CN115433175A - Quinoline and quinazoline compounds containing alkynyl substitution, preparation and application thereof - Google Patents

Quinoline and quinazoline compounds containing alkynyl substitution, preparation and application thereof Download PDF

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CN115433175A
CN115433175A CN202110614492.3A CN202110614492A CN115433175A CN 115433175 A CN115433175 A CN 115433175A CN 202110614492 A CN202110614492 A CN 202110614492A CN 115433175 A CN115433175 A CN 115433175A
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张翱
高大明
宋子兰
王凯华
邢莉
顾王婷
肖若璇
丁春勇
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Shanghai Jiaotong University
Center for Excellence in Molecular Cell Science of CAS
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Center for Excellence in Molecular Cell Science of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The invention provides quinoline and quinazoline compounds containing alkynyl substitution, and preparation and application thereof. Specifically, the invention provides a compound shown as the formula I, or pharmaceutically acceptable salt, enantiomer, diastereoisomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof. The compounds of the present invention have excellent active PGK1 kinase inhibitory activity.

Description

Quinoline and quinazoline compounds containing alkynyl substitution, and preparation and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to quinoline and quinazoline compounds containing alkynyl substitution, and preparation and application thereof.
Background
The Warburg effect is one of the important features of tumor cells, which represents the shift in the way glucose is utilized by tumor cells from oxidative phosphorylation to glycolysis. The normal cells obtain ATP energy through the mitochondrial oxidative phosphorylation pathway, and the tumor cells are in uncontrolled division and proliferation, so the energy demand is particularly strong. Even under normal oxygen concentration, rapidly proliferating tumor cells will preferentially select anaerobic glycolysis for energy. Alterations in tumor metabolic pathways are considered to be one of the important driving forces for tumor development and progression.
Phosphoglycerate kinase 1 (PGK1) is a key metabolic enzyme in the glycolytic pathway, catalyzing the conversion of 1, 3-diphosphoglycerate (1, 3-BPG) to 3-phosphoglycerate (3-PG) and producing the first ATP in the glycolytic pathway, playing an important role in cellular energy metabolism. The research results in recent years show that PGK1 is closely related to the occurrence and development of tumors. A2016 study shows that the severity of liver cancer patients is positively correlated with the expression level of PGK1 protein in the liver cancer patients. After the pgk1 gene is knocked down, the glycolytic capacity of a liver cancer cell line is reduced, the productivity is reduced, the proliferation of cells is inhibited, and the tumor forming capacity is weakened. The result indicates that PGK1 may become a molecular target in liver cancer treatment. Meanwhile, PGK1 is associated with the multidrug resistance phenomenon of various malignant tumors. For example, PGK1 is a predictor of low survival in breast cancer patients and is also a new prognostic biomarker for drug resistance to paclitaxel therapy. Moreover, PGK1 is also significantly up-regulated in pancreatic cancer, colorectal cancer, neuroblastoma, brain glioma and many other malignancies. It follows that targeting PGK1 may be an effective strategy for the treatment of malignancies.
Although studies targeting PGK1 inhibitors have great potential in the treatment of malignancies, PGK1 inhibitor studies are still in the infancy.
In view of the above, there is an urgent need in the art to develop a new class of targeted PGK1 inhibitors.
Disclosure of Invention
The invention aims to provide a novel targeted PGK1 inhibitor.
In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof;
Figure BDA0003097511860000021
wherein, the first and the second end of the pipe are connected with each other,
z is selected from the group consisting of: c (R) d )、N；
R d Selected from the group consisting of: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl (preferably, C1-C3 alkyl);
R 1 selected from the group consisting of: H. -OR a 、-SR a 、-N(R a ) 2 Unsubstituted or substituted by one or more R s1 Substituted 4-10 membered heterocycloalkyl;
R a selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl (preferably C1-C3 alkyl);
R s1 each independently selected from the group consisting of: halogen, substituted or unsubstituted C1-C3 alkyl, cyano;
R 2 and R 3 Each independently of the otherIs selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, cyano;
a is a divalent group selected from the group consisting of: - (C (R) c ) 2 ) n -and a carbonyl group (-C (O) -);
n is 1,2 or 3;
R c each independently selected from the group consisting of: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl (preferably, C1-C3 alkyl);
R 4 selected from the group consisting of: -OR b and-NHR b ；
R b Selected from the group consisting of: H. unsubstituted or substituted by one or more R s2 Substituted C1-C6 alkyl (preferably, C1-C3 alkyl), unsubstituted or substituted with one or more R s2 Substituted C1-C6 alkanoyl (preferably C1-C3 alkanoyl) (i.e., -C (O) -C1-C6 alkyl, preferably, -C (O) -C1-C3 alkyl);
R s2 each independently selected from the group consisting of: halogen, cyano, hydroxy, C1-C3 alkoxy;
R 5 selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl (preferably C1-C3 alkyl);
R 6 selected from the group consisting of: unsubstituted or substituted by one or more R S3 Substituted C6-C10 aryl, unsubstituted or substituted by one or more R S3 Substituted 5-12 membered heteroaryl, unsubstituted or substituted by one or more R S3 Substituted C4-C10 cycloalkyl, unsubstituted or substituted by one or more R S3 Substituted 5-12 membered heterocycloalkyl;
R s3 each independently selected from the group consisting of: halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkanoyl, cyano, oxo (= O);
unless otherwise specified, the substitution means that one or more hydrogens in the group are optionally substituted with a substituent selected from the group consisting of: hydroxy, halogen, amino (-NH) 2 ) -N (C1-C3 alkyl) 2 NH (C1-C3 alkyl), cyano.
In another preferred embodiment, Z is N or CH.
In another preferred embodiment, R 1 Wherein said 4-10 membered heterocycloalkyl group contains at least one N-heterocycloalkyl atom.
In another preferred embodiment, R 1 Wherein the 4-10 membered heterocycloalkyl group is attached to the remainder of the compound through the N-heterocycloalkyl atom thereof.
In another preferred embodiment, R 1 Is H, -N (R) a ) 2 Unsubstituted or substituted by one or more R s1 Substituted 4-10 membered heterocycloalkyl.
In another preferred embodiment, R 1 Is H, -N (R) a ) 2 Unsubstituted or substituted by one or more R s1 Substituted 4-10 membered heterocycloalkyl; and wherein the 4-10 membered heterocycloalkyl group contains at least one N-heterocycloalkyl atom and is attached to the remainder of the compound through the N-heterocycloalkyl atom therein.
In another preferred embodiment, R 2 Selected from the group consisting of: H. halogen, C1-C6 alkyl (preferably, C1-C3 alkyl), cyano.
In another preferred embodiment, R 2 Is halogen.
In another preferred embodiment, R 2 Is Cl.
In another preferred embodiment, R 3 Is H or C1-C6 alkyl (preferably, C1-C3 alkyl).
In another preferred embodiment, R 3 Is H.
In another preferred embodiment, R 2 Selected from the group consisting of: H. halogen, C1-C6 alkyl (preferably, C1-C3 alkyl), cyano; and R is 3 Is H or C1-C6 alkyl (preferably, C1-C3 alkyl).
In another preferred embodiment, R 2 Selected from the group consisting of: H. halogen, C1-C6 alkyl (preferably, C1-C3 alkyl), cyano; and R is 3 Is H.
In another preferred embodiment, R 2 Is halogen (e.g., cl); and R is 3 Is HC1-C6 alkyl (preferably, C1-C3 alkyl, more preferably, methyl).
In another preferred embodiment, R 2 Is halogen (e.g., cl); and R is 3 Is H.
In another preferred embodiment, R c Each independently is hydrogen or deuterium;preferably, it is H.
In another preferred embodiment, A is-CH 2 -or-CH 2 CH 2 -; preferably, A is-CH 2 -。
In another preferred embodiment, A is-CH 2 -。
In another preferred embodiment, R 4 is-OR b 。
In another preferred embodiment, R b Selected from the group consisting of: H. unsubstituted or substituted by one or more R s2 Substituted C1-C6 alkyl (preferably C1-C3 alkyl); r s2 Each independently selected from the group consisting of: halogen, cyano, hydroxy, C1-C3 alkoxy.
In another preferred embodiment, R b Selected from the group consisting of: H. unsubstituted or substituted by one or more R s2 Substituted C1-C6 alkyl (preferably C1-C3 alkyl); r is s2 Each independently selected from the group consisting of: hydroxy, C1-C3 alkoxy.
In another preferred embodiment, R b Is H.
In another preferred embodiment, R 4 is-OR b (ii) a And R is b Selected from the group consisting of: H. unsubstituted or substituted by one or more R s2 Substituted C1-C6 alkyl (preferably, C1-C3 alkyl); r is s2 Each independently selected from the group consisting of hydroxy, C1-C3 alkoxy; preferably, R 4 is-OH.
In another preferred embodiment, R 5 Selected from the group consisting of: hydrogen, C1-C3 alkyl.
In another preferred embodiment, R 5 Selected from the group consisting of: hydrogen, methyl, ethyl.
In another preferred embodiment, R 5 Is methyl.
In another preferred embodiment, R 6 Selected from the group consisting of: unsubstituted or substituted by one or more R S3 Substituted phenyl, unsubstituted or substituted by one or more R S3 Substituted 5-6 membered heteroaryl, unsubstituted or substituted with one or more R S3 Substituted C4-C6 cycloalkyl, unsubstituted or substituted by one or more R S3 Substituted 5-7 membered heterocycloalkyl.
In another preferred embodiment, R 6 Wherein said heteroaryl is a sulfur-containing heteroaryl.
In another preferred embodiment, R 6 In (b), the heterocycloalkyl group is an oxygen-containing heterocycloalkyl group.
In another preferred embodiment, R 6 Selected from the group consisting of: unsubstituted or substituted by one or more R S3 Substituted C4-C10 cycloalkyl, unsubstituted or substituted by one or more R S3 Substituted 5-12 membered heterocycloalkyl.
In another preferred embodiment, R 6 Being unsubstituted or substituted by one or more R S3 Substituted 5-12 membered heterocycloalkyl.
In another preferred embodiment, R 6 Being unsubstituted or substituted by one or more R S3 Substituted 5-7 membered heterocycloalkyl.
In another preferred embodiment, R 6 Is unsubstituted or substituted by one or more R S3 Substituted 5-12 membered heterocycloalkyl, and said heterocycloalkyl contains at least one O heteroatom as a ring atom.
In another preferred embodiment, R 6 Being unsubstituted or substituted by one or more R S3 Substituted 5-7 membered heterocycloalkyl, and said heterocycloalkyl containing at least one O heteroatom as a ring atom.
In another preferred embodiment, R 6 Being unsubstituted or substituted by one or more R S3 Substituted groups shown below:
Figure BDA0003097511860000041
wherein, W 1 、W 2 And W 3 Each independently is none, -O-, -CO-, -CH 2 -or-CH 2 CH 2 -；W 4 is-CO-, -CH 2 -or-CH 2 CH 2 -; with the proviso that W 1 、W 2 And W 3 At most one of them is O, W 1 、W 2 、W 3 And W 4 In which at most one is-CH 2 CH 2 -and W 1 、W 2 And W 3 At most one of which is absent.
