methyl 2-ethoxy-5-isobutyrylaminobenzoate (271mg,1.02mmol) into a reaction bottle, adding THF (3mL) and MeOH (3mL), dissolving lithium hydroxide (32mg,1.33mmol) in water (2mL), dropwise adding into the reaction bottle, stirring at room temperature for reaction after dropping, stopping reaction the next day, concentrating, adding water, extracting with diethyl ether (10 mL), adjusting the pH value of a water layer to about 3 with dilute hydrochloric acid solution, precipitating solids, filtering, washing a filter cake with water to obtain 250mg of white solid with the yield of 97.6%.
1H-NMR(400MHz,CDCl3)δ(ppm):12.51(s,1H),9.76(s,1H),7.87(s,1H),7.67(d, J＝8.8Hz,1H),7.03(d,J＝8.8Hz,1H),4.03(q,J＝6.8Hz,2H),2.50-2.55(m,1H), 1.29(t,J＝6.4Hz,3H),1.07(d,J＝6.8Hz,6H).
3- (thiazol-2-yl) benzaldehyde
Figure BDA0001620885820000792
Pd (AcO)2(1.5g,6.67mmol)，PPh3(7.0g,26.68mmol) was added to dioxane (50mL), reacted under argon at room temperature for 30min, and 2-bromothiazole (10.9g,66.67mmol), Na were added sequentially2CO3(21.2g,200mmol), 3-formylphenylboronic acid (10g,66.67mmol) and 10mL of distilled water were reacted at 110 ℃ for 8h under the protection of argon, and the starting material disappeared. After filtration, the filtrate was concentrated, and EA (50mL) was added to dilute the filtrate, washed with water (20mL × 2), washed with brine (20mL), and subjected to column chromatography (PE/EA 13:1) to obtain 10.7g of a white solid, a yield of 84.9%, m.p.61-62 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.09(s,1H),8.45(s,1H),8.25(d,J＝7.6Hz, 1H),7.93(dd,J＝10.4,5.6Hz,2H),7.63(t,J＝7.8Hz,1H),7.41(d,J＝3.2Hz,1H)； ESI-MS m/z:190.03[M+H]+。
The following intermediates were prepared according to the general procedure described above
Figure BDA0001620885820000791
Figure BDA0001620885820000801
Figure BDA0001620885820000811
3- (2-carbonylpiperidin-1-yl) benzaldehyde
Figure BDA0001620885820000821
The m-bromobenzaldehyde (0.29mL,2.5mmol) is placed in a reaction flask, the dioxane (20mL) is added, and the Pd is added under the protection of argon2(dba)3(229mg,0.25mmol)，xantphos(434mg,0.75mmol)，K3PO4(1.32g, 6.25mmol) and 2-piperidone (248mg,2.5mmol), heating to 100 ℃ for reaction, stopping the reaction after 8h, filtering, concentrating, and performing column chromatography (D: M ═ 200:1, D: M ═ 150:1) to obtain 350mg of a pale yellow oil with a yield of 69%.
1H-NMR(500MHz,CDCl3)δ(ppm):10.00(s,1H),7.79(s,1H),7.76(d,J＝7.0Hz, 1H),7.53-7.59(m,2H),3.70(t,J＝5.5Hz,2H),2.59(t,J＝6.0Hz,2H),1.92-2.00(m, 4H).
The following intermediates were prepared according to the general procedure described above
Figure BDA0001620885820000822
3- (thiazol-2-yl) benzaldoxime
Figure BDA0001620885820000823
3- (Thiazol-2-yl) benzaldehyde (3.5g,18.50mmol) was dissolved in ethanol (20 mL)/water (5mL), hydroxylamine hydrochloride (2.57g,37.00mmol) and sodium acetate (4.55g,55.50mmol) were added in this order, and the reaction was refluxed for 4 hours, and the starting material disappeared. The reaction was stopped, concentrated, and EA (40mL) was added, washed with saturated brine (20mL), and dried over anhydrous Na 2SO4Drying and column chromatography (PE/EA: 8:1) to obtain 2.68g of white solid with yield of 71.1% and m.p. 111-112 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.21(s,2H),7.98(d,J＝7.8Hz,1H),7.90(d,J＝ 3.2Hz,1H),7.65(d,J＝7.8Hz,1H),7.47(t,J＝7.8Hz,1H),7.37(d,J＝3.2Hz,1H)； ESI-MS m/z:205.04[M+H]+。
The following intermediates were prepared according to the general procedure described above
Figure BDA0001620885820000831
Figure BDA0001620885820000841
Figure BDA0001620885820000851
Figure BDA0001620885820000861
Figure BDA0001620885820000871
Figure BDA0001620885820000881
(3- (thiazol-2-yl) phenyl) methanamine
Figure BDA0001620885820000882
3- (Thiazol-2-yl) benzaldoxime (1.0g,4.90mmol) was dissolved in ethanol (20 mL)/water (10mL), Zn (637mg,9.80mmol) and HCl (5N) (5mL,24.5mmol) were added in this order, and the reaction was carried out at room temperature for 4 hours, whereupon the starting material disappeared. The reaction was stopped, saturated sodium bicarbonate solution was added to adjust pH >7, filtered, EA (30mL × 3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 813mg of pale yellow oil in 87.3% yield.
1H-NMR(400MHz,CD3OD)δ(ppm):8.15(s,2H),8.06(d,J＝7.2Hz,1H),7.96(s, 1H),7.71(m,2H),4.26(s,2H)；ESI-MS m/z:191.06[M+H]+。
The following intermediates were prepared according to the general procedure described above
Figure BDA0001620885820000891
Figure BDA0001620885820000901
Figure BDA0001620885820000911
Figure BDA0001620885820000921
Figure BDA0001620885820000931
(3- (tetrahydrofuran-2-yl) phenyl) methylamine
Figure BDA0001620885820000932
3- (furan-2-yl) benzaldoxime (400mg,2.14mmol) was dissolved in methanol (10mL), Pd/C (240mg) was added and the mixture was heated to reflux, ammonium formate (1.35g,21.4mmol) was added and the reaction was refluxed for 10min, and the starting material disappeared. The reaction was stopped, filtered, extracted with water (10mL), ether (15 mL. times.3), combined ether layers and concentrated to give 211mg of a brown oil in 55.8% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.71(s,3H),7.37(s,1H),7.28-7.22(m,2H), 4.80(t,J＝7.2Hz,1H),4.02(dd,J＝14.4,7.2Hz,1H),3.90(s,2H),3.83(dd,J＝14.4, 7.6Hz,1H),2.30-2.24(m,1H),2.00-1.92(m,2H),1.78-1.71(m,1H)；ESI-MS m/z: 178.12[M+H]+。
The following intermediates were prepared according to the general procedure described above
Figure BDA0001620885820000933
Figure BDA0001620885820000941
Figure BDA0001620885820000951
Example 1
2- (dimethylamino) -5-isobutyrylamino-N- (pyridin-2-ylmethyl) benzamide
Figure BDA0001620885820000952
a)2- (dimethylamino) -5-nitro-N- (pyridin-2-ylmethyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (200mg,0.95mmol) was dissolved in DMF (15mL) and DIEA (185mg,1.43mmol), HATU (542mg,1.43mmol) were added sequentially for 20minThen, 2-aminomethylpyridine (93mg,0.86mmol) was added thereto, and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, vol. 2:3) gave 248mg of yellow solid, 95.0% yield, melting point: 140 ℃ and 142 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.58-8.55(m,2H),8.27(s,1H),8.17(dd,J＝9.2, 1.6Hz,1H),7.71(t,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),7.23(d,J＝6.0Hz,1H), 6.96(d,J＝9.2Hz,1H),4.78(d,J＝4.8Hz,2H),2.95(s,6H)；HR-MS(ESI):m/z, calcd.For C15H16O3N4 301.1295[M+H]+,Found:301.1280。
b)2- (dimethylamino) -5-isobutyrylamino-N- (pyridin-2-ylmethyl) benzamide
Dissolving 2- (dimethylamino) -5-nitro-N- (pyridin-2-ylmethyl) benzamide (200mg,0.67mmol) in methanol (20mL), adding pd/C (20mg), introducing hydrogen, stirring overnight at room temperature, filtering, and concentrating to give 175mg of brown oil; isobutyric acid (86mg,0.97mmol) was dissolved in DMF (12mL), DIEA (188mg,1.46mmol) and HATU (553mg,1.46mmol) were added sequentially, and after 20min the above brown oil (175mg,0.65mmol) was added and stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na 2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 88 mg of white solid, yield 40.0%, melting point: 169-170 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.99(s,1H),8.57(d,J＝4.4Hz,1H),8.24(d,J ＝8.8Hz,1H),7.91(d,J＝2.4Hz,1H),7.77(s,1H),7.66(t,J＝7.6Hz,1H),7.34(d,J ＝8.0Hz,1H),7.26(d,J＝8.8Hz,1H),7.21-7.18(m,1H),4.80(d,J＝5.2Hz,2H), 2.71(s,6H),2.59-2.52(m,1H),1.23(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C19H24O2N4341.1972[M+H]+,Found:341.1965。
Example 2
2- (dimethylamino) -5-isobutyrylamino-N- (1- (pyridin-2-yl) ethyl) benzamide
Figure BDA0001620885820000961
a)2- (dimethylamino) -5-nitro-N- (1- (pyridin-2-yl) ethyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (356mg,1.69mmol) was dissolved in DMF (10mL), DIEA (696mg,5.40mmol) and HATU (965mg,2.54mmol) were added in that order, and after stirring for 20min, 1- (pyridin-2-yl) ethylamine hydrochloride (300mg,1.54mmol) was added and stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with saturated ammonium chloride solution (10mL), saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) gave 247mg of yellow solid, yield 51.1%, melting point: 158-160 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.56(d,J＝4.8Hz,1H),8.49(d,J＝2.8Hz,1H), 8.35(d,J＝6.8Hz,1H),8.14(dd,J＝9.2,2.8Hz,1H),7.73(t,J＝7.6Hz,1H),7.35(d, J＝7.6Hz,1H),7.26-7.21(m,1H),6.91(d,J＝9.2Hz,1H),5.34(p,J＝6.8Hz,1H), 2.91(s,6H),1.59(d,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C16H19O3N4 315.1452[M+H]+,Found:315.1439。
b) 5-amino-2- (dimethylamino) -N- (1- (pyridin-2-yl) ethyl) benzamide
2- (dimethylamino) -5-nitro-N- (1- (pyridin-2-yl) ethyl) benzamide (200mg,0.64mmol) was dissolved in THF (20mL), pd/C (20mg) was added, hydrogen was bubbled in, stirred overnight at room temperature, filtered, and concentrated to give 168mg of a yellowish oil in 92.8% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.31(s,1H),8.57(d,J＝4.4Hz,1H),7.64(t,J ＝7.6Hz,1H),7.54(d,J＝2.8Hz,1H),7.32(d,J＝7.6Hz,1H),7.20-7.13(m,1H), 7.09(d,J＝8.4Hz,1H),6.74(dd,J＝8.4,2.8Hz,1H),5.45-5.30(m,1H),3.55(s,2H), 2.65(s,6H),1.59(d,J＝6.8Hz,3H)；ESI-MS m/z:285.17[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (1- (pyridin-2-yl) ethyl) benzamide
Isobutyric acid (279mg,3.17mmol) was dissolved in DMF (10mL), DIEA (409mg, 3.17mmol) and HATU (1.2g,3.17mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (1- (pyridin-2-yl) ethyl) benzamide (300mg,1.06mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with saturated ammonium chloride solution (10mL), saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, 2:3 by volume) gave 109mg of white solid, 29.1% yield, melting point: 161-162 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):11.00(d,J＝7.2Hz,1H),8.58(d,J＝4.4Hz, 1H),8.21(d,J＝8.4Hz,1H),7.85(d,J＝2.4Hz,1H),7.78(s,1H),7.65(t,J＝7.6Hz, 1H),7.29(d,J＝7.6Hz,1H),7.22(d,J＝8.8Hz,1H),7.19-7.16(m,1H),5.38(p,J＝ 6.8Hz,1H),2.69(s,6H),2.58-2.52(m,1H),1.58(d,J＝6.8Hz,3H),1.22(dd,J＝6.8, 1.6Hz,6H)；HR-MS(ESI):m/z,calcd.For C20H26O2N4 355.2129[M+H]+,Found: 355.2113。
Example 3
2- (dimethylamino) -5-isobutyrylamino-N- (pyridin-3-ylmethyl) benzamide
Figure BDA0001620885820000971
a)2- (dimethylamino) -5-nitro-N- (pyridin-3-ylmethyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (777mg,3.70mmol) was dissolved in DCM (30mL), DIEA (525mg,4.07mmol) and HATU (1.55g,4.07mmol) were added in that order, and after stirring for 20min, 3-aminomethylpyridine (400mg,3.70mmol) was added, and the mixture was stirred at room temperature overnight. Dilute with DCM (20mL), wash with saturated ammonium chloride solution (20mL), and saturate NaHCO3Washed (20mL), washed with water (20mL), anhydrous Na2SO4Drying, column chromatography (ethyl acetate-petroleum ether) Volume ratio 1:2) to obtain 591mg of yellow solid, yield 53.2%, melting point: 144 ℃ and 145 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.61(s,1H),8.53(d,J＝4.8Hz,1H),8.51(d,J＝ 2.8Hz,1H),8.13(dd,J＝9.2,2.8Hz,1H),7.80(s,1H),7.76(d,J＝7.6Hz,1H),7.30 (dd,J＝7.6,4.8Hz,1H),6.96(d,J＝9.2Hz,1H),4.65(d,J＝6.0Hz,2H),2.87(s,6H)； ESI-MS m/z:301.13[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (pyridin-3-ylmethyl) benzamide
2- (dimethylamino) -5-nitro-N- (pyridin-3-ylmethyl) benzamide (600mg,2.00mmol) was dissolved in THF (20mL), pd/C (120mg) was added, hydrogen was bubbled in, stirred overnight at room temperature, filtered, and concentrated to give 501mg of yellowish oil in 92.8% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.05(s,1H),8.61(s,1H),8.51(d,J＝4.4Hz, 1H),7.70(d,J＝7.6Hz,1H),7.57(d,J＝2.8Hz,1H),7.26(dd,J＝8.4,4.4Hz,1H), 7.10(d,J＝8.4Hz,1H),6.75(dd,J＝8.4,2.8Hz,1H),4.66(d,J＝5.6Hz,2H),3.71(s, 2H),2.58(s,6H)；ESI-MS m/z:271.16[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (pyridin-3-ylmethyl) benzamide
Isobutyric acid (352mg,4.00mmol) was dissolved in DMF (15mL), DIEA (516mg, 4.00mmol) and HATU (1.52g,4.00mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (pyridin-3-ylmethyl) benzamide (360mg,1.33mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with DCM (30mL), washed with saturated ammonium chloride solution (20mL), and saturated NaHCO3Washing (20mL), washing with water (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-methanol, 50:1 by volume) to obtain 201mg of white solid, 44.4% yield, melting point: 180 ℃ and 181 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.65(s,1H),8.62(s,1H),8.54(d,J＝4.4Hz, 1H),8.24(d,J＝8.8Hz,1H),7.89(d,J＝2.4Hz,1H),7.76-7.61(m,2H),7.32-7.26(m, 2H),4.68(d,J＝5.6Hz,2H),2.64(s,6H),2.60-2.45(m,1H),1.23(d,J＝6.8Hz,6H)； HR-MS(ESI):m/z,calcd.For C19H24O2N4 341.1972[M+H]+,Found:341.1966。
Example 4
2- (dimethylamino) -5-isobutyrylamino-N- (pyridin-4-ylmethyl) benzamide
Figure BDA0001620885820000981
a)2- (dimethylamino) -5-nitro-N- (pyridin-4-ylmethyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (777mg,3.70mmol) was dissolved in DCM (30mL), DIEA (525mg,4.07mmol) and HATU (1.55g,4.07mmol) were added in that order, and after stirring for 20min, 4-aminomethylpyridine (400mg,3.70mmol) was added and the mixture was stirred at room temperature overnight. Dilute with DCM (20mL), wash with saturated ammonium chloride solution (20mL), and saturate NaHCO3Washed (20mL), washed with water (20mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) gave 683mg of yellow solid, yield 61.5%, melting point: 213-214 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):9.19(t,J＝5.6Hz,1H),8.54(d,J＝4.8Hz,2H), 8.10(dd,J＝12.4,2.8Hz,2H),7.35(d,J＝4.8Hz,2H),6.95(d,J＝9.2Hz,1H),4.47 (d,J＝6.0Hz,2H),2.95(s,6H)；ESI-MS m/z:301.13[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (pyridin-4-ylmethyl) benzamide
2- (dimethylamino) -5-nitro-N- (pyridin-4-ylmethyl) benzamide (700mg,2.33mmol) was dissolved in THF (20mL), pd/C (140mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, and concentrated to give 577mg of a yellowish oil in 91.6% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):10.75(s,1H),8.51(d,J＝5.2Hz,2H),7.31(d,J ＝5.2Hz,2H),7.17(d,J＝2.4Hz,1H),7.12(d,J＝8.4Hz,1H),6.68(dd,J＝8.8,2.6 Hz,1H),5.12(s,2H),4.53(d,J＝6.0Hz,2H),2.56(s,6H)；ESI-MS m/z:271.16 [M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (pyridin-4-ylmethyl) benzamide
Isobutyric acid (489mg,5.56mmol) was dissolved in DMF (20mL), DIEA (717mg, 5.56mmol) and HATU (2.11g,5.56mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (pyridin-4-ylmethyl) benzamide (500mg,1.85mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with DCM (30mL), washed with saturated ammonium chloride solution (20mL), and saturated NaHCO 3Washing (20mL), washing with water (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-methanol, 50:1 by volume) to obtain 254mg of white solid, 40.4% yield, melting point: 134 ℃ and 135 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.78(s,1H),8.56(d,J＝6.0Hz,2H),8.25(d,J ＝8.4Hz,1H),7.90(d,J＝2.4Hz,1H),7.74(s,1H),7.29(d,J＝9.6Hz,2H),4.68(d,J ＝6.0Hz,2H),2.68(s,6H),2.57-2.50(m,1H),1.22(d,J＝7.2Hz,6H)；HR-MS(ESI): m/z,calcd.For C19H24O2N4 341.1972[M+H]+,Found:341.1966。
Example 5
2- (dimethylamino) -5-isobutyrylamino-N- (naphthalen-1-ylmethyl) benzamide
Figure BDA0001620885820000991
a)2- (dimethylamino) -N- (naphthalen-1-ylmethyl) -5-nitrobenzamide
2- (dimethylamino) -5-nitrobenzoic acid (294mg,1.40mmol) was dissolved in DMF (10mL), DIEA (271mg,2.10mmol) and HATU (796mg,2.10mmol) were added in this order, and after stirring for 20min, 1-naphthylmethylamine (200mg,1.27mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) gave 313 mg of yellow solid, yield 70.5%, melting point: 179 ℃ and 180 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.56(s,1H),8.12(d,J＝8.4Hz,2H),7.90(d,J＝ 8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.61-7.37(m,5H),6.92(d,J＝9.2Hz,1H),5.10 (d,J＝5.2Hz,2H),2.74(s,6H)；ESI-MS m/z:350.15[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (naphthalen-1-ylmethyl) benzamide
2- (dimethylamino) -N- (naphthalen-1-ylmethyl) -5-nitrobenzamide (280mg,0.80mmol) was dissolved in THF (20mL), pd/C (28mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, and concentrated to give 233mg of a yellowish oil in 91.0% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.03(s,1H),8.14(d,J＝8.4Hz,1H),7.88(d,J ＝8.0Hz,1H),7.80(d,J＝8.4Hz,1H),7.63(d,J＝2.4Hz,1H),7.52(p,J＝6.8Hz, 3H),7.43(t,J＝7.6Hz,1H),7.02(d,J＝8.4Hz,1H),6.72(dd,J＝8.4,2.8Hz,1H), 5.10(d,J＝5.2Hz,2H),3.86(s,2H),2.34(s,6H)；ESI-MS m/z:320.18[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (naphthalen-1-ylmethyl) benzamide
Isobutyric acid (166mg,1.88mmol) was dissolved in DMF (10mL), DIEA (243mg, 1.88mmol) and HATU (714mg,1.88mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (naphthalen-1-ylmethyl) benzamide (200mg,0.63mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain white solid 101mg, yield 40.4%, melting point: 185 ℃ and 186 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.71(s,1H),8.23(d,J＝8.4Hz,1H),8.11(d,J ＝8.0Hz,1H),7.95(s,1H),7.89(d,J＝8.0Hz,1H),7.85(s,1H),7.82(d,J＝8.0Hz, 1H),7.53(m,3H),7.44(t,J＝7.6Hz,1H),7.17(d,J＝8.8Hz,1H),5.12(d,J＝5.6Hz, 2H),2.60-2.53(m,1H),2.38(s,6H),1.21(d,J＝7.2Hz,6H)；HR-MS(ESI):m/z,calcd. For C24H27O2N3390.2176[M+H]+,Found:390.2166。
Example 6
2- (dimethylamino) -5-isobutyrylamino-N- (1- (naphthalen-1-yl) ethyl) benzamide
Figure BDA0001620885820001011
a)2- (dimethylamino) -N- (1- (naphthalen-1-yl) ethyl) -5-nitrobenzamide
2- (dimethylamino) -5-nitrobenzoic acid (200mg,0.95mmol) was dissolved in DMF (15mL), DIEA (185mg,1.43mmol) and HATU (542mg,1.43mmol) were added in this order, 1-naphthylethylamine (148mg,0.87mmol) was added after 20min, and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, vol 2:3) gave 261mg of yellow solid in 83.1% yield, m.p.: 193 ℃ and 194 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.52(s,1H),8.23(d,J＝8.4Hz,1H),8.12(d,J＝ 9.2Hz,1H),7.88(d,J＝7.6Hz,1H),7.83(d,J＝8.0Hz,1H),7.52(m,4H),7.38(d,J ＝7.2Hz,1H),6.92(d,J＝9.2Hz,1H),6.28-6.08(m,1H),2.79(s,6H),1.80(d,J＝6.8 Hz,3H)；ESI-MS m/z:364.17[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (1- (naphthalen-1-yl) ethyl) benzamide
2- (dimethylamino) -N- (1- (naphthalen-1-yl) ethyl) -5-nitrobenzamide (200mg,0.55mmol) was dissolved in methanol (20mL), pd/C (20mg) was added, hydrogen was added, stirring overnight at room temperature, filtration, and concentration to give 178mg of brown oil in 97.1% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):10.65(s,1H),8.22(d,J＝7.6Hz,2H),7.87(d,J ＝7.2Hz,2H),7.79(d,J＝8.0Hz,1H),7.65(s,1H),7.59-7.40(m,3H),7.18(d,J＝8.4 Hz,1H),6.25-6.02(m,1H),2.63-2.37(s,6H),1.75(d,J＝6.8Hz,3H)；ESI-MS m/z: 334.19[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (1- (naphthalen-1-yl) ethyl) benzamide
Isobutyric acid (86)mg,0.97mmol) was dissolved in DMF (12mL), DIEA (188mg,1.46 mmol), HATU (553mg,1.46mmol) were added in that order, and after 20min 5-amino-2- (dimethylamino) -N- (1- (naphthalen-1-yl) ethyl) benzamide (175mg,0.65mmol) was added and stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 79 mg of white solid, yield 36.7%, melting point: 171 ℃ and 172 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.65(s,1H),8.22(d,J＝7.6Hz,2H),7.87(d,J ＝7.2Hz,2H),7.79(d,J＝8.0Hz,1H),7.65(s,1H),7.56-7.45(m,4H),7.18(d,J＝8.4 Hz,1H),6.17-6.10(m,1H),2.57-2.52(m,1H),2.47(s,6H),1.75(d,J＝6.8Hz,3H), 1.21(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C25H29O2N3 404.2333[M+H]+, Found:404.2326。
Example 7
3- ((2- (dimethylamino) -5-isobutyrylaminobenzamido) methyl) benzoic acid methyl ester
Figure BDA0001620885820001021
a)3- (aminomethyl) benzoic acid methyl ester hydrochloride
Methyl 3-cyanobenzoate (500mg,3.1mmol) was dissolved in methanol (20mL) and HCl (4N) (3.9mL,15.5mmol), Pd/C (50mg), room temperature, 60psi/H were added sequentially 2After 24h reaction, the starting material disappeared. The reaction was stopped, filtered, the filtrate was concentrated, diethyl ether (30mL) was added, and filtration afforded 597mg of a white solid with a yield of 95.7%, melting point: 182-183 ℃.
1H-NMR(400MHz,CD3OD)δ(ppm):8.15(s,1H),8.07(d,J＝7.6Hz,1H),7.71(d,J ＝7.6Hz,1H),7.58(t,J＝7.6Hz,1H),4.20(s,2H),3.92(s,3H)；ESI-MS m/z:166.09 [M+H]+。
b)3- ((2- (dimethylamino) -5-nitrobenzoylamino) methyl) benzoic acid methyl ester
2-(dimethylamino) -5-nitrobenzoic acid (345mg,1.64mmol) was dissolved in DMF (10mL), DIEA (606mg,4.70mmol) and HATU (935mg,2.46mmol) were added in that order, and after 20min, methyl 3- (aminomethyl) benzoate hydrochloride (300mg,1.49mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 2:3) to obtain 440mg of yellow solid, yield 82.6%, melting point: 180 ℃ and 181 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.58(d,J＝2.8Hz,1H),8.17(dd,J＝9.2,2.8Hz, 1H),8.04(s,1H),7.98(d,J＝7.6Hz,1H),7.59(d,J＝7.6Hz,2H),7.45(t,J＝7.6Hz, 1H),7.00(d,J＝9.2Hz,1H),4.70(d,J＝6.0Hz,2H),3.92(s,3H),2.90(s,6H)； ESI-MS m/z:357.13[M+H]+。
c)3- ((5-amino-2- (dimethylamino) benzoylamino) methyl) benzoic acid methyl ester
Methyl 3- ((2- (dimethylamino) -5-nitrobenzamido) methyl) benzoate (370mg,1.04mmol) was dissolved in methanol (20mL), pd/C (37mg) was added, hydrogen was added, stirring overnight at room temperature, filtered, and concentrated to give 319mg of brown oil in 94.4% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.12(s,1H),8.04(s,1H),7.95(d,J＝7.6Hz, 1H),7.58(d,J＝6.8Hz,2H),7.42(t,J＝7.6Hz,1H),7.13(d,J＝8.0Hz,1H),6.77(dd, J＝8.4,2.8Hz,1H),4.70(d,J＝5.6Hz,2H),3.91(s,3H),2.61(s,6H)；ESI-MS m/z: 327.16[M+H]+。
d)3- ((2- (dimethylamino) -5-isobutyrylaminobenzamido) methyl) benzoic acid methyl ester
Isobutyric acid (218mg,2.48mmol) was dissolved in DMF (10mL), DIEA (320mg, 2.48mmol), HATU (942mg,2.48mmol) were added sequentially, and after 20min methyl 3- ((5-amino-2- (dimethylamino) benzoylamino) methyl) benzoate (270mg,0.83mmol) was added and stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying, column chromatography (ethyl acetate-petroleum)Ether, volume ratio 1:3) to obtain 147mg of white solid, yield 45.0%, melting point: 150 ℃ to 151 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.69(s,1H),8.26(d,J＝6.8Hz,1H),8.04(s, 1H),7.96(d,J＝7.6Hz,1H),7.91(s,1H),7.71(s,1H),7.56(d,J＝7.6Hz,1H),7.42(t, J＝7.6Hz,1H),7.26(d,J＝8.8Hz,1H),4.72(d,J＝5.6Hz,2H),3.91(s,3H),2.65(s, 6H),2.58-2.51(m,1H),1.22(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C22H27O4N3398.2074[M+H]+,Found:398.2069。
Example 8
3- (1- (2- (dimethylamino) -5-isobutyrylaminobenzamido) ethyl) benzoic acid methyl ester
Figure BDA0001620885820001031
a)3- (1- (2- (dimethylamino) -5-nitrobenzoylamino) ethyl) benzoic acid methyl ester
2- (dimethylamino) -5-nitrobenzoic acid (200mg,0.95mmol) was dissolved in DCM (15mL), DIEA (245mg,1.90mmol) and HATU (543mg,1.43mmol) were added in this order, and after stirring for 20min, methyl 3- (1-aminoethyl) benzoate (170mg,0.95mmol) was added and stirred at room temperature overnight. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying and purification by column chromatography (dichloromethane-methanol, volume ratio 150:1) gave 302mg of yellow solid, yield 85.6%, melting point: 144 ℃ and 145 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.54(d,J＝2.8Hz,1H),8.16(dd,J＝9.2,2.8Hz, 1H),8.06(s,1H),7.97(d,J＝7.6Hz,1H),7.60(d,J＝7.6Hz,1H),7.57(d,J＝7.6Hz, 1H),7.45(t,J＝7.6Hz,1H),6.99(d,J＝9.2Hz,1H),5.38(p,J＝7.2Hz,1H),3.93(s, 3H),2.86(s,6H),1.63(d,J＝6.8Hz,3H)；ESI-MS m/z:372.16[M+H]+。
b)3- (1- (5-amino-2- (dimethylamino) benzoylamino) ethyl) benzoic acid methyl ester
Methyl 3- (1- (2- (dimethylamino) -5-nitrobenzoylamino) ethyl) benzoate (220mg,0.59mmol) was dissolved in THF (15mL), pd/C (44mg) was added, hydrogen was added, the mixture was stirred overnight at room temperature, filtered, and concentrated to give 179mg of a yellowish oil with a yield of 88.6%.
1H-NMR(400MHz,CDCl3)δ(ppm):11.32(s,1H),8.07(s,1H),7.92(d,J＝7.6Hz, 1H),7.58(d,J＝7.2Hz,1H),7.47(s,1H),7.40(t,J＝7.6Hz,1H),7.13(d,J＝8.4Hz, 1H),6.66(d,J＝8.6Hz,1H),5.37-5.32(m,1H),3.91(s,3H),2.65(s,6H),1.57(d,J＝ 6.8Hz,3H)；ESI-MS m/z:342.18[M+H]+。
c)3- (1- (2- (dimethylamino) -5-isobutyrylaminobenzamido) ethyl) benzoic acid methyl ester
Methyl 3- (1- (5-amino-2- (dimethylamino) benzoylamino) ethyl) benzoate (179mg,0.52mmol) was dissolved in anhydrous THF (15mL), TEA (79mg,0.78mmol) and isobutyryl chloride (56mg,0.52mmol) were sequentially added in ice bath, the reaction was continued for 1h, filtered, the filtrate was concentrated, diluted with ethyl acetate 30mL, washed with saturated ammonium chloride solution (10mL), and saturated NaHCO was added3Washing with (10mL), washing with water (10mL), washing with saturated brine (10mL), and washing with anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to give 153mg of white solid, yield 71.2%, melting point: 158-159 ℃.
1H-NMR(500MHz,CDCl3)δ(ppm):10.82(d,J＝7.0Hz,1H),8.28(d,J＝7.5Hz, 1H),8.11(s,1H),7.99(d,J＝7.5Hz,1H),7.87(d,J＝1.5Hz,1H),7.67(s,1H),7.61 (d,J＝7.5Hz,1H),7.46(t,J＝7.5Hz,1H),7.30(s,1H),5.42(p,J＝7.0Hz,1H),3.96 (s,3H),2.73(s,6H),2.59-2.54(m,1H),1.63(d,J＝7.0Hz,3H),1.26(d,J＝7.0Hz, 6H)；HR-MS(ESI):m/z,calcd.For C23H29O4N3 412.2231[M+H]+,Found:412.2215。
Example 9
N- ([1,1' -biphenyl ] -3-ylmethyl) -2- (dimethylamino) -5-isobutyrylaminobenzamide
Figure BDA0001620885820001051
a) [1,1' -Biphenyl ] -3-carbonitrile
Bromobenzene (500mg,3.18mmol) was dissolved in dioxane (20mL), and Pd (PPh) was added sequentially 3)4(368 mg,0.318mmol)，Na2CO3(1.69g,15.9mmol), 3-cyanophenylboronic acid (514mg,3.5mmol) and distilled water (5mL) were reacted at 110 ℃ for 5h under argon atmosphere, and the starting material disappeared. Filtration, concentration of the filtrate, dilution with EA (20mL), washing with water (20mL × 2), washing with saturated brine (20mL), and column chromatography (PE/EA: 40:1) gave 420mg of a white solid, 73.3% yield, melting point: 29-30 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):7.87(s,1H),7.84-7.78(m,1H),7.63(dt,J＝7.6, 1.2Hz,1H),7.59-7.56(m,1H),7.55(d,J＝3.2Hz,2H),7.51-7.45(m,2H),7.42(ddd, J＝7.2,3.6,1.2Hz,1H)；ESI-MS m/z:180.08[M+H]+。
b) [1,1' -Biphenyl ] -3-ylmethylamine hydrochloride
Reacting [1,1' -biphenyl]-3-carbonitrile (300mg,1.68mmol) was dissolved in methanol (20mL) and HCl (4N) (2.1mL,8.38mmol), Pd/C (30mg) were added sequentially at room temperature at 60psi/H2The reaction was carried out for 24h, with a small amount of starting material remaining. The reaction was stopped, filtered, the filtrate was concentrated, diethyl ether (30mL) was added, and filtration gave 311mg of a white solid in 78.0% yield, melting point: 157 ℃ to 159 ℃.
1H-NMR(400MHz,CD3OD)δ(ppm):7.75(s,1H),7.68(dd,J＝13.6,7.6Hz,3H), 7.54(t,J＝7.6Hz,1H),7.47(t,J＝7.2Hz,3H),7.37(t,J＝7.2Hz,1H),4.20(s,2H)； ESI-MS m/z:184.11[M+H]+。
c) N- ([1,1' -biphenyl ] -3-ylmethyl) -2- (dimethylamino) -5-nitrobenzamide
2- (dimethylamino) -5-nitrobenzoic acid (285mg,1.36mmol) was dissolved in DMF (10mL), DIEA (434mg,3.37mmol) and HATU (948mg,2.50mmol) were added in that order, and [1,1' -biphenyl ] was added after 20min]-3-ylmethylamine hydrochloride (270mg,1.23mmol), stirring overnight at room temperature. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na 2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 386mg of yellow solid, yield 83.5%, melting point: 138-139 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.57(d,J＝2.8Hz,1H),8.15(dd,J＝9.2,2.8Hz, 1H),7.60-7.50(m,4H),7.48-7.39(m,4H),7.35(t,J＝7.6Hz,2H),6.96(d,J＝9.2Hz, 1H),4.71(d,J＝5.6Hz,2H),2.88(s,6H)；ESI-MS m/z:375.16[M+H]+。
d) N- ([1,1' -biphenyl ] -3-ylmethyl) -2- (dimethylamino) -5-isobutyrylaminobenzamide
Reacting N- ([1,1' -biphenyl)]-3-ylmethyl) -2- (dimethylamino) -5-nitrobenzamide (310mg,0.83mmol) was dissolved in methanol (20mL), pd/C (31mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, concentrated to give 245mg of a brown oil; isobutyric acid (187mg,2.13mmol) was dissolved in DMF (10mL), DIEA (275mg,2.13mmol) and HATU (809mg,2.13mmol) were added sequentially, and after 20min the above brown oil (245mg,0.71mmol) was added and stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 121mg of white solid, yield 41.2%, melting point: 180 ℃ and 181 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.63(s,1H),8.27(d,J＝8.8Hz,1H),7.93(brs, 2H),7.59-7.51(m,4H),7.45-7.41(m,3H),7.37-7.33(m,2H),7.24(brs,1H),4.75(d,J ＝5.6Hz,2H),2.63(s,6H),2.57-2.52(m,1H),1.21(s,6H)；HR-MS(ESI):m/z,calcd. For C26H29O2N3 416.2333[M+H]+,Found:416.2325。
Example 10
N- (1- ([1,1' -biphenyl ] -3-yl) ethyl) -2- (dimethylamino) -5-isobutyrylaminobenzamide 0
Figure BDA0001620885820001061
a) N- (1- ([1,1' -biphenyl ] -3-yl) ethyl) -2- (dimethylamino) -5-nitrobenzamide
Dissolving 2- (dimethylamino) -5-nitrobenzoic acid (317mg,1.51mmol) in DMF (10mL), sequentially adding DIEA (483mg,3.74mmol) and HATU (859mg,2.26mmol), stirring for 20min, adding 1- ([1,1' -biphenyl) ]-3-yl) ethylamine (320mg,1.37mmol), stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) gave 227mg of yellow solid, yield 51.9%, melting point: 138 ℃ and 141 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.56-8.48(m,1H),8.15(dd,J＝9.2,6.0Hz,1H), 7.59(d,J＝8.0Hz,3H),7.53(d,J＝7.6Hz,1H),7.49-7.32(m,6H),6.95(dd,J＝8.8, 5.2Hz,1H),5.47-5.34(m,1H),2.86(s,6H),1.67(d,J＝6.8Hz,3H)；ESI-MS m/z: 390.18[M+H]+。
b) N- (1- ([1,1' -biphenyl ] -3-yl) ethyl) -5-amino-2- (dimethylamino) benzamide
N- (1- ([1,1' -biphenyl ] -3-yl) ethyl) -2- (dimethylamino) -5-nitrobenzamide (221mg,0.57mmol) was dissolved in THF (20mL), pd/C (22mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, and concentrated to give 200mg of a yellowish oil with 98.5% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.03(s,1H),7.41-7.37(m,10H),7.10(s,1H), 6.74(s,1H),5.38(s,1H),3.78(s,2H),2.62(s,6H),1.62(s,3H)；ESI-MS m/z:360.21 [M+H]+。
c) N- (1- ([1,1' -biphenyl ] -3-yl) ethyl) -2- (dimethylamino) -5-isobutyrylaminobenzamide
Isobutyric acid (147mg,1.67mmol) was dissolved in DMF (10mL), DIEA (215mg, 1.67mmol) and HATU (635mg,1.67mmol) were added in this order, and after stirring and reacting for 20min, N- (1- ([1,1' -biphenyl ] E was added]-3-yl) ethyl) -5-amino-2- (dimethylamino) benzamide (200mg,0.56mmol), stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na 2SO4Drying, columnPurification by chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) gave 142mg of a white solid in 59.4% yield, melting point: 116 ℃ and 118 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.61(s,1H),8.23(d,J＝8.4Hz,1H),7.83(s, 1H),7.57(m,4H),7.49(d,J＝7.6Hz,1H),7.47-7.39(m,3H),7.35(d,J＝6.0Hz,2H), 7.23(d,J＝8.8Hz,1H),5.40(p,J＝7.2Hz,1H),2.64(s,6H),2.58-2.46(m,1H),1.62 (d,J＝6.8Hz,3H),1.22(d,J＝6.4Hz,6H)；HR-MS(ESI):m/z,calcd.For C27H31O2N3 430.2489[M+H]+,Found:430.2482。
Example 11
2- (dimethylamino) -N- (3- (furan-2-yl) benzyl) -5-isobutyrylaminobenzamide
Figure BDA0001620885820001071
a)2- (dimethylamino) -N- (3- (furan-2-yl) benzyl) -5-nitrobenzamide
2- (dimethylamino) -5-nitrobenzoic acid (267mg,1.27mmol) was dissolved in DMF (10mL), DIEA (246mg,1.91mmol) and HATU (727mg,1.91mmol) were added in this order, and after stirring for 20min, (3- (furan-2-yl) phenyl) methylamine (200mg,1.16mmol) was added and stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 344mg of yellow solid, yield 81.5%, melting point: 150 ℃ to 151 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.58(d,J＝2.8Hz,1H),8.17(dd,J＝9.2,2.8Hz, 1H),7.68(s,1H),7.60(d,J＝7.6Hz,1H),7.47(brs,2H),7.38(t,J＝7.6Hz,1H),7.26 (s,1H),7.06(d,J＝9.2Hz,1H),6.67(d,J＝3.2Hz,1H),6.48(dd,J＝3.2,2.0Hz,1H), 4.68(s,2H),2.92(s,6H)；ESI-MS m/z:366.15[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (3- (furan-2-yl) benzyl) benzamide
2- (dimethylamino) -N- (3- (furan-2-yl) benzyl) -5-nitrobenzamide (300mg,0.82mmol) was dissolved in THF (20mL), pd/C (30mg) was added, hydrogen was bubbled in, stirred overnight at room temperature, filtered, concentrated to give 254mg of a yellowish oil in 92.4% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):10.95(s,1H),7.68(s,1H),7.64(s,1H),7.57(d, J＝7.6Hz,1H),7.45(s,1H),7.35(t,J＝7.6Hz,1H),7.27(d,J＝3.6Hz,1H),7.11(d, J＝8.4Hz,1H),6.76(dd,J＝8.4,2.8Hz,1H),6.65(d,J＝3.2Hz,1H),6.46(s,1H), 4.69(d,J＝5.6Hz,2H),3.92(s,2H),2.61(s,6H)；ESI-MS m/z:336.17[M+H]+。
c)2- (dimethylamino) -N- (3- (furan-2-yl) benzyl) -5-isobutyrylaminobenzamide
Isobutyric acid (189mg,2.15mmol) was dissolved in DMF (10mL), DIEA (307mg, 2.38mmol) and HATU (903mg,2.38mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (3- (furan-2-yl) benzyl) benzamide (240mg,0.72mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 2:3) to obtain 113mg of white solid, yield 39.0%, melting point: 138-139 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.64(s,1H),8.27(d,J＝8.0Hz,1H),7.96(s, 2H),7.67(s,1H),7.58(d,J＝8.0Hz,1H),7.45(s,1H),7.36(t,J＝7.6Hz,1H),7.25 (brs,2H),6.65(d,J＝3.2Hz,1H),6.50-6.41(m,1H),4.70(d,J＝5.2Hz,2H),2.64(s, 6H),2.62-2.48(m,1H),1.21(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C24H27O3N4 406.2125[M+H]+,Found:406.2110。
Example 12
2- (dimethylamino) -N- (1- (3- (furan-2-yl) phenyl) ethyl) -5-isobutyrylaminobenzamide
Figure BDA0001620885820001091
a)2- (dimethylamino) -N- (1- (3- (furan-2-yl) phenyl) ethyl) -5-nitrobenzamide
2- (dimethylamino) -5-nitrobenzoic acid (199mg,0.95mmol) was dissolved in DCM (15mL), DIEA (168mg,1.30mmol) and HATU (490mg,1.30mmol) were added in that order, and after stirring for 20min, 1- (3- (furan-2-yl) phenyl) ethylamine (160mg,0.86mmol) was added and stirred at room temperature overnight. Dilute with DCM (20mL), wash with saturated ammonium chloride solution (10mL), and saturate NaHCO 3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) gave 244mg of yellow solid, yield 75.3%, melting point: 154 ℃ and 155 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.53(d,J＝2.8Hz,1H),8.15(dd,J＝9.2,2.8Hz, 1H),7.70(s,1H),7.59(d,J＝7.6Hz,1H),7.46(d,J＝10.8Hz,2H),7.38(t,J＝7.6Hz, 1H),7.27(d,J＝9.6Hz,1H),6.95(d,J＝9.2Hz,1H),6.68(d,J＝3.2Hz,1H), 6.52-6.45(m,1H),5.44-5.30(m,1H),2.85(s,6H),1.64(d,J＝6.8Hz,3H)；ESI-MS m/z:380.16[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (1- (3- (furan-2-yl) phenyl) ethyl) benzamide
2- (dimethylamino) -N- (1- (3- (furan-2-yl) phenyl) ethyl) -5-nitrobenzamide (230mg,0.61mmol) was dissolved in THF (20mL), pd/C (23mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, and concentrated to give 210mg of a yellowish oil in 99.0% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.09(s,1H),7.70(s,1H),7.56(d,J＝11.2Hz, 2H),7.45(s,1H),7.35(t,J＝7.6Hz,1H),7.28(s,1H),7.10(d,J＝8.4Hz,1H),6.74 (dd,J＝8.4,2.8Hz,1H),6.65(d,J＝3.2Hz,1H),6.50-6.43(m,1H),5.34(m,1H), 3.85(s,2H),2.63(s,6H),1.59(d,J＝6.8Hz,2H)；ESI-MS m/z:350.19[M+H]+。
c)2- (dimethylamino) -N- (1- (3- (furan-2-yl) phenyl) ethyl) -5-isobutyrylaminobenzamide
Isobutyric acid (151mg,1.72mmol) was dissolved in DMF (15mL), DIEA (222mg, 1.72mmol) and HATU (654mg,1.72mmol) were added in that order, and reaction 2 was stirredAfter 0min, 5-amino-2- (dimethylamino) -N- (1- (3- (furan-2-yl) phenyl) ethyl) benzamide (200mg,0.57mmol) was added and stirred at room temperature overnight. Concentrating, diluting with EA (20mL), washing with saturated ammonium chloride solution (10mL), and washing with saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain white solid 101mg, yield 42.1%, melting point: 130 ℃ to 131 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.72(d,J＝7.6Hz,1H),8.25(d,J＝8.4Hz, 1H),7.88(s,2H),7.69(s,1H),7.56(d,J＝7.6Hz,1H),7.46(s,1H),7.36(t,J＝7.6Hz, 1H),7.24(d,J＝8.4Hz,2H),6.65(d,J＝3.2Hz,1H),6.47(dd,J＝3.2,1.6Hz,1H), 5.39-5.32(m,1H),2.66(s,6H),2.58-2.51(m,1H),1.60(d,J＝6.8Hz,3H),1.21(dd,J ＝6.8,3.2Hz,6H)；HR-MS(ESI):m/z,calcd.For C25H29O3N3 420.2282[M+H]+,Found: 420.2275。
Example 13
2- (dimethylamino) -5-isobutyrylamino-N- (3- (tetrahydrofuran-2-yl) benzyl) benzamide
Figure BDA0001620885820001101
a)2- (dimethylamino) -5-nitro-N- (3- (tetrahydrofuran-2-yl) benzyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (400mg,1.90mmol) was dissolved in DCM (30mL), DIEA (490mg,3.80mmol) and HATU (1.09g,2.86mmol) were added in that order, and after stirring for 20min, (3- (tetrahydrofuran-2-yl) phenyl) methylamine (336mg,1.90mmol) was added and stirred at room temperature overnight. Dilute with DCM (20mL), wash with saturated ammonium chloride solution (20 mL. times.2), wash with saturated brine (20mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, vol 2:3) gave 417 mg of yellow solid, 59.4% yield, melting point: 137-138 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.55(d,J＝2.4Hz,1H),8.15(dd,J＝9.2,2.4Hz, 1H),7.34-7.31(m,3H),7.25(d,J＝7.2Hz,2H),6.96(d,J＝9.2Hz,1H),4.87(t,J＝ 7.2Hz,1H),4.64(d,J＝5.2Hz,2H),4.09(dd,J＝14.8,7.2Hz,1H),3.93(dd,J＝14.8, 7.2Hz,1H),2.89(s,6H),2.37-2.30(m,1H),2.04-2.00(m,2H),1.81-1.74(m,1H)； ESI-MS m/z:370.18[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (3- (tetrahydrofuran-2-yl) benzyl) benzamide
2- (dimethylamino) -5-nitro-N- (3- (tetrahydrofuran-2-yl) benzyl) benzamide (200mg,0.54mmol) was dissolved in THF (15mL), pd/C (40mg) was added, hydrogen was bubbled in, stirred overnight at room temperature, filtered, and concentrated to give 182mg of a yellowish oil, 98.9% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):10.88(s,1H),7.60(d,J＝2.8Hz,1H),7.33(s, 1H),7.29(d,J＝7.2Hz,1H),7.25-7.22(m,2H),7.09(d,J＝8.4Hz,1H),6.75(dd,J＝ 8.4,2.8Hz,1H),4.87(t,J＝7.2Hz,1H),4.66(dd,J＝5.6,2.4Hz,2H),4.08(dd,J＝ 14.8,7.2Hz,1H),3.92(dd,J＝14.8,7.6Hz,1H),3.71(s,2H),2.57(s,6H),2.35-2.27 (m,1H),2.05-1.96(m,2H),1.83-1.74(m,1H)；ESI-MS m/z:340.20[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (3- (tetrahydrofuran-2-yl) benzyl) benzamide
Dissolving 5-amino-2- (dimethylamino) -N- (3- (tetrahydrofuran-2-yl) benzyl) benzamide (165mg,0.49mmol) in anhydrous THF (15mL), adding TEA (75mg,0.74mmol) and isobutyryl chloride (52mg,0.49mmol) in sequence under ice bath, continuing to react for 1h, filtering, concentrating the filtrate, adding ethyl acetate 30mL for dilution, washing with saturated ammonium chloride solution (10mL), and washing with saturated NaHCO3Washing with (10mL), washing with water (10mL), washing with saturated brine (10mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 143mg of white solid, yield 71.9%, melting point: 147 ℃ and 148 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.54(s,1H),8.25(dd,J＝8.4,2.8Hz,1H),7.92 (d,J＝2.4Hz,1H),7.88(s,1H),7.32(s,1H),7.29(d,J＝7.6Hz,1H),7.24-7.21(m, 3H),4.86(t,J＝7.2Hz,1H),4.66(dd,J＝5.6,1.6Hz,2H),4.10-4.04(m,1H), 3.94-3.86(m,1H),2.61(s,6H),2.58-2.51(m,1H),2.35-2.27(m,1H),2.03-1.95(m, 2H),1.81-1.72(m,1H),1.20(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C24H31O3N3 410.2438[M+H]+,Found:410.2424。
Example 14
2- (dimethylamino) -5-isobutyrylamino-N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001111
a)2- (dimethylamino) -5-nitro-N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (242mg,1.15mmol) was dissolved in DMF (10mL), DIEA (223mg,1.73mmol) and HATU (657mg,1.73mmol) were added in that order, the reaction was stirred for 20min, 1- (3- (tetrahydrofuran-2-yl) phenyl) ethylamine (200mg,1.05mmol) was added, and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na 2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) gave 210mg of yellow solid, yield 52.4%, melting point: 136-138 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.50(d,J＝2.8Hz,1H),8.14(dd,J＝9.2,2.8Hz, 1H),7.34(m,3H),7.29-.20(m,2H),6.98(d,J＝9.2Hz,1H),5.41-5.26(m,1H),4.87(t, J＝7.2Hz,1H),4.17-4.01(m,1H),4.00-3.84(m,1H),2.86(d,J＝6.4Hz,6H),2.34(td, J＝12.8,6.8Hz,1H),2.08-1.94(m,2H),1.78(m,1H),1.61(d,J＝6.8Hz,3H)；ESI-MS m/z:384.19[M+H]+。
b) 5-amino-2- (dimethylamino) -N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide
2- (dimethylamino) -5-nitro-N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide (170mg,0.44 mmol) was dissolved in THF (20mL), pd/C (20mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, and concentrated to give 144mg of a yellowish oil, 91.9% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.01(s,1H),7.55(d,J＝2.8Hz,1H),7.35(s, 1H),7.33-7.27(m,1H),7.25-7.17(m,2H),7.08(d,J＝8.4Hz,1H),6.73(dd,J＝8.4, 2.9Hz,1H),5.36-5.23(m,1H),4.88(t,J＝7.2Hz,1H),4.08(ddd,J＝15.2,10.4,7.2 Hz,1H),3.92(ddd,J＝15.2,7.6,3.2Hz,1H),3.68(s,2H),2.60(s,6H),2.38-2.25(m, 1H),1.99-1.94(m,2H),1.79-1.75(m,1H),1.56(d,J＝6.8Hz,3H)；ESI-MS m/z: 354.22[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide
Isobutyric acid (103mg,1.17mmol) was dissolved in DMF (10mL), DIEA (166mg, 1.29mmol) and HATU (489mg,1.29mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide (138mg,0.39mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 2:3) to obtain 68mg of white solid, yield 41.2%, melting point: 134 ℃ and 136 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.50(d,J＝2.8Hz,1H),8.14(dd,J＝9.2,2.8Hz, 1H),7.34(m,3H),7.29-.20(m,2H),6.98(d,J＝9.2Hz,1H),5.41-5.26(m,1H),4.87(t, J＝7.2Hz,1H),4.17-4.01(m,1H),4.00-3.84(m,1H),2.86(d,J＝6.4Hz,6H),2.34(td, J＝12.8,6.8Hz,1H),2.08-1.94(m,2H),1.78(m,1H),1.61(d,J＝6.8Hz,3H)； ESI-MS m/z:384.19[M+H]+。
d) 5-amino-2- (dimethylamino) -N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide
2- (dimethylamino) -5-nitro-N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide (170mg,0.44 mmol) was dissolved in THF (20mL), pd/C (20mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, and concentrated to give 144mg of a yellowish oil in 91.9% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):11.01(s,1H),7.55(d,J＝2.8Hz,1H),7.35(s, 1H),7.33-7.27(m,1H),7.25-7.17(m,2H),7.08(d,J＝8.4Hz,1H),6.73(dd,J＝8.4, 2.9Hz,1H),5.36-5.23(m,1H),4.88(t,J＝7.2Hz,1H),4.08(ddd,J＝15.2,10.4,7.2 Hz,1H),3.92(ddd,J＝15.2,7.6,3.2Hz,1H),3.68(s,2H),2.60(s,6H),2.38-2.25(m, 1H),1.99-1.94(m,2H),1.79-1.75(m,1H),1.56(d,J＝6.8Hz,3H)；ESI-MS m/z: 354.22[M+H]+。
e)2- (dimethylamino) -5-isobutyrylamino-N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide
Isobutyric acid (103mg,1.17mmol) was dissolved in DMF (10mL), DIEA (166mg, 1.29mmol) and HATU (489mg,1.29mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide (138mg,0.39mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 2:3) to obtain 68mg of white solid, yield 41.2%, melting point: 134-136 ℃.
