TW202233632A - Thienopyrimidine derivative - Google Patents

Abstract

The present invention relates to a thienopyrimidine derivative, in particular to a compound, as represented by formula I, or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof in the preparation of a drug for treating acetyl-CoA carboxylase (ACC)-mediated diseases in individuals, such as insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, lung cancer and pancreatic cancer.

Description

Thienopyrimidine Derivatives

The present application belongs to the field of medicinal chemistry, and relates to thienopyrimidine derivatives, in particular to a compound of formula I or a pharmaceutically acceptable salt thereof, a method for its preparation, a pharmaceutical composition containing the compound, and its use in the treatment of individuals by acetyl-CoA Use in the medicament of carboxylase (ACC)-mediated diseases.

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme for fatty acid synthesis and is mainly distributed in hepatocytes and adipocytes. It uses biotin as a coenzyme to catalyze the formation of malonyl coenzyme A from acetyl coenzyme A, which provides a substrate for the synthesis of fatty acids. The activity of ACC is not only regulated by a variety of factors, insulin, glucagon, thyroid hormone, etc. also have certain regulatory effects on ACC. At first, people's understanding of ACC was mainly limited to fatty acid synthesis. In recent years, studies have found that ACC is widely involved in the occurrence and development of metabolic diseases such as obesity, non-alcoholic steatohepatitis, and diabetes. Therefore, ACC is expected to become a therapeutic tool for various metabolic diseases. potential target of action.

Obesity, non-alcoholic steatohepatitis, diabetes and other metabolic diseases are intractable diseases that have been plaguing people, and there is no clinically effective drug to date. With the improvement of people's living standards, people eat a variety of high-fat foods, which leads to the increasingly serious phenomenon of obesity, and obesity brings a series of metabolic syndromes, such as non-alcoholic steatohepatitis, diabetes, hyperuricemia, hypertension, stroke and arterial Therefore, it is of great significance to develop drugs for the treatment of such diseases.

其中， R ¹和R ²獨立地選自氫或C _1-6烷基，可任選被選自羥基、-O-C _1-6烷基、胺基、鹵素、氰基和硝基的基團取代； R ⁴選自氫、-R’、-O-R’；R’獨立地選自任選被R取代的以下各項的基團：C _1-6烷基，3-8元環烷基，3-8元環烯基，6-10元芳基、3-10元雜環基、5-10元雜芳基； A選自任選被R取代的-O-C _1-6伸烷基，或化學鍵； L選自化學鍵，或者任選被R取代的選自3-10元環烷基、6-10元芳基、3-10元雜環基、5-10元雜芳基的二價基團； Z選自-COOR ³； R ³選自氫，或者任選被R取代的C _1-6烷基、苯基C _1-6烷基、矽烷基； 其中A和L之一為化學鍵； R獨立地為氫、氟、氯、溴、碘、羥基、胺基、硝基、氰基、矽烷基、C _1-6烷基、C _1-6烷氧基、C _2-5烯基、C _2-5炔基、鹵代C _1-6烷基、鹵代C _1-6烷氧基、氰基C _1-6烷基、羥基C _1-6烷基、苯基C _1-6烷基、3-8元環烷基、苯基、苯基C _1-6烷基、鹵代苯基、氰基苯基、具有1、2或3個獨立地選自氮、氧和硫的雜原子的3-8元雜環基，具有1、2、3或4個獨立地選自氮、氧和硫的雜原子的5-6元雜芳基。 The present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof,

Wherein, R ¹ and R ² are independently selected from hydrogen or C _1-6 alkyl, which may be optionally substituted by groups selected from hydroxyl, -OC _1-6 alkyl, amino, halogen, cyano and nitro ; R ⁴ is selected from hydrogen, -R', -O-R';R' is independently selected from the following groups optionally substituted by R: C _1-6 alkyl, 3-8 membered cycloalkyl , 3-8-membered cycloalkenyl, 6-10-membered aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl; A is selected from -OC _1-6 alkylene optionally substituted by R, or chemical bond; L is selected from chemical bond, or optionally substituted by R and is selected from 3-10-membered cycloalkyl, 6-10-membered aryl, 3-10-membered heterocyclic group, 5-10-membered divalent heteroaryl group; Z is selected from -COOR ³ ; R ³ is selected from hydrogen, or optionally R-substituted C _1-6 alkyl, phenyl C _1-6 alkyl, silyl; One of A and L is a chemical bond ; R is independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, silyl, C _1-6 alkyl, C _1-6 alkoxy, C _2-5 alkenyl , C _2-5 alkynyl, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, cyano C _1-6 alkyl, hydroxy C _1-6 alkyl, phenyl C _1-6 Alkyl, 3-8 membered cycloalkyl, phenyl, phenyl C _1-6 alkyl, halophenyl, cyanophenyl, with 1, 2 or 3 independently selected from nitrogen, oxygen and sulfur 3-8 membered heterocyclyl with heteroatoms, 5-6 membered heteroaryl with 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, when A is a chemical bond, the sites of attachment of A and Z to L are different.

In some embodiments, R ¹ and R ² are independently selected from methyl, ethyl.

^In some embodiments, R is selected from hydrogen, -O-R', wherein R' is independently selected from a group optionally substituted by R: C _1-6 alkyl, 3-8 membered ring Alkyl, 5-8 membered cycloalkenyl, 6-10 membered aryl, 4-10 membered heterocyclyl with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1, 2, 5-8 membered heteroaryl with 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

^In some embodiments, R is selected from hydrogen, -O-R', wherein R' is selected from a group optionally substituted with R: -C _1-4 alkyl, 5, 6, 7 or 8 membered cycloalkyl, 5, 6, 7, 8, 9 or 10 membered heterocyclyl with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1 or 2 independently selected from nitrogen 5-6 membered heteroaryl with heteroatoms of , oxygen and sulfur.

^In some embodiments, R is selected from hydrogen, -O-R', wherein R' is selected from a saturated 5- optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur 8-membered heterocyclyl.

^In some embodiments, R4 is selected from hydrogen, -O-R', wherein R' is selected from unsaturated 5 optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur -8-membered heterocyclyl.

^In some embodiments, R is selected from hydrogen, -O-R', wherein R' is selected from saturated 5-8 membered heterocyclyl with 1 nitrogen atom optionally substituted with R, Unsaturated 5-8 membered heterocyclic group, saturated 5-8 membered heterocyclic group with 1 oxygen atom, unsaturated 5-8 membered heterocyclic group with 1 oxygen atom, saturated 5-membered heterocyclic group with 1 sulfur atom 8-membered heterocyclic group, unsaturated 5-8-membered heterocyclic group with 1 sulfur atom, 5-6-membered saturated heterocyclic group with 2 nitrogen atoms, 5-6-membered unsaturated heterocyclic group with 2 nitrogen atoms Ring group, 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 2 oxygen atoms 5-6 membered saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group with 2 oxygen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 nitrogen atom 5-6 membered unsaturated heterocyclic group with 1 sulfur atom, saturated 5-6 membered heterocyclic group with 1 oxygen atom and 1 sulfur atom.

^In some embodiments, R4 is selected from hydrogen, -O-R', wherein R' is selected from 5-6 membered saturated heterocyclyl optionally substituted by R with 1 nitrogen atom, with 1 oxygen atom 5-6 membered saturated heterocyclic group, 5-6 membered saturated heterocyclic group having 1 sulfur atom.

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。 ^In some embodiments, R is selected from hydrogen, or a group optionally substituted with R: methoxy, ethoxy,

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。 In some embodiments, R ⁴ is

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In some embodiments, ^R is selected from hydrogen, or optionally R-substituted C _1-4 alkyl, phenyl C _1-4 alkyl, C _1-6 silyl;

In some embodiments, ^R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, methylphenyl, ethylphenyl, trimethyl Silyl, triethylsilyl, triisopropylsilyl, tertiary butyldimethylsilyl, tertiary butyldiphenylsilyl.

In some embodiments, ^R3 is selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, tert-butyldiphenylsilyl.

In some embodiments, A is selected from -OC _1-6 alkylene optionally substituted with R.

In some embodiments, A is selected from the following groups: -O-CH2-, -O- _CH ( _CH3 )-, -O-CH2CH2-, -O _{- CH} ( _{CH2CH3 )} - , -O-CH(CH ₃ )CH ₂ -, -O-CH ₂ CH(CH ₃ )-, -OC(CH ₃ ) ₂ -, -O-CH ₂ CH ₂ CH ₂ -, -O-CH _{2 CH2CH2CH2-} , -O-CH2CH( _CH3 )CH2-, -O _{- CH} ( _{CH3 )} CH2CH2-, _{-O - CH2CH2CH ( CH3 )} -, -O-CH ₂ C(CH ₃ ) ₂ -, -OC(CH ₃ ) ₂ CH ₂ -, -O-CH ₂ CH(CH ₂ CH ₃ )-, -O-CH(CH ₂ CH ₃ )CH ₂ -, -O- _CH ( _CH2CH2CH3 )-, -OC( _{CH2CH3 )} ( _{CH3 )} -.

In some embodiments, A is selected from the following groups: -O-CH2-, -O- _CH ( _CH3 )-, -O-CH2CH2-, -O _{- CH} ( _{CH2CH3 )} - , -O- _CH ( _CH3 )CH2-, -O-CH2CH( _CH3 )-, -OC( _{CH3 ) 2-} , _{-O - CH2CH2CH2-} .

In some embodiments, A is -OC( _CH3 ) _2- .

