CN115215861A - Aromatic heterocycle substituted alkyne compound and preparation method and application thereof - Google Patents

Aromatic heterocycle substituted alkyne compound and preparation method and application thereof Download PDF

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CN115215861A
CN115215861A CN202210394598.1A CN202210394598A CN115215861A CN 115215861 A CN115215861 A CN 115215861A CN 202210394598 A CN202210394598 A CN 202210394598A CN 115215861 A CN115215861 A CN 115215861A
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optionally substituted
amino
cyano
hydrogen
halogen
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CN115215861B (en
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宋云龙
徐文清
寇红艳
董卫兵
穆永钊
李宁
李英
李磐
刘金镖
尹洲
陈丽光
蔡欣
王琦琳
党群
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Shanghai Yishi Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Abstract

The invention provides a compound with a brand-new structure as a PAK4 inhibitor, a preparation method of the compound and application of the compound in treating diseases mediated by the PAK4 inhibitor. The compound designed by the invention has a novel structure, and provides a new direction for the development of PAK4 inhibitor drugs. Researches show that the compounds have strong inhibition effect on human receptor PAK4, and can be used as a prospect compound for treating diseases mediated by PAK4 inhibitors. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.

Description

Aromatic heterocycle substituted alkyne compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to aromatic heterocycle substituted alkyne compounds, and a preparation method and application thereof.
Background
PAK is P21 activated protein kinases (PAKs), is an evolutionarily conserved serine/threonine protein kinase, and is an effector protein of Rho families Cdc42 and Rac. PAK4 is representative of members of the PAK family II, and is activated by growth factors and other extracellular signals and regulates a variety of biological functions through downstream binding proteins or kinase substrates. PAK4 regulates a variety of cellular functions including cell adhesion, migration, proliferation and survival, and thus deregulated expression and activity of PAK4 contributes to the development of a variety of diseases. PAK4 functions in vivo in several ways: firstly, PAK4 is closely related to the heart development and the nervous system development of embryos; PAK4 regulates the G1 phase of the cell cycle by regulating the protein level of p21, and also regulates G2/M phase transformation by phosphorylating Ran. Secondly, the PAK4 protects cells through different mechanisms, inhibits apoptosis of the cells and promotes survival of the cells; PAK4 may inactivate BAD by phosphorylation, thereby inhibiting apoptosis. In a third aspect, PAK4 can phosphorylate SSH-1L (Slingshot-1L) and LIMK, and realizes dynamic regulation and control of actin. PAK4 plays a key role in the progression of cancer by accelerating epithelial-mesenchymal transition, invasion and metastasis, and PAK4 is highly expressed in most tumor cells, and thus PAK4 is considered as an attractive therapeutic target for a variety of cancers.
At present, a plurality of PAK4 inhibitor projects are under research, wherein most of the PAK4 inhibitor projects are in preclinical stage, such as LCH-7749944 (also known as GNF-Pf-2356), which is a novel and efficient PAK4 inhibitor and can effectively inhibit the proliferation of gastric cancer cells of a human by down-regulating a PAK4/c-Src/EGFR/cyclin D1 pathway. In addition, LCH-7749944 can obviously inhibit the migration and invasion of gastric cancer cells, and simultaneously block the pathways of PAK4/LIMK1/cofilin and PAK4/MEK-1/ERK1/2/MMP 2. Importantly, LCH-7749944 has inhibitory effect on PAK4, successfully inhibits the activity of EGFR, and the results provide new insights for the development of PAK4 inhibitors and potential treatment strategies of gastric cancer. In addition, GL-1196, LC-0882, KY-04031, GNE-2861, CPG74524A and the like are in preclinical stages, which all prove to have potentially good antitumor activity.
Figure BDA0003595294650000011
Also, some PAK4 inhibitors have progressed to the clinical stage, for example KPT-9274 (also known as ATG-019), a dual PAK4 and NAMPT inhibitor, developed by Karyopharm Therapeutics Inc. and Antegene Therapy Limited. Preclinical studies have shown that KPT-9274 and its analog KPT-8752 can reduce the steady-state level of PAK4 protein in triple negative breast cancer cells. These compounds may also prevent the growth of breast cancer cells in vitro and stimulate apoptosis. Most importantly, KPT-9274 taken orally can reduce the tumorigenesis of a human mouse model of triple negative breast cancer, and is a novel method for treating triple negative breast cancer. In addition, the anti-PD-1 combined KPT-9274 has stronger anti-tumor effect on B16 mouse melanoma compared with the single use of the anti-PD-1 and KPT-9274.
Figure BDA0003595294650000021
In conclusion, the PAK4 inhibitor can be used as a potentially powerful new anti-cancer drug. Research on development of new drugs with PAK4 as a target has a positive effect of filling up the blank for solving the unmet clinical requirements.
Disclosure of Invention
The invention aims to provide a compound with a brand-new structure as a PAK4 inhibitor, a preparation method of the compound and application of the compound in treating diseases mediated by the PAK4 inhibitor.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure BDA0003595294650000022
wherein, the first and the second end of the pipe are connected with each other,
Figure BDA0003595294650000023
are respectively a single bond or a double bond, but are not simultaneously a single bond or a double bond;
when in use
Figure BDA0003595294650000024
Selected from single bonds, X 1 Is selected from N; x 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; x 3 Is selected from C (R) 2 ) Or N, wherein R 2 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group is independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Alkylthio radical, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylthio group;
when in use
Figure BDA0003595294650000031
Selected from the group consisting of double bonds, X 1 Is selected from C; x 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionallysubstituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; x 3 Selected from-O-, -S-, -C (R) 3 )(R 3 ) -or-N (R) 3 ) -, wherein each R 3 Independently at occurrence, is selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Alkylthio radical, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylthio groups;
Y 1 、Y 2 、Y 3 are each independently selected from C (R) 4 ) Or N, wherein R 4 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; said optionally substituted means substituted by a substituent groupWherein the hydrogen is unsubstituted or substituted independently at one or more substitutable sites by a substituent selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
Figure BDA0003595294650000032
are respectively a single bond or a double bond, but are not double bonds at the same time;
when in use
Figure BDA0003595294650000033
Is a single bond, and is a single bond,
Figure BDA0003595294650000034
when it is a double bond, Z 1 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 5 )(R 5 ) -or-N (R) 5 ) -, wherein each R 5 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 6 、-O(R 6 )、-S(R 6 )、-NH(R 6 )、-N(R 6 )(R 6 ) One of them, each R 6 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 8 、-O(R 8 )、-S(R 8 )、-NH(R 8 )、-N(R 8 )(R 8 ) One of them, wherein each R 8 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 3 Is selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 10 、-O(R 10 )、-S(R 10 )、-NH(R 10 )、-N(R 10 )(R 10 ) One of them, wherein each R 10 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
when in use
Figure BDA0003595294650000041
Is a single bond, and is a single bond,
Figure BDA0003595294650000042
when it is a single bond, Z 1 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 11 )(R 11 ) -or-N (R) 11 ) -, wherein each R 11 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 12 、-O(R 12 )、-S(R 12 )、-NH(R 12 )、-N(R 12 )(R 12 ) WhereinWherein each R is 12 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is a linear or branched member 2 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 13 )(R 13 ) -or-N (R) 13 ) -, wherein each R 13 Independently at the occurrence is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 14 、-O(R 14 )、-S(R 14 )、-NH(R 14 )、-N(R 14 )(R 14 ) One of them, wherein each R 14 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, carboxyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is a linear or branched member 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 15 )(R 15 ) -or-N (R) 15 ) -, wherein each R 15 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 16 、-O(R 16 )、-S(R 16 )、-NH(R 16 )、-N(R 16 )(R 16 ) One of them, wherein each R 16 Independently at the occurrence is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substitutedSubstituted aryl, optionally substituted 5-6 membered heteroaryl, said optionally substituted meaning unsubstituted by hydrogen on a substituent group or substituted by one or more substitutable sites of a substituent group independently selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
when in use
Figure BDA0003595294650000043
Is a double bond, and is a carboxyl group,
Figure BDA0003595294650000044
when it is a single bond, Z 1 Is selected from C (R) 17 ) Or N, wherein R 17 Independently at each occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 18 、-O(R 18 )、-S(R 18 )、-NH(R 18 )、-N(R 18 )(R 18 ) One of them, wherein each R 18 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 2 Selected from N or C (R) 19 ) Wherein R is 19 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 20 、-O(R 20 )、-S(R 20 )、-NH(R 20 )、-N(R 20 )(R 20 ) One of them, wherein each R 20 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, saidOptionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 21 )(R 21 ) -or-N (R) 21 ) -, wherein each R 21 Independently at the occurrence is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 22 、-O(R 22 )、-S(R 22 )、-NH(R 22 )、-N(R 22 )(R 22 ) One of them, wherein each R 22 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
Z 4 、Z 5 、Z 6 are each independently selected from C (R) 23 ) Or N, wherein R 23 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Of cycloalkyl, 4-6-membered heterocyclyl, aryl, 5-6-membered heteroaryl groupsSubstituted by a group;
p is selected from one of hydrogen, halogen, hydroxyl, sulfydryl, amino and hydroxymethyl;
q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) One of them, wherein each R 24 Independently at the occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted-NH-C 1-6 Alkyl, optionally substituted-NH-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
m is selected from 1,2,3,4;
n is selected from 1,2,3,4.
Unless otherwise specified, the heteroatoms in the above heteroaryl, heterocyclyl groups are independently selected from O, N or S, and the number of heteroatoms is 1,2,3 or 4.
In one embodiment of the invention, the compound of formula (I) is further represented by formula (II) -formula (V):
Figure BDA0003595294650000051
wherein, the definitions of the substituents of the formula (II) to the formula (V) are shown in the formula (I).
In one embodiment of the invention, the compound of formula (I) is further of formula (VI):
Figure BDA0003595294650000061
wherein, each substituent group of the formula (VI) is defined as the formula (I).
In a preferred embodiment of the present invention, X 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; even more preferably, R 1 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, phenyl; most preferably, R 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, methyl, ethyl, n-propyl, isopropyl and cyclopropyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000062
selected from the group consisting of single bonds, X 3 Is selected from C (R) 2 ) Or N, wherein R 2 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a member selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxySubstituted with a substituent of a group, cyclohexyloxy group, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, cyclopropylthio group, n-butylthio group, sec-butylthio group, isobutylthio group, tert-butylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclopropylamino group, n-butylamino group, sec-butylamino group, isobutylamino group, tert-butylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, phenoxy group, phenylthio group, phenylamino group; still more preferably, the optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from halogen, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino; most preferably, the optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from halogen, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino.
In a further preferred embodiment of the present invention,
Figure BDA0003595294650000063
selected from single bonds, X 3 Is selected from C (R) 2 ) Or N, wherein R 2 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and cyclobutyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000071
selected from the group consisting of double bonds, X 3 Selected from-O-, -S-, -C (R) 3 )(R 3 ) -or-N (R) 3 ) -, wherein each R 3 Independently at occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, nitro, -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, phenoxy, phenylthio, phenylamino; even more preferably, said optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutyloxySubstituted by radicals of alkyl, cyclopentyloxy, cyclohexyloxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino and cyclopropylamino; most preferably, the optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, amino, -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino.