In another preferred embodiment, and W 1 、W 2 、W 3 And W 4 Up to 1 or 2 of which are CO.
In another preferred embodiment, W 1 、W 2 And W 3 Each independently is nothing, O, -CH 2 -or-CH 2 CH 2 -；W 4 is-CH 2 -。
In another preferred embodiment, the compound of formula I is represented by formula II
Figure BDA0003097511860000042
In another preferred embodiment, the compound of formula I is represented by formula II-1 or II-2
Figure BDA0003097511860000051
In another preferred embodiment, in the compound, A, Z and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b 、R c 、R d 、R s1 、R s2 、R S3 、n、W 1 、W 2 、W 3 And W 4 Each independently is a group corresponding to a particular compound (e.g., compounds S1-S35) described in example or table 1.
In another preferred embodiment, the compound of formula I is a compound selected from table 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof.
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising (I) a therapeutically effective amount of a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof, and (ii) optionally a pharmaceutically acceptable carrier, excipient or diluent.
In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for the treatment of tumors or a pharmaceutical composition for the treatment of diseases associated with the activity of an energy metabolizing enzyme, preferably a PGK1 enzyme.
In a third aspect of the present invention, there is provided a process for the preparation of a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof,
the preparation method comprises a first preparation method, a second preparation method or a third preparation method.
In another preferred embodiment, the first preparation method comprises the steps of:
Figure BDA0003097511860000052
(vi) Reacting compound if with alkyne reagent R in inert solvent under Pd catalysis 4 -a-C ≡ CH to give compound ig;
(vii) The compound ig is deprotected and then reacted with a carboxylic acid R 6 COOH to obtain a compound of formula I;
in the formula, A, Z and R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined in the first aspect.
In another preferred embodiment, the first preparation method further comprises the following steps:
Figure BDA0003097511860000061
(i) Chlorinating compound ia in the presence of a chlorinating agent to obtain compound ib; wherein;
(ii) Reacting compound ib in the presence of urea to form compound ic; or, the compound ib is reacted with ethyl chloroformylacetate, and then the ring is closed and the ester group is removed under alkaline condition, thereby obtaining a compound ic;
(iii) In the presence of a chlorinating agent, carrying out chlorination reaction on a compound ic to obtain a compound id;
(iv) Under the alkaline condition, carrying out substitution reaction on a compound id and a nucleophilic reagent to obtain a compound ie; and
(v) Under alkaline conditions, the compound ie and a nucleophilic reagent are subjected to substitution reaction, so that the compound if is obtained.
In another preferred embodiment, the second preparation method comprises the steps of:
Figure BDA0003097511860000062
(i) Under alkaline condition, the compound ie is reacted with nucleophilic reagent
Figure BDA0003097511860000063
Substitution to give the compound iia;
(ii) Reacting the compound iia with an alkyne reagent R in an inert solvent under Pd catalysis 4 -a-C ≡ CH to give a compound of formula I;
in the formula, A, Z and R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined in the first aspect.
In another preferred embodiment, the third preparation method comprises the following steps:
Figure BDA0003097511860000064
(i) The compound if is deprotected and then reacted with a carboxylic acid R 6 COOH undergoes a condensation reaction to give a compound iiia;
(ii) Reacting the compound iiia with an alkyne reagent R in an inert solvent under Pd catalysis 4 -a-C ≡ CH to give a compound of formula I;
in the formula, A, Z and R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined in the first aspect.
In a fourth aspect of the present invention, there is provided a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof, or a pharmaceutical composition as described in the second aspect, for use in the manufacture of (I) a PGK1 inhibitor and/or (ii) a medicament for the treatment or prevention of a disease associated with PGK 1.
In another preferred embodiment, the diseases associated with PGK1 include: cancer, abnormal proliferation of cells, morphological changes, abnormal carbohydrate metabolism, hyperkinetic movement, tumor growth, diabetes, or a combination thereof.
In another preferred embodiment, the cancer comprises: liver cancer, stomach cancer, colorectal cancer, breast cancer, bladder cancer, pancreatic ductal adenocarcinoma, neuroblastoma, prostate cancer, or a combination thereof.
In a fifth aspect of the present invention, there is provided a method for the treatment or prophylaxis of a disease associated with PGK1, comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof, or a pharmaceutical composition as described in the second aspect.
In another preferred embodiment, the diseases associated with PGK1 include: cancer, abnormal proliferation of cells, morphological changes, abnormal carbohydrate metabolism, hyperkinesia, tumor growth, diabetes, or a combination thereof.
In another preferred embodiment, the cancer comprises: liver cancer, stomach cancer, colorectal cancer, breast cancer, bladder cancer, pancreatic ductal adenocarcinoma, neuroblastoma, prostate cancer, or a combination thereof.
In another preferred embodiment, the subject is a mammal, preferably a human.
In a sixth aspect of the present invention, there is provided a method of inhibiting PGK1 activity, comprising the steps of: contacting PGK1 with a compound of formula I as described in the first aspect, thereby inhibiting the activity of PGK 1.
In another preferred embodiment, the method is non-therapeutic in vitro.
In a seventh aspect of the invention, there is provided a method of inhibiting cell proliferative activity comprising the steps of: culturing the cell in the presence of a compound of formula I as described in the first aspect, thereby inhibiting the proliferative activity of the cell.
In another preferred embodiment, the method is non-therapeutic in vitro.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors have conducted extensive and intensive studies. The alkynyl is introduced to the 7 th site of the parent nucleus of the existing quinazoline PGK1 inhibitor, so that the PGK1 inhibition activity can be obviously enhanced, and the alkynyl-substituted quinoline/quinazoline compound serving as the PGK1 inhibitor with a novel structure is obtained. Based on this, the inventors have completed the present invention.
Term(s) for
Unless otherwise defined, the term "alkyl", by itself or as part of another substituent, refers to a straight or branched chain hydrocarbon radical having the indicated number of carbon atoms (i.e., C1-C6 represents 1-6 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
As used herein, the term "cycloalkyl" refers to hydrocarbon rings, preferably fully saturated rings, having the indicated number of ring atoms (e.g., C4-C10 cycloalkyl) and being fully saturated or having no more than one double bond between the ring vertices. "cycloalkyl" can be monocyclic (e.g., cyclopropyl, cyclobutyl, cyclohexyl, and the like), and can also refer to bicyclic and polycyclic hydrocarbon rings (e.g., fused, spiro, fused, bridged, and the like). The term "heterocycloalkyl group, which may also be referred to herein as" heterocyclyl ", refers to a cycloalkyl group containing one to five heteroatoms selected from N, O and S as ring atoms, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heterocycloalkyl group may be a monocyclic, bicyclic or polycyclic ring system. Generally, heterocyclyl groups generally include 5-12 ring atoms (i.e., 5-12 membered heterocycloalkyl groups), preferably 5-7 ring atoms (i.e., 5-7 membered heterocyclyl groups) and contain 1,2, 3 or 4 heterocyclic atoms. Non-limiting examples of heterocycloalkyl groups include morpholine rings, piperidine rings, piperazine rings, N-alkyl or acyl substituted piperazine rings, homopiperazine rings, N-alkyl or acyl substituted homopiperazine rings, pyrrole, tetrahydropyrrole, 7H-purine, tetrahydrofuran, tetrahydropyran, and the like. The heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom such as ring N.
The term "alkoxy" is used in its conventional sense to refer to those alkyl groups attached to the rest of the molecule via an oxygen atom. Further, for dialkylamino groups, the alkyl moieties can be the same or different and can be combined with the nitrogen atom to which each alkyl group is attached to form a 3-7 membered ring. Thus, -N (R) a ) 2 The group is represented by including piperidyl, pyrrolidinyl, morpholinyl, azetidinyl (azetidinyl), and the like.
Unless otherwise defined, the term "aryl" denotes a polyunsaturated (usually aromatic) hydrocarbon group which may be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Generally, aryl refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having 6 to 10 ring atoms, and which group has a conjugated pi-electron system. The aryl ring may be fused to a heterocycloalkyl, heteroaryl or cycloalkyl ring, non-limiting examples of which include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzindole, chroman. The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms selected from N, O and S, optionally oxidized nitrogen and sulfur atoms, and 5 to 14 ring atoms, optionally quaternized. Generally, heteroaryl groups have 5-10 ring atoms, i.e., 5-10 membered heteroaryl groups, preferably, 5-6 ring atoms, i.e., 5 or 6 membered heteroaryl groups. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl and naphthyl. The aryl (ring) may be fused to a heterocycloalkyl, heteroaryl or cycloalkyl ring, non-limiting examples of which include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzindole, chroman, and the like. Non-limiting examples of heteroaryl groups include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl group can be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring.
As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).
For the compounds provided herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood to refer to a bond that provides attachment at any available vertex of the aromatic ring. In some embodiments, the description also includes a link on a ring fused to the aromatic ring. For example, a bond drawn to the center of an indole benzene moiety would represent a bond to any available vertex of a six or five membered ring moiety of an indole.
As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Similarly, the term "halo" means that one or more hydrogens or all hydrogens in the group are replaced with the same or different halogen as defined above.
Unless otherwise specified, the structural formulae depicted herein are intended to include all optical and stereoisomeric forms (e.g., enantiomers, diastereomers, geometric isomers or conformational isomers): for example, the R, S configuration containing an asymmetric center. Thus, individual stereochemical isomers, enantiomers, diastereomers or mixtures of geometric or conformational isomers of the compounds of the present invention are within the scope of the present invention.
As used herein, the terms "comprising," "including," or "including" mean that the various ingredients may be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
As used herein, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.
As used herein, the term "therapeutically effective dose" refers to any amount of a drug that, when used alone or in combination with another therapeutic agent, promotes disease regression as manifested by a decrease in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods, or the prevention of a disorder or disability resulting from the disease. A "therapeutically effective dose" of a drug of the invention also includes a "prophylactically effective dose," which is any amount of a drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or suffering from a relapse of a disease, inhibits the occurrence or relapse of the disease.
Quinoline and quinazoline compounds containing alkynyl substitution
The invention relates to an alkynyl substituted quinoline/quinazoline compound with phosphoglycerate kinase 1 (PGK 1) inhibitory activity, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvent compound thereof, a preparation method thereof and application thereof in preparing medicaments for preventing or treating diseases related to abnormal cell proliferation, morphological change, abnormal carbohydrate metabolism, hyperkinesia and the like related to PGK in organisms, in particular to treating or preventing tumor growth and metastasis and diabetes.
As used herein, the term "compound of the invention" or "alkynyl-substituted quinoline/quinazoline-like compound" refers to a compound of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
Wherein the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base, which is suitable for use as a medicament. In the present invention, the pharmaceutically acceptable salt is not particularly limited, and preferably includes: inorganic acid salts, organic acid salts, alkylsulfonic acid salts and arylsulfonic acid salts; the inorganic acid salt comprises hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; the organic acid salt comprises formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate and the like; the alkyl sulfonate includes methyl sulfonate, ethyl sulfonate and the like; the aryl sulfonate includes benzene sulfonate, p-toluene sulfonate and the like.