1H-NMR(500MHz,CDCl3)δ(ppm):10.60(dd,J＝13.5,8.0Hz,1H),8.23(d,J＝8.5 Hz,1H),7.84(s,1H),7.70(s,1H),7.35(s,1H),7.31(td,J＝7.5,1.5Hz,1H), 7.25-7.22(m,3H),5.33(p,J＝7.5Hz,1H),4.88(t,J＝7.0Hz,1H),4.12-4.05(m,1H), 3.95-3.90(m,1H),2.64(d,J＝1.5Hz,6H),2.57-2.51(m,1H),2.35-2.29(m,1H), 2.04-1.97(m,2H),1.82-1.74(m,1H),1.57(d,J＝6.5Hz,4H),1.22(dd,J＝7.0,2.0Hz, 7H)；HR-MS(ESI):m/z,calcd.For C25H33O3N3 424.2595[M+H]+,Found:424.2578。
Example 15
2- (dimethylamino) -5-isobutyrylamino-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001131
a)2- (dimethylamino) -5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide
2- (dimethylamino group)) -5-Nitrobenzoic acid (307mg,1.46mmol) was dissolved in DMF (10mL), DIEA (468mg,3.63mmol) and HATU (862mg,2.19mmol) were added in this order, and after stirring for 20min, (3- (thiazol-2-yl) phenyl) methylamine (300mg,1.33mmol) was added and stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) gave 247mg of yellow solid, yield 48.7%, melting point: 169-170 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.56(d,J＝2.8Hz,1H),8.15(dd,J＝8.8,2.8Hz, 1H),7.99(s,1H),7.87(d,J＝3.2Hz,2H),7.59(s,1H),7.45(s,1H),7.44(s,1H),7.35 (d,J＝3.2Hz,1H),6.96(d,J＝9.2Hz,1H),4.71(d,J＝6.0Hz,2H),2.90(s,6H)； HR-MS(ESI):m/z,calcd.For C19H18O3N4S 383.1172[M+H]+,Found:383.1159。
b) 5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
2- (dimethylamino) -5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide (200mg,0.52mmol) was dissolved in THF (20mL), pd/C (100mg) was added, hydrogen was bubbled in, stirred overnight at room temperature, filtered, and concentrated to give 161mg of a yellowish oil, yield 87.5%.
1H-NMR(400MHz,CDCl3)δ(ppm):11.01(s,1H),7.98(s,1H),7.89-7.82(m,2H), 7.60(d,J＝2.8Hz,1H),7.47-7.37(m,2H),7.33(d,J＝3.2Hz,1H),7.11(d,J＝8.4Hz, 1H),6.76(dd,J＝8.4,2.8Hz,1H),4.73(d,J＝5.6Hz,2H),2.61(s,6H)；ESI-MS m/z: 353.14[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (3- (thiazol-2-yl) benzyl) benzamide
Isobutyric acid (121mg,1.37mmol) was dissolved in DMF (10mL), DIEA (177mg, 1.37mmol) and HATU (521mg,1.37mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide (161mg,0.46mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO 3(10mL) of water(10mL) over anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 73mg of white solid, yield 37.8%, melting point: 149 ℃ and 150 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.72(s,1H),8.27(s,1H),7.99(s,1H),7.91(s, 1H),7.87(d,J＝3.2Hz,2H),7.70(brs,1H),7.43(d,J＝4.8Hz,2H),7.34(d,J＝3.2 Hz,1H),7.25(s,1H),4.75(d,J＝5.6Hz,2H),2.65(s,6H),2.55(s,1H),1.22(d,J＝ 6.0Hz,6H)；HR-MS(ESI):m/z,calcd.For C23H26O2N4S 423.1849[M+H]+,Found: 423.1841。
Example 16
2- (dimethylamino) -5-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001141
a)2- (dimethylamino) -5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (226mg,1.08mmol) was dissolved in DMF (10mL), DIEA (209mg,1.62mmol) and HATU (616mg,1.62mmol) were added in this order, and after stirring for 20min, 1- (3- (thiazol-2-yl) phenyl) ethylamine (200mg,0.98mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) gave 221mg of yellow solid, yield 57.1%, melting point: 139 ℃ and 141 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.52(d,J＝2.8Hz,1H),8.14(dd,J＝8.8,2.8Hz, 1H),8.03(s,1H),7.87-7.84(m,2H),7.58(d,J＝7.6Hz,1H),7.47-7.42(m,2H),7.35 (d,J＝3.2Hz,1H),6.96(d,J＝8.8Hz,1H),5.47-5.32(m,1H),2.87(s,6H),1.65(d,J ＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C20H20O3N4S 397.1329[M+H]+,Found: 397.1308。
b) 5-amino-2- (dimethylamino) -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2- (dimethylamino) -5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (180mg,0.45mmol) was dissolved in THF (20mL), pd/C (90mg) was added, hydrogen was bubbled through, stirred overnight at room temperature, filtered, and concentrated to give 151mg of a yellowish oil in 91.0%.
1H-NMR(400MHz,CDCl3)δ(ppm):11.18(s,1H),8.03(s,1H),7.90-7.81(m,2H), 7.56(d,J＝2.8Hz,1H),7.44(m,2H),7.34(d,J＝3.2Hz,1H),7.12(d,J＝8.4Hz,1H), 6.76(dd,J＝8.4,2.8Hz,1H),5.47-5.29(m,1H),3.70(s,2H),2.66(s,6H),1.62(d,J＝ 6.8Hz,3H)；ESI-MS m/z:367.16[M+H]+。
c)2- (dimethylamino) -5-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Isobutyric acid (180mg,2.05mmol) was dissolved in DMF (10mL), DIEA (265mg, 2.05mmol) and HATU (780mg,2.05mmol) were added in this order, and after stirring for 20min, 5-amino-2- (dimethylamino) -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (250mg,0.68mmol) was added and the mixture was stirred at room temperature overnight. Concentrated, diluted with EA (20mL), washed with HCl (0.5N) (10mL), and saturated NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 159mg of white solid, yield 53.4%, melting point: 143-144 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.76(d,J＝7.6Hz,1H),8.26(d,J＝8.4Hz, 1H),8.04(s,1H),7.88-7.86(m,3H),7.69(s,1H),7.44(d,J＝5.6Hz,2H),7.35(d,J＝ 3.2Hz,1H),7.25(s,1H),5.44-5.37(m,1H),2.70(s,6H),2.58-2.51(m,1H),1.63(d,J ＝6.8Hz,3H),1.23(dd,J＝6.8,2.0Hz,6H)；HR-MS(ESI):m/z,calcd.For C24H28O2N4S 437.2006[M+H]+,Found:437.1990。
Example 17
3- ((4- (dimethylamino) -3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure BDA0001620885820001161
(dl) -N-Boc- β -proline (331mg,1.54mmol) was dissolved in DCM (20mL), DIEA (298mg,2.31mmol), HATU (733mg,1.93mmol) were added in this order, and after reaction at room temperature for 30min, 5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide (270mg,0.77mmol) was added and reacted at room temperature for 8h, and the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHCO3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na 2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 288mg of white solid, yield 68.4%, melting point: 86-88 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.66(s,1H),8.65(brs,1H),8.20(s,1H),8.00(s, 1H),7.97(s,1H),7.85(d,J＝3.2Hz,2H),7.40(d,J＝4.4Hz,2H),7.32(d,J＝3.2Hz, 1H),7.25(brs,1H),4.71(d,J＝4.8Hz,2H),3.56(brs,3H),3.31(s,1H),3.13(s,1H), 2.67(s,6H),2.14(brs,2H),1.44(s,9H)；HR-MS(ESI):m/z,calcd.For C29H35O4N5S 550.2483[M+H]+,Found:550.2477。
Example 18
N- (4- (dimethylamino) -3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) pyrrolidine-3-carboxamide hydrochloride
Figure BDA0001620885820001162
Tert-butyl 3- ((4- (dimethylamino) -3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (80mg,0.15mmol) was dissolved in anhydrous DCM (10mL), HCl EA solution (1mL) was added, reaction was carried out at room temperature for 5h, concentration was carried out, ether (20mL) was added to precipitate a white solid, 59mg was obtained by filtration, yield 83.1%, melting point: 151 ℃ and 153 ℃.
1H-NMR(500MHz,DMSO)δ(ppm):10.94(s,1H),9.98(s,1H),9.56(s,1H),9.35(s, 1H),8.19(s,1H),7.98(s,1H),7.93(s,1H),7.91(s,1H),7.87(s,1H),7.81(d,J＝3.0 Hz,1H),7.50(brs,2H),4.61(d,J＝5.5Hz,2H),3.45(brs,1H),3.38-3.30(m,2H), 3.21(brs,2H),3.11(s,6H),2.29-2.25(m,1H),2.05-2.01(m,1H)；HR-MS(ESI):m/z, calcd.For C24H27O2N5S 450.1958[M+H]+,Found:450.1950。
Example 19
(1- ((4-dimethylamino-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) amino) -1-carbonylpropan-2-yl) carbamic acid tert-butyl ester
Figure BDA0001620885820001171
N-Boc-DL-alanine (284mg,1.50mmol) was dissolved in DCM (20mL), DIEA (258mg,2.00mmol) and HATU (608mg,1.60mmol) were added in this order, and after reaction at room temperature for 30min, 5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide (353mg,1.00mmol) was added and the reaction was carried out at room temperature for 8h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na 2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 422mg of white solid, yield 80.5%, melting point: 98-99 ℃.
1H-NMR(500MHz,CDCl3)δ(ppm):10.51(s,1H),8.48(s,1H),8.12(d,J＝6.5Hz, 1H),7.99(s,1H),7.92(s,1H),7.86(brs,2H),7.43-7.40(m,2H),7.33(d,J＝3.0Hz, 1H),7.24(d,J＝9.0Hz,1H),5.04(s,1H),4.74(d,J＝5.5Hz,2H),4.34(s,1H),2.65 (s,6H),1.46(s,9H),1.44(d,J＝7.0Hz,3H)；HR-MS(ESI):m/z,calcd.For C27H33O4N5S 524.2326[M+H]+,Found:524.2318。
Example 20
5- (2-aminopropionylamino) -2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide hydrochloride
Figure BDA0001620885820001172
Tert-butyl (1- ((4-dimethylamino-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) amino) -1-carbonylpropan-2-yl) carbamate (80mg,0.15mmol) was dissolved in anhydrous DCM (10mL), a solution of HCl in EA (1mL) was added, reaction was carried out at room temperature for 5h, concentration was carried out, ether (20mL) was added to precipitate a white solid, 69mg of the white solid was filtered, yield 98.6%, melting point: 177 ℃ and 178 ℃.
1H-NMR(500MHz,DMSO)δ(ppm):11.53(s,1H),10.03(s,1H),8.51(s,3H),8.19(s, 1H),7.99(s,3H),7.94(d,J＝3.0Hz,1H),7.87(s,1H),7.82(d,J＝3.0Hz,1H),7.51 (d,J＝4.5Hz,2H),5.76(s,1H),4.62(d,J＝5.5Hz,2H),4.17-4.14(m,1H),3.16(s, 6H),1.49(d,J＝7.0Hz,3H)；HR-MS(ESI):m/z,calcd.For C22H25O2N5S 424.1802 [M+H]+,Found:424.1792。
Example 21
2- (dimethylamino) -5- (4-methoxybenzoylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001181
5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide (200mg,0.57mmol) was dissolved in anhydrous THF (15mL), TEA (173mg,1.71mmol), 4-methoxybenzoyl chloride (147mg,0.86mmol) were added sequentially under ice-bath, the reaction was continued for 1h, filtered, the filtrate was concentrated, diluted with ethyl acetate (20mL), washed with HCl (0.5N) aqueous solution (10mL), saturated NaHCO3Washing with (10mL), washing with water (10mL), washing with saturated brine (10mL), and washing with anhydrous Na 2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 139mg of white solid, yield 50.4%, melting point: 173 ℃ and 174 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.64(s,1H),8.36(d,J＝7.6Hz,1H),8.28(s, 1H),8.04(s,1H),7.95(s,1H),7.87(brs,4H),7.43-7.37(m,2H),7.33(d,J＝3.2Hz, 1H),7.30(d,J＝8.8Hz,1H),6.95(d,J＝8.8Hz,2H),4.65(d,J＝5.6Hz,2H),3.84(s, 3H),2.66(s,6H)；HR-MS(ESI):m/z,calcd.For C27H26O3N4S 487.1798[M+H]+, Found:487.1784。
Example 22
5- (Cyclopentylcarboxamido) -2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001182
Cyclopentylcarboxylic acid (146mg,1.28mmol) was dissolved in DCM (20mL), DIEA (248 mg,1.92mmol), HATU (536mg,1.41mmol) were added in this order, and after 30min at room temperature, the substrate 5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide (224mg,0.64mmol) was added and reacted at room temperature for 8h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 125mg of white solid, yield 43.9%, melting point: 165-166 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.67(s,1H),8.25(d,J＝6.8Hz,1H),7.98(s, 1H),7.90(s,1H),7.86(brs,2H),7.73(s,1H),7.42(d,J＝4.8Hz,2H),7.33(d,J＝3.2 Hz,1H),7.23(s,1H),4.74(d,J＝5.6Hz,2H),2.76-2.68(m,1H),2.64(s,6H), 1.94-1.82(m,4H),1.81-1.71(m,2H),1.62-1.56(m,2H)；HR-MS(ESI):m/z,calcd.For C25H28O2N4S 449.2006[M+H]+,Found:449.1999。
Example 23
2- (dimethylamino) -5- (1-isopropylsulfonylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001191
5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide (180mg,0.51mmol) was dissolved in anhydrous THF (20mL), adding isopropyl sulfonyl chloride (145mg,1.02mmol) and pyridine (201mg,2.55mmol) in sequence under ice bath, stirring for reacting for 8h, filtering, concentrating the filtrate, adding ethyl acetate (20mL) for diluting, washing with saturated ammonium chloride solution (10mL), and washing with saturated NaHCO 3Washing (10mL), washing with water (10mL), washing with saturated saline (10mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 57mg of white solid, yield 24.4%, melting point: 130 ℃ to 131 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):10.83(s,1H),8.29(s,1H),8.24(s,1H),8.03(s, 1H),7.91-7.88(m,2H),7.71(dd,J＝8.4,2.8Hz,1H),7.71(dd,J＝8.4,2.8Hz,1H), 7.52-7.44(m,2H),7.36(d,J＝3.2Hz,1H),7.27(brs,1H),4.85(d,J＝5.6Hz,2H), 3.30-3.24(m,1H),2.68(s,6H),1.40(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C22H26O3N4S2459.1519[M+H]+,Found:459.1503。
Example 24
2- (dimethylamino) -5- (1-methylsulfonylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001201
Dissolving 5-amino-2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide (200mg,0.57mmol) in anhydrous THF (15mL), adding methanesulfonyl chloride (78mg,0.68mmol), pyridine (90mg,1.14mmol) in sequence under ice bath, continuing to react for 8h, filtering, concentrating the filtrate, adding ethyl acetate (20mL) for dilution, washing with saturated ammonium chloride solution (10mL), and saturated NaHCO3Washing (10mL), washing with water (10mL), washing with saturated saline (10mL), and washing with anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) gave 127mg of a white solid, yield 52.0%, melting point: 165-166 ℃.
1H-NMR(500MHz,CDCl3)δ(ppm):10.80(s,1H),8.46(s,1H),8.32(d,J＝2.0Hz, 1H),8.01(s,1H),7.86(brs,2H),7.65(dd,J＝9.0,2.0Hz,1H),7.47(d,J＝7.5Hz,1H), 7.43(t,J＝7.5Hz,1H),7.33(d,J＝3.0Hz,1H),7.29(d,J＝8.0Hz,1H),4.83(d,J＝ 5.5Hz,2H),2.95(s,3H),2.68(s,6H)；HR-MS(ESI):m/z,calcd.For C20H22O3N4S2 431.1206[M+H]+,Found:431.1199。
Example 2
N- (4- (dimethylamino) -3- ((1-phenylethyl) carbamoyl) phenyl) -4, 4-difluoropiperidine-1-carboxamide
Figure BDA0001620885820001202
a)2- (dimethylamino) -5-nitro-N- (1-phenylethyl) benzamide
2- (dimethylamino) -5-nitrobenzoic acid (500mg,2.388mmol) was added to anhydrous DMF (25mL), EDC (914mg,4.76mmol) was added, HOBt (643mg,4.76mmol) and DIEA (0.83mL,4.76 mmol) were added, the compound 1-phenylethylamine (0.365mL,2.85mmol) was added, stirred overnight at room temperature, the reaction was poured into water, extracted with ethyl acetate (50 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P: D ═ 1:3:1) to give 600mg of a yellow solid in 80.5% yield. 1H-NMR(400MHz,CDCl3)δ(ppm):8.51(d,J＝2.0Hz,1H),8.14(dd,J1＝9.2Hz,J2＝2.4Hz,1H),7.29-7.39(m,5H),6.95(d,J＝8.8Hz,1H),5.30-5.38(m,1H),2.85(s, 6H),1.61(d,J＝6.8Hz,3H).
b) 5-amino-2- (dimethylamino) -N- (1-phenylethyl) benzamide
2- (dimethylamino) -5-nitro-N- (1-phenylethyl) benzamide (520mg) was added EtOH (25mL), 10% Pd/C (156mg) was added, hydrogenation was carried out at normal temperature and pressure for 4 hours, then the reaction was stopped, and filtration and concentration were carried out to obtain 450mg of an earth yellow solid with a yield of 95.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):10.97(s,1H),7.56(d,J＝2.4Hz,1H),7.31-7.39 (m,5H),7.22-7.25(m,1H),7.08(d,J＝8.4Hz,1H),6.73(dd,J1＝8.4Hz,J2＝2.8 Hz,1H),5.27-5.35(m,1H),2.60(s,6H),1.56(d,J＝6.8Hz,3H).
c) 4-Nitrophenyl (4- (dimethylamino) -3- ((1-phenylethyl) benzamide) phenyl) carbamate
Placing 5-amino-2- (dimethylamino) -N- (1-phenylethyl) benzamide (57mg,0.2mmol) in a reaction bottle, adding DCM (5mL), adding pyridine (0.24mL,3mmol), adding a compound 4-nitrophenyl chloromethyl ester (60.5mg,0.3mmol) under the protection of argon, stirring for reaction at room temperature after the addition is finished, stopping the reaction after 4h, concentrating, adding water, adding a solid, performing suction filtration, washing a filter cake with water, and recrystallizing with ethyl acetate to obtain 50mg of a white solid with the yield of 55.8%.
1H-NMR(400MHz,CDCl3)δ(ppm):10.86(d,J＝6.4Hz,1H),9.26(s,1H),8.36(s, 1H),8.25(d,J＝8.8Hz,2H),8.11(d,J＝7.6Hz,1H),7.24-7.33(m,8H),5.50-5.54(m, 1H),2.64(s,6H),1.54(d,J＝6.8Hz,3H).
d) Tert-butyl 4, 4-difluoropiperidine-1-carboxylic acid ester
Placing N-Boc-4-oxopiperidine (199mg,1mmol) in the reaction solution, adding DCM (10mL), adding a solution of DAST (0.26mL,2mmol) in DCM (2mL) dropwise in a reaction flask under ice bath, stirring under ice bath for 30min, heating to room temperature for reaction, stopping the reaction after 1.5h, pouring the reaction solution into ice water, extracting with DCM (20 mL. times.2), washing the combined organic layers with saturated NaCl (20 mL. times.2), drying over anhydrous magnesium sulfate, concentrating, and performing column chromatography (E: P ═ 1:50, E: P ═ 1:40) to obtain a white solid of 160mg with a yield of 72.4%.
1H-NMR(400MHz,CDCl3)δ(ppm):3.54(t,J＝5.6Hz,4H),1.88-1.98(m,4H),1.47 (s,9H).
e)4, 4-Difluoropiperidine 2,2, 2-Trifluoroacetate
Tert-butyl 4, 4-difluoropiperidine-1-carboxylate (380mg,1.727mmol) was placed in a reaction flask, DCM (15mL) was added, TFA (1.28mL,17.27mmol) was added, the reaction stirred at rt, stopped after 2h, concentrated, ether added, solid washed out, filtered off with suction, and the filter cake washed with ether to give 325mg of a white solid in 79.8% yield.1H-NMR(400MHz,DMSO-d6)δ(ppm):8.23(brs,2H),3.23(t,J＝8.0Hz,4H), 2.14-2.25(m,4H).
f) N- (4- (dimethylamino) -3- ((1-phenylethyl) carbamoyl) phenyl) -4, 4-difluoropiperidine-1-carboxamide
4-Nitrophenyl (4- (dimethylamino) -3- ((1-phenylethyl) benzamide) phenyl) carbamate (45mg,0.1 mmol) was added DCM (10mL), 4-difluoropiperidine 2,2, 2-trifluoroacetate (35mg,0.15mmol) and DIEA (0.05mL,0.3mmol) were added and the reaction was stirred at room temperature for 30min before stopping, DCM (20mL) was added, washed with saturated NaCl (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M: 70:1) to give 30mg of a solid in 69.7% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):10.63(d,J＝7.2Hz,1H),7.88(d,J＝7.2Hz, 1H),7.76(s,1H),7.32-7.36(m,5H),7.21(d,J＝8.8Hz,1H),6.86(s,1H),5.28-5.32 (m,1H),3.98(s,0.5H),3.69-3.70(m,0.5H),3.59(t,J＝5.2Hz,3H),2.64(s,6H),2.37 (brs,0.5H),1.95-2.04(m,3.5H),1.56(d,J＝6.8Hz,3H).
Example 26
N- (4- (dimethylamino) -3- ((1-phenylethyl) carbamoyl) phenyl) -3, 3-difluoropiperidine-1-carboxamide
Figure BDA0001620885820001221
a) Tert-butyl 3, 3-difluoropiperidine-1-carboxylic acid ester
Placing N-Boc-3-oxopiperidine (598mg,3mmol) in a reaction solution, adding DCM (20mL), dropwise adding DAST (0.78mL,6mmol) in DCM (5mL) into a reaction bottle under the protection of argon in ice bath, stopping the reaction after stirring for 1h in ice bath, pouring the reaction solution into ice water, extracting with DCM (30mL x 2), combining organic layers, washing with saturated NaCl (20mL x 2), drying with anhydrous magnesium sulfate, concentrating, and performing column chromatography (E: P ═ 1:50) to obtain 330mg of a colorless oily substance with the yield of 49.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):3.62(t,J＝11.6Hz,2H),3.41(t,J＝4.8Hz,2H), 1.93-2.02(m,2H),1.70-1.77(m,2H),1.47(s,9H).
b)3, 3-Difluoropiperidine 2,2, 2-trifluoroacetate salt
Tert-butyl 3, 3-difluoropiperidine-1-carboxylate (250mg,1.13mmol) was placed in a reaction flask, DCM (10mL) was added, TFA (0.84mL,11.3mmol) was added, the reaction stirred at room temperature, after 2h the reaction stopped, concentrated, ether added, solid washed out, suction filtered and the filter cake washed with ether to give 250mg of a white solid in 93.9% yield.
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.41(brs,2H),3.52(t,J＝12.0Hz,2H),3.07 (t,J＝5.2Hz,2H),2.05-2.15(m,2H),1.82-1.86(m,2H)
c) N- (4- (dimethylamino) -3- ((1-phenylethyl) carbamoyl) phenyl) -3, 3-difluoropiperidine-1-carboxamide
5-amino-2- (dimethylamino) -N- (1-phenylethyl) benzamide (75mg,0.167mmol), DCM (15 mL), 3-difluoropiperidine 2,2, 2-trifluoroacetate (59mg,0.25mmol) and DIEA (0.09mL, 0.5mmol) were added and the reaction was stirred at room temperature for 30min, after which time the reaction was stopped, DCM (20mL) was added, washed with saturated NaCl (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M: 80:1) to give 50mg of a solid in 70.4% yield. Melting point: 76-78 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):10.61(d,J＝8.4Hz,1H),7.87(d,J＝8.8Hz, 1H),7.74(s,1H),7.31-7.35(m,5H),7.20(d,J＝8.8Hz,1H),6.66(s,1H),5.29-5.33 (m,1H),3.69(t,J＝11.6Hz,2H),3.46(t,J＝5.2Hz,2H),2.63(s,6H),1.99-2.08(m, 2H),1.76-1.83(m,2H),1.56(d,J＝6.8Hz,3H).
Example 27
N- (4- (dimethylamino) -3- ((1-phenylethyl) carbamoyl) phenyl) -3, 3-difluoropyrrolidine-1-carboxamide
Figure BDA0001620885820001231
a) Tert-butyl 3, 3-difluoropyrrolidine-1-carboxylic acid ester
Placing N-Boc-3-oxotetrahydropyrrole (1.48g,8mmol) in a reaction solution, adding DCM (40mL), dropwise adding DAST (2.08mL,16mmol) in DCM (10mL) into a reaction bottle under the protection of argon in ice bath, gradually raising the temperature to room temperature after dropwise adding, pouring the reaction solution into ice water, extracting with DCM (50mL multiplied by 2), combining organic layers, washing with saturated NaCl (30mL multiplied by 2), drying with anhydrous magnesium sulfate, concentrating, and performing column chromatography (E: P ═ 1:50) to obtain 1.0g of a colorless oily object with the yield of 60.6%.
1H-NMR(400MHz,CDCl3)δ(ppm):3.62-3.68(m,2H),3.57(brs,2H),2.26-2.37(m, 2H),1.47(s,9H).
b)3, 3-difluoropyrrolidine 2,2, 2-trifluoroacetate salt
Placing tert-butyl 3, 3-difluoropyrrolidine-1-carboxylic ester (830mg,4mmol) in a reaction flask, adding DCM (20mL), adding TFA (2.96mL,40mmol), stirring at room temperature for reaction, stopping reaction after 2h, concentrating, adding diethyl ether, washing out no solid, placing in a refrigerator freezing layer for standing, separating out a solid, performing suction filtration, washing a filter cake with diethyl ether to obtain 600mg of white solid with the yield of 67.8%.
1H-NMR(400MHz,CDCl3)δ(ppm):10.26(brs,2H),3.48-3.56(m,4H),2.42-2.58(m, 2H).
c) N- (4- (dimethylamino) -3- ((1-phenylethyl) carbamoyl) phenyl) -3, 3-difluoropyrrolidine-1-carboxamide 5-amino-2- (dimethylamino) -N- (1-phenylethyl) benzamide (75mg,0.167mmol) was added DCM (15mL), 3-difluoropyrrolidine 2,2, 2-trifluoroacetate (55mg,0.25mmol) and DIEA (0.09mL, 0.5mmol) were added and the reaction was stirred at room temperature, after 30min the reaction was stopped, DCM (20mL) was added, washed with saturated NaCl (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, column chromatographed (D: M ═ 80:1) to give 50 mg of a white viscous solid, yield 71.9%.
1H-NMR(400MHz,CDCl3)δ(ppm):10.64(d,J＝6.8Hz,1H),7.96(d,J＝7.6Hz, 1H),7.76(s,1H),7.31-7.35(m,5H),7.21(d,J＝8.8Hz,1H),6.66(s,1H),5.27-5.31 (m,1H),3.80(t,J＝12.8Hz,2H),3.66(t,J＝7.2Hz,2H),2.63(s,6H),2.35-2.44(m, 2H),1.56(d,J＝6.8Hz,3H).
Example 28
2-ethoxy-5-isobutyrylamino-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001241
2-ethoxy-5-isobutyrylaminobenzoic acid (80mg,0.32mmol) was added to anhydrous DMF (15mL), EDC (123mg,0.64mmol) was added, HOBt (86mg,0.64mmol) and DIEA (0.14mL,0.8 mmol) were added, (3- (thiazol-2-yl) phenyl) methylamine (182mg,0.96mmol) was added, stirred overnight at room temperature, the reaction was poured into water, extracted with ethyl acetate 30mL × 2, the combined organic layers were washed with saturated NaCl 30mL × 2, dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M75: 1) to give 70mg of a white solid in 51.8% yield. Melting point: 157 ℃ and 158 DEG C
1H-NMR(400MHz,CDCl3)δPPm:8.49(s,1H),8.23(d,J＝7.2Hz,1H),7.99(s,1H), 7.87-7.91(m,3H),7.59(s,1H),7.42-7.48(m,2H),7.35(d,J＝2.8Hz,1H),6.93(d,J＝ 8.8Hz,1H),4.73(d,J＝5.2Hz,2H),4.13(q,J＝6.8Hz,2H),2.50-2.55(m,1H),1.31 (t,J＝6.8Hz,3H),1.23(d,J＝6.8Hz,6H).
Example 29
5-benzoylamino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001242
a) 2-ethoxy-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-5-nitrobenzoic acid (300mg,1.42mmol) was dissolved in DCM (20mL), DIEA (275mg,2.13mmol) and HATU (703mg,1.85mmol) were added in that order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (296mg,1.56mmol) was added and reaction at room temperature for 12h, the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated saline (20mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 2:5) to obtain 481mg of white solid, yield 88.3%, melting point: 131-132 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):9.13(d,J＝2.8Hz,1H),8.31(dd,J＝9.2,3.2Hz, 1H),8.13(s,1H),8.01(s,1H),7.90-7.87(m,2H),7.52-7.41(m,2H),7.36(d,J＝3.2 Hz,1H),7.04(d,J＝9.2Hz,1H),4.75(d,J＝5.2Hz,2H),4.27(q,J＝7.2Hz,2H), 1.40(t,J＝7.2Hz,3H)；ESI-MS m/z:384.10[M+H]+。
b) 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide (260mg,0.68mmol) was dissolved in THF (15mL), Pd/C130 mg was added, hydrogen was bubbled in at room temperature, reaction was carried out overnight, filtration was carried out, filtrate was concentrated to obtain 232mg of yellow-green oil with a yield of 96.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.54(s,1H),7.97(s,1H),7.87(t,J＝5.2Hz,2H), 7.59(d,J＝2.0Hz,1H),7.47-7.39(m,2H),7.33(d,J＝3.2Hz,1H),6.76(d,J＝3.6Hz, 2H),4.71(d,J＝5.6Hz,2H),4.04(q,J＝7.2Hz,2H),3.48(s,2H),1.26(t,J＝7.2Hz, 3H)；ESI-MS m/z:354.13[M+H]+。
c) 5-benzoylamino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
Dissolving 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (200mg,0.57mmol) in anhydrous THF (10mL), adding TEA (115mg,1.14mmol) and benzoyl chloride (121 mg,0.86mmol) in sequence under ice bath, continuing to react for 1h, filtering, concentrating the filtrate, adding ethyl acetate (30mL) for dilution, washing with saturated ammonium chloride solution (20mL), and washing with saturated NaHCO 3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to give 177mg of white solid, yield 68.6%, melting point: 143-144 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.48(s,1H),8.37(brs,2H),8.10(d,J＝2.4Hz, 1H),7.92-7.86(m,5H),7.52-7.39(m,5H),7.34(d,J＝3.2Hz,1H),6.98(d,J＝8.8Hz, 1H),4.60(d,J＝5.2Hz,2H),4.15(q,J＝6.8Hz,2H),1.32(t,J＝6.8Hz,3H)；HR-MS (ESI):m/z,calcd.For C26H23O3N3S 458.1533[M+H]+,Found:458.1515。
Example 30
(4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) carbamic acid propyl ester
Figure BDA0001620885820001261
Dissolving 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (133mg,0.38mmol) in anhydrous THF (10mL), adding TEA (77mg,0.76mmol), propyl chloroformate (70 mg,0.57mmol) in sequence under ice bath, continuing to react for 1h, filtering, concentrating the filtrate, adding ethyl acetate (30mL) for dilution, washing with saturated ammonium chloride solution (20mL), and washing with saturated NaHCO3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 72mg of white solid, yield 43.6%, melting point: 182-183 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.52(s,1H),7.99(d,J＝3.6Hz,3H),7.89-7.86 (m,2H),7.45-7.41(m,2H),7.34(d,J＝3.2Hz,1H),7.21(s,1H),6.92(d,J＝9.2Hz, 1H),4.76(d,J＝5.6Hz,2H),4.14-4.08(m,4H),1.71-1.63(m,2H),1.30(t,J＝7.2Hz, 3H),0.94(t,J＝7.6Hz,3H)；HR-MS(ESI):m/z,calcd.For C23H25O4N3S 440.1639 [M+H]+,Found:424.1623。
Example 31
5- (3, 3-Dimethylureido) -2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide)
Figure BDA0001620885820001262
Dissolving 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (160mg,0.45mmol) in anhydrous THF (10mL), adding TEA (136mg,1.35mmol), N, N-dimethylformyl chloride (97mg,0.90mmol) in sequence under ice bath, reacting at 50 ℃ for 7h, filtering, concentrating the filtrate, adding ethyl acetate (30mL) for dilution, washing with saturated ammonium chloride solution (20mL), and washing with saturated NaHCO 3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying, and purifying by column chromatography (dichloromethane-methanol, volume ratio 50:1) to obtain white solid 107mg with yield of 55.7%Melting point: 108 ℃ and 109 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.50(brs,1H),8.03-7.98(m,2H),7.89-7.86(m, 2H),7.77(d,J＝2.8Hz,1H),7.44(brs,2H),7.34(d,J＝3.2Hz,1H),6.91(d,J＝9.2 Hz,1H),6.41(s,1H),4.72(d,J＝5.4Hz,2H),4.12(q,J＝6.8Hz,2H),3.02(s,6H), 1.30(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C22H24O3N4S 425.1642[M+H]+, Found:425.1627。
Example 32
3- ((4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure BDA0001620885820001271
(dl) -N-Boc- β -proline (185mg,0.86mmol) was dissolved in DCM (15mL), DIEA (147mg,1.14mmol) and HATU (346mg,0.91mmol) were added in this order, and after reaction at room temperature for 30min, 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (200mg,0.57mmol) was added and reacted at room temperature for 10h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 251mg of white solid, yield 80.4%, melting point: 135-136 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.51(s,1H),8.21(brs,2H),7.97-7.95(m,2H), 7.86(d,J＝3.2Hz,2H),7.42(d,J＝4.8Hz,2H),7.33(d,J＝3.2Hz,1H),6.92(d,J＝ 8.4Hz,1H),4.71(d,J＝5.6Hz,2H),4.13(q,J＝6.8Hz,2H),3.65(brs,3H),3.31(brs, 1H),3.06(s,1H),2.13(s,2H),1.45(s,9H),1.31(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z, calcd.For C29H34O5N4S 551.2323[M+H]+,Found:551.2302。
Example 33
N- (4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) pyrrolidine-3-carboxamide hydrochloride
Figure BDA0001620885820001281
Tert-butyl 3- ((4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (100mg,0.18mmol) was dissolved in DCM (10 mL)/ethanol (2mL), HCl EA solution (1mL) was added, reaction was carried out at room temperature for 8h, concentration was carried out, diethyl ether (20mL) was added to precipitate a pale green solid, 86mg was obtained by filtration, yield 96.6%, melting point: 142 ℃ and 144 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):10.38(s,1H),9.47(s,1H),9.18(s,1H),8.69(t, J＝5.6Hz,1H),7.98(d,J＝2.4Hz,1H),7.95(s,1H),7.93(d,J＝2.4Hz,1H),7.85 (brs,1H),7.80(d,J＝2.0Hz,1H),7.75(d,J＝8.6Hz,1H),7.48(d,J＝4.4Hz,2H), 7.11(d,J＝8.8Hz,1H),4.59(d,J＝5.6Hz,2H),4.13(q,J＝6.8Hz,2H),3.43-3.38(m, 1H),3.33-3.27(m,2H),3.26-3.17(m,2H),2.26-2.21(m,1H),2.08-2.01(m,1H),1.29 (t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C24H26O3N4S 451.1798[M+H]+, Found:451.1784。
Example 34
(1- ((4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) amino) -1-carbonylpropan-2-yl) carbamic acid tert-butyl ester
Figure BDA0001620885820001282
N-Boc-DL-alanine (219mg,1.02mmol) was dissolved in DCM (15mL), DIEA (175mg,1.36mmol) and HATU (414mg,1.09mmol) were added in this order, and after reaction at room temperature for 30min, 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (240mg,0.68mmol) was added and the reaction was carried out at room temperature for 10h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying, and purifying with column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain white solidBody 297mg, yield 79.4%, melting point: 98-99 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.45(s,1H),8.39(s,1H),8.11(dd,J＝8.8,2.8 Hz,1H),7.98(s,1H),7.93(d,J＝2.8Hz,1H),7.88-7.86(m,2H),7.44-7.40(m,2H), 7.33(d,J＝3.2Hz,1H),6.92(d,J＝9.2Hz,1H),5.03(s,1H),4.73(d,J＝5.2Hz,2H), 4.33(s,1H),4.12(q,J＝6.8Hz,2H),1.46(s,9H),1.43(d,J＝6.8Hz,3H),1.31(t,J＝ 7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C27H32O5N4S 525.2166[M+H]+,Found: 525.2153。
Example 35
5- (2-aminopropionylamino) -2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide hydrochloride
Figure BDA0001620885820001291
Tert-butyl (1- ((4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) amino) -1-carbonylpropan-2-yl) carbamate (80mg,0.15mmol) was dissolved in DCM (10 mL)/ethanol (2mL), HCl EA solution (1mL) was added, reaction was carried out at room temperature for 8h, concentration was carried out, ether (20mL) was added to precipitate a pale green solid, and filtration was carried out to obtain 69mg of a white solid with a yield of 98.6%, melting point: 141 ℃ and 142 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):10.66(s,1H),8.71(brs,1H),8.31(s,3H),7.99 (d,J＝2.4Hz,1H),7.95(s,1H),7.92(brs,1H),7.84(brs,1H),7.79(brs,1H),7.74(dd, J＝8.8,2.4Hz,1H),7.47(d,J＝3.2Hz,2H),7.15(d,J＝9.2Hz,1H),4.59(d,J＝6.0 Hz,2H),4.14(q,J＝7.2Hz,2H),4.02(brs,1H),1.46(d,J＝6.8Hz,3H),1.31(t,J＝ 6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C22H24O3N4S 425.1642[M+H]+,Found: 425.1625。
Example 36
2- ((4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure BDA0001620885820001292
(dl) -N-Boc-proline (163mg,0.86mmol) was dissolved in DCM (15mL), DIEA (147mg,1.14mmol) and HATU (346mg,0.91mmol) were added in this order, and after reaction at room temperature for 30min, 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (200mg,0.57mmol) was added and the reaction was carried out at room temperature for 10h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 233mg of white solid, yield 78.5%, melting point: 152 ℃ and 153 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):9.16(s,1H),8.44(brs,1H),8.10(d,J＝7.2Hz, 1H),7.98(s,1H),7.92(s,1H),7.88-7.86(m,2H),7.44-7.41(m,2H),7.34(d,J＝3.2 Hz,1H),6.92(d,J＝9.2Hz,1H),4.72(d,J＝5.6Hz,2H),4.44(brs,1H),4.12(q,J＝ 6.8Hz,2H),3.49(s,2H),2.47(brs,2H),1.93(brs,2H),1.48(s,9H),1.31(t,J＝6.8Hz, 3H)；HR-MS(ESI):m/z,calcd.For C29H34O5N4S 551.2323[M+H]+,Found:551.2308。
Example 37
N- (4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) pyrrolidine-2-carboxamide hydrochloride
Figure BDA0001620885820001301
Tert-butyl 2- ((4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) phenyl) carbamoyl) pyrrolidine-1-carboxylate (80mg,0.15mmol) was dissolved in DCM (10 mL)/ethanol (2mL), HCl EA solution (1mL) was added, reaction was carried out at room temperature for 8h, concentration was carried out, ether (20mL) was added to precipitate a pale green solid, white solid was filtered at 67mg, yield 94.4%, melting point: 149 ℃ and 150 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):10.84(s,1H),10.02(s,1H),8.71(brs,1H),8.66 (s,1H),8.00(s,1H),7.96(s,1H),7.93(d,J＝2.0Hz,1H),7.84(s,1H),7.80(d,J＝2.8 Hz,1H),7.74(d,J＝8.8Hz,1H),7.48(d,J＝4.4Hz,2H),7.15(d,J＝8.8Hz,1H), 4.59(d,J＝5.6Hz,2H),4.36(brs,1H),4.14(q,J＝6.8Hz,2H),3.26(brs,2H),2.40 (brs,1H),1.95(brs,3H),1.30(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C24H26O3N4S 451.1798[M+H]+,Found:451.1783。
Example 38
2-ethoxy-5- (4-methoxybenzoylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001311
5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (100mg,0.28mmol) was dissolved in anhydrous THF (10mL), TEA (85mg,0.84mmol) and 4-methoxybenzoyl chloride (95mg,0.56mmol) were added sequentially in ice bath, the reaction was continued for 1h, filtered, the filtrate was concentrated, diluted with ethyl acetate (30mL), washed with saturated ammonium chloride solution (20mL), and saturated NaHCO was added3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to give 82mg of white solid, 59.4% yield, melting point: 148 ℃ and 149 ℃.
1H-NMR(400MHz,CDCl3))δ(ppm):8.49(brs,1H),8.34(dd,J＝8.8,2.4Hz,1H), 8.15(s,1H),8.04(d,J＝2.8Hz,1H),7.95(s,1H),7.89-7.85(m,4H),7.47-7.39(m, 2H),7.34(d,J＝3.2Hz,1H),6.98-6.95(m,3H),4.66(d,J＝5.6Hz,2H),4.15(q,J＝ 6.8Hz,2H),3.85(s,3H),1.32(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C27H25O4N3S 488.1639[M+H]+,Found:488.1619。
Example 39
2-ethoxy-5-cyclobutylcarboxamido-N- (1- (3- (thiazol-2-yl) phenyl) methyl) benzamide
Figure BDA0001620885820001312
a) 2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) methyl) benzamide
2-ethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) methyl) benzamide (200mg, 0.52mmol) was dissolved in DCM (2ml)/EtOH (8ml)/H2O (1ml), Fe powder (175mg, 3.13mmol), NH were added4Cl (28mg, 0.52mmol), reflux reaction at 70 ℃ for 2 h. The raw material disappeared. After filtration, concentration, dilution with EA (15ml), washing with water (15 ml. times.2), drying over anhydrous magnesium sulfate, concentration, and addition of petroleum ether, 153mg of a white solid was precipitated in 83% yield.
1H NMR(400MHZ，DMSO-d6)δ(ppm):8.65(t,J＝6.0Hz,1H),7.92-7.94(m,2H), 7.83(d,J＝6.0Hz,1H),7.7983(d,J＝6.0Hz,1H),7.79(d,J＝3.2Hz,1H),7.46-7.49 (m,2H),7.07(d,J＝2.8Hz,1H),6.85(d,J＝8.4Hz,1H),6.66(dd,J1＝2.8Hz,J2＝8.4 Hz,1H),4.85(s,2H),4.57(d,J＝5.6Hz,2H),4.00(q,J＝6.8Hz,2H),1.22(t,J＝6.8 Hz,3H).m.p.124-126℃.
b) 2-ethoxy-5-cyclobutylcarboxamido-N- (1- (3- (thiazol-2-yl) phenyl) methyl) benzamide
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) methyl) benzamide (60mg, 0.17mmol) was dissolved in THF (4mL), TEA (51mg, 0.51mmol) was added in ice bath, cyclobutanecarbonyl chloride (24mg, 0.20mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. Washed with distilled water (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and added with petroleum ether to give 65mg of a white solid in 86% yield.
1H NMR(400MHZ,CDCl3)δ(ppm):8.50(d,J＝4.8Hz,1H),8.25(dd,J1＝2.8Hz,J2＝8.8Hz,1H),7.99(s,1H),7.86-7.90(m,2H),7.44-7.45(m,2H),7.39(brs,1H),7.35 (d,J＝3.2Hz,1H),6.93(d,J＝9.2Hz,1H),4.74(d,J＝5.2Hz,2H),4.13(q,J＝2.8 Hz,2H),3.10-3.21(m,1H),2.33-2.38(m,1H),2.17-2.23(m,1H),1.31(t,J＝6.8Hz, 3H).m.p.166-168.
