CN111410648B - Chiral c-KIT inhibitor drug key intermediate and preparation method thereof - Google Patents

Chiral c-KIT inhibitor drug key intermediate and preparation method thereof Download PDF

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CN111410648B
CN111410648B CN201910012203.5A CN201910012203A CN111410648B CN 111410648 B CN111410648 B CN 111410648B CN 201910012203 A CN201910012203 A CN 201910012203A CN 111410648 B CN111410648 B CN 111410648B
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tautomer
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CN111410648A (en
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别平彦
安泉林
曹琪
张涛
郑国君
陈磊
蒋国平
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Zhejiang Hisun Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a c-KIT inhibitor shown in a formula (III)The preparation method, key intermediates as well as the preparation method of the key intermediates as shown in the formula (I), the formula (II) and the intermediate, wherein each substituent in the formula (I), the formula (II) and the formula (III) is defined as the specification. The invention adopts a chiral induction synthesis method to obtain a product with a single configuration, thereby reducing the cost and improving the ee value.

Description

Chiral c-KIT inhibitor drug key intermediate and preparation method thereof
Technical Field
The invention relates to a preparation method of a c-KIT inhibitor, a key intermediate and a preparation method thereof.
Background
c-KIT (also known as KIT, CD117 and stem cell factor receptor) is a 145kDa transmembrane tyrosine kinase protein that acts as a type III receptor. The c-KIT protooncogene located on chromosome 4q11-21 encodes the c-KIT receptor, the ligand of which is a stem cell factor. The receptor has tyrosine protein kinase activity and binding to ligand SCF results in autophosphorylation of c-KIT and its association with a substrate such as phosphatidylinositol 3-kinase (PI 3K). Protein tyrosine kinases are particularly important for the phosphorylation of tyrosine in cell signaling and can mediate signals for major cellular processes such as proliferation, survival, differentiation, apoptosis, ligation, invasion and migration. The c-KIT mutation is typically present in the DNA encoding the membrane proximal region (exon 11). They also occur at lower frequencies in exons 7, 8, 9, 13, 14, 17 and 18. Mutations make c-KIT function independent of activation by SCF, resulting in high cell division rates and possible genomic instability. Functional increasing mutations in the c-KIT gene and expression of constitutively phosphorylated c-KIT can be seen in most gastrointestinal stromal tumors (GIST), mastocytosis and acute myelogenous leukemia. It has mutations at different positions at different exons, and the first generation of c-KIT mutations and related drugs are mainly imatinib, sunitinib, dasatinib and PKC412.
c-KIT has been found in gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, mastadenoma, glioblastoma multiforme, ovarian tumor, and other tissues, and its protein expression level has a close relationship with the occurrence and development of tumors. Among them, gastrointestinal stromal tumor (gastrointestinal stromal tumor, GIST) is the most common mesenchymal-derived tumor of gastrointestinal tract, and epidemiological studies have shown morbidity of 0.66-2.20/10 ten thousand according to current GIST diagnostic criteria. GIST are extremely insensitive to traditional chemotherapy, the chemotherapy drug efficacy is less than 5%, and the survival rate in the advanced stage is only about 18 months. Even if the tumor is completely resected, the 5-year survival rate of GIST is only 35% -65%, the recurrence and metastasis rate is 40% -50% in 2 years, and up to 15% -50% of patients have metastasis in the first diagnosis. The research shows that the functional activation mutation of the transmembrane tyrosine kinase receptor c-KIT and the platelet-derived growth factor receptor PDGFR alpha gene on the surface of stem cell factor is the key for the development of GIST. Platelet-derived growth factor receptor (PDGF-R) is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. PDGF subunits pdgfα and pdgfβ are important mediators that regulate cell proliferation, cell differentiation, cell growth, development and many diseases including cancer.
With the clinical use of the first generation inhibitor Imatinib (Imatinib), the problem of acquired drug resistance of Imatinib is becoming a serious challenge in the clinical use of such inhibitors. Therefore, research and development of new c-KIT inhibitors are urgently needed to meet market demands. Currently under investigation c-KIT inhibitor drugs, including avapritinib (Blueprint) and ripretinib (Deciphera), are both in phase 3 clinical stage. There has been some progress in the research and use of c-KIT inhibitors, but there is still a great room for improvement, and there is still a need to continue to research and develop new c-KIT inhibitors.