In a further preferred embodiment of the invention,
Figure BDA0003595294650000072
selected from the group consisting of double bonds, X 3 Is selected from-N (R) 3 ) -, wherein R 3 When present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, -CH 2 -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl.
In a preferred embodiment of the present invention, Y is 1 、Y 2 、Y 3 Are each independently selected from C (R) 4 ) Or N, wherein R 4 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propylSubstituted by radicals of the group consisting of alkyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy; even more preferably, R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy; most preferably, R 4 Selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000073
is a single bond, and is a single bond,
Figure BDA0003595294650000074
is a double bond, Z 1 Selected from-O-, -S-, -C (R) 5 )(R 5 ) -or-N (R) 5 ) -, wherein each R 5 Independently at the occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 6 、-O(R 6 )、-S(R 6 )、-NH(R 6 )、-N(R 6 )(R 6 ) One of them, wherein each R 6 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 <xnotran> , 4-6 , , 5-6 , , , , , , , , , , , , , , , , , , , , , , </xnotran>Phenyl substituted by a group; even more preferably, each R is 5 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, each R 5 Independently when present, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl.
In a further preferred embodiment of the invention,
Figure BDA0003595294650000081
is a single bond, and is a single bond,
Figure BDA0003595294650000082
is a double bond, Z 1 Is selected from-C (R) 5 )(R 5 ) -or-N (R) 5 ) -, wherein each R 5 Independently when present, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000083
is a single bond, and is a single bond,
Figure BDA0003595294650000084
is a double bond, Z 2 Is selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 8 、-O(R 8 )、-S(R 8 )、-NH(R 8 )、-N(R 8 )(R 8 ) One of them, wherein each R 8 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6-membered heteroaryl; even more preferably, each R is 8 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl; the optional substitution means that hydrogen on a substituted group is not substituted or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, sulfydryl, amino, cyano, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl.
In a further preferred embodiment of the invention,
Figure BDA0003595294650000085
is a single bond, and is a single bond,
Figure BDA0003595294650000086
is a double bond, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning unsubstituted by hydrogen on the substituent group or substituted by one or more substitutable sites of the substituent group independently by halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000087
is a single bond, and is a single bond,
Figure BDA0003595294650000088
is a double bond, Z 3 Selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 10 、-O(R 10 )、-S(R 10 )、-NH(R 10 )、-N(R 10 )(R 10 ) One of them, wherein each R 10 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, R 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, R 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl and cyclopropyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000089
is a single bond, and is a single bond,
Figure BDA00035952946500000810
is a single bond, Z 1 Selected from-O-, -S-, -C (R) 11 )(R 11 ) -or-N (R) 11 ) -, wherein each R 11 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 12 、-O(R 12 )、-S(R 12 )、-NH(R 12 )、-N(R 12 )(R 12 ) One of them, wherein each R 12 Independently at the occurrence is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethenylAlkynyl and phenyl; even more preferably, each R is 11 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, each R 11 Independently when present, is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000091
is a single bond, and is a single bond,
Figure BDA0003595294650000092
is a single bond, Z 2 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 13 )(R 13 ) -or-N (R) 13 ) -; wherein each R 13 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 14 、-O(R 14 )、-S(R 14 )、-NH(R 14 )、-N(R 14 )(R 14 ) One of them, wherein each R 14 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, each R is 14 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl; said optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, nitro, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexylSubstituted by radicals of the ethenyl, ethynyl and phenyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000093
is a single bond, and is a single bond,
Figure BDA0003595294650000094
is a single bond, Z 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 15 )(R 15 ) -or-N (R) 15 ) -, wherein each R 15 Independently at the occurrence is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 16 、-O(R 16 )、-S(R 16 )、-NH(R 16 )、-N(R 16 )(R 16 ) One of them, wherein each R 16 Independently at the occurrence is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, each R is 15 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, each R 15 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000095
is a double bond, and is a carboxyl group,
Figure BDA0003595294650000096
is a single bond, Z 1 Is selected from C (R) 17 ) Or N, wherein R 17 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 18 、-O(R 18 )、-S(R 18 )、-NH(R 18 )、-N(R 18 )(R 18 ) One of them, wherein each R 18 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl; even more preferably, R 17 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, R 17 Selected from hydrogen, halogen, hydroxyl, amino, cyano, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000101
is a double bond, and is a carboxyl group,
Figure BDA0003595294650000102
is a single bond, Z 2 Selected from N or C (R) 19 ) Wherein R is 19 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 20 、-O(R 20 )、-S(R 20 )、-NH(R 20 )、-N(R 20 )(R 20 ) One of them, wherein each R 20 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, R 19 Selected from hydrogenHalogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning unsubstituted by hydrogen on the substituent group or substituted by one or more substitutable sites of the substituent group independently by halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,
Figure BDA0003595294650000103
is a double bond, and is a hydroxyl group,
Figure BDA0003595294650000104
is a single bond, Z 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 21 )(R 21 ) -or-N (R) 21 ) -, wherein each R 21 Independently at the occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 22 、-O(R 22 )、-S(R 22 )、-NH(R 22 )、-N(R 22 )(R 22 ) One of them, wherein each R 22 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, each R is 21 Independently at occurrence is selected from hydrogen, halo, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, each R 21 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the invention, Z 4 、Z 5 、Z 6 Are each independently selected fromC(R 23 ) Or N, wherein R 23 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl; even more preferably, R 23 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy; most preferably, R 23 Selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl.
In a further preferred embodiment of the invention, Z 4 Is selected from N; z 5 、Z 6 Are each independently selected from C (R) 23 ) Wherein each R is 23 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl.
In a preferred embodiment of the present invention, P is selected from one of hydrogen, halogen, hydroxyl, sulfhydryl, amino; more preferably, P is selected from one of hydrogen, hydroxyl, amino and sulfhydryl; most preferably, P is selected from hydroxyl.
In a preferred embodiment of the invention Q is selected from O, S, C (O))、N(R 24 )、C(R 24 )(R 24 ) One of them, wherein each R 24 Independently at occurrence, selected from the group consisting of hydrogen, halo, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, phenyl; more preferably, Q is selected from O, S, NH, N (CH) 3 )、N(Et)、CH 2 、CH(OCH 3 )、CF 2 、CH(OH)、CH(NH 2 )、CH(NHCH 3 ) CF (OH), CHF; most preferably, Q is selected from O, NH, N (CH) 3 )、CH 2 、CH(OH)、CH(NH 2 )、CF 2 。
In a preferred embodiment of the invention, m is selected from 1,2,3.
In a preferred embodiment of the invention, n is selected from 1,2,3.
In a further preferred embodiment of the invention, m is selected from 1 and n is selected from 2.
In a further preferred embodiment of the invention m is selected from 2 and n is selected from 2.
A compound shown as the following formula (VII), and a stereoisomer, an optical isomer, a medicinal salt, a prodrug and a solvate thereof,
Figure BDA0003595294650000111
wherein X 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Substituted by a substituent of alkynyl;
R 3 selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Alkylthio radical, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylthio groups;
R 4 each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 A cycloalkoxy group; said optionally substituted is optionally selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl groups are substituted by the radicals;
R 5 selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group;
Z 2 selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 A cycloalkyl group, a,Optionally substituted 4-6 membered heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5-6 membered heteroaryl, said optionally substituted meaning optionally selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
Z 3 selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
R 23 each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
Z 4 is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
p is selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, carboxyl and C 1-3 Alkyl radical, C 1-3 One of alkoxy groups;
q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) WhereinWherein each R is 24 Independently at the occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 1-6 Alkylamino, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Substituted by a substituent of alkynyl;
m is selected from 1,2,3;
n is selected from 1,2,3.
Unless otherwise specified, the heteroatoms in the above heteroaryl, heterocyclyl groups are independently selected from O, N or S, and the number of heteroatoms is 1,2,3 or 4.
In a preferred embodiment of the present invention, X 2 Selected from N or C (R) 1 ) Wherein R is 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group.
More preferably, X 2 Is selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-3 Alkyl radical, C 3-4 Cycloalkyl, alkoxy, C 3-4 A cycloalkoxy group.
More preferably, X 2 Is selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyloxy.
More preferably, X 2 Is selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, methyl, ethyl, methoxy and ethoxy.
In a preferred embodiment of the invention, R 3 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substitutedC of (A) 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl radical, C 6-8 Aryl radical, C 1-6 Alkoxy groups.
More preferably, R 3 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, C 1-6 Alkoxy groups.
More preferably, R 3 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkyl, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, phenyl, C 1-6 Alkoxy groups.
More preferably, R 3 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, -CH 2 -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, methoxy, ethoxy, n-propoxy, isopropoxy.
More preferably, R 3 Selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, -CH 2 -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl.
More preferably, R 3 Selected from hydrogen, F, cl, br, hydroxyl, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl.
In a preferred embodiment of the invention, R 4 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, hydroxymethyl and hydroxyethyl.
More preferably, R 4 Selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, methyl, ethyl, methoxy and hydroxymethyl.
In a preferred embodiment of the invention, R 5 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy and cyclopropoxy.
More preferably, R 5 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy and isopropoxy.
Most preferably, R 5 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, methoxy and ethoxy.
In a preferred embodiment of the invention, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6-8 Aryl, optionally substituted 5-6 membered heteroaryl, said optionally substituted meaning optionally selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-3 Alkyl groups.
More preferably, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, said optional substitution being optionally substituted by a group selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl.
More preferably, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, said optional substitution being optionally substituted by a group selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl.
More preferably, Z 2 Is selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrazolyl, said optional substitution being optionally substituted by a group selected from the group consisting of F, cl, br, hydroxy, mercapto, amino, cyano, carboxy, methyl.
More preferably, Z 2 Is selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrazolyl, said optional substitution being optionally substituted by a group selected from F, cl, br, hydroxy, mercapto, amino, cyano, carboxy, methyl.
More preferably, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, ethyl, phenyl, monohydroxy-substituted phenyl, monoamino-substituted phenyl, monocarboxyl-substituted phenyl, pyridyl, monohydroxy-substituted pyridyl, monoamino-substituted pyridyl, monocarboxyl-substituted pyridyl, pyrazolyl, monohydroxy-substituted pyrazolyl, monoamino-substituted pyrazolyl, monocarboxyl-substituted pyrazolyl, monomethyl-substituted phenyl, and monomethyl-substituted pyridyl.
In a preferred embodiment of the invention, Z 3 Is selected from C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 A cycloalkyl group.
More preferably, Z 3 Is selected from C (R) 9 ) Wherein R is 9 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, n-propyl and isopropyl.
In a preferred embodiment of the invention, R 23 Are respectively and independently selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl, alkoxy.
More preferably, R 23 Are respectively and independently selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, methoxyl and ethoxyl.
More preferably, R 23 Are respectively and independently selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl and methoxyl.