Example 40
5- (Cyclopentanamido) -2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001321
Cyclopentylcarboxylic acid (72mg,0.63mmol) was dissolved in DCM (15mL), DIEA (163 mg,1.26mmol), HATU (319mg,0.84mmol) were added in this order, and after reaction at room temperature for 30min, 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (150mg,0.42mmol) was added and the reaction was carried out at room temperature for 10h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, vol 2:3) gave 63mg of a white solid, 33.2% yield, melting point: 171 ℃ and 172 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.49(brs,1H),8.22(d,J＝7.2Hz,1H),7.98(s, 1H),7.88(brs,3H),7.51(s,1H),7.44(brs,2H),7.34(d,J＝3.2Hz,1H),6.92(d,J＝ 9.0Hz,1H),4.73(d,J＝5.2Hz,2H),4.13(q,J＝6.8Hz,2H),2.73-2.65(m,1H), 1.95-1.83(m,4H),1.79-1.73(m,2H),1.64-1.58(m,2H),1.31(t,J＝6.8Hz,3H)； HR-MS(ESI):m/z,calcd.For C25H27O3N3S 450.1846[M+H]+,Found:450.1838。
Example 41
2-ethoxy-5- (2-methoxypropionylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001331
2-Methoxypropionic acid (87mg,0.84mmol) was dissolved in DCM (10mL), DIEA (163 mg,1.26mmol), HATU (400mg,1.05mmol) were added in this order, and after reaction at room temperature for 30min, 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (150mg,0.42mmol) was added and the reaction was allowed to proceed at room temperature for 8h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 3:2) to obtain 116mg of white solid, yield 62.4%, melting point: 149 ℃ and 151 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.46(s,1H),8.41(s,1H),8.22(dd,J＝9.0,2.8 Hz,1H),7.99(s,1H),7.93(d,J＝2.4Hz,1H),7.89-7.86(m,2H),7.45-7.41(m,2H), 7.34(d,J＝3.2Hz,1H),6.94(d,J＝9.2Hz,1H),4.73(d,J＝5.6Hz,2H),4.14(q,J＝ 6.8Hz,2H),3.86(q,J＝6.8Hz,1H),3.48(s,3H),1.46(d,J＝6.8Hz,3H),1.32(t,J＝ 6.8Hz,3H)；HR-MS(ESI):m/z,calcd.For C23H25O4N3S 440.1639[M+H]+,Found: 440.1631。
Example 42
2-ethoxy-5- (methylsulfonylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001332
Dissolving 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (160mg,0.45mmol) in anhydrous THF (15mL), sequentially adding methanesulfonyl chloride (103mg,0.90mmol), pyridine (178 mg,2.25mmol) under ice bath, stirring at room temperature for reaction for 8h, filtering, concentrating the filtrate, adding ethyl acetate (20mL) for dilution, washing with saturated ammonium chloride solution (10mL), and saturated NaHCO3Washing (10mL), washing with water (10mL), washing with saturated brine (10mL), anhydrous Na 2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 3:2) to obtain 142mg of white solid, yield 72.8%, melting point: 164 ℃ and 165 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.63(s,1H),8.34(d,J＝2.8Hz,1H),8.13(s, 1H),8.00(s,1H),7.89-7.85(m,2H),7.63(d,J＝8.8Hz,1H),7.46-7.41(m,2H),7.34 (d,J＝3.2Hz,1H),6.96(d,J＝8.8Hz,1H),4.81(d,J＝5.6Hz,2H),4.15(q,J＝6.8 Hz,2H),2.92(s,3H),1.33(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C20H21O4N3S2 432.1046[M+H]+,Found:432.1042。
Example 43
2-ethoxy-5- (isopropylsulfonylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001341
Dissolving 5-amino-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (100mg,0.28mmol) in anhydrous THF (10mL), adding isopropylsulfonyl chloride (80mg,0.56mmol), pyridine (111mg,1.40mmol) in sequence under ice bath, stirring for reaction for 8h, filtering, concentrating the filtrate, adding ethyl acetate (20mL) for dilution, washing with HCl (0.5N) solution (10mL), and saturating with NaHCO3Washing (10mL), washing with water (10mL), washing with saturated brine (10mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 3:2) to obtain 84mg of white solid, yield 64.6%, melting point: 158 ℃ and 159 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.61(s,1H),8.29(d,J＝2.8Hz,1H),8.07(s, 1H),8.00(s,1H),7.89-7.85(m,2H),7.68(dd,J＝8.8,2.8Hz,1H),7.48-7.41(m,2H), 7.33(d,J＝3.2Hz,1H),6.92(d,J＝9.2Hz,1H),4.80(d,J＝5.2Hz,2H),4.13(q,J＝ 6.8Hz,2H),3.23-3.16(m,1H),1.35(d,J＝6.8Hz,6H),1.31(t,J＝7.2Hz,3H)； HR-MS(ESI):m/z,calcd.For C22H25O4N3S2 460.1359[M+H]+,Found:460.1345。
Example 44
2-ethoxy-5- (2-carbonylpyrrolidin-1-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001342
a)5- (4-Chlorobutylamino) -2-ethoxybenzoic acid methyl ester
Dissolving methyl 5-amino-2-ethoxybenzoate (600mg,3.08mmol) in anhydrous THF (10mL), sequentially adding 4-chlorobutyryl chloride (651mg,4.62mmol) and TEA (778mg,7.70mmol) under ice bath, continuing reaction for 2h, filtering, concentrating the filtrate After dilution with ethyl acetate (20mL), washed with 0.5N aqueous HCl (10mL) and saturated NaHCO3Washing (10mL), washing with water (10mL), washing with saturated saline (10mL), and washing with anhydrous Na2SO4Drying, concentrating, and recrystallizing with PE/EA to obtain light brown solid 899mg, yield 97.4%, melting point: 95-96 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):7.78(d,J＝2.8Hz,1H),7.73(dd,J＝8.8,2.8Hz, 1H),7.35(s,1H),6.92(d,J＝8.8Hz,1H),4.09(q,J＝6.8Hz,2H),3.87(s,3H),3.66(t, J＝6.0Hz,2H),2.54(t,J＝7.2Hz,2H),2.30-2.10(m,2H),1.43(t,J＝7.2Hz,3H)； ESI-MS m/z:300.10[M+H]+。
b) 2-ethoxy-5- (2-carbonylpyrrolidin-1-yl) benzoic acid
Methyl 5- (4-chlorobutyrylamino) -2-ethoxybenzoate (400mg,1.33mmol) was dissolved in THF (15 mL)/water (2mL), NaOH (213mg,5.33mmol) was added with stirring, reaction at room temperature was performed for 6h, reactions 1 and 2 were combined, concentrated, diluted with water (10mL), the aqueous layer was washed with diethyl ether (10mL × 2), the aqueous layer was adjusted to pH 3 with hydrochloric acid, 377mg of solid was precipitated, yield 90.6%, melting point: 132-133 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.39(dd,J＝9.2,2.8Hz,1H),7.90(d,J＝2.8Hz, 1H),7.06(d,J＝9.2Hz,1H),4.34(q,J＝7.2Hz,2H),3.89(t,J＝7.2Hz,2H),2.61(t, J＝8.0Hz,2H),2.26-2.08(m,2H),1.56(t,J＝7.2Hz,3H)；ESI-MS m/z:248.09 [M-H]-。
c) 2-ethoxy-5- (2-carbonylpyrrolidin-1-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-5- (2-carbonylpyrrolidin-1-yl) benzoic acid (262mg,1.05mmol) was dissolved in DCM (20mL), DIEA (204mg,1.58mmol) and HATU (600mg,1.58mmol) were added in this order, and after stirring for 20min, (3- (thiazol-2-yl) phenyl) methylamine (200mg,1.05mmol) was added, and the mixture was stirred at room temperature overnight. Concentrate, dilute with DCM (20mL), wash with HCl (0.5N) (10mL), and saturate NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na 2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to give 237mg of white solid, yield 53.5%, melting point: 144 ℃ and 145 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.48(s,1H),8.23(dd,J＝9.0,2.8Hz,1H),7.98 (d,J＝2.8Hz,2H),7.87(brs,2H),7.45-7.41(m,2H),7.34(d,J＝3.2Hz,1H),6.96(d, J＝8.8Hz,1H),4.73(d,J＝5.2Hz,2H),4.15(q,J＝7.2Hz,2H),3.91(t,J＝7.2Hz, 2H),2.60(t,J＝8.4Hz,2H),2.20-2.12(m,2H),1.32(t,J＝7.2Hz,3H)；HR-MS(ESI): m/z,calcd.For C23H23O3N3S 422.1533[M+H]+,Found:422.1526。
Example 45
2-ethoxy-5- (isobutylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001361
a) 2-ethoxy-5- (isobutylamino) benzoic acid methyl ester
Reaction 1: methyl 5-amino-2-ethoxybenzoate (200mg,1.03mmol) and isobutyraldehyde (81mg,1.03 mmol) were dissolved in isopropanol (10 mL)/water (1mL), and ammonium formate (649mg,10.3mmol) and Pd/C (200mg) were added in this order, and reacted at room temperature for 4 hours, whereupon the starting material disappeared. Reaction 2: methyl 5-amino-2-ethoxybenzoate (400mg,2.06mmol) and isobutyraldehyde (162mg,2.06mmol) were dissolved in isopropanol (10 mL)/water (1mL), and ammonium formate (1.3g,20.60mmol) and Pd/C (400mg) were added in this order to react at room temperature for 4 hours, and the starting material disappeared. Reaction 3: reactions 1, 2 and 3 were combined, concentrated, diluted with EA (50mL), washed with water (20 mL. times.2), brine (20mL), anhydrous Na and concentrated as in reaction 22SO4Drying, and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:7) to obtain light green oil 898mg, yield 70.2%.1H-NMR(400MHz,CDCl3)δ(ppm):7.03(d,J＝3.2Hz,1H),6.85(d,J＝8.8Hz,1H), 6.71(dd,J＝8.8,3.2Hz,1H),4.01(q,J＝7.2Hz,2H),3.88(s,3H),3.69(s,1H),2.90 (d,J＝6.8Hz,2H),1.91-1.81(m,1H),1.39(t,J＝7.2Hz,3H),0.98(d,J＝6.8Hz,6H)； ESI-MS m/z:252.16[M+H]+。
b) 2-ethoxy-5- (isobutylamino) benzoic acid
Reaction 1: methyl 2-ethoxy-5- (isobutylamino) benzoate (160mg,0.64mmol) was dissolved in THF (10 mL)/water (1mL), NaOH (102mg,2.56mmol) was added with stirring, and reacted at room temperature for 6 h. Reaction 2: methyl 2-ethoxy-5- (isobutylamino) benzoate (500mg,2.00mmol) was dissolved in THF (15 mL)/water (2mL), NaOH (320mg,8.00mmol) was added with stirring, the reaction was carried out at room temperature for 6h, reactions 1 and 2 were combined, concentrated, diluted with water (10mL), the aqueous layer was washed with diethyl ether (10mL × 2), the aqueous layer was adjusted to pH 3 with hydrochloric acid, 531mg of a solid was precipitated, yield 85.2%, melting point: 80-81 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):7.39(d,J＝3.2Hz,1H),6.89(d,J＝8.8Hz,1H), 6.79(dd,J＝8.9,3.2Hz,1H),4.23(q,J＝7.2Hz,2H),2.93(d,J＝6.8Hz,2H), 1.92-1.82(m,1H),1.50(t,J＝7.2Hz,3H),0.98(d,J＝6.8Hz,6H)；ESI-MS m/z: 236.13[M-H]-。
c) 2-ethoxy-5- (isobutylamino) -N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-5- (isobutylamino) benzoic acid (249mg,1.05mmol) was dissolved in DCM (20mL), DIEA (204mg,1.58mmol), HATU (600mg,1.58mmol) were added in this order, and after stirring for 20 min, (3- (thiazol-2-yl) phenyl) methylamine (200mg,1.05mmol) was added, and the mixture was stirred at room temperature overnight. Concentrate, dilute with DCM (20mL), wash with HCl (0.5N) (10mL), and saturate NaHCO3Washing with (10mL), washing with water (10mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 181mg of white solid, yield 42.2%, melting point: 89 to 90 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.58(s,1H),7.97(s,1H),7.86(brs,2H),7.54(d, J＝2.8Hz,1H),7.48-7.37(m,2H),7.33(d,J＝3.2Hz,1H),6.81(d,J＝8.8Hz,1H), 6.71(dd,J＝8.8,2.8Hz,1H),4.72(d,J＝5.6Hz,2H),4.03(q,J＝7.2Hz,2H),2.94(d, J＝6.8Hz,2H),1.93-1.83(m,1H),1.26(t,J＝7.2Hz,3H),0.97(d,J＝6.4Hz,6H)； HR-MS(ESI):m/z,calcd.For C23H27O2N3S 410.1897[M+H]+,Found:410.1891。
Example 46
4-ethoxy-N1,N1-dimethyl-N3- (3- (thiazol-2-yl)) Benzyl) isophthalamide
Figure BDA0001620885820001371
a) 2-ethoxy-5-formylbenzoic acid methyl ester
Methyl 2-hydroxy-5-formylbenzoate (2g,11.11mmol) was dissolved in anhydrous DMF (20mL) and K was added sequentially2CO3(3.07g,22.22mmol)、C2H5I (5.20g,33.33mmol), heating to 60 ℃ for reaction for 10h, cooling, adding water to precipitate a white solid, filtering, and washing the filter cake with water (20mL) to obtain 1.77 g of a white solid, with a yield of 76.9%, a melting point: 64-65 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):9.90(s,1H),8.31(d,J＝2.0Hz,1H),7.99(dd,J ＝8.8,2.0Hz,1H),7.08(d,J＝8.8Hz,1H),4.22(q,J＝7.2Hz,2H),3.92(s,3H),1.51 (t,J＝7.2Hz,3H)；ESI-MS m/z:209.08[M+H]+。
b) 4-ethoxy-3- (methoxycarbonyl) benzoic acid
Methyl 2-ethoxy-5-formylbenzoate (600mg,2.88mmol) was dissolved in DMF (15mL), potassium monopersulfate complex salt (3.54g,5.76mmol) was added, the reaction was allowed to proceed at room temperature for 3h, filtered, HCl (2N) (15mL) was added, EA (25 mL. times.3) was added and extraction was carried out with anhydrous Na 2SO4The organic phase was dried, concentrated and recrystallized to yield 375mg of white solid in 58.0% yield, m.p.: 185 ℃ and 187 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):12.90(s,1H),8.21(s,1H),8.06(d,J＝8.8Hz, 1H),7.24(d,J＝8.8Hz,1H),4.19(q,J＝6.8Hz,2H),1.35(t,J＝6.8Hz,3H)；ESI-MS m/z:223.06[M-H]-。
c)5- (dimethylcarbamoyl) -2-ethoxybenzoic acid methyl ester
4-ethoxy-3- (methoxycarbonyl) benzoic acid (300mg,1.05mmol) was dissolved in DCM (20mL), DIEA (519mg,4.02mmol) and HATU (1.02g,2.68mmol) were added in this order, and after reaction at room temperature for 30min, the hydrochloride of dimethylamine (164mg,2.01mmol) was added, and the reaction was carried out under argon atmosphere at room temperature for 5h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturateAnd NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 317mg of white solid, yield 94.3%, melting point: at the temperature of 55-57 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):7.89(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.4Hz, 1H),6.97(d,J＝8.8Hz,1H),4.15(q,J＝7.2Hz,2H),3.88(s,3H),3.05(s,6H),1.47(t, J＝7.2Hz,3H)；ESI-MS m/z:252.12[M+H]+。
d)5- (dimethylcarbamoyl) -2-ethoxybenzoic acid
Methyl 5- (dimethylcarbamoyl) -2-ethoxybenzoate (300mg,1.20mmol) was dissolved in THF (20 mL)/water (10mL), NaOH (192mg,4.80mmol) was added with stirring, the reaction was carried out at room temperature for 6h, concentrated, and the aqueous layer was washed with diethyl ether (20mL), the pH of the aqueous layer was adjusted to 3 with hydrochloric acid, and 244mg of a solid was precipitated, yield was 86.2%, melting point: 102-103 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):12.72(s,1H),7.65(s,1H),7.54(d,J＝8.8Hz, 1H),7.14(d,J＝8.4Hz,1H),4.14(q,J＝7.2Hz,2H),2.95(s,6H),1.34(t,J＝6.8Hz, 3H)；ESI-MS m/z:236.09[M-H]-。
e) 4-ethoxy-N1,N1-dimethyl-N 3- (3- (thiazol-2-yl) benzyl) isophthalamide
5- (dimethylcarbamoyl) -2-ethoxybenzoic acid (200mg,0.84mmol) was dissolved in DCM (20mL), DIEA (217mg,1.68mmol) and HATU (479mg,1.26mmol) were added in that order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (160mg,0.84mmol) was added, and the reaction was carried out at room temperature under argon atmosphere for 5h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying and column chromatography (ethyl acetate-petroleum ether, 1:1 by volume) gave 319mg of white solid in 88.6% yield, melting point: 78-79 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.32(d,J＝2.0Hz,2H),7.99(s,1H),7.87(brs, 2H),7.61(dd,J＝8.4,2.4Hz,1H),7.44(brs,2H),7.34(d,J＝3.2Hz,1H),6.98(d,J＝ 8.4Hz,1H),4.73(d,J＝5.2Hz,2H),4.18(q,J＝6.8Hz,2H),3.07(brs,6H),1.34(t,J ＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C22H23O3N3S 410.1533[M+H]+,Found: 410.1521。
Example 47
4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) benzyl (isopropyl) carbamate
Figure BDA0001620885820001391
a) 2-ethoxy-5- ((isopropylamino) methyl) benzoic acid methyl ester
Methyl 2-ethoxy-5-formylbenzoate (500mg,2.40mmol) was dissolved in trifluoroethanol (20mL), isopropylamine (1.42g,24mmol) was added, the reaction was allowed to proceed at room temperature for 2h, then NaBH was added4(180mg,4.80mmol) and the reaction was continued for 2h, after completion of the reaction of the starting materials. Combine reactions 1 and 2, saturated NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na 2SO4Drying and column chromatography (EtOAc-petroleum ether, vol.1: 3) afforded 477mg of a pale green oil in 71.9% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.72(d,J＝2.0Hz,1H),7.42(dd,J＝8.4,2.0Hz, 1H),6.92(d,J＝8.4Hz,1H),4.10(q,J＝7.2Hz,2H),3.88(s,3H),3.73(s,2H), 2.90-2.79(m,1H),1.44(t,J＝7.2Hz,3H),1.10(d,J＝6.4Hz,5H)；ESI-MS m/z: 252.16[M+H]+。
b)5- ((((benzyloxy) carbonyl) (isopropyl) amino) methyl) -2-ethoxybenzoate methyl ester
Methyl 2-ethoxy-5- ((isopropylamino) methyl) benzoate (450mg,0.08mmol) was dissolved in anhydrous THF (10mL), CbzCl (612mg,3.60mmol) and TEA (545mg,5.40mmol) were added in that order and the reaction was completed at room temperature for 3 h. Concentrated, diluted with EA (30mL) and saturated NaHCO3Washing (20mL), washing with water (20mL), washing with saturated saline (20mL), and washing with anhydrous Na2SO4Drying, and column chromatography (EtOAc-stone)Oily ether with the volume ratio of 1:10) to obtain 677mg of colorless oil with the yield of 98.1%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.64(s,1H),7.44-7.15(m,6H),6.88(s,1H), 5.14(s,2H),4.37(brs,3H),4.09(q,J＝7.2Hz,2H),1.45(t,J＝6.8Hz,3H),1.11(d,J ＝6.4Hz,6H)；ESI-MS m/z:386.20[M+H]+。
c)5- ((((benzyloxy) carbonyl) (isopropyl) amino) methyl) -2-ethoxybenzoic acid
Methyl 5- ((((benzyloxy) carbonyl) (isopropyl) amino) methyl) -2-ethoxybenzoate (630mg,1.63mmol) was dissolved in methanol (20 mL)/water (10mL), NaOH (326mg,8.15mmol) was added with stirring, the reaction was carried out at room temperature for 6 hours, concentration was carried out, the aqueous layer was washed with diethyl ether (20mL), the pH was adjusted to 3 with hydrochloric acid, EA (25mL × 3) was added for extraction, and concentration was carried out to obtain 533mg of a colorless oil with a yield of 87.8%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.04(s,1H),7.53-7.11(m,7H),6.94(s,1H), 5.12(brs,2H),4.69(s,1H),4.40(brs,2H),4.29(brs,2H),1.54(t,J＝6.0Hz,3H),1.11 (d,J＝6.4Hz,6H)；ESI-MS m/z:370.17[M-H]-。
d) Benzyl 4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) benzyl (isopropyl) carbamate 5- ((((benzyloxy) carbonyl) (isopropyl) amino) methyl) -2-ethoxybenzoic acid (300mg,0.81mmol) was dissolved in DCM (20mL), DIEA (157mg,1.22mmol), HATU (400mg,1.05 mmol) were added in that order, and after 30min at room temperature, (3- (thiazol-2-yl) phenyl) methylamine (169mg,0.89mmol) was added and reacted under argon at room temperature for 5h, and the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHCO 3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying, and purifying with column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain colorless oil 303 mg, with yield of 69.1%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.42(brs,1H),8.13(s,1H),7.99(s,1H), 7.89-7.86(m,2H),7.47-7.41(m,2H),7.30(brs,6H),6.84(s,1H),5.15(s,2H),4.73(d, J＝5.2Hz,2H),4.42(brs,3H),4.12(q,J＝6.8Hz,2H),1.32(t,J＝7.2Hz,3H),1.12 (d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C31H33O4N3S 544.2265[M+H]+, Found:544.2259。
Example 48
2-ethoxy-5- ((isopropylamino) methyl) -N- (3- (thiazol-2-yl) benzyl) benzamide hydrobromide
Figure BDA0001620885820001401
Benzyl 4-ethoxy-3- ((3- (thiazol-2-yl) benzyl) carbamoyl) benzyl (isopropyl) carbamate (80 mg,0.15mmol) was dissolved in ethanol (5mL), and HBr in acetic acid (30%) (1.0mL) was added with stirring, followed by reflux reaction for 6h, concentration, precipitation of a red solid by addition of diethyl ether (20mL), filtration to 54mg, yield 75.0%, melting point: 139 ℃ and 140 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):8.72(s,1H),8.63(s,2H),7.98(s,1H),7.94(s, 2H),7.85(s,1H),7.81(s,1H),7.61(d,J＝7.6Hz,1H),7.49(s,2H),7.24(d,J＝7.6 Hz,1H),4.62(s,2H),4.21(brs,2H),4.15(s,2H),3.32(brs,1H),1.34(brs,3H),1.28 (d,J＝5.2Hz,6H)；HR-MS(ESI):m/z,calcd.For C23H27O2N3S 410.1897[M+H]+, Found:410.1886。
Example 49
4-ethoxy-N1-isopropyl-N3- (3- (thiazol-2-yl) benzyl) isophthalamide
Figure BDA0001620885820001411
a) 2-ethoxy-5- (isopropylcarbamoyl) benzoic acid methyl ester
4-ethoxy-3- (methoxycarbonyl) benzoic acid (300mg,1.34mmol) was dissolved in DCM (20mL), DIEA (260mg,2.01mmol) and HATU (764mg,2.01mmol) were added in this order, and after reaction at room temperature for 30min, isopropylamine (95mg,1.61mmol) was added and the reaction was carried out under argon atmosphere at room temperature for 5h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHC O3Washing (20mL), washing with water (20mL), washing with saturated saline (20mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 311mg of white solid, yield 87.6%, melting point: 107-108 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.11(d,J＝2.4Hz,1H),7.96(dd,J＝8.8,2.4Hz, 1H),6.99(d,J＝8.8Hz,1H),4.35-4.21(m,1H),4.16(q,J＝7.2Hz,2H),3.89(s,3H), 1.47(t,J＝7.2Hz,3H),1.25(t,J＝7.2Hz,6H)；ESI-MS m/z:266.14[M+H]+。
b) 2-ethoxy-5- (isopropylcarbamoyl) benzoic acid
Methyl 2-ethoxy-5- (isopropylcarbamoyl) benzoate (310mg,1.17mmol) was dissolved in methanol (20 mL)/water (10mL), NaOH (234mg,5.85mmol) was added with stirring, the reaction was carried out at room temperature for 6 hours, concentration was carried out, the aqueous layer was washed with diethyl ether (20mL), pH was adjusted to 3 with hydrochloric acid to precipitate a solid, and filtration was carried out to obtain 239 mg of a white solid, yield 81.3%, melting point: 175 ℃ to 176 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):12.71(s,1H),8.21(d,J＝7.6Hz,1H),8.14(s, 1H),7.97(d,J＝8.8Hz,1H),7.15(d,J＝8.8Hz,1H),4.14(q,J＝6.8Hz,2H),4.07(dt, J＝13.2,6.8Hz,1H),1.34(t,J＝6.8Hz,3H),1.15(d,J＝6.8Hz,6H)；ESI-MS m/z: 250.11[M-H]-。
c) 4-ethoxy-N1-isopropyl-N3- (3- (thiazol-2-yl) benzyl) isophthalamide
2-ethoxy-5- (isopropylcarbamoyl) benzoic acid (200mg,0.80mmol) was dissolved in DCM (20mL), DIEA (206mg,1.60mmol) and HATU (456mg,1.20mmol) were added in this order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (151mg,0.80mmol) was added, and the reaction was carried out at room temperature under argon atmosphere for 5h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying, and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 232mg of white solid, yield 68.8%, melting point: 132 ℃ and 133 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.48(d,J＝2.4Hz,1H),8.39(s,1H),8.10(dd,J ＝8.4,2.4Hz,1H),8.00(s,1H),7.88-7.86(m,2H),7.46-7.42(m,2H),7.36(d,J＝3.6 Hz,1H),7.02(d,J＝8.8Hz,1H),6.11(d,J＝7.2Hz,1H),4.74(d,J＝5.2Hz,2H), 4.32-4.25(m,1H),4.21(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H),1.25(d,J＝6.8Hz, 6H)；HR-MS(ESI):m/z,calcd.For C23H25O3N3S 424.1689[M+H]+,Found:424.1673。
Example 50
5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001421
a) 5-bromo-2-ethoxybenzoic acid
5-Bromosalicylic acid (10g,46.00mmol) was dissolved in anhydrous DMF (20mL) and K was added sequentially2CO3 (12.70g,92.00mmol)、C2H5I (14.40g,92.00mmol), heating to 60 ℃ to react for 10h, cooling to room temperature after completion of the reaction, sequentially adding water (5mL) and NaOH (3.68g,92.00mmol), continuing to stir for 2h, concentrating, adding hydrochloric acid to adjust pH to 3, precipitating a solid, filtering to obtain 6.71g of a white solid, yield 59.4%, melting point: 128-130 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):12.88(s,1H),7.73-7.68(m,1H),7.63(dd,J＝ 8.8,1.6Hz,1H),7.09(d,J＝8.8Hz,1H),4.08(q,J＝6.8Hz,2H),1.31(t,J＝6.8Hz, 3H)；ESI-MS m/z:242.97[M-H]-。
b) 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
5-bromo-2-ethoxybenzoic acid (360mg,1.89mmol) was dissolved in DCM (20mL), DIEA (488mg,3.78mmol) and HATU (1.08g,2.84mmol) were added in this order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (463mg,1.89mmol) was added and reaction at room temperature for 10h, the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated saline (20mL), and washing with anhydrous Na2SO4Drying and column chromatography(Ethyl acetate-Petroleum ether, volume ratio 2:5) to obtain 609mg of white solid, yield 77.3%, melting point: 104-105 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.36(s,1H),8.30(s,1H),7.98(s,1H),7.87(s, 2H),7.50(d,J＝8.8Hz,1H),7.44(brs,2H),7.34(d,J＝2.4Hz,1H),6.82(d,J＝8.8 Hz,1H),4.72(d,J＝5.2Hz,2H),4.12(q,J＝6.8Hz,2H),1.32(t,J＝6.8Hz,3H)； HR-MS(ESI):m/z,calcd.For C19H17O2N2BrS 417.0267[M+H]+,Found:417.0259。
Example 51
5- (3, 3-difluoropyrrolidin-1-yl) -2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001431
Reaction 1: 3, 3-difluoropyrrolidine trifluoroacetate (265mg,1.20mmol), Pd2(dba)3(22mg,0.024mmol), BINAP (30mg,0.048mmol), sodium tert-butoxide (58mg,5.25mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50mg,0.12mmol) was added to anhydrous toluene (25mL) and reacted at 100 ℃ for 5h under argon. Reaction 2: 3, 3-difluoropyrrolidine trifluoroacetate (2.28g, 10.30mmol), Pd2(dba)3(183mg,0.20mmol), BINAP (250mg,0.40mmol), sodium tert-butoxide (495mg,5.15mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (430 mg,1.03mmol) was added to anhydrous toluene (30mL) and reacted at 100 ℃ for 5h under argon. Reactions 1 and 2 were combined, diluted with DCM (30mL), washed with saturated brine (20mL), anhydrous Na2SO4Drying and column chromatography (ethyl acetate-petroleum ether, 1:2 by volume) gave 179mg of a pale yellow solid, 35.2%, melting point: 124 ℃ and 125 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.59(s,1H),7.98(s,1H),7.89-7.86(m,2H), 7.50(d,J＝3.2Hz,1H),7.49-7.41(m,2H),7.34(d,J＝3.2Hz,1H),6.89(d,J＝8.8Hz, 1H),6.63(dd,J＝8.8,3.2Hz,1H),4.73(d,J＝5.6Hz,2H),4.07(q,J＝7.2Hz,2H), 3.67(t,J＝13.2Hz,2H),3.52(t,J＝7.2Hz,2H),2.54-2.43(m,2H),1.29(t,J＝7.2Hz, 3H)；HR-MS(ESI):m/z,calcd.For C23H23O2N3F2S 444.1552[M+H]+,Found:444.1535。
Example 52
5- (4, 4-Difluoropiperidin-1-yl) -2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001441
Reaction 1: 4, 4-Difluoropiperidine hydrochloride (189mg,1.20mmol), Pd2(dba)3(22mg,0.024mmol), BINAP (30mg,0.048mmol), sodium tert-butoxide (115mg,1.20mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50mg,0.12mmol) were added to anhydrous toluene (25mL) and reacted at 90 ℃ for 5h under argon. Reaction 2: 4, 4-Difluoropiperidine hydrochloride (756mg,4.80mmol), Pd 2(dba)3(220mg,0.24mmol), BINAP (299mg,0.48mmol), sodium tert-butoxide (1.15g,12.0 mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (500mg,1.20mmol) was added to anhydrous toluene (30mL) and reacted at 90 ℃ for 5h under argon. Reactions 1 and 2 were combined, diluted with DCM (30mL), washed with saturated brine (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 149mg of light yellow solid, 24.8%, melting point: 130 ℃ and 131 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.52(s,1H),7.98(s,1H),7.87(dd,J＝6.8,3.2 Hz,3H),7.51-7.39(m,2H),7.34(d,J＝3.2Hz,1H),7.02(dd,J＝8.8,3.2Hz,1H), 6.88(d,J＝8.8Hz,1H),4.73(d,J＝5.6Hz,2H),4.09(q,J＝7.2Hz,2H),3.37-3.22(m, 4H),2.15-2.05(m,4H),1.30(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C23H23O2N3F2S 444.1552[M+H]+,Found:444.1535。
Example 53
2-ethoxy-5- (pyridin-4-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001442
Reaction 1: 4-Pyridineboronic acid (148mg,1.2mmol), Pd (PPh)3)4(14mg,0.012mmol)，Na2CO3(64mg,0.6mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50mg,0.12 mmol) was added to dioxane (10 mL)/water (3mL) and reacted at 100 ℃ for 5h under argon. Reaction 2: 4-Pyridineboronic acid (886mg,7.20mmol), Pd (PPh)3)4(83mg,0.072mmol)，Na2CO3(763mg,7.20mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (300mg, 0.72mmol) was added to dioxane (30 mL)/water (8mL) and reacted at 100 ℃ for 5h under argon. Reactions 1 and 2 were combined, concentrated, and EA (30mL) was added, washed with saturated brine (20mL), anhydrous Na 2SO4Drying and purifying by column chromatography (acetone-petroleum ether, volume ratio 1:2) to obtain light yellow solid 233mg, 66.6%, melting point: 167 ℃ and 168 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.65(d,J＝5.6Hz,2H),8.61(d,J＝2.4Hz,1H), 8.39(s,1H),8.01(s,1H),7.90-7.87(m,2H),7.74(dd,J＝8.8,2.4Hz,1H),7.56(d,J＝ 5.6Hz,2H),7.49-7.43(m,2H),7.35(d,J＝3.2Hz,1H),7.07(d,J＝8.8Hz,1H),4.76 (d,J＝5.4Hz,2H),4.22(q,J＝6.8Hz,2H),1.38(t,J＝6.8Hz,3H)；HR-MS(ESI): m/z,calcd.For C24H21O2N3S 416.1427[M+H]+,Found:416.1417。
Example 54
2-ethoxy-5- (pyridin-3-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001451
Reaction 1: 3-Pyridineboronic acid (148mg,1.2mmol), Pd (PPh)3)4(14mg,0.012mmol)，Na2CO3(64mg,0.6mmol)5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50mg,0.12 mmol) was added to dioxane (10 mL)/water (3mL) and reacted at 100 ℃ for 5h under argon. Reaction 2: 3-pyridine boronic acid (886mg,7.20mmol), Pd (PPh)3)4(83mg,0.072mmol)，Na2CO3(763mg,7.20mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (300mg, 0.72mmol) was added to dioxane (30 mL)/water (8mL) and reacted at 100 ℃ for 5h under argon. Reactions 1 and 2 were combined, concentrated, and EA (30mL), brine (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (acetone-petroleum ether, volume ratio 1:2) to obtain light yellow solid 217mg, 62.0%, melting point: 121-122 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.86(s,1H),8.57(d,J＝4.0Hz,1H),8.52(d,J＝ 2.4Hz,1H),8.41(s,1H),8.01(s,1H),7.93-7.86(m,2H),7.66(dd,J＝8.8,2.4Hz,1H), 7.47-7.42(m,2H),7.37-7.34(m,2H),7.06(d,J＝8.8Hz,1H),4.76(d,J＝5.6Hz,2H), 4.21(q,J＝7.2Hz,2H),1.37(t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C24H21O2N3S 416.1427[M+H]+,Found:416.1419。
Example 55
2-ethoxy-5- (1H-pyrazol-5-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001461
Reaction 1: (1H-pyrazol-5-yl) boronic acid (27mg,0.24mmol), Pd (PPh)3)4(28mg,0.024mmol)， Na2CO3(64mg,0.6mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50mg,0.12 mmol) was added to dioxane (10 mL)/water (3mL) and reacted at 100 ℃ for 5h under argon. Reaction 2: (1H-pyrazol-5-yl) boronic acid (161mg,1.44mmol), Pd (PPh) 3)4(166mg,0.144 mmol)，Na2CO3(382mg,3.60mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (300mg,0.72mmol) was addedPut into dioxane (30 mL)/water (8mL) and react for 5h at 100 ℃ under the protection of argon. Reactions 1 and 2 were combined, concentrated, and EA (30mL), brine (20mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-dichloromethane-methanol, vol 15:15:1) gave 177mg of a pale yellow solid, 52.2%, m.p.: 192 ℃ and 193 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):12.83(s,1H),8.72(s,1H),8.15(s,1H),7.98(s, 1H),7.93(brs,1H),7.85-7.76(m,3H),7.50-7.46(m,2H),7.17(d,J＝7.6Hz,1H), 6.66(s,1H),4.60(d,J＝5.6Hz,2H),4.18(q,J＝6.8Hz,2H),1.32(t,J＝6.8Hz,3H)； HR-MS(ESI):m/z,calcd.For C22H20O2N4S 405.1380[M+H]+,Found:405.1371。
Example 56
2-ethoxy-5- (1H-imidazol-1-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001462
Reaction 1: imidazole (82mg,1.20mmol), 1,10-phenanthroline (216mg,1.20mmol), K2CO3(166mg,1.20mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50 mg,0.12mmol), CuI (228mg,1.2mmol) were added to anhydrous DMF (10mL) and reacted at 120 ℃ for 8h under argon. Reaction 1: imidazole (653mg,9.6mmol), 1,10-phenanthroline (1.73g,9.6mmol), K2CO3(1.32g,9.6mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (400mg,0.96mmol), CuI (1.82g,9.6mmol) were dissolved in anhydrous DMF (20mL), reacted at 120 ℃ for 8h under argon protection, reactions 1 and 2 were combined, concentrated, EA (30mL), brine wash (20mL), anhydrous Na 2SO4Drying and purification by column chromatography (ethyl acetate-dichloromethane-methanol, volume ratio 25:25:1) gave 245mg of white solid, 56.1%, melting point: 136-137 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.41(s,1H),8.32(d,J＝2.8Hz,1H),8.01(s, 1H),7.89-7.85(m,3H),7.46-7.43(m,3H),7.35(d,J＝3.2Hz,1H),7.29(s,1H),7.20 (s,1H),7.05(d,J＝8.8Hz,1H),4.75(d,J＝5.6Hz,2H),4.20(q,J＝7.2Hz,2H),1.38 (t,J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C22H20O2N4S 405.1380[M+H]+, Found:405.1363。
Example 57
2-ethoxy-5- (1H-pyrazol-4-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001471
Reaction 1: reaction of 4-Pyrazoleboronic acid pinacol ester (47mg,0.24mmol), Pd (PPh)3)4(28mg,0.024mmol)， Na2CO3(51mg,0.48mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50 mg,0.12mmol) was added to dioxane (10 mL)/water (3mL) and reacted at 100 ℃ for 7h under argon. Reaction 2: reaction of 4-Pyrazoleboronic acid pinacol ester (282mg,1.44mmol), Pd (PPh)3)4(166mg,0.144 mmol)，Na2CO3(306mg,2.88mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (300mg,0.72mmol) was added to dioxane (30 mL)/water (8mL) and reacted at 100 ℃ for 5h under argon. Reactions 1 and 2 were combined, concentrated, and EA (30mL), brine (20 mL), anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-dichloromethane-methanol, vol 15:15:1) gave 179mg, 53.3% pale yellow solid, m.p.: 159 ℃ and 160 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.46(s,1H),8.39(d,J＝2.0Hz,1H),8.00(s, 1H),7.87(s,4H),7.56(dd,J＝8.0,2.0Hz,1H),7.48-7.42(m,2H),7.34(d,J＝3.2Hz, 1H),6.96(d,J＝8.0Hz,1H),4.76(d,J＝5.6Hz,2H),4.16(q,J＝7.2Hz,2H),1.34(t, J＝7.2Hz,3H)；HR-MS(ESI):m/z,calcd.For C22H20O2N4S 405.1380[M+H]+,Found: 405.1372。
Example 58
2-ethoxy-5- (1H-pyrazol-1-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001481
Reaction 1: pyrazole (82mg,1.20mmol), iron acetylacetonate (424mg,1.20mmol), Cs 2CO3(391mg,1.20mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (50mg,0.12 mmol), CuO (95mg,1.20mmol) were added to anhydrous DMF (10mL) and reacted at 90 ℃ for 12h under argon. Reaction 2: pyrazole (490mg,7.2mmol), iron acetylacetonate (1.25g,3.60mmol), Cs2CO3(2.35g,7.20mmol), 5-bromo-2-ethoxy-N- (3- (thiazol-2-yl) benzyl) benzamide (300 mg,0.72mmol), CuO (282mg,3.6mmol) were added to anhydrous DMF (20mL), reacted at 90 ℃ for 12h under argon protection, reactions 1 and 2 were combined, concentrated, EA (30mL), brine washed (20mL), anhydrous Na2SO4Drying and purification by column chromatography (petrol ether-acetone, volume ratio 7:1) to obtain 58mg of white solid, 17.2%, melting point: 108 ℃ and 109 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.78(brs,1H),8.46(s,1H),8.12(d,J＝2.4Hz, 1H),7.98(s,1H),7.93(d,J＝3.2Hz,1H),7.89(dd,J＝8.8,2.4Hz,1H),7.85(d,J＝6.4Hz,1H),7.79(d,J＝2.8Hz,1H),7.72(s,1H),7.54-7.45(m,2H),7.26(d,J＝8.8 Hz,1H),6.52(s,1H),4.61(d,J＝6.0Hz,2H),4.20(q,J＝6.8Hz,2H),1.32(t,J＝6.8 Hz,3H)；HR-MS(ESI):m/z,calcd.For C22H20O2N4S 405.1380[M+H]+,Found: 405.1369。
Example 59
2-ethoxy-5- (1H-imidazol-2-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001482
a) 2-ethoxy-5- (1H-imidazol-2-yl) benzoic acid methyl ester
Reacting 2-ethoxy-5-formylbenzoic acid methyl ester(500mg,2.40mmol) was dissolved in methanol (25mL), glyoxal (6.96g,120mmol) was added, NH 3. H2O (4.20g,120mmol) was added dropwise with stirring at room temperature, the reaction was continued for 12H, and the reaction was stopped. Diluting with water (20mL), extracting with EA (30 mL. times.3), washing the organic phase with saturated brine (20mL), and removing anhydrous Na 2SO4Drying and purification by column chromatography (ethyl acetate-dichloromethane-methanol, vol 15:15:1) gave 67mg of a yellowish solid, yield 10.3%, melting point: 149 ℃ and 150 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.21(d,J＝2.0Hz,1H),8.02(dd,J＝8.8,1.6Hz, 1H),7.13(s,2H),6.97(d,J＝8.8Hz,1H),4.12(q,J＝6.8Hz,2H),3.85(s,3H),1.45(t, J＝7.2Hz,3H)；ESI-MS m/z:247.11[M+H]+。
b) 2-ethoxy-5- (1H-imidazol-2-yl) benzoic acid
Reaction 1: methyl 2-ethoxy-5- (1H-imidazol-2-yl) benzoate (50mg,0.20mmol) was dissolved in methanol (15 mL)/water (5mL), NaOH (40mg,1.00mmol) was added with stirring, reaction was carried out at room temperature for 6 hours, concentration was carried out, dilution was carried out with water (5mL), the aqueous layer was washed with diethyl ether (20mL), the pH of the aqueous layer was adjusted to 3 with hydrochloric acid, and a solid was precipitated to obtain 23mg of a slightly brown solid with a yield of 48.9%. Reaction 2: methyl 2-ethoxy-5- (1H-imidazol-2-yl) benzoate (70mg,0.28mmol) was dissolved in methanol (15 mL)/water (5mL), NaOH (56mg,1.40mmol) was added with stirring, and the reaction was carried out at room temperature for 6 hours, concentrated, diluted with water (5mL), the aqueous layer was washed with diethyl ether (20mL), and the pH of the aqueous layer was adjusted to 3 with hydrochloric acid to precipitate a solid, which was 41mg as a slightly brown solid, yield 62.1%, melting point: 261-262 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):8.42(brs,2H),7.72(s,2H),7.39(d,J＝8.8Hz, 1H),4.22(q,J＝6.8Hz,2H),1.36(t,J＝6.8Hz,3H)；ESI-MS m/z:231.08[M-H]-。
c) 2-ethoxy-5- (1H-imidazol-2-yl) -N- (3- (thiazol-2-yl) benzyl) benzamide
Dissolving 2-ethoxy-5- (1H-imidazol-2-yl) benzoic acid (50mg,0.22mmol) in DCM (10mL), adding DIEA (43mg,0.33mmol), adding HATU (110mg,0.29mmol), reacting at room temperature for 30min, adding (3- (thiazol-2-yl) phenyl) methylamine (46mg,0.24mmol), reacting at room temperature for 8H under the protection of argon, and removing the raw material And (6) losing. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated saline (20mL), and washing with anhydrous Na2SO4Drying, column chromatography (ethyl acetate-dichloromethane-methanol, volume ratio 15:15:1) to give 17mg, yield 19.5%, melting point: 240 ℃ and 241 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):12.44(s,1H),8.71(brs,1H),8.27(s,1H),7.98 (brs,2H),7.91(d,J＝3.2Hz,1H),7.83(d,J＝6.4Hz,1H),7.77(d,J＝3.2Hz,1H), 7.53-7.42(m,2H),7.20(d,J＝8.8Hz,1H),7.16(s,1H),6.96(s,1H),4.59(d,J＝6.0 Hz,2H),4.18(q,J＝6.8Hz,2H),1.31(t,J＝6.8Hz,3H)；HR-MS(ESI):m/z,calcd. For C22H20O2N4S 405.1380[M+H]+,Found:405.1368。
Example 60
2-ethoxy-5- (N-methylisobutylamido) -N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820001501
a) 2-ethoxy-5-isobutyrylaminobenzoic acid methyl ester
Dissolving 5-amino-2-ethoxybenzoic acid methyl ester (300mg,1.54mmol) in anhydrous THF (15mL), adding TEA (622mg,6.16mmol) and isobutyryl chloride (328mg,3.08mmol) in sequence under ice bath, continuing to react for 1h, filtering, concentrating the filtrate, adding ethyl acetate (20mL) for dilution, washing with HCl (0.5N) aqueous solution (10mL), and saturated NaHCO3Washing with 10mL of water, washing with 10mL of saturated brine and anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 337mg of white solid, yield 82.8%, melting point: 88-89 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):7.78(d,J＝6.8Hz,2H),7.22(s,1H),6.92(d,J＝ 9.6Hz,1H),4.09(q,J＝7.2Hz,2H),3.87(s,3H),2.51-2.46(m,1H),1.43(t,J＝7.2 Hz,3H),1.24(d,J＝6.8Hz,6H)；ESI-MS m/z:266.14[M+H]+。
b) 2-ethoxy-5-isobutyrylaminobenzoic acid
Dissolving methyl 2-ethoxy-5-isobutyrylaminobenzoate (300mg,1.13mmol) in anhydrous DMF (10mL), adding NaH (54mg,2.26mmol), reacting at room temperature for 20min, adding CH 3I (160mg,1.13mmol) was reacted for 4h, and after completion of the reaction, NaOH (226mg,5.65mmol) and water (5mL) were added in this order and the reaction was stirred for 1 h. Adjusting pH to 3 with hydrochloric acid, extracting with EA (25 mL. times.2), washing with saturated brine (20mL), and removing anhydrous Na2SO4Drying and concentration gave 238mg of a white solid in 79.3% yield, melting point: 98-99 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.04(s,1H),7.38(d,J＝7.6Hz,1H),7.09(d,J＝ 8.0Hz,1H),4.37(q,J＝6.8Hz,2H),3.23(s,3H),2.43(s,1H),1.60(t,J＝6.8Hz,3H), 1.02(d,J＝6.0Hz,6H)；ESI-MS m/z:264.12[M-H]-。
c) 2-ethoxy-5- (N-methylisobutylamido) -N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (150mg,0.57mmol) was dissolved in DCM (15mL), DIEA (111mg,0.86mmol), HATU (258mg,0.68mmol) were added in this order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (108mg,0.57mmol) was added and reacted at room temperature for 8h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated saline (20mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 185mg of white solid, yield 74.9%, melting point: 96-97 ℃.1H-NMR(400MHz,CDCl3)δ(ppm):8.40(s,1H),8.12(s,1H),8.01(s,1H),7.88(brs, 2H),7.47(brs,2H),7.36(s,1H),7.24(s,1H),6.98(d,J＝8.8Hz,1H),4.74(d,J＝5.2 Hz,2H),4.19(q,J＝6.8Hz,2H),3.24(s,3H),2.52-2.45(m,1H),1.37(t,J＝6.8Hz, 3H),1.03(d,J＝6.4Hz,6H)；HR-MS(ESI):m/z,calcd.For C24H27O3N3S 438.1846 [M+H]+,Found:438.1848。
Example 61
2-ethoxy-5-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001511
2-ethoxy-5-isobutyrylaminobenzoic acid (125mg,0.5mmol) was added to anhydrous DMF (15mL), EDC (192mg,1.0mmol) was added, HOBt (135mg,1.0mmol) and DIEA (0.22mL,1.25 mmol) were added, 1- (3- (thiazol-2-yl) phenyl) ethylamine (128mg,0.625mmol) was added, stirred at room temperature overnight, the reaction was poured into water, extracted with ethyl acetate 30 mL. times.2, the combined organic layers were washed with saturated NaCl 30 mL. times.2, dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M. RTM. 70:1) to give 190mg of a white solid in 84% yield. Melting point: 89 to 90 ℃.
1H-NMR(400MHz,CDCl3)δPPm:8.56(d,J＝6.8Hz,1H),8.23(d,J＝8.8Hz,1H), 8.01(s,1H),7.84-7.87(m,3H),7.67(s,1H),7.40-7.48(m,2H),7.34(s,1H),6.93(d,J ＝9.2Hz,1H),5.34-5.38(m,1H),4.16(q,J＝6.8Hz,2H),2.44-2.52(m,1H),1.63(d,J ＝7.2Hz,3H),1.42(t,J＝6.8Hz,3H),1.20(d,J＝6.8Hz,6H).
Example 61-1
(+) -2-ethoxy-5-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Example 61-2
(-) -2-ethoxy-5-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
The compound 2-ethoxy-5-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide shown in example 61 was resolved using a normal-phase chiral column (ChiralPak AD-H5 μm 10 mm. times.250 mm) to give example 61-1 and example 61-2. The specific process is as follows: the compound example 61 is dissolved in anhydrous acetone, and after complete dissolution, the sample is filtered through an organic filter membrane. The mobile phase was isopropanol and n-hexane (volume ratio: 3/7), the flow rate was 3.0mL/min, and the detection was carried out at a wavelength of 254 nm. Example 61-1 and example 61-2 were collected separately.
Specific optical rotation of example 61-1 [ α ]]589 20(MeOH) +24.6, and the specific optical rotation of example 61-2 is [ α ]]589 20(MeOH)＝-22.6。
Example 62
2-ethoxy-5-acetamido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001521
a) 2-ethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-ethoxy-5-nitrobenzoic acid (475mg,2.25mmol) was dissolved in DCM (25mL), HATU (1.285g, 3.38mmol) and DIEA (872mg, 6.75mmol) were added and reacted at room temperature for 30min, 1- (3-methylphenyl) ethyl-1-amine (690mg, 3.38mmol) was added and reacted at room temperature overnight. Washed with 0.5N HCl (20mL), washed with water (20mL), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1-1:1) afforded 756mg of white solid in 85% yield. Melting point: 137-138 deg.C
1H NMR(500MHZ,CDCl3)δ(ppm):9.07(d,J＝3.0Hz,1H),8.29(dd,J1＝3.0Hz, J2＝9.0Hz,1H),8.04(s,1H)7.84-7.87(m,2H),7.46-7.47(m,2H),7.04(d,J＝9.0Hz, 1H),5.35-5.40(m,1H),4.27-4.32(m,2H),1.66(d,J＝7.0Hz,3H),1.50(t,J＝7.5Hz, 3H).
b) 2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-ethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (400mg, 1.01mmol) was dissolved in THF (15mL), H2Reaction at room temperature for 8 h. The raw material disappeared. Filtering, concentrating, adding petroleum ether, precipitating white solid 294mg, and subjecting the filtrate to column chromatography to obtain 44mg, 338mg in total, with a yield of 91%. Melting point: 125 ℃ and 127 ℃.
1H NMR(500MHZ,DMSO-d6)δ(ppm):8.64(d,J＝7.5Hz,1H),7.99(s,1H),7.95(d, J＝2.5Hz,1H),7.85(d,J＝7.5Hz,1H),7.81(d,J＝7.5Hz,1H),7.49-7.54(m,2H), 7.05(d,J＝2.0Hz,1H),6.89(d,J＝10.5Hz,1H),6.69(dd,J1＝2.0Hz,J2＝10.5Hz, 1H),5.20(t,J＝7.0Hz,1H),4.87(s,1H),4.05(q,J＝6.5Hz,2H),1.52(d,J＝6.5Hz, 3H),1.32(d,J＝7.0Hz,3H).
c) 2-ethoxy-5-acetamido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (100mg, 0.27mmol) was dissolved in THF (3mL), TEA (82mg, 0.81mmol) was added in ice bath, acetyl chloride (26mg, 0.33mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (5 mL. times.2) and dried over anhydrous magnesium sulfate. 60mg of a yellowish white solid was obtained with a yield of 55%. Melting point: 156 and 158 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.54(d,J＝6.5Hz,1H),8.13(d,J＝7.5Hz, 1H),8.01(s,1H),7.82-7.86(m,3H),7.66(brs,1H),7.40-7.44(m,2H),7.33(d,J＝6.5 Hz,1H),6.92(d,J＝9.0Hz,1H),5.35(t,J＝7.0Hz,1H),4.16(d,J＝6.5Hz,2H), 2.12(s,3H),1.62(d,J＝6.5Hz,3H),1.43(t,J＝6.0Hz,3H).
Example 63
2-ethoxy-5-propionamido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001531
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (100mg, 0.27mmol) was dissolved in THF (3mL), TEA (82mg, 0.81mmol) was added in ice bath, propionyl chloride (31mg, 0.33mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (5 mL. times.2) and dried over anhydrous magnesium sulfate. 88mg of yellowish solid are obtained in 77% yield. Melting point: 153-155 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.64(d,J＝7.0Hz,1H),8.18(d,J＝7.0Hz, 1H),8.01(s,1H),7.83-7.87(m,2H),7.64(brs,1H),7.41-7.46(m,2H),7.42(t,J＝7.0 Hz,3H),7.33(d,J＝8.0Hz,1H),6.92(d,J＝9.0Hz,1H),5.35(t,J＝7.0Hz,1H), 4.16(t,J＝7.0Hz,1H),2.34(q,J＝7.5Hz,2H),1.62(d,J＝7.0Hz,3H),1.19(t,J＝ 7.5Hz,3H).
Example 64
2-ethoxy-5-cyclopropylcarboxamido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001532
2-ethoxy-5-amino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide (100mg, 0.27mmol) was dissolved in THF (3mL), TEA (82mg, 0.81mmol) was added in ice bath, cyclopropanecarbonyl chloride (35mg, 0.33mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (5 mL. times.2) and dried over anhydrous magnesium sulfate. 95mg of a white solid was obtained in a yield of 81%. Melting point: 202-203 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.54(d,J＝5.5Hz,1H),8.17(d,J＝7.5Hz, 1H),8.06(brs,1H),8.00(s,1H),7.83-7.88(m,3H),7.41-7.43(m,2H),7.33(s,1H), 6.90(d,J＝10.5Hz,1H),5.36(t,J＝6.5Hz,1H),4.16(d,J＝6.5Hz,2H),1.62(d,J＝ 7.0Hz,3H),1.52(brs,1H),1.42(t,J＝6.0Hz,3H),1.03(s,1H),0.76(d,J＝4.5Hz, 2H).
Example 65
2-ethoxy-5-cyclobutylcarboxamido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001541
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (100mg, 0.27mmol) was dissolved in THF (3mL), TEA (82mg, 0.81mmol) was added in an ice bath, cyclobutanecarbonyl chloride (39mg, 0.33mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (5 mL. times.2) and dried over anhydrous magnesium sulfate. 60mg of white solid are obtained with a yield of 83%. Melting point: 168 ℃ and 170 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.53(d,J＝6.0Hz,1H),8.21(d,J＝8.0Hz, 1H),8.02(s,1H),7.85(d,J＝11.0Hz,2H),7.41-7.45(m,2H),7.34(s,1H),6.92(d,J ＝9.0Hz,1H),5.36(t,J＝6.5Hz,1H),4.16(d,J＝5.0Hz,2H),3.12-3.15(m,1H), 2.33-2.35(m,2H),1.90-1.99(m,2H),1.63(t,J＝6.0Hz,3H),1.42(t,J＝6.5Hz,3H).
Example 66
2-ethoxy-5-cyclopentylamido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001542
2-ethoxy-5-amino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide (60mg, 0.16mmol) was dissolved in anhydrous THF (5mL), TEA (49mg, 0.48mmol) was added in ice bath, cyclopentylcarbonyl chloride (22mg, 0.20mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. Concentration, dilution with EA (15mL), washing with distilled water (15 mL. times.2), drying over anhydrous magnesium sulfate, concentration, and addition of petroleum ether gave 58mg of a white solid in 78% yield. Melting point: 172 ℃ and 174 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.53(d,J＝7.2Hz,1H),8.20(dd,J1＝2.8Hz,J2＝9.2Hz,1H),8.03(s,1H),7.87-7.88(m,2H),7.79(d,J＝9.2Hz,1H),7.41-7.48(m, 2H),7.37(brs,1H),7.35(d,J＝3.2Hz,1H),6.92(d,J＝9.2Hz,1H),5.32-5,39(m, 1H),4.17(q,J＝6.8Hz,2H),2.63-2.69(m,1H),1.85-1.93(m,4H),1.74-1.81(m,2H), 1.83(d,J＝6.8Hz,3H),1.59-1.61(m,2H),1.43(d,J＝6.8Hz,3H).