A series of c-KIT inhibitor patents are disclosed, including WO2014039714, WO2014100620, WO2015134536A1, WO2015057873 and the like, wherein WO2015057873 discloses a series of preparation methods of the c-KIT inhibitor, and simultaneously discloses synthesis of intermediate 1- (4-fluorophenyl) -1- (2- (piperazin-1-yl) pyrimidin-5-yl) ethanol, chiral resolution of racemate by HPLC is adopted to obtain optically pure isomer, and the ee value of the product is lower.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a novel synthesis method for preparing a chiral c-KIT inhibitor, which is used for carrying out asymmetric nucleophilic addition reaction on a substrate by using an S-type chiral ligand-induced Grignard reagent, so that the yield and ee value of the obtained product are obviously improved.
The present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
wherein:
R 1 each independently selected from a hydrogen atom, a halogen, an alkyl group, or an alkoxy group, wherein the alkyl group or alkoxy group is optionally further substituted with one or more substituents selected from a hydroxy group, a halogen, or an alkoxy group; preferably, R 1 Each independently selected from hydrogen atom, fluorine, chlorine, methyl or methoxy; and is also provided with
m is selected from 0, 1,2,3, 4 or 5.
Compounds of formula (I) include, but are not limited to:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The present invention provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or salt thereof, which process comprises:
reacting a compound of formula (II) under acidic conditions in an organic solvent to remove the amino protecting group R 2 Obtaining an acid salt of the compound of formula (I), optionallyFurther reacting under alkaline conditions to obtain a compound of formula (I);
wherein:
R 2 selected from methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, benzyl, p-methoxybenzyl or 2- (trimethylsilyl) ethoxymethyl, preferably t-butoxycarbonyl;
R 1 and m is as defined in formula (I).
Preferably, a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or salt thereof, the acidic condition of the acid reagent being selected from trifluoroacetic acid or a hydrogen chloride solution which is a dioxane or methanol solution containing hydrogen chloride.
Preferably, a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or salt thereof, the alkaline agent of alkaline conditions being selected from sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Preferably, a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer or salt thereof, the organic solvent being selected from dichloromethane, acetonitrile, methanol, ethanol, methyl tert-butyl ether or isopropyl ether, more preferably acetonitrile.
The present invention provides a compound of formula (II):
wherein:
R 2 selected from methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, benzyl, p-methoxybenzyl or 2- (trimethylsilyl) ethoxymethyl, preferably t-butoxycarbonyl;
R 1 and m is as defined in formula (I).
Compounds of formula (II) include, but are not limited to:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The present invention provides a process for the preparation of a compound of formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which process comprises:
dissolving a compound of a formula (IIA) and a chiral ligand formula (IIC) in an anhydrous organic solvent, firstly cooling to-45-0 ℃, then adding a compound of a formula (IIB), and then heating to 0-50 ℃ for reaction to obtain a compound of a formula (II);
wherein:
R 5 selected from-MX;
m is a metal element, preferably Mg;
x is selected from halogen, preferably bromine;
r is selected from hydrogen atom, phenyl or
R A Selected from methyl, methoxy or ethoxy;
n is selected from 0, 1,2,3, 4 or 5, preferably 0 or 1;
the chiral ligands of formula (IIC) are preferably:
and is also provided with
R 1 And m is as defined in formula (I), R 2 The definition of (a) is as described in formula (II).
Preferably, a process for the preparation of a compound of formula (II) or a stereoisomer, tautomer or salt thereof, wherein the molar ratio of the compound of formula (IIA), compound of formula (IIB) and chiral ligand of formula (IIC) is 1 (4-6): 1, more preferably 1 (5-6): 1.
Preferably, a process for the preparation of a compound of formula (II) or a stereoisomer, tautomer or salt thereof, the anhydrous organic solvent being selected from anhydrous tetrahydrofuran, anhydrous toluene, anhydrous diethyl ether, anhydrous isopropyl ether, anhydrous methyl tert-butyl ether or anhydrous 1, 4-dioxane, more preferably anhydrous tetrahydrofuran.
Preferably, a process for the preparation of a compound of formula (II) or a stereoisomer, tautomer or salt thereof, the temperature of which is reduced from-45 to-35 ℃, more preferably-45 ℃.
Preferably, a process for the preparation of a compound of formula (II) or a stereoisomer, tautomer or salt thereof, the elevated temperature being in the range of from 0 to 30 ℃, more preferably in the range of from 15 to 30 ℃.