In some embodiments, L is selected from the group consisting of 3-10 membered cycloalkyl, phenyl, 3- with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally substituted with R 8-membered heterocyclyl, divalent group of 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, L is selected from a divalent group of 3-8 membered cycloalkyl optionally substituted with R.

In some embodiments, L is selected from a saturated 3-8 membered heterocyclyl divalent group optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, L is selected from an unsaturated 3-8 membered heterocyclyl divalent group optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, L is selected from saturated 3-8 membered heterocyclyl with 1 nitrogen atom, unsaturated 3-8 membered heterocyclyl with 1 nitrogen atom, optionally substituted with R, with 1 A saturated 3-8-membered heterocyclic group with 1 oxygen atom, an unsaturated 3-8-membered heterocyclic group with 1 oxygen atom, a saturated 3-8-membered heterocyclic group with 1 sulfur atom, a saturated 3-8-membered heterocyclic group with 1 sulfur atom Unsaturated 3-8 membered heterocyclic group, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 1 nitrogen atom and 1 oxygen 5-6 membered saturated heterocyclic group of atoms, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered saturated heterocyclic group with 2 oxygen atoms, 2 5-6 membered unsaturated heterocyclic group with oxygen atom, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated group with 1 nitrogen atom and 1 sulfur atom Heterocyclic group, divalent group of saturated 5-6 membered heterocyclic group having 1 oxygen atom and 1 sulfur atom.

In some embodiments, L is selected from a divalent group of 5-6 membered heteroaryl optionally substituted with R having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, L is selected from 4-6 membered heteroaryl with 1 nitrogen atom, 5-6 membered heteroaryl with 1 oxygen atom, optionally substituted with R, with 1 sulfur atom 5-6-membered heteroaryl group, 5-6-membered heteroaryl group with 2 nitrogen atoms, divalent group of 5-6-membered heteroaryl group with 3 nitrogen atoms.

In some embodiments, L is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[1.1.1]pentyl, optionally substituted with R, Bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, Bicyclo[3.3.1]nonyl, bicyclo[4.2.2]decyl, bicyclo[3.3.2]decyl, phenyl, epoxy, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2 ,5-dihydrofuranyl, furanyl, tetrahydropyranyl, pyrrolyl, 2,3-dihydropyrrolyl, 2,5-dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, tetrahydropyrazole base, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, pyridyl, piperidinyl, piperazinyl, pyrimidinyl, pyridazinyl, thienyl, thienyl, thiazolidine base divalent group.

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等。 In some embodiments, L is selected from a group optionally substituted with R:

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Wait.

In some embodiments, L is selected from a divalent group optionally substituted with R selected from cyclobutyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl.

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。 In some embodiments, L is selected from groups optionally substituted with R

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In some embodiments, R is selected from C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, halo C _1-4 alkyl, halo C _1-4 alkoxy, cyano C _1-4 alkyl, hydroxy C _1-4 alkyl, phenyl C _1-3 alkyl, 3-6 membered cycloalkyl, phenyl, phenyl C _1-3 Alkyl, halophenyl, cyanophenyl.

In some embodiments, R is selected from saturated 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from unsaturated 3-8 membered heterocyclyl groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from saturated 3-8 membered heterocyclyl having 1 nitrogen atom, unsaturated 3-8 membered heterocyclyl having 1 nitrogen atom, saturated 3-8 membered heterocyclyl having 1 oxygen atom Member heterocyclic group, unsaturated 3-8 membered heterocyclic group with 1 oxygen atom, saturated 3-8 membered heterocyclic group with 1 sulfur atom, unsaturated 3-8 membered heterocyclic group with 1 sulfur atom base, 4-8 membered saturated heterocyclic group with 2 nitrogen atoms, 4-8 membered unsaturated heterocyclic group with 2 nitrogen atoms, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom Ring group, 4-8-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 4-8-membered saturated heterocyclic group having 2 oxygen atoms, 4-8-membered non-saturated heterocyclic group having 2 oxygen atoms Saturated heterocyclic group, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 4-8 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen A saturated 4-8 membered heterocyclic group with 1 sulfur atom.

In some embodiments, R is selected from 4-6 membered saturated heterocyclyl having 1 nitrogen atom, 4-6 membered unsaturated heterocyclyl having 1 nitrogen atom, 4-6 membered having 1 oxygen atom Saturated heterocyclic group, 4-6 membered unsaturated heterocyclic group with 1 oxygen atom, 4-6 membered saturated heterocyclic group with 1 sulfur atom, 4-6 membered unsaturated heterocyclic group with 1 sulfur atom base, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom Ring group, 5-6-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 5-6-membered saturated heterocyclic group having 2 oxygen atoms, 5-6-membered non-saturated heterocyclic group having 2 oxygen atoms Saturated heterocyclic group, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen A saturated 5-6 membered heterocyclic group with 1 sulfur atom.

In some embodiments, R is selected from 5-6 membered heteroaryl groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from 4-6 membered heteroaryl with 1 nitrogen atom, 5-6 membered heteroaryl with 1 oxygen atom, 5-6 membered heteroaryl with 1 sulfur atom , 5-6-membered heteroaryl with 2 nitrogen atoms, 5-6-membered heteroaryl with 3 nitrogen atoms.

In some embodiments, R is selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, benzyl base, methylphenyl, ethylphenyl, furyl, pyranyl, pyrrolidinyl, pyridyl, piperidinyl, piperazinyl, pyrimidinyl, thienyl, trimethylsilyl, triethylsilane base, triisopropylsilyl, tertiary butyldimethylsilyl, tertiary butyldiphenylsilyl.

In some embodiments, R is selected from the group consisting of hydrogen, methyl, ethyl, tert-butyl, methoxy, ethoxy, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilane group, tertiary butyldiphenylsilyl group.

其中A、L、Z、R ³、R ⁴、R’和R和如上定義。 In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula II, or a pharmaceutically acceptable salt thereof,

wherein ^A , L, Z, ^R3 , R4, R' and R are as defined above.

其中A、L、R ¹、R ⁴、R’和R和如上定義。 In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula III, or a pharmaceutically acceptable salt thereof,

wherein ^A , L, R1, ^R4 , R' and R are as defined above.

其中A、L、Z、R ³、R’和R如上定義。 In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula II-A or a pharmaceutically acceptable salt thereof,

wherein A, L, Z, ^R3 , R' and R are as defined above.

其中A、L、R’和R如上定義。 In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula II-B, or a pharmaceutically acceptable salt thereof,

wherein A, L, R' and R are as defined above.

其中L、R ¹、R’和R如上定義。 In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula III-A, or a pharmaceutically acceptable salt thereof,

wherein L, R1, R ^' and R are as defined above.

其中R ¹、R’和R如上定義。 In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula III-A-1 to III-A-6 or a pharmaceutically acceptable salt thereof,

wherein R ¹ , R' and R are as defined above.

其中A、R ¹、R’和R如上定義。 In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula III-B or a pharmaceutically acceptable salt thereof,

wherein ^A , R1, R' and R are as defined above.

其中A、L和R ¹如上定義。 In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IV, or a pharmaceutically acceptable salt thereof,

wherein A, L and R ¹ are as defined above.

其中L和R ¹如上定義。 In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IV-A, or a pharmaceutically acceptable salt thereof,

wherein L and R ¹ are as defined above.

。 In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula IV-A-1 to IV-A-6 or a pharmaceutically acceptable salt thereof,

.

其中A和R ¹如上定義。 In some embodiments, a compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula IV-B or a pharmaceutically acceptable salt thereof,

wherein A and R ¹ are as defined above.

其中A和L如上定義。 In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula V, or a pharmaceutically acceptable salt thereof,

wherein A and L are as defined above.

其中L如上定義。 In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula VA or a pharmaceutically acceptable salt thereof,

wherein L is as defined above.

。 In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula VA-1 to VA-6 or a pharmaceutically acceptable salt thereof,

.

其中A如上定義。 In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula VB, or a pharmaceutically acceptable salt thereof,

wherein A is as defined above.

。 In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

.

In another aspect, the present application relates to pharmaceutical compositions comprising a compound of formula I of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present application further include pharmaceutically acceptable excipients.

In another aspect, the present application relates to a method of treating a disease mediated by acetyl-CoA carboxylase (ACC) in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of formula I or its A pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

In another aspect, the present application relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.

In another aspect, the present application relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.

In another aspect, the present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.

In some embodiments, acetyl-CoA carboxylase (ACC)-mediated diseases include, but are not limited to, insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease Steatohepatitis, lung cancer, pancreatic cancer.

The compound of the present invention can inhibit ACC1 enzyme and ACC2 enzyme with high activity, has good inhibitory effect on ACC-mediated diseases such as lung cancer and pancreatic cancer, has good metabolic stability in vivo and good pharmacokinetic absorption.

definition

Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered indeterminate or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are substituted, and oxo does not occur on an aromatic group.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the non-occurrence of said event or circumstance. For example, an ethyl group "optionally" substituted with halogen means that the ethyl group can be unsubstituted ( _{CH2CH3 )} , monosubstituted (eg CH2CH2F ₎ , polysubstituted (eg _CHFCH2F , _{CH 2} CHF ₂ etc.) or fully substituted (CF ₂ CF ₃ ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.

_Cmn in this context, is that the moiety has an integer number of carbon atoms in the given range. For example " _C1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a chemical bond.

When one of the variables is selected from a chemical bond, it means that the two groups connected to it are directly connected. For example, when L in A-L-Z represents a chemical bond, it means that the structure is actually A-Z.