Example 67
2-ethoxy-5-ethanesulfonamide-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001551
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (80mg, 0.22mmol) was dissolved in THF (2mL), TEA (67mg, 0.66mmol) was added in ice bath, ethanesulfonyl chloride (33mg, 0.26mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (20 mL. times.2) and dried over anhydrous magnesium sulfate to give 62mg of a white solid with a yield of 61%. Melting point: 160-162 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.67(d,J＝7.5Hz,1H),8.20(s,1H),8.05(s, 1H),7.63(d,J＝8.5Hz,1H),7.51(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),7.34(d, J＝2.5Hz,1H),6.94(d,J＝8.5Hz,1H),5.49-5.52(m,1H),4.18(d,J＝6.0Hz,2H), 3.02(q,J＝7.5Hz,2H),1.63(d,J＝6.5Hz,3H),1.45(t,J＝7.0Hz,3H),1.31(t,J＝ 7.5Hz,3H).
Example 68
4-ethoxy-3- ((1- (3- (thiazol-2-yl) phenyl) ethyl) carbamoyl) phenylcarbamic acid ethyl ester
Figure BDA0001620885820001552
2-ethoxy-5-amino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide (80mg, 0.22mmol) was dissolved in THF (5mL), TEA (66mg, 0.65mmol) was added in ice bath, diethyl pyrocarbonate (36mg, 0.22mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 5 h. Washed with distilled water (15 mL. times.2) and dried over anhydrous magnesium sulfate to give 30mg of an off-white solid in a yield of 31%. Melting point: 167 ℃ and 170 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.55(d,J＝6.5Hz,1H),8.02(s,1H),7.93(brs, 1H),7.86(s,3H),7.41-7.47(m,2H),7.33(d,J＝1.0Hz,1H),6.85(brs,1H),5.37-5.40 (m,1H),4.21(q,J＝7.5Hz,2H),4.15(q,J＝3.5Hz,2H),1.63(d,J＝6.5Hz,3H), 1.42(t,J＝7.0Hz,3H),1.29(t,J＝7.0Hz,3H).
Example 69
4-ethoxy-3- ((1- (3- (thiazol-2-yl) phenyl) ethyl) carbamoyl) phenylcarbamic acid isopropyl ester
Figure BDA0001620885820001561
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (80mg, 0.22mmol) was dissolved in THF (5mL), TEA (66mg, 0.66mmol) was added in ice bath, isopropyl chloride (32mg, 0.26mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (15 mL. times.2) and dried over anhydrous magnesium sulfate to give 75mg of a white solid in a yield of 76%. m.p.165-167 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.54(d,J＝7.2Hz,1H),8.02(s,1H),7.92(brs, 1H),7.86(d,J＝5.2Hz,1H),7.83-7.84(m,1H),7.40-7.47(m,2H),7.33(d,J＝3.2Hz, 1H),6.92(d,J＝8.8Hz,1H),8.74(brs,1H),5.34-5.41(m,1H),4.97-5.03(m,1H), 4.15(q,J＝7.2Hz,2H),1.63(d,J＝6.8Hz,3H),1.41(t,J＝6.8Hz,3H),1.28(t,J＝ 6.4Hz,6H).
Example 70
2-ethoxy-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) -5(2,2, 2-trifluoroacetylamino) benzoyl
Figure BDA0001620885820001562
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (80mg, 0.22mmol) was dissolved in THF (5mL), TEA (66mg, 0.65mmol) was added in ice bath, trifluoroacetic anhydride (139mg, 0.66mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 5 h. Washed with distilled water (20 mL. times.2) and dried over anhydrous magnesium sulfate to give an off-white solid (90 mg, 88% yield). Melting point: 177 and 179 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.56(brs,1H),8.47(d,J＝6.5Hz,1H),7.06(d, J＝6.5Hz,2H),7.98(s,1H),7.87(d,J＝2.5Hz,2H),7.82(d,J＝6.0Hz,2H),7.42(d, J＝6.0Hz,1H),7.33(d,J＝3.0Hz,1H),6.96(d,J＝9.5Hz,1H),5.33-5.36(m,1H), 4.18(d,J＝6.5Hz,2H),1.62(d,J＝7.0Hz,3H),1.44(t,J＝7.0Hz,3H).
Example 71
N- (3-bromophenyl-methyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001571
2-ethoxy-5-isobutyrylaminobenzoic acid (440mg,1.76mmol) was added to anhydrous DMF (20mL), EDC (676mg,3.52mmol) was added, HOBt (475mg,3.52mmol) and DIEA (0.92mL,5.28 mmol) were added, the compound m-bromophenethylamine (424mg,2.29mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixed solution of ethyl acetate and methanol 10:1 (60mL × 2), the combined organic layers were washed with a saturated NaCl solution (50mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P ═ 1:2.5, E: P ═ 1:1.5) to give 520mg of a white solid in 70.7% yield. Melting point: 153-155 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.22(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.69(s,1H),7.51(t,J＝1.6Hz,1H),7.39-7.40 (m,0.5H),7.37-7.38(m,0.5H),7.30-7.31(m,0.5H),7.28-7.29(m,0.5H),7.21(t,J＝ 8.0Hz,1H),6.93(t,J＝9.2Hz,1H),5.25-5.29(m,1H),4.18(q,J＝6.8Hz,2H), 2.46-2.50(m,1H),1.55(d,J＝6.8Hz,3H),1.46(t,J＝6.8Hz,3H),1.19(dd,J1＝6.8 Hz,J1＝2.0Hz,6H).
Example 72
N- (1- (3-bromophenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001572
After adding 2-ethoxy-5-isobutyrylaminobenzoic acid (900mg,3.60mmol) to anhydrous DMF (50mL), adding EDC (1.38mg,7.2mmol), HOBt (972mg,7.2mmol) and DIEA (1.90mL,10.8 mmol), adding compound (21) (931mg,4.68mmol), stirring overnight at room temperature, pouring the reaction mixture into water, extracting with a mixed solution of ethyl acetate and methanol (10: 1) (60mL × 2), washing the combined organic layers with a saturated NaCl solution (50mL × 2), drying over anhydrous magnesium sulfate, concentrating, and performing column chromatography (E: P ═ 1:3, E: P ═ 1:2) to obtain 1.2g of a white solid with a yield of 76.9%. Melting point: 142 ℃ and 144 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.22(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.69(s,1H),7.51(t,J＝1.6Hz,1H),7.39-7.40 (m,0.5H),7.37-7.38(m,0.5H),7.30-7.31(m,0.5H),7.28-7.29(m,0.5H),7.21(t,J＝8.0Hz,1H),6.93(t,J＝9.2Hz,1H),5.25-5.29(m,1H),4.18(q,J＝6.8Hz,2H), 2.46-2.50(m,1H),1.55(d,J＝6.8Hz,3H),1.46(t,J＝6.8Hz,3H),1.19(dd,J1＝6.8 Hz,J1＝20Hz,6H).
Example 73
2-ethoxy-5-isobutyrylamino-N- (3- (2-carbonylpiperidin-1-yl) benzyl) benzamide
Figure BDA0001620885820001581
2-ethoxy-5-isobutyrylaminobenzoic acid (60mg,0.24mmol) was added to anhydrous DMF (10mL), EDC (92mg,0.48mmol) was added, HOBt (65mg,0.48mmol) and DIEA (0.125mL,0.72 mmol) were added, 1- (3- (aminomethyl) phenyl) piperidin-2-one (54mg,0.264mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture (20mL × 2) of ethyl acetate: methanol ═ 10:1, the combined organic layers were washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and a white solid was obtained at 70mg in 66.6% yield. Melting point: 179 and 181 DEG C
1H-NMR(500MHz,CDCl3)δ(ppm):8.38(s,1H),8.21(d,J＝9.0Hz,1H),7.86(s, 1H),7.75-7.79(m,1H),7.37(d,J＝7.5Hz,1H),7.24-7.29(m,2H),7.17(d,J＝7.5Hz, 1H),6.88(d,J＝9.0Hz,1H),4.66(d,J＝5.0Hz,2H),4.09(q,J＝6.5Hz,2H),3.64(s, 2H),2.50-2.56(m,3H),2.05(brs,4H),1.32(t,J＝6.5Hz,3H),1.21(d,J＝6.5Hz, 6H).
Example 74
2-ethoxy-5-isobutyrylamino-N- (1- (3- (2-carbonylpiperidin-1-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001582
Placing N- (1- (3-bromophenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide (150mg,0.347mmol) in a reaction flask, adding dioxane (15mL), and adding Pd under the protection of argon2(dba)3(63mg,0.07mmol)， xantphos(80mg,0.14mmol)，K3PO4(184mg,0.87mmol) and piperidin-2-one (52mg, 0.52mmol), and the reaction was raised to 100 ℃ and stopped the next day, followed by filtration, concentration and column chromatography (D: M: 50:1, D: M: 40:1) to give 9mg of a pale yellow solid. Melting point: 105-107℃
1H-NMR(500MHz,CDCl3)δPPm:8.44(d,J＝7.0Hz,1H),8.18(d,J＝7.0Hz,1H), 7.80(s,1H),7.32-7.39(m,2H),7.26-7.28(m,2H),7.15(d,J＝7.5Hz,1H),6.92(d,J＝ 9.0Hz,1H),5.37-5.41(m,1H),4.15(q,J＝7.0Hz,2H),3.63(s,2H),2.55(s,2H), 2.48-2.51(m,1H),1.94(s,4H),1.65(d,J＝7.0Hz,3H),1.43(t,J＝7.0Hz,3H),1.22 (d,J＝6.5Hz,6H).
Example 75
2-ethoxy-5-isobutyrylamino-N- (3- (2-carbonylpyrrolidin-1-yl) benzyl) benzamide
Figure BDA0001620885820001591
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (3- (aminomethyl) phenyl) pyrrolidin-2-one (106mg,0.56mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and a white solid was obtained (D: M: 60:1, D: M: 40:1) at a yield of 49.4%. Melting point: 157 ℃ 159 DEG C
1H-NMR(500MHz,CDCl3)δPPm:8.44(s,1H),8.22(d,J＝7.0Hz,1H),7.91(s,1H), 7.67(s,1H),7.62(s,1H),7.53(d,J＝8.0Hz,1H),7.35(d,J＝7.5Hz,1H),7.15(d,J＝ 7.5Hz,1H),6.92(d,J＝9.0Hz,1H),4.67(d,J＝5.5Hz,2H),4.13(q,J＝7.0Hz,2H), 3.86(t,J＝7.0Hz,2H),2.61(t,J＝8.0Hz,2H),2.51-2.54(m,1H),2.14-2.19(m,2H), 1.33(t,J＝6.5Hz,3H),1.22(d,J＝7.0Hz,6H).
Example 76
2-ethoxy-5-isobutyrylamino-N- (1- (3- (2-carbonylpyrrolidin-1-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001592
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (3- (1-aminoethyl) phenyl) pyrrolidin-2-one (110mg,0.54mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M: 100:1, D: M: 75:1) to give 100mg of a white solid in 57.1% yield. Melting point: 93-95 deg.C
1H-NMR(400MHz,DMSO-d6)δPPm:9.79(s,1H),8.54(d,J＝8.0Hz,1H),7.90(d, J＝2.8Hz,1H),7.75(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.69(s,1H),7.51(dd,J1＝8.8 Hz,J2＝2.0Hz,1H),7.34(t,J＝7.6Hz,1H),7.17(d,J＝7.6Hz,1H),7.07(d,J＝9.2 Hz,1H),5.09-5.13(m,1H),4.12(q,J＝6.8Hz,2H),3.83(td,J1＝8.0Hz,J2＝2.0Hz, 1H),2.50-2.56(m,1H),2.46-2.50(m,2H),2.03-2.09(m,2H),1.46(d,J＝7.2Hz,3H), 1.34(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H).
Example 77
2-ethoxy-5-isobutyrylamino-N- (3- (pyrrolidin-1-yl) benzyl) benzamide
Figure BDA0001620885820001601
Placing N- (3-bromophenyl methyl) -2-ethoxy-5-isobutyrylaminobenzamide (110mg,0.26mmol) in a reaction bottle, adding toluene (15mL), and adding Pd under the protection of argon2(dba)3(47mg,0.052mmol), xanthphos (59mg,0.104mmol), sodium tert-butoxide (75mg,0.78mmol) and tetrahydropyrrole (0.54mL,6.5 mmol) were reacted at elevated temperature to 90 ℃ for 5h, then the reaction was stopped, filtered, concentrated and column chromatographed (E: P ═ 1:3, E: P ═ 1:1.5) to give 83mg of a white solid in 78.3% yield. Melting point: 194 ℃ 196 DEG C
1H-NMR(500MHz,CDCl3)δ(ppm):8.40(d,J＝4.0Hz,1H),8.23(dd,J1＝9.0Hz,J1＝3.0Hz,1H),7.62(s,1H),7.20(t,J＝7.5Hz,1H),6.91(d,J＝9.0Hz,1H),6.67(brs, 1H),6.51-6.55(m,2H),4.61(d,J＝5.5Hz,2H),4.12(q,J＝7.0Hz,2H),3.28(brs, 4H),2.52-2.55(m,1H),2.00(brs,4H),1.33(t,J＝7.0Hz,3H),1.23(d,J＝6.5Hz, 6H).
Example 78
2-ethoxy-5-isobutyrylamino-N- (1- (3- (pyrrolidin-1-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001602
Placing N- (1- (3-bromophenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide (110mg,0.255mmol) in a reaction flask, adding toluene (15mL), and adding Pd under the protection of argon2(dba)3(46mg,0.051mmol), xanthphos (58mg,0.102mmol), sodium tert-butoxide (74mg,0.77mmol) and tetrahydropyrrole (0.53 mL,6.4mmol) were reacted at elevated temperature to 90 ℃ for 5h, then the reaction was stopped, filtered, concentrated and column chromatographed (E: P ═ 1:3, E: P ═ 1:2) to give 60mg of white solid in 55.5% yield. Melting point: 100 ℃ and 102 DEG C
1H-NMR(500MHz,CDCl3)δ(ppm):8.48(d,J＝7.5Hz,1H),8.22(dd,J1＝9.0Hz,J1＝2.5Hz,1H),7.86(d,J＝2.5Hz,1H),7.63(s,1H),7.20(t,J＝8.0Hz,1H),6.91(d,J ＝9.0Hz,1H),6.69(brs,1H),6.56(brs,1H),6.48(brs,1H),5.22-5.26(m,1H), 4.09-4.17(m,2H),3.28(s,4H),2.50-2.53(m,1H),1.99(s,4H),1.57(d,J＝7.0Hz, 3H),1.41(t,J＝7.0Hz,3H),1.21(d,J1＝6.5Hz,J2＝2.0Hz,6H).
Example 79
Tert-butyl 4- (3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) phenyl) piperazine-1-carboxylate
Figure BDA0001620885820001611
N- (3-bromophenyl methyl) -2-ethoxy-5-isobutyrylaminobenzamide (100mg,0.24mmol) was placed in a reaction flask,toluene (15mL) was added and Pd was added under argon2(dba)3(45mg,0.048mmol), xanthphos (55mg,0.096mmol), sodium tert-butoxide (69mg,0.72mmol) and N-Boc piperazine (133mg,0.72 mmol) were heated to 100 ℃ for reaction, and after 5 hours the reaction was stopped, filtered, concentrated and subjected to column chromatography (D: M: 80:1, D: M: 70:1) to give 50mg of a pale yellow solid in 39.7% yield. Melting point: 186 ℃ plus 187 DEG C
1H-NMR(500MHz,CDCl3)δ(ppm):8.39(brs,1H),8.22(dd,J1＝8.5Hz,J1＝2.5Hz, 1H),7.89(d,J＝2.5Hz,1H),7.52(s,1H),7.24-7.27(m,1H),6.85-6.93(m,4H),4.61 (d,J＝5.5Hz,2H),4.12(q,J＝7.0Hz,2H),3.58(s,4H),3.14(s,4H),2.51-2.54(m, 1H),1.48(s,9H),1.32(t,J＝7.0Hz,3H),1.23(d,J＝7.0Hz,6H).
Example 80
2-ethoxy-5-isobutyrylamino-N- (3- (piperazin-1-yl) benzyl) benzamide 2,2, 2-trifluoroacetate salt
Figure BDA0001620885820001612
Tert-butyl 4- (3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) phenyl) piperazine-1-carboxylate (190mg,0.36mmol), DCM (5mL) was added, TFA (0.27mL,3.6mmol) was added, the reaction was stirred at room temperature, the next day was stopped, ether was added without solid precipitation, the mixture was concentrated to dryness, ether was added with solid precipitation, and suction filtration was carried out to obtain 180mg of off-white solid in 93.3% yield. Melting point: 160 ℃ C. and 162 ℃ C
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.82(s,1H),8.89(s,1H),8.54(t,J＝5.6Hz, 1H),7.97(d,J＝2.8Hz,1H),7.72(dd,J1＝8.8Hz,J1＝2.8Hz,1H),7.23(t,J＝8.0Hz, 1H),7.07(d,J＝9.2Hz,1H),6.97(s,1H),6.86-6.91(m,2H),4.46(d,J＝6.0Hz,2H), 4.10(q,J＝7.2Hz,2H),3.32-3.35(m,4H),3.24-3.26(m,4H),2.50-2.57(m,1H),1.28 (t,J＝7.2Hz,3H),1.09(d,J＝6.8Hz,6H).
Example 81
Tert-butyl 4- (3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) phenyl) piperazine-1-carboxylate
Figure BDA0001620885820001621
Placing N- (1- (3-bromophenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide (300mg,0.69mmol) in a reaction flask, adding toluene (25mL), and adding Pd under the protection of argon2(dba)3(127mg,0.14mmol), xanthphos (159mg,0.28mmol), sodium tert-butoxide (200mg,2.08mmol) and N-Boc piperazine (387 mg,2.08mmol) were heated to 100 ℃ for reaction, and after 8h the reaction was stopped, filtered, concentrated, and column chromatographed (E: P ═ 1:3, E: P ═ 1:1.5) to give 180mg of a pale yellow solid in 48.5% yield. Melting point: 63-65 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):8.44(d,J＝7.0Hz,1H),8.21(dd,J1＝9.0Hz,J1＝2.5Hz,1H),7.84(d,J＝2.5Hz,1H),7.56(s,1H),7.25(t,J＝8.0Hz,1H),6.89-6.93 (m,3H),6.82(d,J＝8.0Hz,1H),5.23-5.27(m,1H),4.11-4.16(m,2H),3.57(s,4H), 3.13(s,4H),2.48-2.52(m,1H),1.56(d,J＝6.5Hz,3H),1.48(s,9H),1.41(t,J＝7.0 Hz,3H),1.21(d,J＝6.5Hz,6H).
Example 82
2-ethoxy-5-isobutyrylamino-N- (1- (3- (piperazin-1-yl) phenyl) ethyl) benzamide 2,2, 2-trifluoroacetate salt
Figure BDA0001620885820001622
Tert-butyl 4- (3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) phenyl) piperazine-1-carboxylate (120mg,0.22mmol), DCM (5mL) was added, TFA (0.16mL,2.2mmol) was added, the reaction was stirred at room temperature, the next day the reaction was stopped, ether was added, solid precipitated, suction filtered, and the filter cake was washed with ether to give 110mg of gray solid in 90.9% yield.
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.81(s,1H),8.85(brs,2H),8.48(d,J＝8.0 Hz,1H),7.93(d,J＝2.8Hz,1H),7.72(dd,J1＝9.2Hz,J1＝2.8Hz,1H),7.23(t,J＝ 7.6Hz,1H),7.07(d,J＝9.2Hz,1H),7.01(s,1H),6.91(d,J＝7.6Hz,1H),6.87(dd,J1＝7.6Hz,J1＝2.0Hz,1H),5.05-5.09(m,1H),4.11(q,J＝6.4Hz,2H),3.33-3.46(m, 4H),3.23-3.26(m,4H),2.51-2.57(m,1H),1.44(d,J＝6.8Hz,3H),1.33(t,J＝7.2Hz, 3H),1.08(d,J＝6.8Hz,6H).
Example 83
3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) benzoic acid methyl ester
Figure BDA0001620885820001631
2-ethoxy-5-isobutyrylaminobenzoic acid (530mg,2.12mmol) was added to anhydrous DMF (30mL), EDC (814mg,4.24mmol) was added, HOBt (572mg,4.24mmol) and DIEA (1.1mL,6.36 mmol) were added, methyl 3- (aminomethyl) benzoate (403mg,2.44mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (60 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M. 70:1) to give 480mg of a white solid in 56.9% yield. Melting point: 131-133 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.52(t,J＝5.2Hz,1H),8.21(dd,J1＝9.2Hz,J2＝2.8Hz,1H),8.03(brs,1H),7.97(td,J1＝7.6Hz,J2＝1.6Hz,1H),7.91(brs,1H), 7.65(brs,1H),7.56-7.58(m,1H),7.43(t,J＝7.6Hz,1H),6.94(d,J＝8.8Hz,1H), 4.71(d,J＝5.6Hz,2H),4.14(q,J＝7.2Hz,2H),3.92(s,3H),2.48-2.56(m,1H),1.33 (t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H).
Example 84
3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) benzoic acid methyl ester
Figure BDA0001620885820001632
2-ethoxy-5-isobutyrylaminobenzoic acid (320mg,1.28mmol) was added to anhydrous DMF (20mL), EDC (492mg,2.56mmol) was added, HOBt (346mg,2.56mmol) and DIEA (0.67mL,3.84 mmol) were added, methyl 3- (1-aminoethyl) benzoate (341mg,1.92mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (60 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M75: 1) to give 500mg of a white solid in 94.7% yield. Melting point: 105 ℃ C. and 107 ℃ C
1H-NMR(400MHz,CDCl3)δ(ppm):8.52(d,J＝7.6Hz,1H),8.21(dd,J1＝8.8Hz,J1＝2.8Hz,1H),8.05-8.06(m,1H),,7.95-7.96(m,0.5H),7.93-7.94(m,0.5H),7.81(d,J ＝2.8Hz,1H),7.57(d,J＝7.6Hz,1H),7.52(s,1H),7.42(d,J＝8.0Hz,1H),6.93(d,J ＝9.2Hz,1H),5.32-5.36(m,1H),4.14-4.20(m,2H),3.90-3.92(m,3H),2.45-2.50(m, 1H),1.59(d,J＝6.8Hz,3H),1.45(t,J＝7.2Hz,3H),1.21(dd,J1＝6.8Hz,J2＝1.6Hz, 6H).
Example 85
3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) benzoic acid
Figure BDA0001620885820001641
Methyl 3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) benzoate (350mg,0.878mmol), MeOH (5mL), THF (5mL) were added and LiOH (31.6mg,1.32mmol) was dissolved in H2O (3mL) was added to the reaction flask, and the reaction was stirred at room temperature, and the next day, the reaction was stopped, concentrated, water was added, extraction was performed with diethyl ether (15 mL), the pH of the aqueous layer was adjusted to about 2 with dilute HCl solution, no solid was formed, extraction was performed with a mixture of dichloromethane and methanol (10: 1) (60 mL. times.2), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give 310mg of a white solid in 91.9% yield. Melting point: 187 ℃ 189 DEG C
1H-NMR(400MHz,DMSO-d6)δ(ppm):12.94(s,1H),9.80(s,1H),8.66(t,J＝5.6Hz, 1H),7.95(s,1H),7.90(d,J＝2.8Hz,1H),7.83(d,J＝7.6Hz,1H),7.77(dd,J1＝9.2 Hz,J2＝2.8Hz,1H),7.60(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.07(d,J＝8.8 Hz,1H),4.56(d,J＝6.0Hz,2H),4.11(q,J＝6.8Hz,2H),2.53-2.57(m,1H),1.30(t,J ＝6.8Hz,3H),1.09(d,J＝6.8Hz,6H).
Example 86
3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) benzoic acid
Figure BDA0001620885820001642
Methyl 3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) benzoate (250mg,0.606mmol), MeOH (4mL), THF (4mL) were added and LiOH (21.8mg,0.909mmol) was dissolved in H2Adding O (2.5mL) into a reaction flask, stirring at room temperature after adding, stopping reaction the next day, concentrating, adding water, extracting with diethyl ether (15 mL), adjusting pH of the water layer to about 2 with dilute HCl solution, filtering, and washing the filter cake with water to obtain 220 mg of white solid with a yield of 91.2%. Melting point: 99-101 deg.C
1H-NMR(500MHz,DMSO-d6)δ(ppm):12.96(brs,1H),9.78(s,1H),8.58(d,J＝7.0 Hz,1H),7.85(s,1H),7.83(d,J＝7.5Hz,1H),7.76(d,J＝8.5Hz,1H),7.65(d,J＝7.5 Hz,1H),7.47(t,J＝7.5Hz,1H),7.07(d,J＝9.0Hz,1H),5.16-5.19(m,1H),4.10-4.13 (m,2H),2.52-2.55(m,1H),1.47(d,J＝7.0Hz,3H),1.34(t,J＝6.5Hz,3H),1.08(d,J ＝6.5Hz,6H).
Example 87
N- (3-carbamoylbenzyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001651
3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) benzoic acid (80mg,0.208mmol) was added to anhydrous DMF (10mL), EDC (78mg,0.408mmol) was added, HOBt (55mg,0.408mmol) and DIEA (0.18mL,1.04mmol) were added, the compound ammonia (0.05mL,0.408mmol) was added, stirred overnight at room temperature, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol 10:1 (30 mL. times.8), the combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M60: 1, D: M20: 1) to give 14mg of a white solid in 17.5% yield. Melting point: 184 ℃ and 186 DEG C
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.80(s,1H),8.62(t,J＝6.8Hz,1H),7.95(s, 1H),7.92(d,J＝2.4Hz,1H),7.68(s,1H),7.74-7.79(m,2H),7.50(d,J＝7.2Hz,1H), 7.40(t,J＝7.6Hz,1H),7.34(s,1H),7.07(d,J＝8.8Hz,1H),4.54(d,J＝5.6Hz,2H), 4.11(q,J＝6.8Hz,2H),2.53-2.57(m,1H),1.29(t,J＝6.8Hz,3H),1.09(d,J＝6.8Hz, 6H).
Example 88
N- (1- (3-carbamoylphenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001652
Putting 3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) benzoic acid methyl ester (100mg,0.24mmol) in a microwave reaction tube, adding 7M ammonia methanol solution (3.5mL,24.5mmol) for microwave reaction, keeping a large amount of raw materials at 100 ℃ for time3+3+3h, and concentrating and performing column chromatography (D: M is 50:1, D: M is 25:1) to obtain 40mg of the product. Melting point: 134 ℃ and 136 DEG C
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.79(d,J＝6.4Hz,1H),8.56(brs,1H), 7.90-7.96(m,3H),7.76-7.78(m,2H),7.56(brs,1H),7.34-7.43(m,2H),7.08(brs,1H), 5.16(brs,1H),4.12(brs,2H),2.51(brs,1H),1.49(brs,3H),1.35(brs,3H),1.09(brs, 6H).
Example 89
2-ethoxy-5-isobutyrylamino-N- (3- (methylcarbamoyl) benzyl) benzamide
Figure BDA0001620885820001662
3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) benzoic acid (90mg,0.234mmol) was added to anhydrous DMF (10mL), EDC (90mg,0.468mmol) was added, HOBt (63mg,0.468mmol) and DIEA (0.20mL,1.17mmol) were added, methylamine hydrochloride (31mg,0.468mmol) was added, stirring was performed at room temperature overnight, the reaction solution was poured into water, extraction was performed with a mixed solution of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (20mL × 2) and dried over anhydrous magnesium sulfate, concentrated, and column chromatography was performed (D: M: 60:1, D: M: 30:1) to obtain 49mg of a white solid with a yield of 52.6%. Melting point: 185 ℃ C., 187 ℃ C
1H-NMR(400MHz,CDCl3)δ(ppm):8.47(d,J＝5.2Hz,1H),8.17(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.88(d,J＝2.4Hz,1H),7.77(s,1H),7.65-7.68(m,2H),7.47(d,J＝7.6 Hz,1H),7.39(t,J＝7.6Hz,1H),6.90(d,J＝9.2Hz,1H),6.34(brs,1H),4.68(d,J＝ 5.6Hz,2H),4.11(q,J＝7.2Hz,2H),2.99(d,J＝4.8Hz,3H),2.51-2.55(m,1H),1.32 (t,J＝7.2Hz,3H),1.22(d,J＝6.8Hz,6H).
Example 90
2-ethoxy-5-isobutyrylamino-N- (1- (3- (methylcarbamoyl) phenyl) ethyl) benzamide
Figure BDA0001620885820001663
3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) benzoic acid (80mg,0.201mmol) was added to anhydrous DMF (10mL), EDC (77mg,0.402mmol) was added, HOBt (54mg,0.402 mmol) and DIEA (0.21mL,1.206mmol) were added, the compound methylamine hydrochloride (20.4mg,0.301 mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M ═ 60:1, D: M ═ 30:1) to give 35mg of a white solid in 42.7% yield. Melting point: 249 ℃ 251 ℃
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.79(s,1H),8.55(d,J＝7.6Hz,1H),7.88(d, J＝2.8Hz,1H),7.85(s,1H),7.76(dd,J1＝9.2Hz,J1＝2.4Hz,1H),7.69(d,J＝7.6Hz, 1H),7.54(d,J＝7.6Hz,1H),7.42(t,J＝7.6Hz,1H),7.07(d,J＝8.8Hz,1H), 5.13-5.18(m,1H),4.11(q,J＝7.2Hz,2H),2.78(d,J＝4.4Hz,3H),2.52-2.56(m,1H), 1.48(d,J＝6.8Hz,3H),1.34(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H).
Example 91
N- (3- (dimethylcarbamoyl) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001671
3- ((2-ethoxy-5-isobutyrylaminobenzamido) methyl) benzoic acid (90mg,0.234mmol) was added to anhydrous DMF (10mL), EDC (90mg,0.468mmol) was added, HOBt (63mg,0.468mmol) and DIEA (0.20mL,1.17mmol) were added, the compound dimethylamine hydrochloride (39mg,0.468mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixed solution of ethyl acetate: methanol ═ 10:1 (30mL × 2), the combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M ═ 60:1, D: M ═ 30:1) to give 40mg of a white solid in 41.6% yield. Melting point: 150 ℃ and 152 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.42(t,J＝4.8Hz,1H),8.21(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.87(d,J＝2.8Hz,1H),7.63(s,1H),7.45(s,1H),7.37-7.40(m,2H), 7.26-7.31(m,1H),6.90(d,J＝9.2Hz,1H),4.68(d,J＝5.2Hz,2H),4.10(q,J＝7.2Hz, 2H),3.11(brs,3H),2.97(brs,3H),2.51-2.54(m,1H),1.31(t,J＝7.2Hz,3H),1.23(d,J ＝6.8Hz,6H).
Example 92
N- (1- (3- (dimethylcarbamoyl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001681
3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) benzoic acid (90mg,0.226mmol) was added to anhydrous DMF (10mL), EDC (87mg,0.45mmol) was added, HOBt (61mg,0.45mmol) and DIEA (0.35mL,1.356mmol) were added, the compound dimethylamine hydrochloride (28mg,0.34mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol 10:1 (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M60: 1, D: M: 30:1) to give 50mg of a white solid with a yield of 52.1%. Melting point: 67-69 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.47(d,J＝7.2Hz,1H),8.19(dd,J1＝8.8Hz,J1＝2.4Hz,1H),7.80(d,J＝2.8Hz,1H),7.43-7.47(m,3H),7.37(t,J＝7.2Hz,1H), 7.29(d,J＝7.6Hz,1H),6.92(d,J＝8.8Hz,1H),5.30-5.34(m,1H),4.16(q,J＝6.8Hz, 2H),3.09(brs,3H),2.96(brs,3H),1.57(d,J＝6.8Hz,3H),1.47(t,J＝6.8Hz,3H), 1.22(d,J＝6.8Hz,6H).
Example 93
2-ethoxy-N- (1- (3- ((2-hydroxyethyl) carbamoyl) phenyl) ethyl) -5-isobutyrylaminobenzamide
Figure BDA0001620885820001682
Methyl 3- (1- (2-ethoxy-5-isobutyrylaminobenzamido) ethyl) benzoate (230mg,0.56mmol) was added to isopropanol (8mL), ethanolamine (36mg,0.586mmol) and K3PO4(59mg,0.28mmol), reflux reaction under heating, reaction stopped after 6h, concentration, and column chromatography (D: M: 30:1) afforded 120mg of a viscous solid in 48.5% yield.
1H-NMR(500MHz,CDCl3)δ(ppm):8.57(d,J＝7.0Hz,1H),8.40(s,1H),8.19(dd, J1＝8.5Hz,J1＝2.0Hz,1H),7.76(s,1H),7.63(d,J＝7.5Hz,1H),7.59(s,1H),7.41 (d,J＝7.5Hz,1H),7.31(t,J＝7.5Hz,1H),6.87(d,J＝9.0Hz,1H),5.13-5.16(m,1H), 4.14(q,J＝7.0Hz,2H),3.81(s,2H),3.68-3.72(m,1H),3.51-3.55(m,1H),2.55-2.58 (m,1H),1.53(d,J＝6.5Hz,3H),1.47(t,J＝7.0Hz,3H),1.17-1.19(m,6H).
Example 94
N- (1- (3- (4, 5-dihydrooxazol-2-yl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001691
DDQ (68mg,0.3mmol), PPh3(78mg,0.3mmol) was placed in a reaction flask, DCM (5mL) was added, after stirring for a while at room temperature, 2-ethoxy-N- (1- (3- ((2-hydroxyethyl) carbamoyl) phenyl) ethyl) -5-isobutyrylaminobenzamide (90mg,0.20mmol) was dissolved in THF (5mL) and added to the reaction flask, after the addition was complete, the reaction was stirred at room temperature, the next day, TLC showed a large amount of remaining starting material, concentrated, DCM (30mL) was added, saturated NaHCO was used3The solution was washed with 10mL of water, saturated NaCl solution (10mL) was washed with water, dried over anhydrous magnesium sulfate, concentrated, and dissolved in THF (5mL) and the compound DDQ (136mg,0.6mmol), PPh was added dropwise3(156mg,0.6 mmo) in DCM (5mL) and heated to 40 deg.C for the next day, the material disappeared, concentrated to dryness, DCM (30mL) was added and saturated NaHCO was used 3The solution (10mL) was washed with saturated NaCL solution (10mL), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M: 90:1, D: M: 75:1, D: M: 60:1, D: M: 35:1) to give 40mg of off-white solid in 47% yield. Melting point: 75-77 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.49(d,J＝7.6Hz,1H),8.20(dd,J1＝9.2Hz,J1＝2.8Hz,1H),7.97(s,1H),7.85(d,J＝8.0Hz,1H),7.81(d,J＝2.8Hz,1H),7.57(s, 1H),7.50(d,J＝8.0Hz,1H),7.40(t,J＝8.0Hz,1H),6.92(d,J＝9.2Hz,1H), 5.30-5.34(m,1H),4.43(t,J＝9.6Hz,2H),4.16(q,J＝6.8Hz,2H),4.06(t,J＝9.2Hz, 2H),2.47-2.51(m,1H),1.59(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.21(dd,J1＝ 7.2Hz,J2＝1.6Hz,6H).
Example 95
2-ethoxy-5-isobutyrylamino-N- (3-methylbenzyl) benzamide
Figure BDA0001620885820001692
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, compound 3-methylbenzylamine (106mg,0.878mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M ═ 80:1) to give 130mg of a white solid in 83.9% yield. Melting point: 168 ℃ C
1H-NMR(400MHz,CDCl3)δ(ppm):8.41(t,J＝4.4Hz,1H),8.25(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.95(d,J＝2.8Hz,1H),7.82(s,1H),7.23(d,J＝7.6Hz,1H),7.14-7.17 (m,2H),7.10(d,J＝7.6Hz,1H),6.92(d,J＝9.2Hz,1H),4.63(d,J＝5.6Hz,2H), 4.12(q,J＝6.8Hz,2H),2.50-2.57(m,1H),2.35(s,3H),1.32(t,J＝6.8Hz,3H),1.21 (d,J＝7.2Hz,6H).
Example 96
2-ethoxy-5-isobutyrylamino-N- (1- (m-benzyl) ethyl) benzamide
Figure BDA0001620885820001701
2-ethoxy-5-isobutyrylaminobenzoic acid (900mg,3.585mmol) was added to anhydrous DMF (40mL), EDC (1.38g,7.17mmol) was added, HOBt (968mg,7.17mmol) and DIEA (1.87mL,10.76 mmol) were added, 1- (m-benzyl) ethylamine (630mg,4.66mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (60mL × 2), the combined organic layers were washed with a saturated NaCl solution (40mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P1: 3, E: P ═ 1:1.5) to give 1.09g of a white solid in 82.5% yield. Melting point: 161-163 ℃ C
1H-NMR(500MHz,CDCl3)δ(ppm):8.46(d,J＝7.0Hz,1H),8.22(dd,J1＝9.0Hz,J1＝2.5Hz,1H),7.86-7.87(m,1H),7.61(brs,1H),7.24(t,J＝7.5Hz,1H),7.16-7.18(m, 2H),7.08(d,J＝7.0Hz,1H),6.92(d,J＝9.0Hz,1H),5.25-5.28(m,1H),4.11-4.18(m, 2H),2.48-2.51(m,1H),2.35(s,3H),1.57(d,J＝6.5Hz,3H),1.41(t,J＝7.0Hz,3H), 1.22(dd,J1＝5.6Hz,J1＝2.4Hz,6H).
Example 97
5- (2-Cyclopropylacetylamino) -2-ethoxy-N- (1- (3-methylphenyl) ethyl) benzamide
Figure BDA0001620885820001702
a) 2-ethoxy-5-nitro-N- (1- (3-methylphenyl) ethyl) benzamide
2-ethoxy-5-nitrobenzoic acid (600mg, 2.84mmol) was dissolved in DCM (25mL), HATU (1.620g, 4.26mmol), DIEA (1.10g, 8.52mmol) were added and reacted at room temperature for 20min, 1- (3-methylphenyl) ethyl-1-amine (576mg, 4.26mmol) was added and reacted at room temperature overnight. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 3:1) gave 740mg of white solid in 79% yield. Melting point: 82-84 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):9.10(d,J＝3.2Hz,1H),8.29(dd,J1＝3.2Hz, J2＝9.2Hz,1H),8.11(d,J＝7.2Hz,1H),7.24(d,J＝7.2Hz,1H),7.18(d,J＝8.0Hz, 1H),7.10(d,J＝8.0Hz,1H),7.03(d,J＝9.2Hz,1H),5.24-5.31(m,1H),4.22-4.33(m, 1H),2.36(s,3H),1.69(d,J＝7.2Hz,1H),1.49(t,J＝7.2Hz,3H).
b) 2-ethoxy-5-amino-N- (1- (3-methylphenyl) ethyl) benzamide
2-ethoxy-5-nitro-N- (1- (m-methylphenyl) ethyl) benzamide (200mg, 0.47mmol) was dissolved in THF (10mL), H2Reaction at 50 ℃ for 17 h. The raw material disappeared. Filtration, concentration and column chromatography (P: E ═ 1:1) gave 129mg of a yellowish solid in 70% yield. Melting point: 121 ℃ and 123 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.79(d,J＝7.6Hz,1H),7.97(d,J＝1.6Hz, 1H),7.92(d,J＝3.2Hz,1H),7.82(dt,J1＝1.6Hz,J27.2Hz 1H),7.79(d, J ═ 3.2Hz,1H), 7.45-7.53(m,2H),7.09(d, J ═ 3.2Hz,1H),5.16-5.23(m,1H),3.84(d, J ═ 7.2Hz, 2H),1.51(d, J ═ 7.2Hz,3H),1.16-1.25(m,1H),0.46-0.51(m,2H),0.29-0.30(m,2H) c)5- (2-cyclopropylacetamido) -2-ethoxy-N- (1- (3-methylphenyl) ethyl) benzamide
Cyclopropylacetic acid (24mg, 0.24mmol) was dissolved in DCM (2mL), HATU (111mg, 0.29mmol) and DIEA (62mg, 0.48mmol) were added and reacted at room temperature for 1h, and 2-ethoxy-5-amino-N- (1- (3-methyl) phenyl) ethylamine) benzamide (80mg, 0.29mmol) was added and reacted at room temperature overnight. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1) afforded 40mg of white solid, yield 44%. Melting point: 185 ℃ and 187 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.45(d,J＝7.2Hz,1H),8.17(dd,J1＝2.8Hz,J2＝8.8Hz,1H),7.80(d,J＝2.8Hz,1H),7.49(s,1H),7.23(d,J＝7.6Hz,1H),7.18(d,J ＝8.8Hz,1H),7.08(d,J＝7.6Hz,1H),6.90(d,J＝8.8Hz,1H),5.23-5.30(m,1H), 4.10-4.18(m,2H),2.35(s,3H),1.57(d,J＝6.8Hz,3H),1.44(d,J＝3.6Hz,3H),1.41 (d,J＝7.2Hz,3H),1.29(q,J＝2.8Hz,2H),0.67(q,J＝2.8Hz,2H).
Example 98
2-ethoxy-5- (1-methylcyclopropyl-1-carboxamide) -N- (1- (m-methylphenyl) ethyl) benzamide
Figure BDA0001620885820001711
1-methylcyclopropylcarboxylic acid (24mg, 0.24mmol) was dissolved in DCM (2mL), HATU (111mg, 0.29mmol), DIEA (62mg, 0.48mmol) were added and reacted at room temperature for 1h, 2-ethoxy-5-amino-N- (1- (3-methyl) phenyl) ethylamine) benzamide (80mg, 0.29mmol) was added and reacted at room temperature for 3.5 h. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 2:1) gave 82mg of white solid in 90% yield. Melting point: 168-170 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.47(d,J＝7.2Hz,1H),8.22(dd,J1＝2.8Hz,J2＝8.8Hz,1H),7.83(d,J＝7.6Hz,2H),7.23(d,J＝7.2Hz,1H),7.18(d,J＝8.0Hz, 1H),7.08(d,J＝7.2Hz,1H),6.93(d,J＝8.8Hz,1H),5.22-5.29(m,1H),4.10-4.19(m, 2H),2.35(s,3H),2.31(d,J＝7.2Hz,3H),1.57(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz, 3H),0.99-1.07(m,1H),0.66-0.71(q,J＝6.5Hz,2H),0.25-0.29(q,J＝6.5Hz,2H).
Example 99
N- (4-ethoxy-3- ((1-m-methylphenyl) ethyl) carbamoyl) phenyl) thiazole-5-carboxamide
Figure BDA0001620885820001721
5-Thiazolecarboxylic acid (31mg, 0.24mmol) was dissolved in DCM (3mL), HATU (111mg, 0.29mmol) and DIEA (62mg, 0.48mmol) were added and the mixture was reacted at room temperature for 20min, a solution of 1- (3-methylphenyl) ethyl-1-amine (80mg, 0.29mmol) in DCM (2mL) was added and the reaction was reacted at room temperature for 6 h. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1) afforded 77mg of white solid in 78% yield. Melting point: 111-113 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.97(brs,1H),8.89(s,1H),8.53(s,1H),8.48(d, J＝8.4Hz,1H),8.21(d,J＝8.4Hz,1H),8.09(d,J＝2.8Hz,1H),7.15(t,J＝7.6Hz, 1H),7.02(d,J＝11.6Hz,3H),6.94(d,J＝9.2Hz,1H),5.06-5.13(m,1H),4.12-4.19 (m,2H),2.28(s,3H),1.47(d,J＝6.8Hz,3H),1.41(t,J＝6.8Hz,3H).
Example 100
N- (4-ethoxy-3- ((1- (3-methylphenyl) ethyl) carbamoyl) phenyl) thiazole-4-carboxamide
Figure BDA0001620885820001722
4-Thiazolecarboxylic acid (31mg, 0.24mmol) was dissolved in DCM (3mL), HATU (111mg, 0.29mmol) and DIEA (62mg, 0.48mmol) were added and the mixture was reacted at room temperature for 20min, and a solution of 1- (3-methylphenyl) ethyl-1-amine (80mg, 0.29mmol) in DCM (2mL) was added and the reaction was allowed to proceed overnight at room temperature. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1) afforded 76mg of white solid in 77% yield. Melting point: 125-127 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.80(d,J＝2.0Hz,1H),8.44(d,J＝7.6Hz, 1H),8.34(dd,J1＝2.8Hz,J2＝9.2Hz,1H),8.25(d,J＝2.0Hz,1H),8.03(d,J＝3.2Hz, 1H),7.23(d,J＝7.6Hz,1H),7.19(d,J＝8.4Hz,1H),7.08(d,J＝7.2Hz,1H),6.98(d, J＝8.8Hz,1H),5.25-5.32(m,1H),4.13-4.21(m,2H),2.36(s,3H),1.58(d,J＝6.8Hz, 3H),1.43(t,J＝6.8Hz,3H).
Example 101
N- (3- (difluoromethoxy) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001731
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, the compound (3- (difluoromethoxy) phenyl) methylamine (104mg,0.6mmol) was added, stirred overnight at room temperature, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with saturated NaCl solution (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M. times.80: 1) to give 120mg of a white solid in 61.7% yield. Melting point: 123-125 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):8.45(brs,1H),8.23(dd,J1＝9.0Hz,J1＝2.5Hz, 1H),7.89(d,J＝2.5Hz,1H),7.57(brs,1H),7.35(t,J＝7.5Hz,1H),7.21(d,J＝8.0 Hz,1H),7.12(s,1H),7.05(d,J＝8.0Hz,1H),6.94(d,J＝9.0Hz,1H),4.67(d,J＝5.5 Hz,2H),4.15(q,J＝7.0Hz,2H),2.49-2.53(m,1H),1.35(t,J＝6.5Hz,3H),1.23(d,J ＝7.0Hz,6H).
Example 102
N- (1- (3- (difluoromethoxy) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001741
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, the compound 1- (3- (difluoromethoxy) phenyl) ethylamine (90mg,0.48mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P1: 2.5, E: P ═ 1:2) to give 70mg of a white solid with a yield of 41.6%. Melting point: 137℃ and 139 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.47(d,J＝7.6Hz,1H),8.21(d,J＝9.2Hz,1H), 7.85(s,1H),7.68(s,1H),7.34(td,J1＝8.0Hz,J1＝1.6Hz,1H),7.22(d,J＝7.6Hz, 1H),7.12(s,1H),7.01(d,J＝8.0Hz,1H),6.93(dd,J1＝8.8Hz,J1＝1.2Hz,1H), 5.28-5.32(m,1H),4.17(q,J＝6.8Hz,2H),2.47-2.51(m,1H),1.56(d,J＝6.8Hz,3H), 1.44(t,J＝6.8Hz,3H),1.20(dd,J1＝6.8Hz,J2＝2.8Hz,6H).
Example 103
2-ethoxy-5-isobutyrylamino-N- (3-methoxybenzyl) benzamide
Figure BDA0001620885820001742
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.4mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.8mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.60mL,3.2 mmol) were added, M-methoxybenzylamine (71mg,0.52mmol) was added, the mixture was stirred overnight at room temperature, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (40 mL. times.2), the combined organic layers were washed with saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P: 1:2.5, D: M: 60:1) to give 120mg of a white solid in 81% yield. Melting point: 152 ℃ and 154 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.43(brs,1H),8.24(dd,J1＝8.8,J2＝2.8,1H), 7.91(d,J＝2.8Hz,1H),7.66(s,1H),7.27(t,J＝8.0Hz,1H),6.89-6.95(m,3H), 6.81-6.84(m,1H),4.64(d,J＝5.2Hz,2H),4.13(q,J＝6.8Hz,2H),3.83(s,3H), 2.51-2.55(m,1H),1.33(t,J＝7.2Hz,3H),1.22(d,J＝6.8Hz,6H).
Example 104
2-ethoxy-5-isobutyrylamino-N- (1- (3-methoxyphenyl) ethyl) benzamide
Figure BDA0001620885820001751
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (10mL), EDC (156mg,0.8mmol) was added, HOBt (108mg,0.8mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (3-methoxyphenyl) ethylamine (121mg,0.8mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M. 70:1) to give a white solid 140mg, 90.9% yield. Melting point: 138-140 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.47(d,J＝7.6Hz,1H),8.22(dd,J1＝9.2Hz,J1＝2.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.66(s,1H),7.27(t,J＝7.6Hz,1H),6.95-6.97 (m,1H),6.90-6.93(m,2H),6.78-6.82(m,1H),5.26-5.29(m,1H),4.11-4.18(M,2H), 3.80(s,3H),2.46-2.51(m,1H),1.56(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.20 (dd,J1＝6.8Hz,J2＝2.0Hz,6H).
Example 105
2-ethoxy-5-isobutyrylamino-N- (3- (pyridin-2-yl) benzyl) benzamide
Figure BDA0001620885820001752
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, (3- (pyridin-2-yl) phenyl) methylamine (216mg,0.8mmol) was added, stirred at room temperature overnight, the reaction was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M80: 1) to give 80mg of a white solid in 47.9% yield. Melting point: 119 ℃ and 121 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.70(d,J＝5.2Hz,1H),8.49(t,J＝5.0Hz,1H), 8.23(dd,J1＝8.8Hz,J2＝2.4Hz,1H),8.03(s,1H),7.90-7.94(m,2H),7.73-7.78(m, 2H),7.48(t,J＝7.6Hz,1H),7.42-7.45(m,1H),7.24-7.28(m,1H),6.92(d,J＝9.2Hz, 1H),4.75(d,J＝5.2Hz,2H),4.11(q,J＝7.2Hz,2H),2.51-2.55(m,1H),1.28(t,J＝ 6.8Hz,3H),1.22(d,J＝6.8Hz,6H).
Example 106
2-ethoxy-5-isobutyrylamino-N- (1- (3- (pyridin-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001761
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (3- (pyridin-2-yl) phenyl) ethane-1-amine (95mg,0.48mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M: 80:1) to give 105mg of a white solid in 60.7% yield. Melting point: 185 ℃ C., 187 ℃ C
1H-NMR(400MHz,CDCl3)δ(ppm):9.75(s,1H),8.62-8.63(m,1H),8.56(d,J＝6.8 Hz,1H),8.09(s,1H),7.91-7.93(m,2H),7.82-7.85(m,2H),7.72(td,J1＝9.2Hz,J2＝ 2.8Hz,1H),7.42-7.44(m,2H),7.29-7.33(m,1H),7.03(dd,J1＝8.8Hz,J2＝2.0Hz, 1H),5.16-5.19(m,1H),4.04-4.10(m,2H),2.48-2.52(m,1H),1.48(d,J＝5.2Hz,3H), 1.27(t,J＝7.2Hz,3H),1.04(d,J＝6.4Hz,6H).
Example 107
2-ethoxy-5-isobutyrylamino-N- (3- (pyridazin-3-yl) benzyl) benzamide
Figure BDA0001620885820001762
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, 3- (pyridazin-3-yl) phenyl) methylamine (120mg,0.65mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixed solution (30mL × 2) of ethyl acetate: methanol ═ 10:1, the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M ═ 60:1, D: M ═ 50:1) to give 45mg of a white solid in 26.9% yield. Melting point: 128-130 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):9.18(s,1H),8.52(s,1H),8.21(d,J＝7.5Hz, 1H),8.13(s,1H),7.98(s,1H),7.91(s,1H),7.88(d,J＝8.5Hz,1H),7.51-7.59(m,4H), 6.92(d,J＝8.5Hz,1H),4.77(s,2H),4.12-4.13(m,2H),2.50-2.58(m,1H),1.31(brs, 3H),1.23(d,J＝5.5Hz,6H).