The invention provides a preparation method of a compound shown in a formula (III) or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof,
the method comprises the following steps:
(i) Reacting a compound of formula (I) with a compound of formula (IIIA) under basic conditions to obtain a compound of formula (IIIB);
(ii) Combining a compound of formula (IIIB) with boric acid or R 3 Reacting the substituted borate to obtain a compound of formula (III);
wherein:
R 1 each independently selected from a hydrogen atom, a halogen, an alkyl group, or an alkoxy group, wherein the alkyl group or the alkoxy groupThe radicals being optionally further substituted by one or more substituents selected from hydroxy, halogen or alkoxy; preferably, R 1 Each independently selected from hydrogen atom, fluorine, chlorine, methyl or methoxy;
R 3 selected from the group consisting of heterocyclyl or heteroaryl, preferably pyrazolyl or tetrahydropyridinyl, wherein the pyrazolyl is optionally further substituted with one or more groups selected from the group consisting of alkyl, heterocyclyl and-C (O) R 4 Is substituted by a substituent of (2); the tetrahydropyridinyl group is preferably
R 4 Is alkyl;
X 1 halogen, preferably chlorine or bromine;
X 2 halogen, preferably bromine;
said R is 3 The substituted borates are preferably:
and is also provided with
m is selected from 0, 1,2,3, 4 or 5;
preferably, the method comprises the steps of,
in step (i), the solvent for the reaction is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, N-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane, acetonitrile, N-dimethylformamide N, N-dimethylacetamide or water, preferably dichloromethane;
in step (i), the temperature of the reaction is selected from 0 to 50 ℃, preferably 15 to 45 ℃;
preferably, the method comprises the steps of,
in the step (ii), the solvent for the reaction is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, N-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tertiary butyl ether, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide or water, preferably a mixed solvent of 1, 4-dioxane and water, wherein the volume ratio of water to 1, 4-dioxane is 3:1;
in step (ii), the temperature of the reaction is selected from 80 to 120 ℃, preferably 80 to 90 ℃.
Preferably, a process for the preparation of a compound of formula (III) or a stereoisomer, tautomer or salt thereof, by reacting a compound of formula (II) under acidic or basic conditions in an organic solvent to deaminate the protecting group R 2 The preparation method comprises the following steps:
wherein:
R 2 selected from methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, benzyl, p-methoxybenzyl or 2- (trimethylsilyl) ethoxymethyl, preferably t-butoxycarbonyl;
R 1 and m is as defined in formula (I);
the acid reagent of the acid condition is selected from trifluoroacetic acid or hydrogen chloride solution, and the hydrogen chloride solution is preferably dioxane or methanol solution containing hydrogen chloride;
the alkaline reagent of the alkaline condition is selected from sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide;
the organic solvent is selected from dichloromethane, acetonitrile, methanol, ethanol, methyl tert-butyl ether or isopropyl ether, more preferably acetonitrile.
Preferably, a method for preparing a compound of formula (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula (III) or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof includes, but is not limited to:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched saturated aliphatic hydrocarbon groups. For example, C 1 -C 20 Is meant to include 1 to 20 carbon atoms, and may include, for example, 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged and spiro rings. Preferably having a 4 to 7 membered mono-or 7 to 10 membered bi-or tri-ring, which may contain 1,2,3 or 4 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, pyrazolyl, tetrahydropyridinyl, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted. The heterocyclyl may contain 3 to 14 (e.g., 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, or 14) atoms.
"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group wherein the monocyclic rings share one atom with each other, one or more of which may contain 1 or more double bonds, but none of which has a completely conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen and/or S (O) p (wherein p is selected from 0, 1 and/or 2) 1,2,3 or 4 heteroatoms, the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5 ]]Decyl, 2-oxa-7-azaspiro [4.4 ]]Nonyl, 7-oxaspiro [3.5 ]]Nonyl and 5-oxaspiro [2.4 ]]A heptyl group. The spiroheterocyclyl may contain 3 to 18 (e.g. 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18) atoms.
"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen and/or S (O) p (wherein p is selected from heteroatoms of 0, 1 and/or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, pyridone or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo [3,4-c ]]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0 ]]Hexyl, octahydrobenzo [ b ]][1,4]Dioxin (dioxin). The fused heterocyclyl may contain 3 to 18 (e.g., 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) atoms.
"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen and/or S (O) p (wherein p is selected from heteroatoms of 0, 1 and/or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or pyridone group, more preferably a bicyclic or tricyclic group. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]And (3) a decyl group. The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl. The heterocyclyl group may be optionally substituted or unsubstituted. The bridged heterocyclyl may contain 3 to 18 (e.g., 3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) atoms.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl and benzisoxazolyl. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups may contain 6 to 10 (e.g., 6, 7, 8, 9, or 10) atoms. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkoxy, halogen, mercapto, hydroxy, heterocyclyl, aryl, heteroaryl or-C (O) R 4 ；
R 4 Selected from alkyl groups, alkyl groups are defined herein.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use.