The term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio. "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water. In the present invention, the pharmaceutically acceptable solvate of the compound represented by the general formula (I) is not particularly limited, and preferably includes: solvates of the compounds represented by the general formula (I) with water, ethanol, isopropanol, ether, acetone, etc.
In addition, the compounds of the present invention also include prodrugs of the compounds of formula I. The term "prodrug" includes a class of compounds which are biologically active or inactive in nature and which, when administered by an appropriate method, undergo a metabolic or chemical reaction in the body to convert the compound to formula I, or a salt or solution of a compound of formula I. The prodrugs include, but are not limited to, carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amide, carbamate, azo, phosphoramide, glucoside, ether, acetal forms of the compounds.
The invention aims to provide a PGK1 kinase inhibitor which has a novel structure and excellent activity.
In a first aspect of the present invention, there is provided a compound of formula I, as shown below, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof.
Figure BDA0003097511860000101
Wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 Z and a are as defined in the first aspect.
In one particular embodiment of the present invention,
R 1 selected from hydrogen, -OR a ,-SR a ,-NH 2 Substituted or unsubstituted 4-10 membered heterocycloalkyl. Wherein R is a Selected from hydrogen, C1-C3 alkyl. The substitution may be selected from halogen, C1-C3 alkyl, cyano. Wherein said C1-C3 alkyl may be further substituted with hydroxy, halogen, amino, cyano; and/or
R 2 、R 3 Selected from hydrogen, halogen, cyano; and/or
R 4 Selected from OR b ，NHR b . Wherein R is b Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkanoyl; the substitution may be selected from halogen, cyano, hydroxy, C1-C3 alkoxy;
R 5 selected from hydrogen, C1-C3 alkyl; and/or
R 6 Selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-12 membered heterocycloalkyl; the substitution may be selected from halogen, C1-C3 alkyl, C1-C3 alkanoyl, cyano. Wherein said C1-C3 alkyl may be further substituted with hydroxy, halogen, amino, cyano; and/or
Z is selected from carbon atoms and nitrogen atoms; and/or
A is selected from- (CH) 2 ) n -、-CR c R d -, carbonyl group. Wherein n is 1-3; r c 、R d Are respectively selected from hydrogen, deuterium and C1-C3 alkyl.
In another embodiment, the compounds are those wherein A, Z, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 Each of which is a group corresponding to the particular compound described in the examples.
Preferably, the quinazoline compound shown in the general formula (I) of the present invention is selected from the following compounds in table 1:
TABLE 1
Figure BDA0003097511860000111
Figure BDA0003097511860000121
Figure BDA0003097511860000131
Preparation method
The invention also provides a process for the preparation of a compound of formula I according to the first aspect of the invention. The process for preparing the compound of formula (I) according to the present invention is described more specifically below. However, these specific methods do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
The compounds of the invention can be prepared, for example, by preparative methods one, two or three.
The preparation method comprises the following steps:
Figure BDA0003097511860000141
(i) Carrying out chlorination reaction on the compound ia under the action of a chlorination reagent to obtain a compound ib;
(ii) And (3) under the urea condition or firstly with ethyl chloroformylacetate to generate an intermediate, and then under the alkaline condition, closing the ring and removing the ester group to obtain a compound ic.
(iii) Carrying out chlorination reaction on the compound ic under a chlorination reagent to obtain a compound id;
(iv) Carrying out substitution reaction on the compound id and a nucleophilic reagent under an alkaline condition to obtain a compound ie;
(v) Carrying out substitution reaction on the compound ie and a nucleophilic reagent under an alkaline condition to obtain a compound if;
(vi) Carrying out Pd catalytic coupling reaction on the compound if and different alkyne reagents in an inert solvent to obtain a compound ig;
(vii) The protecting group of the compound ig is removed, and then the compound ig and different carboxylic acids are subjected to condensation reaction to obtain a compound ih.
The second preparation method comprises the following steps:
Figure BDA0003097511860000142
(i) Carrying out substitution reaction on the compound ie and a nucleophilic reagent under an alkaline condition to obtain a compound iia;
(ii) And carrying out Pd-catalyzed coupling reaction on the compound if and different alkyne reagents in an inert solvent to obtain a compound iib.
The preparation method comprises the following steps:
Figure BDA0003097511860000143
(i) Removing a protecting group of the compound if, and then carrying out condensation reaction with different carboxylic acids to obtain a compound iiia;
(ii) The compound iiia is subjected to Pd-catalyzed coupling reaction with different alkyne reagents in an inert solvent to obtain the compound iiib.
In each formula, each group is as defined above.
Generally, in the preparative schemes, each reaction is generally carried out in an inert solvent at room temperature to reflux temperature. The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent phosphoglycerate kinase 1 (PGK 1) inhibitory activity, the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention and alleviation of diseases associated with phosphoglycerate kinase 1 (PGK 1). According to the prior art, the compounds of the invention are useful for the treatment of the following diseases: cancer, abnormal proliferation of cells, morphological changes, abnormal carbohydrate metabolism, hyperkinesia, tumor growth, diabetes, or a combination thereof; wherein the cancer comprises: liver cancer, stomach cancer, colorectal cancer, breast cancer, bladder cancer, pancreatic ductal adenocarcinoma, neuroblastoma, prostate cancer, or a combination thereof.
The invention also provides application of the compound (alkynyl-substituted quinoline/quinazoline compound) shown in the formula I or an isomer thereof or a pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, and application of the compound serving as a PGK1 inhibitor in preparing medicines for preventing and/or treating PGK 1-related diseases, wherein the PGK 1-related diseases comprise various cancers (liver cancer, gastric cancer, colorectal cancer, breast cancer, bladder cancer, pancreatic cancer, neuroblastoma and the like).
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof, and optionally a pharmaceutically acceptable carrier, excipient or diluent, and the like.
In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for the treatment of tumors or a pharmaceutical composition for the treatment of diseases associated with the activity of an energy metabolizing enzyme, preferably a PGK1 enzyme.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000mg of a compound of the invention per dose, more preferably, 10 to 500mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solidsA bulk or liquid filling or a gel substance which is suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), and the like
Figure BDA0003097511860000161
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) Disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary amine compounds; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such a composition may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, in particular, cottonseed, groundnut, corn germ, olive, castor, and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When using pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the administration is a pharmaceutically acceptable and effective dose, and the daily dose for a human of 60kg body weight is usually 1 to 2000mg, preferably 20 to 500mg. Of course, the particular dosage will also take into account such factors as the route of administration, the health of the patient, and the like, which are within the skill of the skilled practitioner.
The main advantages of the invention include
1. Terazosin (shown below) inhibits PGK1 at high concentrations (2.5-25. Mu.M), and the preferred compounds in the present invention inhibit PGK1 IC 50 Values less than 100nM;
Figure BDA0003097511860000171
2. the compound of the invention has obvious proliferation inhibition activity on human liver cancer SNU 739.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
For the following examples, standard procedures and purification methods known to those skilled in the art can be used. Unless otherwise specified, the starting materials are generally available from commercial sources. Commercial solvents and reagents were generally used without further purification, anhydrous solvents were processed by standard methods, and other reagents were commercially available analytically pure. Unless otherwise indicated, all temperatures are expressed in degrees Celsius (C.), room temperature or ambient temperatureThe degree is 20-25 ℃. Purification of the product was performed by column chromatography on silica gel (200-300 mesh) except as indicated. The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR). The nuclear magnetic resonance hydrogen spectral shift (δ) is given in parts per million (ppm). NMR spectra were obtained using a Varian MercuryAMX300 model instrument, deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD) and deuterated dimethyl sulfoxide (d 6-DMSO) are used as solvents, and Tetramethylsilane (TMS) is used as an internal standard.
Abbreviations:
NCS: n-chlorosuccinimide
TBTU: O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate
DIPEA: n, N-diisopropylethylamine
DMF: n, N-dimethylformamide
Et 3 N: triethylamine
DCC: dicyclohexylcarbodiimide
TFA: trifluoroacetic acid
Preparation example 1: preparation of Compound S1
Figure BDA0003097511860000181
Step 1: compound 1a (2.28g, 1 eq) was weighed into a single vial, dissolved by adding DMF and then NCS (1.65g, 1.5 eq) was added with stirring and reacted at 70 ℃ for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compounds 1b,1c and 1d, respectively. Analytical data for compound 1 b: 1 H NMR(400MHz,CDCl 3 ) δ 7.86 (s, 1H), 7.23 (s, 1H), 5.69 (s, 2H), 3.87 (s, 3H); analytical data for compound 1 c: 1 H NMR(400MHz,CDCl 3 ) δ 8.16 (d, J =8.9hz, 1h), 7.89 (d, J =8.9hz, 1h); analytical data for compound 1 d: 1 H NMR(400MHz,CDCl 3 )δ8.31(s,1H)。
Figure BDA0003097511860000182
step 2: compound 1b (3.12g, 1 eq) and urea (6.06g, 10 eq) were weighed into a sealed tube and reacted at 200 ℃ for 5 hours. After the reaction is completed, cooling to room temperature, adding water into the reaction solution, performing suction filtration, and drying to obtain a compound 1e.
Figure BDA0003097511860000183
And 3, step 3: compound 1e (3.06g, 1 eq) was weighed into a single-neck bottle, and phosphorus oxychloride (8.80ml, 10 eq), DIPEA (6.30ml, 4 eq) were added and reacted at 110 ℃ for 4 hours. After the reaction is completed, partial phosphorus oxychloride is distilled out under reduced pressure, then the reaction solution is poured into ice water, a saturated sodium bicarbonate solution is used for neutralization, ethyl acetate is used for extraction, an organic phase is washed by saturated common salt, dried by anhydrous sodium sulfate, and then the mixture is mixed with a sample and loaded onto a column to obtain a compound 1f. Analytical data for compound 1 f: 1 H NMR(400MHz,d6-DMSO)δ8.73(s,1H),8.40(s,1H).
Figure BDA0003097511860000191
and 4, step 4: compound 1f (539mg, 1 equivalent) was weighed into a single-neck flask, and tetrahydrofuran solvent and morpholine (0.26ml, 2 equivalents) were added thereto and reacted at room temperature for 1 hour. After the reaction is completed, the reaction solution is poured into water, a large amount of solid is separated out, and 1g of the compound is obtained by suction filtration. Analytical data for compound 1 g: 1 H NMR(400MHz,CDCl 3 )δ8.39(s,1H),7.88(s,1H),3.88(d,J＝5.0Hz,8H).
