CN115215861B - 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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CN115215861B
CN115215861B CN202210394598.1A CN202210394598A CN115215861B CN 115215861 B CN115215861 B CN 115215861B CN 202210394598 A CN202210394598 A CN 202210394598A CN 115215861 B CN115215861 B CN 115215861B
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optionally substituted
hydroxy
amino
cyano
hydrogen
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CN115215861A (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 novel structure and provides a new direction for the development of medicaments of PAK4 inhibitors. Research shows that the compounds have strong inhibition effect on human acceptor PAK4, and can be used as a prospect compound for treating PAK4 inhibitor-mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has 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 an aromatic heterocycle substituted alkyne compound, and a preparation method and application of the compound.
Background
PAK is a P21-activated protein kinase (P21-activated protein kinases, PAKs), an evolutionarily conserved class of serine/threonine protein kinases, an effector protein of the Rho family Cdc42 and Rac. PAK4 is a representative of PAK family II members, can be activated by growth factors and other extracellular signals, and modulates a variety of biological functions via downstream binding proteins or kinase substrates. PAK4 regulates a variety of cellular functions including cell adhesion, migration, proliferation and survival, and therefore, deregulation of PAK4 expression and activity contributes to the development of a variety of diseases. PAK4 has several functions in vivo: first, PAK4 has a close relationship with embryonic heart development, nervous system development; PAK4 can regulate the G1 phase of the cell cycle by modulating protein levels of p21, and can also regulate G2/M phase conversion by phosphorylating Ran. Secondly, PAK4 protects cells through different mechanisms, inhibits apoptosis of the cells and promotes survival of the cells; PAK4 can inactivate BAD by phosphorylating it, thereby inhibiting apoptosis. In a third aspect, PAK4 phosphorylates SSH-1L (Slingshot-1L) and LIMK, enabling dynamic regulation of actin. PAK4 plays a key role in the progression of cancer by accelerating epithelial-mesenchymal transformation, invasion and metastasis, and PAK4 is highly expressed in most tumor cells, therefore, PAK4 is considered as an attractive therapeutic target for a variety of cancers.
There are many PAK4 inhibitor projects currently being studied, most of which are in preclinical stages, such as LCH-7749944 (also known as GNF-Pf-2356), which are novel and highly potent PAK4 inhibitors effective in inhibiting proliferation of human gastric cancer cells by down-regulating the PAK4/c-Src/EGFR/cyclin D1 pathway. In addition, LCH-7749944 can obviously inhibit migration and invasion of gastric cancer cells, and simultaneously block PAK4/LIMK1/cofilin and PAK4/MEK-1/ERK1/2/MMP2 channels. Importantly, LCH-7749944 has an inhibitory effect on PAK4, successfully inhibiting EGFR activity, and these results provide new insight into the development of PAK4 inhibitors and potential therapeutic strategies for gastric cancer. In addition, GL-1196, LC-0882, KY-04031, GNE-2861, CPG74524A and the like are also in preclinical stages, which all prove to have potentially good antitumor activity.
There are also some PAK4 inhibitors that have been advanced to the clinical stage, such as KPT-9274 (also known as ATG-019), a dual inhibitor of PAK4 and NAMPT, developed by Karyopharm Therapeutics inc. And Antegene Therapy Limited. Preclinical studies have shown that KPT-9274 and its analogs KPT-8752 can reduce the steady state levels of PAK4 protein in triple negative breast cancer cells. These compounds can also prevent the growth of breast cancer cells in vitro and stimulate apoptosis. Most importantly, oral KPT-9274 can reduce the tumorigenesis of a human triple negative breast cancer mouse model, and is a novel method for treating triple negative breast cancer. In addition, the anti-PD-1 combined KPT-9274 can be used for treating B16 mouse melanoma, and has stronger anti-tumor effect compared with the single anti-PD-1 and KPT-9274.
In summary, PAK4 inhibitors can be used as a potentially powerful new anticancer agent. The research on the development of new drugs with PAK4 as a target spot has the positive effect of filling the blank for solving the unmet clinical demands.
Disclosure of Invention
The invention aims to provide a compound with a brand new structure serving 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 of formula (I) as follows, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof,
wherein,are respectively single bond or double bond, but the two are not single bond or double bond at the same time;
when (when)Selected from single bonds, X 1 Selected from N; x is X 2 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; x is X 3 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, optionallySubstituted 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 member selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkoxy radicals C 3-6 Cycloalkylamino, C 3-6 A cycloalkylthio group;
when (when)Selected from double bonds, X 1 Selected from C; x is X 2 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; x is X 3 Selected from-O-, -S-, -C (R) 3 )(R 3 ) -or-N (R) 3 ) -, each R is 3 Independently at the 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-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 heteroarylThe optional substitution means that hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted with a member selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Alkylthio, C 3-6 Cycloalkoxy radicals C 3-6 Cycloalkylamino, C 3-6 A cycloalkylthio group;
Y 1 、Y 2 、Y 3 are 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 unsubstituted or one or more substitutable sites of the substituted group are independently substituted with a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
are respectively single bond or double bond, but the two are not double bond at the same time;
when (when)Is a single bond (I)>In the case of double bonds, Z 1 Selected from the group consisting of-S-, -S (O) -, S (O) (NH) -, -S (O) 2 -、-C(R 5 )(R 5 ) -or-N (R) 5 ) -, each R is 5 Is independently 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 which, each R 6 Independently at the occurrence 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 8 、-O(R 8 )、-S(R 8 )、-NH(R 8 )、-N(R 8 )(R 8 ) One of which, each R 8 Independently at the occurrence 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is Z 3 Selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 10 、-O(R 10 )、-S(R 10 )、-NH(R 10 )、-N(R 10 )(R 10 ) One of which, each R 10 Independently at the occurrence selected from optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionallyOptionally substituted aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution meaning that the hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted with a moiety selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
when (when)Is a single bond (I)>Z is a single bond 1 Selected from the group consisting of-S-, -S (O) -, S (O) (NH) -, -S (O) 2 -、-C(R 11 )(R 11 ) -or-N (R) 11 ) -, each R is 11 Is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 12 、-O(R 12 )、-S(R 12 )、-NH(R 12 )、-N(R 12 )(R 12 ) One of which, each R 12 Independently at the occurrence 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is Z 2 Selected from the group consisting of-S-, -S (O) -, S (O) (NH) -, -S (O) 2 -、-C(R 13 )(R 13 ) -or-N (R) 13 ) -, each R is 13 Is independently 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 which, each R 14 Independently at the occurrence 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is Z 3 Selected from the group consisting of-S-, -S (O) -, S (O) (NH) -, -S (O) 2 -、-C(R 15 )(R 15 ) -or-N (R) 15 ) -, each R is 15 Is independently 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 which, each R 16 Independently at the occurrence 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
when (when)Is double bond (I)>Z is a single bond 1 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 which, each R 18 Independently at the occurrence 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is Z 2 Selected from N or C (R) 19 ) Wherein R is 19 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 20 、-O(R 20 )、-S(R 20 )、-NH(R 20 )、-N(R 20 )(R 20 ) One of which, each R 20 Independently at the occurrence 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 one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; z is Z 3 Selected from the group consisting of-S-, -S (O) -, S (O) (NH) -, -S (O) 2 -、-C(R 21 )(R 21 ) -or-N (R) 21 ) -, each R is 21 Is independently 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 which, each R 22 Independently at the occurrence 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 being meantThe hydrogen on the substituted group being unsubstituted or one or more substitutable sites of the substituted group being independently selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl;
Z 4 、Z 5 、Z 6 are 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 hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, 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, sulfhydryl, amino and hydroxymethyl;
q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) One of which, each R 24 Independently 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 hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted by a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, 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 indicated, the heteroatoms in the heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4.