In a preferred embodiment of the invention, Z 4 Is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group.
More preferably, Z 4 Is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, and methylEthyl, n-propyl, isopropyl, methoxy, ethoxy.
More preferably, Z 4 Is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, methoxy and ethoxy.
More preferably, Z 4 Is selected from N.
In a preferred embodiment of the present invention, P is selected from one of hydrogen, halogen, hydroxy, mercapto, amino, carboxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy.
More preferably, P is selected from one of hydrogen, F, cl, br, hydroxyl, thiol, amino, carboxyl, methyl, ethyl, methoxy, and ethoxy.
More preferably, P is selected from one of hydrogen, F, cl, br, hydroxyl, mercapto, amino and methyl.
In a preferred embodiment of the invention Q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) One of them, wherein each R 24 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 An alkylamino group.
More preferably, Q is selected from C (R) 24 )(R 24 ) Wherein each R is 24 Independently when present, is selected from hydrogen, F, cl, br, hydroxyl, mercapto, amino, cyano, nitro, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 An alkylamino group.
More preferably, Q is selected from C (R) 24 )(R 24 ) Wherein each R is 24 Independently when appearing, is selected from hydrogen, F, cl, br, hydroxyl and methyl.
In a preferred embodiment of the present invention, m is selected from 1,2,3; n is selected from 1,2,3.
More preferably, m is selected from 1 and n is selected from 1.
More preferably, m is selected from 1 and n is selected from 2.
More preferably, m is selected from 2 and n is selected from 1.
More preferably, m is selected from 2 and n is selected from 2.
More preferably, m is selected from 2 and n is selected from 3.
More preferably, m is selected from 3 and n is selected from 2.
Most preferably, m is selected from 2 and n is selected from 2.
In a preferred embodiment of the present invention, said compound, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, are selected from the group consisting of:
Figure BDA0003595294650000141
Figure BDA0003595294650000151
Figure BDA0003595294650000161
Figure BDA0003595294650000171
the invention also provides a pharmaceutical composition which comprises the compounds shown in the formulas (I) to (VII) and stereoisomers, optical isomers, medicinal salts, prodrugs and solvates thereof.
The invention also provides a medicinal composition which comprises the compounds shown in the formulas (I) - (VII), and stereoisomers, optical isomers, medicinal salts, prodrugs, solvates and pharmaceutically acceptable auxiliary materials thereof.
The invention also aims to provide the compounds shown in formulas (I) - (VII) in the invention, and the application of stereoisomers, optical isomers, medicinal salts, prodrugs and solvates thereof in preparing medicines for treating diseases mediated by PAK4 inhibitors.
Further, the diseases mediated by PAK4 inhibitors according to the present invention are cancer or tumor-related diseases.
The use of compounds of formulae (I) - (VII), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof in the preparation of a medicament for the treatment of cancer or neoplastic disease.
In some contexts in the art, the cancer may also be referred to as a malignancy.
The invention relates to application of compounds shown in formulas (I) - (VII) and stereoisomers, optical isomers, medicinal salts, prodrugs and solvates thereof in preparing a medicament for treating diseases mediated by PAK4 inhibitors, wherein the compounds shown in formulas (I) - (VII) and the stereoisomers, optical isomers, medicinal salts, prodrugs and solvates thereof are used for being combined with another anticancer agent or immune checkpoint inhibitor for treating cancers or tumors.
The compounds of the present invention, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, or isotopically labeled analogs thereof, can provide enhanced anti-cancer effects when administered in combination with an additional anti-cancer agent or immune checkpoint inhibitor for the treatment of cancer or tumors.
It is also an object of the present invention to provide a method for preventing and/or treating diseases mediated by PAK4 inhibitors, which comprises administering to a patient a therapeutically effective amount of a compound of formulae (I) - (VII), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, or a pharmaceutical composition of the present invention.
An exemplary method of preparation of a compound of the present invention, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is as follows:
Figure BDA0003595294650000181
the compound 1 is subjected to Sonogashira cross-coupling reaction to obtain a compound 2, the compound 2 is subjected to halogenation reaction to obtain a compound 3, the parent nucleus indole NH of the compound 3 is substituted to obtain a compound 4, and then Suzuki cross-coupling reaction is carried out to obtain a compound 5 (each substituent of the compound 5 is defined as a reference formula (VII)).
Definition of
The terms "optional," "any," "optionally," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C) 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C) 1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C) 1-6 Alkyl) such as "C 1-6 By alkyl is meant that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2,3,4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having the specified number of carbon atoms, preferably containing from 3 to 12 carbon atoms (i.e., C) 3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C) 3-10 Cycloalkyl group), further preferably 3 to 6 carbon atoms (C) 3-6 Cycloalkyl), 4 to 6 carbon atoms (C) 4-6 Cycloalkyl), 5 to 6 carbon atoms (C) 5-6 Cycloalkyl groups). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
Unless otherwise specified, the term "alkoxy" refers to an-O-alkyl group, as defined above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2,3,4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
The term "halogen" or "halo" means, unless otherwise specified, F, cl, br, I. The term "haloalkyl" means an alkyl group as defined above wherein one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CF 2 CF 3 And the like.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e. C) 2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C) 2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl), 2-5 carbon atoms (i.e., C) 2-5 Alkenyl), 2-4 carbon atoms (i.e., C) 2-4 Alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C) 2 Alkenyl) such as "C 2-6 By alkenyl "is meant that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond consisting of carbon atoms and hydrogen atoms. Alkynyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C) 2-10 Alkynyl), further preferred includesContaining 2 to 8 carbon atoms (C) 2-8 Alkynyl) and more preferably contains 2 to 6 carbon atoms (i.e., C) 2-6 Alkynyl), 2-5 carbon atoms (i.e., C) 2-5 Alkynyl), 2-4 carbon atoms (i.e., C) 2-4 Alkynyl), 2-3 carbon atoms (i.e., C) 2-3 Alkynyl), 2 carbon atoms (i.e., C) 2 Alkynyl), for example "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl, and the like.
Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, non-aromatic in structure, containing from 3 to 20 ring atoms, wherein 1,2,3, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably 3 to 12 ring atoms, further preferably 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 4 to 6 ring atoms, or 5 to 6 ring atoms. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e. 1,2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
Unless otherwise specified, the term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, preferably from 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring radical". Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, or the like.
Unless otherwise specified, the term "heteroaryl" denotes an aromatic monocyclic or polycyclic ring system containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2,3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms being preferably 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, phthalizinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
Unless otherwise specified, the term "optical isomer" refers to substances that have identical molecular structures and similar physicochemical properties, but differ in optical activity.
Unless otherwise specified, the term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can interconvert through low energy barriers. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as R, S configuration containing asymmetric centers, (Z), (E) isomers of double bonds, and conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention. Unless otherwise specified, the terms "pharmaceutically acceptable salt," "pharmaceutically acceptable salt," or "pharmaceutically acceptable salt" refer to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base or free acid with a suitable reagent.
Unless otherwise specified, the term "solvate" means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In certain instances, the solvate will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a disordered arrangement. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. "solvate" encompasses both solution phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
Unless otherwise specified, the terms "isotopically labeled analog", "isotopic derivative" refer to a molecule that is isotopically labeled, thereby providing an isotopically labeled analog that may have improved pharmacological activity. Isotopes commonly used as isotopic labels are: an isotope of hydrogen, 2 h and 3 h; carbon isotope: 11 C, 13 c and 14 c; chlorine isotope: 35 cl and 37 cl; fluorine isotope: 18 f; iodine isotope: 123 i and 125 i; isotope of nitrogen： 13 N and 15 n; oxygen isotope: 15 O, 17 o and 18 isotopes of O and sulfur 35 And S. These isotopically labeled compounds can be used to study the distribution of pharmaceutically acceptable molecules in tissues. In particular deuterium 3 H and carbon 13 C, because they are easy to label and convenient to detect, the application is more extensive. Certain heavy isotopes, such as deuterium: (A), (B) 2 H) The substitution can enhance metabolic stability and prolong half-life so as to achieve the aim of reducing dosage and provide curative effect advantage. Isotopically-labeled compounds are generally synthesized by known synthetic techniques as are non-isotopically-labeled compounds, starting from a starting material which has been labeled. Typically, the compounds of the present invention comprise isotopic derivatives (e.g., deuterons) thereof. The term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they can be bioavailable by oral administration, whereas the parent cannot. The prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. An example, but not limiting of, of a prodrug would be any compound of formula I that is administered as an ester ("prodrug") to facilitate delivery across a cell membrane, where water solubility is detrimental to mobility, but once intracellular water solubility is beneficial, it is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show an active moiety.
The term "optionally substituted" means, unless otherwise specified, that the hydrogen of the substitutable site of the group is unsubstituted or substituted with one or more substituents, preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxy, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring group, wherein C is 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 3-10 Cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaromatic ring radicals optionally substituted by one or more radicals selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 And one or more of the alkoxy groups are substituted, and the oxo group means that two H at the same substitution position are substituted by the same O to form a double bond.