The room temperature is 15 to 30℃and preferably 25 ℃.
Synthesis method of compound of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the preparation method of the compound shown in the formula (I) or (II) or pharmaceutically acceptable salt or pharmaceutical composition thereof comprises the following steps:
dissolving a compound of a formula (IIA) and a chiral ligand formula (IIC) in an anhydrous organic solvent, firstly cooling to-45-0 ℃, then adding a compound of a formula (IIB), and then heating to 0-50 ℃ for reaction to obtain a compound of a formula (II); reacting a compound of formula (II) under acidic conditions in an organic solvent to remove the amino protecting group R 2 Obtaining an acid salt of the compound of formula (I), optionally further reacting under alkaline conditions to obtain the compound of formula (I); reacting a compound of formula (I) with a compound of formula (IIIA) under basic conditions to obtain a compound of formula (IIIB); combining a compound of formula (IIIB) with R 3 Substituted borates or R 3 Reacting the substituted boric acid to obtain a compound of formula (III);
wherein:
R 3 selected from the group consisting of heterocyclyl or heteroaryl, preferably pyrazolyl or tetrahydropyridinyl, wherein the pyrazolyl is optionally further substituted with one or more groups selected from the group consisting of alkyl, heterocyclyl and-C (O) R 4 Is substituted by a substituent of (2); the tetrahydropyridinyl group is preferably
R 4 Is alkyl;
X 1 halogen, preferably chlorine or bromine;
X 2 halogen, preferably bromine;
said R is 3 The substituted borates are preferably:
and->
R 5 Selected from-MX;
m is a metal element, preferably Mg;
x is selected from halogen, preferably bromine;
r is selected from hydrogen atom, phenyl or
R A Selected from methyl, methoxy or ethoxy;
n is selected from 0, 1,2,3, 4 or 5, preferably 0 or 1;
the chiral ligands of formula (IIC) are preferably:
and is also provided with
R 1 And m is as defined in formula (I), R 2 The definition of (a) is as described in formula (II).
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Examples
The preparation of representative compounds represented by formula (I), formula (II) and formula (III) and related structural identification data are given in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The ee values of chiral compounds were determined on a Agilent Technologies 1260 affinity high performance liquid chromatograph using chiral columns using chiral PakAD-H, 250X 4.6mm I.D.,5 μm, chiral Pak OD-RH, 250X 4.6mm I.D.,5 μm and chiral Pak IC, 250X 4.6mm I.D.,5 μm.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, aldrich Chemical Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology limited, and vision chemical technology limited, etc.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound by using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane and ethyl acetate systems; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
Example 1
(R) -1- (2, 4-difluorophenyl) -1- (2- (1- (6- (1-methyl-1H-pyrazol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethan-1-ol
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First step
(2, 4-difluorophenyl) magnesium bromide
Magnesium turnings (374 mg,15.6 mmol) and iodine (45 mg,0.35 mmol) were dissolved in 10mL dry tetrahydrofuran under argon. 1-bromo-2, 4-difluorobenzene 1a (2.3 g,12.0 mmol) was dissolved in 2mL of dry tetrahydrofuran, then 0.4mL of a tetrahydrofuran solution of 1-bromo-2, 4-difluorobenzene 1a was added dropwise to the above reaction solution, and the bottom of the reaction flask was heated with a blower to initiate the reaction. Slowly adding the residual tetrahydrofuran solution of 1-bromo-2, 4-difluorobenzene 1a, and keeping the reaction liquid slightly boiling. After the completion of the dropping, the reaction was carried out at room temperature for 1 hour. After the reaction was completed, (2, 4-difluorophenyl) magnesium bromide 1b (12 ml,1m/THF, pale yellow liquid) was obtained, yield: 100%.
Second step
2- (1- (tert-Butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidine-5-carboxylic acid ethyl ester
Under argon, ethyl 2-chloropyrimidine-5-carboxylate 1c (12.97 g,69.51 mmol) and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate 1d (27.94 g,90.36 mmol), tetrakis (triphenylphosphine) palladium (4.0 g,3.48 mmol), cesium carbonate (67.9 g,208.5 mmol) were dissolved in a mixed solvent of 360mL ethylene glycol dimethyl ether and water (V: V=5:1) and reacted at 85℃for 4 hours. After the reaction was completed, cooled to room temperature, 300mL of ethyl acetate and 150mL of water were added, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (150 mL), the organic phases were combined, washed with water (150 ml×3) and saturated sodium chloride solution (150 mL) in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: a system) to give ethyl 2- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidine-5-carboxylate 1e (21.2 g, pale yellow solid), yield: 91.5%.