In one embodiment of the present invention, the compound of formula (I) is further represented by formula (II) -formula (V):
wherein each substituent of the formulas (II) - (V) is defined as the formula (I).
In one embodiment of the present invention, the compound of formula (I) is further represented by formula (VI):
wherein each substituent of formula (VI) is defined as in formula (I).
In a preferred embodiment of the invention, X 2 Selected from C (R) 1 ) Or N, wherein R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -O-C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl; 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, cyclopentoxy, cyclohexyloxy, phenyl; most preferably, R 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyanoA group, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,selected from single bonds, X 3 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 substituent 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, cyclopropyloxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylthio, ethylthio, n-propylthio, isopropylthio, cyclopropylthio, n-butylthio, sec-butylthio, cyclohexylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, tert-butylamino, cyclohexylamino, phenethylamino; still more preferably, the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted with a member 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, cyclobutyl, cyclopentoxy, cyclohexyl Substituted with groups of oxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino; most preferably, the optional substitution 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 group selected from halogen, hydroxy, amino, 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 present invention,selected from single bonds, X 3 Selected from C (R) 2 ) Or N, wherein R 2 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.
In a preferred embodiment of the present invention,selected from double bonds, X 3 Selected from-O-, -S-, -C (R) 3 )(R 3 ) -or-N (R) 3 ) -, each R is 3 Independently at the 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 the 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 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,A group substituted with an isopropoxy, cyclopropyloxy, 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; still more preferably, the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted with a moiety 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, cyclopropyloxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, methylthio, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino; most preferably, the optional substitution means that the hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted with a moiety 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 present invention,selected from double bonds, X 3 Selected from-N (R) 3 ) -, wherein R is 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, hydroxy-isopropyl.
In a preferred embodiment of the invention, Y 1 、Y 2 、Y 3 Are 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 the hydrogen on the substituted group is unsubstituted or that one or more substitutable sites of the substituted group are independently substituted with 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, cyclopropyloxy; more preferably, R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropoxy; most preferably, R 4 Selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, t-butyl, cyclobutyl.
In a preferred embodiment of the present invention,is a single bond (I)>Is a double bond, Z 1 Selected from-O-, -S-, -C (R) 5 )(R 5 ) -or-N (R) 5 ) -, each R is 5 When present, are independently 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 which, each R 6 Independently at the occurrence 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 with 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; still more preferably, each R 5 Independently at the occurrence selected from hydrogen, halogen, hydroxy, mercapto, 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, each R 5 Independently at the occurrence 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 present invention,is a single bond (I)>Is a double bond, Z 1 Selected from-C (R) 5 )(R 5 ) -or-N (R) 5 ) -, each R is 5 And is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, and t-butyl.
In a preferred embodiment of the present invention,is a single bond (I)>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, R 8 、-O(R 8 )、-S(R 8 )、-NH(R 8 )、-N(R 8 )(R 8 ) One of which, each R 8 Independently at the occurrence 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; still more preferably, each R 8 Independently at the occurrence 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 the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently selected from halogen, hydroxy, mercapto, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl.
In a further preferred embodiment of the present invention,is a single bond (I)>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 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 group selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,is a single bond (I)>Is a double bond, Z 3 Selected from N or C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 10 、-O(R 10 )、-S(R 10 )、-NH(R 10 )、-N(R 10 )(R 10 ) One of which, each R 10 Independently at the occurrence 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; more preferably, R 9 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, 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 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,is a single bond (I)>Is a single bond, Z 1 Selected from-O-, -S-, -C (R) 11 )(R 11 ) -or-N (R) 11 ) -, each R is 11 Is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 12 、-O(R 12 )、-S(R 12 )、-NH(R 12 )、-N(R 12 )(R 12 ) One of which, each R 12 Independently at the occurrence 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 with 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; still more preferably, each R 11 Independently at the occurrence selected from hydrogen, halogen, hydroxy, mercapto, 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, each R 11 Independently at the occurrence selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,is a single bond (I)>Is a single bond, Z 2 Selected from the group consisting of-S-, -S (O) -, -S (O))(NH)-、-S(O) 2 -、-C(R 13 )(R 13 ) -or-N (R) 13 ) -; wherein each R is 13 Is independently 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 which, each R 14 Independently at the occurrence 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; still more preferably, each R 14 Independently at the occurrence 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; by optionally substituted is meant that the hydrogen on the substituted group is unsubstituted or one or more substitutable sites of the substituted group are independently substituted with 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, vinyl, ethynyl, phenyl.
In a preferred embodiment of the present invention, Is a single bond (I)>Is a single bond, Z 3 Selected from the group consisting of-S-, -S (O) -, S (O) (NH) -, -S (O) 2 -、-C(R 15 )(R 15 ) -or-N (R) 15 ) -, each R is 15 When present, are independently 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 which, each R 16 Independently at the occurrence 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; still more preferably, each R 15 Independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, 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, each R 15 And is independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, and cyclopropyl.
In a preferred embodiment of the present invention,is double bond (I)>Is a single bond, Z 1 Selected from C (R) 17 ) Or N, wherein R 17 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 which, each R 18 Independently at the occurrence 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 with 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; more preferably, R 17 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, n-butylA group, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl; most preferably, R 17 Selected from hydrogen, halogen, hydroxy, amino, cyano, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention, Is double bond (I)>Is a single bond, Z 2 Selected from N or C (R) 19 ) Wherein R is 19 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, R 20 、-O(R 20 )、-S(R 20 )、-NH(R 20 )、-N(R 20 )(R 20 ) One of which, each R 20 Independently at the occurrence 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; more preferably, R 19 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 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 group selected from halogen, hydroxy, mercapto, amino, cyano, carboxy, methyl, ethyl, n-propyl, isopropyl, cyclopropyl.