Example 108
2-ethoxy-5-isobutyrylamino-N- (1- (3- (pyridazin-3-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001771
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (3- (pyridazin-3-yl) phenyl) ethane-1-amine (119mg,0.6mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M: 60:1) to give 32mg of a white solid in 18.6% yield. Melting point: 65-67 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):9.16(d,J＝4.5Hz,1H),8.56(d,J＝7.0Hz,1H), 8.19(d,J＝9.0Hz,1H),8.16(s,1H),7.92(d,J＝6.5Hz,1H),7.86(d,J＝8.5Hz,1H), 7.81(s,1H),7.50-7.56(m,3H),7.39-7.43(m,1H),6.92(d,J＝9.0Hz,1H),5.37-5.41 (m,1H),4.17(q,J＝7.0Hz,2H),2.48-2.51(m,1H),1.65(d,J＝7.0Hz,3H),1.43(t,J ＝7.0Hz,3H),1.22(d,J＝6.5Hz,6H).
Example 109
N- (3- (1H-pyrazol-3-yl) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001772
Placing N- (3-bromophenylmethyl) -2-ethoxy-5-isobutyrylaminobenzamide (125mg,0.3mmol) in a reaction flask, adding dioxane (10mL), and adding Pd (PPh) under the protection of argon3)4(70mg,0.06mmol), (1H-pyrazol-3-yl) boronic acid (50mg,0.45mmol), prepared from Na2CO3(80g,12mmol) was dissolved in water (2.5mL) and added to a reaction flask, and the reaction was warmed to 100 ℃, the next day TLC showed no difference from TLC for 3h, the starting material remained, the reaction was stopped, concentrated, DCM (60mL) was added, washed with saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, and column chromatographed (D: M: 100:1, D: M: 60:1) to give 25mg of a pale yellow solid in 20.5% yield. Melting point: 195 + 197 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):8.48(s,1H),8.21(d,J＝7.0Hz,1H),7.92(s, 1H),7.81(s,1H),7.67(d,J＝7.0Hz,1H),7.62(s,2H),7.40(t,J＝7.5Hz,1H),7.33(d, J＝7.5Hz,1H),6.90(d,J＝9.0Hz,1H),6.62(s,1H),4.71(d,J＝5.0Hz,2H), 4.07-4.13(m,2H),2.51-2.54(m,1H),1.28(t,J＝7.0Hz,3H),1.24(d,J＝6.5Hz,6H).
Example 110
N- (1- (3- (1H-pyrazol-3-yl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001781
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, compound (35) (57mg,0.305mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixed solution of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (D: M: 50:1, D: M: 35:1, D: M: 25:1) to give 90mg of a colorless viscous liquid with a yield of 53%. Melting point: 114-
1H-NMR(400MHz,CDCl3)δPPm:8.55(d,J＝7.2Hz,1H),8.19(dd,J1＝9.2Hz,J1＝1.6Hz,1H),7.88-7.90(m,2H),7.85(s,1H),7.58-7.62(m,2H),7.31-7.39(m,2H), 6.87(d,J＝8.8Hz,1H),6.57(d,J＝1.6Hz,1H),5.31-5.38(m,1H),4.07-4.14(m,2H), 2.48-2.51(m,1H),1.59(d,J＝6.8Hz,3H),1.38(t,J＝7.2Hz,3H),1.21(dd,J1＝6.8 Hz,J2＝1.2Hz,6H).
Example 111
N- (3- (5- ((dimethylamino) methyl) thiazol-2-yl) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001782
a) 2-bromo-5- (bromomethyl) thiazole
2-bromo-5-methylthiazole (354mg,2mmol) was added to CCl4(15mL), acetonitrile (3mL), NBS (392 mg,2.2mmol) and AIBN (66mg,0.4mmol) were heated under reflux for 4h, the reaction was stopped, concentrated, EA (40mL) was added, washed with saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, and column chromatographed (E: P ═ 1:100) to give 320mg of a pale yellow solid in 62.8% yield. Melting point: 59-60 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):7.77(s,1H),5.03(s,2H).
b)1- (2-bromothiazol-5-yl) -N, N-dimethylmethylamine
2-bromo-5- (bromomethyl) thiazole (300mg,1.18mmol) was placed in a reaction flask, DCM (15mL) was added, the compound was dissolved and propyl was addedKetone (7.5mL), dimethylamine hydrochloride (191mg,2.36mmol), K was added2CO3(488mg,3.54mmol), the reaction was stirred at room temperature, stopped the next day, filtered, the filtrate was concentrated, and column chromatography (D: M: 30:1) was performed to give 210mg of a pale yellow oil with a yield of 80.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.37(s,1H),3.61(s,2H),2.27(s,6H).
c) N- (3- (5- ((dimethylamino) methyl) thiazol-2-yl) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide 2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.4mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.8mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.60mL,3.2 mmol) were added, 1- (2- (3- (aminomethyl) phenyl) thiazol-5-yl) -N, N-dimethylmethylamine (170mg,0.60 mmol) was added, stirring overnight at room temperature, the reaction was poured into water, extracted with a mixture of ethyl acetate: methanol 10:1 (40 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (D: M: 30:1, D: M: 25:1) to obtain 55mg of a white solid in 28.6% yield. Melting point: 134 ℃ and 136 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.33(s,1H),8.12(d,J＝7.6Hz,1H),7.94(s, 1H),7.86(d,J＝2.4Hz,1H),7.80-7.83(m,1H),7.61(s,1H),7.38-7.40(m,2H), 7.21-7.24(m,1H),6.91(d,J＝8.8Hz,1H),4.70(d,J＝5.6Hz,2H),4.10-4.15(m,2H), 3.68(s,2H),2.48-2.52(m,1H),2.31(s,6H),1.28-1.32(m,3H),1.23-1.25(m,6H).
Example 112
N- (1- (3- (5- ((dimethylamino) methyl) thiazol-2-yl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001791
2-ethoxy-5-isobutyrylaminobenzoic acid (63mg,0.25mmol) was added to anhydrous DMF (10mL), EDC (96mg,0.5mmol) was added, HOBt (68mg,0.50mmol) and DIEA (0.35mL,2.0mmol) were added, 1- (3- (5- ((dimethylamino) methyl) thiazol-2-yl) phenyl) ethylamine (70mg,0.21mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography was performed (D: M ═ 40:1, D: M ═ 30:1, D: M ═ 25:1) to give 40mg of a viscous solid with a yield of 38.8%.
1H-NMR(500MHz,CDCl3)δ(ppm):8.51(d,J＝6.5Hz,1H),8.20(d,J＝8.0Hz,1H), 7.96(s,1H),7.82(s,1H),7.78(d,J＝7.0Hz,1H),7.65(s,1H),7.59(s,1H),7.39-7.43 (m,1H),6.92(d,J＝9.0Hz,1H),5.30-5.35(m,1H),4.16(q,J＝6.5Hz,2H),3.80(s, 2H),2.49-2.52(m,1H),2.38(s,6H),1.61(d,J＝6.5Hz,3H),1.41(t,J＝6.5Hz,3H), 1.21(d,J＝6.5Hz,6H).
Example 113
N- (3- (4- ((dimethylamino) methyl) thiazol-2-yl) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001801
a) 2-bromo-4- (bromomethyl) thiazole
2-bromo-4-methylthiazole (1.78g,10mmol) was added to CCl4(80mL), acetonitrile (15mL), NBS (1.96 g,11mmol) and AIBN (324mg,2mmol) were heated to reflux, the reaction was stopped after 3h, concentrated, EA (160mL) was added, washed with saturated NaCl solution (50 mL. times.2), dried over anhydrous magnesium sulfate, and column chromatographed (E: P. RTM. 1:120) to give 1.15g of a pale yellow solid in 45.27% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.27(s,1H),4.52(s,2H).
b)1- (2-bromothiazol-4-yl) -N, N-dimethylmethylamine
2-bromo-4- (bromomethyl) thiazole (1.05g,4.13mmol) was placed in a reaction flask, DCM (40mL) was added, dimethylamine hydrochloride (669mg,8.26mmol), K 2CO3(1.7g,12.39mmol), the reaction was stirred at room temperature, stopped the next day, filtered, concentrated, and column chromatographed (D: M: 30:1) to give 700mg of a pale yellow oil in 77% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.09(s,1H),3.57(s,2H),2.30(s,6H).
c) N- (3- (4- ((dimethylamino) methyl) thiazol-2-yl) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide 2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (156mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (2- (3- (aminomethyl) phenyl) thiazol-4-yl) -N, N-dimethylmethylamine (130mg,0.52 mmol) was added, stirring was carried out overnight at room temperature, the reaction was poured into water, extracted with a mixture of ethyl acetate: methanol 10:1 (40 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (D: M: 20:1, D: M: 15:1) to obtain 62mg of a white solid in a yield of 32.2%. Melting point: 113 ℃ and 115 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.54(t,J＝5.2Hz,1H),8.23(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.97(s,1H),7.90(d,J＝2.8Hz,1H),7.85-7.88(m,1H),7.60(s,1H), 7.40-7.43(m,2H),7.22(m 1H),6.93(d,J＝8.8Hz,1H),4.72(d,J＝5.2Hz,2H),4.13 (q,J＝6.8Hz,2H),3.73(s,2H),2.51-2.55(m,1H),2.40(s,6H),1.31(t,J＝7.2Hz, 3H),1.23(d,J＝6.8Hz,6H).
Example 114
N- (1- (3- (4- ((dimethylamino) methyl) thiazol-2-yl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001811
2-ethoxy-5-isobutyrylaminobenzoic acid (80mg,0.32mmol) was added to anhydrous DMF (10mL), EDC (123mg,0.64mmol) was added, HOBt (86mg,0.64mmol) and DIEA (0.17mL,0.96 mmol) were added, 1- (3- (4- ((dimethylamino) methyl) thiazol-2-yl) phenyl) ethylamine (100mg,0.384mmol) was added, stirred overnight at room temperature, the reaction solution was poured into water, extracted with a mixed solution of ethyl acetate and methanol (10: 1) (40mL × 2), the combined organic layers were washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (D: M: 30:1, D: M: 25:1) gave 12mg of a white solid in 12.6% yield. Melting point: 53-55 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.54(d,J＝7.2Hz,1H),8.22(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.98(s,1H),7.82-7.85(m,2H),7.53(s,1H),7.38-7.45(m,2H),7.22(m 1H),6.93(d,J＝9.2Hz,1H),5.32-5.36(m,1H),4.14-4.20(m,2H),3.73(s,2H), 2.47-2.52(m,1H),2.39(s,6H),1.62(d,J＝6.8Hz,3H),1.43(t,J＝7.2Hz,3H),1.21 (dd,J1＝6.8Hz,J2＝2.0Hz,6H).
Example 115
2-ethoxy-5-isobutyrylamino-N- (3- (trifluoromethoxy) benzyl) benzamide
Figure BDA0001620885820001821
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.4mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.8mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.60mL,3.2 mmol) were added, m-trifluoromethoxybenzylamine (115mg,0.60mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (40 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P ═ 1:2.5, E: P ═ 1:2) to give 130mg of a white solid in 76.4% yield. Melting point: 135 ℃ of 133-
1H-NMR(400MHz,CDCl3)δ(ppm):8.49(d,J＝5.2Hz,1H),8.26(dd,J1＝9.2,J2＝ 2.8,1H),7.94(d,J＝2.8Hz,1H),7.86(s,1H),7.39(t,J＝7.6Hz,1H),7.30(d,J＝7.6 Hz,1H),7.21(s,1H),7.14-7.16(m,1H),6.94(d,J＝8.8Hz,1H),4.69(d,J＝5.6Hz, 2H),4.15(q,J＝7.2Hz,2H),2.48-2.54(m,1H),1.34(t,J＝7.2Hz,3H),1.20(d,J＝ 7.2Hz,6H).
Example 116
N- (3- (1H-imidazol-1-yl) benzyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001822
N- (3-bromophenyl-methyl) -2-ethoxy-5-isobutyrylaminobenzamide (125mg,0.3mmol) was added to anhydrous DMF (15mL), and imidazole (205mg,3mmmol), 1, 10-phenanthroline (540mg, 3mmol), K were added under argon protection2CO3(415mg,3mmol) and CuI (570mg,3mmol) were heated to 120 ℃ for reaction, and after 8h, the reaction was stopped, water was added, extraction was performed with a mixed solution (30mL × 2) of ethyl acetate and methanol at 10:1, the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography was performed (D: M: 60:1, D: M: 35:1, D: M: 30:1) to obtain 52mg of a white solid with a yield of 42.6%. Melting point: 201 ℃ 203 DEG C
1H-NMR(500MHz,CDCl3)δ(ppm):8.48-8.52(m,1H),,8.22(dd,J1＝9.0Hz,J1＝ 2.5Hz,1H),7.89(d,J＝2.5Hz,1H),7.86(s,1H),7.61(s,1H),7.46(t,J＝8.0Hz,1H), 7.40(s,1H),7.36(d,J＝7.5Hz,1H),7.31(d,J＝7.5Hz,1H),7.28(s,1H),7.20(s, 1H),6.94(d,J＝9.0Hz,1H),4.73(d,J＝5.5Hz,2H),4.15(q,J＝7.0Hz,2H), 2.50-2.54(m,1H),1.30(t,J＝7.0Hz,3H),1.23(d,J＝6.5Hz,6H).
Example 117
N- (1- (3- (azetidin-1-yl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001831
Placing N- (1- (3-bromophenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide (120mg,0.278mmol) in a reaction bottle, adding toluene (15mL), and adding Pd under the protection of argon2(dba)3(50mg,0.056mmol), xanthphos (63mg,0.112mmol), sodium tert-butoxide (80mg,0.834mmol) and azetidine (79 mg,1.39mmol) were reacted at elevated temperature to 100 ℃ for 1h, then the reaction was stopped, filtered, concentrated and column chromatographed (E: P ═ 1:3, E: P ═ 1:2) to give 89mg of a white solid in 78% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.45(d,J＝7.6Hz,1H),8.21(dd,J1＝8.8Hz,J1＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.60(s,1H),7.18(t,J＝8.0Hz,1H),6.91(d,J ＝8.8Hz,1H),6.74(d,J＝7.6Hz,1H),6.42(d,J＝2.0Hz,1H),6.33-6.37(m,1H), 5.21-5.30(m,1H),4.09-4.18(m,2H),3.87(t,J＝7.6Hz,4H),2.49-2.53(m,1H), 2.31-2.39(m,2H),1.56(d,J＝6.8Hz,3H),1.40(t,J＝6.8Hz,3H),1.22(dd,J1＝ 6.8Hz,J2＝2.0Hz,6H).
Example 118
N- (1- (3- ((dimethylamino) methyl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001832
a)1- (3- (bromomethyl) phenyl) ethanone
Metamethylacetophenone (1.34g,10mmol) was added to CCl4(50mL), acetonitrile (20mL), NBS (1.96 g,11mmol) and AIBN (328mg,2mmol), and the reaction was refluxed for 2 hours, and then the reaction was stopped, concentrated, and EA (100mL) was added, washed with a saturated NaCl solution (40 mL. times.2), dried over anhydrous magnesium sulfate, and subjected to column chromatography (E: P: 1:80, E: P: 1:50), and as an anhydrous oil, 1.6g was obtained, and the yield was 75.5%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.98(t,J＝1.2Hz,1H),7.88(d,J＝8.0Hz,1H), 7.60(d,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,1H),4.53(s,2H),2.59-2.60(m,3H).
b)1- (3- ((dimethylamino) methyl) phenyl) ethanone
1- (3- (bromomethyl) phenyl) ethanone (212mg,1mmol) was placed in a reaction flask, DCM (15mL) was added, dimethylamine hydrochloride (162mg,2mmol), K, was added 2CO3(414mg,3mmol), the reaction was stirred at room temperature, stopped the next day, filtered, the filtrate was concentrated, and column chromatography (D: M: 35:1) was performed to obtain 130mg of a pale yellow oil, 73.4% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.89-7.91(m,1H),7.85-7.87(m,1H),7.53-7.55 (m,1H),7.40-7.45(m,1H),3.48-3.49(m,2H),2.61-2.62(m,3H),2.25-2.26(m,6H).
c) N- (1- (3- ((dimethylamino) methyl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Anhydrous DMF (15mL) was added to 2-ethoxy-5-isobutyraminobenzoic acid (100mg,0.40mmol), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (3- ((dimethylamino) methyl) phenyl) ethylamine (107mg,0.6mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixed solution (30mL × 2) of ethyl acetate: methanol ═ 10:1, the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M35: 1, D: M ═ 20:1) to obtain 80mg of a colorless viscous liquid.
1H-NMR(500MHz,CDCl3)δ(ppm):8.40(d,J＝6.5Hz,1H),8.22(dd,J1＝9.0Hz,J1＝2.5Hz,1H),8.12(s,1H),7.93(d,J＝2.5Hz,1H),7.41(s,1H),7.31-7.35(m,2H), 7.28(s,1H),6.92(d,J＝9.0Hz,1H),5.17-5.20(m,1H),4.12-4.18(m,2H),2.56-2.60 (m,1H),2.52(s,6H),1.56(d,J＝7.0Hz,3H),1.45(t,J＝6.5Hz,3H),1.21(d,J＝7.0 Hz,6H).
Example 119
2-ethoxy-5-isobutyrylamino-N- (1-phenylethyl) benzamide
Figure BDA0001620885820001841
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (15mL), EDC (154mg,0.80mmol) was added, HOBt (108mg,0.80mmol) and DIEA (0.21mL,1.20 mmol) were added, the compound 1-phenylethylamine (63mg,0.52mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixed solution of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P ═ 1:3, E: P ═ 1:2) to give 120mg of a white solid in 84.5% yield. Melting point: 146- & ltSUB & gt 148- & lt/SUB & gt
1H-NMR(500MHz,CDCl3)δ(ppm):8.48(d,J＝7.0Hz,1H),8.22(d,J＝9.0Hz,1H), 7.84-7.85(m,1H),7.57(brs,1H),7.33-7.39(m,4H),7.26-7.28(m,1H),6.92(d,J＝ 9.0Hz,1H),5.23-5.29(m,1H),4.11-4.18(m,2H),2.48-2.51(m,1H),1.58(d,J＝6.5 Hz,3H),1.41(t,J＝6.5Hz,3H),1.21(d,J＝4.5Hz,6H).
Example 120
(3- (1- (2-ethoxy-5-isobutyramidobenzamido) ethyl) benzyl) (methyl) carbamic acid benzyl ester
Figure BDA0001620885820001851
a)3- (2-methyl-1, 3-dioxan-2-yl) benzonitrile
3-cyanoacetophenone (435mg,3mmol), benzene (20mL), dihydrate and P-toluenesulfonic acid (57 mg,0.3mmol) and ethylene glycol (0.33mL,6mmol) were added, a water separator was installed, the reaction was heated under reflux, and after 2 hours, the reaction was stopped, ethyl acetate (50mL) was added, the mixture was washed with a saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, and subjected to column chromatography (E: P. RTM. 1:30) to give 420mg of a colorless oil with a yield of 74%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.79-7.81(m,1H),7.71-7.73(m,1H),7.57-7.61 (m,1H),7.43-7.48(m,1H),4.04-4.09(m,2H),3.74-3.78(m,2H),1.63(s,3H).
b) (3- (2-methyl-1, 3-dioxolan-2-yl) phenyl) methanamine
3- (2-methyl-1, 3-dioxolan-2-yl) benzonitrile (1.2g), MeOH (50mL), 10% Pd/C (0.4g) were added, hydrogenation was carried out at room temperature under normal pressure, and after 5h the reaction was stopped, filtration and concentration gave 1.1g of a pale yellow oil with a yield of 90.1%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.41-7.43(m,1H),7.35-7.38(m,1H),7.29-7.33 (m,1H),7.23-7.26(m,1H),4.01-4.05(m,2H),3.88(s,2H),3.76-3.80(m,2H),1.65(s, 3H).
c)3- (2-methyl-1, 3-dioxan-2-yl) benzyl) carbamic acid benzyl ester
Ethyl acetate (8 mL), water (4mL), sodium bicarbonate (156mg,1.86mmol) were added to (3- (2-methyl-1, 3-dioxan-2-yl) phenyl) methylamine (120mg,0.62mmol), CBZ-Cl (0.13mL,0.93 mmol) was added dropwise to the reaction flask, the reaction was continued stirring at room temperature for 1h, and the reaction was stopped by adding ethyl acetate 20mL, washing with saturated NaCl solution (10mL × 2), drying over anhydrous magnesium sulfate, and column chromatography (E: P ═ 1:7, E: P ═ 1:6) gave 100mg of colorless oil, yield 49.5%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.23-7.40(m,9H),5.15(s,2H),5.10(brs,1H), 4.40(d,J＝6.0Hz,2H),4.00-4.03(m,2H),3.76(t,J＝7.2Hz,2H),1.63(s,3H).
d) Methyl (3- (2-methyl-1, 3-dioxan-2-yl) benzyl) carbamate
Benzyl 3- (2-methyl-1, 3-dioxan-2-yl) benzyl) carbamate (80mg,0.244mmol) was added to 10mL of DMF, NaH (15mg,0.36mmol) was added at room temperature under argon protection, stirring was carried out at room temperature for 1h, methyl iodide (42mg,0.29mmol) was added, the reaction was carried out at room temperature with stirring, 2h later, the reaction was stopped, water was added, extraction was carried out with 40mL of ethyl acetate, the organic layer was washed with 20mL × 2 saturated NaCl solution, dried over anhydrous magnesium sulfate, and column chromatography was carried out (E: P ═ 1:6) to obtain 70mg of the product, yield 84.3%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.29-7.40(m,8H),7.10-7.20(m,1H),5.19(s, 2H),4.51(d,J＝10.4Hz,2H),4.02(t,J＝6.8Hz,2H),3.74-3.76(m,2H),2.87-2.92(m, 3H),1.63-1.65(m,3H).
e) (3-Acetylbenzyl) (methyl) carbamic acid benzyl ester
Benzyl methyl (3- (2-methyl-1, 3-dioxan-2-yl) benzyl) carbamate (160mg,0.468mmol) was added THF (4mL), H2O (1mL), 2.5N HCl solution (0.5mL,1.25mmol) was added and the reaction stirred at room temperature for 2h before stopping, 20mL ethyl acetate was added and washed with 10 mL. times.2 saturated NaHCO3 solution, dried over anhydrous magnesium sulfate and concentrated to give 120mg of a colorless oil in 86% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.77-7.87(m,2H),7.32-7.50(m,7H),5.19(s, 2H),4.54-4.56(m,2H),2.89-2.93(m,3H),2.53-2.59(m,3H).
f) (3- (1- (2-ethoxy-5-isobutyramide benzamido) ethyl) benzyl) (methyl) carbamic acid benzyl ester
2-ethoxy-5-isobutyrylaminobenzoic acid (160mg,0.637mmol) was added to anhydrous DMF (15mL), EDC (244mg,1.274mmol) was added, HOBt (172mg,1.274mmol) and DIEA (0.33mL, 1.911mmol) were added, benzyl (3- (1-aminoethyl) benzyl) (methyl) carbamate (218mg,0.733 mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (40 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (D: M: 100:1) to give 290mg of a viscous liquid with a yield of 85.7%.
1H-NMR(500MHz,CDCl3)δ(ppm):8.39-8.45(m,1H),8.21(d,J＝7.0,1H),7.82(brs, 1H),7.07-7.48(m,10H),6.91(d,J＝8.5,1H),5.28(brs,1H),5.15-5.17(m,2H),4.48 (s,2H),4.13(s,2H),2.85-2.90(m,3H),2.48-2.51(m,1H),1.54(s,3H),1.38(s,3H), 1.22(d,J＝6.5Hz,6H).
Example 121
2-ethoxy-5-isobutyrylamino-N- (1- (3- ((methylamino) methyl) phenyl) ethyl) benzamide
Figure BDA0001620885820001871
Benzyl (3- (1- (2-ethoxy-5-isobutyramide benzamido) ethyl) benzyl) (methyl) carbamate (235mg) was hydrogenated with MeOH (15mL) and 10% Pd/C (70.5mg) at room temperature under normal pressure for 2h, filtered, concentrated, and subjected to column chromatography (D: M: 50:1, D: M: ammonia: 300:20:1) to give an off-white solid (95 mg, 54.3% yield). Melting point: 63-65 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.49(d,J＝7.2Hz,1H),8.22(dd,J1＝9.2Hz,J2＝3.2Hz,1H),7.75-7.80(m,2H),7.23-7.34(m,4H),6.91(d,J＝8.8,1H),5.23-5.27(m, 1H),4.13-4.16(m,2H),3.78(s,2H),2.52-2.56(m,1H),2.45(s,3H),1.56(d,J＝6.8 Hz,3H),1.42(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H).
Example 122
(3- (1- (2-ethoxy-5-isobutyramide benzamido) ethyl) phenyl) (methyl) carbamic acid benzyl ester
Figure BDA0001620885820001872
a) (3-Acetylphenyl) carbamic acid benzyl ester
After ethyl acetate (40mL) and water (20mL) were added to 3-aminoacetophenone (1.35g,10mmol), sodium bicarbonate (2.52g,30mmol) was added, CBZ-Cl (2.1mL,15mmol) was added dropwise to the reaction flask, the reaction was continued at room temperature, after 1 hour, the reaction was stopped, ethyl acetate 80mL was added, washing was performed with saturated NaCl solution (40mL × 2), drying was performed with anhydrous magnesium sulfate, and column chromatography was performed (E: P ═ 1:6, E: P ═ 1:5) to obtain 2.3g of a white solid with a yield of 85.5%. Melting point: 108 temperature 109 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):7.94(brs,1H),7.67-7.70(m,1H),7.63-7.66(m, 1H),7.34-7.42(m,6H),6.91(brs,1H),5.22(s,2H),2.53(s,3H).
b) (3-Acetylphenyl) (methyl) carbamic acid benzyl ester
Benzyl (3-acetylphenyl) carbamate (1.0g,3.72mmol) was added to DMF 25mL, NaH (178mg,4.46mmol) was added at room temperature under argon protection, stirring was performed at room temperature for 1h, methyl iodide (554mg,3.91mmol) was added, stirring was performed at room temperature, the reaction was stopped after 2h, water was added, extraction was performed with ethyl acetate 80mL, the organic layer was washed with saturated NaCl solution 20mL × 2, dried over anhydrous magnesium sulfate, and column chromatography was performed (E: P ═ 1:7.5, E: P ═ 1:6) to obtain 770mg of the product, yield 87%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.85(s,1H),7.77-7.80(m,1H),7.41-7.47(m, 2H),7.29-7.35(m,5H),5.18(s,2H),3.36(s,3H),2.56(s,3H).
c) (3- (1- (2-ethoxy-5-isobutyramide benzamido) ethyl) phenyl) (methyl) carbamic acid benzyl ester
2-ethoxy-5-isobutyrylaminobenzoic acid (230mg,0.916mmol) was added to anhydrous DMF (25mL), EDC (352mg,1.832mmol) was added, HOBt (247mg,1.832mmol) and DIEA (0.48mL, 2.748mmol) were added, benzyl (3- (1-aminoethyl) phenyl) (methyl) carbamate (338mg,1.19mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (40mL × 2), the combined organic layers were washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P1: 2, D: M: 75:1) to give 420mg of an off-white solid in 88.6% yield. Melting point: 58-60 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):8.43(d,J＝8.0Hz,1H),8.21(d,J＝8.0,1H), 7.84(s,1H),7.56-7.62(m,1H),7.21-7.34(m,8H),5.27-5.31(m,1H),5.15(s,2H), 4.09-4.13(m,2H),3.31(s,3H),2.48-2.51(m,1H),1.54(d,J＝6.5Hz,3H),1.36(t,J＝ 6.5Hz,3H),1.21(d,J＝6.5Hz,6H).
Example 123
2-ethoxy-5-isobutyrylamino-N- (1- (3- (methylamino) phenyl) ethyl) benzamide
Figure BDA0001620885820001881
Benzyl (3- (1- (2-ethoxy-5-isobutyramide benzamido) ethyl) phenyl) (methyl) carbamate (310mg) was hydrogenated with MeOH (15mL) and 10% Pd/C (93mg) at room temperature under normal pressure for 4h, then quenched, filtered, concentrated, and subjected to column chromatography (D: M: 80:1) to give 153mg of a white solid in 66.8% yield. Melting point: 138 ℃ and 140 DEG C
1H-NMR(500MHz,CDCl3)δ(ppm):8.46(d,J＝7.0Hz,1H),8.21(d,J＝8.5,1H), 7.87(s,1H),7.72(s,1H),7.17(t,J＝8.0,1H),6.91(d,J＝9.0,1H),6.73(d,J＝7.0, 1H),6.62(s,1H),6.52(d,J＝7.5,1H),5.20-5.24(m,1H),4.10-4.15(m,2H),3.98(brs, 1H),2.82(s,3H),2.50-2.53(m,1H),1.56(d,J＝6.5Hz,3H),1.41(t,J＝7.0Hz,3H), 1.21(d,J＝5.0Hz,6H).
Example 124
(3- (1- (2-ethoxy-5-isobutyramide benzamido) ethyl) phenyl) carbamic acid benzyl ester
Figure BDA0001620885820001891
2-ethoxy-5-isobutyrylaminobenzoic acid (360mg,1.434mmol) was added to anhydrous DMF (30mL), EDC (551mg,2.868mmol) was added, HOBt (387mg,2.868mmol) and DIEA (0.75mL, 4.302mmol) were added, benzyl (3- (1-aminoethyl) phenyl) carbamate (581mg,2.15mmol) was added, stirring was carried out overnight at room temperature, the reaction mixture was poured into water, extraction was carried out with a mixture (40 mL. times.2) of ethyl acetate: methanol: 10:1, the combined organic layers were washed with a saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography was carried out (E: P: 1:2, D: M: 50:1) to give 600mg of a white solid with a yield of 87%
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.76(s,1H),8.52(d,J＝7.6Hz,1H),7.96(s, 1H),7.92(d,J＝2.8,1H),7.79(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.52(s,1H), 7.31-7.44(m,6H),7.25(t,J＝8.0,1H),7.07(d,J＝9.2,1H),7.04(d,J＝7.6,1H),5.15 (s,2H),5.03-5.08(m,1H),4.08-4.15(m,2H),2.53-2.57(m,1H),1.44(d,J＝6.8Hz, 3H),1.33(t,J＝7.2Hz,3H),1.08(d,J＝6.8Hz,6H).
Example 125
N- (1- (3-aminophenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001892
Benzyl (3- (1- (2-ethoxy-5-isobutyramide benzamido) ethyl) phenyl) carbamate (600mg) was hydrogenated at room temperature and pressure to EtOH (25mL) and 10% Pd/C (180mg), which was then stopped, filtered, concentrated, and subjected to column chromatography (D: M: 40:1, DM: 30:1) to give 320mg of a white solid with a yield of 72.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.50(d,J＝6.0Hz,1H),8.23(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.85(d,J＝2.8,1H),7.81(s,1H),7.12(t,J＝8.0,1H),6.91(d,J＝8.8, 1H),6.81(d,J＝5.6,1H),6.77(s,1H),6.62(d,J＝8.0,1H),5.13-5.17(m,1H), 4.09-4.18(m,2H),2.50-2.58(m,1H),1.524(d,J＝6.8Hz,3H),1.43(t,J＝6.8Hz,3H), 1.22(dd,J1＝6.8Hz,J2＝2.4Hz,6H).
Example 126
2-ethoxy-5-isobutyrylamino-N- (1- (3- (2,2, 2-trifluoroethoxy) phenyl) ethyl) benzamide
Figure BDA0001620885820001901
a)1- (3- (2,2, 2-trifluoroethoxy) phenyl) ethanone
3-hydroxyacetophenone (953mg,7.0mmol), DMF (30mL), cesium carbonate (3.4g,10.5 mmol), 2,2, 2-trifluoroethyl trifluoromethanesulfonate (1.95g,8.4mmol) were added, the reaction was stirred at room temperature, the reaction was stopped after 30min, the reaction solution was poured into water, a solid precipitated, suction filtration was carried out, and the filter cake was washed with water to obtain 1.4g of a white solid with a yield of 91.7%. Melting point: 70-71 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):7.62-7.65(m,1H),7.51-7.53(m,1H),7.43(t,J＝ 8.0Hz,1H),7.16-7.19(m,1H),4.41(q,J＝8.0Hz,2H),2.61(s,3H).
b) 2-ethoxy-5-isobutyrylamino-N- (1- (3- (2,2, 2-trifluoroethoxy) phenyl) ethyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 1- (3- (2,2, 2-trifluoroethoxy) phenyl) ethylamine (192mg,0.876mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P. times.1: 1.5) to give 139mg of a white solid with a yield of 70%. Melting point: 75-77 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.46(d,J＝7.2Hz,1H),8.21(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.81(s,1H),7.44(brs,1H),7.30(t,J＝8.0Hz,1H),7.06(d,J＝7.6Hz, 1H),6.98-6.99(m,1H),6.93(d,J＝9.2Hz,1H),6.81(dd,J1＝8.0Hz,J2＝2.4Hz,1H), 5.24-5.31(m,1H),4.34(q,J＝8.0Hz,2H),4.14-4.20(m,2H),2.45-2.53(m,1H),1.56 (d,J＝6.8Hz,3H),1.44(t,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H).
Example 127
N- (1- (3-cyclopropylphenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001902
a)1- (3-cyclopropylphenyl) ethanones
3-bromoacetophenone (796mg,4mmol) was placed in a reaction flask, toluene (30mL), water (1.5mL) were added, cyclopropylphenylboronic acid (447mg,5.2mmol), palladium acetate (90mg,0.4mmol), tricyclohexylphosphorus (162mg,0.8mmol) and potassium phosphate (2.97mg,14mmol) were added under argon to heat to 100 ℃ for reaction, the reaction was stopped after 4h, filtered, ethyl acetate (60mL) was added, washed with saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, and column chromatography (E: P ═ 1:80) gave 440mg of a yellow oil in 68.7% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.72(dd,J1＝7.6Hz,J1＝1.6Hz,1H),7.67(t,J ＝7.6Hz,1H),7.25-7.28(m,1H),2.59(s,3H),1.93-1.98(m,1H),0.98-1.03(m,2H), 0.72-0.76(m,2H).
b) N- (1- (3-cyclopropylphenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 1- (3-cyclopropylphenyl) ethylamine (141mg,0.876mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P1: 3.5, E: P ═ 1:2.5) to give 120mg of a white solid in 69.3% yield. Melting point: 143-145 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.45(d,J＝7.2Hz,1H),8.22(dd,J1＝8.8Hz,J1＝2.8Hz,1H),7.84(d,J＝2.8Hz,1H),7.56(s,1H),7.23(t,J＝7.6Hz,1H),7.15(dt, J1＝7.6Hz,J1＝1.2Hz,1H),7.12(d,J＝1.6Hz,1H),6.90-6.94(m,2H),5.24-5.28(m, 1H),4.12-4.17(m,2H),2.48-2.52(m,1H),1.86-1.90(m,1H),1.56(d,J＝6.8Hz,3H), 1.41(t,J＝6.8Hz,3H),1.21(dd,J1＝7.2Hz,J1＝2.0Hz,6H),0.92-0.97(m,2H), 0.66-0.71(m,2H).
Example 128
N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001911
a)1- (3- (cyclopropylmethoxy) phenyl) ethanone
3-hydroxyacetophenone (953mg,7mmol) was placed in a reaction flask, DMF (25ml) was added, Cs was added2CO3(3.4g,10.5mmol), the reaction solution was yellow, bromomethylcyclopropane (0.8mL,8.4mmol) was added and the reaction was stirred at room temperature, the reaction was stopped the next day, the reaction solution was poured into water, extracted with ethyl acetate (40mL × 2), the organic layers were combined, washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, and column-chromatographed (E: P ═ 1:50, E: P ═ 1:25) to give 1.29g of a colorless oil, with a yield of 96.9%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.50-7.754(m,1H),7.46-7.47(m,1H),7.32-7.38 (m,1H),7.09-7.14(m,1H),3.83-3.87(m,2H),2.57-2.59(m,3H),1.25-1.31(m,1H), 0.62-0.67(M,2H),0.33-0.38(m,2H).
b) N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 1- (3- (cyclopropylmethoxy) phenyl) ethylamine (167mg,0.876mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixed solution (30mL × 2) of ethyl acetate: methanol ═ 10:1, the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (E: P ═ 1:3.5, E: P ═ 1:2.5) was performed to obtain 150mg of a white solid with a yield of 80.6%. Melting point: 129-130 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.46(d,J＝7.2Hz,1H),8.22(dd,J1＝8.8Hz,J1＝2.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.68(s,1H),7.25(t,J＝8.0Hz,1H),6.90-6.96 (m,3H),6.77-6.80(m,1H),5.23-5.30(m,1H),4.11-4.18(m,2H),3.79(d,J＝6.8Hz, 2H),2.46-2.53(m,1H),1.56(d,J＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.22-1.28(m, 1H),1.20(dd,J1＝6.8Hz,J1＝2.0Hz,6H),0.62-0.65(m,2H),0.32-0.36(m,2H).
Example 129
2-ethoxy-5-isobutyrylamino-N- (1- (3- (methylsulfonylamino) phenyl) ethyl) benzamide
Figure BDA0001620885820001921
a) N- (3-acetylphenyl) methanesulfonamide
Placing 3-aminoacetophenone (1g,7.4mmol) in a reaction bottle, adding DCM (30mL), adding pyridine (3 mL,37.3mmol), dropping methanesulfonyl chloride (0.86mL,11.2mmol) in an ice bath, adding dropwise into the reaction bottle, reacting to room temperature after the dropwise addition, stopping the reaction after 4h, adding DCM (30mL), washing with 1N HCl solution (20mL), washing with saturated NaCl solution (20mL multiplied by 2), drying over anhydrous magnesium sulfate, concentrating, recrystallizing with ethanol to obtain 1.05g of orange solid with the yield of 66.6%. Melting point: 93-94 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):7.83(s,1H),7.76(d,J＝7.5Hz,1H),7.48(t,J＝ 8.0Hz,1H),7.27(s,1H),3.06(s,3H),2.62(s,3H).
b) 2-ethoxy-5-isobutyrylamino-N- (1- (3- (methylsulfonylamino) phenyl) ethyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, N- (3- (1-aminoethyl) phenyl) methanesulfonamide (175mg,0.818mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M ═ 75:1, D: M ═ 60:1) to give 150mg of a white solid in 76.5% yield. Melting point: 84-86 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.68(d,J＝6.8Hz,1H),8.29(dd,J1＝8.8Hz,J1＝2.8Hz,1H),8.22(brs,1H),7.95(d,J＝2.8Hz,1H),7.80(brs,1H),7.38(s,1H),7.32 (d,J＝5.2Hz,2H),7.13-7.16(m,1H),6.92(d,J＝9.2Hz,1H),5.26-5.31(m,1H), 4.14-4.21(m,2H),2.96(s,3H),2.48-2.54(m,1H),1.57(d,J＝6.8Hz,3H),1.47(t,J＝ 6.8Hz,3H),1.23(d,J＝6.8Hz,6H).
Example 130
N- (1- (3- (azetidin-1-ylsulfonyl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001931
a)1- (3- (azetidin-1-ylsulfonyl) phenyl) ethanones
Azetidine (128mg,2.25mmol) was placed in a reaction flask, DCM (10mL) was added, pyridine (0.6mL,7.5mmol) was added, a solution of 3-acetylbenzylsulfontyl chloride (327mg,1.5mmol) in DCM (5mL) was added under ice bath, the reaction was stirred at room temperature for 2h, the reaction was stopped, concentrated to dryness, DCM (40mL) was added, washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (E: P ═ 1:7, E: P ═ 1:5, E: P ═ 1:4) gave 310mg of white solid in 86.3% waxy yield. Melting point: 65-66 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):8.38(brs,1H),8.22(d,J＝6.5Hz,1H), 8.03-8.05(m,1H),7.71(t,J＝7.5Hz,1H),3.80-3.85(m,4H),2.67-2.68(m,1H), 2.09-2.13(m,2H).
b) N- (1- (3- (azetidin-1-ylsulfonyl) phenyl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (39mg,0.155mmol) was added to anhydrous DMF (6mL), EDC (59mg,0.31mmol) was added, HOBt (42mg,0.31mmol) and DIEA (0.08mL,0.465 mmol) were added, 1- (3- (azetidin-1-ylsulfonyl) phenyl) ethylamine (48mg,0.2mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M: 100:1) to give 50mg of a white solid in 68.4% yield. Melting point: 71-73 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.53(d,J＝6.8Hz,1H),8.16(dd,J1＝8.8Hz,J1＝2.8Hz,1H),7.84(t,J＝1.6Hz,1H),7.77(d,J＝2.8Hz,1H),7.73(dt,J1＝7.6Hz,J2＝1.6Hz,1H),7.64-7.67(m,1H),7.55(t,J＝8.0Hz,1H),5.34-5.38(m,1H),4.18-4.24 (m,2H),3.75(t,J＝7.6Hz,4H),2.45-2.51(m,1H),2.00-2.09(m,2H),1.60(d,J＝7.2 Hz,3H),1.49(t,J＝7.2Hz,3H),1.23(d,J＝6.8Hz,6H).
Example 131
2-ethoxy-5-isobutyrylamino-N- (1- (3-sulfamoylphenyl) ethyl) benzamide
Figure BDA0001620885820001941
a) 3-acetylbenzenesulfonamides
3-Acetylbenzenesulfonyl chloride (327mg,1.5mmol) was added 7M NH under ice bath3After the addition of the methanol solution, the reaction was stirred at room temperature for 15min, concentrated and subjected to column chromatography (D: M: 50:1) to obtain 290 mg of a white solid, which was 97.3% in yield. m.p.144-146 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.35(t,J＝1.6Hz,1H),8.18(dt,J1＝8.0Hz, J1＝1.6Hz,1H),8.04-8.07(m,1H),7.74(t,J＝8.0Hz,1H),7.50(brs,2H),2.64(s, 3H).
b) 2-ethoxy-5-isobutyrylamino-N- (1- (3-sulfamoylphenyl) ethyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (48mg,0.19mmol) was added to anhydrous DMF (10mL), EDC (73mg,0.38mmol) was added, HOBt (51mg,0.38mmol) and DIEA (0.10mL,0.57 mmol) were added, 3- (1-aminoethyl) benzenesulfonamide (50mg,0.258mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M: 40:1, D: M: 30:1) to give 50mg of a white solid with a yield of 60.9%. Melting point: 93-95 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.78(s,1H),8.60(d,J＝7.6Hz,1H),7.87(d, J＝2.8Hz,1H),7.84(s,1H),7.71-7.77(m,2H),7.63(d,J＝7.6Hz,1H),7.54(t,J＝ 8.0Hz,1H),7.35(s,2H),7.08(d,J＝9.2Hz,1H),5.16-5.21(m,1H),4.12(q,J＝6.8 Hz,2H),2.52-2.56(m,1H),1.48(d,J＝7.2Hz,3H),1.37(t,J＝6.8Hz,3H),1.08(d,J ＝6.8Hz,6H).
Example 132
2-ethoxy-5-isobutyrylamino-N- (1- (3- (tetrahydrofuran-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001951
2-ethoxy-5-isobutyrylaminobenzoic acid (120mg,0.48mmol) was added to anhydrous DMF (15mL), EDC (184mg,0.96mmol) was added, HOBt (130mg,0.96mmol) and DIEA (0.25mL,1.44 mmol) were added, 1- (3- (tetrahydrofuran-2-yl) phenyl) ethylamine (183mg,0.96mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M. times.100: 1) to give 100mg of a white solid in 49.2% yield. Melting point: 121-123 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):8.46(d,J＝7.5Hz,1H),8.21(d,J＝9.0Hz,1H), 7.86(s,1H),7.70(d,J＝7.0Hz,1H),7.32-7.35(m,1H),7.30(d,J＝7.5Hz,1H), 7.22-7.27(m,2H),6.91(d,J＝8.5Hz,1H),5.29-5.33(m,1H),4.87(t,J＝7.5Hz,1H), 4.04-4.17(m,3H),3.89-3.95(m,1H),2.47-2.53(m,1H),2.28-2.32(m,1H),1.97-2.04 (m,2H),1.76-1.81(m,1H),1.57(d,J＝7.0Hz,3H),1.40(t,J＝7.0Hz,3H),1.20(d,J1＝6.5Hz,J2＝2.5Hz,6H).
Example 133
2-ethoxy-5-isobutyrylamino-N- (1- (3- (pyrimidin-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820001952
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 1- (3- (pyrimidin-2-yl) phenyl) ethylamine (192mg,0.876mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M: 70:1) to give 135mg of a white solid in 71.4% yield. Melting point: 161 ℃ C. -
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.79(s,1H),8.91(d,J＝4.8Hz,1H),8.44(s, 1H),8.29(d,J＝7.6Hz,1H),7.88(d,J＝2.8Hz,1H),7.77(dd,J1＝8.8Hz,J2＝2.8Hz, 1H),7.58(d,J＝7.2Hz,1H),7.51(t,J＝7.6Hz,1H),7.46(t,J＝4.8Hz,1H),7.08(d, J＝8.8Hz,1H),5.19-5.28(m,1H),4.10-4.15(m,2H),2.52-2.56(m,1H),1.52(d,J＝ 7.2Hz,3H),1.34(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,6H).
Example 134
2-ethoxy-5-isobutyrylamino-N- ((6-methylpyridin-2-yl) methyl) benzamide
Figure BDA0001620885820001961
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (10mL), EDC (156mg,0.8mmol) was added, HOBt (108mg,0.8mmol) and DIEA (0.21mL,1.20 mmol) were added, compound (6-methylpyridin-2-yl) methylamine (74mg,0.8mmol) was added, stirred overnight at room temperature, the reaction solution was poured into water, extracted with a mixed solution (30mL × 2) of ethyl acetate: methanol ═ 10:1, the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M ═ 80:1, D: M ═ 50:1, D: M ═ 40:1) to give 115mg of a white solid in 80.98% yield. Melting point: 138-140 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):9.01(s,1H),8.23(dd,J1＝8.8Hz,J1＝2.8Hz, 1H),7.91-7.92(m,1H),7.65(brs,1H),7.56(t,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,1H), 7.07(d,J＝7.6Hz,1H),6.96(d,J＝9.2Hz,1H),4.78(d,J＝4.8Hz,2H),4.22(q,J＝ 7.2Hz,2H),2.58(s,3H),2.51-2.55(m,1H),1.49(t,J＝6.8Hz,3H),1.23(d,J＝6.8 Hz,6H).
Example 135
2-ethoxy-5-isobutyrylamino-N- (1- (6-methylpyridin-2-yl) ethyl) benzamide
Figure BDA0001620885820001962
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.40mmol) was added to anhydrous DMF (10mL), EDC (156mg,0.8mmol) was added, HOBt (108mg,0.8mmol) and DIEA (0.21mL,1.20 mmol) were added, 1- (6-methylpyridin-2-yl) ethylamine (82mg,0.6mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M80: 1, D: M50: 1) to give 110mg of a white solid with a yield of 74.8%. Melting point: 189 deg.C, 191 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):9.13(d,J＝7.2Hz,1H),8.21(dd,J1＝8.8Hz,J1＝2.8Hz,1H),7.87(d,J＝2.8Hz,1H),7.62(s,1H),7.53(t,J＝7.6Hz,1H),7.02-7.08 (m,2H),6.94(d,J＝8.8Hz,1H),5.32-5.36(m,1H),4.19-4.25(m,2H),2.56(s,3H), 2.51-2.55(m,1H),1.52-1.56(m,6H),1.22(dd,J1＝6.8Hz,J2＝2.0Hz,6H).
Example 136
2-ethoxy-5-isobutyrylamino-N- (1- (4-methylpyridin-2-yl) ethyl) benzamide
Figure BDA0001620885820001971
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 1- (4-methylpyridin-2-yl) ethylamine (119mg,0.876mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M ═ 80:1, D: M ═ 50:1) to give 88mg of a white solid in 54.6% yield. Melting point: 129 ℃ 131-
1H-NMR(500MHz,CDCl3)δ(ppm):9.28(d,J＝6.0Hz,1H),8.42(d,J＝5.0Hz,1H), 8.20(d,J＝7.0Hz,1H),7.87(s,1H),7.54(s,1H),7.11(s,1H),7.03(s,1H),6.94(d,J ＝9.0Hz,1H),5.30-5.34(m,1H),4.16-4.23(m,2H),2.51-2.54(m,1H),2.36(s,3H), 1.56-1.59(m,6H),1.23(d,J＝6.0Hz,6H).
Example 137
2-ethoxy-5-isobutyrylamino-N- (1- (6-methoxypyridin-2-yl) ethyl) benzamide
Figure BDA0001620885820001972
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 1- (6-methoxypyridin-2-yl) ethylamine (133mg,0.876mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P ═ 1:3, E: P ═ 1:1.5) to give 130mg of a white solid in 76.9% yield. Melting point: 178-
1H-NMR(400MHz,CDCl3)δ(ppm):8.73(d,J＝7.6Hz,1H),8.22(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.69(s,1H),7.52(t,J＝7.2Hz,1H),6.94(d,J ＝9.2Hz,1H),6.87(d,J＝7.2Hz,1H),6.62(dd,J1＝8.4Hz,J2＝0.8Hz,1H), 5.28-5.36(m,1H),4.14-4.21(m,2H),3.95(s,3H),2.48-2.56(m,1H),1.57(d,J＝6.8 Hz,3H),1.43(t,J＝6.8Hz,3H),1.22(dd,J1＝6.8Hz,J2＝1.6Hz,6H).
Example 138
2-ethoxy-5-isobutyrylamino-N- (1- (2-methoxypyridin-4-yl) ethyl) benzamide
Figure BDA0001620885820001981
a)1- (2-methoxypyridin-4-yl) ethanones
Adding 2-methoxy-4-cyano-pyridine (670mg,5mmol), adding tert-butyl methyl ether (10mL), cooling to 0 ℃, dropwise adding a 1M methyl magnesium bromide THF solution (6mL,6mmol) into a reaction bottle under the protection of argon, reacting at 0 ℃ for 3h after dropwise adding, supplementing a 1M methyl magnesium bromide THF solution (0.25mL,0.25mmol) and continuing to react at 0 ℃ for 5h, adding water for 6mL, stirring at room temperature for reacting overnight, extracting with ethyl acetate (40mL multiplied by 2), combining organic layers, and using saturated NH4The Cl solution (20mL × 2) and a saturated NaCl solution (20mL × 2) were washed, dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (E: P ═ 1:20, E: P ═ 1:15), to obtain 160mg of a colorless oil in a yield of 21.2%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.31(d,J＝5.6Hz,1H),7.30(dd,J1＝5.6 Hz,J2＝1.6Hz,1H),7.17-7.18(m,1H),3.98(s,3H),2.58(s,3H).
b) 2-ethoxy-5-isobutyrylamino-N- (1- (2-methoxypyridin-4-yl) ethyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (95mg,0.378mmol) was added to anhydrous DMF (10mL), EDC (145mg,0.756mmol) was added, HOBt (102mg,0.756mmol) and DIEA (0.20mL, 1.13mmol) were added, 1- (2-methoxypyridin-4-yl) ethylamine (86mg,0.57mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, column-chromatographed (D: M75: 1),
103mg of a white solid was obtained in 70.5% yield. Melting point: 94-96 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.78(s,1H),8.54(d,J＝7.6Hz,1H),8.10 (dd,J1＝5.6Hz,J2＝0.4Hz,1H),7.82(d,J＝2.8Hz,1H),7.75(dd,J1＝9.2Hz,J2＝ 2.8Hz,1H),7.07(d,J＝8.8Hz,1H),7.01(dd,J1＝5.2Hz,J2＝1.2Hz,1H),6.80-6.81 (m,1H),5.04-5.08(m,1H),4.12(q,J＝7.2Hz,2H),3.83(s,3H),2.52-2.56(m,1H), 1.42(d,J＝7.2Hz,3H),1.38(t,J＝7.2Hz,3H),1.08(d,J＝6.8Hz,6H).