Figure BDA0003097511860000192
and 5: in a single-neck flask, 1g (375mg, 1 eq) and 1h (270mg, 1.2 eq) of the compound were weighed, 1, 4-dioxane solvent was added, DIPEA (0.50mL, 3 eq) was added and the reaction was carried out at 100 ℃ for 3 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfateAfter drying, the mixture is applied to a column to obtain a compound 1i. Analytical data for compound 1 i: 1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),7.68(s,1H),7.46(dd,J＝5.0,1.1Hz,1H),7.36(dd,J＝3.7,1.0Hz,1H),7.06(dd,J＝5.0,3.7Hz,1H),5.01(d,J＝13.4Hz,2H),4.63(br,1H),3.90–3.85(m,4H),3.66–3.60(m,4H),3.02(s,3H),2.93(s,2H),1.86–1.76(m,4H).
Figure BDA0003097511860000193
and 5: weigh Compound 1i (60mg, 1 eq), pdCl 2 (PPh 3 ) 2 (7mg, 0.1 equivalent) and CuI (4mg, 0.2 equivalent) in a single-neck flask, tetrahydrofuran solvent was added, and methyl propynyl ether (14mg, 2 equivalents) and Et were added 3 N (55. Mu.L, 4 equivalents), nitrogen was replaced, and microwave reaction was carried out at 80 ℃ for 1.5 hours. After the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compound S1. Analytical data for compound S1: 1 H NMR(400MHz,CDCl 3 )δ7.64(s,1H),7.64(s,1H),7.45(dd,J＝5.0,1.0Hz,1H),7.35(dd,J＝3.6,0.8Hz,1H),7.05(dd,J＝5.0,3.7Hz,1H),5.01(d,J＝13.2Hz,2H),4.63(br,1H),4.39(s,2H),3.92–3.82(m,4H),3.65–3.57(m,4H),3.48(s,3H),3.02(s,3H),2.92(t,J＝12.0Hz,2H),1.86–1.76(m,4H).
preparation example 2: preparation of Compound S2
See compound S1 for synthesis of compound S2. Analytical data for compound S2: 1 H NMR(400MHz,CDCl 3 )δ7.64(s,1H),7.60(s,1H),7.46(dd,J＝5.0,1.1Hz,1H),7.35(dd,J＝3.7,0.9Hz,1H),7.06(dd,J＝5.0,3.7Hz,1H),5.01(d,J＝13.3Hz,2H),4.62(br,1H),3.89–3.83(m,6H),3.68–3.55(m,4H),3.02(s,3H),2.96–2.84(m,2H),2.77(t,J＝6.2Hz,2H),2.17(t,J＝5.7Hz,1H),1.86–1.75(m,4H).
preparation example 3: preparation of Compound S3
See compound S1 for a synthetic method for compound S3. Analytical data for compound S3: 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝2.8Hz,2H),7.45(dd,J＝5.0,1.0Hz,1H),7.35(dd,J＝3.6,0.9Hz,1H),7.05(dd,J＝4.9,3.7Hz,1H),5.01(d,J＝13.1Hz,2H),4.60(br,1H),4.50(s,2H),3.93–3.84(m,4H),3.81(s,2H),3.79–3.73(m,2H),3.62(dd,J＝10.4,5.9Hz,4H),3.02(s,3H),2.92(t,J＝15.3Hz,2H),2.19(s,1H),1.86–1.76(m,4H).
preparation example 4: preparation of Compound S4
See compound S1 for a synthetic method of compound S4. Analytical data for compound S4: 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝2.5Hz,2H),7.45(d,J＝4.8Hz,1H),7.34(d,J＝2.8Hz,1H),7.08–7.02(m,1H),5.00(d,J＝13.1Hz,2H),4.95(s,2H),4.60(br,1H),3.87(s,4H),3.61(d,J＝3.8Hz,4H),3.01(s,3H),2.91(t,J＝11.0Hz,2H),2.13(s,3H),1.86–1.76(m,4H).
preparation example 5: preparation of Compound S5
Figure BDA0003097511860000201
Compound S4 (57mg, 1 equivalent) was weighed into a single-necked flask, a mixed solvent of tetrahydrofuran and water (1) was added thereto, and LiOH · H was further added 2 O (8mg, 2 equiv.) was reacted at room temperature for 2 hours. After the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compound S5. Analytical data for compound S5: 1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝6.0Hz,2H),7.45(d,J＝5.0Hz,1H),7.35(d,J＝3.4Hz,1H),7.07–7.02(m,1H),4.99(d,J＝13.3Hz,2H),4.62(br,1H),4.53(s,2H),3.92–3.82(m,4H),3.62(d,J＝4.2Hz,4H),3.01(s,3H),2.97–2.85(m,2H),1.86–7.02(m,4H).
preparation example 6: preparation of Compound S6
Figure BDA0003097511860000211
Step 1: weigh compound 1g (575mg, 1 equiv.) and 6a (450mg, 1.5 equiv.) in a single-neck bottle, add 1, 4-dioxane solvent, add DIPEA (0.70mL, 3 equivalent)Amount), and reacted at 100 ℃ for 3 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column with stirring to obtain compound 6b. Analytical data for compound 6 b: 1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),7.68(s,1H),4.97(d,J＝13.4Hz,2H),4.28(s,1H),3.91–3.83(m,4H),3.66–3.58(m,4H),2.89(t,J＝12.1Hz,2H),2.71(s,3H),1.79–1.59(m,4H),1.48(s,9H).
Figure BDA0003097511860000212
step 2: compound 6b (528mg, 1 eq), pdCl were weighed 2 (PPh 3 ) 2 (63mg, 0.1 equiv.) and CuI (34mg, 0.2 equiv.) were placed in a single vial, and then tetrahydrofuran solvent was added, followed by propinyl acetate (0.18mL, 2 equiv.) and DIPEA (0.60mL, 4 equiv.) and the reaction was carried out under nitrogen at 80 ℃ for 5 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compound 6c. Analytical data for compound 6 c: 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝3.3Hz,2H),4.98(d,J＝10.8Hz,4H),4.30(br,1H),3.93–3.82(m,4H),3.67–3.56(m,4H),2.89(t,J＝12.3Hz,2H),2.70(s,3H),2.14(s,3H),1.73(d,J＝11.3Hz,2H),1.62(d,J＝7.7Hz,2H),1.48(s,9H).
Figure BDA0003097511860000213
and step 3: compound 6c (56mg, 1 eq) was weighed into a single vial, dichloromethane solvent added, TFA (74 μ L,10 eq) added and reacted at room temperature for 1.5 h. After the reaction was complete, the reaction solution was spin-dried. Then, methylene chloride was added thereto as a solvent, and 2-tetrahydropyranoic acid (20mg, 1.5 equiv), TBTU (64mg, 2 equiv), DIPEA (83. Mu.L, 5 equiv) were added in this order to react at room temperature for 3 hours. After the reaction was completed, dichloromethane and water were used for extraction, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then applied to a column with stirring to obtain compound 6d. Analysis of Compound 6dData: 1 H NMR(400MHz,CDCl 3 )δ7.64(s,2H),5.08–4.92(m,4H),4.72(t,J＝11.6Hz,0.7H),4.15(d,J＝9.5Hz,0.3H),4.08–4.03(m,2H),3.88(s,4H),3.61(d,J＝3.5Hz,4H),3.56–3.46(m,1H),3.12–3.00(m,1H),2.98–2.85(m,4H),2.78(s,1H),2.53–2.48(m,1H),2.02–1.71(m,6H),1.54(d,J＝10.7Hz,2H).
Figure BDA0003097511860000221
and 4, step 4: compound 6d (54mg, 1 eq) was weighed into a single vial, tetrahydrofuran and water (2. After the reaction, water and dichloromethane were added to the reaction solution to extract, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to the column with stirring to obtain compound S6. Analytical data for compound S6: 1 H NMR(400MHz,CD 3 OD)δ7.78(d,J＝2.0Hz,1H),7.59(d,J＝2.0Hz,1H),4.99(d,J＝12.0Hz,2H),4.67–4.58(m,0.6H),4.50(s,2H),4.36–4.33(m,0.4H),4.24–4.21(m,0.6H),4.18–4.10(m,0.4H),4.05–3.98(m,1H),3.91–3.84(m,4H),3.78–3.71(m,0.2H),3.71–3.64(m,4H),3.63–3.51(m,0.8H),3.05–2.95(m,2H),2.94(s,1.7H),2.78(s,1.3H),2.01–1.90(m,1H),1.85–1.50(m,9H),1.38(t,J＝6.3Hz,1H).
preparation example 7: preparation of Compound S7
Synthesis of compound S7 referring to compound 6d, 2-tetrahydropyranic acid is replaced with (R) -tetrahydrofuranic acid. Analytical data for compound S7: 1 H NMR(400MHz,CDCl 3 )δ7.63(s,2H),5.06–4.90(m,4H),4.78–4.66(m,1H),4.65–4.58(m,1H),4.01–3.84(m,6H),3.60(d,J＝4.2Hz,4H),2.99–2.85(m,4H),2.78(s,1H),2.37-2.34(m,0.5H),2.25–2.06(m,4.5H),2.01–1.76(m,3H),1.67-1.58(m,3H).
preparation example 8: preparation of Compound S8
Synthesis of compound S8 referring to compound 6d, 2-tetrahydropyranic acid is replaced with (S) -tetrahydrofuranic acid. Analytical data for compound S8: 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝3.5Hz,2H),5.06–4.95(m,4H),4.73-4.61(m,2H),4.03–3.84(m,6H),3.61(s,4H),3.00–2.88(m,4H),2.79(s,1H),2.38(d,J＝10.7Hz,0.5H),2.23-2.19(m,1H),2.14(s,3H),2.10–1.89(m,3.5H),1.73–1.66(m,3H).
preparation example 9: preparation of Compound S9
Figure BDA0003097511860000231
Compound S7 (28 mg) was weighed into a single-necked flask, methanol was added, and 4N HCl (1 mL) was further added to the flask, followed by reaction at room temperature for 3 hours. After the reaction was complete, the reaction solution was spin-dried. Then adding ethanol, precipitating a large amount of solid, and filtering to obtain a compound S9. Analytical data for compound S9: 1 H NMR(400MHz,d6-DMSO)δ12.83(s,1H),8.24(s,1H),8.08(s,1H),4.87–4.77(m,2.5H),4.66-4.57(m,1.5H),4.43(s,2H),4.02(s,4H),3.83–3.70(m,6H),3.21(br,2H),2.85(s,1.7H),2.66(s,1.3H),2.10–1.96(m,2H),1.90-1.77(m,5H),1.62(d,J＝10.1Hz,1H).
preparation example 10: preparation of Compound S10
Figure BDA0003097511860000232
See compound S9 for synthesis of compound S10. Analytical data for compound S10: 1 H NMR(400MHz,d6-DMSO)δ12.94(s,1H),8.29(s,1H),8.07(s,1H),4.90–4.77(m,2.5H),4.68–4.51(m,1.5H),4.43(s,2H),4.01(s,4H),3.81–3.71(m,6H),3.20(br,2H),2.84(s,1.7H),2.66(s,1.3H),2.13–1.96(m,2H),1.91–1.69(m,5H),1.61(d,J＝12.2Hz,1H).