In a preferred embodiment of the present invention,is double bond (I)>Is a single bond, Z 3 Selected from the group consisting of-S-, -S (O) -, S (O) (NH) -, -S (O) 2 -、-C(R 21 )(R 21 ) -or-N (R) 21 ) -, each R is 21 When present, are independently 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 which, each R 22 Independently at the occurrence 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; still more preferably, each R 21 Independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, 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, each R 21 And is independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, and cyclopropyl.
In a preferred embodiment of the invention, Z 4 、Z 5 、Z 6 Are 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 with 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; more preferably, R 23 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methyleneMethyl, 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 the group consisting of hydrogen, halogen, hydroxy, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, t-butyl, cyclobutyl.
In a further preferred embodiment of the invention Z 4 Selected from N; z is Z 5 、Z 6 Are independently selected from C (R) 23 ) Wherein each R is 23 And is independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, trifluoromethyl, ethyl, trifluoromethyl methylene, n-propyl, isopropyl, cyclopropyl, t-butyl, cyclobutyl.
In a preferred embodiment of the invention, P is selected from one of hydrogen, halogen, hydroxy, mercapto, amino; more preferably, P is selected from one of hydrogen, hydroxy, amino, mercapto; 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 which, each R 24 Independently at the occurrence 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, 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 represented by the following formula (VII), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs and solvates thereof,
Wherein X is 2 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 A cycloalkoxy group, said optional substitution being optionally selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl substituent is substituted;
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 optional substitution being optionally selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 1-6 Alkoxy, C 1-6 Alkylamino group,C 1-6 Alkylthio, C 3-6 Cycloalkoxy radicals C 3-6 Cycloalkylamino, C 3-6 A cycloalkylthio group;
R 4 independently 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 A cycloalkoxy group; the optional substitution means that the amino group is optionally substituted with a member selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl groups are substituted;
R 5 selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, 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 Cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted 5-6 membered heteroaryl, said optional substitution being optionally substituted by halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted;
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 A cycloalkoxy group, said optional substitution being optionally selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted;
R 23 are independently selected from hydrogen, halogen, hydroxy, mercapto and aminoCyano, 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 optional substitution being optionally selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted;
Z 4 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 A cycloalkoxy group, said optional substitution being optionally selected from halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted;
p is selected from hydrogen, halogen, hydroxy, mercapto, amino, carboxyl, and C 1-3 Alkyl, C 1-3 One of the alkoxy groups;
q is selected from O, S, C (O), N (R) 24 )、C(R 24 )(R 24 ) One of which, each R 24 Independently 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 optional substitution means that it is optionally substituted with a member selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl substituent is substituted;
m is selected from 1,2,3;
n is selected from 1,2,3.
Unless otherwise indicated, the heteroatoms in the heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4.
In a preferred embodiment of the invention, X 2 Selected from N or C (R) 1 ) Wherein R is 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro、C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 A cycloalkoxy group.
More preferably, X 2 Selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-3 Alkyl, C 3-4 Cycloalkyl, alkoxy, C 3-4 A cycloalkoxy group.
More preferably, X 2 Selected from C (R) 1 ) Wherein R is 1 Selected from the group consisting of hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, cyclopropyloxy.
More preferably, X 2 Selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, methoxy, 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 substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 Cycloalkoxy, said optional substitution being optionally selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 Aryl, C 1-6 The groups of the alkoxy groups are substituted.
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 optional substitution being optionally selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, C 1-6 The groups of the alkoxy groups are substituted.
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 optional substitution means optionally substituted with a member selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, phenyl, C 1-6 The groups of the alkoxy groups are substituted.
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, 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, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl.
More preferably, R 3 Selected from the group consisting of hydrogen, F, cl, br, hydroxy, 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, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropylCyclopropyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl.
More preferably, R 4 Selected from hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, methoxy, hydroxymethyl.
In a preferred embodiment of the invention, R 5 Selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, and cyclopropyloxy.
More preferably, R 5 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy.
Most preferably, R 5 Selected from hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, ethyl, methoxy, 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 optional substitution being optionally substituted by halogen, hydroxy, mercapto, amino, cyano, carboxy, C 1-3 The groups of the alkyl groups are substituted.
More preferably, 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 phenyl, optionally substituted 5-6 membered heteroaryl, said optionally substituted meaning optionally substituted with a group selected from halogen, hydroxy, mercapto, amino, cyano, carboxyl, methyl, ethyl.
More preferably, Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methylEthyl, n-propyl, isopropyl, cyclopropyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, said optionally substituted meaning optionally substituted with a group selected from 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, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazolyl, said optionally substituted meaning optionally substituted with 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, mercapto, amino, cyano, nitro, methyl, ethyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazolyl, said optionally substituted meaning optionally substituted with a group selected from the group consisting of 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, 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, monomethyl-substituted pyridyl.
In a preferred embodiment of the invention, Z 3 Selected from C (R) 9 ) Wherein R is 9 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl groups.
More preferably, Z 3 Selected from C (R) 9 ) Wherein R is 9 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl.
In a preferred embodiment of the invention, R 23 Independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl, alkoxy.
More preferably, R 23 Each independently selected from hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, ethyl, methoxy, ethoxy.
More preferably, R 23 Each independently selected from hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, methoxy.
In a preferred embodiment of the invention, Z 4 Selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 A cycloalkoxy group.
More preferably, Z 4 Selected from C (R) 25 ) Or N, wherein R 25 Selected from the group consisting of hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy.
More preferably, Z 4 Selected from C (R) 25 ) Or N, wherein R 25 Selected from hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, ethyl, methoxy, ethoxy.
More preferably, Z 4 Selected from N.
In a preferred embodiment of the invention, P is selected from one of hydrogen, halogen, hydroxy, mercapto, amino, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy.
More preferably, P is selected from one of hydrogen, F, cl, br, hydroxy, mercapto, amino, carboxyl, methyl, ethyl, methoxy, ethoxy.
More preferably, P is selected from one of hydrogen, F, cl, br, hydroxy, mercapto, amino, 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 which, each R 24 When present, is independently selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 An alkylamino group.
More preferably, Q is selected from C (R 24 )(R 24 ) Wherein each R is 24 When present, is independently selected from hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 An alkylamino group.
More preferably, Q is selected from C (R 24 )(R 24 ) Wherein each R is 24 And is independently selected from hydrogen, F, cl, br, hydroxy, methyl.