The invention has the beneficial effects that:
the invention designs a compound with a novel structure, and provides a new direction for the development of PAK4 inhibitor drugs. The research on the inhibitor of the human receptor PAK4 shows that the compounds have stronger inhibition effect on the human receptor PAK4 and can be used as prospect compounds for treating diseases mediated by the PAK4 inhibitor. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials are shown herein for illustrative purposes only.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography coupled with mass spectrometry (LCMS) or/and liquid chromatography (HPLC). NMR was measured using a Bruker AVANCE NEO 400MHz instrument used in LCMS WATERS ACQUITY UPLC H-Class PLUS or/and SQD2; the instruments used for HPLC were WATERS ACQUITYUPLC or/and Agilent 1260.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
Example 1
Preparation of 1- ((3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000221
first step 1- ((1H-indol-5-yl) ethynyl) cyclohexan-1-ol preparation:
Figure BDA0003595294650000222
5-iodo-1H-indole (4.00g, 16.46mmol, 1.0eq) and 1-ethynylcyclohexan-1-ol (10.22g, 82.29mmol, 5.0eq) were dissolved in DMF (N, N-dimethylformamide) (40 mL), and CuI (cuprous iodide) (312mg, 1.40mmol, 0.1eq), ethylenediamine (3.61g, 49.37mmol, 3.0eq.) and Pd (dppf) Cl were added 2 ([ 1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride) (292mg, 0.4mmol, 0.02eq), stirred at room temperature under nitrogen overnight. LCMS detection reaction was complete. Water (30 mL) was added to the reaction system, followed by extraction with ethyl acetate (30mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spin-dried to give the crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate = 10). LCMS: [ M + H] + ＝240.1； 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),7.61(d,J＝0.7Hz,1H),7.37(dd,J＝7.9,5.3Hz,2H),7.09(dd,J＝8.4,1.5Hz,1H),6.42(dd,J＝2.5,1.6Hz,1H),5.32(s,1H),1.91–1.79(m,2H),1.73(s,2H),1.57–1.45(m,6H)。
Second step preparation of 1- ((3-bromo-1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000223
crude 1- ((1H-indol-5-yl) ethynyl) cyclohexan-1-ol (1.20g, 5.01mmol, 1.0eq) was dissolved in DMF (N, N-dimethylformamide) (15 mL), and N-bromosuccinimide (1.07g, 6.01mmol, 1.2eq.) was added to the mixture and stirred at 25 ℃ for 12H under nitrogen. LCMS detection reaction was complete. Water (20 mL) was added to the reaction system, followed by extraction with ethyl acetate (30mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spin-dried to give the crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate = 5) to give the product 1- ((3-bromo-1H-indol-5-yl) ethynyl) cyclohexan-1-ol (1.40g, 4.4m mol, yield 87.7%). LCMS: [ M + H] + ＝318.1，[M+2+H] + ＝320.1； 1 H NMR(400MHz,DMSO-d6)δ11.70(s,1H),7.61(d,J＝2.6Hz,1H),7.46–7.33(m,2H),7.19(dd,J＝8.6,1.3Hz,1H),5.37(s,1H),1.95–1.80(m,2H),1.71–1.31(m,8H)。
Third step preparation of 1- ((3-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000231
1- ((3-bromo-1H-indol-5-yl) ethynyl) cyclohexan-1-ol (1.00g, 3.14mmol, 1.0eq.) was dissolved in DMF (N, N-dimethylformamide) (15 mL), 60% NaH (sodium hydride) (377mg, 9.42mmol,3.0eq, 60%) was added, and after stirring at 0 ℃ for half an hour at room temperature, SEMCl (2- (trimethylsilanyl) ethoxymethyl chloride) (0.78g, 4.71mmol, 1.5eq.) was added to the reaction solution, and the reaction was stirred under nitrogen at room temperature overnight. LCMS detection reaction was complete. Water (20 mL) was added to the reaction system, followed by extraction with ethyl acetate (30mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spin-dried to give the crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate =5: 1) and dried to give the material 1- ((3-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (650mg, 1.45mmol, 46.1%). LCMS: [ M + H ]] + ＝449.1； 1 H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.72(d,J＝8.5Hz,1H),7.54(d,J＝1.0Hz,1H),7.38(dd,J＝8.5,1.4Hz,1H),5.65(s,2H),5.49(s,1H),3.63–3.50(m,2H),1.97(d,J＝10.6Hz,2H),1.84–1.39(m,8H),0.97–0.84(m,2H),0.00(d,J＝3.2Hz,9H)。
Fourth step preparation of 1- ((3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000232
1- ((3-bromo-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (200mg, 0.44mmol, 1.0eq.), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] was added]Pyridine (163mg, 0.66mmol, 1.5eq.), na 2 CO 3 (sodium carbonate) (63mg, 0.59mmol, 1.3eq) and Pd (PPh) 3 ) 4 (tetrakis (triphenylphosphine) palladium) (36mg, 0.22mmol, 0.5eq) was added to Dioxane/H 2 O (dioxane and aqueous = 5). The reaction was stirred under nitrogen for 1 hour and LCMS monitored the reaction. Water (30 mL) was added to the reaction, followed by extraction with ethyl acetate (30mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate =3: 1) and dried by rotary evaporation to give the product 1- ((3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (100mg, 0.20mmol, 46.2%). LCMS: [ M + H] + ＝486.3； 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.38(d,J＝4.9Hz,1H),8.23(s,1H),7.97(s,1H),7.41(dd,J＝5.0,3.2Hz,2H),6.73(dd,J＝3.5,1.9Hz,1H),5.79(s,2H),5.47(s,1H),3.74–3.58(m,2H),2.02(dd,J＝55.7,9.8Hz,3H),1.84–1.56(m,7H),0.94(dd,J＝9.6,6.3Hz,3H),0.02–0.10(m,9H)。
Fifth step preparation of 1- ((3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000241
1- ((3- (1H-pyrrolo [2, 3-b))]Pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-ylethynyl) cyclohexan-1-ol (100mg, 0.21mol, 1.0eq) was dissolved in THF (tetrahydrofuran) (5 mL), TBAF (tetrabutylammonium fluoride) (269mg, 1.03mmol, 5.0eq.) was added and stirred at 80 ℃ under nitrogen for 4H, the reaction was monitored for completion by LCMS, and the reaction was cooled to room temperature and spin-dried. The crude was purified using preparative TLC plates (dichloromethane: methanol =15 = 1), eluted with ethyl acetate and spin-dried to give the product 1- ((3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (60mg, 0.174mmol, 64.7%). LCMS: [ M + H] + ＝356.1。 1 HNMR(400MHz,DMSO-d6)δ11.78(s,1H),11.66(s,1H),8.27(d,J＝4.9Hz,1H),7.95(d,J＝2.5Hz,1H),7.87(s,1H),7.49(t,J＝5.8Hz,2H),7.29(d,J＝4.9Hz,1H),7.22(dd,J＝8.4,1.2Hz,1H),6.63(dd,J＝3.3,1.9Hz,1H),5.35(s,1H),1.85(d,J＝11.6Hz,2H),1.73–1.39(m,8H)。
The following examples were synthesized in the same manner as in example 1
Figure BDA0003595294650000242
Figure BDA0003595294650000251
Figure BDA0003595294650000261
Figure BDA0003595294650000271
Figure BDA0003595294650000281
Figure BDA0003595294650000291
Example 22
Preparation of 1- ((3- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000292
first step preparation of 4-bromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
Figure BDA0003595294650000293
the raw material 4-bromo-1H-pyrrolo [2,3-b ] is added]Pyridine (5.0g, 25.38mmol, 1.0eq) is added into THF (tetrahydrofuran) (50 mL), the mixture is cooled in an ice-water bath, naH (1.12g, 27.91mmol,1.1eq, 60 percent by mass) is added under stirring, the temperature is kept at 0 ℃ for stirring for 30 minutes, then the raw material compound 2 (4.93g, 27.91mmol, 1.1eq) is added under the condition of the ice-water bath, the temperature is slowly increased to room temperature after the addition is finished, the mixture is stirred for 16 hours, and the reaction is detected to be finished by LCMS. Water (50 mL) was added to the reaction system, followed by extraction with ethyl acetate (30mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spin-dried to give the crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate =4: 1) to give the product 4-bromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] -c]Pyridine (7.5 g, yield 87.6%). LCMS: [ M + H] + ＝338.9.
Second step preparation of 2, 4-dibromo-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
Figure BDA0003595294650000301
the raw material 4-bromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine (3.00g, 8.90mmol)1.0 eq) was added to THF (tetrahydrofuran) (30 mL), the mixture was cooled to-78 ℃ in a dry ice acetone bath and LDA (7mL, 13.35mmol, 1.5eq) was added with stirring, the temperature was maintained at-78 ℃ with stirring for 30 minutes, then 1, 2-dibromo-1, 2-tetrachloroethane (3.77g, 11.57mmol, 1.3eq) was added at this temperature, the temperature was maintained at-78 ℃ with stirring for 3 hours after the addition was complete, saturated NH was added 4 Cl (30 mL), then extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, the organic phase concentrated and column chromatographed (PE: EA = 4)]Pyridine (3.00 g, yield 81.0%). LCMS (ESI) [ < M + H ]]+＝416.8。
Third step preparation of 4-bromo-2-phenyl-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
Figure BDA0003595294650000302
reacting 2, 4-dibromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ]]Pyridine (1.2g, 2.88mmol, 1eq), phenylboronic acid (351.64mg, 2.88mmol, 1eq), sodium carbonate (611.35mg, 5.77mmol, 2eq) and Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride) (210mg, 0.288mmol, 0.1eq) was added to dioxane (20 mL) and water (2 mL), replaced with argon 5 times, and heated to 80 ℃ with stirring for 3 hours. Reaction completion was monitored by LCMS and reaction cooled to room temperature and saturated NH added 4 Cl (100 mL), then extracted with ethyl acetate (50mL × 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the mother liquor was spin dried to give the crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate = 5) to give the product (600 mg, yield, 50.3%). LCMS: [ M + H] + ＝412.9。
Fourth step preparation of (2-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) boronic acid
Figure BDA0003595294650000303
Reacting 4-bromo-2-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ]]Pyridine (300mg, 0.73mmol, 1eq), 4,4,4', 5' -octamethyl-2, 2' -bi (1, 3, 2-dioxaborane) (368.66mg, 1.45mmol, 2eq), potassium acetate (284.95mg, 2.90mmol, 4eq) and Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride) (53.3mg, 0.073mmol, 0.1eq.) was added to dioxane (10 mL), replaced with argon 5 times, heated to 100 ℃ and stirred for 16 hours. LCMS monitor reaction complete. Reaction completion was monitored by LCMS and reaction cooled to room temperature and saturated NH added 4 Cl (30 mL) and then extracted with ethyl acetate (30mL x 3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered and the mother liquor was spun dry to give the crude product (276 mg) which was used directly in the next step. LCMS: [ M + H ]] + ＝379.0。
Fifth step preparation of 1- ((3- (2-phenyl-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -1- (benzenesulfonyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000311
reacting (2-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) boronic acid (150mg, 0.33mmol, 1eq), 1- ((3-bromo-1- (benzenesulfonyl) -1H-indol-5-yl) ethynyl) cyclohex-1-ol (149.35mg, 0.33mmol, 1eq), sodium carbonate (103.60mg, 0.98mmol, 3eq) and Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphino) ferrocene)]Palladium dichloride) (24mg, 0.033mmol, 0.1eq.) was added to dioxane (5 mL) and water (0.5 mL), replaced with argon for 5 times, heated to 100 ℃ and stirred for 5 hours. LCMS monitored reaction completion. Reaction completion was monitored by LCMS and reaction cooled to room temperature and saturated NH added 4 Cl (20 mL), then ethyl acetate (20mL x 3), and the organic phases are combined, dried by anhydrous sodium sulfate, filtered, and mother liquor is dried in a spinning mode to obtain a crude product. The crude product was isolated and purified by flash chromatography (dichloromethane: methanol = 20). LCMS: [ M + H] + ＝712.0。
Sixth step preparation of 1- ((3- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl ] -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000312
1- ((3- (2-phenyl-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1- (benzenesulfonyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (100mg, 0.14mmol, 1equ.) and sodium hydroxide (22.48mg, 0.56mmol, 4eq) were added to a mixed solution of THF (1 mL) and methanol (1 mL), and the reaction was stirred at room temperature for 3H. LCMS check complete reaction of starting material. Adding saturated NH to the reaction solution 4 Cl (5 mL), then ethyl acetate (5mL x3), the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and the mother liquor was spin-dried to give the crude product. The crude product was isolated and purified by flash chromatography (DCM: meOH = 10) to give crude product, which was purified by Prep-HPLC (0.1% nh 3 H 2 O in water, meCN) purification yielded the product (6.02 mg, 9.9% yield). LCMS: [ M + H]+＝432.1，1H NMR(400MHz,CD3OD)δ8.22(d,J＝5.1Hz,1H),8.00(s,1H),7.87(d,J＝7.0Hz,3H),7.50–7.42(m,3H),7.39–7.26(m,3H),7.04(s,1H),2.04–1.92(m,2H),1.75–1.54(m,7H),1.28(s,1H).