或

表示其可在環己基或者環己二烯上的任意一個位置發生取代。 When a substituent's bond is cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring. For example, structural unit

or

Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "hydroxy" refers to the -OH group.

The term "cyano" refers to the -CN group.

The term "amine group" refers to the _-NH2 group.

The term "nitro" refers to the -NO ₂ group.

The term "alkyl" refers to a hydrocarbon group of the general formula _{CnH2n+1 .} The alkyl group can be straight or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing ₁ to ₆ carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moieties (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups have the same definitions above.

The term "silyl" refers to a silyl group substituted with an alkyl group, which may be straight or branched chain. For example, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, the silyl group can also be further substituted with phenyl, such as tert-butyldiphenylsilyl base.

The term "alkylene" refers to a straight-chain or straight-chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the remainder through two points of attachment. Non-limiting examples of this term include _-CH2- , -CH( _CH3 )-, _-CH2CH2- , -CH( _{CH2CH3 ) -} , -CH2CH( _{CH3 )} -, -CH ₂ CH ₂ CH ₂ -, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH(CH ₃ )CH ₂ CH ₂ - , -CH ₂ C(CH ₃ ) ₂ -.

The term "alkoxy" refers to -O-alkyl.

The term "alkylamino" refers to -NH-alkyl.

The term "dialkylamino" refers to -N(alkyl) ₂ .

The term "alkylsulfonyl" refers to _-SO2 -alkyl.

The term "alkylthio" refers to -S-alkyl.

The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C- _CH3 ), 2-propynyl ( _-CH2 -C≡CH), 1,3-Butadiynyl (-C≡CC≡CH) and the like.

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The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

The term "heterocyclyl" refers to fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic, eg, having 1 or 2 double bonds), and may exist as a monocyclic, bridged or spirocyclic ring non-aromatic ring. Unless otherwise indicated, the heterocycle is typically one containing 1, 2, 3 or 4 heteroatoms independently selected from sulfur S(O) _n (wherein n is 0, 1 or 2), oxygen and/or nitrogen ( 3, 4, 5, 6, 7, 8, 9, 10 membered rings with 1 or 2 heteroatoms) are preferred.

Examples of saturated 3-membered heterocyclyl groups include, but are not limited to, oxiranyl, oxiranyl, azithryl, and non-limiting examples of saturated 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, Examples of oxetanyl, thibutanyl, saturated 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl , thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of saturated 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazine base, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, saturated 7-membered heterocycle Examples of cyclic groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl.

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The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetralin, and the like.

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The term "treating" means administering a compound or formulation described herein to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) preventing the emergence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not been diagnosed with the disease state; (ii) inhibiting the disease or disease state, i.e. arresting its development; (iii) Alleviation of a disease or disease state, even if the disease or disease state resolves.

The term "therapeutically effective amount" means (i) treatment or prevention of a particular disease, condition or disorder, (ii) alleviation, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay herein The amount of the compound of the present application to be used for the onset of one or more symptoms of the particular disease, condition or disorder. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without excessive of toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.

As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids can be mentioned salt etc.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, ie, "including but not limited to".

The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogens. Valence tautomers include interconversions through recombination of some of the bonding electrons.

The present application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, ^3H , ^11C , ^13C , ^14C , ¹³ , ^respectively N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl and the like.

Certain isotopically-labeled compounds of the present application (eg, those labeled ^{with3H and14C} ) are useful in compound and/or matrix tissue distribution assays. Tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are especially preferred for their ease of preparation and detectability. Positron emitting isotopes such ^as15O , ^13N , ^{11C and18F} can be used in positron emission tomography (PET) studies to determine matrix occupancy. Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

In addition, substitution with heavier isotopes such as deuterium (ie 2H ⁾ may provide certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, where the deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

The compounds of the present application may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as paraphalangeal and non-oppolar isomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Exemplary stereoisomeric compounds are shown below, but are not limited thereto.

The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, Powder, granule, ointment, emulsion, suspension, suppository, injection, inhalation, gel, microsphere and aerosol, etc.

Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and equivalents known to those skilled in the art Alternatively, preferred embodiments include, but are not limited to, the examples of this application.

The chemical reactions of the specific embodiments of the present application are carried out in suitable solvents suitable for the chemical changes of the present application and the required reagents and materials. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.

1) 式A化合物、式B化合物與縮合劑反應，得到式C化合物；

2) 式C化合物發生環合反應，得到式D化合物；

3) 在溶劑的存在下，式D化合物與鹵代物反應，得到式E化合物；

4) 式E化合物與R ¹C≡CH反應，得到式F化合物；

5) 式F化合物與2-(2-甲氧基苯基)-2-((四氫-2H-吡喃-4-基)氧基)乙烷-1-醇反應，得到式G化合物；

6) 式G化合物可按照本領域的常規方法，脫去R ³基團，製備得到式IV化合物。 其中，A、L、R ¹、R ³和R如上定義，X為F、Cl、Br、I；C*為R構型、S構型或外消旋體。 In some embodiments, the compounds of general formula IV of the present application can be prepared by the following routes, including the following steps:

1) the compound of formula A, the compound of formula B react with a condensing agent to obtain the compound of formula C;

2) the compound of formula C undergoes cyclization reaction to obtain the compound of formula D;

3) in the presence of a solvent, the compound of formula D reacts with a halide to obtain a compound of formula E;

4) The compound of formula E is reacted with R ¹ C≡CH to obtain the compound of formula F;

5) The compound of formula F is reacted with 2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethane-1-ol to obtain the compound of formula G;

6) The compound of formula G can be prepared by removing the R ³ group according to conventional methods in the art to obtain the compound of formula IV. Wherein, A, L, R ¹ , R ³ and R are as defined above, X is F, Cl, Br, I; C* is R configuration, S configuration or racemate.

In some embodiments, X is Br.

In some embodiments, the compound of formula F in step 5) is combined with ( R )-2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl Alkan-1-ol reaction.

1) 式A化合物、式B化合物與縮合劑反應，得到式C化合物；

2) 式C化合物發生環合反應，得到式D化合物；

3) 式D化合物與式H化合物反應，在溶劑的存在下反應，得到式J化合物；

4) 式J化合物與鹵化物反應，得到式K化合物；

5) 式K化合物與R ¹C≡CH反應，得到式G化合物；

6) 式G化合物可按照本領域的常規方法，脫去R ³基團，製備得到式IV化合物。 其中，A、L、R ¹、R ³和R如上定義，X為F、Cl、Br、I；C*為R構型、S構型或外消旋體。 In some embodiments, the compound of general formula IV of the present application can also be prepared by the following route, including the following steps:

1) the compound of formula A, the compound of formula B react with a condensing agent to obtain the compound of formula C;

2) the compound of formula C undergoes cyclization reaction to obtain the compound of formula D;

3) the compound of formula D reacts with the compound of formula H, reacts in the presence of a solvent, and obtains the compound of formula J;

4) the compound of formula J is reacted with a halide to obtain the compound of formula K;

5) The compound of formula K is reacted with R ¹ C≡CH to obtain the compound of formula G;

6) The compound of formula G can be prepared by removing the R ³ group according to conventional methods in the art to obtain the compound of formula IV. Wherein, A, L, R ¹ , R ³ and R are as defined above, X is F, Cl, Br, I; C* is R configuration, S configuration or racemate.

In some embodiments, X is Br.

In some embodiments, the compound of formula H is ( R )-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro- 2H -pyran.

The following abbreviations are used in this application: Cbz stands for benzyloxycarbonyl; TMS stands for trimethylsilyl; TES stands for triethylsilyl; TIPS stands for triisopropylsilyl; TBS stands for tert-butyldimethylsilyl Silyl; TBDPS for tert-butyldiphenylsilyl; MS for mesyl; DCM for dichloromethane; PE for petroleum ether; DMF for N,N -dimethylformamide; EtOAc for ethyl acetate Ester; i-PrOH for isopropanol; EtOH for ethanol; MeOH for methanol; THF for tetrahydrofuran.

For the sake of clarity, the present invention is further illustrated by examples, which do not limit the scope of the application. All reagents used in this application were commercially available and used without further purification.

Example 1 : ( R )-3-(1-(2-(2 -methoxyphenyl )-2-(( tetrahydro - 2H - pyran- 4 -yl ) oxy ) ethyl )- 5 -Methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3- d ] pyrimidine -3( 2H )- base ) bicyclo [1.1.1] pentane - 1 - carboxylic acid (compound of formula I-1 )

step one: 3-((( benzyloxy ) carbonyl ) Amine ) double ring [1.1.1] Pentane -1- Synthesis of Methyl Carboxylate

Combine 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (22 g, 129 mmol), toluene (660 mL) and triethylamine (54.1 mL, 388 mmol), diphenyl Phosphine hydrazine (57.4 mL, 259 mmol) was mixed, heated under reflux for 3 hours, then benzyl alcohol (41.9 g, 388 mmol) was added, and the reflux reaction was continued for 4 hours. The reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethyl acetate (200 mL), washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 24.5 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.10 (s, 1H), 7.50-7.27 (m, 5H), 5.01 (s, 2H), 3.61 (s, 3H), 2.19 (s, 6H) ).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 169.87, 155.51, 137.37, 128.84, 128.31, 65.66, 54.05, 51.97, 45.86, 35.43.

MS (ESI) m/z: 276.4[M+H] ⁺ .