preparation example 11: preparation of Compound S11
Synthesis of Compound S11 referring to Compound S6, 2-tetrahydropyranoic acid is replaced with 1, 4-dioxane-2-carboxylic acid. Analytical data for compound S11: 1 H NMR(400MHz,CD 3 OD)δ7.75(s,1H),7.56(s,1H),4.96(d,J＝11.8Hz,2H),4.60–4.50(m,1H),4.48(s,2H),4.40(dd,J＝9.5,2.7Hz,0.5H),4.18–4.10(m,0.5H),3.90–3.82(m,6H),3.81–3.68(m,3H),3.68–3.58(m,5H),3.04–2.90(m,3.7H),2.75(s,1.3H),1.87–1.65(m,4H).
preparation example 12: preparation of Compound S12
The synthetic route of the compound S12 is shown in the compound S6, and the raw material 4-N-tert-butyloxycarbonyl-4-N-methylaminopiperidine is replaced by 4-tert-butyloxycarbonyl aminopiperidine, and the 2-tetrahydropyranoic acid is replaced by (R) -tetrahydrofuran formic acid. Analytical data for compound S12: 1 H NMR(400MHz,CDCl 3 )δ7.64(s,2H),6.61(d,J＝8.4Hz,1H),4.74(d,J＝10.8Hz,2H),4.56(s,2H),4.34(dd,J＝8.3,5.9Hz,1H),4.10–3.99(m,1H),3.94–3.82(m,6H),3.65–3.56(m,4H),3.15–3.03(m,2H),2.34–2.25(m,1H),2.10–1.80(m,6H),1.49–1.36(m,2H).
preparation example 13: preparation of Compound S13
Synthesis of compound S13 referring to compound S6, starting material 1b was replaced with 1c. Analytical data for compound S13: 1 H NMR(400MHz,CD 3 OD)δ7.64(dd,J＝8.6,1.6Hz,1H),7.13(dd,J＝8.6,1.6Hz,1H),5.11(d,J＝11.9Hz,2H),4.85–4.83(m,0.5H),4.73–4.70(m,0.5H),4.65–4.60(m,0.5H),4.49(s,2H),4.21–4.12(m,0.5H),4.02–3.80(m,6H),3.64(s,4H),3.05–2.93(m,2H),2.91(s,1.7H),2.78(s,1.3H),2.32–2.18(m,1H),2.15–1.91(m,3H),1.87–1.67(m,4H).
preparation example 14: preparation of Compound S14
Synthesis of compound S14 referring to compound S6, starting material 1b was replaced with 1d. Analytical data for compound S14: 1 H NMR(600MHz,CD 3 OD)δ7.71(d,J＝2.6Hz,1H),5.09(d,J＝11.1Hz,2H),4.86–4.83(m,0.5H),4.72–4.70(m,0.5H),4.65–4.60(m,0.5H),4.55(s,2H),4.16(br,0.5H),3.98–3.93(m,1H),3.90–3.82(m,5H),3.64(d,J＝4.0Hz,4H),3.02–2.95(m,2H),2.91(s,1.7H),2.77(s,1.3H),2.25–2.20(m,1H),2.14–2.06(m,0.5H),2.03–1.92(m,2.5H),1.88–1.64(m,4H).
preparation example 15: preparation of Compound S15
Figure BDA0003097511860000241
Step 1: compound 1f (450 mg) was weighed into a single-necked flask, and tetrahydrofuran solvent (4 mL) was added thereto, followed by addition of aqueous ammonia solution (2 mL) and reaction at room temperature for 3 hours. After the reaction is completed, water is added into the reaction solution, a large amount of white solid is separated out, and the compound 15a is obtained by suction filtration. Analytical data for compound 15 a: 1 H NMR(400MHz,CDCl 3 )δ8.51(m,3H),8.23(s,1H).
for subsequent synthesis see synthetic procedure for compound S6, analytical data for compound S15: 1 H NMR(400MHz,d6-DMSO)δ8.20(s,1H),7.59(br,2H),7.34(s,1H),5.47(t,J＝6.0Hz,1H),4.91(d,J＝12.3Hz,2H),4.79–4.74(m,0.5H),4.66–4.61(m,0.5H),4.50–4.43(m,0.5H),4.38(d,J＝6.0Hz,2H),4.13–4.05(m,0.5H),3.81-3.71(m,2H),2.91–2.76(m,3.7H),2.64(s,1.3H),2.07–1.96(m,2H),1.90–1.78(m,2H),1.68-1.63(m,2H),1.59-1.50(m,2H).
preparation example 16: preparation of Compound S16
Compound S16 synthesis see synthesis procedure for compound S15, analytical data for compound S16: 1 H NMR(400MHz,d6-DMSO)δ8.20(s,1H),7.59(br,2H),7.34(s,1H),5.47(t,J＝6.0Hz,1H),4.91(d,J＝11.9Hz,2H),4.79–4.74(m,0.5H),4.65-4.62(m,.0.5H),4.48(dd,J＝19.7,4.2Hz,0.5H),4.38(d,J＝6.0Hz,2H),4.10(dd,J＝12.2,5.8Hz,0.5H),3.81–3.71(m,2H),2.89–2.77(m,3.7H),2.64(s,1.3H),2.09–1.96(m,2H),1.90–1.79(m,2H),1.66(t,J＝9.6Hz,2H),1.59-1.53(m,2H).
preparation example 17: preparation of Compound S17
Compound S17 synthesis see synthesis procedure for compound S15, analytical data for compound S17: 1 H NMR(400MHz,CD 3 OD)δ7.99(d,J＝2.0Hz,1H),7.47(s,1H),4.96(d,J＝13.2Hz,2H),4.83(t,J＝6.8Hz,0.5H),4.78–4.67(m,1.5H),4.65–4.55(m,0.5H),4.16–4.07(m,0.5H),4.00–3.80(m,2H),2.97–2.84(m,3.7H),2.77(s,1.3H),2.24-2.18(m,1H),2.13-1.92(m,3H),1.85–1.62(m,4H),1.53(d,J＝6.6Hz,3H).
preparation example 18 preparation of Compound S18
Figure BDA0003097511860000251
Step 1: compound 1f (359mg, 1 equivalent) was weighed into a single-necked flask, methanol was added as a solvent (8 mL), and sodium methoxide (162mg, 3 equivalents) was added thereto, followed by reaction at room temperature for 24 hours. After the reaction is completed, water is added into the reaction solution, a large amount of solid is precipitated, and the compound 18a is obtained by suction filtration. Analytical data for compound 18 a: 1 H NMR(400MHz,d6-DMSO)δ8.52(d,J＝1.9Hz,1H),8.23(d,J＝2.5Hz,1H),4.16(s,3H).
Figure BDA0003097511860000252
step 2: compound 18a (332mg, 1 eq) and 6a (300mg, 1.5 eq) were weighed into a single vial, and 1, 4-dioxane solvent and DIPEA (0.46mL, 3 eq) were added and reacted at 100 ℃ for 5 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compound 18b. Analytical data for compound 18 b: 1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),7.94(s,1H),5.03(d,J＝13.5Hz,2H),4.33(br,1H),4.09(s,3H),2.95(t,J＝12.3Hz,2H),2.73(s,3H),1.81–1.65(m,4H),1.50(s,9H).
Figure BDA0003097511860000261
and 3, step 3: compound 18b (461mg, 1 eq), pdCl were weighed out 2 (PPh 3 ) 2 (61mg, 0.1 equiv.) and CuI (33mg, 0.2 equiv.) were placed in a single vial, to which was added tetrahydrofuran solvent, propinyl acetate (170mg, 2 equiv.), DIPEA (0.57mL, 4 equiv.), and the reaction was carried out under nitrogen at 80 ℃ for 5 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compound 18c. Analytical data for compound 18 c: 1 H NMR(400MHz,d6-DMSO)δ7.89(s,1H),7.62(s,1H),5.01(d,J＝13.5Hz,2H),4.97(s,2H),4.30(br,1H),4.07(s,3H),2.92(t,J＝12.2Hz,2H),2.71(s,3H),1.75(d,J＝9.6Hz,2H),1.70–1.61(m,2H),1.48(s,9H).
Figure BDA0003097511860000262
and 4, step 4: compound 18c (320mg, 1 eq) was weighed into a single-neck flask, dichloromethane solvent was added, TFA (0.48ml, 10 eq) was added and the reaction was allowed to proceed at room temperature for 3 hours. After the reaction was complete, the reaction solution was spin-dried. Methylene chloride was then added as a solvent, and (R) -tetrahydrofuran carboxylic acid (111mg, 1.5 eq), TBTU (411mg, 2 eq), DIPEA (0.53mL, 5 eq) were added in that order and reacted at room temperature for 3 hours. After the reaction was completed, dichloromethane and water were used for extraction, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then applied to a column with stirring to obtain compound 18d. Analytical data for compound 18 d: 1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝4.5Hz,1H),7.64(d,J＝4.8Hz,1H),5.07(d,J＝14.8Hz,2H),4.98(s,2H),4.79–4.69(m,1H),4.65(dd,J＝7.4,5.7Hz,0.5H),4.18(t,J＝11.7Hz,0.5H),4.09(d,J＝3.2Hz,3H),4.04–3.86(m,2H),3.04–2.94(m,2H),2.92(s,2H),2.81(s,1H),2.43–2.36(m,0.3H),2.29–2.19(m,0.7H),2.16(s,3H),2.13–2.02(m,2H),1.99–1.86(m,2H),1.81–1.61(m,4H).
Figure BDA0003097511860000263
and 5: compound 18d (356mg, 1 eq) was weighed into a single vial, tetrahydrofuran and water (2). After the reaction, water and methylene chloride were added to the reaction solution to extract, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then applied to a column with stirring to obtain compound S18. Analytical data for compound S18:
1 H NMR(400MHz,CD 3 OD)δ7.85(d,J＝1.4Hz,1H),7.53(s,1H),5.01(d,J＝12.9Hz,2H),4.87–4.82(m,0.5H),4.74–4.69(m,0.5H),4.67–4.59(m,0.6H),4.48(s,2H),4.22–4.13(m,0.4H),4.09(d,J＝2.3Hz,3H),4.00–3.82(m,2H),3.01(dd,J＝23.8,10.8Hz,2H),2.91(s,1.7H),2.78(s,1.3H),2.30–2.17(m,1H),2.16–1.93(m,3H),1.93–1.69(m,4H).
preparation example 19: preparation of Compound S19
Figure BDA0003097511860000271
Compound S18 (115mg, 1 eq) was weighed into a single vial, 1, 2-dichloroethane (8 mL) was added as solvent, aluminum chloride (167mg, 5 eq) was added, and the reaction was allowed to warm to 65 ℃ for 3h. After the reaction, the reaction solution was cooled to room temperature, dichloromethane and water were extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then applied to a column with stirring to obtain compound S19. Analytical data for compound S19:
1 H NMR(400MHz,CD 3 OD)δ7.95(s,1H),7.46(s,1H),4.85–4.80(m,0.5H),4.72–4.69(m,0.5H),4.66–4.42(m,4.6H),4.19(br,0.4H),4.00–3.80(m,2H),3.08(br,2H),2.93(s,1.8H),2.79(s,1.2H),2.29–1.71(m,8H).
preparation example 20: preparation of Compound S20
Figure BDA0003097511860000272
Step 1: compound 1f (200mg, 1 eq) was weighed into a single-neck flask, and 1, 4-dioxane was added as solvent (10 mL), followed by addition of sodium thiomethoxide (43mg, 1.1 eq) and reaction at room temperature for 2 hours. After the reaction was completed, water was added to the reaction solution to precipitate a large amount of white solid, and the compound 20a was obtained by suction filtration. Analytical data for compound 20 a: 1H NMR (400MHz, CDCl) 3 )δ8.48(s,1H),8.11(s,1H),2.74(s,3H).