The following examples were synthesized in the same manner as in example 22
Figure BDA0003595294650000313
Figure BDA0003595294650000321
Figure BDA0003595294650000331
Figure BDA0003595294650000341
Examples 33 and 34
Preparation of 1- ((1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) — 1H-indazol-6-yl) ethynyl) cyclohex-1-ol (the compound of example 33):
Figure BDA0003595294650000342
preparation of 1- ((2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazol-6-yl) ethynyl) cyclohexan-1-ol (the compound of example 34)
Figure BDA0003595294650000343
First step preparation of 4-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine:
Figure BDA0003595294650000351
4-fluoro-1H-pyrrolo [2,3-b ] at 0 DEG C]Pyridine (700mg, 5.142mmol, 1eq) was dissolved in tetrahydrofuran (10 mL), then sodium hydride (185mg, 7.710mmol, 1.5eq) was added and reacted at this temperature for 30 minutes, then (2- (chloromethoxy) ethyl) trimethylsilane (1.03g, 6.170mmol, 1.2eq) was added to the reaction solution, the reaction was continued for 16 hours, and LCMS monitored that the reaction was completed. The reaction was concentrated to give a solid, water was added to quench the reaction, the reaction was extracted with ethyl acetate (20mL × 3), and the combined organic phases were washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Purification by reverse phase separation (0.01% of FA in water, meCN) to give the product 4-fluoro-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b)]Pyridine 800mg (yield 58.4%). LCMS: [ M + H] + ＝267.2
Second step preparation of 6-iodo-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indazole and 6-iodo-2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazole
Figure BDA0003595294650000352
4-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] at room temperature]Pyridine (200mg, 0.751mmol, 1eq) and 6-iodo-1H-indazole (183mg, 0.751mmol, 1eq) and potassium carbonate (311mg, 2.252mmol, 3eq) were dissolved in NMP (5 mL) and then treated with N 2 The displacement was 3 times and stirring was continued for 2 hours with slow increase to 150 ℃ and LCMS to check the reaction was complete. Then 5mL of DMF solvent was added thereto and the product was purified by reverse phase to give 6-iodo-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]]Pyridin-4-yl) -1H-indazole (140mg, 38%) and the solid product 6-iodo-2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b%]Pyridin-4-yl) -2H-indazole (100mg, 27.2%). LCMS: [ M + H]+＝490.9，LCMS:[M+H]+＝490.9
Third step preparation of 6-iodo-1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indazole
Figure BDA0003595294650000353
6-iodo-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indazole (140mg, 0.285mmol, 1eq) was dissolved in DCM (5 mL) at room temperature, and trifluoroacetic acid (163mg, 1.427mmol, 5eq) was added dropwise thereto, followed by reaction at room temperature for 2 hours, addition of aqueous ammonia (5 mL) and stirring continued for 2 hours. The reaction was monitored by LCMS for completion, water (20 mL) was added to the reaction and extracted with ethyl acetate (20mL. Times.3), the combined organic phases were washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by reverse phase to give the product 6-iodo-1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indazole (70 mg, yield 68.1%). LCMS [ M + H ] + =354.2
Fourth step preparation of 1- ((1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) — 1H-indazol-6-yl) ethynyl) cyclohexan-1-ol
Figure BDA0003595294650000361
Reacting 6-iodo-1- (1H-pyrrolo [2,3-b ]]Pyridin-4-yl) -1H-indazole (50mg, 0.139mmol, 1eq) and 1-ethynylcyclohexan-1-ol (69mg, 0.555mmol, 4eq), diethylamine (30mg, 0.416mmol, 3eq) and Pd (dppf) Cl 2 (17mg, 0.0139mmol, 0.1eq) cuprous iodide (26mg, 0.138mmol, 1eq) was dissolved in DMF (5 mL), replaced 3 times with nitrogen, and the reaction was continued at room temperature for 16h. LCMS monitored the reaction and the crude product was purified by flash chromatography (petroleum ether: ethyl acetate =5]Pyridin-4-yl]) -1H-indazol-6-yl) ethynyl) cyclohexan-1-ol (1.78 mg, yield 3.6%). LCMS: [ M + H] + ＝357.2， 1 HNMR(400MHz,MeOD)δ8.38(d,J＝6.8Hz,2H),7.88(d,J＝8.7Hz,2H),7.48(d,J＝3.5Hz,2H),7.34(d,J＝8.2Hz,1H),6.70(d,J＝3.5Hz,1H),2.01–1.94(m,2H),1.73(d,J＝4.8Hz,2H),1.69–1.55(m,5H),1.33(s,1H).
Fifth step preparation of 6-iodo-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazole
Figure BDA0003595294650000362
6-iodo-2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazole (100mg, 0.204mmol, 1eq) was dissolved in DCM (5 mL) at room temperature, and trifluoroacetic acid (116mg, 1.120mmol, 5eq) was added dropwise thereto, followed by reaction at room temperature for 2 hours, followed by addition of aqueous ammonia (5 mL) and stirring for an additional 2 hours. The reaction was monitored by LCMS, water (20 mL) was added to the reaction and extracted with ethyl acetate (20mL x3), and the combined organic phases were washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by reverse phase to give the product 6-iodo-2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazole (50 mg, yield 68%). LCMS: [ M + H ] + =361.1.
Sixth step preparation of 1- ((2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazol-6-yl) ethynyl) cyclohexan-1-ol
Figure BDA0003595294650000371
Reacting 6-iodo-2- (1H-pyrrole)And [2,3-b ]]Pyridin-4-yl) -2H-indazole (40mg, 0.111mmol, 1eq) and diethylamine (21mg, 0.111mmol, 1eq), 1-ethynylcyclohexane-1-ol (55mg, 0.444mmol, 4eq) and Pd (dppf) Cl 2 (10mg, 0.0111mmol, 0.1eq) was dissolved in DMF (5 mL), and the mixture was replaced with nitrogen gas 3 times, followed by further reaction at room temperature for 16 hours. The reaction was monitored by LCMS and the crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate =5]Pyridin-4-yl) -2H-indazol-6-yl) ethynyl) cyclohexan-1-ol (4.42 mg, yield 11.2%). LCMS: [ M + H ]] + ＝357.2， 1 HNMR(400MHz,CD3OD)δ9.00(s,1H),8.37(d,J＝5.4Hz,1H),7.83(s,1H),7.79(d,J＝8.7Hz,1H),7.68(d,J＝5.4Hz,1H),7.57(d,J＝3.5Hz,1H),7.14(d,J＝8.6Hz,1H),7.10(d,J＝3.5Hz,1H),2.02(d,J＝8.6Hz,2H),1.81–1.59(m,7H),1.34(s,1H).
The following examples were synthesized in the same manner as in example 33 and example 34
Figure BDA0003595294650000372
Example 38
Preparation of 1- ((2-methyl-1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-benzo [ d ] imidazol-6-yl) ethynyl) cyclohexan-1-ol
Figure BDA0003595294650000381
First step preparation of 4-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
Figure BDA0003595294650000382
the raw material 4-nitro-1H-pyrrolo [2,3-b]Pyridine (3.00g, 18.39mmol, 1.0eq) was added to THF (tetrahydrofuran) (30 mL), the mixture was cooled in an ice-water bath, naH (956 mg,23.91mmol,1.3eq, 60% by mass) was added with stirring, the temperature was maintained at 0 ℃ with stirring for 30 minutes, and then the starting benzenesulfonyl chloride was added under ice-water bath conditions(3.57g, 20.23mmol, 1.1eq), after the addition was complete, the temperature was slowly raised to room temperature and stirred for 16 hours. LCMS monitors reaction completion and H is added 2 O (10 mL), then extracted with ethyl acetate (30mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated after filtration, and the crude product was purified by flash chromatography (petroleum ether: ethyl acetate = 4) the product 4-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine (4.2 g, yield 75.3%). LCMS: [ M + H ]]+＝304.0。
Second step preparation of 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine:
Figure BDA0003595294650000383
the raw material 4-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine (2.0 g,6.59mmol,1.0 eq) was added to MeOH (methanol) (20 mL) and Raney nickel (1.0 g) was added with stirring, and after the addition, hydrogen was replaced three times. Stir at rt for 16h and LCMS to monitor reaction completion. Filtering and concentrating the organic phase to obtain the product 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine (1.4 g, 77.7% yield). LCMS: [ M + H] + ＝274.0。
Third step preparation of N- (5-bromo-2-nitrophenyl) -1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine:
Figure BDA0003595294650000391
the raw material 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine (930mg, 3.40mmol, 1.0eq) was added to DMF (N, N-dimethylformamide) (10 mL), the mixture was cooled in an ice-water bath, naH (163mg, 4.08mmol,1.2eq, mass fraction 60%) was added under stirring, the temperature was maintained at 0 ℃ and stirring was carried out for 30 minutes, then the starting material 4-bromo-2-fluoro-1-nitrobenzene (898mg, 4.08mmol, 1.2eq) was added under ice-water bath conditions, and after completion of the addition, the temperature was slowly raised to room temperature and stirring was carried out for 2 hours. After completion of reaction monitored by LCMS, H was added 2 O (5 mL), then extracted with ethyl acetate (20mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the organic phase was concentratedThe crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate = 4) as product N- (5-bromo-2-nitrophenyl) -1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine (483 mg, 30.0% yield). LCMS (ESI) [ < M + H ]]+＝472.9。
Fourth step preparation of 5-bromo-N1- (1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) benzene-1, 2-diamine:
Figure BDA0003595294650000392
the raw material N- (5-bromo-2-nitrophenyl) -1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine (483mg, 1.02mmol, 1.0eq) was added to EtOH (5 mL) and H 2 O (1 mL), and Fe powder (199mg, 3.57mmol, 3.5eq) and NH were added under stirring 4 Cl (273mg, 5.10mmol, 5.0eq) was added, and after the addition, the temperature was slowly raised to 85 ℃ and the mixture was stirred for 4 hours. LCMS monitoring was complete. Cooling the reaction solution, filtering, and adding H into the filtrate 2 O (5 mL), the organic phases were combined with ethyl acetate (20mL × 3) and dried over anhydrous sodium sulfate, the organic phase was concentrated after filtration, and the crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate = 1) to obtain 5-bromo-N1- (1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-4-yl) benzene-1, 2-diamine (383 mg, 84.7% yield). LCMS (ESI) [ < M + H ]] + ＝444.8。
Fifth step preparation of 6-bromo-2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-benzo [ d ] imidazole:
Figure BDA0003595294650000393
the raw material 5-bromo-N1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) benzene-1, 2-diamine (150mg, 0.34mmol, 1.0eq) was added to triethyl orthoacetate (2 mL), and the mixture was slowly warmed to 100 ℃ and stirred for 16 hours. LCMS monitor reaction complete. Cooling to room temperature and adding H 2 O (5 mL), then extracted with ethyl acetate (20mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, the organic phase was concentrated after filtration, and the crude product was isolated and purified by flash chromatography (DCM: meOH =20:1) The product 6-bromo-2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b) is obtained]Pyridin-4-yl) -1H-benzo [ d]Imidazole (150 mg, yield: 95.0%). LCMS (ESI) [ < M + H ]]+＝469.0。
Sixth step 1- ((2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-benzo [ d ] imidazol-6-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000401
the raw material 6-bromo-2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-benzo [ d]Imidazole (80mg, 0.17mmol,1.0 eq) was added to DMSO (1 mL), and 1-ethynylcyclohexane-1-ol (213mg, 1.71mmol,10.0 eq), triethylamine (Et) 3 N) (52mg, 0.51mmol,3.0 eq) and Pd (dppf) Cl 2 (15mg, 0.02mmol, 0.1eq), after the addition was completed, the nitrogen gas was replaced three times, and the temperature was slowly raised to 90 ℃. The reaction was stirred for 3 hours and LCMS showed completion of the reaction. After cooling to room temperature, H was added 2 O (5 mL), then extracted with ethyl acetate (10mL × 3), the organic phases were combined and dried with anhydrous sodium sulfate, the organic phase was concentrated after filtration, and the crude product was isolated and purified by flash chromatography (DCM: meOH = 20) to give the product 1- ((2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-4-yl) -1H-benzo [ d]Imidazol-6-yl) ethynyl) cyclohexan-1-ol (80mg, 91.5%). LCMS (ESI) [ < M + H ]]+＝511.0。
Seventh step preparation of 1- ((2-methyl-1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-benzo [ d ] imidazol-6-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000402
the starting material 1- ((2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-benzo [ d]Imidazol-6-yl) ethynyl) cyclohexan-1-ol (55mg, 0.11mmol, 1.0eq) was added to MeOH (methanol) (1 mL) and THF (tetrahydrofuran) (1 mL), and NaOH (sodium hydroxide) (22mg, 0.54mmol, 5.0eq) was added under stirring, and after the addition was completed, stirring was carried out at room temperature for 1 hour.LCMS monitors the reaction is complete and H is added to the reaction 2 O (5 mL), followed by extraction with ethyl acetate (10mL × 3), combination of organic phases and drying over anhydrous sodium sulfate, concentration of the organic phase after filtration, separation and purification of the crude product by flash chromatography (DCM: meOH = 20) to give a crude product, which was separated and purified by Prep-HPLC (C18, 0.1% per min fa in water, mecn) to give the compound 1- ((2-methyl-1- (1H-pyrrolo [2,3-b ]]Pyridin-4-yl) -1H-benzo [ d]Imidazol-6-yl) ethynyl) cyclohexan-1-ol (9.43mg, 11.8%). LCMS: [ M + H] + ＝371.0， 1 H NMR(400MHz,CD3OD)δ8.52(s,1H),8.46(d,J＝5.1Hz,1H),7.64(d,J＝8.3Hz,1H),7.55(d,J＝3.5Hz,1H),7.36(d,J＝8.3Hz,1H),7.27(d,J＝5.1Hz,1H),7.10(s,1H),6.17(d,J＝3.5Hz,1H),2.52(s,3H),1.91(s,2H),1.73–1.48(m,7H),1.28(s,1H).