Step 2: 3- Amino bicyclic [1.1.1] Pentane -1- Synthesis of Carboxylic Acid Methyl Hydrochloride

Combine methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (24.5 g, 89 mmol), methanol (800 mL) and palladium on carbon (2.45 g, 23.02 mmol) were mixed, reacted at room temperature for 7 hours under a hydrogen atmosphere, filtered through celite, concentrated, the residue was dissolved in ethyl acetate (200 mL), and 4 M hydrochloric acid dioxane solution (22.25 mL, 89 mL) was added thereto. mmol), suction filtered to obtain 14.3 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 9.21 (s, 3H), 3.62 (s, 3H), 2.24 (s, 6H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 168.48, 53.18, 52.31, 43.68, 35.31.

Step 3: 2-(3-(3-( Methoxycarbonyl ) double ring [1.1.1] E -1- base ) Urea group )-4- methylthiophene -3- Synthesis of Ethyl Carboxylate

Ethyl 2-amino-4-methylthiophene-3-carboxylate (12 g, 64.8 mmol) was dissolved in dichloromethane (120 mL), to which was added N , N -carbonyldiimidazole ( 11.55 g, 71.3 mmol), react at room temperature for 12 hours, add triethylamine (9.93 mL, 71.3 mmol) and 3-aminobicyclo[1.1.1]pentane-1-carboxylate methyl ester hydrochloride (12.66 g, 71.3 mmol), and reacted at room temperature for 2 hours. Water (200 mL) was added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration, concentrated, the residue was slurried with petroleum ether (800 mL), and suction filtered to obtain 21.5 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 10.29 (s, 1H), 8.64 (s, 1H), 6.46 (s, 1H), 4.30 (q, J = 7.0 Hz, 2H), 3.63 ( s, 3H), 2.27 (s, 3H), 2.26 (s, 6H), 1.31 (t, J = 7.0 Hz, 3H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 169.81, 165.76, 153.29, 152.83, 133.93, 112.03, 109.57, 60.48, 54.22, 52.02, 45.79, 35.73, 18.22, 14.

MS (ESI) m/z: 351.1 [MH] ^- .

Step 4: 3-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) double ring [1.1.1] Pentane -1- Synthesis of Methyl Carboxylate

Ethyl 2-(3-(3-(methoxycarbonyl)bicyclo[1.1.1]pent-1-yl)ureido)-4-methylthiophene-3-carboxylate (21.5 g, 61.0 mmol) , cesium carbonate (39.8 g, 122 mmol) and N,N -dimethylformamide (300 mL) were mixed and reacted at 80 °C for 1 hour. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (500 mL) and ethyl acetate (500 mL) were added, the organic phase was washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. After suction filtration, concentrated, the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (100 mL, petroleum ether:ethyl acetate=10:1), and suction filtered to obtain 16 g of the title compound.

MS (ESI) m/z: 305.2 [MH] ^- .

Step 5: 3-(6- bromine -5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) double ring [1.1.1] Pentane -1- Synthesis of Methyl Carboxylate

At 0 °C, N -bromobutadiimide (9.47 g, 53.2 mmol) was added in three portions to 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[ 2,3] -d ]pyrimidin-3( 2H )-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (16.3 g, 53.2 mmol) in dichloromethane (380 mL), The reaction was carried out at 0°C for 30 minutes, the reaction solution was diluted with dichloromethane (200 mL), the organic phase was washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered with suction, concentrated, and the residue was mixed with petroleum ether and ethyl acetate The solvent (360 mL, petroleum ether:ethyl acetate=5:1) was slurried and filtered with suction to obtain 20.67 g of the title compound.

MS (ESI) m/z: 383.2 [MH] ^- .

Step 6: 3-(5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) double ring [1.1.1] Pentane -1- Synthesis of Methyl Carboxylate

3-(6-Bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)bicyclo[1.1. 1] Methyl pentane-1-carboxylate (0.5 g, 1.298 mmol), triethylamine (5.23 mL, 37.5 mmol), N,N -dimethylformamide (5 mL), bis(triphenyl) phosphine) palladium dichloride (0.046 g, 0.065 mmol), cuprous iodide (0.025 g, 0.130 mmol), propyne (1M tetrahydrofuran solution) (5.19 mL, 5.19 mmol) were added to a pressure-resistant tube, and the mixture was sealed at 80 °C The tube was reacted for 4 hours. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 0.147 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.05 (s, 1H), 3.64 (s, 3H), 2.62 (s, 6H), 2.36 (s, 3H), 2.11 (s, 3H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 169.25, 159.73, 150.48, 138.67, 112.70, 108.88, 94.56, 71.51, 56.01, 52.09, 48.04, 37.12, 15.15, 4.75.

MS (ESI) m/z: 343.2 [MH] ^- .

Step seven: 3-(5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) double ring [1.1.1] Pentane -1- Synthesis of Carboxylic Acids

3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3- d ]pyrimidine-3( 2H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (3.1 g, 9.00 mmol), methanol (30 mL), water (6 mL) were mixed, lithium hydroxide (1.889 mL) was added under ice bath g, 45.0 mmol), and reacted at room temperature for 1 hour. The pH of the reaction solution was adjusted to acidity with 1N hydrochloric acid solution, ethyl acetate (100 mL) was added, the organic phase was washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration to obtain 2.652 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.40 (brs, 2H), 2.57 (s, 6H), 2.35 (s, 3H), 2.10 (s, 3H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 170.58, 159.75, 150.40, 138.54, 112.68, 108.99, 94.46, 71.56, 55.80, 47.94, 37.43, 15.13, 4.76.

MS (ESI) m/z: 329.2 [MH] ^- .

Step 8: 3-(5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) double ring [1.1.1] Pentane -1- Synthesis of tert-butyldiphenylsilyl carboxylate

3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3- d ]pyrimidine-3( 2H )-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (1 g, 3.03 mmol), 1 H -imidazole (0.495 g, 7.26 mmol), N,N -dimethylformamide (30 mL), N,N -lutidine-4-amine (0.037 g, 0.303 mmol) and tert-butylchlorodiphenylsilane (0.998 g, 3.63 mmol) were mixed and reacted at room temperature for 4 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 1.19 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.12 (s, 1H), 7.66-7.64 (m, 2H), 7.63-7.62 (m, 2H), 7.52-7.48 (m, 2H), 7.47 -7.44 (m, 4H), 2.73 (s, 6H), 2.37 (s, 3H), 2.11 (s, 3H), 1.04 (s, 9H).

¹³ C-NMR (125 MHz, DMSO- D ₆ ): Δ 168.07, 159.74, 150.50, 150.35, 138.66, 135.11, 131.57, 130.76, 128.43, 112.75, 108.55, 71.50, 56.06, 38.53, 26.84, 19.13, 19.13, 19.13. , 15.13, 4.76.

MS (ESI) m/z: 567.4 [MH] ^- .

Step nine: ( R )-3-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) double ring [1.1.1] Pentane -1- tert-butyldiphenylsilyl carboxylate (formula I-9 compound) synthesis

3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3- d ]pyrimidine-3( 2H )-yl)bicyclo[1.1.1]pentane-1-carboxylic acid tert-butyldiphenylsilyl ester (0.6 g, 1.055 mmol), ( R )-2-(2-methoxybenzene yl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethane-1-ol (0.399 g, 1.582 mmol), tetrahydrofuran (6 mL), triphenylphosphine (0.830 g , 3.16 mmol) and diisopropyl azodicarboxylate (0.615 mL, 3.16 mmol) were mixed and reacted at room temperature for 12 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified with a C18 column (water:acetonitrile=1:20) to obtain 0.1 g of the compound of formula I-9.

MS (ESI) m/z: 803.7 [M+H] ⁺ .

Step ten: formula I-1 compound synthesis

The compound of formula I-9 (0.1 g, 0.097 mmol), tetrabutylammonium fluoride (1 mL, 1 mmol) and tetrahydrofuran (0.5 mL) were mixed and reacted at room temperature for 1 hour. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (dichloromethane:methanol=40:1) to obtain 0.025 g of the compound of formula I-1.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.53 (s, 1H), 7.47-7.43 (m, 1H), 7.32-7.27 (m, 1H), 7.04-6.99 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.25-5.23 (m, 1H), 4.01-3.83 (m, 2H), 3.74 (s, 3H), 3.62-3.56 (m, 1H), 3.54-3.49 (m , 1H), 3.40-3.35 (m, 1H), 3.30-3.27 (m, 1H), 3.26-3.23 (m, 1H), 2.59 (s, 6H), 2.38 (s, 3H), 2.12 (s, 3H) ), 1.68-1.61 (m, 2H), 1.37-1.31 (m, 1H), 1.23-1.16 (m, 1H).

MS (ESI) m/z: 563.6 [MH] ^- .

Example 2 : ( 1R , 3R )-3-(1-((R ) -2-(2 -methoxyphenyl )-2-(( tetrahydro - 2H - pyran- 4 -yl ) oxy ) ethyl )-5- methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H ) -yl ) cyclobutane- 1 - carboxylic acid (compound of formula 1-2 )

step one: ( 1S , 3S )-3- Hydroxycyclobutane -1- Synthesis of tert-butyl carboxylate

3-Oxocyclobutane-1-carboxylate 3-butyl ester (45 g, 264 mmol), tetrahydrofuran (432 mL) and methanol (54 mL) were mixed, and sodium borohydride ( 5.00 g, 132 mmol), kept at 0 °C for 1 hour. 20% potassium carbonate solution (500 mL) and ethyl acetate (500 mL) were added to the reaction solution, the organic phase was washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration to obtain 44.96 g of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 4.16-4.08 (m, 1H), 2.83 (s, 1H), 2.57-2.43 (m, 3H), 2.13-2.02 (m, 2H), 1.41 (s , 9H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 174.42, 80.42, 63.16, 36.86, 30.04, 28.02.