Example 139
N- (1- (2-aminopyridin-4-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820001991
a)1- (2-aminopyridin-4-yl) ethanones
2-amino isonicotinic acid methyl ester (608mg,4mmol) was placed in a reaction flask, dry THF (25mL) was added, 1.3M methyllithium in diethyl ether (12.3mL,16mmol) was added dropwise to the reaction flask at-78 ℃ under argon protection, and after dropping, the reaction was continued at-78 ℃ for 1h and then the temperature was raised to 0 ℃. After reaction for 3 hours, isopropanol (6mL) was added, ethyl acetate (60mL) was added, and the mixture was washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (D: M ═ 50:1) to obtain an off-white solid 110mg with a yield of 20%. m.p.129-130 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.22(dd,J1＝5.2Hz,J2＝0.8Hz,1H),7.06(dd, J1＝5.2Hz,J2＝1.6Hz,1H),6.94-6.95(m,1H),4.69(brs,2H),2.56(s,3H).
b) N- (1- (2-aminopyridin-4-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (90mg,0.36mmol) was added to anhydrous DMF (10mL), EDC (138mg,0.72mmol) was added, HOBt (97mg,0.72mmol) and DIEA (0.19mL,1.08 mmol) were added, 4- (1-aminoethyl) pyridin-2-amine (71mg,0.52mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M35: 1, D: M: 20:1) to give 99mg of a white solid with a yield of 74.4%. m.p.82-84 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.80(s,1H),8.47(d,J＝8.0Hz,1H),7.91(d, J＝2.8Hz,1H),7.83(d,J＝5.6Hz,1H),7.78(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.08 (d,J＝8.8Hz,1H),6.51(dd,J1＝5.6Hz,J2＝1.6Hz,1H),6.39-6.40(m,1H),5.87(s, 2H),4.91-4.95(m,1H),4.13(q,J＝7.2Hz,2H),2.51-2.56(m,1H),1.35-1.41(m,6H), 1.08(d,J＝6.8Hz,6H).
Example 140
N- (1- (6-chloropyridin-2-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820002001
a) 6-chloro-N-methoxy-N-methyl picolinamide
6-chloropyridine-2-carboxylic acid (785mg,5.0mmol) was added to anhydrous DMF (40mL), HBTU (3.79g, 10.0mmol) was added, HOBt (1.35g,10.0mmol) and DIEA (5.2mL,30.0mmol) were added, N, O-dimethylhydroxylamine (972mg,10.0mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (50 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (25 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P1: 5, E: P. times.1: 4) to give 800mg of a colorless oil in 80% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.76(t,J＝8.0Hz,1H),7.58(brs,1H),7.41(dd, J1＝8.0Hz,J2＝0.8Hz,1H),3.80(s,3H),3.38(s,3H).
b)1- (6-chloropyridin-2-yl) ethanone
6-chloro-N-methoxy-N-methyl picolinamide (760mg,3.80mmol) was added to dry THF (25mL), 1M THF solution of methyl magnesium bromide (4.94mL,4.94mmol) was added dropwise to the reaction flask at 0 deg.C under argon shield, the reaction was continued at 0 deg.C with stirring, after 2h, saturated ammonium chloride solution was added to the reaction flask, extracted with EA (40 mL. times.2), the organic layers were combined, washed with saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (E: P ═ 1:15) to give 355mg of colorless oil in 60.3% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.96(dd,J1＝8.4Hz,J2＝0.8Hz,1H),7.81(t,J ＝6.8Hz,1H),7.51(dd,J1＝8.0Hz,J2＝0.8Hz,1H),2.71(s,3H).
c) N- (1- (6-chloropyridin-2-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (129mg,0.51mmol) was added to anhydrous DMF (20mL), EDC (196mg,1.02mmol) was added, HOBt (138mg,1.02mmol) and DIEA (0.27mL,1.53 mmol) were added, 1- (6-chloropyridin-2-yl) ethylamine (100mg,0.64mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M75: 1) to give 165mg of a white solid in 83.3% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):9.09(d,J＝7.2Hz,1H),8.20(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.82(d,J＝2.8Hz,1H),7.63(t,J＝8.4Hz,1H),7.41(brs,1H),7.23(d, J＝8.4Hz,2H),5.34-5.42(m,1H),4.21-4.27(m,2H),2.48-2.55(m,1H),1.55-1.62(m, 6H),1.24(dd,J1＝6.8Hz,J2＝1.2Hz,6H).
Example 141
N- (1- (2-aminopyrimidin-4-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820002011
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.398mmol) was added to anhydrous DMF (10mL), EDC (153mg,0.796mmol) was added, HOBt (107mg,0.796mmol) and DIEA (0.21mL, 1.19mmol) were added, 4- (1-aminoethyl) pyrimidin-2-amine (99mg,0.717mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography was performed (D: M ═ 35:1, D: M ═ 20:1) to obtain 100mg of a white solid with a yield of 68.9%. m.p.192-194 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.81(s,1H),8.73(d,J＝7.2Hz,1H),8.19(d, J＝5.2Hz,1H),7.97(d,J＝2.8Hz,1H),7.79(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.01(d, J＝8.8Hz,1H),6.62(d,J＝4.8Hz,1H),6.59(s,2H),4.87-4.91(m,1H),4.13-4.19(m, 2H),2.53-2.57(m,1H),1.37-1.41(m,6H),1.09(d,J＝6.8Hz,6H).
Example 142
2-ethoxy-5-isobutyrylamino-N- (1- (6-methylpyrazin-2-yl) ethyl) benzamide
Figure BDA0001620885820002012
a) N-methoxy-N, 6-dimethylpyrazine-2-carboxamide
6-methyl-pyrazine-2-carboxylic acid (414mg,3mmol) was added to anhydrous DMF (30mL), EDC (1.15g, 6mmol) was added, HOBt (810mg,6mmol) and DIEA (3.1mL,18mmol) were added, N, O-dimethylhydroxylamine (437mg,4.5mmol) was added, the reaction mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) in (40 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P. times.1: 2) to give 400mg of a white solid in 73.7% yield.1H-NMR(400MHz,CDCl3)δ(ppm):8.69(s,1H),3.74(s,3H),3.40(s,3H),2.66(s, 3H).
b)1- (6-methylpyrazin-2-yl) ethanone
N-methoxy-N, 6-dimethylpyrazine-2-carboxamide (362mg,2mmol) was added to dry THF (15mL), 1M methyl magnesium bromide in THF (2.6mL,2.6mmol) was added dropwise to a reaction flask at 0 ℃ under argon protection, after completion of the addition, the reaction was continued with stirring at 0 ℃ for 2h, then saturated ammonium chloride solution was added to the reaction flask, extracted with EA (30mL × 2), the organic layers were combined, washed with saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (E: P ═ 1:10, E: P ═ 1:6) to give a waxy solid 200mg, yield 73.5%.
1H-NMR(400MHz,CDCl3)δ(ppm):9.03(s,1H),8.62(s,1H),2.71(s,3H),2.65(s, 3H).
c) 2-ethoxy-5-isobutyrylamino-N- (1- (6-methylpyrazin-2-yl) ethyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (80mg,0.32mmol) was added to anhydrous DMF (15mL), EDC (123mg,0.64mmol) was added, HOBt (86mg,0.64mmol) and DIEA (0.17mL,0.96 mmol) were added, 1- (6-methylpyrazin-2-yl) ethylamine (66mg,0.48mmol) was added, the mixture was stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture (30mL × 2) of ethyl acetate and methanol (10: 1), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M70: 1, D: M: 40:1) to give 34mg of a white solid with a yield of 50.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.97(d,J＝7.6Hz,1H),8.43(s,1H),8.36(s, 1H),8.21(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.81(s,1H),7.36-7.43(m,1H),6.95(d,J ＝9.2Hz,1H),5.42-5.47(m,1H),4.21-4.25(m,2H),2.59(s,3H),2.48-2.55(m,1H), 1.54-1.59(m,6H),1.21(d,J＝6.8Hz,6H).
Example 143
2-ethoxy-5-isobutyrylamino-N- (1- (2-methylpyrimidin-4-yl) ethyl) benzamide
Figure BDA0001620885820002021
a) N-methoxy-N, 2-dimethylpyrimidine-4-carboxamide
2-methyl-pyrimidine-4-carboxylic acid (450mg,3.26mmol) was added to anhydrous DMF (30mL), EDC (1.25 g,6.52mmol) was added, HOBt (880mg,6.52mmol) and DIEA (3.4mL,19.6mmol) were added, N, O-dimethylhydroxylamine (475mg,4.89mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (40mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P ═ 1:2) to give 480mg of a pale yellow oil in 81.35% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.73(d,J＝4.8Hz,1H),7.29(brs,1H),3.70(s, 3H),3.35(s,3H),2.75(s,3H).
b)1- (2-methylpyrimidin-4-yl) ethanones
N-methoxy-N, 2-dimethylpyrimidine-4-carboxamide (430mg,2.37mmol) was added to dry THF (15mL), a 1M THF solution of methylmagnesium bromide (3.09mL,3.09mmol) was added dropwise to a reaction flask under argon atmosphere at 0 ℃, the reaction was continued at 0 ℃ and stirred for 2h, then a saturated ammonium chloride solution was added to the reaction flask, extracted with EA (30mL × 2), the organic layers were combined, washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (E: P ═ 1:10, E: P ═ 1:7.5) to give 200mg of colorless oil in 62.1% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.85(d,J＝5.2Hz,1H),7.67(d,J＝4.8Hz,1H), 2.82(s,3H),2.71(s,3H).
c) 2-ethoxy-5-isobutyrylamino-N- (1- (2-methylpyrimidin-4-yl) ethyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (90mg,0.36mmol) was added to anhydrous DMF (15mL), EDC (138mg,0.72mmol) was added, HOBt (97mg,0.72mmol) and DIEA (0.19mL,1.08 mmol) were added, 1- (2-methylpyrimidin-4-yl) ethylamine (66mg,0.48mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixed solution (30mL × 2) of ethyl acetate: methanol ═ 10:1, the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M ═ 60:1, D: M ═ 40:1, D: M ═ 30:1) to give 36mg of a white solid in 27% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):9.01(d,J＝7.6Hz,1H),8.58(d,J＝3.6Hz,1H), 8.21(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.81(d,J＝2.8Hz,1H),7.35(s,1H),7.18(d,J ＝5.2Hz,1H),6.97(d,J＝8.8Hz,1H),5.28-5.32(m,1H),4.25(q,J＝7.2Hz,2H), 2.75(s,3H),2.47-2.54(m,1H),1.54-1.60(m,6H),1.24(dd,J1＝6.8Hz,J2＝0.8Hz, 6H).
Example 144
2-ethoxy-5-isobutyrylamino-N- (1- (5-methylthiophen-2-yl) ethyl) benzamide
Figure BDA0001620885820002031
2-ethoxy-5-isobutyrylaminobenzoic acid (90mg,0.358mmol) was added to anhydrous DMF (10mL), EDC (137mg,0.716mmol) was added, HOBt (97mg,0.716mmol) and DIEA (0.19mL,1.074 mmol) were added, 1- (5-methylthiophen-2-yl) ethylamine (60mg,0.425mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (20 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M. times.150: 1) to give 20mg of a white solid in 16.8% yield. Melting point: 101-103 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.45(d,J＝6.8Hz,1H),8.26(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.87(d,J＝2.0,1H),7.59(s,1H),6.91(d,J＝8.8Hz,1H),6.79(d,J＝ 3.2Hz,1H),6.59(s,1H),5.46-5.53(m,1H),4.10-4.17(m,2H),2.48-2.56(m,1H), 2.44(s,3H),1.62(d,J＝6.8Hz,3H),1.41(t,J＝7.2Hz,3H),1.23(d,J＝6.8Hz,6H).
Example 145
N- (1- (2-aminothiazol-4-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820002041
a)1- (2-aminothiazol-5-yl) ethanones
Thiourea (760mg,10mmol) was added to DCM (20mL) and DMF-DMA (3.5mL,26 mmol) was added and the reaction heated to reflux, after 4h the reaction was stopped, concentrated to dryness and recrystallized from DCM and diethyl ether to give 800mg of a pale yellow solid. THF (20mL) was added to the above solid (580mg,3.12mmol), chloroacetone (0.5mL,6.24mmol) was added, stirring was carried out at 20 ℃ for 30min, triethylamine (0.84mL,6.24mmol) was added, the temperature was raised to 55 ℃ and the reaction was carried out for 5h, then an aqueous methylamine solution (2.9mL) was added, and after reaction at room temperature for 1h, DCM (30mL) was added, dried over anhydrous magnesium sulfate, and column chromatography (D: M: 50:1) was carried out to obtain 290mg of an earth-yellow solid with a yield of 65.4%.
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.99(s,2H),7.91(s,1H),2.34(s,3H).
b) N- (1- (2-aminothiazol-4-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.398mmol) was added to anhydrous DMF (10mL), EDC (153mg,0.796mmol) was added, HOBt (107mg,0.796mmol) and DIEA (0.21mL, 1.19mmol) were added, 5- (1-aminoethyl) thiazol-2-amine (114mg,0.796mmol) was added, stirring was carried out overnight at room temperature, the reaction mixture was poured into water, extraction was carried out with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (E: P: 1:2.5) gave 90mg of a white solid in 60.4% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.40(d,J＝7.6Hz,1H),8.18(dd,J1＝8.4Hz,J2＝2.4Hz,1H),7.86-7.89(m,2H),6.94(s,1H),6.90(d,J＝8.8Hz,1H),5.30-5.41(m, 1H),4.10-4.16(m,2H),2.51-2.58(m,1H),1.60(d,J＝6.8Hz,3H),1.43(t,J＝7.2Hz, 3H),1.22(d,J＝6.8Hz,6H).
Example 146
2-ethoxy-5-isobutyrylamino-N- (1- (2-methylthiooxazol-4-yl) ethyl) benzamide
Figure BDA0001620885820002051
a)1- (2-methylthio-oxazol-5-yl) ethanone
Thioacetamide (751mg,10mmol) is added into DCM (20mL), DMF-DMA (2.7mL,20mmol) is added for heating reflux reaction, the reaction is stopped after 4h, concentration is carried out till dryness, THF (30mL) is added into the solid (1.3g,10mmol), chloropropone (1.6mL,20mmol) is added, stirring is carried out for 30min at 20 ℃, triethylamine (2.7mL,20mmol) is added, reaction is carried out for 5h after warming to 55 ℃, aqueous methylamine solution (10mL) is added after stirring for 1h at room temperature, DCM (30mL) is added, anhydrous magnesium sulfate is dried, and column chromatography (D: M ═ 50:1) is carried out to obtain 150mg of earthy yellow solid with the yield of 10.6%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.17(s,1H),2.76(s,3H),2.57(s,3H).
b) 2-ethoxy-5-isobutyrylamino-N- (1- (2-methylthiooxazol-4-yl) ethyl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (45mg,0.18mmol) was added to anhydrous DMF (10mL), EDC (69mg,0.36mmol) was added, HOBt (49mg,0.36mmol) and DIEA (0.095mL,0.54 mmol) were added, 1- (2-methylthiooxazol-5-yl) ethylamine (30mg,0.21mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30mL × 2), the combined organic layers were washed with a saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (D: M ═ 60:1, D: M ═ 50:1) to give 34mg of a white solid with a yield of 50.7%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.44(d,J＝8.0Hz,1H),8.20(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.51(s,1H),7.36(s,1H),6.92(d,J＝9.2Hz,1H),5.52-5.59(m,1H), 4.15(q,J＝7.2Hz,2H),2.67(s,3H),2.47-2.55(m,1H),1.65(d,J＝6.8Hz,3H),1.43 (t,J＝7.2Hz,3H),1.24(d,J＝7.2Hz,6H).
Example 147
N- (1- (benzo [ d ] [1,3] dioxazol-5-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820002061
2-ethoxy-5-isobutyrylaminobenzoic acid (120mg,0.478mmol) was added to anhydrous DMF (15mL), EDC (184mg,0.956mmol) was added, HOBt (129mg,0.956mmol) and DIEA (0.25mL, 1.434mmol) were added, 1- (benzo [ D ] [1,3] dioxazol-5-yl) ethylamine (126mg,0.765mmol) was added, stirred overnight at room temperature, the reaction solution was poured into water, extracted with a mixed solution of ethyl acetate: methanol ═ 10:1 (40mL × 2), the combined organic layers were washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography was performed (E: P ═ 1:2, D: M ═ 70:1) to give 150mg of a white solid, yield 78.9%. Melting point: 72-74 deg.C
1H-NMR(500MHz,CDCl3)δ(ppm):8.41(d,J＝6.5Hz,1H),8.21(d,J＝6.5,1H), 7.81(s,1H),7.41-7.46(m,1H),6.92(d,J＝8.5Hz,1H),6.84-6.86(m,2H),6.77(d,J＝ 8.0Hz,1H),5.94(s,2H),5.19-5.22(m,1H),4.12-4.18(m,2H),2.48-2.52(m,1H), 1.54(d,J＝7.0Hz,3H),1.43(t,J＝6.5Hz,3H),1.22(d,J＝6.5Hz,6H).
Example 148
N- (1- (2-aminobenzo [ d ] thiazol-5-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820002062
a)1- (2-aminobenzo [ d ] thiazol-6-yl) ethanones
4-Aminoacetophenone (946mg,7mmol) was added to acetic acid (12mL), stirred at room temperature until the compound was completely dissolved, and 1M Br was added2The acetic acid solution is added into a reaction bottle at room temperature, the reaction is stirred at room temperature after the acetic acid solution is added, the reaction solution is poured into ice water, the pH value is adjusted to be about 9 by ammonia water, the filtration is carried out, a filter cake is dissolved in a mixed solution of DCM and methanol, anhydrous magnesium sulfate is dried, and column chromatography is carried out (D: M is 70:1, D: M is 60:1, D: M is 50:1), so that 330mg of light yellow solid is obtained, and the yield is 24.5%.
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.32(d,J＝1.6Hz,1H),7.91(brs,2H),7.83 (dd,J1＝8.4Hz,J2＝1.6Hz,1H),7.37(d,J＝8.4Hz,1H),2.55(s,3H).
b) N- (1- (2-aminobenzo [ d ] thiazol-5-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (10mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 5- (1-aminoethyl) benzo [ D ] thiazol-2-amine (150mg,0.78mmol) was added, the mixture was stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M: 30:1, D: M: 25:1) to give 165mg of a white solid in 88.2% yield. Melting point: 135 ℃ 137 ℃
1H-NMR(400MHz,CDCl3)δ(ppm):8.51(d,J＝6.8Hz,1H),8.17(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.85(s,1H),7.78(s,1H),7.56(s,1H),7.45(d,J＝8.0Hz,1H), 7.27-7.30(m,1H),6.90(d,J＝9.2Hz,2H),5.74(brs,2H),5.29-5.33(m,1H), 4.10-4.15(m,2H),2.49-2.53(m,1H),1.58(d,J＝6.8Hz,3H),1.41(t,J＝6.8Hz,3H), 1.19(dd,J1＝6.8Hz,J2＝2.8Hz,6H).
Example 149
N- (1- (2-amino-1H-benzo [ d ] imidazol-5-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide
Figure BDA0001620885820002071
a) N- (4-acetyl-2-nitrophenyl) acetamide
4-aminoacetophenone (1.35g,10mmol) was put in a reaction flask, DCM (50mL) was added, bismuth nitrate pentahydrate (4.85g,10mmol) was added under stirring at room temperature, acetic anhydride (5.64mL,60mmol) was added dropwise to the reaction flask, the reaction was stopped at room temperature with stirring the next day, the reaction solution was poured into saturated NaHCO3 solution, extracted with ethyl acetate (30mL × 2), washed with saturated NaCl solution (15mL × 2), dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography (E: P ═ 1:5, E: P ═ 1:3) to obtain 1.59g of pale yellow solid with a yield of 71.6%. m.p.140-142 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):10.55(s,1H),8.94(d,J＝8.8Hz,1H),8.81(d,J ＝2.0Hz,1H),8.21(dd,J1＝8.8Hz,J2＝2.0Hz,1H),2.64(s,3H),2.34(s,3H).
b)1- (4-amino-3-nitrophenyl) ethanone
Placing N- (4-acetyl-2-nitrophenyl) acetamide (1.46g,6.57mmol) in a reaction flask, adding 6N HCl (20mL,120mmol), heating and refluxing for reaction, stopping the reaction after 2h, cooling, adjusting the pH value to about 8 by using NaOH solution, performing suction filtration, and washing a filter cake to obtain 1.1g of yellow solid with the yield of 93.2%. m.p.148-150 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.73(d,J＝2.0Hz,1H),7.98(dd,J1＝8.8Hz,J2＝2.0Hz,1H),6.85(d,J＝8.8Hz,1H),6.52(brs,2H),2.56(s,3H).
c)1- (3, 4-diaminophenyl) ethanones
1- (4-amino-3-nitrophenyl) ethanone (300mg) was placed in a reaction flask, methanol (10mL) was added, Raney Ni was added, hydrogenation reaction was stopped after 4 hours at normal temperature and pressure, filtration was performed, concentration was performed, and column chromatography (D: M: 80:1, D: M: 70:1) was performed to obtain 227mg of an off-white solid with a yield of 91.1%. m.p.129-131 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.10-7.14(m,2H),6.49-6.52(m,1H),5.36 (brs,2H),4.63(brs,2H),2.35(s,3H).
d)1- (2-amino-1H-benzo [ d ] imidazol-5-yl) ethanone
Placing 1- (3, 4-diaminophenyl) ethanone (150mg,1mmol) into a reaction bottle, adding HFIP (6mL), adding BrCN (157mg,1.5mmol), stirring at room temperature for reaction, adding H2O (1.5mL) after 3 days to continue stirring at room temperature for reaction, stopping reaction the next day, adding DCM (30mL), drying with anhydrous magnesium sulfate, concentrating, and performing column chromatography (D: M: 35:1, D: M: 15:1) to obtain 150mg of an earthy yellow solid with the yield of 85.7%. Discoloration at m.p. 210 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):12.46(brs,1H),8.30(s,2H),7.82-7.85(m, 2H),7.40(d,J＝8.4Hz,1H),2.59(s,3H).
e) N- (1- (2-amino-1H-benzo [ D ] imidazol-5-yl) ethyl) -2-ethoxy-5-isobutyrylaminobenzamide 2-ethoxy-5-isobutanoylaminobenzoic acid (55mg,0.22mmol) was added to anhydrous DMF (10mL), EDC (85mg,0.44mmol) was added, HOBt (59mg,0.44mmol) and DIEA (0.12mL,0.66 mmol) were added, 5- (1-aminoethyl) -1H-benzo [ D ] imidazol-2-amine (77mg,0.44mmol) was added, stirring was carried out at room temperature overnight, the reaction solution was poured into water, extraction was carried out with a mixture of dichloromethane: methanol 10:1 (20mL × 5), the organic layers were combined, dried over anhydrous magnesium sulfate, concentrated, column chromatography was carried out (D: M: 20:1, d: M ammonia: 15:1:0.125) to give 35mg of off-white solid in 38.9% yield. m.p. >250 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):10.67(s,1H),9.82(s,1H),8.49(d,J＝7.6 Hz,1H),7.94(s,1H),7.79(d,J＝8.8Hz,1H),7.13(s,1H),7.05(t,J＝8.0Hz,2H), 6.90(d,J＝8.0Hz,1H),6.12(brs,2H),5.08-5.13(m,1H),4.06-4.14(m,2H), 2.54-2.56(m,1H),1.47(d,J＝6.4Hz,3H),1.32(t,J＝6.8Hz,3H),1.08(d,J＝6.8Hz, 6H).
Example 150
2-ethoxy-5-isobutyrylamino-N- (1- (2-methyl-1H-benzo [ d ] imidazol-5-yl) ethyl) benzamide
Figure BDA0001620885820002081
a)1- (2-methyl-1H-benzo [ d ] imidazol-5-yl) ethanone
1- (3, 4-diaminophenyl) ethanone (180mg,1.2mmol) was placed in a reaction flask, DMF (6mL) was added, triethyl orthoacetate (2.3mL,12mmol) concentrated HCl (0.3mL,3.6mmol) was added and the reaction was stirred at room temperature for 4h, after which the reaction was stopped, water was added, extraction was performed with a mixed solution of ethyl acetate and methanol (10: 1) (30mL × 4), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (D: M: 40:1, D: M: 30:1) gave 135mg of an off-white solid in 64.6% yield. m.p.191-193 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):12.53(s,1H),8.09(s,1H),7.77(dd,J1＝8.4 Hz,J1＝1.6Hz,1H),7.52(d,J＝8.0Hz,1H),2.61(s,3H),2.53(s,3H).
b) 2-ethoxy-5-isobutyrylamino-N- (1- (2-methyl-1H-benzo [ d ] imidazol-5-yl) ethyl) benzamide 2-ethoxy-5-isobutyraminobenzoic acid (60mg,0.24mmol) was added to anhydrous DMF (10mL), EDC (92mg,0.48mmol) was added, HOBt (65mg,0.48mmol) and DIEA (0.13mL,0.72 mmol) were added, 1- (2-methyl-1H-benzo [ d ] imidazol-5-yl) ethylamine (84mg,0.48mmol) was added, stirring was carried out overnight at room temperature, the reaction solution was poured into water, extraction was carried out with a mixture of ethyl acetate: methanol 10:1 (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentration and column chromatography (D: M25: 1, D: M20: 1) gave 50mg of a white solid in 51% yield. m.p.203-205 deg.C
1H-NMR(400MHz,DMSO-d6)δ(ppm):12.17(s,1H),9.80(s,1H),8.53(d,J＝7.6 Hz,1H),7.92(d,J＝2.4Hz,1H),7.78(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.39-7.47(m, 2H),7.16(d,J＝8.4Hz,1H),7.07(d,J＝9.2Hz,1H),5.17-5.24(m,1H),4.07-4.14(m, 2H),2.52-2.56(m,1H),2.47(s,3H),1.50(d,J＝6.8Hz,3H),1.33(t,J＝7.2Hz,3H), 1.08(d,J＝6.8Hz,6H).
Example 151
5-isobutyrylamino-2-propyl-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820002091
a) 2-propyl-5-nitrobenzoic acid methyl ester
A solution of ZnCl2 in diethyl ether (1.36g,10.00mmol), a solution of propylmagnesium bromide in THF (1.47g,10.00mmol) was added to the flask in succession under Ar gas, and the reaction was stirred at room temperature for 2 h. Then methyl 2-bromo-5-nitrobenzoate (1.04g,4.00mmol) and PdCl were sequentially added2(dppf) (292mg,0.40mmol) and LiCl (336mg,8.00mmol) were added to the above reaction system, the temperature was raised to 55 ℃ under the protection of argon to react for 24 hours, saturated NH4Cl (20mL) was added, EA (30mL) was extracted, the organic phase was washed with saturated brine (20mL), anhydrous Na was added2SO4Drying, and purifying by column chromatography (petroleum ether-ethyl acetate, volume ratio 50:1) to obtain colorless oil 362mg, with yield of 40.1%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.73(d,J＝2.4Hz,1H),8.25(dd,J＝8.4,2.4Hz, 1H),7.43(d,J＝8.4Hz,1H),3.95(s,3H),3.04(t,J＝7.6Hz,2H),1.65(sext,J＝7.6 Hz,2H),0.99(t,J＝7.2Hz,3H).
b) 2-propyl-5-nitrobenzoic acid
Methyl 2-propyl-5-nitrobenzoate (450mg,2.02mmol) was dissolved in methanol (15 mL)/water (8mL), NaOH (404mg,10.10mmol) was added with stirring, the reaction was carried out at room temperature for 8 hours, the mixture was concentrated, water (5mL) was added, the aqueous layer was washed with diethyl ether (20mL), the pH of the aqueous layer was adjusted to 3 with hydrochloric acid, a white solid was precipitated, and the product was filtered to obtain 378mg, yield 89.6%, melting point: 115 ℃ and 117 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):13.58(s,1H),8.51(s,1H),8.29(dd,J＝8.4,2.4 Hz,1H),7.61(d,J＝8.4Hz,1H),3.01(t,J＝7.6Hz,2H),1.65(sext,J＝7.6Hz,2H), 0.91(t,J＝7.2Hz,3H)；ESI-MS m/z:208.06[M-H]-。
c) 5-nitro-2-propyl-N- (3- (thiazol-2-yl) benzyl) benzamide
Dissolving 2-propyl-5-nitrobenzoic acid (200mg,0.96mmol) in DCM (15mL), sequentially adding DIEA (248mg,1.92mmol) and HATU (475mg,1.25mmol), reacting at room temperature for 30min, adding (3- (thiazol-2-yl) phenyl) methylamine (182mg,0.96mmol), reacting at room temperature for 10h under the protection of argon, and allowing the raw materials to disappear. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (petroleum ether-ethyl acetate, vol 4:1) to obtain 210mg of white solid, yield 57.7%, melting point: 135-137 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.23(d,J＝1.6Hz,1H),8.18(d,J＝8.4Hz,1H), 8.00(s,1H),7.89-7.87(m,2H),7.46(d,J＝4.8Hz,2H),7.41(d,J＝8.4Hz,1H),7.36 (d,J＝2.8Hz,1H),6.29(s,1H),4.71(d,J＝5.6Hz,2H),2.86(t,J＝7.6Hz,2H),1.65 (sext,J＝7.6Hz,2H),0.92(t,J＝7.2Hz,3H)；ESI-MS m/z:382.12[M+H]+。
d) 5-amino-2-propyl-N- (3- (thiazol-2-yl) benzyl) benzamide
5-Nitro-2-propyl-N- (3- (thiazol-2-yl) benzyl) benzamide (180mg,0.47mmol) was dissolved in THF (20mL), pd/C (90mg) was added, hydrogen was bubbled in, stirred overnight at room temperature, filtered, concentrated to give 153mg of colorless oil in 92.7% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.96(s,1H),7.88-7.86(m,2H),7.44(d,J＝4.8 Hz,2H),7.34(d,J＝3.2Hz,1H),7.04-6.96(m,1H),6.70(d,J＝2.4Hz,1H),6.66(dd, J＝8.0,2.4Hz,1H),6.12(brs,1H),4.66(d,J＝6.0Hz,2H),3.44(s,2H),2.63(t,J＝ 7.6Hz,2H),1.65(sext,J＝7.6Hz,2H),0.87(t,J＝7.2Hz,3H)；ESI-MS m/z:352.15 [M+H]+。
e) 5-isobutyramido-2-propyl-N- (3- (thiazol-2-yl) benzyl) benzamide
Dissolving 5-amino-2-propyl-N- (3- (thiazol-2-yl) benzyl) benzamide (140mg,0.40mmol) in anhydrous THF (15mL), sequentially adding TEA (121mg,1.20mmol) and isobutyryl chloride (85mg, 0.80mmol) in ice bath, continuing to react for 1h, filtering, concentrating the filtrate, adding ethyl acetate (30mL) for dilution, washing with saturated ammonium chloride solution (20mL), and washing with saturated NaHCO 3Washing with (20mL), washing with water (20mL), washing with saturated brine (20mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) to obtain 91mg of white solid, yield 54.2%, melting point: 162 ℃ and 163 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):7.95(s,1H),7.84(d,J＝3.2Hz,2H),7.56(s, 2H),7.48(d,J＝8.0Hz,1H),7.41(brs,2H),7.34(d,J＝3.2Hz,1H),7.14(d,J＝8.4 Hz,1H),6.42(brs,1H),4.63(d,J＝6.0Hz,2H),2.70(t,J＝7.6Hz,2H),2.53-2.46(m, 1H),1.65(sext,J＝7.6Hz,2H),1.21(d,J＝6.8Hz,6H),0.87(t,J＝7.2Hz,3H)； HR-MS(ESI):m/z,calcd.For C24H27O2N3S 422.1897[M+H]+,Found:422.1884。
Example 152
2-cyclopropyl-5-isobutyrylamino-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820002111
a) 2-cyclopropyl-5-nitrobenzoic acid
Methyl 2-bromo-5-nitrobenzoate (500mg,1.90mmol), PdCl2(dppf) (280mg,0.38mmol), Na2CO3(600mg,5.70mmol), cyclopropylboronThe acid (330mg,3.80mmol) was added to dioxane (16 mL)/water (4mL) in sequence and reacted at 100 ℃ for 15h under argon. Filtration, concentration, dilution with water (10mL), washing with diethyl ether (10mL × 2), concentration of the aqueous phase, pH adjustment to 3, precipitation of a grey solid, purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:4) to 147mg of a white solid, 36.9%, melting point: 144 ℃ and 145 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.86(d,J＝2.0Hz,1H),8.29(dd,J＝8.8,2.0Hz, 1H),7.14(d,J＝8.8Hz,1H),3.08-2.94(m,1H),1.28-1.23(m,2H),0.91-0.87(m,2H)； ESI-MS m/z:206.05[M-H]-。
b) 2-cyclopropyl-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide
Reaction 1: 2-cyclopropyl-5-nitrobenzoic acid (50mg,0.24mmol) was dissolved in DCM (10mL), DIEA (62mg,0.48mmol), HATU (118mg,0.31mmol) were added in that order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (46mg,0.24mmol) was added and reaction at room temperature for 8h, the starting material disappeared. Reaction 2: 2-cyclopropyl-5-nitrobenzoic acid (70mg,0.34mmol) was dissolved in DCM (15mL), DIEA (88mg,0.68mmol), HATU (167mg,0.44mmol) were added in that order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (65mg,0.34mmol) was added and reaction at room temperature for 8h, the starting material disappeared. Reactions 1 and 2 were combined, diluted with DCM (20mL), washed with HCl (0.5N) (20mL), and saturated NaHCO 3Washing (20mL), washing with water (20mL), washing with saturated saline (20mL), and washing with anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:3) gave 158mg of white solid, yield 71.8%, melting point: 168-169 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.28(d,J＝2.0Hz,1H),8.15(d,J＝8.8Hz,1H), 8.01(s,1H),7.88(brs,2H),7.46(d,J＝4.4Hz,2H),7.36(d,J＝3.2Hz,1H),7.02(d,J ＝8.8Hz,1H),6.35(s,1H),4.75(d,J＝5.6Hz,2H),2.38(brs,1H),1.15(q,J＝6.4Hz, 2H),0.84(q,J＝5.2Hz,2H)；ESI-MS m/z:380.11[M+H]+。
c) 2-cyclopropyl-5-amino-N- (3- (thiazol-2-yl) benzyl) benzamide
2-cyclopropyl-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide (120mg,0.32mmol) was dissolved in THF (15mL), Pd/C60 mg was added, hydrogen was bubbled in at room temperature, reaction was overnight, filtration was performed, filtrate was concentrated to obtain 106mg of colorless oil with a yield of 95.5%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.97(s,1H),7.88-7.86(m,2H),7.43(brs,2H), 7.34(d,J＝3.2Hz,1H),6.86(d,J＝2.4Hz,1H),6.80(d,J＝8.4Hz,1H),6.64(dd,J＝ 8.4,2.4Hz,1H),6.49(s,1H),4.70(d,J＝5.6Hz,2H),2.11-2.05(m,1H),0.85-0.81(m, 2H),0.62-0.59(m,2H)；ESI-MS m/z:350.13[M+H]+。
d) 2-cyclopropyl-5-isobutyrylamino-N- (3- (thiazol-2-yl) benzyl) benzamide
Dissolving 2-cyclopropyl-5-amino-N- (3- (thiazol-2-yl) benzyl) benzamide (100mg,0.29mmol) in anhydrous THF (10mL), sequentially adding TEA (117mg,1.16mmol) and isobutyryl chloride (61mg, 0.58mmol) in ice bath, continuing to react for 1h, filtering, concentrating the filtrate, adding ethyl acetate (20mL) for dilution, washing with aqueous HCl (0.5N) (10mL), and washing with saturated NaHCO (NaHCO) (0.5N)3Washing with (10mL), washing with water (10mL), washing with saturated brine (10mL), and washing with anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 97mg of white solid, yield 69.3%, melting point: 167-168 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):7.97(s,1H),7.85(brs,2H),7.57(brs,2H),7.47 (s,H),7.43-7.40(m,2H),7.34(d,J＝3.2Hz,1H),6.90(d,J＝8.4Hz,1H),6.60(s,1H), 4.69(d,J＝5.6Hz,2H),2.52-2.47(m,1H),2.22-2.17(m,1H),1.22(d,J＝6.8Hz,6H), 0.94-0.85(m,2H),0.66(q,J＝4.8Hz,2H)；HR-MS(ESI):m/z,calcd.For C24H25O2N3S 420.1740[M+H]+,Found:420.1734。
Example 153
2-methoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820002131
a) 2-methoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-methoxy-5-nitrobenzoic acid (177mg, 0.90mmol) was dissolved in DCM (15mL), HATU (616mg, 1.62mmol), DIEA (418mg, 3.24mmol) were added, reaction was carried out at room temperature for 30min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (690mg, 3.38mmol) was added, and reaction was carried out overnight at room temperature. 0.5N HCl (15 mL. times.2) and water (20 mL. times.2) were washed, and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1) gave 285mg of white solid in 83% yield. Melting point: 143 ℃ and 145 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):9.06(d,J＝2.5Hz,1H),8.32(dd,J1＝2.5Hz,J2＝9.0Hz 1H),8.08(s,1H),8.00(d,J＝6.5Hz,1H),8.00(d,J＝6.5Hz,1H),7.87(d,J ＝2.5Hz,1H),7.83(d,J＝9.0Hz,1H),7.43-7.46(m,2H),7.35(d,J＝3.0Hz,1H), 7.08(d,J＝9.5Hz,1H),5.37-5.43(m,1H),4.11(s,3H),3.31(d,J＝7.0Hz,3H).
b) 2-methoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-methoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (250mg, 0.65mmol) was dissolved in THF (15mL), H2Reaction at 50 ℃ overnight. The raw material disappeared. Filtration, concentration and column chromatography (P: E ═ 1:1-1:2) gave 203mg of yellow oil in 88% yield.
1H NMR(400MHZ,CDCl3)δ(ppm):8.58(d,J＝7.6Hz,1H),7.96(d,J＝2.0Hz, 1H),7.80-7.84(m,1H),7.79(d,J＝3.2Hz,1H),7.45-7.50(m,2H),7.05(d,J＝2.8Hz, 1H),6.85(d,J＝7.6Hz,1H),6.66(dd,J1＝3.2Hz,J2＝8.8Hz,1H),5.15-5.22(m,1H), 3.92(t,J＝6.4Hz,2H),1.64-1.73(m,2H),1.49(d,J＝6.8Hz,3H),0.88(t,J＝7.2 Hz,3H).
c) 2-methoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-methoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (150mg, 0.27mmol) was dissolved in THF (3mL), TEA (129mg, 1.27mmol) was added in ice bath, isobutyryl chloride (45mg, 0.51mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 2 h. Washed with distilled water (5 mL. times.2), washed with saturated NaCl (15 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 1) gave 125mg of white solid in 70% yield. Melting point: 140 ℃ and 142 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.32(d,J＝7.0Hz,1H),8.22(d,J＝10.5Hz, 1H),8.03(s,1H),7.81-7.87(m,3H),7.39-7.45(m,3H),7.34(d,J＝3.0Hz,1H),6.96(d, J＝9.0Hz,1H),5.36-5.40(m,1H),3.97(s,3H),2.47-2.52(m,1H),1.63(d,J＝7.0Hz, 3H),1.22(d,J＝7.0Hz,6H).
Example 154
2-propoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820002141
a) 2-propoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-methoxy-5-nitrobenzoic acid (307mg, 1.36mmol) was dissolved in DCM (20mL), HATU (776mg, 2.04mmol) and DIEA (527mg, 4.08mmol) were added and reacted at room temperature for 30min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (335mg, 1.64mmol) was added and reacted at room temperature overnight. 0.5N HCl (15mL), water (20mL) and anhydrous magnesium sulfate. Column chromatography (P: E ═ 3:1) afforded 477mg of a white solid in 85% yield. Melting point: 65-66 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):9.09(d,J＝2.5Hz,1H),8.29(dd,J1＝2.5Hz, J2＝9.0Hz 1H),8.17(d,J＝6.5Hz,1H),8.03(s,1H)7.85-7.87(m,2H),7.42-7.47(m, 2H),7.35(d,J＝3.0Hz,1H),7.04(d,J＝9.0Hz,1H),5.36-5.41(m,1H),4.14-4.21(m, 2H),1.84-1.91(m,2H),1.66(d,J＝7.0Hz,3H),0.99(t,J＝7.5Hz,3H).
b) 2-propoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-methoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (200mg, 0.48mmol) was dissolved in THF (10mL), H2Reaction at 50 ℃ overnight. The raw material disappeared. Filtration, concentration and column chromatography (P: E ═ 1:1) gave 92mg of reddish solid in 50% yield. Melting point: 140 ℃ and 141 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.58(d,J＝7.6Hz,1H),7.96(d,J＝2.0Hz, 1H),7.80-7.84(m,1H),7.79(d,J＝3.2Hz,1H),7.45-7.50(m,2H),7.05(d,J＝2.8Hz, 1H),6.85(d,J＝7.6Hz,1H),6.66(dd,J1＝3.2Hz,J2＝8.8Hz 1H),5.15-5.22(m,1H), 3.92(t,J＝6.4Hz,2H),1.64-1.73(m,2H),1.49(d,J＝6.8Hz,3H),0.88(t,J＝7.2 Hz,3H).
c) 2-propoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-propoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (60mg, 0.15mmol) was dissolved in THF (6mL), TEA (48mg, 0.47mmol) was added in ice bath, isobutyryl chloride (20mg, 0.19mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (10 mL. times.2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 1) gave 50mg of white solid in 75% yield. Melting point: 142 ℃ and 143 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.51(d,J＝6.8Hz,1H),8.20(dd,J1＝2.8Hz, J2＝9.2Hz 1H),8.01(s,1H),7.82-7.87(m,3H),7.40-7.46(m,2H),7.34(d,J＝3.2Hz, 1H),6.93(d,J＝9.2Hz,1H),5.34-5.41(m,1H),4.06(t,J＝6.4Hz,2H),2.46-2.53(m, 1H),1.76-1.84(m,2H),1.63(d,J＝7.2Hz,3H),1.22(d,J＝6.8Hz,6H),0.96(t,J＝ 6.4Hz,3H).
Example 155
2-isopropoxy-5-isobutyramido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820002151
a) 2-isopropoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Isopropoxy-5-nitrobenzoic acid (250mg, 1.11mmol) was dissolved in DCM (20mL), HATU (633mg, 1.66mmol) and DIEA (430mg, 3.33mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (272mg, 1.33mmol) was added and reacted at room temperature overnight. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 3:1) gave 387mg of an off-white solid in 85% yield. Melting point: 99-101 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):9.10(d,J＝2.8Hz,1H),8.29(dd,J1＝2.8Hz,J2＝9.2Hz,1H),8.13(d,J＝7.2Hz,1H),8.03(t,J＝1.6Hz,1H),7.84-7.87(m,2H), 7.45(t,J＝1.6Hz,1H),7.35(d,J＝3.2Hz,1H),7.03(d,J＝9.2Hz,1H),3.97(d,J＝ 6.4Hz,2H),2.09-2.19(m,1H),1.66(d,J＝7.2Hz,3H),1.01(d,J＝9.8Hz,3H),0.95 (d,J＝9.8Hz,3H).
b) 2-isopropoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Isopropoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (200mg, 0.47mmol) was dissolved in DCM (2mL)/EtOH (8mL)/H2O (1mL), Fe powder (163mg, 2.92mmol), NH4Cl (26mg, 0.49mmol), reflux reaction at 70 ℃ for 3 h. The raw material disappeared. Filtering, concentrating, adding EA (15mL), diluting, washing with water (15 mL. times.2), drying over anhydrous magnesium sulfate, concentrating, and performing column chromatography (P: E ═ 1:1) to obtain white solid 155mg with a yield of 84%. Melting point: 134 ℃ and 136 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.68(d,J＝7.2Hz,1H),7.96(s,1H),7.92(d, J＝3.2Hz,1H),7.83(d,J＝6.0Hz,1H),7.80(d,J＝3.2Hz,1H),7.48(d,J＝6.0Hz, 2H),7.04(d,J＝8.8Hz,1H),6.66(dd,J1＝2.8Hz,J2＝8.8Hz,1H),5.13-5.18(m,1H), 4.89(s,2H),4.47-4.53(m,1H),1.50(d,J＝2.8Hz,3H),1.20(q,J＝6.0Hz,6H).
c) 2-isopropoxy-5-isobutyramido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Isopropoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (100mg, 0.26mmol) was dissolved in THF (7mL), TEA (80mg, 0.79mmol) was added in ice bath, isobutyryl chloride (34mg, 0.32mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. Concentration, dilution with EA (15mL), washing with distilled water (15 mL. times.2), drying over anhydrous magnesium sulfate, concentration, and addition of petroleum ether gave 99mg of a white solid with a yield of 84%. Melting point: 149 ℃ and 151 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.62(d,J＝6.8Hz,1H),8.20(dd,J1＝2.4Hz,J2＝8.8Hz,1H),8.01(s,1H),7.86(d,J＝2.4Hz,1H),7.83(d,J＝9.2Hz,1H),7.43(d,J ＝7.2Hz,2H),7.33(d,J＝3.2Hz,1H),6.95(d,J＝9.2Hz,1H),5.32-5.39(m,1H), 4.67-4.73(m,1H),2.46-2.53(m,1H),1.63(d,J＝6.8Hz,3H),1.34(q,J＝6.0Hz,6H), 1.21(d,J＝6.4Hz,6H).
Example 156
2-isobutoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820002161
a) 2-isobutoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-isobutoxy-5-nitrobenzoic acid (300mg, 1.25mmol) was dissolved in DCM (20mL), HATU (713mg, 1.88mmol) and DIEA (485mg, 3.75mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (282mg, 1.38mmol) was added and reacted at room temperature overnight. Concentrated, diluted with EA (20mL), washed with water (20mL) and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 5:1) afforded 470mg of pale yellow solid in 88% yield.
1H NMR(400MHZ,CDCl3)δ(ppm):9.10(d,J＝2.8Hz,1H),8.29(dd,J1＝2.8Hz,J2＝9.2Hz,1H),8.13(d,J＝7.2Hz,1H),8.03(t,J＝1.6Hz,1H),7.84-7.87(m,2H), 7.45(t,J＝1.6Hz,1H),7.35(d,J＝3.2Hz,1H),7.03(d,J＝9.2Hz,1H),3.97(d,J＝ 6.4Hz,2H),2.09-2.19(m,1H),1.66(d,J＝7.2Hz,3H),1.01(d,J＝9.8Hz,3H),0.95 (d,J＝9.8Hz,3H).
b) 2-isopropoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-isobutoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (300mg, 0.52mmol) was dissolved in DCM (2mL)/EtOH (8mL)/H2O (1mL), Fe powder (236mg, 4.23mmol), NH4Cl (38mg, 0.71mmol), reflux reaction at 70 ℃ for 2 h. The raw material disappeared. Filtered, concentrated, diluted with EA (20mL), washed with water (15 mL. times.2), dried over anhydrous magnesium sulfate,after concentration, petroleum ether was added to precipitate 240mg of a white solid in 86% yield. Melting point: 118 ℃ and 120 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.55(d,J＝7.6Hz,1H),7.97(s,1H),7.92(d, J＝3.2Hz,1H),7.81-7.83(m,1H),7.79(d,J＝9.6Hz,1H),7.48(d,J＝2.4Hz,1H), 7.06(d,J＝2.8Hz,1H),6.84(d,J＝8.4Hz,1H),5.18-5.21(m,1H),4.83(s,2H),3.74 (d,J＝6.4Hz,2H),1.94-2.01(m,1H),1.50(d,J＝7.2Hz,3H),0.90(d,J＝6.4Hz, 3H),0.87(d,J＝6.4Hz,3H).
c) 2-isobutoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-isobutoxy-5-amino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide (100mg, 0.25mmol) was dissolved in THF (5mL), TEA (76mg, 0.75mmol) was added in ice bath, isobutyryl chloride (32mg, 0.30mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. Concentration, dilution with EA (15mL), washing with distilled water (10 mL. times.2), drying over anhydrous magnesium sulfate, concentration, and addition of petroleum ether gave 103mg of a white solid in 89% yield. Melting point: 119 ℃ and 121 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.47(d,J＝7.2Hz,1H),8.20(dd,J1＝2.8Hz, J2＝9.2Hz,1H),8.01(s,1H),7.86(d,J＝2.8Hz,1H),7.83(d,J＝6.8Hz,1H), 7.39-7.44(m,2H),7.33(d,J＝3.2Hz,1H),6.91(d,J＝9.2Hz,1H),5.35-5.42(m,2H), 3.86(d,J＝6.4Hz,2H),2.46-2.53(m,1H),2.02-2.10(m,1H),1.63(d,J＝6.8Hz,3H), 1.22(s,6H),0.98(d,J＝6.4Hz,3H),0.93(d,J＝6.4Hz,3H).
Example 157
2-cyclopropylmethoxy-5-isobutyrylamino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
Figure BDA0001620885820002181
a) 2-Cyclopropylmethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Cyclopropylmethoxy-5-nitrobenzoic acid (230mg, 0.97mmol) was dissolved in DCM (15mL), HATU (553mg, 1.46mmol) and DIEA (376mg, 2.91mmol) were added and reacted at room temperature for 30min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (237mg, 1.16mmol) was added and reacted at room temperature overnight. Washed with water (20mL) and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 3:1) afforded 399mg of white solid in 98% yield. Melting point: 69-71 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):9.11(d,J＝2.8Hz,1H),8.46(d,J＝7.2Hz,1H), 8.28(dd,J1＝2.8Hz,J2＝8.8Hz,1H),7.83-7.86(m,2H),7.41-7.49(m,2H),7.34(d,J ＝2.8Hz,1H),6.97(d,J＝8.8Hz,1H),5.36-5.43(m,1H),4.00-4.09(m,2H),1.66(d,J ＝6.8Hz,3H),1.51(d,J＝7.2Hz,3H),1.33-1.37(m,1H),0.61-0.69(m,2H),0.37-0.42 (m,2H).
b) 2-Cyclopropylmethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Cyclopropylmethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (200mg, 0.47mmol) was dissolved in THF (10mL), H2Reaction at 50 ℃ for 17 h. The raw material disappeared. Filtration, concentration and column chromatography (P: E ═ 1:1) gave 129mg of a yellowish solid in 70% yield. Melting point: 156 ℃ and 157 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.79(d,J＝7.6Hz,1H),7.97(d,J＝1.6Hz,1H), 7.92(d,J＝3.2Hz,1H),7.82(dt,J1＝1.6Hz,J2＝7.2Hz 1H),7.79(d,J＝3.2Hz,1H), 7.45-7.53(m,2H),7.09(d,J＝3.2Hz,1H),5.16-5.23(m,1H),3.84(d,J＝7.2Hz,2H), 1.51(d,J＝7.2Hz,3H),1.16-1.25(m,1H),0.46-0.51(m,2H),0.29-0.30(m,2H).
c) 2-cyclopropylmethoxy-5-isobutyrylamino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
2-Cyclopropylmethoxy-5-amino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide (80mg, 0.20mmol) was dissolved in THF (5mL), TEA (61mg, 0.60mmol) was added in ice bath, isobutyryl chloride (32mg, 0.3mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Washed with distilled water (20mL) and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 1:1) gave 78mg of white solid in 85% yield. Melting point: 168-170 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.76(d,J＝7.6Hz,1H),8.20(dd,J1＝6.8Hz, J2＝8.8Hz 1H),8.03(d,J＝1.2Hz,1H),7.82-7.86(m,3H),7.41-7.47(m,3H),7.33(d, J＝1.2Hz,1H),6.86(d,J＝8.8Hz,1H),5.35-5.42(m,1H),3.88-4.00(m,1H), 2.46-2.53(m,1H),1.64(d,J＝7.2Hz,3H),1.21(d,J＝6.8Hz,6H),0.55-0.61(m,2H), 0.32-0.36(m,2H).