In a preferred embodiment of the 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 invention, the compounds, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, are selected from the group consisting of:
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the present invention also provides a pharmaceutical composition comprising the compounds of formulas (I) - (VII) as shown herein, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof.
The invention also provides a pharmaceutical composition which comprises the compounds shown in the formulas (I) - (VII), stereoisomers, optical isomers, pharmaceutical salts, prodrugs and solvates thereof and pharmaceutically acceptable auxiliary materials.
The invention also provides the use of the compounds of formulas (I) - (VII) and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs and solvates thereof for the manufacture of a medicament for the treatment of a disease mediated by a PAK4 inhibitor.
Further, the diseases mediated by PAK4 inhibitors of the present invention are cancers or tumor-related diseases.
The use of compounds of formulae (I) - (VII), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, in the manufacture of a medicament for the treatment of cancer or tumour diseases.
In some contexts in the art, the cancer may also be referred to as malignancy.
The invention provides the use of the compounds of formula (I) - (VII), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, and solvates thereof, for the manufacture of a medicament for the treatment of diseases mediated by PAK4 inhibitors, wherein the compounds of formula (I) - (VII), and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, and solvates thereof, are administered in combination with an additional anti-cancer agent or immune checkpoint inhibitor for the treatment of cancer or tumour.
The compounds of the present invention, as well as stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates thereof, 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 tumor.
The object of the present invention is also to provide a method for the prevention and/or treatment of diseases mediated by PAK4 inhibitors, comprising administering to a patient a therapeutically effective dose of a compound of formulae (I) - (VII), as well as stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or pharmaceutical compositions thereof.
The compounds of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, are prepared by the following methods:
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, substitution is carried out on indole NH which is a parent nucleus of the compound 3 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 definition
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, straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl groups), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl groups), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl), e.g. "C 1-6 Alkyl "meansIs an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (in particular 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 a specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 Cycloalkyl), more preferably 3 to 6 carbon atoms (C 3-6 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
The term "alkoxy", unless otherwise specified, refers to an-O-alkyl group, which is as defined above, i.e. comprising 1 to 20 carbon atoms, preferably comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 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, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
The term "halogen" or "halo" refers to F, cl, br, I unless otherwise specified. The term "haloalkyl" means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above 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 Etc.
Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Alkenyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkenyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkenyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkenyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkenyl), 2 carbon atoms (i.e. C 2 Alkenyl), e.g. "C 2-6 Alkenyl "means 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, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, having at least one triple bond, unless otherwise specified. Alkynyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkynyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkynyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl groups), e.g. "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, 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, which is a non-aromatic structure, containing 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, more 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 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
Unless otherwise specified, the term "aryl" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring group". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and the like.
Unless otherwise specified, the term "heteroaryl" means 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 being independently selected from O, N or S, the number of heteroatoms preferably being 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, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, 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, [1,5-a ] triazolo [1,5-a ] pyridyl, and the like.
The term "optical isomer" refers to a substance that has identical molecular structure, similar physicochemical properties, but different optical rotation, unless otherwise specified.
The term "stereoisomer" refers to compounds having the same chemical structure, but spatially different arrangements of atoms or groups, unless otherwise specified. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers and the like. The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers include interconversions by recombination of some of the bond-forming electrons.
Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention. The term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are, unless otherwise specified, suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or the free acid with a suitable reagent alone.
The term "solvate" means, unless otherwise specified, the 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 some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art.
Unless otherwise specified, the terms "isotopically-labeled analog," "isotopically-derivative" refer to isotopically-labeled molecules, thereby providing isotopically-labeled analogs that may have improved pharmacological activity. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, 2 h and 3 h is formed; carbon isotopes: 11 C, 13 c and C 14 C, performing operation; chlorine isotopes: 35 cl and Cl 37 Cl; fluorine isotopes: 18 f, performing the process; iodine isotopes: 123 i and 125 i, a step of I; nitrogen isotopes: 13 n and 15 n; oxygen isotopes: 15 O, 17 o and 18 isotopes of O and sulfur 35 S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular deuterium 3 H and carbon 13 C, because they are easily labeled and conveniently detected, the application is wider. Certain heavy isotopes, such as heavy hydrogen @, for example 2 H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing curative effect advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds. Typically, the compounds of the invention comprise isotopic derivatives (e.g., deuterated) 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 more than the parent drug It is easier to administer. For example, they may be bioavailable orally, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of formula I that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but once inside the cell is beneficial, it is then 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, wherein the peptide is metabolized to reveal 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, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaryl ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaryl ring groups may optionally be selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy is substituted by one or more of the substituents, which means that two H's in the same substitution position are replaced by the same O to form a double bond.