For subsequent synthetic methods see synthetic procedure for compound S18, analytical data for compound S20:
1 H NMR(400MHz,CD 3 OD)δ7.77(s,1H),7.53(s,1H),5.06(d,J＝13.0Hz,2H),4.88–4.82(m,0.5H),4.74–4.69(m,0.5H),4.68–4.59(m,0.5H),4.49(s,2H),4.24–4.12(m,0.5H),4.01–3.83(m,2H),3.03(dd,J＝23.9,11.1Hz,2H),2.91(s,1.7H),2.78(s,1.3H),2.62(d,J＝2.3Hz,3H),2.25–2.19(m,1H),2.15–2.07(m,0.5H),2.03–1.93(m,2.5H),1.90–1.69(m,4H).
preparation example 21: preparation of Compound S21
Figure BDA0003097511860000281
Step 1: compound 15a (423mg, 1 eq) was weighed into a single vial, tetrahydrofuran solvent (10 mL) was added, isoamyl nitrate (0.33mL, 2 eq) was added, and the reaction was allowed to proceed at 60 ℃ for 2 days. After completion of the reaction, water and ethyl acetate were added to the reaction mixture to extract, the organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and then applied to a column with stirring to obtain compound 21a. Analytical data for compound 21 a: 1 H NMR(400MHz,d6-DMSO)δ9.55(s,1H),8.66(s,1H),8.49(s,1H).
Figure BDA0003097511860000282
step 2: compound 21a (180mg, 1 equiv.) and 6a (178mg, 1.5 equiv.) were weighed into a single-necked flask, and 1, 4-dioxane solvent and DIPEA (0.27mL, 3 equiv.) were added thereto, followed by reaction at 100 ℃ for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to the column with stirring to obtain Compound 21b. Analytical data for compound 21 b: 1 H NMR(400MHz,CDCl 3 )δ8.89(s,1H),8.18(s,1H),7.69(s,1H),5.05(d,J＝13.2Hz,2H),4.32(br,1H),2.97(t,J＝13.0Hz,2H),2.71(s,3H),1.78(d,J＝10.1Hz,2H),1.65(d,J＝10.1Hz,2H),1.48(s,9H).
Figure BDA0003097511860000283
and 3, step 3: compound 21b (203mg, 1 eq), pdCl were weighed 2 (PPh 3 ) 2 (28mg, 0.1 eq) and CuI (15mg, 0.2 eq) were placed in a single neck flask, and the tetrahydrofuran solvent was added, followed by addition of propinyl acetate (90mg, 2 eq) and DIPEA (0.16mL, 4 eq) and heating at 80 ℃ for 5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column with stirring to obtain compound 21c. Analytical data for compound 21 c: 1 H NMR(400MHz,CDCl 3 )δ8.89(s,1H),7.71(s,1H),7.64(s,1H),5.05(d,J＝13.7Hz,2H),4.98(s,2H),4.43–4.22(m,1H),2.96(t,J＝12.7Hz,2H),2.71(s,3H),2.15(s,3H),1.77(d,J＝11.2Hz,2H),1.65(d,J＝11.7Hz,2H),1.48(s,9H).
Figure BDA0003097511860000291
and 4, step 4: compound 21c (85mg, 1 eq) was weighed into a single vial, dichloromethane solvent added, and TFA (0.13ml, 10 eq) added and reacted at room temperature for 4 hours. After the reaction was complete, the solvent and TFA were spin-dried. Methylene chloride was then added as a solvent, followed by addition of (R) -tetrahydrofuran carboxylic acid (31mg, 1.5 equiv.), TBTU (115mg, 2 equiv.), DIPEA (0.15mL, 5 equiv.) and reaction at room temperature for 3 hours. After the reaction was completed, the mixture was extracted with dichloromethane and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compound 21d.
Figure BDA0003097511860000292
And 5: compound 21d (111mg, 1 eq) was weighed into a single-necked flask, and tetrahydrofuran and water (2). After the reaction was completed, dichloromethane and water were extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column with stirring to obtain compound S21. Analytical data for compound S21: 1 H NMR(400MHz,CD 3 OD)δ9.01(d,J＝3.4Hz,1H),7.82(d,J＝2.2Hz,1H),7.64(s,1H),5.07(d,J＝12.8Hz,2H),4.88–4.82(m,0.5H),4.74–4.60(m,1H),4.49(s,2H),4.21(br,1H),4.01–3.81(m,2H),3.03(dd,J＝23.7,10.6Hz,2H),2.90(s,1.7H),2.77(s,1.3H),2.26–2.17(m,1H),2.14–2.06(m,0.5H),2.03–1.93(m,2.5H),1.92–1.68(m,4H).
preparation example 22: preparation of Compound S22
Synthetic route to compound 22 see synthetic procedure for compound 21, analytical data for compound S22:
1 H NMR(400MHz,CD 3 OD)δ9.01(d,J＝3.6Hz,1H),7.82(d,J＝2.3Hz,1H),7.63(s,1H),5.07(d,J＝13.4Hz,2H),4.88–4.81(m,0.5H),4.74–4.60(m,1H),4.49(s,2H),4.23–4.16(m,0.5H),3.99–3.81(m,2H),3.03(dd,J＝23.6,10.6Hz,2H),2.90(s,1.7H),2.77(s,1.3H),2.29–2.17(m,1H),2.14–1.91(m,3H),1.88–1.67(m,4H).
preparation example 23: preparation of Compound S23
Figure BDA0003097511860000293
Step 1: compound 1b (1.246g, 1 eq) was weighed into a single-neck flask, dichloromethane was added as solvent, and ethyl chloroformylacetate (0.60mL, 1.1 eq) and pyridine (0.35mL, 1.1 eq) were added in sequence and reacted at room temperature for 2 hours. After the reaction was completed, dichloromethane and water were extracted, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column with stirring to obtain compound 23a. Analytical data for compound 23 a: 1 H NMR(400MHz,d6-DMSO)δ11.37(s,1H),9.30(s,1H),8.04(s,1H),4.27(q,J＝7.2Hz,2H),3.95(s,3H),3.51(s,2H),1.31(t,J＝7.2Hz,3H).
Figure BDA0003097511860000301
and 2, step: compound 23a (1.14g, 1 eq) was weighed into a single neck bottle, toluene (25 mL) was added as solvent, sodium methoxide solution in methanol (5.4 mol/L,0.50ml,1 eq) was added, and the reaction was allowed to warm to 100 ℃ for 5 hours. After the reaction is completed, cooling the reaction solution to room temperature, then pouring the reaction solution into ice water, carrying out reduced pressure distillation on the organic phase, adjusting the pH of the residual water phase to acidity by using a 4N hydrochloric acid solution, and carrying out suction filtration to obtain a compound 23b.
Figure BDA0003097511860000302
And 3, step 3: weigh compound 23b (885mg, 1 equivalent) into a single-neck bottle and add H to the inside 2 O (20 mL) was used as a solvent, and potassium hydroxide (631mg, 5 eq) was added thereto in portions, and the mixture was heated to 100 ℃ for 20 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the pH was adjusted to about 1 with 1N hydrochloric acid solution, and the mixture was filtered under suction to obtain compound 23c. Analytical data for compound 23 c: 1 H NMR(400MHz,d6-DMSO)δ11.69(s,1H),11.29(s,1H),7.81(d,J＝3.4Hz,2H),5.75(s,1H).
Figure BDA0003097511860000303
and 4, step 4: compound 23c (684mg, 1 eq) was weighed into a single neck bottle, phosphorus oxychloride (1.98ml, 10 eq) was added, DIPEA (1.40ml, 5 eq) was added slowly and the reaction was allowed to proceed to 110 ℃ for 3 hours. After the reaction is completed, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, separating out a large amount of solid, performing suction filtration, drying a filter cake, and then passing through a column to obtain a compound 23d. Analytical data for compound 23 d: 1 H NMR(400MHz,CDCL 3 )δ8.62(s,1H),8.25(s,1H),7.54(s,1H).
Figure BDA0003097511860000311
and 5: compound 23d (1.576g, 1 eq) was weighed into a single vial, toluene was added as solvent (25 mL), and morpholine (0.77mL, 2 eq), et were added sequentially 3 N (1.80mL, 3 equiv.) was heated to 110 deg.C and reacted overnight. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain a mixture of 23e and 23 f.
Figure BDA0003097511860000312
Step 6: a mixture of 23e and 23f (1.61g, 1 eq) was weighed into a sealed tube, ethanol was added as solvent (20 mL), followed by the addition of compound 6a (1.68g, 2 eq) and DIPEA (1.95mL, 3 eq) in that order, and heated to 130 deg.C for 1 day. After the reaction was completed, the reaction solution was cooled to room temperature, extracted with dichloromethane and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column with stirring to obtain a mixture of 23g and 23 hours.
Figure BDA0003097511860000321
And 7: 23g and 23h of a mixture (270mg, 1 eq) were weighed into a single-neck flask, tetrahydrofuran was added as solvent (10 mL), and PdCl was added successively 2 (PPh 3 ) 2 (32mg, 0.1 eq), cuI (18mg, 0.2 eq), propinyl acetate (91. Mu.L, 2 eq), DIPEA (0.30mL, 4 eq), with nitrogen being replaced, and the reaction was heated at 80 ℃ for 5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain a mixture of 23i and 23 j.
Figure BDA0003097511860000322
And 8: a mixture of 23i and 23j (170mg, 1 eq) was weighed into a single-neck flask, and dichloromethane solvent was added, followed by TFA (0.23mL, 10 eq) and allowed to react at room temperature for 4 hours. After the reaction was completed, the reaction mixture was neutralized with saturated sodium bicarbonate, extracted with dichloromethane, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and applied to a column to obtain 23l and 23m.
Figure BDA0003097511860000331
And step 9: compound 23m (33mg, 1 eq) was weighed into a single-neck flask, dichloromethane was added as solvent, followed by the sequential addition of (R) -tetrahydrofuranic acid (13mg, 1.5 eq), TBTU (46mg, 2 eq), DIPEA (60 μ L,5 eq) and reaction at room temperature for 3 hours. After the reaction was completed, the mixture was extracted with dichloromethane and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column with stirring to obtain compound 23n. Analytical data for compound 23 n: 1 H NMR(400MHz,CDCl 3 )δ7.85(s,1H),7.79(d,J＝4.1Hz,1H),6.45(s,1H),5.00(s,2H),4.77–4.59(m,4H),4.03–3.88(m,6H),3.15(s,4H),3.08–2.98(m,2H),2.93(s,1.8H),2.82(s,1.2H),2.18(s,3H),2.14–2.00(m,4H),1.98–1.88(m,2H),1.83–1.70(m,3H),1.68–1.64(m,1H).