Example 158
2-phenoxy-5-isobutyramido-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
Figure BDA0001620885820002191
a) 2-phenoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-phenoxy-5-nitrobenzoic acid (120mg, 0.46mmol) was dissolved in DCM (15mL), HATU (213mg, 0.56mmol), DIEA (118mg, 0.92mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (113mg, 0.56mmol) was added and reacted at room temperature for 8 h. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 5:1) gave 170mg of yellowish oil in 83% yield. Directly put into the next step.
b) 2-phenoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-phenoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (150mg, 0.33mmol) was dissolved in DCM (2mL)/EtOH (8mL)/H2O (1mL), Fe powder (113mg, 2.02mmol), NH4Cl (18mg, 0.33mmol), reflux reaction at 60 ℃ for 3 h. The raw material disappeared. After filtration and concentration, EA (15mL) was added to dilute the filtrate, washed with water (10mL × 2), dried over anhydrous magnesium sulfate, and subjected to column chromatography (P: E: 2:1) to obtain a yellowish oily substance 95mg with a yield of 69%.
1H NMR(400MHZ，DMSO-d6)δ(ppm):8.49(d,J＝7.2Hz,1H),7.93(t,J＝3.2Hz, 1H),7.89(brs,1H),7.75-7.79(m,2H),7.70-7.74(m,1H),7.66-7.69(m,1H),7.29-7.36 (m,2H),7.21-7.26(m,2H),6.96(d,J＝7.6Hz,1H),6.77-5.84(m,4H),6.67(dt,J1＝2.4Hz,J2＝8.8Hz,1H),5.21(s,2H),7.21-7.26(m,2H).
c) 2-phenoxy-5-isobutanoylamino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
2-phenoxy-5-amino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide (80mg, 0.19mmol) was dissolved in THF (2mL), TEA (58mg, 0.57mmol) was added in ice bath, isobutyryl chloride (25mg, 0.23mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. After concentration, the mixture was diluted with EA (10mL), washed with distilled water (10mL × 2), dried over anhydrous magnesium sulfate, and subjected to column chromatography (P: E ═ 2:1) to obtain 61mg of a white solid with a yield of 66%. Melting point: 93-95 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.19(dd,J1＝2.4Hz,J2＝8.8Hz,1H),8.01 (d,J＝7.6Hz,1H),7.91(s,1H),7.87(brs,1H),7.86(d,J＝3.2Hz,1H),7.80(dd,J1＝1.2Hz,J2＝7.6Hz,1H),7.55(brs,1H),7.29-7.33(m,1H),7.12(d,J＝7.6Hz,1H), 6.97(d,J＝8.0Hz,2H),6.92(d,J＝9.2Hz,1H),5.28-5.35(m,1H),2.47-2.54(m,1H), 1.51(d,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,6H).
Example 159
2-benzyloxy-5-isobutanoylamino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
Figure BDA0001620885820002201
a) 2-benzyloxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-benzyloxy-5-nitrobenzoic acid (274mg, 1.0mmol) was dissolved in DCM (20mL), HATU (570 mg, 1.5mmol) and DIEA (492mg, 3.0mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (340mg, 1.66mmol) was added and reacted at room temperature for 12 h. Concentrated, diluted with EA (20mL), washed with water (20mL) and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 4:1) gave 206mg of pale yellow solid in 40% yield.
1H NMR(400MHZ,CDCl3)δ(ppm):8.75(s,1H),8.36(d,J＝2.4Hz,1H),8.19(dd, J1＝2.4Hz,J2＝9.6Hz,1H),8.01(s,1H),7.87(d,J＝3.2Hz,1H),7.44-7.46(m,2H), 7.34(d,J＝3.2Hz,1H),7.11(d,J＝9.6Hz,1H),6.55(d,J＝7.2Hz,3H),5.24-5.31(m, 1H),2.48-2.54(m,1H),0.84-0.90(m,2H),5.58-5.82(m,2H).
b) 2-benzyloxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-benzyloxy-5-nitro-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide (240mg, 0.52mmol) was dissolved in DCM (2mL)/EtOH (8mL)/H 2O (1mL), Fe powder (175mg, 3.13mmol), NH4Cl (28mg, 0.52mmol), reflux reaction at 70 ℃ for 2.5 h. The raw material disappeared. Filtration, concentration, dilution with EA (15mL), water washing (15 mL. times.2), drying over anhydrous magnesium sulfate, concentration, addition of petroleum ether, precipitation of white solid 170mg, 76% yield. Melting point: 135-137 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.56(d,J＝7.6Hz,1H),7.91(d,J＝3.2Hz,1H), 7.87(s,1H),7.78(d,J＝3.2Hz,2H),7.48(d,J＝7.6Hz,2H),7.31-7.38(m,4H),7.26 (d,J＝7.6Hz,1H),7.01(t,J＝2.8Hz,1H),6.68(dd,J1＝2.8Hz,J2＝8.8Hz,1H), 5.08(m,2H),4.87(m,1H),1.26(d,J＝7.2Hz,3H).
c) 2-benzyloxy-5-isobutanoylamino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
2-benzyloxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (80mg, 0.18mmol) was dissolved in THF (5mL), TEA (55mg, 0.54mmol) was added in ice bath, isobutyryl chloride (24mg, 0.22mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. After concentration, EA (15mL) was added for dilution, washed with distilled water (10 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated, and anhydrous ether was added to precipitate 90mg of a white solid in 83% yield. Melting point: 162 ℃ and 164 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.39(d,J＝7.6Hz,1H),8.26(dd,J1＝2.8Hz,J2＝9.2Hz,1H),7.83-7.86(m,3H),7.79(d,J＝8.0Hz,1H),7.48(brs,1H),7.43(dd,J1＝ 2.0Hz,J2＝7.6Hz,2H),7.13(d,J＝8.0Hz,1H),7.07(d,J＝9.2Hz,1H),5.14-5.29 (m,2H),2.46-2.53(m,2H),1.30(d,J＝7.2Hz,3H),1.23(d,J＝1.6Hz,3H).
Example 160
2-phenethyloxy-5-isobutanoylamino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
Figure BDA0001620885820002211
a) 2-phenethyloxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Phenoethoxy-5-nitrobenzoic acid (205mg, 0.71mmol) was dissolved in DCM (20mL), HATU (407mg, 1.07mmol) and DIEA (275mg, 2.13mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (220mg, 1.07mmol) was added and reacted at room temperature overnight. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 3:2) gave 387mg of an off-white solid in 85% yield.
1H NMR(400MHZ,CDCl3)δ(ppm):8.30(dd,J1＝3.2Hz,J2＝9.2Hz,1H),8.01(s, 1H),7.92(d,J＝7.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.41(t,J＝7.6Hz,1H),7.36(s, 1H),7.34(d,J＝1.2Hz,1H),7.25(d,J＝1.6Hz,1H),7.24-7.25(m,1H),7.16(d,J＝ 1.6Hz,1H),7.14(s,1H),7.08(d,J＝9.2Hz,1H),5.32-5.36(m,1H),4.47-4.53(m, 2H),3.19(q,J＝2.8Hz,2H),1.48(d,J＝6.8Hz,3H).
b) 2-phenethyloxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Phenylethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (200mg, 0.42mmol) was dissolved in DCM (2mL)/EtOH (8mL)/H2O (1mL), Fe powder (142mg, 2.53mmol), NH4Cl (23mg, 0.42mmol), reflux reaction at 70 ℃ for 3 h. The raw material disappeared. Filtration, concentration, dilution with EA (20mL), water washing (15 mL. times.2), drying over anhydrous magnesium sulfate, concentration, and addition of petroleum ether gave 162mg of a yellowish solid, 87% yield.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.43(d,J＝7.6Hz,1H),7.95(s,1H),7.92(d, J＝3.2Hz,1H),7.81(d,J＝3.6Hz,1H),7.78(d,J＝3.2Hz,1H),7.40-7.47(m,2H), 7.15-7.26(m,5H),7.03(d,J＝2.8Hz,1H),6.66(dd,J1＝2.8Hz,J2＝8.8Hz,1H), 5.11-5.18(m,1H),4.85(s,2H),4.23(dt,J1＝2.8Hz,J ＝7.6Hz,2H),3.10-3.04(dt,J1＝3.2Hz,J2＝7.6Hz,2H),1.37(d,J＝7.6Hz,3H).
c) 2-phenethyloxy-5-isobutanoylamino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide
2-Phenoethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (60mg, 0.14mmol) was dissolved in THF (5mL), TEA (41mg, 0.41mmol) was added in ice bath, isobutyryl chloride (17mg, 0.16mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. Concentration, dilution with EA (15mL), washing with distilled water (15 mL. times.2), drying over anhydrous magnesium sulfate, concentration, and addition of petroleum ether gave 44mg of a white solid in 64% yield. Melting point: 102-105 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.26(d,J＝7.2Hz,1H),8.22(dd,J1＝2.8 Hz,J2＝9.2Hz,1H),7.98(s,1H),7.81-7.84(m,3H),7.41(brs,1H),7.37(d,J＝7.6Hz, 1H),7.34(brs,1H),7.31(d,J＝7.2Hz,1H),7.25(brs,1H),7.20(d,J＝7.2Hz,1H), 7.15(d,J＝6.8Hz,1H),6.96(d,J＝9.2Hz,1H),5.28-5.35(m,1H),4.35-4.41(dd,J1＝ 2.8Hz,J2＝8.8Hz,1H),5.11-5.18(m,1H),4.85(s,2H),4.23(dt,J1＝2.8Hz,J2＝7.6 Hz,2H),3.10-3.04(dt,J1＝3.2Hz,J2＝7.6Hz,2H),1.37(d,J＝7.6Hz,3H).
Example 161
2-cyclopropylamino-5-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820002221
a) Preparation of 2-cyclopropylamino-5-nitro-benzoic acid
2-chloro-5-nitrosalicylic acid (500mg, 2.48mmol), cyclopropylamine (1.416mg, 24.8mmol) was added and the mixture was heated to 70 ℃ for 12 h. The two treatments were combined, cooled, diluted with EA (20mL), washed with water (20mL × 2), dried over anhydrous magnesium sulfate, and subjected to column chromatography (D: M: 30:1) to obtain 590mg of a yellow solid with a yield of 88%.
1H NMR(400MHZ,DMSO-d6)δ(ppm):7.57(s,1H),7.42(t,J＝1.6Hz,1H),7.03 (dd,J1＝2.0Hz,J2＝7.6Hz,1H),6.02(dd,J1＝1.2Hz,J2＝7.6Hz,1H),3.07(t,J＝4.8 Hz,2H),1.37-1.45(m,1H),0.92-0.94(m,2H),0.73-0.75(m,2H).
b) 2-cyclopropylamino-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Cyclopropylamino-5-nitro-benzoic acid (282mg, 1.27mmol) was dissolved in DCM (15mL), HATU (726mg, 1.91mmol) and DIEA (492mg, 3.81mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (340mg, 1.66mmol) was added and reacted at room temperature overnight. Washed with water (20mL) and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 1:1) gave 206mg of pale yellow solid in 40% yield. Melting point: 145-147 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.75(s,1H),8.36(d,J＝2.4Hz,1H),8.19(dd, J1＝2.4Hz,J2＝9.6Hz,1H),8.01(s,1H),7.87(d,J＝3.2Hz,1H),7.44-7.46(m,2H), 7.34(d,J＝3.2Hz,1H),7.11(d,J＝9.6Hz,1H),6.55(d,J＝7.2Hz,3H),5.24-5.31(m, 1H),2.48-2.54(m,1H),0.84-0.90(m,2H),5.58-5.82(m,2H).
c) 2-cyclopropylamino-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Cyclopropylamino-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (200mg, 0.47mmol) was dissolved in DCM (2mL)/EtOH (8mL)/H2O (1mL), Fe powder (139mg, 2.50mmol), NH4Cl (22mg, 0.41mmol), at 70 ℃ under reflux for 6 h. The raw material disappeared. After filtration and concentration, EA (15mL) was added and the mixture was washed with water (15 mL. times.2) to give 120mg of a brown oil, which was directly used in the next step.
d) 2-cyclopropylamino-5-isobutyramido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
2-Cyclopropylamino-5-amino-N- (1- (3- (2-thiazolyl) phenyl) ethylamine) benzamide was dissolved in THF (5mL), TEA (79mg, 0.78mmol) was added in ice bath, isobutyryl chloride (42mg, 0.39mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 30 min. Concentrated, diluted with EA (20mL), washed with distilled water (15 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 5:1) gave 75mg of white solid in 65% yield. Melting point: 205-207 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.08(s,1H),7.87(d,J＝3.2Hz,1H),7.80-7.83 (m,2H),7.43(t,J＝1.6Hz,1H),7.28(dd,J1＝2.0Hz,J2＝8.8Hz 1H),7.07(d,J＝8.8 Hz,1H),6.47(d,J＝7.2Hz,1H),5.23-5.30(m,1H),2.45-2.52(m,1H),2.34-2.39(m, 1H),1.58(d,J＝7.2Hz,3H),1.24(d,J＝6.8Hz,6H),0.69-0.73(m,1H),0.47-0.49(m, 1H).
Example 162
2-ethoxy-5-isobutyramido-N-methyl-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820002241
a) 2-ethoxy-N-methyl-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide (300mg,0.78mmol) was dissolved in anhydrous DMF (5mL), NaH (37mg,1.56mmol) was added, the reaction stirred at room temperature for 20min, CH was added3I (111mg,0.78mmol), and the reaction was continued for 4h, after which the starting material was reacted. Diluting with EA (25mL), washing with saturated brine (20mL), and adding anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 2:3) to obtain 201mg of white solid, yield 64.6%, melting point: 133-135 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.28-8.24(m,2H),7.99(s,1H),7.91-7.84(m, 2H),7.52(d,J＝7.2Hz,1H),7.48-7.43(m,1H),7.37(d,J＝3.2Hz,1H),6.98(d,J＝ 9.8Hz,1H),5.29(brs,1H),4.42(brs,1H),4.18(q,J＝6.8Hz,2H),3.09(s,1H),2.80 (s,2H),1.43(t,J＝7.2Hz,1H),1.37(t,J＝7.2Hz,2H)；ESI-MS m/z:398.12[M+H]+。
b) 2-ethoxy-5-isobutyramido-N-methyl-N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-N-methyl-5-nitro-N- (3- (thiazole-2-yl)) Benzyl) benzamide (140mg,0.35mmol) was dissolved in THF (15mL), Pd/C70 mg was added, hydrogen was introduced at room temperature overnight for reaction, filtration was performed, the filtrate was concentrated to give 110mg of colorless oil, the colorless oil (100mg,0.27mmol) was dissolved in anhydrous THF (15mL), TEA (136mg,1.35mmol) and isobutyryl chloride (57 mg,0.54mmol) were sequentially added under ice bath, the reaction was continued for 1h, filtration was performed, the filtrate was concentrated, ethyl acetate (20mL) was added for dilution, HCl (0.5N) aqueous solution (10mL) was washed, saturated NaHCO was added3Washing with 10mL of water, washing with 10mL of saturated brine and anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:2) to obtain 69mg of white solid, yield 58.0%, melting point: 168 ℃ and 169 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.00(s,1H),7.95(s,1H),7.87(d,J＝3.6Hz, 2H),7.76-7.68(m,1H),7.52(d,J＝7.2Hz,1H),7.45-7.38(m,2H),7.35-7.33(m,1H), 7.23(s,1H),6.80(d,J＝8.8Hz,1H),5.35(brs,1H),4.44(s,1H),4.33(brs,1H), 4.05-4.01(m,2H),3.03(s,1H),2.82(s,2H),2.53-2.45(m,1H),1.35(t,J＝6.8Hz,1H), 1.30(t,J＝6.8Hz,2H),1.19(d,J＝6.8Hz,6H)；HR-MS(ESI):m/z,calcd.For C24H27O3N3S 438.1846[M+H]+,Found:438.1826。
Example 163
2-ethoxy-5-isobutanoylamino-N- (1- (3-methoxyphenyl) propyl-2-yl) benzamide
Figure BDA0001620885820002251
a)1- (3-methoxyphenyl) propyl-2-amine
Meta-methyl propiophenone (200mg, 1.22mmol) was dissolved in ethanol (10 mL)/water (5mL), ammonium formate (845mg, 13.40mmol) was added, and after all were dissolved, Pd/C (130mg, 0.12mmol) was added and reacted at 40 ℃ for 10 hours. The reaction was stopped, concentrated, washed with diethyl ether (10 mL. times.2), and the aqueous layer was added with saturated NaHCO 3The mixture was made basic, dichloromethane (10mL) was added, the mixture was stirred and filtered, and the mixture was extracted with D: M ═ 10:1, and the organic layers were combined and dried over anhydrous magnesium sulfate. 148mg of yellow oil are obtained in 74% yield. Direct input ofAnd (5) next step.
b) 2-ethoxy-5-nitro-N- (1- (3-methoxyphenyl) propyl-2-yl) benzamide
2-ethoxy-5-nitrobenzoic acid (122mg, 0.58mmol) was dissolved in DCM (10mL), HATU (331mg, 0.87mmol) and DIEA (224mg, 1.74mmol) were added and reacted at room temperature for 10min, a solution of 1- (3-methoxyphenyl) propyl-2-amine (145mg, 0.87mmol) in DCM (2mL) was added and reacted at room temperature overnight. Concentrated, diluted with EA (15mL), washed with water (20 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1) gave 170mg of white solid in 84% yield. Melting point: 91-93 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):9.10(d,J＝2.8Hz,1H),8.29(dd,J1＝2.8Hz, J2＝9.2Hz,1H),7.72(d,J＝7.6Hz,1H),8.21(dt,J1＝0.8Hz,J2＝7.6Hz,1H),7.02 (d,J＝9.2Hz,1H),6.82-6.76(m,3H),4.54-4.47(m,1H),4.25(q,J＝6.8Hz,2H),3.77 (s,3H),2.96(dd,J1＝5.2Hz,J2＝13.6Hz,1H),2.79(dd,J1＝7.2Hz,J2＝13.6Hz, 1H),1.43(d,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,3H).
c) 2-ethoxy-5-amino-N- (1- (3-methoxyphenyl) propyl-2-yl) benzamide
2-ethoxy-5-nitro-N- (1- (3-methoxyphenyl) propyl-2-yl) benzamide (160mg, 0.45mmol) was dissolved in DCM (2mL)/EtOH (6mL)/H2O (1mL), Fe powder (150mg, 2.68mmol), NH4Cl (24mg, 0.45mmol), reflux reaction at 50 ℃ for 2 h. The raw material disappeared. After filtration, concentration, dilution with EA (15mL), washing with water (10 mL. times.2), drying over anhydrous magnesium sulfate, and concentration, the yield was 69%. Melting point: 98-100 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.10(d,J＝7.6Hz,1H),7.20(t,J＝8.8Hz, 1H),7.09(d,J＝2.8Hz,1H),6.83-6.76(m,4H),6.64(dd,J1＝2.8Hz,J2＝8.8Hz,1H), 4.83(s,2H),4.26-4.19(m,1H),3.96(d,J＝7.2Hz,2H),3.70(s,3H),2.81(q,J＝6.8 Hz,1H),2.72(q,J＝6.8Hz,1H),1.22(t,J＝7.2Hz,3H),1.11(d,J＝6.4Hz,3H).
d) 2-ethoxy-5-isobutyramido-N- (1- (3-methoxyphenyl) propyl-2-yl) benzamide
2-ethoxy-5-amino-N- (1- (3-methoxyphenyl) propyl-2-yl) benzamide (60mg, 0.18mmol) was dissolved in THF (3mL), TEA (55mg, 0.54mmol) was added in ice bath, isobutyryl chloride (23mg, 0.22mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 10 min. After concentration, the mixture was diluted with EA (10mL), washed with distilled water (10 mL. times.2), and dried over anhydrous magnesium sulfate to obtain a white solid (60 mg) with a yield of 85%. Melting point: 111-113 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.21(dd,J1＝2.8Hz,J2＝8.8Hz,1H),8.10 (d,J＝7.6Hz,1H),7.85(d,J＝2.8Hz,1H),7.50(brs,1H),7.19(dt,J1＝0.8Hz,J2＝ 7.6Hz,1H),6.91(d,J＝9.2Hz,1H),6.80(d,J＝7.6Hz,1H),6.75-6.78(m,2H), 4.94-4.50(m,1H),4.11(d,J＝7.2Hz,2H),3.75(s,3H),2.95(dd,J1＝5.2Hz,J2＝13.2 Hz,1H),2.77(dd,J1＝7.2Hz,J2＝13.6Hz,1H),2.48-2.57(m,1H),1.34(t,J＝7.2Hz, 3H),1.24(d,J＝7.2Hz,6H),1.19(d,J＝6.8Hz,3H).
Example 164
2-ethoxy-5-isobutyrylamino-N- (2- (m-benzyl) propan-2-yl) benzamide
Figure BDA0001620885820002261
a)2- (m-benzyl) propan-2-amine
Adding cerium trichloride (1.47g,6mmol) into dry THF (25mL), dropwise adding a 1.6M methyllithium solution (3.75mL,6mmol) into a reaction bottle at the temperature of 66 ℃ below zero under the protection of argon, continuously reacting at the temperature of 66 ℃ below zero for 1.5h after dropwise adding, dropwise adding a THF (5mL) solution of M-methylbenzonitrile (0.23mL,2mmol) into the reaction bottle, reacting at the temperature of 66 ℃ below zero for 0.5h, gradually raising the temperature to room temperature for reaction, adding ammonia water after 1h, and filtering. The filtrate was concentrated, acetic acid and water were added, extraction was performed with diethyl ether, the aqueous layer was adjusted to PH 9 with aqueous ammonia, extraction was performed with a mixture of DCM: MeOH 10:1, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give 150mg of pale yellow oil with a yield of 50.3%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.33(s,1H),7.29(d,J＝8.0Hz,1H),7.22(t,J＝ 7.6Hz,1H),7.04(d,J＝7.6Hz,1H),2.36(s,3H),1.49(s,6H).
b) 2-ethoxy-5-isobutyrylamino-N- (2- (m-benzyl) propan-2-yl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.398mmol) was added to anhydrous DMF (10mL), EDC (153mg,0.796mmol) was added, HOBt (107mg,0.796mmol) and DIEA (0.21mL, 1.19mmol) were added, 2- (m-benzyl) propane-2-amine (118mg,0.79mmol) was added, stirring was carried out overnight at room temperature, the reaction mixture was poured into water, extraction was carried out with a mixture (30 mL. times.2) of ethyl acetate: methanol: 10:1, the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography was carried out (E: P: 1:2.5) to give 90mg of a white solid in 59.2% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.58(s,1H),8.17(dd,J1＝9.2Hz,J2＝2.8Hz, 1H),7.73(d,J＝2.8Hz,1H),7.33(s,1H),7.18-7.26(m,3H),7.02-7.04(m,1H),6.93 (d,J＝9.2Hz,1H),4.18(q,J＝6.8Hz,2H),2.40-2.48(m,1H),2.34(s,3H),1.78(s, 6H),1.44(t,J＝6.8Hz,3H),1.20(d,J＝6.8Hz,6H).
Example 165
2-ethoxy-5-isobutyrylamino-N- (1- (m-benzyl) propyl) benzamide
Figure BDA0001620885820002271
2-ethoxy-5-isobutyrylaminobenzoic acid (100mg,0.398mmol) was added to anhydrous DMF (10mL), EDC (153mg,0.796mmol) was added, HOBt (107mg,0.796mmol) and DIEA (0.21mL, 1.19mmol) were added, 1- (m-benzyl) propylamine (118mg,0.79mmol) was added, stirred at room temperature overnight, the reaction mixture was poured into water, extracted with a mixture of ethyl acetate and methanol (10: 1) (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P1: 2.5) to give 100mg of a white solid in 65.7% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.46(d,J＝8.0Hz,1H),8.23(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.73(s,1H),7.22(t,J＝7.6Hz,1H),7.11-7.13 (m,2H),7.06(d,J＝7.6Hz,1H),6.93(d,J＝8.8Hz,1H),5.07(q,J＝7.6Hz,1H), 4.12-4.22(m,2H),2.46-2.49(m,1H),2.34(s,3H),1.87-1.93(m,2H),1.47(t,J＝7.2 Hz,3H),1.18(dd,J1＝6.8Hz,J2＝4.0Hz,6H),0.93(t,J＝7.2Hz,3H).
Example 166
2-ethoxy-5-isobutyrylamino-N- (2- (6-methoxypyridin-2-yl) propan-2-yl) benzamide
Figure BDA0001620885820002281
a)2- (6-methoxypyridin-2-yl) propan-2-amine
Adding cerium trichloride (1.86g,7.5mmol) into dry THF (25mL), dropwise adding 1.6M methyllithium solution (4.7mL,7.5mmol) into a reaction bottle under the protection of argon at-66 ℃, continuously reacting at-66 ℃ for 1.5 h after dropwise adding, dropwise adding M-methylbenzonitrile (335mg,2.5mmol) THF (5mL) solution into the reaction bottle, reacting at-66 ℃ for 0.5h after dropwise adding, gradually raising to room temperature for reacting, adding ammonia water after 1h, and filtering. The filtrate was concentrated, acetic acid and water were added, extraction was performed with diethyl ether, the aqueous layer was adjusted to PH 9 with aqueous ammonia, extraction was performed with a mixture of DCM: MeOH 10:1, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give 153mg of brown oil with a yield of 36.8%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.52(t,J＝7.6Hz,1H),6.95(dd,J1＝7.6Hz,J2＝0.8Hz,1H),6.58(dd,J1＝8.0Hz,J2＝0.8Hz,1H),3.94(s,3H),2.20(brs,2H),1.49 (s,6H).
b) 2-ethoxy-5-isobutyrylamino-N- (2- (6-methoxypyridin-2-yl) propan-2-yl) benzamide
2-ethoxy-5-isobutyrylaminobenzoic acid (110mg,0.438mmol) was added to anhydrous DMF (15mL), EDC (168mg,0.876mmol) was added, HOBt (118mg,0.876mmol) and DIEA (0.23mL, 1.314mmol) were added, 2- (6-methoxypyridin-2-yl) propan-2-amine (110mg,0.66mmol) was added, stirred at room temperature overnight, the reaction was poured into water, extracted with a mixture of ethyl acetate: methanol: 10:1 (30 mL. times.2), the combined organic layers were washed with a saturated NaCl solution (15 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M: 90:1) to give 130mg of a white solid in 74.7% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.82(s,1H),8.16(dd,J1＝8.8Hz,J2＝2.8Hz, 1H),7.72(d,J＝2.8Hz,1H),7.54(t,J＝7.6Hz,1H),7.31(brs,1H),7.00(d,J＝7.6 Hz,1H),6.94(d,J＝9.2Hz,1H),6.59(d,J＝8.4Hz,1H),4.19(q,J＝7.2Hz,2H), 3.90(s,3H),2.43-2.50(m,1H),1.86(s,6H),1.46(t,J＝7.2Hz,3H),1.19-1.22(m, 6H).
Example 167
2-ethoxy-5-isobutyrylamino-4-methyl-N- (3- (thiazol-2-yl) benzyl) benzamide
Figure BDA0001620885820002291
a) 2-ethoxy-4-methyl-5-nitrobenzoic acid methyl ester
Methyl 2-hydroxy-4-methyl-5-nitrobenzoate (200mg,0.95mmol) was dissolved in anhydrous DMF (10mL) and K was added sequentially2CO3(262mg,1.90mmol)、C2H5I (445mg, 2.85mmol) was heated to 60 ℃ for reaction for 10h, cooled, water was added to precipitate a white solid, filtered, and the filter cake was washed with water (20mL) to give 210mg of a white solid, yield 92.9%, melting point: 103-104 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.62(s,1H),6.83(s,1H),4.21(q,J＝7.2Hz, 2H),3.91(s,3H),2.69(s,3H),1.51(t,J＝7.2Hz,3H)；ESI-MS m/z:240.09[M+H]+. b) 2-ethoxy-4-methyl-5-nitrobenzoic acid
Methyl 2-ethoxy-4-methyl-5-nitrobenzoate (200mg,0.84mmol) was dissolved in THF (20 mL)/water (10mL), NaOH (168mg,4.20mmol) was added with stirring to react at room temperature for 6h, concentrated, the aqueous layer was washed with diethyl ether (20mL), the aqueous layer was adjusted to pH 3 with hydrochloric acid, 174mg of solid was precipitated, yield was 92.6%, melting point: 163-164 ℃.1H-NMR(400MHz,DMSO)δ(ppm):13.03(s,1H),8.34(s,1H), 7.21(s,1H),4.22(q,J＝6.8Hz,2H),2.60(s,3H),1.34(t,J＝6.8Hz,3H)；ESI-MS m/z:224.06[M-H]-。
c) 2-ethoxy-4-methyl-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-4-methyl-5-nitrobenzoic acid (150mg,0.67mmol) was dissolved in DCM (15mL), DIEA (173mg,1.34mmol) and HATU (357mg,0.94mmol) were added in that order, and after reaction at room temperature for 30min, (3- (thiazol-2-yl) phenyl) methylamine (152mg,0.80mmol) was added and the reaction at room temperature was allowed to proceed for 8h, whereupon the starting material disappeared. Dilute with DCM (20mL), wash with HCl (0.5N) (20mL), and saturate NaHCO 3Washing (20mL), washing with water (20mL), washing with saturated brine (20mL), anhydrous Na2SO4Drying and purifying by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) to obtain 232mg of white solid, yield 87.5%, melting point: 172 ℃ and 173 ℃.
1H-NMR(400MHz,CDCl3)δ(ppm):8.96(s,1H),8.12(brs,1H),7.99(s,1H),7.89–7.86(m,2H),7.44(d,J＝4.8Hz,2H),7.35(d,J＝3.2Hz,1H),6.82(s,1H),4.73(d,J ＝5.2Hz,2H),4.23(q,J＝7.2Hz,2H),2.66(s,3H),1.38(t,J＝7.2Hz,3H)；ESI-MS m/z:398.12[M+H]+。
d) 5-amino-2-ethoxy-4-methyl-N- (3- (thiazol-2-yl) benzyl) benzamide
2-ethoxy-4-methyl-5-nitro-N- (3- (thiazol-2-yl) benzyl) benzamide (210mg,0.53mmol) was dissolved in THF (15mL), Pd/C (110mg) was added, hydrogen was bubbled in at room temperature for reaction overnight, filtered, and concentrated to give 182mg of colorless oil in 93.8% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.53(brs,1H),7.96(s,1H),7.90-7.82(m,2H), 7.60(s,1H),7.46-7.38(m,2H),7.33(d,J＝3.2Hz,1H),6.68(s,1H),4.70(d,J＝5.2 Hz,2H),4.05(q,J＝7.2Hz,2H),3.26(s,2H),2.19(s,3H),1.26(t,J＝6.8Hz,3H)； ESI-MS m/z:368.14[M+H]+。
e) 2-ethoxy-5-isobutyrylamino-4-methyl-N- (3- (thiazol-2-yl) benzyl) benzamide
Reacting 5-amino-2-ethoxy-4-methyl-N- (3- (thiazol-2-yl) benzyl) benzeneFormamide (160mg,0.44mmol) was dissolved in anhydrous THF (10mL), DIEA (114mg,0.88mmol) and isobutyryl chloride (70mg,0.66mmol) were added sequentially under ice-bath, reaction was continued for 1h, filtration was performed, the filtrate was concentrated, diluted with ethyl acetate (20mL), washed with HCl (0.5N) in water (10mL), saturated NaHCO3Washing with 10mL of water, washing with 10mL of saturated brine and anhydrous Na2SO4Drying and purification by column chromatography (ethyl acetate-petroleum ether, volume ratio 1:1) gave 127mg of white solid, yield 66.8%, melting point: 146 ℃ and 147 ℃.
1H-NMR(400MHz,DMSO)δ(ppm):9.21(s,1H),8.61(brs,1H),7.94(s,1H),7.92(d, J＝3.2Hz,1H),7.83(d,J＝5.6Hz,1H),7.78(d,J＝3.2Hz,1H),7.65(s,1H), 7.49-7.46(m,2H),7.01(s,1H),4.58(d,J＝5.6Hz,2H),4.16(q,J＝6.8Hz,2H),2.60 (m,1H),2.19(s,3H),1.31(t,J＝6.8Hz,3H),1.11(d,J＝6.8Hz,6H)；HR-MS(ESI): m/z,calcd.For C24H27O3N3S 438.1846[M+H]+,Found:438.1838。
Example 168
2-ethoxy-5-isobutanoylamino-N- (1- (3-methylphenyl) ethyl) nicotinamide
Figure BDA0001620885820002301
a) 2-hydroxy-5-nitro-nicotinic acid
Concentrated sulfuric acid was cooled to 0 ℃ and nicotinic acid (1g, 7.19mmol) was added in portions, after complete dissolution, 1mL fuming nitric acid was added and heated to 50 ℃ for reaction for 2.5 h. After the disappearance of the starting material, ice water was added to the reaction solution to obtain a yellowish solid (1.048 g, yield 79%). Melting point: 185 ℃ and 187 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):9.00(d,J＝2.8Hz,1H),8.71(t,J＝3.2Hz, 1H).
b) 2-hydroxy-5-nitronicotinic acid methyl ester
2-hydroxy-5-nitronicotinic acid (1g, 5.43mmol) was dissolved in anhydrous methanol (20mL) and SOCl was added slowly with stirring2The solution was reacted at 50 ℃ for 7h, cooled, filtered and the filter cake washed with ice methanol to give 738mg of a white solid in 69% yield. Melting point: 90-92℃.
1H NMR(500MHZ,DMSO-d6)δ(ppm):13.19(brs,1H),8.87(d,J＝3.2Hz,1H), 8.62(d,J＝3.2Hz,1H),3.79(s,3H).
c) 2-ethoxy-5-nitronicotinic acid methyl ester
Methyl 2-hydroxy-5-nitronicotinate (700mg, 3.53mmol) was dissolved in anhydrous DMF (8mL) and K was added2CO3(975mg, 7.06mmol), iodoethane (0.85mL, 10.59mmol) was added and the reaction was heated to 60 ℃ for 10 h. After disappearance of the starting material, cooling, EA extraction, washing with water, drying, and column chromatography (P: E ═ 1:1) to give 500mg of a white solid, yield 63%. Melting point: 113 ℃ and 115 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):8.87(d,J＝3.2Hz,1H),8.80(d,J＝3.2Hz, 1H),4.16(q,J＝7.2Hz,2H),3.94(s,3H),1.48(t,J＝7.2Hz,3H).
d) 2-ethoxy-5-nitronicotinic acid
Methyl 2-ethoxy-5-nitronicotinate (400mg, 1.77mmol) was dissolved in THF (10mL)/(10mL), NaOH (354mg, 8.84mmol) was added with stirring, the reaction was allowed to stand overnight at room temperature, concentrated, adjusted to pH 2 with concentrated hydrochloric acid, extracted with EA, dried, concentrated, and added with diethyl ether and a small amount of ethyl acetate to give 311mg of a white solid in 83% yield. Melting point: 160-162 ℃.
1H NMR(500MHZ,CDCl3)δ(ppm):9.24(d,J＝2.8Hz,1H),8.86(d,J＝2.8Hz, 1H),4.28(q,J＝7.2Hz,2H),1.55(t,J＝7.2Hz,3H).
e) 2-ethoxy-5-nitro-N- (1- (3-methylphenyl) ethyl) nicotinamide
2-ethoxy-5-nitronicotinic acid (100mg, 0.47mmol) was dissolved in DCM (5mL), HATU (214 mg, 0.56mmol) and DIEA (121mg, 0.94mmol) were added and reacted at room temperature for 5min, 1- (3-methylphenyl) ethyl-1-amine (76mg, 0.56mmol) was added and reacted at room temperature for 5 h. Washed with water (20 mL. times.2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 3:2) gave 135mg of yellow oil in 87% yield. Directly put into the next step.
f) 2-ethoxy-5-amino-N- (1- (3-methylphenyl) ethyl) nicotinamide
2-ethoxy-5-nitro-N- (1- (3-methylphenyl) ethyl) nicotinamide (130mg, 0)39mmol) in DCM (2mL)/EtOH (6mL)/H2O (1mL), Fe powder (132mg, 2.36mmol), NH4Cl (21mg, 0.39mmol), at 50 ℃ reflux for 2 h. The raw material disappeared. Filtration, concentration, dilution with EA (10mL), water washing (10 mL. times.2), drying over anhydrous magnesium sulfate, concentration, and addition of ether gave 95mg of a pale green solid in 94% yield.
1H NMR(400MHZ,DMSO-d6)δ(ppm):10.69(d,J＝8.0Hz,1H),8.00(d,J＝2.8Hz, 1H),7.25-7.21(m,2H),7.15-7.12(m,2H),7.06(d,J＝7.2Hz,1H),5.09-5.09(m,1H), 4.66(brs,2H),4.01-3.91(m,2H),2.30(s,3H),1.43(d,J＝7.2Hz,3H),1.23(t,J＝7.2 Hz,3H).
g) 2-ethoxy-5-isobutyramido-N- (1- (3-methylphenyl) ethyl) nicotinamide
2-ethoxy-5-amino-N- (1- (3-methylphenyl) ethyl) nicotinamide (60mg, 0.20mmol) was dissolved in THF (6mL), TEA (70mg, 0.69mmol) was added in ice bath, isobutyryl chloride (30mg, 0.28mmol) was added dropwise with stirring, and the reaction was stirred at room temperature for 20 min. Concentration, dilution with EA (10mL), washing with distilled water (10mL × 2), drying over anhydrous magnesium sulfate, concentration, and column chromatography (P: E ═ 1:1) gave 48mg of a white solid in 65% yield. Melting point: 157 ℃ to 159 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):10.59(d,J＝8.0Hz,1H),8.76(d,J＝3.2Hz, 1H),8.47(d,J＝3.2Hz,2H),7.21(d,J＝7.2Hz,2H),7.16(d,J＝7.2Hz,1H),7.05(d, J＝7.2Hz,1H),5.29-5.22(m,1H),4.15-4.05(m,2H),2.57-2.50(m,1H),2.34(s,3H), 1.57(d,J＝7.2Hz,3H),1.42(t,J＝7.2Hz,3H),1.16(dd,J1＝2.0Hz,J2＝6.8Hz,1H).
Example 169
2-ethoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) nicotinamide
Figure BDA0001620885820002321
a) 2-ethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) nicotinamide
2-ethoxy-5-nitronicotinic acid (184mg, 0.86mmol) was dissolved in DCM (10mL), HATU (494 mg, 1.30mmol) and DIEA (336mg, 2.60mmol) were added and reacted at room temperature for 8min, S2(266mg, 1.30mmol) was added and reacted at room temperature for 8 h. Concentrated, diluted with EA (15mL), washed with water (10 mL. times.2), and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 2:1) gave 333mg of pale yellow oil in 97% yield.
1H NMR(400MHZ,CDCl3)δ(ppm):9.70(d,J＝6.8Hz,1H),9.22(d,J＝2.8Hz, 1H),8.74(d,J＝2.8Hz,1H),8.01(s,1H),7.83-7.87(m,2H),7.41-7.48(m,2H),7.33 (d,J＝2.8Hz,1H),5.30-5.37(m,1H),4.19(q,J＝7.2Hz,2H),1.65(d,J＝6.8Hz, 3H),1.50(t,J＝7.2Hz,3H).
b) 2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) nicotinamide
(330mg, 0.82mmol) was dissolved in DCM (2mL)/EtOH (8mL)/H2O (1mL), Fe powder (275mg, 4.92mmol), NH4Cl (44mg, 0.82mmol), reflux reaction at 60 ℃ for 2 h. The raw material disappeared. Filtration, concentration, dilution with EA (20mL), water washing (20 mL. times.2), drying over anhydrous magnesium sulfate, concentration, addition of petroleum ether, freezing to give a greenish solid 220mg, 73% yield.
1HNMR(400MHZ,DMSO-d6)δ(ppm):10.80(d,J＝7.6Hz,1H),8.00(d,J＝3.2Hz, 1H),7.93(d,J＝2.8Hz,2H),7.81-7.79(m,2H),7.51-7.45(m,2H),7.26(d,J＝2.8Hz, 1H),5.21-5.14(m,1H),4.65(s,1H),4.01-3.91(m,2H),1.50(d,J＝6.8Hz,3H),1.25 (t,J＝7.2Hz,3H).
c) 2-ethoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) nicotinamide
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) nicotinamide (80mg, 0.22mmol) was dissolved in THF (6mL), TEA (66mg, 0.65mmol) was added in ice bath, isobutyryl chloride (28mg, 0.26mmol) was added dropwise with stirring, and the reaction was stirred for 30min in ice bath. EA (10mL) was added for dilution, washed with distilled water (10 mL. times.2), dried over anhydrous magnesium sulfate, and concentrated to give an off-white solid (92 mg, 97% yield). Melting point: 195 + 197 deg.C
1H NMR(400MHZ,CDCl3)δ(ppm):10.61(d,J＝8.0Hz,1H),8.71(d,J＝2.8Hz, 1H),8.39(d,J＝2.8Hz,1H),7.97(s,1H),7.88-7.84(m,2H),7.45-7.40(m,2H),7.33 (d,J＝3.2Hz,1H),5.37-5.30(m,1H),4.13-4.04(m,2H),2.56-2.49(m,1H),1.64(d,J ＝6.8Hz,3H),1.42(t,J＝6.8Hz,3H),1.17(dd,J1＝1.2Hz,J2＝6.8Hz,6H)..
Example 170
2-ethoxy-5-isobutyramido-N- (1- (3-methylphenyl) ethyl) isonicotinamide
Figure BDA0001620885820002331
a) 2-hydroxy-5-nitroisonicotinic acid
Concentrated sulfuric acid was cooled to 0 ℃, isonicotinic acid (1g, 7.19mmol) was added in portions, after complete dissolution, fuming nitric acid 1mL was added, and the mixture was heated to 50 ℃ for reaction for 6 h. After the starting material disappeared, ice water was added to obtain a yellowish solid (650 mg, yield 45%). Melting point: 212 ℃ and 214 ℃.
b) 2-hydroxy-5-nitroisonicotinic acid methyl ester
2-hydroxy-5-nitroisonicotinic acid (630mg, 3.42mmol) was dissolved in anhydrous methanol (12mL) and SOCl was added slowly with stirring2The solution reacts for 5h at 60 ℃, is cooled, filtered and filter cake is washed by ice methanol to obtain 300 mg of off-white solid, the yield is 44 percent of melting point: 123-125 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):11.04(s,1H),8.70(s,1H),8.45(s,1H),4.10(s, 3H).
c) 2-ethoxy-5-nitroisonicotinic acid methyl ester
Methyl 2-hydroxy-5-nitroisonicotinate (290mg, 1.46mmol) was dissolved in anhydrous DMF (8mL) and K was added2CO3(404mg, 2.93mmol), iodoethane (0.35mL, 4.38mmol) was added and the reaction was heated to 70 ℃ for 10 h. After the starting material disappeared, it was cooled, extracted with EA, washed with water, dried, and subjected to column chromatography (P: E ═ 4:1) to give 130mg of a white solid in 39% yield. Melting point: 90-92 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.60(s,1H),8.34(s,1H),4.42-4.37(m,2H), 3.98(s,3H),4.10(s,3H),1.56(t,J＝7.2Hz,3H).
d) 2-ethoxy-5-nitroisonicotinic acid
Methyl 2-ethoxy-5-nitroisonicotinate (125mg, 0.55mmol) was dissolved in THF (6mL), 0.5N NaOH 5.5mL, reacted at room temperature for 3h, concentrated to pH 2 with concentrated hydrochloric acid, EA extracted, dried, and concentrated to give 90mg of a white solid in 77% yield. Melting point: 214-216 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):13.88(s,1H),8.57(s,3H),8.43(s,1H),4.43(q, J＝6.8Hz,2H),1.39(t,J＝6.8Hz,3H).
e) 2-ethoxy-5-nitro-N- (1- (3-methylphenyl) ethyl) isonicotinamide
2-ethoxy-5-nitroisonicotinic acid (90mg, 0.42mmol) was dissolved in DCM (12mL), HATU (240 mg, 0.63mmol) and DIEA (163mg, 1.26mmol) were added and the reaction was carried out at room temperature for 5min, 1- (3-methylphenyl) ethyl-1-amine (114mg, 0.84mmol) was added and the reaction was carried out at room temperature for 10 h. Washed with water (10 mL. times.2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1) afforded 85mg of white solid in 62% yield. Melting point: 133-135 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):9.00(s,1H),8.33(s,1H),8.03(d,J＝7.2Hz, 1H),7.17(d,J＝7.6Hz,2H),7.12(d,J＝7.2Hz,1H),5.29-5.22(m,1H),4.49-4.40(m, 2H),2.37(s,3H),1.60(d,J＝6.8Hz,3H),1.53(t,J＝6.8Hz,3H).
f) 2-ethoxy-5-amino-N- (1- (3-methylphenyl) ethyl) isonicotinamide
2-ethoxy-5-nitro-N- (1- (3-methylphenyl) ethyl) isonicotinamide (75mg, 0.22mmol) was dissolved in DCM (1mL)/EtOH (4mL)/H2O (0.5mL), Fe powder (76mg, 1.36mmol), NH4Cl (12mg, 0.22mmol), at 50 ℃ reflux for 1.5 h. The raw material disappeared. Filtration, concentration, dilution with EA (10mL), water washing (10 mL. times.2), drying over anhydrous magnesium sulfate, and concentration gave 60mg of a yellow solid in 92% yield. Melting point: 146-149 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.58(d,J＝8.0Hz,1H),7.80(s,1H), 7.24-7.16(m,3H),7.06(d,J＝7.2Hz,1H),6.69(s,1H),5.72(s,2H),5.08-5.01(m, 1H),4.05-3.99(m,2H),2.30(s,3H),1.42(d,J＝7.2Hz,3H),1.27(t,J＝7.2Hz,3H).
g) 2-ethoxy-5-isobutyramido-N- (1- (3-methylphenyl) ethyl) isonicotinamide
2-ethoxy-5-amino-N- (1- (3-methylphenyl) ethyl) isonicotinamide (50mg, 0.18mmol) was dissolved in THF (7mL), TEA (55mg, 0.54mmol) was added in ice bath, isobutyryl chloride (22mg, 0.22mmol) was added dropwise with stirring, and the reaction was stirred for 10min in ice bath. EA (10mL) was added thereto for dilution, washed with distilled water (10mL), dried over anhydrous magnesium sulfate, and subjected to column chromatography (P: E: 2:1) to obtain 45mg of a yellowish oil in a yield of 67%.
1H NMR(400MHZ,CDCl3)δ(ppm):8.80(s,1H),7.99(s,2H),7.89(brs,1H),7.23(d, J＝7.6Hz,1H),7.17(d,J＝8.8Hz,1H),7.09(d,J＝7.2Hz,1H),5.31-7.24(m,1H), 4.24-4.16(m,2H),2.57-2.50(m,1H),2.36(s,3H),1.57(d,J＝6.8Hz,3H),1.42(t,J＝ 6.8Hz,3H),1.25(d,J＝6.8Hz,6H).
Example 171
2-ethoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) isonicotinamide
Figure BDA0001620885820002351
a) 2-ethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) isonicotinamide
2-ethoxy-5-nitroisonicotinic acid (100mg, 0.47mmol) was dissolved in DCM (12mL), HATU (357mg, 0.94mmol) and DIEA (182mg, 1.41mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (192mg, 0.94mmol) was added and reacted at room temperature for 10 h. Washed with water (10 mL. times.2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E ═ 2:1) gave 85mg of white solid in 45% yield. Melting point: 115 ℃ and 117 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.99(s,1H),8.35(s,1H),8.13(d,J＝6.8Hz, 1H),8.09(s,1H),7.88(d,J＝3.6Hz,2H),7.46(d,J＝5.2Hz,1H),7.37(d,J＝3.2Hz, 1H),5.40-5.33(m,1H),4.51-4.44(m,1H),1.67(d,J＝6.8Hz,3H),1.54(t,J＝6.8Hz, 3H).
b) 2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) isonicotinamide
2-ethoxy-5-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) isonicotinamide (80mg, 0.20mmol) dissolved in DCM (1mL)/EtOH(6mL)/H2O (1mL), Fe powder (89mg, 1.60mmol), NH4Cl (32mg, 0.60mmol), reflux reaction at 50 ℃ for 2 h. The raw material disappeared. Filtration, concentration, dilution with EA (10mL), washing with water (10 mL. times.2), drying over anhydrous magnesium sulfate, and concentration gave 60mg of a yellow solid in 92% yield. Melting point: 164-166 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.71(d,J＝8.0Hz,1H),7.97(s,1H),7.93(d, J＝3.2Hz,1H),7.84-7.79(m,3H),7.52-7.45(m,2H),6.65(s,1H),5.71(s,2H), 5.20-5.13(m,1H),4.04-3.99(m,2H),1.48(d,J＝6.8Hz,3H),1.24(t,J＝6.8Hz,3H).
c) 2-ethoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) isonicotinamide
2-ethoxy-5-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) isonicotinamide (32mg, 0.08mmol) was dissolved in THF (5mL), TEA (24mg, 0.24mmol) was added in ice bath, isobutyryl chloride (17mg, 0.16mmol) was added dropwise with stirring, and the reaction was stirred for 30min in ice bath. EA (10mL) was added thereto for dilution, washed with distilled water (10mL), dried over anhydrous magnesium sulfate, and subjected to column chromatography (P: E: 1) to obtain an off-white solid (15 mg, yield 43%). Melting point: 166 ℃ and 168 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.80(s,1H),8.06(d,J＝7.6Hz,1H),8.00(d,J ＝7.6Hz,1H),7.94(s,1H),7.87-7.84(m,2H),7.47-7.41(m,2H),7.34(d,J＝3.2Hz, 1H),5.41-5.30(m,1H),4.25-4.18(m,2H),2.58-2.51(m,2H),1.63(d,J＝6.8Hz,3H), 1.41(t,J＝6.8Hz,3H),1.25(d,J＝6.4Hz,6H).