MS(EI) m/z: 172[M] ⁺ .

Step 2: ((1 R , 3 R )-3-(1,3- Dioxisoindoline -2- base ) Cyclobutane -1- Synthesis of tert-butyl carboxylate

Combine ( 1S ,3S)-3-hydroxycyclobutane-1-carboxylic acid tert-butyl ester (25 g, 145 mmol), isoindoline-1,3-dione (25.6 g, 174 mmol) , triphenylphosphine (57.1 g, 218 mmol) and tetrahydrofuran (600 mL) were mixed, and diisopropyl azodicarboxylate (45.4 g, 218 mmol) was added dropwise thereto at 0 °C, and the reaction was carried out at room temperature for 18 hours. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=20:1) to obtain 29.2 g of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.85-7.80 (m, 2H), 7.74-7.69 (m, 2H), 5.06-4.98 (m, 1H), 3.22-3.16 (m, 1H), 3.14 -3.06 (m, 2H), 2.61-2.54 (m, 2H), 1.50 (s, 9H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 174.86, 168.25, 133.97, 131.89, 123.15, 80.44, 42.62, 33.75, 30.31, 28.08.

MS (ESI) m/z: 302.3[M+H] ⁺ .

Step 3: (1 R , 3 R )-3- Aminocyclobutane -1- Synthesis of tert-butyl carboxylate hydrochloride

(( 1R , 3R )-3-(1,3-dioxoisoindolin-2-yl)cyclobutane-1-carboxylate tert-butyl ester (30 g, 100 mmol), ethanol (400 mL) and hydrazine hydrate (17.59 g, 299 mmol) were mixed and reacted at room temperature for 12 hours. Filtration, concentration, the residue was dissolved in ethyl acetate (500 mL), to which was added a 4 M hydrochloric acid dioxane solution (25.00 mL, 100 mmol), suction filtered to obtain 17.69 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.53 (s, 3H), 3.75-3.64 (m, 1H), 3.19-3.12 (m, 1H), 2.40-2.35 (m, 4H), 1.41 (s, 9H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 174.02, 80.52, 43.54, 34.05, 29.87, 28.12.

Step 4: 2-(3-(((1 R , 3 R )-3-( tertiary butoxycarbonyl ) cyclobutyl ) Urea group )-4- methylthiophene -3- Synthesis of Ethyl Carboxylate

Ethyl 2-amino-4-methylthiophene-3-carboxylate (14 g, 76 mmol) was dissolved in dichloromethane (140 mL), and N,N -carbonyldiimidazole ( 13.76 g, 83 mmol), the reaction was carried out at room temperature for 12 hours, and triethylamine (1.59 mL, 83 mmol) and (1 R , 3 R )-3-aminocyclobutane-1-carboxylic acid were successively added thereto. Butyl ester hydrochloride (17.27 g, 83 mmol) was reacted at room temperature for 2 hours. Water (200 mL) was added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration, concentrated, the residue was slurried with petroleum ether (800 mL), and suction filtered to obtain 27.85 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 10.31 (s, 1H), 8.23 (s, 1H), 6.43 (s, 1H), 4.34-4.19 (m, 3H), 2.94-2.85 (m , 1H), 2.44-2.37 (m, 2H), 2.27 (s, 3H), 2.19-2.10 (m, 2H), 1.43 (s, 9H), 1.32 (t, J = 7.0 Hz, 3H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 174.77, 165.91, 153.47, 152.99, 133.83, 111.81, 109.18, 80.18, 60.44, 43.57, 33.58, 33.21, 28.15, 18.

MS (ESI) m/z: 383.4[M+H] ⁺ .

Step 5: (1 R , 3 R )-3-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H ) - base ) Cyclobutane -1- Synthesis of tert-butyl carboxylate

Ethyl 2-(3-(( 1R , 3R )-3-(tert-butoxycarbonyl)cyclobutyl)ureido)-4-methylthiophene-3-carboxylate (19.85 g, 51.9 mmol), cesium carbonate (33.8 g, 104 mmol) and N,N -dimethylformamide (240 mL) were mixed, and the mixture was reacted at 100° C. for 1 hour. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (500 mL) and ethyl acetate (500 mL) were added, the organic phase was washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. After suction filtration, concentrated, the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (100 mL, petroleum ether:ethyl acetate=10:1), and suction filtered to obtain 16.21 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.06 (s, 1H), 6.65 (s, 1H), 5.50-5.41 (m, 1H), 3.32-3.00 (m, 3H), 2.51-2.29 (m, 5H), 1.44 (s, 9H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 175.12, 159.93, 151.91, 150.87, 134.66, 113.34, 111.89, 80.15, 44.30, 33.39, 29.92, 28.18, 16.27.

Step 6: (1 R , 3 R )-3-(6- bromine -5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H ) - base ) Cyclobutane -1- Synthesis of tert-butyl carboxylate

At 0 °C, N -bromobutadiimide (8.58 g, 48.2 mmol) was added in three portions to ( 1R , 3R )-3-(5-methyl-2,4-dioxo- 1,4-Dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)cyclobutane-1-carboxylic acid tert-butyl ester (16.21 g, 48.2 mmol) in dichloromethane (350 mL) solution, react at 0 °C for 30 minutes, the reaction solution was diluted with dichloromethane (200 mL), the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated, and the residue was washed with petroleum ether and A mixed solvent of ethyl acetate (150 mL, petroleum ether:ethyl acetate=5:1) was slurried, and suction filtered to obtain 21 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.06 (s, 1H), 5.47-5.38 (m, 1H), 3.12-3.00 (m, 3H), 2.38-2.27 (m, 5H), 1.44 (s, 9H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 179.82, 159.05, 151.19, 150.32, 134.23, 112.84, 99.95, 80.20, 44.56, 33.42, 29.99, 28.18, 14.92.

Step seven: (1 R , 3 R )-3-(6- bromine -5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H ) - base ) Cyclobutane -1- Synthesis of Carboxylic Acids

Trifluoroacetic acid (45 ml, 584 mmol) was slowly added to ( 1R , 3R )-3-(6-bromo-5-methyl-2,4-dioxo-1,4- at 0°C A solution of tert-butyl dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)cyclobutane-1-carboxylate (18 g, 43.3 mmol) in dichloromethane (225 mL) , the mixture was reacted at room temperature for 12 hours. The reaction solution was poured into ice water (1500 mL) and filtered with suction to obtain 13.5 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.06 (s, 1H), 5.49-5.39 (m, 1H), 3.12-3.02 (m, 3H), 2.41-2.33 (m, 2H), 2.28 (s, 3H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 177.28, 159.01, 151.14, 150.31, 134.19, 112.78, 99.93, 44.58, 32.39, 29.96, 14.89.

MS (ESI) m/z: 357.1 [MH] ^- .

Step 8: (1 R ,3 R )-3-(6- bromine -5- methyl -twenty four- Dioxygen -1,4- dihydrothieno [2,3- d ] Pyrimidine -3-( 2H )- base ) Cyclobutane -1- Synthesis of methyl formate

(1 R , 3 R )-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidine-3-( 2H )-yl)cyclobutane-1-carboxylic acid (5.0 g, 13.92 mmol) and dichloromethane (50 mL) were mixed, to which was added N,N -carbonyldiimidazole (2.7 g, 16.70 mmol) in portions at 0°C, After the addition was completed, the reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added to the residue, stirred for 30 minutes, suction filtered, the filter cake was washed with water, and dried to obtain 4.1 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.18 (s, 1H), 5.45 (m, 1H), 3.66 (s, 3H), 3.18 (m, 1H), 3.11 (m, 2H), 2.40 (m, 2H), 2.30 (s, 3H).

MS (ESI) m/z: 373.1 [M+H] ⁺ .

Step nine: (1 R ,3 R )-3-(5- methyl -twenty four- Dioxygen -6-( C -1- Alkyne -1- base )-1, 4- dihydrothieno [2, 3- d ] Pyrimidine -3-( 2H )- base ) Cyclobutane -1- Synthesis of methyl formate

(1 R , 3 R )-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidine-3-( 2H )-yl)cyclobutane-1-carboxylic acid methyl ester (4.0 g, 10.72 mmol), triethylamine (43.2 ml, 310 mmol), N,N -dimethylformamide (50 mL), bis(triethylamine) Phenylphosphine) palladium dichloride (0.38 g, 0.536 mmol), cuprous iodide (0.21 g, 1.072 mmol), propyne (1M tetrahydrofuran solution) (21.84 mL, 21.84 mmol) were added to a pressure-resistant tube, the mixture was 80 The tube was sealed and reacted for 6 hours. The reaction solution was cooled to room temperature, poured into water (300 mL), extracted with ethyl acetate (3×100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to the crude product obtained It was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain 870 mg of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.13 (s, 1H), 5.44 (m, 1H), 3.66 (s, 3H), 3.18 (m, 1H), 3.10 (m, 2H), 2.40 (m, 2H), 2.37 (s, 3H), 2.11 (s, 3H).

MS (ESI) m/z: 331.3 [MH] ^- .