Figure BDA0003097511860000332
step 10: compound 23n (36mg, 1 equivalent) was weighed into a single-necked flask, tetrahydrofuran and water (2. After the reaction, water and dichloromethane were added to the reaction solution to extract, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to the column with stirring to obtain compound S23. Analytical data for compound S23:
1 H NMR(400MHz,CD 3 OD)δ7.79(d,J＝6.3Hz,1H),7.70(d,J＝4.5Hz,1H),6.62(d,J＝3.0Hz,1H),4.84(t,J＝6.8Hz,0.5H),4.73–4.62(m,3H),4.48(s,2H),4.15(br,0.5H),4.00–3.82(m,6H),3.12(s,4H),3.05–2.97(m,2H),2.90(s,1.7H),2.77(s,1.3H),2.29–2.17(m,1H),2.14–2.06(m,0.5H),2.04–1.91(m,2.5H),1.90–1.66(m,4H).
preparation example 24: preparation of Compound S24
Synthesis of compound S24 referring to compound S23, (S) -tetrahydrofuranic acid is replaced with 2-tetrahydropyranic acid. Analytical data for compound S24: 1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝6.0Hz,1H),7.76(d,J＝6.3Hz,1H),6.42(d,J＝7.3Hz,1H),4.75–4.53(m,5H),4.35(dd,J＝9.4,2.9Hz,0.3H),4.28(dd,J＝9.4,2.9Hz,0.7H),3.98–3.93(m,4H),3.90(dd,J＝9.2,4.6Hz,1H),3.85(br,1H),3.84–3.66(m,4H),3.13(d,J＝4.1Hz,4H),3.00(dd,J＝21.4,12.1Hz,2H),2.91(s,2H),2.78(s,1H),1.90–1.84(m,1H),1.75–1.67(m,3H).
preparation example 25: preparation of Compound S25
Figure BDA0003097511860000341
Step 1: compound 6b (176mg, 1 eq) was weighed into a single-neck flask, dichloromethane solvent was added, TFA (0.22ml, 10 eq) was added and the reaction was allowed to proceed at room temperature for 5 hours. After the reaction was complete, the reaction solution was spin-dried. Then, methylene chloride was added thereto as a solvent, followed by addition of (R) - (-) -5-oxo-2-tetrahydrofuranic acid (59mg, 1.5 equiv.), TBTU (193mg, 2 equiv.), DIPEA (0.25mL, 5 equiv.) in that order, and reaction at room temperature for 3 hours. After the reaction was completed, the mixture was extracted with dichloromethane and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column to obtain compound 25a. Analytical data for compound 25 a: 1 H NMR(400MHz,d6-DMSO)δ8.09(d,J＝3.6Hz,1H),7.68(d,J＝3.6Hz,1H),5.30–5.25(m,0.3H),5.18(dd,J＝8.0,4.2Hz,0.7H),5.00(d,J＝12.5Hz,2H),4.73–4.65(m,0.6H),4.03–3.95(m,0.4H),3.91–3.84(m,4H),3.65–3.62(m,4H),3.00–2.89(m,4H),2.83(s,1H),2.77–2.48(m,4H),2.43–2.32(m,1H),1.95–1.66(m,4H).
Figure BDA0003097511860000342
step 2: compound 25a (180mg, 1 eq), pdCl were weighed 2 (PPh 3 ) 2 (21mg, 0.1 eq.) and CuI (111mg, 0.2 eq.) were placed in a single-neck flask, and tetrahydrofuran solvent was added, followed by addition of 2-propyn-1-ol (34mg, 2 eq.) and DIPEA (0.20mL, 4 eq.) and reaction under nitrogen at 80 ℃ for 5h. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and applied to a column with stirring to obtain a compound S25. Analytical data for compound S25:
1 H NMR(400MHz,CD 3 OD)δ7.73(s,1H),7.54(s,1H),5.63–5.57(m,0.3H),5.44(t,J＝6.1Hz,0.6H),4.96(d,J＝11.5Hz,2H),4.67–4.55(m,0.7H),4.48(s,2H),4.02(br,0.4H),3.84(d,J＝3.6Hz,4H),3.64(s,4H),3.07–2.91(m,3.8H),2.81(s,1.2H),2.64–2.48(m,3H),2.38–2.23(m,1H),1.91–1.66(m,4H).
preparation example 26: preparation of Compound S26
See compound S25, analytical data for compound S26 for synthesis of compound S26: 1 H NMR(400MHz,CD 3 OD)δ7.86(d,J＝1.4Hz,1H),7.57(s,1H),5.02(d,J＝12.9Hz,2H),4.89–4.84(m,0.5H),4.75–4.71(m,0.5H),4.67–4.59(m,0.6H),4.25–4.16(m,0.4H),4.03–3.85(m,6H),3.68(s,4H),3.03(dd,J＝23.8,10.8Hz,2H),2.94(s,1.7H),2.80(s,1.3H),2.31–2.19(m,1H),2.17–1.65(m,7H),1.48(s,6H).
preparation example 27: preparation of Compound S27
See compound 6d for synthesis of compound S27, replacement of propiolate acetate with methyl propiolate, analytical data for compound S27:
1 H NMR(400MHz,CD 3 OD)δ7.78(d,J＝1.8Hz,1H),7.66(s,1H),4.98(d,J＝13.1Hz,2H),4.86–4.82(m,0.5H),4.73–4.69(m,0.5H),4.66–4.57(m,0.5H),4.21–4.12(m,0.5H),4.00–3.94(m,1H),3.89–3.80(m,8H),3.67(s,4H),2.98(dd,J＝23.7,11.0Hz,2H),2.91(s,1.7H),2.77(s,1.3H),2.26–2.18(m,1H),2.14–1.93(m,3H),1.87–1.66(m,4H).
preparation example 28: preparation of Compound S28
Figure BDA0003097511860000351
Compound S27 (34mg, 1 equivalent) was weighed into a single-necked flask, tetrahydrofuran and water (2). After the reaction, the pH of the reaction solution was adjusted to weak acidity (pH 5) with 1N diluted hydrochloric acid, then a small amount of water and dichloromethane were added to extract, and the organic phase was extracted with a small amount of waterWashing with saturated salt water, drying with anhydrous sodium sulfate, mixing with the sample, and loading onto a column to obtain a compound S28. Analytical data for compound S28: 1 H NMR(400MHz,CD 3 OD)δ8.10(s,1H),7.88(t,J＝3.8Hz,1H),4.87–4.82(m,0.5H),4.78–4.59(m,3H),4.30(br,0.5H),4.16–4.08(m,4H),3.99–3.80(m,6H),3.35–3.26(m,2H),2.95(s,1.8H),2.79(s,1.2H),2.29–2.12(m,1.5H),2.04–1.80(m,6.5H).
preparation example 29: preparation of Compound S29
Figure BDA0003097511860000352
Compound S27 (25mg, 1 equivalent) was weighed into a single-necked flask, 3mL of an ammonia methanol solution (7 mol/L) was added thereto, and the mixture was reacted at room temperature for 2 hours. And after the reaction is finished, spin-drying the reaction liquid, then adding methanol, separating out solids, and performing suction filtration to obtain a compound S29. Analytical data for compound S29:
1 H NMR(400MHz,CDCl 3 )δ7.72(d,J＝5.1Hz,1H),7.66(d,J＝4.2Hz,1H),5.99(s,1H),5.87(s,1H),5.00(t,J＝14.3Hz,2H),4.75–4.68(m,1H),4.63(dd,J＝7.4,5.7Hz,0.6H),4.15(t,J＝11.4Hz,0.4H),4.02–3.91(m,1H),3.90–3.84(m,5H),3.67–3.58(m,4H),3.01–2.87(m,4H),2.79(s,1H),2.42–2.33(m,0.5H),2.25–1.98(m,3H),1.97–1.72(m,3H),1.67–1.58(m,1.5H).
preparation example 30: preparation of Compound S30
Figure BDA0003097511860000361
Compound S28 (53mg, 1 equiv) was weighed into a single-neck flask, dichloromethane was added as a solvent, and dicyclohexylcarbodiimide (DCC, 31mg,1.5 equiv) and DIPEA (66. Mu.L, 2 equiv) were sequentially added thereto, and reacted at room temperature for 4 hours. After the reaction, dichloromethane and water are used for extraction, the organic phase is washed by saturated salt water, dried by anhydrous sodium sulfate, and then mixed with a sample and loaded on a column to obtain a compound S30. Analytical data for compound S30:
1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝4.8Hz,1H),7.64(d,J＝4.8Hz,1H),5.07(t,J＝12.6Hz,2H),4.70–4.59(m,1H),4.33–4.21(m,3.5H),4.04–3.88(m,6.5H),3.70–3.63(m,6H),3.05–2.90(m,4H),2.81(s,1H),2.44–2.35(m,0.5H),2.27–2.00(m,3H),2.00–1.75(m,3H),1.69–1.60(m,1.5H).
preparation example 31: preparation of Compound S31
Figure BDA0003097511860000362
2mL of ultra-dry tetrahydrofuran is put into a single-mouth bottle, deuterated lithium aluminum hydride (8mg, 2 equiv) is added, under the protection of nitrogen, the ultra-dry tetrahydrofuran solution of S27 is added under ice bath, and then the temperature is raised to room temperature for reaction for 2 days. After the reaction is finished, adding saturated ammonium chloride solution for quenching, extracting by using ethyl acetate and water, washing an organic phase by using saturated salt solution, drying by using anhydrous sodium sulfate, mixing the sample, and loading the sample on a column to obtain a compound S31. Analytical data for compound S31: 1 H NMR(400MHz,CD 3 OD)δ7.87(d,J＝1.4Hz,1H),7.56(s,1H),5.04(d,J＝12.9Hz,2H),4.86–4.82(m,0.5H),4.76–4.72(m,0.5H),4.65–4.57(m,0.6H),4.27–4.18(m,0.4H),4.01–3.82(m,6H),3.65(s,4H),3.10–3.01(m,2H),2.95(s,1.7H),2.78(s,1.3H),2.32–2.19(m,1H),2.18–1.64(m,7H).
preparative example 32: preparation of Compound S32
Synthesis of Compound S32 referring to Compound S6, 2-tetrahydropyranoic acid is replaced with (R) -1, 4-dioxane-2-carboxylic acid. Analytical data for compound S32: 1 H NMR(400MHz,CD 3 OD)δ7.74(s,1H),7.57(s,1H),4.97(d,J＝11.8Hz,2H),4.60–4.51(m,1H),4.48(s,2H),4.40(dd,J＝9.5,2.7Hz,0.5H),4.18–4.10(m,0.5H),3.90–3.82(m,6H),3.81–3.68(m,3H),3.68–3.58(m,5H),3.04–2.90(m,3.7H),2.75(s,1.3H),1.87–1.65(m,4H).