MS m/z(ESI)：278.0[M-55]
1 H NMR(400MHz,CDCl 3 )δ9.23(s,2H),7.43(s,1H),4.44(d,J＝7.1Hz,2H),4.23(d,J＝2.5Hz,2H),3.65(t,J＝5.6Hz,2H),2.75(s,2H),1.50(s,9H),1.43(t,J＝7.1Hz,3H).
Third step
2- (1- (tert-Butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidine-5-carboxylic acid
Ethyl 2- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidine-5-carboxylate 1e (21.2 g,63.6 mmol) and lithium monohydrate (4.0 g,95.38 mmol) were dissolved in a mixed solvent of 135mL of tetrahydrofuran, methanol and water (V: v=10:2.5:1) and reacted at 30 ℃ for 1 hour. A large amount of solid precipitated, filtered and washed with water (50 mL. Times.2). The filter cake was dried in a vacuum oven at 50 ℃ to give 1f (17.3 g, pale yellow solid) of 2- (1- (tert-butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidine-5-carboxylic acid, yield: 89.2%.
Fourth step
4- (5- (methoxy (methyl) carbamoyl) pyrimidin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
2- (1- (tert-Butoxycarbonyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidine-5-carboxylic acid 1f (17.3 g,56.7 mmol), N, O-dimethylhydroxylamine hydrochloride (8.29 g,84.99 mmol) and N, N-diisopropylethylamine (38 mL,226.64 mmol) were dissolved in 200mL of dichloromethane, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (33.0 g,84.99 mmol) was added while ice water, and after stirring at room temperature for 5 minutes, the reaction was continued for 2 hours at 30 ℃. After the completion of the reaction, 200mL of water was added, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with methylene chloride (100 mL), the organic phases were combined, washed with water (100 ml×2) and saturated sodium chloride solution (100 mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: a system) to give 1g (14.6 g, white solid) of tert-butyl 4- (5- (methoxy (meth) carbamoyl) pyrimidin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate, yield: 73.9%.
MS m/z(ESI)：292.9[M-55]
1 H NMR(400MHz,CDCl 3 )δ8.99(s,2H),7.26(s,1H),4.14(d,J＝2.0Hz,2H),3.57(d,J＝4.9Hz,2H),3.53(s,3H),3.34(s,3H),2.67(s,2H),1.42(s,9H).
Fifth step
(5-Acetylpyrimidin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Under the protection of argon, 1g (516 g,1480 mmol) of tert-butyl 4- (5- (methoxy (methyl) carbamoyl) pyrimidin-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate is dissolved in 5L tetrahydrofuran in an ice bath, and a methyl magnesium bromide reagent (2.96L, 1M/THF) is slowly added dropwise under the ice bath, and the mixture is reacted at 0 ℃ for 1.5 hours. After the completion of the reaction, the above reaction solution was poured into 5L of a saturated ammonium chloride ice water solution, stirred while inverting, then 1L of ethyl acetate was added, stirred for 10min, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (1L), the organic layers were combined, washed with a saturated sodium chloride solution (3L), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give tert-butyl (5-acetylpyrimidin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (395 g, pale yellow solid) in 88% yield.
Sixth step
(R) -4- (5- (1- (2, 4-difluorophenyl) -1-hydroxyethyl) pyrimidin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Under the protection of argon, (5-acetyl pyrimidine-2-yl) -5, 6-dihydropyridine-1 (2H) -tert-butyl formate (2.53 g,8.35 mmol) and (S) -3,3' -di (3, 3-dimethylbutyl) - [1,1' -binaphthyl ] -2,2' -diol 1i (3.8 g,8.35 mmol) are dissolved in 80mL of anhydrous tetrahydrofuran, cooled to-45 ℃, and (2, 4-difluorophenyl) magnesium bromide 1b (50 mL,1 mol/L) is dropwise added, and after the addition, the reaction is slowly warmed to room temperature and continued for 30min at room temperature. After the completion of the reaction, the temperature was lowered to 0 ℃,20 mL of saturated ammonium chloride solution was added to quench the reaction, 15mL of 1n diluted hydrochloric acid was added, extraction was performed with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: C system) to give (R) -4- (5- (1- (2, 4-difluoro) -1-hydroxyethyl) -pyrimidin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 1j (3.0 g), yield: 86%,95.42% ee. ( ee value measurement method: chiral column: chiralPak AD-H,250×4.6mm I.D.,5 μm; column temperature: 25 ℃; flow rate: 1.0mL/min; concentration: 1.0mg/mL; sample injection amount: 1.0. Mu.L; mobile phase: n-hexane/isopropanol/diethylamine=95/10/0.1 (V/V); retention time of R configuration: 14.126min, content 97.711%; s configuration retention time: 16.035min, content 2.289%. )
MS m/z(ESI)：418.0[M+1]
1 H NMR(400MHz,CDCl 3 )δ8.69(s,2H),7.68(q,J＝8.0Hz,1H),7.18(s,1H),6.92(t,J＝8.0Hz,1H),6.77(t,J＝8.0Hz,1H),4.15(s,2H),3.61(t,J＝8.0Hz,2H),2.69(s,2H),2.00(s,3H),1.48(s,9H).