Step ten: (1 R ,3 R )-3-(5- methyl -2,4- Dioxygen -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3-( 2H )- base ) Cyclobutane -1- Synthesis of Formic Acid

(1 R , 3 R )-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3 - d ]pyrimidin-3-( 2H )-yl)cyclobutane-1-carboxylic acid methyl ester (0.80 g, 2.407 mmol), tetrahydrofuran (10 mL), water (10 mL) and lithium hydroxide monohydrate (0.12 g, 4.81 mmol) were mixed and reacted at room temperature for 10 minutes. The pH value of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid solution, ethyl acetate (40 mL) was added to the reaction solution for extraction, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated, The residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (15 mL, petroleum ether:ethyl acetate=1:1) to obtain 0.73 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.18 (br, 2H), 5.62-5.18 (m, 1H), 3.19-2.92 (m, 3H), 2.44-2.25 (m, 5H), 2.11 (s, 3H).

MS (ESI) m/z: 317.3 [MH] ^- .

Step eleven: (1 R ,3 R )-3-(5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2, 3- d ] Pyrimidine -3-( 2H )- base ) Cyclobutane -1- Synthesis of tert-butyldiphenylsilyl carboxylate

(1 R ,3 R )-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3 - d ]pyrimidin-3-( 2H )-yl)cyclobutane-1-carboxylic acid (0.68 g, 2.136 mmol), imidazole (0.18 g, 2.56 mmol), tetrahydrofuran (10 mL), tert-butyldiphenyl Chlorosilane (0.71 g, 0.658 ml, 2.56 mmol) was mixed and reacted at room temperature for 4 hours. The reaction solution was suction filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1) to obtain 0.9 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.16 (s, 1H), 7.84-7.60 (m, 4H), 7.57-7.41 (m, 6H), 5.55 (m, 1H), 3.45-3.35 (m, 1H), 3.20 (m, 2H), 2.56-2.51 (m, 2H), 2.39 (s, 3H), 2.11 (s, 3H), 1.06 (s, 9H).

Step 12: Formula I-2 compound synthesis

(1 R , 3 R )-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2, 3- d ]pyrimidin-3-( 2H )-yl)cyclobutane-1-carboxylic acid tert-butyldiphenylsilyl ester (0.83 g, 1.491 mmol), ( R )-2-(2- Methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethane-1-ol (0.38 g, 1.491 mmol), tetrahydrofuran (2.5 mL) and triphenyl Phosphine (1.17g, 4.47 mmol) was mixed, nitrogen was replaced three times, the ice-salt bath was cooled to below 0 ° C, diisopropyl azodicarboxylate (0.91 g, 4.47 mmol) was added dropwise to the reaction, and the reaction was completed at room temperature for 5 Hour. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the residue was separated by a Biotage C18 120 g reverse phase chromatography column Purification (water:acetonitrile=1:1) gave 70 mg of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 12.27 (s, 1H), 7.46 (dd, J = 7.5, 1.4 Hz, 1H), 7.34-7.25 (m, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.97-6.96 (m, 1H), 5.59-5.44 (m, 1H), 5.30-5.25 (m, 1H), 4.05-3.96 (m, 2H), 3.73 (s, 3H), 3.63-3.55 (m, 1H), 3.54-3.48 (m, 1H), 3.38 (m, 2H), 3.30-3.15 (m, 3H), 3.14-2.98 (m, 3H), 2.45-2.33 (m, 5H) ), 2.12 (s, 3H), 1.64 (m, 2H).

MS (ESI) m/z: 551.5 [MH] ^- .

Example 3 : ( R )-4-(1-(2-(2 -methoxyphenyl )-2-(( tetrahydro - 2H - pyran- 4 -yl ) oxy ) ethyl )- 5 -Methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3- d ] pyrimidine -3( 2H )- base ) benzoic acid (compound of formula I-3 )

step one: 2-(3-(4-( Ethoxycarbonyl ) phenyl ) Urea group )-4- methylthiophene -3- Synthesis of Ethyl Carboxylate

Ethyl 2-amino-4-methylthiophene-3-carboxylate (10 g, 54 mmol) was dissolved in dichloromethane (70 mL), cooled in an ice-water bath, and N , N -carbonyldiimidazole was slowly added in portions (9.63 g, 59.4 mmol), after the addition was completed, the ice bath was removed, and the reaction was carried out at room temperature overnight. Triethylamine (8.25 ml, 59.4 mmol) and ethyl 4-aminobenzoate (9.81 g, 59.4 mmol) were sequentially added to the reaction solution, and the reaction was carried out at room temperature overnight. Water (100 mL) was added to the reaction solution, and a solid was precipitated, which was filtered off with suction, and the filter cake was dried to obtain 5.7 g of the title compound. The organic phase of the obtained filtrate was separated, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to obtain 3.8 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 10.77 (s, 1H), 10.63 (s, 1H), 7.92 (d, J =8.5Hz, 2H), 7.64 (d, J =8.5Hz, 2H), 6.58 (s, 1H), 4.35-4.27 (m, 4H), 2.31 (s, 3H), 1.36-1.30 (m, 6H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 165.92, 165.83, 152.08, 151.37, 144.12, 134.16, 130.87, 123.93, 118.05, 112.82, 110.60, 60.83, .64.70.70

MS (ESI) m/z: 377.3 [M+H] ⁺ .

Step 2: 4-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of Ethyl Benzoate

Combine 2-(3-(4-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylate (7.5 g, 19.92 mmol) with N,N -dimethylmethane amide (75 mL) was mixed, and under nitrogen protection, sodium hydride (1.20 g, 29.9 mmol) was added in three batches, and the mixture was heated to 100° C. to react for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (225 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 3.6 g of the title compound.

MS (ESI) m/z: 329.2 [MH] ^- .

Step 3: ( R )-4-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of Ethyl Benzoate

Ethyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoate (3.0 g, 9.08 mmol), cesium carbonate (4.14 g, 12.71 mmol), ( R )-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro- 2H -pyran (4.01 g, 12.71 mmol) and N -methylpyrrolidone (30 mL) were mixed, heated to 100 °C and reacted for 20 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL×2), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, After concentration, it was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 2.1 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.09 (d, J =8.5Hz, 2H), 7.47 (d, J =7.0Hz, 1H), 7.40 (d, J =8.0Hz, 2H) , 7.32 (t, J =7.5Hz, 1H), 7.05-7.00 (m, 2H), 6.89 (s, 1H), 5.33 (s, 1H), 4.37 (q, J =7.0Hz, 2H), 4.09- 4.01 (m, 2H), 3.78 (s, 3H), 3.58-3.56 (m, 2H), 3.39 (s, 1H), 3.30-3.28 (m, 2H), 2.37 (s, 3H), 1.65 (s, 2H), 1.38-1.35 (m, 4H), 1.25 (s, 1H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 165.71, 158.66, 157.08, 156.11, 150.29, 140.80, 135.28, 130.32, 130.26, 130.03, 129.73, 127.69, 127.05, 121.28, 113.66, 113.20, 111.45, 71.91 , 69.61, 64.59, 64.29, 61.45, 55.98, 53.45, 33.31, 31.41, 16.45, 14.64.

MS (ESI) m/z: 565.4 [M+H] ⁺ .

Step 4: ( R )-4-(6- bromine -1-(2-(2- methoxyphenyl )-2 -(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of Ethyl Benzoate

( R )-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl Ethyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoate (1.5 g, 2.66 mmol) and dichloromethane (15 mL), mixed, cooled in an ice-water bath, added bromosuccinimide (0.52 g, 2.92 mmol), and reacted at 0°C for 1 hour. The reaction solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=9:1) to obtain 1.45 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.10 (d, J =8.0Hz, 2H), 7.48 (d, J =7.0Hz, 1H), 7.41 (d, J =8.0Hz, 2H) , 7.33 (t, J =7.0Hz, 1H), 7.06-7.00 (m, 2H), 5.27 (s, 1H), 4.37 (q, J =7.0Hz, 2H), 4.10-4.07 (m, 1H), 3.92 (s, 1H), 3.77 (s, 3H), 3.61-3.60 (m, 2H), 3.41 (s, 1H), 3.29-3.27 (m, 2H), 2.34 (s, 3H), 1.68 (t, J =14.5Hz, 2H), 1.36 (t, J =7.0Hz, 3H), 1.35-1.25 (m, 2H).

MS (ESI) m/z: 643.5 [M+H] ⁺ .

Step 5: ( R )-4-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Ethyl benzoate (formula I-10 compound) synthesis

( R )-4-(6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoic acid ethyl ester (750 mg, 1.165 mmol) , bistriphenylphosphine palladium dichloride (82 mg, 0.117 mmol), cuprous iodide (44.4 mg, 0.233 mmol) and N,N -dimethylformamide (7.5 mL) were mixed. After purging with nitrogen, triethylamine (0.487 mL, 3.50 mmol) and propyne (1M tetrahydrofuran solution) (2.91 mL, 2.91 mmol) were added, and the reaction was carried out at 80° C. for 10 hours. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and washed with silica gel Purification by column chromatography (petroleum ether:ethyl acetate=10:1) gave 456 mg of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.10 (d, J =8.0Hz, 2H), 7.48-7.40 (m, 3H), 7.32 (t, J =7.0Hz, 1H), 7.06- 7.00 (m, 2H), 5.29 (s, 1H), 4.37 (q, J =7.0Hz, 2H), 4.10-4.07 (m, 1H), 3.95-3.91 (m, 1H), 3.76 (s, 3H) , 3.60 (s, 2H), 3.41 (s, 1H), 3.30-3.27 (m, 2H), 2.40 (s, 3H), 2.15 (s, 3H), 1.69-1.65 (m, 2H), 1.36 (t , J =7.0Hz, 3H), 1.35-1.25 (m, 2H).

MS (ESI) m/z: 603.5 [M+H] ⁺ .