Example 39 the same procedure as in example 38 was used to synthesize
Example 39
Preparation of 6- ((1-hydroxycyclohexyl) ethynyl) -1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-benzo [ d ] imidazol-2-ol
Figure BDA0003595294650000411
LCMS(ESI):[M+H] + ＝373.1； 1 H NMR(400MHz,CD3OD)δ8.28(d,J＝5.1Hz,1H),7.38(d,J＝3.5Hz,1H),7.19(d,J＝5.2Hz,1H),7.14(d,J＝8.1Hz,1H),7.04(d,J＝8.1Hz,1H),6.84(s,1H),6.21(d,J＝3.5Hz,1H),1.81(d,J＝7.8Hz,2H),1.58(d,J＝5.0Hz,2H),1.53–1.40(m,5H),1.18–1.13(m,1H).
Example 40
Preparation of 1- ((3- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-4-yl ] -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000412
first step preparation of 5-fluoro-1H-pyrrolo [2,3-b ] pyridine 7-oxide:
Figure BDA0003595294650000413
reacting 5-fluoro-1H-pyrrolo [2,3-b ] at room temperature]Pyridine (2.0g, 14.69mmol, 1eq) was dissolved in methylene chloride (30 mL), and then m-chloroperoxybenzoic acid (7.61g, 44.07mmol, 3eq) was added. And the reaction was continued at this temperature for 16 hours. LCMS detection reaction was complete. The reaction was concentrated to a solid, quenched with saturated sodium bicarbonate, extracted with EtOAC (ethyl acetate) (30mL x 3), and the combined organic phases were washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Column chromatography with DCM: meOH =15 gave the product 5-fluoro-1H-pyrrolo [2, 3-b)]900mg of pyridine 7-oxide (yield 40.5%). 1 H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.42(d,J＝5.3Hz,1H),7.63(d,J＝10.3Hz,1H),7.52(d,J＝5.0Hz,1H),6.58(d,J＝4.6Hz,1H)。
Second step preparation of 4-bromo-5-fluoro-1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003595294650000414
Reacting 5-fluoro-1H-pyrrolo [2,3-b ] at room temperature]Pyridine 7-oxide (600mg, 3.94mmol, 1eq) was dissolved in DMF (10 mL), then tetrabutylammonium bromide (1.27g, 3.94mmol, 3eq) was added, and trifluoromethanesulfonic anhydride (1.11g, 3.94mmol, 3eq) was added dropwise with vigorous stirring thereof. And the reaction was continued at this temperature for 16 hours. LCMS detection reaction was complete. The reaction was concentrated to give a solid, water (10 mL) was added to quench the reaction, extraction was performed with EtOAC (10 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The product 4-bromo-5-fluoro-1H-pyrrolo [2,3-b was obtained by column chromatography (DCM: meOH = 15)]Pyridine (387 mg, yield 45.6%). 1 H NMR(400MHz,DMSO-d6)δ12.20(d,J＝30.8Hz,1H),8.27(d,J＝1.7Hz,1H),7.75–7.68(m,1H),6.46(dt,J＝5.8,3.0Hz,1H).
Third step preparation of 5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003595294650000421
Compound 1 (300mg, 1.758mmol, 1eq) was dissolved in dioxane (15 mL), and then potassium acetate (519mg, 5.28mmol, 3eq) and pinacol ester diboron (1.341g, 5.28mmol, 3eq) were added, and after 3 nitrogen replacements, pd (dppf) Cl was added 2 (129mg, 0.1758mmol, 0.1eq). The reaction was slowly raised to 90 ℃ and allowed to continue for 16 hours, LCMS (monitor reaction completion, reaction concentrated to give solid, add water to quench the reaction, extract with EtOAC (ethyl acetate) (30mL. Times.3), combined organic phases washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated to give crude product, prep-HPLC separation and purification (0.01% NH) 3 .H 2 O in water, meCN) to give 5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ]]Pyridine (120 mg, yield 26%).
LCMS:[M+H] + ＝263.1
Preparation of 1- ((3- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol
Figure BDA0003595294650000422
Reacting 5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2,3-b ]]Pyridine (100mg, 0.382mmol, 1eq) was dissolved in dioxane (2 mL) and H 2 O (0.4 mL), then 1- ((3-bromo-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (171.32mg, 0.076mmol, 1eq), sodium carbonate (121.3mg, 1.145mmol, 3eq), replaced 3 times with nitrogen, then Pd (dppf) Cl 2 (28mg, 0.0382mmol, 0.1eq) was added. The reaction mixture was slowly raised to 85 ℃ and the reaction was continued for 16 hours. LCMS to detect reaction completion, reaction was concentrated to give a solid, saturated sodium bicarbonate (60 mL) was added to adjust pH =8, extracted with EA (ethyl acetate) (10mL × 3), and combined organic phases were saturated with saturated foodBrine (10 mL) was washed, then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by reverse phase separation to give 1- ((3- (5-fluoro-1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (20 mg, yield 10.4%). LCMS (ESI) [ M + H ]]+＝504.1。
Fifth step preparation of 1- ((3- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-4-yl ] -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
Figure BDA0003595294650000431
1- ((3- (5-fluoro-1H-pyrrolo [2, 3-b))]Pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (20mg, 0.040mmol) was added to the MeOH (5 mL) solution, tetrabutylammonium fluoride (103.82mg, 0.3970 mmol, 10eq) was added to the reaction solution, and the mixture was stirred at 80 ℃ for 2 hours. After completion of the reaction by LCMS, concentration under reduced pressure gave a crude product which was subjected to Prep-HPLC (0.1% FA in water, meCN) to give 1- ((3- (5-fluoro-1H-pyrrolo [2, 3-b) product]Pyridin-4-yl]-1H-indol-5-yl) ethynyl) cyclohexan-1-ol (1.47 mg, yield 9.9%). LCMS (ESI) [ M + H ]] + ＝374.3, 1 H NMR(400MHz,CD3OD)δ8.18(s,1H),7.70(d,J＝15.4Hz,2H),7.45(t,J＝5.9Hz,2H),7.26(dd,J＝8.4,1.4Hz,1H),6.54(d,J＝3.5Hz,1H),1.96(dd,J＝16.5,5.1Hz,2H),1.65(tdd,J＝13.5,9.9,3.4Hz,7H),1.35–1.24(m,1H).19F NMR(377MHz,CD3OD)δ-144.81(s)。
Test example 1 detection of inhibitory Effect of a Compound on PAK4 kinase Activity Using a method of Caliper mobility Shift assay (Caliper mobility Shiftassay)
The test method comprises the following steps: on the kinase PAK4, the final concentration of the compound tested was 10 μ M starting, 10 concentrations diluted 3-fold. 250nL of 100-fold final concentration of the compound was transferred to the target plate 3573 using a dispenser Echo 550, 10. Mu.L of each 0.625nM PAK4 kinase solution was added, and the plate was incubated at room temperature for 60 minutes (10. Mu.L of kinase buffer and 250nL of 100% DMSO in negative control wells; 10. Mu.L of kinase solution and 250nL of 100% DMSO in positive control wells). On the kinase PAK4, 15. Mu.L of a mixed solution of ATP at a final concentration of km and 3. Mu.M of the substrate polypeptide was added and reacted for 60 minutes. The kinase reaction was stopped by adding 30. Mu.L of a termination assay solution containing EDTA. The conversion was read with a Caliper EZ Reader. Conversion inhibition% = (positive control conversion mean% sample conversion mean%/(positive control conversion mean% negative control conversion mean%). Where: negative control wells represent conversion readings without enzyme-activated wells; positive control wells represent conversion readings without compound-inhibited wells.with log of concentration as X-axis and percent inhibition as Y-axis, an energy efficiency curve was fitted using the analytical software GraphPad Prism5 log (inhibitor) vs. responsee-Variable slope to derive IC50 values for each compound against enzyme activity.