preparation example 33: preparation of Compound S33
Synthesis of Compound S33 referring to Compound S6, 2-tetrahydropyranoic acid is replaced with (S) -1, 4-dioxane-2-carboxylic acid. Analytical data for compound S33: 1 H NMR(400MHz,CD 3 OD)δ7.77(s,1H),7.55(s,1H),4.96(d,J＝11.8Hz,2H),4.61–4.50(m,1H),4.48(s,2H),4.40(dd,J＝9.5,2.7Hz,0.5H),4.18–4.10(m,0.5H),3.90–3.82(m,6H),3.81–3.68(m,3H),3.68–3.58(m,5H),3.04–2.90(m,3.7H),2.75(s,1.3H),1.87–1.65(m,4H).
preparation example 34: preparation of Compound S34
The synthesis of compound S34 is described in compound S23, replacing (R) -tetrahydrofuranic acid with (R) -1, 4-dioxane-2-carboxylic acid. Analytical data for compound S34: 1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝6.0Hz,1H),7.75(d,J＝6.3Hz,1H),6.44(d,J＝7.3Hz,1H),4.75–4.53(m,5H),4.34(dd,J＝9.4,2.9Hz,0.3H),4.28(dd,J＝9.4,2.9Hz,0.7H),3.98–3.93(m,4H),3.90(dd,J＝9.2,4.6Hz,1H),3.85(br,1H),3.84–3.66(m,4H),3.13(d,J＝4.1Hz,4H),3.00(dd,J＝21.4,12.1Hz,2H),2.91(s,2H),2.78(s,1H),1.90–1.84(m,1H),1.75–1.66(m,3H).
preparation example 35: preparation of Compound S35
For the synthesis of compound S35, see compound S23, (R) -tetrahydrofuranic acid was replaced with (S) -1, 4-dioxane-2-carboxylic acid. Analytical data for compound S35: 1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝6.0Hz,1H),7.77(d,J＝6.3Hz,1H),6.41(d,J＝7.3Hz,1H),4.75–4.53(m,5H),4.35(dd,J＝9.4,2.9Hz,0.3H),4.27(dd,J＝9.4,2.9Hz,0.7H),3.99–3.93(m,4H),3.90(dd,J＝9.2,4.6Hz,1H),3.85(br,1H),3.84–3.66(m,4H),3.13(d,J＝4.1Hz,4H),3.00(dd,J＝21.4,12.1Hz,2H),2.91(s,2H),2.78(s,1H),1.90–1.84(m,1H),1.75–1.67(m,3H).
2. examples of biological Activity tests
Example 1 test of the inhibitory Activity of Compounds on PGK1 enzyme
mu.L of 50mM potassium dihydrogen phosphate, pH 7.0, 4. Mu.L of 50mM GAP, 6. Mu.L of 10mM β NAD, 4. Mu.L of 10mM adenosine diphosphate, 10. Mu.L of 100mM magnesium sulfate, 20. Mu.L of 1M Glycine, 4. Mu.L of 0.25. Mu.g/. Mu.L GAPDH, 32. Mu.L deionized water were added to each reaction, totaling 100ul of substrate mix. PGK1 protein was diluted to 0.1 ng/. Mu.L, and 100uL of PGK1 protein dilution was added to each reaction and mixed. The reaction is carried out for 30min at 37 ℃.
And (3) using ATP detection diluent to perform reaction according to the weight ratio of 1: and (5) diluting by 10. Adding 100uL of diluted detection solution into each well of a 96-well white board, reacting for 5min at room temperature (removing background ATP influence), adding 100uL of enzyme activity reaction solution, reacting for at least 2s, and reading a fluorescence value in a chemiluminescence detector.
Setting compound concentration gradient, adding compounds with different concentrations into a 200uL reaction system in the reaction process, setting at least 3 multiple holes, reading fluorescence values, comparing with a control group, calculating relative enzyme activity, drawing a fitting curve by using GraphPad Prism, and calculating IC 50 The value is obtained.
TABLE 2 inhibitory Activity of Compounds on PGK1 enzymes
Figure BDA0003097511860000381
Example 2 Compounds assay for inhibitory Activity on SNU739 cell proliferation
The experimental steps are as follows:
1) Culturing corresponding target cell lines, counting the cells by using a blood cell plate counting plate, laying 96 well plates with 1000 cells/well, and waiting for the cells to adhere to the wall.
2) After the cells are attached to the wall, a compound concentration gradient is set, 10% serum culture solution containing compounds with different concentrations is prepared and added into a 96-well plate, and each concentration is at least 3 multiple wells.
3) After 72 hours, prepare CCK8 assay, dilute 1 2 Culturing for 2 hours under the conditions of (1), and detecting OD value at a wavelength of 450nm with a multi-mode microplate detector (microplate reader)
4) Relative cell numbers were calculated compared to controls, and IC was calculated by plotting a fitted curve using GraphPad Prism 50 The value is obtained.
TABLE 3 inhibitory Activity of Compounds on SNU739 cell proliferation
Figure BDA0003097511860000382
Figure BDA0003097511860000391
Therefore, the invention provides a novel alkynyl-substituted quinoline/quinazoline PGK1 inhibitor, and the compound has obvious advantages compared with the existing PGK1 inhibitor.
3. Comparative example
The invention also provides the activity of the compounds which are not substituted by alkynyl at the 7-position of the parent nucleus and are measured by the methods of the above example 1 and example 2, and the test results are shown in the table 4
TABLE 4
Figure BDA0003097511860000392
It can be seen that under the condition that other substituents at other positions are the same, the 7-position alkynyl substituted compound of the parent nucleus has the effects of remarkably improving the activity of PGK1 inhibitory enzyme and the activity of inhibiting SNU739 cell proliferation, compared with the 7-position methoxy compound PGK1 inhibitory enzyme activity IC50 of the 7-position alkynyl substituted compound, the activity is only less than 1/6, even less than 1/50, and simultaneously, the activity is only less than 1/5, even less than 1/24, of the activity of inhibiting SNU739 cell proliferation IC 50.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof;
Figure FDA0003097511850000011
wherein the content of the first and second substances,
z is selected from the group consisting of: c (R) d )、N；
R d Selected from the group consisting of: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl;
R 1 selected from the group consisting of: H. -OR a 、-SR a 、-N(R a ) 2 Unsubstituted or substituted by one or more R s1 Substituted 4-10 membered heterocycloalkyl;
R a selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl;
R s1 each independently selected from the group consisting of: halogen, substituted or unsubstituted C1-C3 alkyl, cyano;
R 2 and R 3 Each independently selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, cyano;
a is a divalent group selected from the group consisting of: - (C (R) c ) 2 ) n -and a carbonyl group (-C (O) -);
n is 1,2 or 3;
R c each independently selected from the group consisting of: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl;
R 4 selected from the group consisting of: -OR b and-NHR b ；
R b Selected from the group consisting of: H. unsubstituted or substituted by one or more R s2 Substituted C1-C6 alkyl, unsubstituted or substituted by one or more R s2 Substituted C1-C6 alkanoyl;
R s2 each independently selected from the group consisting of: halogen, cyano, hydroxy, substituted or unsubstituted C1-C3 alkoxy;
R 5 selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C3 alkyl;
R 6 selected from the group consisting of: unsubstituted or substituted by one or more R S3 Substituted C6-C10 aryl, unsubstituted or substituted by one or more R S3 Substituted 5-12 membered heteroaryl, unsubstituted or substituted by one or more R S3 Substituted C4-C10 cycloalkyl, unsubstituted or substitutedOne or more R S3 Substituted 5-12 membered heterocycloalkyl;
R s3 each independently selected from the group consisting of: halogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkanoyl, cyano, oxo (= O);
unless otherwise specified, the substitution means that one or more hydrogens in the group are optionally substituted with a substituent selected from the group consisting of: hydroxy, halogen, amino (-NH) 2 ) -N (C1-C3 alkyl) 2 -NH (C1-C3 alkyl), cyano.
2. The compound of claim 1, wherein Z is N or CH.
3. A compound of formula I according to claim 1, wherein R is 1 Is H, -N (R) a ) 2 Unsubstituted or substituted by one or more R s1 Substituted 4-10 membered heterocycloalkyl; and wherein the 4-10 membered heterocycloalkyl group contains at least one N-heterocycloalkyl atom and is attached to the remainder of the compound through the N-heterocycloalkyl atom therein.
4. A compound of formula I according to claim 1, wherein R is 2 Is halogen; and R is 3 Is H or C1-C6 alkyl.
5. A compound of formula I according to claim 1, wherein R is 4 is-OR b (ii) a And R is b Selected from the group consisting of: H. unsubstituted or substituted by one or more R s2 Substituted C1-C6 alkyl; r s2 Each independently selected from the group consisting of hydroxy, C1-C3 alkoxy.
6. A compound of formula I according to claim 1, wherein R is 6 Selected from the group consisting of: unsubstituted or substituted by one or more R S3 Substituted C4-C10 cycloalkyl, unsubstituted or substituted by one or more R S3 Substituted 5-12 membered heterocycloalkyl.
7. The compound of formula I according to claim 1, wherein the compound of formula I is a compound selected from the group consisting of the compounds of Table 1 below,
TABLE 1
Figure FDA0003097511850000021
Figure FDA0003097511850000031
Figure FDA0003097511850000041
Or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof.
8. A pharmaceutical composition comprising (I) a therapeutically effective amount of a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof, and (ii) optionally a pharmaceutically acceptable carrier, excipient or diluent.
9. A process for the preparation of a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof,
the preparation method is a first preparation method, a second preparation method or a third preparation method;
wherein the content of the first and second substances,
the first preparation method comprises the following steps:
Figure FDA0003097511850000042
(vi) Reacting compound if with alkyne reagent R in inert solvent under Pd catalysis 4 -a-C ≡ CH to give compound ig;
(vii) The compound ig is deprotected and then reacted with a carboxylic acid R 6 COOH to obtain the compound of formula I;
the second preparation method comprises the following steps:
Figure FDA0003097511850000051
(i) Under alkaline condition, the compound ie is reacted with nucleophilic reagent
Figure FDA0003097511850000052
Substitution to give the compound iia;
(ii) Reacting the compound iia with an alkyne reagent R in an inert solvent under Pd catalysis 4 -a-C ≡ CH to give a compound of formula I;
the preparation method III comprises the following steps:
Figure FDA0003097511850000053
(i) The compound if is deprotected and then reacted with a carboxylic acid R 6 COOH undergoes a condensation reaction to give a compound iiia;
(ii) Reacting the compound iiia with an alkyne reagent R in an inert solvent under Pd catalysis 4 -a-C ≡ CH to give a compound of formula I;
in the formula, A, Z and R 1 、R 2 、R 3 、R 4 、R 5 And R 6 As defined in claim 1.
10. Use of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, optical isomer, racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 8, for the manufacture of (I) a PGK1 inhibitor and/or (ii) a medicament for the treatment or prevention of a disease associated with PGK 1.
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