Step 6: I-3 compound synthesis

( R )-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl yl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzene Methyl formate (400 mg, 0.664 mmol) was mixed with methanol (1.5 mL), tetrahydrofuran (1 mL), and an aqueous solution (0.5 mL) of lithium hydroxide hydrate (278 mg, 6.64 mmol), and reacted at room temperature for 5 hours. 2N dilute hydrochloric acid was added under ice bath to adjust pH to 5-6, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was separated and extracted with ethyl acetate (10 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 75 mg of compound I-3.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.25 (d, J =8.0Hz, 2H), 7.57 (d, J =7.0Hz, 1H), 7.36-7.32 (m, 3H), 7.06 (t, J =7.5Hz, 1H), 6.89 (d, J =8.5Hz, 1H), 5.46 (dd, J ₁ =8.5Hz, J ₂ =4.5Hz, 1H), 4.25-4.23 (m, 1H), 4.05- 4.02 (m, 1H), 3.85 (s, 3H), 3.81-3.77 (m, 2H), 3.51-3.47 (m, 1H), 3.43-3.39 (m, 2H), 2.54 (s, 3H), 2.17 ( s, 3H), 1.83-1.77 (m, 2H), 1.63-1.57 (m, 1H), 1.51-1.45 (m, 1H).

¹³ C-NMR (125 MHz, CDCL ₃ ): Δ 169.82, 158.38, 156.95, 154.21, 150.29, 140.17, 140.00, 131.38, 129.70, 129.00, 127.07, 120.99, 110.96, 94.03, 72.35, 110.96, 110.96, 110.96, 94.03, 72.03, 72.03, 72.03, 72.03, 72.03, 72.03, 72.03, 72.03, 72.03, 72.03, 72.03, 94.03, 72.03, 94.03, 72.03, 94.03, 72.035. , 70.87, 69.70, 65.34, 65.02, 55.45, 53.85, 33.19, 31.38, 15.06, 4.84.

MS (ESI) m/z: 575.3 [M+H] ⁺ .

Example 4 : ( R )-3-(1-(2-(2 -methoxyphenyl )-2-(( tetrahydro - 2H - pyran- 4 -yl ) oxy ) ethyl )- 5 -Methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3- d ] pyrimidine -3( 2H )- base ) benzoic acid (compound of formula I-4 )

step one: 2-(3-(3-( Ethoxycarbonyl ) phenyl ) Urea group )-4- methylthiophene -3- Synthesis of Ethyl Carboxylate

Ethyl 2-amino-4-methylthiophene-3-carboxylate (15 g, 81 mmol) was mixed with dichloromethane (140 mL), cooled in an ice-water bath, and carbonyldiimidazole (14.44 g, 89 mmol), removed the ice bath after the addition, and reacted at room temperature overnight. Triethylamine (12.42 mL, 89 mmol) and ethyl 3-aminobenzoate (14.71 g, 89 mmol) were sequentially added to the reaction solution, and the reaction was carried out at room temperature overnight. Water (100 mL) was added to the reaction solution, extracted with dichloromethane (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (dichloromethane) to obtain The title compound 4.3 g.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 10.72 (s, 1H), 10.50 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.55 (s, 1H), 4.33 (q, J = 7.2 Hz, 4H), 2.30 (s, 3H), 1.34 (td, J = 7.2, 3.5 Hz, 6H).

¹³ C-NMR (125 MHz, DMSO- D ₆ ): Δ 166.04, 165.94, 152.32, 151.53, 140.01, 134.10, 130.99, 129.78, 123.55, 119.08, 112.61, 110.27, 60.65, 18.65, 14.65, 14.65, .

MS (ESI) m/z: 377.4 [M+H] ⁺ .

Step 2: 3-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of Ethyl Benzoate

Combine ethyl 2-(3-(3-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylate (4 g, 10.63 mmol) with N,N -dimethylmethane amide (40 mL) was mixed, cooled in an ice-water bath, and under nitrogen purge, sodium hydride (0.638 g, 15.94 mmol) was added in three batches, and the mixture was heated to 100 °C for 1 h. After cooling to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 2.3 g of the title compound.

MS (ESI) m/z: 329.2 [MH] ^- .

Step 3: ( R )-3-(1-(2-(2- methoxyphenyl )-2 -(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of Ethyl Benzoate

Ethyl 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoate (2.3 g, 3.48 mmol), cesium carbonate (1.361 g, 4.18 mmol), ( R )-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro- 2H -pyran (1.207 g, 3.83 mmol) was mixed with N -methylpyrrolidone (20 mL), heated to 100 °C under nitrogen protection, and reacted overnight. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, the aqueous phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 550 mg of the title compound.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 8.04 (d, J = 7.9 Hz, 1H), 7.81 (s, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.08-6.98 (m, 2H), 6.89 (s, 1H), 5.34 (t , J = 6.7 Hz, 1H), 4.36 (q, J = 7.4 Hz, 2H), 4.12-3.93 (m, 2H), 3.83 (s, 1H), 3.79 (s, 3H), 3.66-3.53 (m, 2H), 3.44-3.35 (m, 2H), 3.30 (d, J = 8.8 Hz, 2H), 2.37 (s, 3H), 1.75-1.61 (m, 2H), 1.36-1.32 (m, 3H).

MS (ESI) m/z: 565.3 [M+H] ⁺ .

Step 4: ( R )-3-(6- bromine -1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H- Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of Ethyl Benzoate

( R )-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl Ethyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoate (0.53 g, 0.939 mmol) and dichloromethane (5 mL), mixed, cooled in an ice-water bath, added bromosuccinimide (0.184 g, 1.032 mmol), and reacted at 0 ^o C for 3 hours. The reaction solution was washed successively with water and saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 475 mg of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 8.05 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.51-7.45 (m, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.08-6.97 (m, 2H), 5.29 (dd, J = 8.5, 4.6 Hz, 1H ), 4.35 (q, J = 7.2 Hz, 2H), 4.08 (d, J = 13.3 Hz, 1H), 3.93 (s, 1H), 3.83 (s, 1H), 3.78 (s, 3H), 3.62 (dd , J = 11.9, 5.8 Hz, 2H), 3.52-3.38 (m, 2H), 3.32-3.24 (m, 2H), 2.34 (s, 3H), 1.76-1.60 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H).

MS (ESI) m/z: 643.4 [M+H] ⁺ .

Step 5: ( R )-3-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Ethyl benzoate (formula I-11 compound) synthesis

( R )-3-(6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoic acid ethyl ester (213 mg, 0.331 mmol) , bistriphenylphosphine palladium dichloride (23.23 mg, 0.033 mmol), cuprous iodide (12.61 mg, 0.066 mmol) and N,N -dimethylformamide (3 mL) were mixed. After purging with nitrogen, triethylamine (0.138 ml, 0.993 mmol), propyne (1M tetrahydrofuran solution) (0.824 mL, 0.824 mmol) were added, and the reaction was carried out overnight at 80° C. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and washed with silica gel Purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 77 mg of the compound of formula I-11.

MS (ESI) m/z: 603.4 [M+H] ⁺ .

Step 6: Formula I-4 compound synthesis

The compound of formula I-11 (77 mg, 0.128 mmol), methanol (6 mL), tetrahydrofuran (2 mL) and lithium hydroxide hydrate (107 mg, 2.56 mmol) in water (2 mL) were mixed and reacted at room temperature for 1 Hour. 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:2) to obtain 44 mg of compound of formula I-4 .

¹ H NMR (500 MHz, DMSO- d ₆ ): 13.22 (br, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H) , 7.49 (t, J = 7.9 Hz, 2H), 7.32 (t, J = 7.8 Hz, 1H), 7.10 – 6.94 (m, 2H), 5.30 (dd, J = 8.5, 4.9 Hz, 1H), 4.08 ( s, 1H), 3.93 (s, 1H), 3.77 (s, 3H), 3.60 (dt, J = 10.8, 5.7 Hz, 2H), 3.47 – 3.39 (m, 3H), 2.40 (s, 3H), 2.15 (s, 3H), 1.68 (t, J = 15.8 Hz, 2H), 1.41–1.32 (m, 1H), 1.28 (s, 1H).

MS (ESI) m/z: 573.4 [MH] ^- .

Example 5 : ( R )-4-(1-(2-(2 -methoxyphenyl )-2-(( tetrahydro - 2H - pyran- 4 -yl ) oxy ) ethyl )- 5 -Methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3- d ] pyrimidine -3( 2H )- base ) pyridine -2- carboxylic acid (compound of formula 1-5 )

step one: 4- methyl -2-(( Phenoxycarbonyl ) Amine ) Thiophene -3- Synthesis of Ethyl Carboxylate

Ethyl 2-amino-4-methylthiophene-3-carboxylate (60.2 g, 325 mmol) was mixed with ethyl acetate (500 mL), saturated aqueous sodium bicarbonate (500 mL), to which was added chloroformic acid Phenyl ester (61.1 g, 390 mmol) was reacted at room temperature for 17 h. Ethyl acetate (1 L) was added to the reaction solution until the solid was completely dissolved, the aqueous phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was slurried with petroleum ether, filtered with suction, and the filter cake was dried to obtain 88.3 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 10.74(s, 1H), 7.45-7.48(m, 2H), 7.29-7.33(m, 3H), 6.74(s, 1H), 4.33(q , J = 7.0 Hz, 2H), 2.32(s, 3H), 1.34(t, J = 7.0Hz, 3H).