The beneficial effects of the invention are as follows:
the invention designs a compound with a novel structure, and provides a novel direction for the development of PAK4 inhibitor medicines. The human acceptor PAK4 inhibitor research shows that the compounds have strong inhibition effect on human acceptor PAK4 and can be used as the prospect compounds for treating PAK4 inhibitor mediated diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has 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 specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. 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. 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 methods and materials are presented herein for illustrative purposes only.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and Liquid Chromatography (LCMS) or/and liquid chromatography (HPLC). The NMR measurement used an instrument of Bruker AVANCE NEO 400MHz and LCMS used an instrument of LCMS WATERS ACQUITY UPLC H-Class PLUS or/and SQD2; the instrument used for HPLC was 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:
first step 1- ((1H-indol-5-yl) ethynyl) cyclohexan-1-ol preparation:
5-iodo-1H-indole (4.00 g,16.46mmol,1.0 eq) and 1-ethynyl cyclohexane-1-ol (10.22 g,82.29mmol,5.0 eq) were dissolved in DMF (N, N-dimethylTo formamide) (40 mL) was added CuI (cuprous iodide) (312 mg,1.40mmol,0.1 eq), ethylenediamine (3.61 g,49.37mmol,3.0 eq.) and Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride) (292 mg,0.4mmol,0.02 eq) was stirred overnight at room temperature under nitrogen. LCMS detects completion of the reaction. Water (30 mL) was added to the reaction system, followed by extraction with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry to give a crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate=10:1) to give crude 1- ((1H-indol-5-yl) ethynyl) cyclohexane-1-ol (4.00 g,16.71mmol, containing 1-ethynyl cyclohexane-1-ol). 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) cyclohexane-1-ol:
crude 1- ((1H-indol-5-yl) ethynyl) cyclohexane-1-ol (1.20 g,5.01mmol,1.0 eq) was dissolved in DMF (N, N-dimethylformamide) (15 mL) and N-bromosuccinimide (1.07 g,6.01mmol,1.2 eq.) was added to the mixture and stirred under nitrogen at 25℃for 12H. LCMS detects completion of the reaction. Water (20 mL) was added to the reaction system, followed by extraction with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry to give a crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate=5:1) to give the product 1- ((3-bromo-1H-indol-5-yl) ethynyl) cyclohexane-1-ol (1.40 g,4.4 mmol, 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)。
Preparation of third step 1- ((3-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
1- ((3-bromo-1H-indol-5-yl) ethynyl) cyclohexane-1-ol (1.00 g,3.14mmol,1.0 eq.) was dissolved in DMF (N, N-dimethylformamide) (15 mL), 60% NaH (sodium hydride) (377 mg,9.42mmol,3.0eq, 60%) was added, after stirring at 0℃for half an hour at room temperature, SEMCl (2- (trimethylsilyl) ethoxymethyl chloride) (0.78 g,4.71mmol,1.5 eq.) was added to the reaction solution and the reaction was stirred at room temperature under nitrogen overnight. LCMS detects completion of the reaction. Water (20 mL) was added to the reaction system, followed by extraction with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry to give a crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate=5:1) by spin-drying to give the material 1- ((3-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexane-1-ol (650 mg,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)。
Preparation of fourth step 1- ((3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
1- ((3-bromo-1- (((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol (200 mg,0.44mmol,1.0 eq.) 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2, 3-b)]Pyridine (163 mg,0.66mmol,1.5 eq.) Na 2 CO 3 (sodium carbonate) (63 mg, 0.5)9mmol,1.3 eq) and Pd (PPh 3 ) 4 (tetrakis (triphenylphosphine) palladium) (36 mg,0.22mmol,0.5 eq) was added to the Dioxane/H 2 O (dioxane and aqueous solution=5:1) (5 mL), after the addition was completed, was raised to 90 ℃. 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 (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried by spinning. The crude product was purified by flash chromatography (petroleum ether: ethyl acetate=3:1) and dried to give the product 1- ((3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-yl) ethynyl) cyclohexane-1-ol (100 mg,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:
1- ((3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indol-5-ylethynyl) cyclohexane-1-ol (100 mg,0.21mol,1.0 eq) was dissolved in THF (tetrahydrofuran) (5 mL), TBAF (tetrabutylammonium fluoride) (279 mg,1.03mmol,5.0 eq.) was added and stirred at 80 ℃ under nitrogen for 4H, lcms monitored reaction was complete, and the reaction solution cooled to room temperature and dried by spinning. The crude product was purified by preparative TLC plate (dichloromethane: methanol=15:1), eluting with ethyl acetate and spin-drying to give product 1- ((3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-indol-5-yl-ethynyl) cyclohexane-1-ol (60 mg,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
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Example 22
Preparation of 1- ((3- (2-phenyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indol-5-yl) ethynyl) cyclohexan-1-ol:
preparation of first step 4-bromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
starting material 4-bromo-1H-pyrrolo[2,3-b]Pyridine (5.0 g,25.38mmol,1.0 eq) was added to THF (tetrahydrofuran) (50 mL), the mixture was cooled in an ice-water bath, naH (1.12 g,27.91mmol,1.1 eq) was added with stirring, the temperature was kept at 0 ℃ for 30 min, then starting compound 2 (4.93 g,27.91mmol,1.1 eq) was added under ice-water bath conditions, and after completion of the addition, the mixture was slowly warmed to room temperature and stirred for 16 hours, LCMS detection. Water (50 mL) was added to the reaction system, followed by extraction with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry to give a crude product. The crude product was purified by flash chromatography (petroleum ether: ethyl acetate=4:1) to give the product 4-bromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ]Pyridine (7.5 g, yield 87.6%). LCMS [ M+H ]] + ＝338.9.
Second step preparation of 2, 4-dibromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
starting material 4-bromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine (3.00 g,8.90mmol,1.0 eq) was added to THF (tetrahydrofuran) (30 mL), the mixture was cooled to-78℃in a dry ice acetone bath, LDA (7 mL,13.35mmol,1.5 eq) was added with stirring, the temperature was maintained at-78℃for 30 min, then 1, 2-dibromo-1, 2-tetrachloroethane (3.77 g,11.57mmol,1.3 eq) was added at that temperature, the temperature was maintained at-78℃with stirring for 3 h after the addition, saturated NH was added 4 Cl (30 mL) and then ethyl acetate (100 mL), dried over anhydrous sodium sulfate, and the organic phase concentrated, column chromatography (PE: EA=4:1) afforded the product 2, 4-dibromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine (3.00 g, 81.0% yield). LCMS (ESI) [ M+H ]]+＝416.8。
Preparation of the third step 4-bromo-2-phenyl-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