Seventh step
The method comprises the following steps: (R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethanol hydrochloride
(R) -4- (5- (1- (2, 4-difluoro) -1-hydroxyethyl) -pyrimidin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 1j (6.0 g,14.4 mmol) was dissolved in 20mL dioxane hydrochloride solution (4M) and reacted at room temperature for 16 hours. After the reaction, the precipitated solid was filtered to obtain (R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethanol hydrochloride 1k.
The second method is as follows: (R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethanol trifluoroacetate
(R) -4- (5- (1- (2, 4-difluoro) -1-hydroxyethyl) -pyrimidin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 1j (6.0 g,14.4 mmol) was dissolved in 20mL dichloromethane, 6mL trifluoroacetic acid was added and stirred overnight at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 3mL of methylene chloride, isopropyl ether was slowly added dropwise with stirring to precipitate a solid, and the solid was filtered to obtain a crude product (4.2 g, earthy yellow)A solid); 4.2g of crude product is dissolved in 8mL of acetonitrile, the solid is fully dissolved by heating, the temperature is reduced to-5-0 ℃, and solid is precipitated and filtered to obtain (R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidine-5-yl) ethanol trifluoro formate 1R (3.13 g), the yield is: 50%,99.48% ee. (ee value measurement method: chiral column: chiralPak OD-RH, 150X 4.6mM I.D.,5 μm, column temperature: 25 ℃ C., flow rate: 0.4mL/min, concentration: 1.0mg/mL, sample introduction amount: 1.0. Mu.L, mobile phase: acetonitrile/50 mM KPF) 6 Aqueous = 40/60 (V/V); retention time of R configuration: 5.27min, content 99.74%; s configuration retention time: 6.00min, content 0.26%. )
MS m/z(ESI)：317.9[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ8.89-8.80(m,2H),8.75(s,2H),7.85-7.79(m,1H),7.18-7.09(m,3H),3.86-3.85(m,2H),3.31-3.30(m,2H),2.78-2.77(m,2H),1.91(s,3H).
Eighth step
(R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethanol
The method comprises the following steps: dissolving 1k obtained in the first method in the step seven in 20mL of methanol, dropwise adding saturated sodium bicarbonate solution, regulating the pH value to be 7-8, extracting with ethyl acetate (20 mL multiplied by 3), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, dissolving the obtained residue in 12mL of acetonitrile, heating to completely dissolve, cooling to-5-0 ℃, precipitating crystals, filtering, and obtaining (R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethanol 1m (3.05 g), wherein the yield is: 67%,99.0% ee. (ee value measurement method: chiral column: chiralPak OD-RH, 150X 4.6mM I.D.,5 μm, column temperature: 25 ℃ C., flow rate: 0.5mL/min, concentration: 1.0mg/mL, sample introduction amount: 1.0. Mu.L, mobile phase: acetonitrile/100 mM KPF) 6 Aqueous = 40/60 (V/V); retention time of R configuration: 6.99min, content 99.50%; s configuration retention time: 8.02min, content 0.50%)
MS m/z(ESI)：317.9[M+1]
1 H NMR(400MHz,CDCl 3 )δ8.67(s,2H),7.73-7.67(m,1H),7.19(s,1H),6.95-6.90(m,1H),6.77-6.71(m,1H),3.57(d,J＝2.4Hz,2H),3.06(t,J＝5.6Hz,2H),2.55-2.54(m,2H),1.99(s,3H).
The second method is as follows: taking the 1R obtained in the second method in the seventh step as a raw material, and preparing the (R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethanol 1m according to the same operation steps of the first method in the eighth step.