And (4) test conclusion: the scheme shows that the compounds of the embodiment shown in the invention show the biological activities in the PAK4 enzyme activity inhibition test shown in the following table 1
Table 1: IC of compound for inhibiting PAK4 enzyme activity 50 Value of
Figure BDA0003595294650000432
Figure BDA0003595294650000441
Note: a represents IC 50 <100nΜ。
The results shown in the table show that the series of compounds have stronger PAK4 enzyme inhibition activity and can be used for treating diseases mediated by PAK4 inhibitors.

Claims (43)

1. A compound of formula (I), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof:
Figure FDA0003595294640000011
wherein the content of the first and second substances,
Figure FDA0003595294640000012
are respectively a single bond or a double bond, but are not simultaneously a single bond or a double bond;
when in use
Figure FDA0003595294640000013
Selected from single bonds, X 1 Is selected from N; x 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; x 3 Is selected from C (R) 2 ) Or N, wherein R 2 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Alkylthio radical, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylthio group;
when in use
Figure FDA0003595294640000014
Selected from the group consisting of double bonds, X 1 Is selected from C; x 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; x 3 Selected from-O-, -S-, -C (R) 3 )(R 3 ) -or-N (R) 3 ) -, wherein each R 3 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Alkylthio radical, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylthio groups;
Y 1 、Y 2 、Y 3 are each independently selected from C (R) 4 ) Or N, wherein R 4 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; the optional substitution means that hydrogen on the substituted group is not substituted or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, sulfydryl, amino, cyano and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
Figure FDA0003595294640000021
are respectively a single bond or a double bond, but are not double bonds at the same time;
when in use
Figure FDA0003595294640000022
Is a single bond, and is a single bond,
Figure FDA0003595294640000023
when it is a double bond, Z 1 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 5 )(R 5 ) -or-N (R) 5 ) -, wherein each R 5 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 6 、-O(R 6 )、-S(R 6 )、-NH(R 6 )、-N(R 6 )(R 6 ) One of them, each R 6 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, any ofOptionally substituted means that hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 8 、-O(R 8 )、-S(R 8 )、-NH(R 8 )、-N(R 8 )(R 8 ) One of them, wherein each R 8 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is a linear or branched member 3 Selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 10 、-O(R 10 )、-S(R 10 )、-NH(R 10 )、-N(R 10 )(R 10 ) One of them, wherein each R 10 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
when in use
Figure FDA0003595294640000024
Is a single bond, and is a single bond,
Figure FDA0003595294640000025
when it is a single bond, Z 1 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 11 )(R 11 ) -or-N (R) 11 ) -, wherein each R 11 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 12 、-O(R 12 )、-S(R 12 )、-NH(R 12 )、-N(R 12 )(R 12 ) One of them, wherein each R 12 Independently at the occurrence is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 2 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 13 )(R 13 ) -or-N (R) 13 ) -, wherein each R 13 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 14 、-O(R 14 )、-S(R 14 )、-NH(R 14 )、-N(R 14 )(R 14 ) One of them, wherein each R 14 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, carboxyl, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 15 )(R 15 ) -or-N (R) 15 ) -, wherein each R 15 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 16 、-O(R 16 )、-S(R 16 )、-NH(R 16 )、-N(R 16 )(R 16 ) One of them, wherein each R 16 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
when in use
Figure FDA0003595294640000031
Is a double bond, and is a carboxyl group,
Figure FDA0003595294640000032
when it is a single bond, Z 1 Is selected from C (R) 17 ) Or N, wherein R 17 Independently at each occurrence, selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 18 、-O(R 18 )、-S(R 18 )、-NH(R 18 )、-N(R 18 )(R 18 ) One of them, wherein each R 18 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano、C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is a linear or branched member 2 Selected from N or C (R) 19 ) Wherein R is 19 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 20 、-O(R 20 )、-S(R 20 )、-NH(R 20 )、-N(R 20 )(R 20 ) One of them, wherein each R 20 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 21 )(R 21 ) -or-N (R) 21 ) -, wherein each R 21 Independently at the occurrence is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 22 、-O(R 22 )、-S(R 22 )、-NH(R 22 )、-N(R 22 )(R 22 ) One of them, wherein each R 22 Independently at the occurrence is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
Z 4 、Z 5 、Z 6 are each independently selected from C (R) 23 ) Or N, whereinR 23 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
p is selected from one of hydrogen, halogen, hydroxyl, sulfydryl, amino and hydroxymethyl;
q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) One of them, wherein each R 24 Independently at the occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted-NH-C 1-6 Alkyl, optionally substituted-NH-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
m is selected from 1,2,3,4;
n is selected from 1,2,3,4.
2. The compound of claim 1, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein the compound of formula (I) is further represented by formula (II) -formula (V):
Figure FDA0003595294640000041
wherein, the definitions of the substituents of the formula (II) to the formula (V) are shown in the formula (I).
3. The compound of claim 1, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein the compound of formula (I) is further represented by formula (VI):
Figure FDA0003595294640000042
wherein, each substituent group of the formula (VI) is defined as the formula (I).
4. A compound according to any one of claims 1 to 3, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein X 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; even more preferably, R 1 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, phenyl; most preferably, R 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, methyl, ethyl, n-propyl, isopropyl and cyclopropyl.
5. The compound of any one of claims 1 to 4, and a stereoisomer thereofIsomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, wherein,
Figure FDA0003595294640000051
selected from the group consisting of single bonds, X 3 Is selected from C (R) 2 ) Or N, wherein R 2 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, cyclopentylamino, cyclohexylamino, phenylthio; it is still further preferred that, said optionally substituted means that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylthio, methylamino, ethylamino, n-butoxy, cyclopentyloxy, cyclohexyloxy, methylthio, methylamino, n-butoxy, and cyclohexylSubstituted by a group selected from propylamino, isopropylamino and cyclopropylamino; most preferably, the optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from halogen, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino.
6. The compound according to any one of claims 1 to 5, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000052
selected from single bonds, X 3 Is selected from C (R) 2 ) Or N, wherein R 2 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and cyclobutyl.
7. The compound according to any one of claims 1 to 4, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000053
selected from the group consisting of double bonds, X 3 Selected from-O-, -S-, -C (R) 3 )(R 3 ) -or-N (R) 3 ) -, wherein each R 3 Independently at the occurrence is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, mercapto, amino, cyanoRadical, nitro radical, -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio, n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, phenoxy, phenylthio, phenylamino; even more preferably, said optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from the group consisting of halogen, hydroxy, amino, -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino; most preferably, the optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a substituent selected from halogen, hydroxy, amino, -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino.
8. RightsThe compound according to any one of claims 1 to 4, and a stereoisomer, an optical isomer, a pharmaceutically acceptable salt, a prodrug, a solvate thereof,
Figure FDA0003595294640000061
selected from the group consisting of double bonds, X 3 Is selected from-N (R) 3 ) -, wherein R 3 When present, are selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, -CH 2 -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl.
9. The compound according to any one of claims 1 to 8, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein Y 1 、Y 2 、Y 3 Are each independently selected from C (R) 4 ) Or N, wherein R 4 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy; even more preferably, R 4 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl and cycloPropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy; most preferably, R 4 Selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl.
10. The compound according to any one of claims 1 to 9, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000062
is a single bond, and is a single bond,
Figure FDA0003595294640000063
is a double bond, Z 1 Selected from-O-, -S-, -C (R) 5 )(R 5 ) -or-N (R) 5 ) -, wherein each R 5 Independently at the occurrence is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 6 、-O(R 6 )、-S(R 6 )、-NH(R 6 )、-N(R 6 )(R 6 ) One of them, wherein each R 6 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl; even more preferably, each R is 5 Independently at the occurrence, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butylA group selected from the group consisting of a sec-butyl group, an isobutyl group, a tert-butyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a phenyl group; most preferably, each R 5 Independently when present, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl.
11. The compound according to any one of claims 1 to 10, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000071
is a single bond, and is a single bond,
Figure FDA0003595294640000072
is a double bond, Z 1 Is selected from-C (R) 5 )(R 5 ) -or-N (R) 5 ) -, wherein each R 5 Independently when present, is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl.
12. The compound according to any one of claims 1 to 11, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000073
is a single bond, and is a single bond,
Figure FDA0003595294640000074
is a double bond, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 8 、-O(R 8 )、-S(R 8 )、-NH(R 8 )、-N(R 8 )(R 8 ) One of them, wherein each R 8 Independently at the occurrence is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, each R is 8 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl; the optional substitution means that hydrogen on a substituted group is not substituted or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxyl, sulfydryl, amino, cyano, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl.
13. The compound according to any one of claims 1 to 12, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000075
is a single bond, and is a single bond,
Figure FDA0003595294640000076
is a double bond, Z 2 Is selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution means unsubstituted by a hydrogen on a substituent group or substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, independently of one or more substitutable sites of a substituent group.
14. The compound according to any one of claims 1 to 13, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000077
is a single bond, and is a single bond,
Figure FDA0003595294640000078
is a double bond, Z 3 Selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 10 、-O(R 10 )、-S(R 10 )、-NH(R 10 )、-N(R 10 )(R 10 ) One of them, wherein each R 10 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, R 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, R 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl and cyclopropyl.
15. The compound according to any one of claims 1 to 9, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000079
is a single bond, and is a single bond,
Figure FDA00035952946400000710
is a single bond, Z 1 Selected from-O-, -S-, -C (R) 11 )(R 11 ) -or-N (R) 11 ) -, wherein each R 11 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 12 、-O(R 12 )、-S(R 12 )、-NH(R 12 )、-N(R 12 )(R 12 ) One of them, wherein each R 12 Independently at the occurrence is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl; even more preferably, each R is 11 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, each R 11 Independently when present, is selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl.
16. The compound according to any one of claims 1 to 9 and 15, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000081
is a single bond, and is a single bond,
Figure FDA0003595294640000082
is a single bond, Z 2 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 13 )(R 13 ) -or-N (R) 13 ) -; wherein each R 13 Independently at the occurrence, is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 14 、-O(R 14 )、-S(R 14 )、-NH(R 14 )、-N(R 14 )(R 14 ) One of them, wherein each R 14 When appeared, it is uniqueIs selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, each R is 14 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl; the optionally substituted means that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, nitro, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, ethynyl, phenyl.
17. The compound according to any one of claims 1 to 9 and 15 to 16, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000083
is a single bond, and is a single bond,
Figure FDA0003595294640000084
is a single bond, Z 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 15 )(R 15 ) -or-N (R) 15 ) -, wherein each R 15 Independently at the occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 16 、-O(R 16 )、-S(R 16 )、-NH(R 16 )、-N(R 16 )(R 16 ) One of them, wherein each R 16 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, each R is 15 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino,Cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, each R 15 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl.
18. The compound according to any one of claims 1 to 9, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000085
is a double bond, and is a hydroxyl group,
Figure FDA0003595294640000086
is a single bond, Z 1 Is selected from C (R) 17 ) Or N, wherein R 17 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 18 、-O(R 18 )、-S(R 18 )、-NH(R 18 )、-N(R 18 )(R 18 ) One of them, wherein each R 18 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted by a group selected from hydrogen, halo, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl; even more preferably, R 17 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cycloButyl, cyclopentyl, cyclohexyl, phenyl; most preferably, R 17 Selected from hydrogen, halogen, hydroxyl, amino, cyano, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl.