2, 4-dibromo-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine (1.2 g,2.88mmol,1 eq), phenylboronic acid (351.64 mg,2.88mmol,1 eq), sodium carbonate (611.35 mg,5.77mmol,2 eq) and Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphine) ferrocene)]Palladium dichloride) (210 mg,0.288mmol,0.1 eq) was added to dioxane (20 mL) and water (2 mL), replaced with argon 5 times, and heated to 80℃and stirred for 3 hours. LCMS monitors completion of the reaction, cools the reaction to room temperature and then adds saturated NH 4 Cl (100 mL) and then extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry to give the crude product. The crude product was isolated and purified by flash chromatography (petroleum ether: ethyl acetate=5:1) to give the product (600 mg, yield, 50.3%). LCMS [ M+H ]] + ＝412.9。
Preparation of (2-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) boronic acid
4-bromo-2-phenyl-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine (300 mg,0.73mmol,1 eq), 4', 5',5 '-octamethyl-2, 2' -bi (1, 3, 2-dioxaborane) (368.66 mg,1.45mmol,2 eq), potassium acetate (284.95 mg,2.90mmol,4 eq) and Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphine) ferrocene)]Palladium dichloride) (53.3 mg,0.073mmol,0.1 eq.) was added to dioxane (10 mL), replaced with argon 5 times, heated to 100deg.C, and stirred for 16 hours. LCMS monitored reaction was complete. LCMS monitors completion of the reaction, cools the reaction to room temperature and then adds saturated NH 4 Cl (30 mL) and then extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, 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 1 preparation of- ((3- (2-phenyl-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -1- (benzenesulfonyl) -1H-indol-5-yl) ethynyl) cyclohexane-1-ol:
(2-phenyl-1- (phenylsulfonyl) -1H-pyrrolo [2, 3-b)]Pyridine-4-yl) boronic acid (150 mg,0.33mmol,1 eq), 1- ((3-bromo-1- (benzenesulfonyl) -1H-indol-5-yl) ethynyl) cyclohex-1-ol (149.35 mg,0.33mmol,1 eq), sodium carbonate (103.60 mg,0.98mmol,3 eq) and Pd (dppf) Cl 2 ([ 1,1' -bis (diphenylphosphine) ferrocene)]Palladium dichloride) (24 mg,0.033mmol,0.1 eq.) was added to dioxane (5 mL) and water (0.5 mL), argon was displaced 5 times, heated to 100deg.C, and stirred for 5 hours. LCMS monitored reaction was complete. LCMS monitors completion of the reaction, cools the reaction to room temperature and then adds saturated NH 4 Cl (20 mL) and then extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry to give the crude product. The crude product was isolated and purified by flash chromatography (dichloromethane: methanol=20:1) to give the product (100 mg, yield 43.1%). 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:
1- ((3- (2-phenyl-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1- (benzenesulfonyl) -1H-indol-5-yl) ethynyl) cyclohexane-1-ol (100 mg,0.14mmol,1 equiv.) and sodium hydroxide (22.48 mg,0.56mmol,4 eq.) were added to a mixed solution of THF (1 mL) and methanol (1 mL) and reacted at room temperature with stirring for 3H. LCMS detects complete reaction of starting material. Adding saturated NH to the reaction solution 4 Cl (5 mL) and then extracted with ethyl acetate (5 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the mother liquor was spun dry to give the crude product. The crude product was purified by flash chromatography (DCM: meoh=10:1) to give the crude product which was purified by Prep-HPLC (0.1% nh 3 H 2 O in water, meCN) to give 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 by the same method as in example 22
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Examples 33 and 34
Preparation of 1- ((1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indazol-6-yl) ethynyl) cyclohex-1-ol (compound of example 33):
preparation of 1- ((2- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazol-6-yl) ethynyl) cyclohexan-1-ol (compound of example 34)
Preparation of first step 4-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine:
at 0 ℃, 4-fluoro-1H-pyrrolo [2,3-b]Pyridine (700 mg,5.142mmol,1 eq) was dissolved in tetrahydrofuran (10 mL), then sodium hydride (185 mg,7.710mmol,1.5 eq) was added and reacted at this temperature for 30 minutes, then (2- (chloromethoxy) ethyl) trimethylsilane (1.03 g,6.170mmol,1.2 eq) was added to the reaction solution and the reaction was continued for 16 hours, LCMS monitored the reaction was complete. The reaction was concentrated to a solid, quenched with water, extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude product. Purification by reverse phase separation (0.01%FA in water,MeCN) gives 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
4-fluoro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridine (200 mg,0.751mmol,1 eq) and 6-iodo-1H-indazole (183 mg,0.751mmol,1 eq) and potassium carbonate (311 mg,2.252mmol,3 eq) were dissolved in NMP (5 mL) followed by N 2 The displacement was 3 times and stirring was continued for 2 hours slowly up to 150 ℃, LCMS detected reaction completion. Then 5mL of DMF solvent was added thereto and the product 6-iodo-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-b) was purified in reverse phase]Pyridin-4-yl) -1H-indazole (140 mg, 38%) and solid product 6-iodo-2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b]Pyridin-4-yl) -2H-indazole (100 mg, 27.2%). LCMS: [ M+H ]]+＝490.9，LCMS:[M+H]+＝490.9
Preparation of 6-iodo-1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indazole
6-iodo-1- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-indazole (140 mg, 0.284 mmol,1 eq) was dissolved in DCM (5 mL) at room temperature, and trifluoroacetic acid (163 mg,1.427mmol,5 eq) was added dropwise thereto, and after reaction at room temperature for 2 hours, aqueous ammonia (5 mL) was added and stirring was continued for 2 hours. LCMS monitored completion of the reaction, water (20 mL) was added to the reaction and extracted with ethyl acetate (20 mL 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 which was purified in 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
6-iodo-1- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-indazole (50 mg,0.139mmol,1 eq) and 1-ethynylcyclohexane-1-ol (69 mg, 0.55mmol, 4 eq), diethylamine (30 mg,0.416mmol,3 eq) and Pd (dppf) Cl 2 (17 mg,0.0139mmol,0.1 eq) of cuprous iodide (26 mg,0.138mmol,1 eq) 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=5:1) to give product 1- ((1- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl]) -1H-indazol-6-yl) ethynyl) cyclohexane-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
6-iodo-2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) -2H-indazole (100 mg,0.204mmol,1 eq) was dissolved in DCM (5 mL) at room temperature, trifluoroacetic acid (116 mg,1.120mmol,5 eq) was added dropwise thereto, and after reacting at room temperature for 2 hours, aqueous ammonia (5 mL) was added and stirring was continued for 2 hours. LCMS monitored completion of the reaction, water (20 mL) was added to the reaction and extracted with ethyl acetate (20 mL 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. 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, 68% yield). 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
6-iodo-2- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -2H-indazole (40 mg,0.111mmol,1 eq) and diethylamine (21 mg,0.111mmol,1 eq), 1-ethynylcyclohexane-1-ol (55 mg,0.444mmol,4 eq) and Pd (dppf) Cl 2 (10 mg,0.0111mmol,0.1 eq) in DMF (5 mL) was 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=5:1) to give product 1- ((2- (1H-pyrrolo [2, 3-b)]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 by the same method as in example 33 and example 34
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
Preparation of first step 4-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridine:
the raw material 4-nitro-1H-pyrrolo [2,3-b]Pyridine (3.00 g,18.39mmol,1.0 eq) was added to THF (tetrahydrofuran) (30 mL), the mixture was cooled in an ice-water bath, and NaH (956 mg,23.91mmol,1.3eq, mass fraction 60%) was added with stirring, the temperature was kept at 0 ℃ for 30 min, then the raw material benzenesulfonyl chloride (3.57 g,20.23mmol,1.1 eq) was added under ice-water bath conditions, and after addition was slowly warmed to room temperature and stirred for 16h. LCMS monitored reaction was complete and H was added 2 O (10 mL), then ethyl acetate (30 mL x 3), combined organic phases and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was purified by flash chromatography (petroleum ether: ethyl acetate=4:1) to give 4-nitro-1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridine (4.2 g, 75.3% yield). LCMS [ M+H ]]+＝304.0。