Ninth step
(R) -1- (2- (1- (6-bromopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) -1- (2, 4]
Difluorophenyl) ethan-1-ol
(R) -1- (2, 4-difluorophenyl) -1- (2- (1, 2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethanol 1m (4.8 g,15 mmol), 6-bromo-4-chloropyrrolo [2,1-f ] [1,2,4] triazine 1N (3.5 g,15mmol, prepared according to patent U.S. Pat. No. 5, 20160031892) and N, N-diisopropylethylamine (2.9 g,22.5 mmol) were dissolved in 72mL dichloromethane and reacted at room temperature for 3 hours. After the reaction is finished, concentrating under reduced pressure, adding 120mL of a mixed solvent of n-heptane and water (V: V=3:2), stirring at room temperature for 1 hour, precipitating a solid, dissolving the obtained solid in 77mL of 95% ethanol, heating to 50-60 ℃, cooling to room temperature when the solid is completely dissolved, and stirring for 2 hours, precipitating a solid; 38mL of water was added dropwise to the reaction system, the temperature was lowered to 0-10℃and stirring was continued for 2 hours, filtration and drying were carried out to give (R) -1- (2- (1- (6-bromopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) -1- (2, 4-difluorophenyl) ethan-1-ol 1p (5.8 g), yield: 75%.
MS m/z(ESI)：512.8[M+1]
Tenth step
(R) -1- (2, 4-difluorophenyl) -1- (2- (1- (6- (1-methyl-1H-pyrazol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazine-4 ]
Phenyl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethan-1-ol
(R) -1- (2- (1- (6-bromopyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -pyrimidin-5-yl) -1- (2, 4-difluorophenyl) ethan-1-ol 1p (12.8 g,25 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole 1q (6.3 g,30 mmol), cesium carbonate (16.3 g,50 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.44 g,0.6 mmol) were dissolved in a mixed solvent of 173ml1, 4-dioxane and water (V: V=3:1) under argon atmosphere and reacted at 80-90℃for 4 hours. After the reaction, cooling to 40-50 ℃, adding 220mL under stirring, adding 260mL of ethyl acetate, continuing stirring at room temperature for 10 minutes, separating a water layer, collecting an organic phase, washing with 10% sodium chloride solution (200 mL), drying with anhydrous sodium sulfate, filtering with diatomite, concentrating the filtrate to 50mL under reduced pressure, adding 100mL of n-heptane, stirring at room temperature, precipitating a solid, continuing stirring for 1 hour, filtering, and drying a filter cake to obtain a earthy yellow solid. The solid was dissolved in 160mL of ethyl acetate, an ethylene diamine tetraacetic acid disodium solution (0.02 mol/L,80 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the aqueous layer was separated. Then, disodium ethylenediamine tetraacetate solution (0.02 mol/L,80 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour, followed by separation of the aqueous layer. The organic phase was filtered through celite, concentrated under reduced pressure, and the solid was dissolved in 160mL of ethyl acetate and purified by silica gel column chromatography (eluent: A system) to give (R) -1- (2, 4-difluorophenyl) -1- (2- (1-methyl-1H-pyrazol-4-yl) pyrrolo [2,1-f ] [1,2,4] triazin-4-yl) -1,2,3, 6-tetrahydropyridin-4-yl) pyrimidin-5-yl) ethan-1-ol 1 (9.5 g), yield: 73%,99.54% ee. ( ee value measurement method: chiral column: chiralPak IC,250×4.6mm I.D.,5 μm; column temperature: 25 ℃; flow rate: 0.5mL/min; concentration: 1.0mg/mL; sample injection amount: 1.0. Mu.L; mobile phase: isopropanol/methanol/ethyl acetate=40/60/0.1 (V/V); retention time of R configuration: 20.32min with a content of 99.77%; s configuration retention time: 22.59min, content 0.23%. )
MS m/z(ESI)：514.9[M+1]
1 H NMR(400MHz,DMSO)δ8.75(s,2H),8.06(s,1H),7.99(s,1H),7.87(d,J＝5.4Hz,1H),7.86-7.75(m,2H),7.28(d,J＝7.6Hz,2H),7.20-7.09(m,2H),6.33(s,1H),4.75(s,2H),4.16(t,J＝5.4Hz,2H),3.86(s,3H),2.83(s,2H),1.92(s,3H).
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (17)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
wherein:
R 1 each independently selected from hydrogen atom, halogen, C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, wherein the alkyl or alkoxy is optionally further substituted with one or more groups selected from hydroxy, halogen or C 1 -C 6 Substituted with alkoxy;
m is selected from 0, 1,2,3, 4 or 5.