Example 172
2-ethoxy-5-isobutanoylamino-N- (1- (6-methoxypyridin-2-yl) ethyl) isonicotinamide
Figure BDA0001620885820002361
a) 2-ethoxy-5-nitro-N- (1- (6-methoxypyridin-2-yl) ethyl) isonicotinamide
2-ethoxy-5-nitroisonicotinic acid (100mg, 0.47mmol) was dissolved in DCM (15mL), HATU (270mg, 0.71mmol) and DIEA (183mg, 1.42mmol) were added and reacted at room temperature for 20min, 1- (6-methoxypyridin-2-yl) ethyl-1-amine (107mg, 0.71mmol) was added and reacted at room temperature for 10 h. Washed with water (10 mL. times.2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 2:1) gave 70mg of white solid in 43% yield. Melting point: 129-131 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.99(s,1H),8.35(s,1H),8.13(d,J＝6.8Hz, 1H),8.09(s,1H),7.88(d,J＝3.6Hz,2H),7.46(d,J＝5.2Hz,1H),7.37(d,J＝3.2Hz, 1H),5.40-5.33(m,1H),4.51-4.44(m,1H),1.67(d,J＝6.8Hz,3H),1.54(t,J＝6.8Hz, 3H).
b) 2-ethoxy-5-amino-N- (1- (6-methoxypyridin-2-yl) ethyl) isonicotinamide
2-ethoxy-5-nitro-N- (1- (6-methoxypyridin-2-yl) ethyl) isonicotinamide (60mg, 0.17mmol) was dissolved in DCM (1mL)/EtOH (4mL)/H2O (1mL), Fe powder (58mg, 1.04mmol), NH4Cl (27mg, 0.51mmol), reflux reaction at 50 ℃ for 2 h. The raw material disappeared. Filtration, concentration, dilution with EA (10mL), water washing (10 mL. times.2), drying over anhydrous magnesium sulfate, and concentration gave 50mg of a pale yellow solid with a yield of 94%. Melting point: 133 ℃ and 134 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):8.74(d,J＝7.6Hz,1H),7.84(s,1H),7.67(d, J＝7.6Hz,1H),7.02(d,J＝7.2Hz,1H),6.80(s,1H),6.71(d,J＝8.4Hz,1H),5.74(s, 2H),5.12-5.05(m,1H),4.09-4.03(m,2H),3.88(s,2H),1.45(d,J＝6.8Hz,3H),1.28 (t,J＝6.8Hz,3H).
c) 2-ethoxy-5-isobutanoylamino-N- (1- (6-methoxypyridin-2-yl) ethyl) isonicotinamide
2-ethoxy-5-amino-N- (1- (6-methoxypyridin-2-yl) ethyl) isonicotinamide (48mg, 0.15mmol) was dissolved in THF (6mL), TEA (45mg, 0.45mmol) was added in ice bath, isobutyryl chloride (24mg, 0.22mmol) was added dropwise with stirring, and the reaction was stirred for 30min in ice bath. EA (10mL) was added for dilution, washed with distilled water (15mL), dried over anhydrous magnesium sulfate, and column-chromatographed (P: E ═ 1:1) to give 47mg of a white solid, yield 81%. Melting point: 103 ℃ and 104 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.77(s,1H),8.37(d,J＝7.6Hz,1H),8.01(s, 1H),7.92(brs,1H),7.55(t,J＝7.6Hz,1H),6.88(d,J＝7.2Hz,1H),6.64(d,J＝8.4 Hz,1H),5.36-5.29(m,1H),4.24-4.18(m,2H),3.95(s,1H),2.58-2.49(m,1H),1.56(d, J＝6.4Hz,3H),1.43(t,J＝6.8Hz,3H),1.26(d,J＝6.8Hz,6H).
Example 173
2-ethoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) picolinamide
Figure BDA0001620885820002371
a) 3-Hydroxypyridinecarboxylic acid methyl ester
3-Hydroxypicolinic acid (1g, 7.19mmol) was dissolved in dry methanol (20mL), concentrated sulfuric acid (2mL) was added dropwise with stirring at room temperature, and then the temperature was raised to 80 ℃ for reaction for 24 h. EA (20mL) and water (20mL) were added for extraction, the aqueous layer (20 mL. times.2) was extracted with DCM, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to give 750mg of an off-white solid in 68% yield. Melting point: 68-69 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):10.64(s,1H),8.30(d,J＝3.2Hz,1H),7.44(dd, J1＝4.0Hz,J2＝8.4Hz,1H),7.39(dd,J1＝1.2Hz,J2＝8.4Hz,1H),4.07(s,3H).
b) 3-hydroxy-5-bromopicolinic acid methyl ester
Methyl 3-hydroxypicolinate (1g,6.49mmol) was dissolved in acetonitrile (20mL), NBS (1.270g,7.14 mmol) was dissolved in acetonitrile (20mL), and the mixture was slowly dropped into the reaction system to react at room temperature for 8 hours. The solvent was removed by evaporation, EA (20mL) was added for dilution, water (20mL), NaCl (20mL) was washed, the organic layer was dried and concentrated to give 1.2g of a pale yellow solid in 79% yield. Melting point: is more than 250 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):10.69(s,1H),7.56(d,J＝8.8Hz,1H),7.27(d, J＝7.6Hz,1H),4.05(s,3H).
c) 3-ethoxy-5-bromopicolinic acid methyl ester
3-hydroxy-5-bromopicolinic acid methyl ester was dissolved in DMF (8mL) and K was added2CO3(1.534g, 11.12mmol), iodoethane (1.039g, 6.66mmol) was added and the reaction was heated to 40 ℃ for 1 h. After the disappearance of the starting material, cooling, EADilution (20mL), water washing (15mL × 3), EA (20mL × 2) extraction, drying over anhydrous magnesium sulfate, and column chromatography (P: E ═ 10:1) gave 480mg of a yellowish waxy solid with a yield of 83%.
1H NMR(400MHZ,CDCl3)δ(ppm):7.53(d,J＝8.8Hz,1H),7.23(d,J＝8.8Hz, 1H),4.22(q,J＝6.8Hz,2H),3.95(s,3H),1.47(t,J＝6.8Hz,3H).
d) 2-ethoxy-5-isobutyramidopicolinic acid methyl ester
Methyl 3-ethoxy-5-bromopicolinate (460mg, 1.77mmol), isobutyramide (462mg, 5.30mmol), CsCO3(1.727g，5.30mmol)、Pd2(dba)3(324mg, 0.35mmol) and X-phos (338mg, 0.71mmol) were dissolved in dioxane (3mL) and reacted with a microwave (100 ℃ C.) under argon for 30 min. Washed with water (20mL), and subjected to column chromatography (P: E ═ 2:1) to give an off-white solid, 420mg, yield 89%. Melting point: 45-146 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.37(d,J＝9.2Hz,1H),7.88(brs,1H),7.41(d, J＝9.2Hz,1H),4.13(q,J＝7.2Hz,2H),3.98(s,3H),1.45(t,J＝7.2Hz,3H),1.25(d, J＝6.8Hz,6H).
e) 2-ethoxy-5-isobutyramidopicolinic acid
Methyl 2-ethoxy-5-isobutyramidopicolinate (300mg, 1.13mmol) was dissolved in THF (15 mL)/0.5M NaOH (11mL), reacted at room temperature for 2h, concentrated, the aqueous layer was washed with diethyl ether, and concentrated hydrochloric acid was adjusted to pH 2 to precipitate 205mg of a white solid in 72% yield. Melting point: 134 ℃ and 135 ℃.
1H NMR(400MHZ,DMSO-d6)δ(ppm):13.16(s,3H),10.46(s,1H),8.14(d,J＝9.2 Hz,1H),7.63(d,J＝9.2Hz,1H),4.08(q,J＝6.8Hz,2H),1.30(t,J＝7.2Hz,3H), 1.07(d,J＝6.8Hz,6H).
f) 2-ethoxy-5-isobutanoylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) picolinamide
2-ethoxy-5-isobutyramidopicolinic acid (80mg, 0.32mmol) was dissolved in DCM (5mL), HATU (243mg, 0.64mmol) and DIEA (124mg, 0.96mmol) were added and reacted at room temperature for 20min, 1- (3-thiazol-2-yl) phenyl) ethyl-1-amine (65mg, 0.48mmol) was added and reacted at room temperature for 10 h. Washed with water (20 mL. times.2) and dried over anhydrous magnesium sulfate. Column chromatography (P: E: 1) gave 81mg of white solid in 69% yield. Melting point: 75-76 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.34(d,J＝7.2Hz,1H),8.06(d,J＝8.0Hz, 1H),7.40(d,J＝8.8Hz,1H),7.24(d,J＝7.2Hz,1H),7.20(d,J＝9.2Hz,2H),7.09(d, J＝7.2Hz,2H),5.37-5.29(m,1H),4.18-4.10(m,2H),2.36(s,3H),1.60(d,J＝6.8Hz, 3H),1.42(t,J＝6.8Hz,3H),1.25(d,J＝6.8Hz,6H).
Example 174
2-ethoxy-5-isobutanoylamino-N- (1- (3-methylphenyl) ethyl) picolinamide
Figure BDA0001620885820002391
2-ethoxy-5-isobutyramidopicolinic acid (80mg, 0.32mmol) was dissolved in DCM (5mL), HATU (243mg, 0.64mmol) and DIEA (98mg, 0.48mmol) were added and the reaction was carried out at room temperature for 20min, 1- (3-methylphenyl) ethyl-1-amine (65mg, 0.48mmol) was added and the reaction was carried out at room temperature for 10 h. Washed with water (15mL × 2), dried over anhydrous magnesium sulfate, and subjected to column chromatography (P: E ═ 1:1), giving 75mg of a white solid in 54% yield. Melting point: 92-94 ℃.
1H NMR(400MHZ,CDCl3)δ(ppm):8.29(d,J＝8.8Hz,2H),8.02(brs,1H),7.86 (d,J＝3.2Hz,1H),7.83(d,J＝7.2Hz,1H),7.46-7.40(m,3H),7.34(d,J＝3.2Hz, 1H),5.40-5.36(m,1H),4.16(q,J＝2.8Hz,2H),2.55-2.46(m,1H),1.64(d,J＝6.8Hz, 3H),1.42(t,J＝6.8Hz,3H),1.20(d,J＝7.0Hz,6H).
Example 175
5-isobutyrylamino-N- (3- (thiazol-2-yl) benzyl) -2- (2,2, 2-trifluoroethoxy) benzamide
Figure BDA0001620885820002401
a) 2-fluoro-5-nitrobenzoic acid methyl ester
The compound 2-fluoro-5-nitrobenzoic acid (1.5g) was added to methanol (40mL), sulfoxide chloride (1mL) was added dropwise, the reaction was heated under reflux, and the next day, the reaction was stopped, concentrated to dryness, ethyl acetate was added, washed with saturated NaCl solution 30mL × 2, dried over anhydrous magnesium sulfate, and concentrated to give a pale yellow solid 1.3g, yield 81.2%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.84-8.87(m,1H),8.41-8.44(m,1H),7.33(t,J＝ 9.2Hz,1H),4.00(s,3H).
b) 5-Nitro-2- (2,2, 2-trifluoroethoxy) benzoic acid methyl ester
Trifluoroethanol (0.18mL,2.4mmol) was added to dry THF (15mL), potassium tert-butoxide (246mg,2.2mmol) was added under argon protection, the mixture was stirred at room temperature for 10min and then moved to an ice bath, a THF (15mL) solution of the compound methyl 2-fluoro-5-nitrophenylate (398mg,2mmol) was added dropwise to the reaction flask and the reaction was continued under ice bath, after 1.5h the reaction was stopped, water was added, extraction was performed with ethyl acetate 30mL × 2, the organic layers were combined, washed with a saturated NaCl solution 20mL × 2, dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P ═ 1:12, E: P ═ 1:10) to give 340mg of a white solid in 60.9% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.76(d,J＝2.4Hz,1H),8.39(dd,J1＝9.2Hz,J2＝2.4Hz,1H),7.08(d,J＝9.2Hz,1H),4.54(q,J＝8.0Hz,2H),3.96(s,3H).
c) 5-amino-2- (2,2, 2-trifluoroethoxy) benzoic acid methyl ester
Methyl 5-nitro-2- (2,2, 2-trifluoroethoxy) benzoate (300mg) was added to EtOH (20mL), 10% Pd/C (90mg) was added, hydrogenation was carried out at normal temperature and pressure for 4 hours, and the reaction was stopped, followed by filtration and concentration to give 260mg of a pale yellow oil with a yield of 97.3%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.14(s,1H),6.90(d,J＝8.8Hz,1H),6.78(d,J＝ 8.4Hz,1H),4.32(q,J＝8.4Hz,2H),3.89(s,3H),3.66(brs,2H).
d) 5-Isobutyrylamino-2- (2,2, 2-trifluoroethoxy) benzoic acid methyl ester
Methyl 5-amino-2- (2,2, 2-trifluoroethoxy) benzoate (226mg,0.907mmol), DMF (15mL), EDC (348mg,1.8mmol), HOBt (243mg,1.8mmol), DIEA (0.3mL,1.8mmol) and isobutyric acid (0.084mL,0.907mmol) were added, the reaction was stirred at room temperature, the reaction was stopped the next day, water was added, ethyl acetate 30mL × 2 was used, the combined organic layers were washed with saturated NaCl solution 20mL × 2, dried over anhydrous magnesium sulfate, and column chromatography (E: P ═ 1:5) gave 210mg of a white solid in 72.6% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.84-7.86(m,2H),7.33(s,1H),6.99(d,J＝9.2 Hz,1H),4.32(q,J＝8.4Hz,2H),3.89(s,3H),2.49-2.54(m,1H),1.25(d,J＝6.8Hz, 6H).
e) 5-isobutyrylamino-2- (2,2, 2-trifluoroethoxy) benzoic acid
Methyl 5-isobutyramido-2- (2,2, 2-trifluoroethoxy) benzoate (181mg,0.567mmol) is placed in a reaction bottle, THF (3mL) and MeOH (3mL) are added, lithium hydroxide (18mg,0.737mmol) is dissolved in water (2 mL), the solution is dripped into the reaction bottle, the reaction is stirred at room temperature after dripping, the reaction is stopped the next day, concentration is carried out, water is added, 10mL of diethyl ether is used for extraction, the pH value of a water layer is adjusted to about 3 by dilute hydrochloric acid solution, solid is separated out, suction filtration is carried out, a filter cake is washed by water, and 140mg of white solid is obtained, and the yield is 81.4%.
1H-NMR(400MHz,CDCl3)δ(ppm):12.83(s,1H),9.87(s,1H),7.95(s,1H),7.73(d, J＝8.8Hz,1H),7.15(d,J＝8.8Hz,1H),4.69(q,J＝8.8Hz,2H),2.49-2.58(m,1H), 1.05(d,J＝6.4Hz,6H).
f) 5-isobutyrylamino-N- (3- (thiazol-2-yl) benzyl) -2- (2,2, 2-trifluoroethoxy) benzamide
5-Isobutyrylamino-2- (2,2, 2-trifluoroethoxy) benzoic acid (120mg,0.39mmol) was added to anhydrous DMF (15mL), EDC (150mg,0.78mmol) was added, HOBt (105mg,0.78mmol) and DIEA (0.17mL,0.975mmol) were added, 3- (thiazol-2-yl) phenyl) methylamine (186mg,0.98mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with ethyl acetate (30 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (D: M75: 1) to give 55mg of a white solid in 26.8% yield. Melting point: 182 ℃ and 184 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.28(d,J＝6.8Hz,1H),7.95(s,1H),7.86-7.90 (m,4H),7.68(s,1H),7.40-7.45(m,2H),7.34(s,1H),6.87(d,J＝8.8Hz,1H),4.71(d, J＝5.2Hz,2H),4.42(q,J＝8.0Hz,2H),2.50-2.54(m,1H),1.22(d,J＝6.4Hz,6H).
Example 176
5-isobutyramido-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) -2- (2,2, 2-trifluoroethoxy) benzamide
Figure BDA0001620885820002411
5-isobutyrylamino-2- (2,2, 2-trifluoroethoxy) benzoic acid (120mg, 0.39mmol) was added to anhydrous DMF (15mL), EDC (150mg,0.78mmol) was added, HOBt (105mg,0.78mmol) and DIEA (0.17mL,0.975mmol) were added, 1- (3- (thiazol-2-yl) phenyl) ethylamine (96mg,0.47mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with ethyl acetate (30 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P ═ 1:2, E: P ═ 1:1.5) to give 155mg of a white solid with a yield of 80.7%. Melting point: 178-
1H-NMR(400MHz,CDCl3)δ(ppm):8.27(d,J＝8.8Hz,1H),7.97(s,1H),7.81-7.89 (m,4H),7.66(s,1H),7.40-7.46(m,2H),7.33(s,1H),6.85(d,J＝8.8Hz,1H), 5.32-5.36(m,1H),4.44-4.53(m,2H),2.45-2.50(m,1H),1.60(d,J＝7.2Hz,3H),1.19 (d,J＝6.8Hz,6H).
Example 177
2-nitro-N- (3- (thiazol-2-yl) benzyl) -5- (2,2, 2-trifluoroethoxy) benzamide
Figure BDA0001620885820002421
a) 5-fluoro-2-nitro-benzoic acid methyl ester
2-Nitro-5-fluorobenzoic acid (1.5g) was added to 40mL of methanol, 1mL of thionyl chloride was added dropwise, the reaction was refluxed with heating, and the next day, the reaction was stopped, concentrated to dryness, ethyl acetate was added, washed with 30mL of saturated NaCl solution × 2, dried over anhydrous magnesium sulfate, and concentrated to give a pale yellow solid with a yield of 80.7% of 1.3 g.
1H-NMR(400MHz,CDCl3)δ(ppm):8.84～8.86(m,1H),8.41～8.44(m,1H),7.34(t, J＝9.2Hz,1H),4.00(s,3H).
b) 2-Nitro-5- (2,2, 2-trifluoroethoxy) benzoic acid methyl ester
Trifluoroethanol (0.36mL,4.8mmol) was added to dry THF (20mL), potassium tert-butoxide (493mg,4.4mmol) was added under argon protection, the mixture was stirred at room temperature for 10min and then moved to an ice bath, a THF (15mL) solution of 5-fluoro-2-nitro-methyl benzoate (796mg,4mmol) was added dropwise to the reaction flask, the reaction was continued under ice bath, 1h later the reaction was stopped, water was added, ethyl acetate 50mL × 2 extraction was performed, the organic layers were combined, the mixture was washed with a saturated NaCl solution 40mL × 2, dried over anhydrous magnesium sulfate, concentrated, and column chromatography was performed (E: P ═ 1:12, E: P ═ 1:10) to obtain 900mg of a white solid with a yield of 80.6%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.76(d,J＝2.4Hz,1H),8.39(dd,J1＝9.2Hz,J2＝2.4Hz,1H),7.08(d,J＝9.2Hz,1H),4.54(q,J＝8.0Hz,2H),3.96(s,3H).
c) 2-nitro-5- (2,2, 2-trifluoroethoxy) benzoic acid
Putting 2-nitro-5- (2,2, 2-trifluoroethoxy) methyl benzoate (200mg,0.716mmol) into a reaction bottle, adding THF (3mL) and MeOH (3mL), dissolving lithium hydroxide (22.3mg,0.93mmol) into water (2mL), dropwise adding into the reaction bottle, stirring at room temperature for reaction after dropwise adding, stopping reaction after 2h, concentrating, adding water, extracting with diethyl ether (10 mL), adjusting the pH value of a water layer to be about 3 with dilute hydrochloric acid solution, separating out solids, performing suction filtration, and washing a filter cake with water to obtain 150mg of white solid with the yield of 78.9%.
1H-NMR(400MHz,DMSO-d6)δPPm:13.45(s,1H),8.49(s,1H),8.43(d,J＝9.2Hz, 1H),7.46(d,J＝9.2Hz,1H),5.03(q,J＝8.4Hz,2H).
d) 2-nitro-N- (3- (thiazol-2-yl) benzyl) -5- (2,2, 2-trifluoroethoxy) benzamide
2-Nitro-5-trifluoroethoxybenzoic acid (80mg,0.3mmol) was added to anhydrous DMF (15mL), EDC (115mg,0.6mmol) was added, HOBt (81mg,0.6mmol) and DIEA (0.13mL,0.75mmol) were added, (3- (thiazol-2-yl) phenyl) methylamine (171mg,0.9mmol) was added, stirred at room temperature overnight, the reaction was poured into water, extracted with ethyl acetate (30 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P ═ 1:4, E: P ═ 1:2.5) to give 90mg of a white solid in 68.7% yield. Melting point: 120 ℃ C. & 122 ℃ C
1H-NMR(400MHz,CDCl3)δ(ppm):9.11(d,J＝3.2Hz,1H),8.35(dd,J1＝9.2Hz, J2＝2.8Hz,1H),7.98(s,1H),7.59(brs,1H),7.43-7.47(m,2H),7.35(d,J＝3.2Hz, 1H),7.01(d,J＝9.2Hz,1H),4.73(d,J＝5.6Hz,2H),4.58(q,J＝7.6Hz,2H).
Example 178
2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) -5- (2,2, 2-trifluoroethoxy) benzamide
Figure BDA0001620885820002431
a) 2-amino-5- (2,2, 2-trifluoroethoxy) benzoic acid methyl ester
Methyl 2-amino-5- (2,2, 2-trifluoroethoxy) benzoate (750mg) was added to EtOH (25mL), 10% Pd/C (225mg) was added, hydrogenation was carried out at normal temperature and pressure for 16 hours, and the reaction was stopped, filtered, and concentrated to give 650mg of a yellow oil in 97.1% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):7.15(s,1H),6.91(d,J＝8.8Hz,1H),6.79(d,J＝ 8.4Hz,1H),4.32(q,J＝8.4Hz,2H),3.89(s,3H).
b) 2-dimethylamino-5- (2,2, 2-trifluoroethoxy) benzoic acid methyl ester
Placing methyl 2-amino-5- (2,2, 2-trifluoroethoxy) benzoate (105mg,0.42mmol) in a reaction bottle, adding acetonitrile (8mL), adding potassium carbonate (174mg,1.26mmol), adding methyl iodide (0.06mL,0.93mmol), heating and refluxing for 4h, adding methyl iodide (0.03mL,0.465mmol), continuing heating and refluxing for 3h, stopping reaction, filtering, concentrating, and performing column chromatography (E: P: 1:15, E: P: 1:8) to obtain the target compound 40mg with a yield of 34.4%.
1H-NMR(400MHz,CDCl3)δ(ppm):7.17(s,1H),6.99(d,J＝8.8Hz,1H),6.84(d,J＝ 8.0Hz,1H),4.32(q,J＝8.4Hz,2H),3.91(s,3H),2.94(s,6H).
c) 2-dimethylamino-5- (2,2, 2-trifluoroethoxy) benzoic acid
Methyl 2-dimethylamino-5- (2,2, 2-trifluoroethoxy) benzoate (180mg,0.65mmol) was placed in a reaction flask, THF (3mL) and MeOH (3mL) were added, lithium hydroxide (24mg,0.97mmol) was dissolved in water (2mL), the solution was added dropwise to the reaction flask, the reaction was stirred at room temperature for 6 hours, the reaction was stopped, the reaction was concentrated, water was added, ether (10 mL) was used for extraction, the PH of the aqueous layer was adjusted to about 3 with dilute hydrochloric acid solution, no solid was precipitated, the aqueous layer was extracted with a mixture of DCM: MeOH 10:1, the organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 145mg of pale yellow solid, yield 85.2%.
1H-NMR(400MHz,DMSO-d6)δ(ppm):12.75(s,1H),7.06(d,J＝8.8Hz,1H),6.98 (s,1H),6.88(d,J＝9.2Hz,1H),4.57(q,J＝9.2Hz,2H),2.85(s,6H).
d)2- (dimethylamino) -N- (3- (thiazol-2-yl) benzyl) -5- (2,2, 2-trifluoroethoxy) benzamide
2-dimethylamino-5- (2,2, 2-trifluoroethoxy) benzoic acid (80mg,0.3mmol) was added to anhydrous DMF (15 mL), EDC (115mg,0.6mmol) was added, HOBt (81mg,0.6mmol) and DIEA (0.13mL, 0.75mmol) were added, (3- (thiazol-2-yl) phenyl) methylamine (171mg,0.9mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with ethyl acetate (30 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P ═ 1:4, E: P ═ 1:2.5) to give 80mg of a white solid in 61% yield. Melting point: 122 ℃ C
1H-NMR(400MHz,CDCl3)δ(ppm):7.95(s,1H),7.85～7.95(m,3H),7.62(brs,1H), 7.42-7.45(m,2H),7.32(d,J＝3.2Hz,1H),6.82-6.85(m,2H),4.71(d,J＝5.6Hz,2H), 4.36(q,J＝8.0Hz,2H),2.96(s,6H).
Example 179
2- (dimethylamino) -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) -5- (2,2, 2-trifluoroethoxy) benzamide
Figure BDA0001620885820002441
The compound 2-dimethylamino-5- (2,2, 2-trifluoroethoxy) benzoic acid (110mg,0.418mmol) was taken, anhydrous DMF (15mL) was added, EDC (160mg,0.836mmol) was added, HOBt (113mg,0.836mmol) and DIEA (0.18mL,1.05mmol) were added, 1- (3- (thiazol-2-yl) phenyl) ethylamine (102mg,0.50mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with ethyl acetate (30mL × 2), the combined organic layers were washed with saturated NaCl (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P ═ 1:4, E: P ═ 1:2.5) to give 130mg of a white solid, 69.1% yield. Melting point: 126 ℃ and 127 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):7.95-7.98(m,2H),7.83-7.85(m,2H),7.58(brs, 1H),7.38-7.46(m,2H),7.31(d,J＝2.8Hz,1H),6.78-6.86(m,2H),5.32-5.36(m,1H), 4.38-4.46(m,2H),2.93(s,6H),1.60(d,J＝7.2Hz,3H),.
Example 180
2-fluoro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) -5- (trifluoromethyl) benzamide
Figure BDA0001620885820002451
2-fluoro-5-trifluoromethylbenzoic acid (120mg,0.577mmol) was added to anhydrous DMF (15mL), EDC (221mg,1.15mmol) was added, HOBt (156mg,1.15mmol) and DIEA (0.4mL,2.3mmol) were added, 1- (3- (thiazol-2-yl) phenyl) ethylamine (141mg,0.69mmol) was added, stirring was carried out at room temperature overnight, the reaction mixture was poured into water, extraction was carried out with ethyl acetate (30 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography was carried out (E: P. RTM.1: 4, E: P. RTM.1: 2) to give 160mg of a white solid in 70.4% yield. Melting point: 118-119 deg.C
1H-NMR(400MHz,CDCl3)δ(ppm):8.41(d,J＝6.8Hz,1H),8.03(s,1H),7.84-7.88 (m,2H),7.70-7.78(m,1H),7.42-7.46(m,2H),7.34(d,J＝3.2Hz,1H),7.23-7.28(m, 1H),6.96-7.04(m,1H),5.39-5.44(m,1H),1.67(d,J＝7.2Hz,3H).
Example 181
2- (dimethylamino) -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) -5- (trifluoromethyl) benzamide
Figure BDA0001620885820002452
a)2- (dimethylamino) -5- (trifluoromethyl) benzoic acid
2-fluoro-5-trifluoromethylbenzoic acid (624mg,3mmol) was placed in a reaction flask, acetonitrile (25mL) was added, dimethylamine hydrochloride (316mg,3.9mmol) was added, DIEA (1.05mL,6mmol) was added, the reaction was stirred at room temperature, dimethylamine hydrochloride (316mg,3.9mmol) was added the next day, DIEA (1.05mL,6mmol) was added, the reaction was heated under reflux, 20 hours later, the reaction was stopped, the reaction was concentrated, ethyl acetate (60mL) was added, the mixture was washed with a saturated NaCl solution (20mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (D: M ═ 70:1) was performed to obtain 350mg of a white solid with a yield of 50%.
1H-NMR(400MHz,CDCl3)δ(ppm):8.59(s,1H),7.87(d,J＝8.4Hz,1H),7.63(d,J＝ 8.4Hz,1H),2.88(s,6H).
b)2- (dimethylamino) -N- (1- (3- (thiazol-2-yl) phenyl) ethyl) -5- (trifluoromethyl) benzamide
2- (dimethylamino) -5- (trifluoromethyl) benzoic acid (120mg,0.51mmol) was added to anhydrous DMF (15mL), EDC (196mg,1.02mmol) was added, HOBt (138mg,1.02mmol) and DIEA (0.22mL, 1.275mmol) were added, 1- (3- (thiazol-2-yl) phenyl) ethylamine (126mg,0.62mmol) was added, stirred at room temperature overnight, the reaction was poured into water, extracted with ethyl acetate (30 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P. RTM. 1:4, E: P. RTM. 1:2) to give 180mg of a white solid in 84.1% yield. Melting point: 128-129 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):9.25(d,J＝7.2Hz,1H),8.30(s,1H),8.05(s, 1H),7.84-7.88(m,2H),7.62(d,J＝8.0Hz,1H),7.41-7.47(m,2H),7.35(t,J＝2.8Hz, 1H),7.22(d,J＝8.8Hz,1H),5.40-5.45(m,1H),2.75(s,6H),1.64(d,J＝6.8Hz,3H).
Example 182
3-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Figure BDA0001620885820002461
a) 3-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
3-Nitrobenzoic acid (125mg,0.748mmol) was added to anhydrous DMF (15mL), EDC (287mg, 1.5mmol) was added, HOBt (202mg,1.5mmol) and DIEA (0.32mL,1.87mmol) were added, 1- (3- (thiazol-2-yl) phenyl) ethylamine (168mg,0.82mmol) was added, stirred at room temperature overnight, the reaction was poured into water, extracted with ethyl acetate (30 mL. times.2), the combined organic layers were washed with saturated NaCl (30 mL. times.2), dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (E: P. times.1: 2) to give 250mg of a white solid in 94.6% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.60(s,1H),8.35(d,J＝8.4Hz,1H),8.16(d,J＝ 8.0Hz,1H),7.83-7.87(m,2H),7.63(t,J＝8.0Hz,1H),7.42-7.49(m,2H),7.35(d,J＝ 2.8Hz,1H),6.63(d,J＝6.8Hz,1H),5.38-5.42(m,1H),1.69(d,J＝6.8Hz,3H).
b) 3-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
The reaction mixture was hydrogenated at room temperature and pressure using 3-nitro-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (200mg) and EtOH (15mL) in the presence of 10% Pd/C (60mg) and was stopped the next day, followed by filtration and concentration to give 170mg of off-white solid in 92.8% yield.
1H-NMR(400MHz,CDCl3)δ(ppm):8.01(s,1H),7.86(s,1H),7.83(d,J＝7.2Hz, 1H),7.39-7.46(m,2H),7.33(s,1H),7.13-7.20(m,2H),7.07(d,J＝6.4Hz,1H),6.78 (d,J＝8.0Hz,1H),6.37(d,J＝6.8Hz,1H),5.34-5.39(m,1H),1.63(d,J＝6.8Hz, 3H).
c) 3-isobutyrylamino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide
Isobutyric acid (0.04mL,0.41mmol) was added to anhydrous DMF (15mL), EDC (157mg,0.82 mmol) was added, HOBt (111mg,0.82mmol) and DIEA (0.18mL,1.025mmol) were added, followed by 3-amino-N- (1- (3- (thiazol-2-yl) phenyl) ethyl) benzamide (132mg,0.41mmol) and stirred at room temperature overnight, the reaction solution was poured into water, extracted with ethyl acetate (30mL × 2), the combined organic layers were washed with saturated NaCl (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column chromatography (E: P ═ 1:2, E: P ═ 1:1.5) gave 50mg of a white solid in 37.3% yield. Melting point: 184 ℃ and 186 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):8.01(s,1H),7.86-7.89(m,2H),7.81(d,J＝6.8 Hz,2H),7.71(s,1H),7.31-7.49(m,5H),6.57(d,J＝6.8Hz,1H),5.34-5.38(m,1H), 2.47-2.53(m,1H),1.62(d,J＝6.8Hz,3H),1.21(d,J＝6.8Hz,6H).
Example 183
N- (3- (thiazol-2-yl) benzyl) -2, 5-bis (2,2, 2-trifluoroethoxy) benzamide
Figure BDA0001620885820002471
2, 5-bistrifluoroethoxybenzoic acid (120mg,0.38mmol) was added to anhydrous DMF (15mL), EDC (146mg,0.76mmol) was added, HOBt (103mg,0.76mmol) and DIEA (0.17mL,0.95mmol) were added, (3- (thiazol-2-yl) phenyl) methylamine (179mg,0.94mmol) was added, stirring was carried out overnight at room temperature, the reaction solution was poured into water, extracted with ethyl acetate (30mL × 2), the combined organic layers were washed with saturated NaCl (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P ═ 1:4, E: P ═ 1:3) to give 60mg of white solid, yield 32.2%. Melting point: 124 ℃ and 126 DEG C
1H-NMR(400MHz,CDCl3)δ(ppm):7.96(s,1H),7.85-7.90(m,3H),7.80(d,J＝3.2 Hz,1H),7.44(d,J＝4.4Hz,2H),7.34(d,J＝3.2Hz,1H),7.10(dd,J1＝8.8Hz,J2＝ 2.8Hz,1H),6.88(d,J＝9.2Hz,1H),4.71(d,J＝5.6Hz,2H),4.35-4.45(m,4H).
Example 184
N- (1- (3- (thiazol-2-yl) phenyl) ethyl) -2, 5-bis (2,2, 2-trifluoroethoxy) benzamide
Figure BDA0001620885820002481
2, 5-bistrifluoroethoxybenzoic acid (120mg,0.38mmol) was added to anhydrous DMF (15mL), EDC (146mg,0.76mmol) was added, HOBt (103mg,0.76mmol) and DIEA (0.17mL,0.95mmol) were added, 1- (3- (thiazol-2-yl) phenyl) ethylamine (92mg,0.45mmol) was added, stirred at room temperature overnight, the reaction solution was poured into water, extracted with ethyl acetate (30mL × 2), the combined organic layers were washed with saturated NaCl (30mL × 2), dried over anhydrous magnesium sulfate, concentrated, and column-chromatographed (E: P ═ 1:4, E: P ═ 1:3) to give 160mg of a colorless oil in 80.8% yield.
1H-NMR(400MHz,CDCl3)δPPm:7.99(s,1H),7.91(d,J＝6.4Hz,1H),7.82-7.86 (m,2H),7.75(d,J＝2.8Hz,1H),7.40-7.46(m,2H),7.33(d,J＝2.8Hz,1H),7.09(dd, J1＝8.8Hz,J2＝2.8Hz,1H),6.87(d,J＝9.2Hz,1H),5.30-5.35(m,1H),4.40～4.55 (m,2H),4.34(q,J＝8.0Hz,1H),1.61(d,J＝6.8Hz,3H).
Pharmacological experiments:
example 1 in vitro screening test results
1. IC of compound for inhibiting Kv2.1 potassium current50
1.1 Experimental methods:
1.1.1 cell culture
HEK293 cells transfected with human Kv2.1 potassium channel subtype (HEK293/Kv2.1) were cultured in DMEM medium containing 0.2g/L G418, 10% fetal bovine serum, 1 ten thousand U/L penicillin and streptomycin; passages were performed when the cells reached 80% confluence and were seeded in 35mm dishes for subsequent electrophysiological recording.
1.1.2 electrophysiological recording
Record the extracellular fluid fraction (mmol. L) of Kv2.1 potassium channel current-1):NaCl 140,KCl 5,MgCl 21, HEPES 10, glucose 10, pH 7.40; electrode internal liquid component (mmol. L)-1):KCl 140,MgCl22, EGTA 10, HEPES 10, ATP-2Na 2, pH 7.20. Cultured HEK293/Kv2.1 was rinsed 2 times with extracellular fluid and placed under an inverted phase contrast microscope. The glass microelectrode (raw material: GG17, external diameter: 15mm, internal diameter: 7.5mm) is drawn by a P-97 type drawing instrument, and the resistance is 3-5M omega after filling the electrode internal liquid. Selecting the fine particles with regular edges and no obvious particles in cells under a microscopeAnd moving the electrode, slightly pressing the surface of the cell, forming a G omega seal between the tip of the electrode and the surface of the cell by using negative pressure, and then breaking the membrane by using larger negative pressure to compensate the capacitance and the series impedance of the electrode so as to form a whole-cell recording mode. The cells were clamped at-70 mV, depolarized at a step of 20mV from-50 mV to +50mV for 300ms, and the current amplitude measured at the +50mV potential was the Kv2.1 potassium current. Whole-cell currents were recorded by an EPC-10 patch-clamp amplifier, with 3kHz low-pass filtering and a sampling rate of 20 kHz. Pulse 8.5 software was used for stimulus delivery and signal acquisition. All experiments were performed at room temperature (23-25 ℃).
1.1.3 statistical analysis
To calculate the IC of the compound to inhibit Kv2.150At least 3 concentrations of each compound, at least n-3 per concentration, were chosen and IC was fitted using Origin 7.550。
The results are shown in Table 1
TABLE 1 IC inhibition of Kv2.1 by some of the compounds50
Figure BDA0001620885820002491
Example 2 results of in vivo Whole animal pharmacodynamics experiments
1. EXAMPLE 61 Whole animal Experimental results
1.1 Effect of intraperitoneal injection of 61 on blood lipids in KKAY mice
1.1.1 Experimental methods
Administration dose: 3mg/kg of the blood lipid is administrated in the abdominal cavity continuously for four days, after fasting for 1 hour at the last time, and the blood lipid is measured 1 hour after the medicine is taken.
Preparing the medicine: 10% DMSO + 30% PEG-400+ physiological saline
Neither control nor model was given solvent.
1.1.2 the results of the experiments are shown in Table 2
Example 61 has a significant blood lipid lowering effect.
TABLE 2 Effect of example 61 administration on blood lipids in KKay mice
Figure BDA0001620885820002501
The data are represented as: the average value is +/-SD,##p<0.01vs.C57,*p<0.05vs. model set
1.2 example 61 Effect of oral administration on blood lipids in KKAY mice
1.2.1 Experimental methods
Administration dose: 10. 20mg/kg was administered orally for four days, after the last 1 hour of fasting, and blood lipids were measured 1 hour after administration.
Preparing the medicine: 0.5% CMC-Na suspension milling
The control and model were administered with solvent, fasted for 1 hour, blood was taken 1 hour after the drug administration, and blood lipid was measured. 1.2.2 the results of the experiment are shown in Table 3:
Example 61 has a certain lowering effect on triglycerides and is dose dependent. See table 3 for details:
TABLE 3 Effect of example 61 Single administration on blood glucose and blood lipids in KKay mice
Figure BDA0001620885820002502
The data are represented as: the mean value. + -. SEM,##p<0.01vs.C57,*p<0.05vs. model set
1.3 study of the improving effects of example 61 on scopolamine-induced learning and memory deficits in mice
1.3.1 methods of experiment:
a compound: example 61 white powder
Positive drug Anrishu (donepezil) tablet purchased from pharmacy network (Beijing toilet pharmacy)
Molding medicine: scopolamine, cat # A4559 available from Sigma
Experimental animals: male ICR mice 112 (actually 115), SPF grade. The weight of the test is 20-30 g, and the test is purchased from Beijing Weitonglihua laboratory animal technology Co.
Experimental grouping:
mice were randomly divided into 7 groups: blank group, solvent group, model group, positive drug group, therapeutic drug example 61 small dose group (ip.0.3mg/kg mouse body weight), therapeutic drug example 61 medium dose group (ip.1mg/kg mouse body weight), therapeutic drug example 61 large dose group (ip.3mg/kg mouse body weight).
The positive drug group and the therapeutic drug group were administered donepezil (ig.3mg/kg mouse body weight) and therapeutic drug example 61, respectively, continuously, 1 day after the therapeutic drug was administered continuously, a jump bench test was started, the therapeutic drug and the positive drug were administered intragastrically 1 hour before the start of the behavioral test every day, and scopolamine was administered intraperitoneally 30 minutes before the start of the behavioral test until the end of the test. The model group was intraperitoneally injected with scopolamine at a dose of 10ml/kg mouse weight, and the solvent group was intraperitoneally injected with solvent (20% DMSO, 10% PEG400, and 70% N.S.) at a dose of 10ml/kg mouse weight.
1.3.2 the results of the experiment are shown in FIG. 1:
examples 610.3, 1 and 3mg/kg significantly reduced the number of scopolamine-induced bench jump errors in demented mice, showing improved learning and memory effects.
1.4 antidepressant action of example 61
1.4.2 Experimental methods
Medicine preparation: example 61, white powder, insoluble in water.
The preparation method comprises the following steps: 0.5 percent of sodium carboxymethyl cellulose is prepared into a suspension solution.
Animals: ICR mice, male 20-22 g.
Mouse tail suspension experiment:
mice were dosed one by one in turn at 10min intervals per round. After administration for 60min, the mouse was held with a small clamp at 1cm from its tip on a tail suspension with the mouse's head facing down and more than 15cm from the ground. Adjacent mice are separated by a partition board with the distance of 15 cm. The video is recorded for 6min, and the immobility time of the mice within 4min is counted. And calculating the change rate of the tail suspension immobility time of the mice of the test drug compared with the control group and carrying out statistical analysis.
The administration mode comprises the following steps: the dosage volume is 10ml/kg by intraperitoneal injection
Animal grouping: the groups were randomly divided into 4 groups, normal groups, and the group of examples 61 was intraperitoneally injected with 0.3, 1, 3mg/kg doses.
1.4.2 the results of the experiment are shown in FIG. 2:
examples 611 and 3mg/kg significantly reduced immobility time in tail-suspended mice, showing antidepressant effect.
1.5 EXAMPLE 61 Effect study on resistance to acute hypoxia (decapitation)
1.5.1 Experimental methods
After 26-30g of ICR mice were intraperitoneally administered to example 611, 3,10mg/kg for 15min, decapitation was performed. The mice were observed for mouth-opening breathing time.
1.5.2 the results of the experiment are shown in Table 4 and FIG. 3
Example 61 showed a significant prolongation of the breath time after decapitation in ICR mice.
TABLE 4 Effect of example 61 on acute hypoxia (decapitation)
Figure BDA0001620885820002521
1.6 Effect of example 61 on anoxia resistance (jar-closed method)
1.6.1 Experimental methods
22-26g of ICR mice were intraperitoneally administered to example 611, 3,10mg/kg for 15min, and then the jar was sealed. Mice were observed for survival time.
1.6.2 the results of the experiment are shown in Table 5 and FIG. 4
Example 61 has a significant effect on the prolongation of survival time after hypoxia in ICR mice.
TABLE 5 Effect of example 61 on cerebral hypoxia (cupping)
Figure BDA0001620885820002522
1.7 example 61 Effect of intravenous injection on the cerebral infarct volume in MCAO rats
1.7.1 Experimental methods
Medicine preparation: example 61, white powder, insoluble in water.
The preparation method comprises the following steps: 20% DMSO was now dissolved, 30% PEG400 was co-dissolved, 50% n.s.
Experimental animals: SD rat, male, 280-300g
The administration mode comprises the following steps: the injection is administered 5min after ischemia surgery, and the administration volume is 1ml/kg
Animal grouping: randomized into 4 groups, model, example 61 intravenous 0.1, 1, 3mg/kg dose groups.
1.7.2 the results of the experiment are shown in Table 6:
example 61 has a significant anti-cerebral ischemic effect.
TABLE 6 example 61 pharmacodynamic study of intravenous injection on SD rat MCAO model
Figure BDA0001620885820002531
The data are represented as: the mean value of the values is. + -. SD,**p<0.01vs. model set
2. EXAMPLE 61 optical isomers Overall animal test results
2.1 Effect of example 61, example 61-1(+) and example 61-2(-) on KKAY mouse blood lipids
2.1.1 Experimental methods
Administration dose: 20mg/kg oral administration
Preparing the medicine: 10% DMSO 40% PEG-40050% physiological saline
The test substance: example 61-1(+), example 61-2(-) and example 61
Administration volume: 0.1ml/10g bw
The administration period is as follows: the administration is continued for 4 days, once a day; fasting was performed for 1 hour before the last administration, and blood index was measured after 1 hour of fasting.
Both control and model were given solvent.
2.1.2 the results of the experiment are shown in Table 7:
the continuous oral administration of example 61-1(+), example 61-2(-) and example 61 gave a more significant effect on the reduction of triglyceride TG.
TABLE 7 Effect of example 61 administration on blood lipids in KKay mice (Mean + -SEM)
Figure BDA0001620885820002541
The data are represented as: the mean value. + -. SEM,##p<0.01vs.C57,*p<0.05vs. model set
2.2 Effect of examples 61-1(+) and 61-2(-) on ICR mouse decapitation experiments
2.2.1 Experimental methods
Test compounds: example 61-1(+), example 61-2(-)
Positive drugs: nimodipine
Solvent: 5% DMSO + 45% polyethylene glycol 400+ 50% physiological saline
The method comprises the following steps: 22-26g of ICR mice were intraperitoneally administered 10mg/kg (10ml/kg) of each compound for 30min, and then decapitation was performed. Observing the mouth opening times and survival time of the ICR mouse; the positive tool drug nimodipine 120mg/kg needs to be orally taken 60min in advance (10ml/kg), 30min before head breaking, and the same solvent is taken in the abdominal cavity. The ICR mice were observed for the number of mouth openings and the length of survival.
2.2.2 the results of the experiments are shown in Table 8
TABLE 8 influence of examples 61-1(+) and 61-2(-) on the number of decapitations and the length of survival of ICR mice.
Figure BDA0001620885820002542
Figure BDA0001620885820002551
The data are represented as: mean value. + -. SD**P<0.01,***P<0.001vs solvent control
The examples 61-1(+) and 61-2(-) have significant anti-hypoxia effects.
2.3 Effect of example 61, example 61-1(+) and example 61-2(-) on ICR mouse jar test
2.3.1 Experimental methods
Test compounds: example 61, example 61-1(+), example 61-2(-)
Positive drugs: atenolol
Solvent: 5% DMSO + 45% polyethylene glycol 400+ 50% physiological saline
The method comprises the following steps: taking 22-26g of ICR mice, carrying out intraperitoneal administration on each compound 10mg/kg (10ml/kg) for 15min, and then carrying out tank sealing. ICR mice were observed for survival time. The positive tool drug atenolol 50mg/kg (10ml/kg) needs to be orally taken 30min in advance, 15min before jar sealing, and the same solvent is given to the abdominal cavity.
2.3.2 the results of the experiments are shown in Table 9
TABLE 9 Effect of example 61, example 61-1(+), example 61-2(-) on ICR mouse smoldering pot survival time
Figure BDA0001620885820002552
The data are represented as: the mean value of the values is. + -. SD,**P<0.01,***P<0.001vs solvent control
Example 61, example 61-1(+) and example 61-2(-) have significant anti-hypoxic effects.

Claims (11)

1. A compound as shown in the general formula IA-1a or a medicinal salt thereof,
Figure FDA0003618394780000011
in the formula IA-1a,
x is selected from CRx(ii) a Y is selected from CRy(ii) a Z is selected from CRz；Rx、RyAnd RzIndependently selected from H;
R4is selected from
Unsubstituted C1-8 straight or branched chain alkyl;
R7is selected from H;
R8is selected from
CORf′1、COORf′2Wherein Rf'1、Rf′2Independently selected from the group consisting of unsubstituted C1-8 straight or branched chain alkyl;
or Rf'1Selected from unsubstituted C3-7 cycloalkyl;
or Rf'1Selected from unsubstituted five-membered aromatic heterocycles; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S;
R10is H;
R9is selected from
Hydrogen, unsubstituted C1-4 straight or branched chain alkyl;
a is selected from CRaN; b is selected from CRbN; c is selected from CRcN; d is selected from CRd、N；Ra、Rb、RcAnd RdIndependently selected from H;
R11selected from the group consisting of:
(1)ORs1、NRs3Rt1、COORs5，
the Rs1Selected from H, substituted or non-substituted C1-8 straight chain or branched chain alkyl, and the substituent is selected from F;
The Rs5Is selected from H; the Rs3Selected from H, Rt1Selected from H, unsubstituted C1-8 straight or branched chain alkyl;
(2) an unsubstituted 3-to 8-membered ring azacycloalkyl group;
(3) an unsubstituted five-membered aromatic heterocycle;
the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S.
2. A compound represented by the general formula IB-1a or a pharmaceutically acceptable salt thereof, wherein:
Figure FDA0003618394780000021
in the formula IB-1a,
x is selected from CRx(ii) a Y is selected from CRy(ii) a Z is selected from CRz；Rx、RyAnd RzIndependently selected from H;
R5、R6independently selected from C1 alkyl;
R7is selected from H;
R8is selected from CORf'1Rf'1Selected from the group consisting of unsubstituted C1-8 straight or branched chain alkyl;
R10is H;
R9is selected from
Hydrogen, unsubstituted C1-4 alkyl;
a is selected from CRaN; b is selected from CRbN; c is selected from CRcN; d is selected from CRd、N；Ra、Rb、RcAnd RdIndependently selected from H;
R11is selected from
(1) An unsubstituted oxacycloalkyl group having 3 to 8 membered rings.
3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003618394780000022
Figure FDA0003618394780000031
。
4. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt of the compound is selected from salts formed in combination with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases capable of providing a physiologically acceptable cation selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine, and ammonium salts.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycic acid, maleic acid, tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions.
6. A process for the preparation of a compound according to any one of claims 1 to 3, characterized in that it comprises the following steps:
Figure FDA0003618394780000041
reagents and reaction conditions: (a) o-benzotriazole-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole, diisopropylethylamine and N, N-dimethylformamide at room temperature; or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, diisopropylethylamine, N-dimethylformamide, at room temperature; (b) thionyl chloride, anhydrous methanol, 60 ℃; (c) r4I or R4Br, potassium carbonate, anhydrous N, N-dimethylformamide, 60 ℃; (d) sodium hydroxide, tetrahydrofuran/water, room temperature; (e) tetratriphenylpalladium phosphide, sodium carbonate, R11B(OH)21, 4-dioxane, water and argon at 110 ℃; or azacycloalkyl, tris (dibenzylideneacetone) dipalladium, (±) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl, sodium tert-butoxide, toluene, argon, 100 ℃; (f) methyl magnesium bromide, anhydrous tetrahydrofuran, argon, 0 ℃; (g) methyllithium, anhydrous tetrahydrofuran, argon, -66 ℃; (h) 50% hydroxylamine aqueous solution, ethanol, water, 60 ℃; (i) zinc powder, hydrochloric acid, ethanol and water at room temperature; or 10% palladium on carbon, ammonium formate, methanol, refluxing; (k) 10% palladium/carbon, hydrogen, ethanol, room temperature; or iron powder, ammonium chloride, ethanol and water are refluxed; (l) Rf' 1COCl or Rf'2OCOCOCl, triethylamine, dichloromethane, 0 ℃; (n) R5R6-NH, acetonitrile, diisopropylethylAmine, 65 ℃; wherein said X, Y, Z, A, B, C, D, R4、R5、R6、R7、R8、R9、R11、Rf′1And Rf'2Is as defined in any one of claims 1-2.
7. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of an inhibitor of kv 2.1.
9. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of diseases associated with kv 2.1.
10. Use according to claim 9, wherein the disease associated with kv2.1 is selected from a psychiatric neurological disease, a metabolic disease or a cardiovascular disease.
11. Use according to claim 10, characterized in that said Kv2.1 related disease is selected from the group consisting of Alzheimer's disease, depression, diabetes, atherosclerosis and stroke.
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