Second step preparation of 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine:
starting 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, after which the hydrogen was replacedThe flow of air is three times. Stirring at room temperature for 16 hours, LCMS monitored reaction completion. Filtration and concentration of the organic phase gave the product 1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-amine (1.4 g, 77.7% yield). LCMS [ M+H ]] + ＝274.0。
Step three preparation of N- (5-bromo-2-nitrophenyl) -1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine:
starting material 1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridine-4-amine (930 mg,3.40mmol,1.0 eq) was added to DMF (N, N-dimethylformamide) (10 mL), the mixture was cooled in an ice-water bath, naH (163 mg,4.08mmol,1.2 eq) was added with stirring, the temperature was kept at 0deg.C for 30 min, then 4-bromo-2-fluoro-1-nitrobenzene (898 mg,4.08mmol,1.2 eq) was added under ice-water bath conditions, and the mixture was slowly warmed to room temperature after addition and stirred for 2 h. After completion of the LCMS reaction, H was added 2 O (5 mL), then ethyl acetate (20 mL x 3), combining the organic phases and drying over anhydrous sodium sulfate, filtering and concentrating the organic phase, separating and purifying the crude product N- (5-bromo-2-nitrophenyl) -1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b) by flash chromatography (petroleum ether: ethyl acetate=4:1)]Pyridin-4-amine (483 mg, yield 30.0%). 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:
starting material N- (5-bromo-2-nitrophenyl) -1- (benzenesulfonyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine (4813 mg,1.02mmol,1.0 eq) was added to EtOH (5 mL) and H 2 O (1 mL) and Fe powder (199mg, 3.57mmol,3.5 eq) and NH were added with stirring 4 Cl (279 mg,5.10mmol,5.0 eq) was added and after completion the temperature was slowly raised to 85℃and stirred for 4 hours. LCMS monitored complete. The reaction solution is cooled and filteredLiquid addition H 2 O (5 mL), the organic phases were combined with ethyl acetate (20 mL x 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=1:1) as product 5-bromo-N1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) benzene-1, 2-diamine (383 mg, yield 84.7%). 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:
starting material 5-bromo-N1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) benzene-1, 2-diamine (150 mg,0.34mmol,1.0 eq) was added to triethyl orthoacetate (2 mL), and the mixture was stirred for 16 hours at 100℃with slow temperature rise. LCMS monitored reaction was complete. Cooling to room temperature, adding H 2 O (5 mL), then ethyl acetate (20 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and the organic phase concentrated, and the crude product was purified by flash chromatography (DCM: meOH=20:1) to give the product 6-bromo-2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]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:
starting material 6-bromo-2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-benzo [ d ]]Imidazole (80 mg,0.17mmol,1.0 eq) was added to DMSO (1 mL) and 1-ethynylcyclohexane-1-ol (213 mg,1.71mmol,10.0 eq), triethylamine (Et 3 N) (52 mg,0.51mmol,3.0 eq) and Pd (dppf) Cl 2 (15 mg,0.02mmol,0.1 eq), nitrogen was replaced three times after addition, and the temperature was slowly raised to 90 ℃.The reaction was stirred for 3 hours and monitored by LCMS to completion. After cooling to room temperature, H was added 2 O (5 mL), then extracted with ethyl acetate (10 mL x 3), the organic phases combined and dried over anhydrous sodium sulfate, filtered and the organic phase concentrated, the crude product was purified by flash chromatography (DCM: meoh=20:1) to give product 1- ((2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-benzo [ d ]]Imidazol-6-yl) ethynyl) cyclohexane-1-ol (80 mg, 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:
starting material 1- ((2-methyl-1- (1- (benzenesulfonyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) -1H-benzo [ d ]]Imidazol-6-yl) ethynyl cyclohexane-1-ol (55 mg,0.11mmol,1.0 eq) was added to MeOH (methanol) (1 mL) and THF (tetrahydrofuran) (1 mL), and NaOH (sodium hydroxide) (22 mg,0.54mmol,5.0 eq) was added with stirring, and after the addition was completed, stirred at room temperature for 1 hour. LCMS monitors completion of the reaction, and H is added to the reaction solution 2 O (5 mL), followed by extraction with ethyl acetate (10 mL x 3), combining the organic phases and drying over anhydrous sodium sulfate, filtering and concentrating the organic phase, separating and purifying the crude product by flash chromatography (DCM: meoh=20:1) to give the crude product, which was separated and purified by Prep-HPLC (C18, 0.1%FA in water,MeCN) to give compound 1- ((2-methyl-1- (1H-pyrrolo [2, 3-b) ]Pyridin-4-yl) -1H-benzo [ d ]]Imidazol-6-yl) ethynyl) cyclohexane-1-ol (9.43 mg, 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 was synthesized in the same manner as in example 38
Example 39
Preparation of 6- ((1-hydroxycyclohexyl) ethynyl) -1- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -1H-benzo [ d ] imidazol-2-ol
/>
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:
first step preparation of 5-fluoro-1H-pyrrolo [2,3-b ] pyridine 7-oxide:
at room temperature, 5-fluoro-1H-pyrrolo [2,3-b]Pyridine (2.0 g,14.69mmol,1 eq) was dissolved in dichloromethane (30 mL) followed by the addition of m-chloroperoxybenzoic acid (7.61 g,44.07mmol,3 eq). And the reaction was continued at this temperature for 16 hours. LCMS detects completion of the reaction. The reaction was concentrated to a solid, quenched with saturated sodium bicarbonate, extracted with EtOAC (ethyl acetate) (30 mL. Times.3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude product. The product 5-fluoro-1H-pyrrolo [2,3-b ] was obtained using column chromatography technique DCM, meoh=15:1]900mg of pyridine 7-oxide (40.5% yield). 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
At room temperature, 5-fluoro-1H-pyrrolo [2,3-b]Pyridine 7-oxide (600 mg,3.94mmol,1 eq) was dissolved in DMF (10 mL), then tetrabutylammonium bromide (1.27 g,3.94mmol,3 eq) was added and trifluoromethanesulfonic anhydride (1.11 g,3.94mmol,3 eq) was added dropwise with vigorous stirring. And the reaction was continued at this temperature for 16 hours. LCMS detects completion of the reaction. The reaction was concentrated to a solid, quenched with water (10 mL), extracted with EtOAC (ethyl acetate) (10 mL x 3) and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. Column chromatography (DCM: meoh=15:1) afforded the product 4-bromo-5-fluoro-1H-pyrrolo [2,3-b]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).
Preparation of the third step 5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2,3-b ] pyridine
Compound 1 (300 mg,1.75 mmol,1 eq) was dissolved in dioxane (15 mL), then potassium acetate (719 mg,5.28mmol,3 eq) was added, pinacol biborate (1.3411 g,5.28mmol,3 eq) was replaced with nitrogen 3 times before Pd (dppf) Cl was added 2 (129 mg,0.1758mmol,0.1 eq). The reaction was slowly warmed to 90 ℃ for 16 h, LCMS (monitored reaction complete, reaction concentrated to a solid, quenched with water, extracted with EtOAC (ethyl acetate) (30 mL x 3), the combined organic phases washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, concentrated to a crude product, prep-HPLC isolated and purified (0.01% nh) 3 .H 2 O in water, meCN) to give 5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2, 3-b)]Pyridine (120 mg, 26% yield).