19. The compound according to any one of claims 1 to 9 and 18, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000091
is a double bond, and is a carboxyl group,
Figure FDA0003595294640000092
is a single bond, Z 2 Selected from N or C (R) 19 ) Wherein R is 19 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and R 20 、-O(R 20 )、-S(R 20 )、-NH(R 20 )、-N(R 20 )(R 20 ) One of them, wherein each R 20 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, R 19 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, and optionally substituted C 6 Aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning unsubstituted by hydrogen on the substituent group or substituted by one or more substitutable sites of the substituent group independently by halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
20. The compound according to any one of claims 1 to 9 and 18 to 19, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
Figure FDA0003595294640000093
is a double bond, and is a hydroxyl group,
Figure FDA0003595294640000094
is a single bond, Z 3 Selected from-S-, -S (O) (NH) -, -S (O) 2 -、-C(R 21 )(R 21 ) -or-N (R) 21 ) -, wherein each R 21 Independently at the occurrence is selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, R 22 、-O(R 22 )、-S(R 22 )、-NH(R 22 )、-N(R 22 )(R 22 ) One of them, wherein each R 22 Independently at the occurrence, is selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl; even more preferably, each R is 21 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, each R 21 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl.
21. The compound of any one of claims 1 to 20, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein Z 4 、Z 5 、Z 6 Are each independently selected from C (R) 23 ) Or N, wherein R 23 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted-O-C 1-6 Alkyl, optionally substituted-O-C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that one or more of the substituents on the substituted group may be unsubstituted or one or more of the substituents may be substitutedThe substitution site is independently substituted with a substituent selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, ethynyl, phenyl; even more preferably, R 23 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethylmethylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy; most preferably, R 23 Selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, tert-butyl, cyclobutyl.
22. The compound of any one of claims 1 to 21, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein P is selected from one of hydrogen, halogen, hydroxy, mercapto, amino; more preferably, P is selected from one of hydrogen, hydroxyl, amino and sulfhydryl; most preferably, P is selected from hydroxyl.
23. The compound of any one of claims 1-22, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein Q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) One of them, wherein each R 24 Independently when present, is selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino,N-butylamino, sec-butylamino, isobutylamino, tert-butylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, phenyl; more preferably, Q is selected from O, S, NH, N (CH) 3 )、N(Et)、CH 2 、CH(OCH 3 )、CF 2 、CH(OH)、CH(NH 2 )、CH(NHCH 3 ) CF (OH), CHF; most preferably, Q is selected from O, NH, N (CH) 3 )、CH 2 、CH(OH)、CH(NH 2 )、CF 2 。
24. The compound of any one of claims 1 to 23, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein m is selected from 1,2,3.
25. The compound of any one of claims 1 to 24, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein n is selected from 1,2,3.
26. The compound of any one of claims 1 to 25, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein m is selected from 1 and n is selected from 2.
27. The compound of any one of claims 1 to 25, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein m is selected from 2 and n is selected from 2.
28. A compound shown as the following formula (VII), and a stereoisomer, an optical isomer, a medicinal salt, a prodrug and a solvate thereof,
Figure FDA0003595294640000101
wherein, X 2 Is selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substitutedC of (A) 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Substituted by a substituent of alkynyl;
R 3 selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 1-6 Alkylthio radical, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, C 3-6 Cycloalkylthio groups;
R 4 each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 A cycloalkoxy group; said optionally substituted is optionally selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl groups are substituted by the radicals;
R 5 selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group;
Z 2 is selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy radical,Optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted 5-6 membered heteroaryl, said optionally substituted meaning optionally selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
Z 3 selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
R 23 each independently selected from hydrogen, halogen, hydroxyl, sulfhydryl, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
Z 4 is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl group;
p is selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, carboxyl and C 1-3 Alkyl radical, C 1-3 One of alkoxy groups;
q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) One of them, wherein each R 24 Independently at the occurrence, selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 1-6 Alkylamino, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Substituted by a substituent of alkynyl;
m is selected from 1,2,3;
n is selected from 1,2,3.
29. The compound of claim 28, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein X 2 Selected from N or C (R) 1 ) Wherein R is 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group;
more preferably, X 2 Is selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-3 Alkyl radical, C 3-4 Cycloalkyl, alkoxy, C 3-4 A cycloalkoxy group;
more preferably, X 2 Is selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, F, cl, br, hydroxyl, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyloxy;
more preferably, X 2 Is selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, methyl, ethyl, methoxy and ethoxy.
30. The compound of claim 28 or 29, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein R 3 Selected from hydrogen, halogen, hydroxy, mercaptoRadical, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 Aryl radical, C 1-6 Alkoxy groups;
more preferably, R 3 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, C 1-6 Alkoxy is substituted by the radical of alkoxy;
more preferably, R 3 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted sulfonyl, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkyl, said optionally substituted meaning optionally substituted by a group selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, phenyl, C 1-6 Alkoxy is substituted by the radical of alkoxy;
more preferably, R 3 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, -CH 2 -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethylEthyl, hydroxy-n-propyl, hydroxy-isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy;
more preferably, R 3 Selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, -CH 2 -O-CH 2 CH 2 - (trimethylsilyl), methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl;
more preferably, R 3 Selected from hydrogen, F, cl, br, hydroxyl, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl.
31. The compound of any one of claims 28 to 30, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein R 4 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, hydroxymethyl and hydroxyethyl;
more preferably, R 4 Selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, methyl, ethyl, methoxy and hydroxymethyl.
32. The compound of any one of claims 28 to 31, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein R 5 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy;
more preferably, R 5 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy and isopropoxy;
most preferably, R 5 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, methoxy and ethoxy.
33. The compound of any one of claims 28 to 32, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein Z is 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, optionally substituted C 1-4 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6-8 Aryl, optionally substituted 5-6 membered heteroaryl, said optionally substituted meaning optionally selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-3 Alkyl groups;
more preferably, Z 2 Is selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, said optional substitution being optionally substituted by a group selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl;
more preferably, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, said optional substitution being optionally substituted by a group selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl;
more preferably, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, nitro, methyl, ethyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazolyl, said optional substitution being optionally substituted by a group selected from F, cl, br, hydroxylSubstituted by radicals of mercapto, amino, cyano, carboxyl and methyl;
more preferably, Z 2 Is selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrazolyl, said optional substitution being optionally substituted by a group selected from F, cl, br, hydroxy, mercapto, amino, cyano, carboxy, methyl;
more preferably, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from the group consisting of hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, ethyl, phenyl, monohydroxy-substituted phenyl, monocarboxylic-substituted phenyl, pyridyl, monohydroxy-substituted pyridyl, monoamino-substituted pyridyl, monocarboxylic-substituted pyridyl, pyrazolyl, monohydroxy-substituted pyrazolyl, monoamino-substituted pyrazolyl, monocarboxylic-substituted pyrazolyl, monomethyl-substituted phenyl, and monomethyl-substituted pyridyl.
34. The compound of any one of claims 28 to 33, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein Z is 3 Is selected from C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 A cycloalkyl group;
more preferably, Z 3 Is selected from C (R) 9 ) Wherein R is 9 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, n-propyl and isopropyl.
35. The compound of any one of claims 28 to 34, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein R 23 Are respectively and independently selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl, alkoxy;
more preferably, R 23 Each independently selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, methoxy and ethoxy;
more preferably, R 23 Are respectively and independently selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl and methoxy.
36. The compound of any one of claims 28 to 35, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein Z is 4 Is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano, nitro and C 1-6 Alkyl radical, C 3-6 Cycloalkyl radical, C 1-6 Alkoxy radical, C 3-6 A cycloalkoxy group;
more preferably, Z 4 Is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy;
more preferably, Z 4 Is selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, methoxy, ethoxy;
more preferably, Z 4 Is selected from N.
37. The compound of any one of claims 28 to 36, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein P is selected from one of hydrogen, halogen, hydroxy, mercapto, amino, carboxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy;
more preferably, P is selected from one of hydrogen, F, cl, br, hydroxyl, sulfydryl, amino, carboxyl, methyl, ethyl, methoxy and ethoxy;
more preferably, P is selected from one of hydrogen, F, cl, br, hydroxyl, mercapto, amino and methyl.
38. The method of any one of claims 28 to 37The compound, and stereoisomer, optical isomer, medicinal salt, prodrug and solvate thereof, wherein Q is selected from O, S, C (O) and N (R) 24 )、C(R 24 )(R 24 ) One of them, wherein each R 24 Independently when present, is selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 An alkylamino group;
more preferably, Q is selected from C (R) 24 )(R 24 ) Wherein each R is 24 Independently when present, is selected from hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino, cyano, nitro, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 An alkylamino group;
more preferably, Q is selected from C (R) 24 )(R 24 ) Wherein each R is 24 Independently when appearing, is selected from hydrogen, F, cl, br, hydroxyl and methyl.
39. A compound according to any one of claims 28 to 38, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, wherein m is selected from 1,2,3; n is selected from 1,2,3;
more preferably, m is selected from 1 and n is selected from 1;
more preferably, m is selected from 1 and n is selected from 2;
more preferably, m is selected from 2 and n is selected from 1;
more preferably, m is selected from 2 and n is selected from 2;
more preferably, m is selected from 2 and n is selected from 3;
more preferably, m is selected from 3 and n is selected from 2;
most preferably, m is selected from 2 and n is selected from 2.
40. A compound selected from the group consisting of the following, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof:
Figure FDA0003595294640000141
Figure FDA0003595294640000151
Figure FDA0003595294640000161
Figure FDA0003595294640000171
41. a pharmaceutical composition comprising a compound of any one of claims 1-40, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, and pharmaceutically acceptable excipients.
42. Use of a compound according to any one of claims 1 to 40, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or compositions according to claim 41 thereof, in the manufacture of a medicament for the treatment of a disease mediated by a PAK4 inhibitor.
43. The use of claim 42, wherein the disease mediated by a PAK4 inhibitor is cancer or a tumor-associated disease.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101189243A (en) * 2005-04-06 2008-05-28 阿斯利康(瑞典)有限公司 Substituted heterocycles and their use as CHK1, PDK1 and PAK inhibitors
WO2009158011A1 (en) * 2008-06-26 2009-12-30 Amgen Inc. Alkynyl alcohols as kinase inhibitors
WO2016164641A1 (en) * 2015-04-08 2016-10-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101189243A (en) * 2005-04-06 2008-05-28 阿斯利康(瑞典)有限公司 Substituted heterocycles and their use as CHK1, PDK1 and PAK inhibitors
WO2009158011A1 (en) * 2008-06-26 2009-12-30 Amgen Inc. Alkynyl alcohols as kinase inhibitors
WO2016164641A1 (en) * 2015-04-08 2016-10-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

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