2. A compound of formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 Each independently selected from a hydrogen atom, fluorine, chlorine, methyl or methoxy.
3. A compound of formula (I) according to claim 1 or 2, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:
4. a process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, or a stereoisomer, tautomer or salt thereof, which process comprises:
compounds of formula (II)Reacting the mixture in an organic solvent under an acidic condition to remove amino protecting groups R 2 Obtaining an acid salt of the compound of formula (I), optionally further reacting under alkaline conditions to obtain the compound of formula (I);
wherein:
R 2 selected from methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, benzyl, p-methoxybenzyl or 2- (trimethylsilyl) ethoxymethyl;
R 1 and m is as defined in claim 1.
5. The process according to claim 4, wherein R 2 Is tert-butyloxycarbonyl.
6. The method of claim 4, wherein the acidic reagent is selected from trifluoroacetic acid or hydrogen chloride solution.
7. The method according to claim 6, wherein the hydrogen chloride solution is dioxane or methanol solution containing hydrogen chloride.
8. The method according to claim 4, wherein the alkaline reagent is selected from sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
9. The process according to claim 4, wherein the organic solvent is selected from the group consisting of methylene chloride, acetonitrile, methanol, ethanol, methyl tert-butyl ether and isopropyl ether.
10. The method of claim 9, wherein the organic solvent is acetonitrile.
11. A method for preparing a compound shown in a formula (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
the method comprises the following steps:
(i) Reacting a compound of formula (I) with a compound of formula (IIIA) under basic conditions to obtain a compound of formula (IIIB);
(ii) Combining a compound of formula (IIIB) with R 3 Substituted borates or R 3 Reacting the substituted boric acid to obtain a compound of formula (III);
wherein:
R 1 each independently selected from hydrogen atom, halogen, C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy, wherein the alkyl or alkoxy is optionally further substituted with one or more groups selected from hydroxy, halogen or C 1 -C 6 Substituted with alkoxy;
R 3 selected from pyrazolyl, wherein said pyrazolyl is optionally further substituted with one or more substituents selected from C 1 -C 6 Alkyl and-C (O) R 4 Is substituted by a substituent of (2);
R 4 is C 1 -C 6 An alkyl group;
X 1 is halogen;
X 2 is halogen;
said R is 3 The substituted borates are:
and is also provided with
m is selected from 0, 1,2,3, 4 or 5.
12. The method of manufacturing according to claim 11, wherein:
R 1 each independently selected from hydrogen atom, fluorine, chlorine, methyl or methoxy;
X 1 is chlorine or bromine;
X 2 is bromine.
13. The method according to claim 11, wherein,
in step (i), the solvent for the reaction is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, N-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide or water;
in the step (i), the temperature of the reaction is selected from 0-50 ℃;
in step (ii), the solvent of the reaction is selected from one or more of dichloromethane, methanol, ethanol, isopropanol, N-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide or water;
in step (ii), the temperature of the reaction is selected from 80 to 120 ℃.
14. The method according to claim 11, wherein,
in step (i), the solvent of the reaction is methylene chloride;
in the step (i), the temperature of the reaction is 15-45 ℃;
in the step (ii), the solvent for the reaction is a mixed solvent of 1, 4-dioxane and water, wherein the volume ratio of the water to the 1, 4-dioxane is 3:1;
in step (ii), the temperature of the reaction is 80 to 90 ℃.
15. The process according to claim 11 or 13, wherein the compound of formula (I)The compound is prepared by reacting a compound of formula (II) under acidic or alkaline conditions in an organic solvent to remove amino protecting groups R 2 The preparation method comprises the following steps:
wherein:
R 2 selected from methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, benzyl, p-methoxybenzyl or 2- (trimethylsilyl) ethoxymethyl;
R 1 and m is as defined in claim 1;
the acid reagent of the acid condition is selected from trifluoroacetic acid or hydrogen chloride solution;
the alkaline reagent of the alkaline condition is selected from sodium bicarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide;
the organic solvent is selected from dichloromethane, acetonitrile, methanol, ethanol, methyl tertiary butyl ether or isopropyl ether.
16. The method of manufacturing according to claim 15, wherein:
R 2 t-butoxycarbonyl;
the acid reagent in the acidic condition is dioxane or methanol solution containing hydrogen chloride;
the organic solvent is acetonitrile.
17. The process for the preparation of a compound of formula (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 11, wherein the compound of formula (III) or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is selected from the group consisting of:
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