LCMS:[M+H] + ＝263.1
Fourth step 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
5-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrrolo [2,3-b]Pyridine (100 mg,0.382mmol,1 eq) 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) cyclohexane-1-ol (171.32 mg,0.076mmol,1 eq), sodium carbonate (121.3 mg,1.145mmol,3 eq), nitrogen was added 3 times before Pd (dppf) Cl was replaced 2 (28 mg,0.0382mmol,0.1 eq) was added. The reaction mixture was slowly warmed to 85℃and the reaction was continued for 16 hours. LCMS detected completion of the reaction, the reaction was concentrated to a solid, ph=8 was adjusted by adding saturated sodium bicarbonate (60 mL) solution, extracted with EA (ethyl acetate) (10 mL x 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 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) cyclohexane-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:
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,0.040 mmol) was added to a solution of MeOH (5 mL) followed by the addition of tetrabutylammonium fluoride (103.82 mg, 0.397)mmol,10 eq), and stirred for 2 hours at 80 ℃. After completion of the reaction by LCMS, the crude product was concentrated under reduced pressure and purified by Prep-HPLC (0.1% FA in water, meCN) to give product 1- ((3- (5-fluoro-1H-pyrrolo [2, 3-b))]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 inhibition of PAK4 kinase activity by Compounds was tested using the Caliper mobility shift assay (Caliper mobility shiftassay)
The test method comprises the following steps: on kinase PAK4, the compound test was initiated at a final concentration of 10 μm, diluted 3-fold for 10 concentrations. The compound was transferred to the target plate 3573 at 250nL of 100-fold final concentration using a dispenser Echo 550, and 10. Mu.L of PAK4 kinase solution at 0.625nM each was added and incubated at room temperature for 60 minutes (negative control wells containing 10. Mu.L of kinase buffer and 250nL of 100% DMSO; positive control wells containing 10. Mu.L of kinase solution and 250nL of 100% DMSO). On kinase PAK4, 15. Mu.L of ATP was added to a final concentration of km and the substrate polypeptide mixture 3. Mu.M was reacted for 60 minutes. The kinase reaction was stopped by adding 30. Mu.L of stop detection solution containing EDTA. The conversion was read with Caliper EZ Reader. Conversion inhibition% = (positive control conversion mean%sample conversion%/(positive control conversion mean%negative control conversion mean%)) wherein, negative control wells represent conversion readings without enzyme activity wells, positive control wells represent conversion readings without compound inhibition wells, log values of concentration are used as X-axis, percentage inhibition is Y-axis, log (inhibitor) vs. response-Variable slope fit-effect curve of analytical software GraphPad Prism5 is used to obtain IC50 values of each compound for enzyme activity.
Conclusion of the test: from the above scheme, the compounds of the examples of the present invention showed the following biological activities in PAK4 enzyme activity inhibition test as shown in Table 1
Table 1: IC of compounds for PAK4 enzyme activity inhibition 50 Value of
Note that: a represents IC 50 <100nΜ。
The results shown in the table above indicate that the series of compounds have stronger PAK4 enzyme inhibition activity and can be used for treating PAK4 inhibitor-mediated diseases.

Claims (13)

1. A compound represented by the following formula (VII), and optical isomer and medicinal salt thereof,
wherein X is 2 Selected from C (R) 1 ) Wherein R is 1 Selected from hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, methoxy, ethoxy;
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 optional substitution means optionally substituted with a member selected from halogen, hydroxy, mercapto, amino, cyano, -O-C 1-6 Alkyl- (trimethylsilyl), C 1-6 Alkyl, phenyl, C 1-6 The group of the alkoxy group is substituted;
R 4 selected from hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, methoxy, hydroxymethyl;
R 5 selected from hydrogen, F, cl, br, hydroxy, amino, cyano Nitro, methyl, ethyl, methoxy, ethoxy;
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 phenyl, optionally substituted 5-6 membered heteroaryl, said optionally substituted meaning optionally substituted with a group selected from halogen, hydroxy, mercapto, amino, cyano, carboxyl, methyl, ethyl;
Z 3 selected from C (R) 9 ) Wherein R is 9 Selected from hydrogen, F, cl, br, hydroxyl, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl;
R 23 each independently selected from hydrogen, F, cl, br, hydroxy, amino, cyano, nitro, methyl, methoxy;
Z 4 selected from N;
p is selected from one of hydrogen, F, cl, br, hydroxyl, sulfhydryl, amino and methyl;
q is selected from C (R) 24 )(R 24 ) Wherein each R is 24 Independently selected from hydrogen, F, cl, br, hydroxy, methyl;
m is selected from 1,2,3;
n is selected from 1,2,3.
2. The compound of claim 1, wherein,
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.
3. The compound of claim 1, optical isomer, pharmaceuticalSalts, wherein R 3 Selected from hydrogen, F, cl, br, 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, benzenesulfonyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl.
4. The compound of claim 1, wherein R 3 Selected from the group consisting of hydrogen, F, cl, br, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl.
5. The compound of any one of claim 1 to 4, wherein,
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 phenyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, said optionally substituted meaning optionally substituted with a group selected from halogen, hydroxy, mercapto, amino, cyano, carboxyl, methyl, ethyl.
6. The compound of any one of claims 1-4, wherein Z 2 Selected from N or C (R) 7 ) Wherein R is 7 Selected from hydrogen, halogen, hydroxy, mercapto, amino, cyano, nitro, methyl, ethyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazolyl, said optionally substituted meaning optionally substituted with a group selected from F, cl, br, hydroxy, mercapto, amino, cyano, carboxy, methyl.
7. The compound of any one of claims 1-4, wherein Z 2 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 pyridyl, optionally substituted pyrazolyl, said optionally substituted meaning optionally substituted with a group selected from the group consisting of F, cl, br, hydroxy, mercapto, amino, cyano, carboxy, methyl.
8. The compound of any one of claims 1-4, wherein 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, 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, monomethyl-substituted pyridyl.
9. The compound of any one of claim 1 to 4, wherein,
m is selected from 1, and n is selected from 1;
alternatively, m is selected from 1 and n is selected from 2;
alternatively, m is selected from 2 and n is selected from 1;
alternatively, m is selected from 2 and n is selected from 2.
10. A compound selected from the group consisting of:
11. a pharmaceutical composition comprising a compound according to any one of claims 1 to 10, as well as optical isomers, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.
12. Use of a compound according to any one of claims 1 to 10, as well as optical isomers, pharmaceutically acceptable salts thereof or a composition according to claim 11 in the manufacture of a medicament for the treatment of a disease mediated by PAK 4.
13. The use of claim 12, wherein the PAK 4-mediated disease is cancer or a tumor-related 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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