¹³ C-NMR (125 MHz, DMSO- d ₆ ): δ 165.6, 151.3, 150.6, 150.2, 135.1, 130.1, 126.6, 122.1, 113.7, 61.2, 17.9, 14.5.

MS (ESI) m/z: 327.9 [M+Na] ⁺ .

Step 2: 4-(3-(3-( Ethoxycarbonyl )-4- methylthiophene -2- base ) Urea group ) Pyridine -2- Synthesis of methyl formate

4-Aminopyridine-2-carboxylic acid methyl ester (10 g, 65.7 mmol), 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (24.08 g, 79 mmol), triethylamine (12.83 ml, 92 mmol) and toluene (100 mL) were mixed, and the mixture was heated to 110° C. to react for 5 hours. The reaction solution was cooled to room temperature, filtered with suction, the filter cake was slurried with petroleum ether and ethyl acetate, filtered with suction, and the filter cake was dried to obtain 17.6 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 10.93 (s, 1H), 10.85 (s, 1H), 8.52 (d, J =5.5Hz, 1H), 8.23 (s, 1H), 7.63 ( d, J =5.0Hz, 1H), 6.62 (s, 1H), 4.33 (q, J =7.0Hz, 2H), 3.89 (s, 3H), 2.31 (s, 3H), 1.35 (t, J =7.0 Hz, 3H).

¹³ C-NMR (125 MHz, DMSO- D ₆ ): Δ 165.94, 165.74, 151.53, 151.27, 150.97, 148.80, 147.56, 134.27, 115.55, 113.96, 111.07, 60.81, 52.88, 18.54.

MS (ESI) m/z: 364.4 [M+H] ⁺ .

Step 3: 4-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- methyl formate /4-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3-d] Pyrimidine -3( 2H )- base ) Pyridine -2- Synthesis of Ethyl Formate

Methyl 4-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate (9 g, 24.77 mmol) was mixed with N,N -dimethyl Formamide (140 mL) was mixed, sodium hydride (1.19 g, 29.7 mmol) was added in three batches under nitrogen protection, and the mixture was heated to 60° C. to react for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (420 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 4.1 g of the title compound (a mixture of methyl ester and ethyl ester, the ratio of the two being 3:2).

MS (ESI) m/z: 316.1 [MH] ^- (methyl ester), 330.2 [MH] ^- (ethyl ester).

Step 4: ( R )-4-(1-(2-(2- methoxyphenyl )-2-(( Tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- methyl formate /( R )-4-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Synthesis of Ethyl Formate

Methyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylate was mixed with 4-(5-Methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylic acid ethyl ester mixture ( 3 g), ( R )-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro- 2H -pyran (4.17 g, 13.24 mmol), cesium carbonate (4.31 g, 13.24 mmol) was mixed with N -methylpyrrolidone (30 ml), and the mixture was heated to 100 °C for 7 hours. Suction filtration, the filter cake was washed with ethyl acetate, water (100 mL) was added to the filtrate, the aqueous phase was separated, extracted with ethyl acetate (100 ml×3), the organic phases were combined and washed with water and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 2.7 g of the title compound (ratio of methyl ester to ethyl ester: 1:1).

MS (ESI) m/z: 552.4 [M+H] ⁺ (methyl ester), 566.4 [M+H] ⁺ (ethyl ester).

Step 5: ( R )-4-(6- bromine -1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- methyl formate /( R )-4-(6- bromine -1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Synthesis of methyl formate

( R )-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl ( R )-4-((R) -4- ( 1-(2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo -1,4-Dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester mixture (2.7 g) was mixed with dichloromethane (30 mL), cooled in an ice-water bath , bromosuccinimide (0.871 g, 4.89 mmol) was added, and the reaction was carried out at 0 °C for 1 hour. The reaction solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, dissolved in acetonitrile after concentration, and purified with a Biotage C18 120g reverse phase chromatography column (water:acetonitrile=2:3) to obtain the title compound 0.89g ( The ratio of methyl ester to ethyl ester is 1:1).

MS (ESI) m/z: 630.3 [M+H] ⁺ (methyl ester), 644.4 [M+H] ⁺ (ethyl ester).

Step 6: ( R )-4-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Methyl formate (formula I-12 compound) /( R )-4-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Ethyl formate (formula I-13 compound) synthesis

( R )-4-(6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl) -5-Methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylic acid methyl ester with (R) -4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -2,4-Dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester mixture (700 mg), bis(triphenylene) phosphine) palladium dichloride (78 mg, 0.111 mmol), cuprous iodide (42.3 mg, 0.222 mmol) was mixed with N,N -dimethylformamide (10 mL). After purging with nitrogen, triethylamine (0.464 mL, 3.33 mmol) and propyne (1M tetrahydrofuran solution) (2.78 mL, 2.78 mmol) were added, and the reaction was carried out at 80° C. for 2 hours. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed with water and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 456 mg of a mixture of compounds of formula I-12 and compound of formula I-13 (methyl ester) The ratio to ethyl ester is 1:1).

Compound of formula 1-12: MS (ESI) m/z: 590.5 [M+H] ⁺ ; compound of formula 1-13: MS (ESI) m/z: 604.5 [M+H] ⁺ .

Step 7: Formula I-5 compound synthesis

The compound of formula I-12 and the mixture of compounds of formula I-13 (250 mg), methanol (1.5 mL), and an aqueous solution (0.5 mL) of lithium hydroxide hydrate (49.7 mg, 1.185 mmol) were mixed and reacted at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6. Separate the aqueous phase, extract the aqueous phase with ethyl acetate (10 mL×4), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, dissolve in tetrahydrofuran after concentration, and purify with a Biotage C18 120g reverse-phase chromatography column (water:acetonitrile= 2:3) to obtain 87 mg of the compound of formula I-5.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.77 (s, 1H), 8.13 (s, 1H), 7.54 (d, J=7.0Hz, 1H), 7.45 (s, 1H), 7.34 (t, J=7.8Hz, 1H), 7.05 (t, J=7.5Hz, 1H), 6.88 (d, J=8.5Hz, 1H), 5.43 (dd, J1=8.3Hz, J2=4.8Hz, 1H), 4.22 -4.19 (m, 1H), 4.05-4.02 (m, 1H), 3.83 (s, 3H), 3.81-3.79 (m, 2H), 3.51-3.46 (m, 1H), 3.41-3.37 (m, 2H) , 2.50 (s, 3H), 2.16 (s, 3H), 1.84-1.75 (m, 2H), 1.62-1.55 (m, 1H), 1.50-1.44 (m, 1H).

¹³ C-NMR (125 MHz, CDCl ₃ ): δ 157.40, 156.95, 154.35, 149.53, 139.77, 129.51, 127.12, 127.04, 121.00, 113.20, 110.43, 94.26, 72.04, 70.70, 69.69, 65.40, 65.10, 55.50, 53.90 , 33.23, 31.52, 14.99, 4.81.

HRMS (ESI) m/z: 576.1832 [M+H] ⁺ .

Example 6 : ( R )-6-(1-(2-(2 -methoxyphenyl )-2-(( tetrahydro - 2H - pyran- 4 -yl ) oxy ) ethyl )- 5 -Methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3- d ] pyrimidine -3( 2H )- base ) pyridine -2- carboxylic acid (compound of formula I-6 )

step one: 6-(3-(3-( Ethoxycarbonyl )-4- methylthiophene -2- base ) Urea group ) Pyridine -2- Synthesis of methyl formate

Mix 6-aminopyridine-2-carboxylic acid methyl ester (10 g, 65.7 mmol), 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (24.08 g, 79 mmol), triethylamine (12.83 mL, 92 mmol) and toluene (100 mL) were mixed, and the mixture was heated to 110° C. to react for 12 hours. The reaction solution was cooled to room temperature, filtered with suction, the filter cake was slurried with petroleum ether and ethyl acetate, filtered with suction, and the filter cake was dried to obtain 16.6 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 11.23 (s, 1H), 11.01 (s, 1H), 8.08 (d, J =7.5Hz, 1H), 7.96 (t, J =8.0Hz, 1H), 7.71 (d, J =7.5Hz, 1H), 6.60 (s, 1H), 4.32 (q, J =7.3Hz, 2H), 3.88 (s, 3H), 2.31 (s, 3H), 1.32 ( t, J = 7.0Hz, 3H).

¹³ C-NMR (125 MHz, DMSO- D ₆ ): Δ 165.34, 164.82, 152.83, 151.69, 150.80, 146.19, 140.08, 134.49, 119.79, 116.60, 111.58, 60.49, 52.18, 14.66.

MS (ESI) m/z: 364.4 [M+H] ⁺ .

Step 2: 6-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- methyl formate /6-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3-d] Pyrimidine -3(2H)- base ) Pyridine -2- Synthesis of Ethyl Formate

Combine methyl 6-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate (8 g, 22.02 mmol) with N,N -dimethyl carbamide (50 mL) was mixed, sodium hydride (1.23 g, 30.8 mmol) was added in three batches under nitrogen protection, and the mixture was heated to 60° C. to react for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (250 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 3.5 g of the title compound (a mixture of methyl ester and ethyl ester, the ratio of the two being 3:2).

MS (ESI) m/z: 316.1 [MH] ^- (methyl ester), 330.2 [MH] ^- (ethyl ester).

Step 3: ( R )-6-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- methyl formate /( R )-6-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Synthesis of Ethyl Formate

Methyl 6-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylate was mixed with Mixture of ethyl 6-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate ( 3 g), ( R )-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro- 2H -pyran (4.17 g, 13.24 mmol), cesium carbonate (4.31 g, 13.24 mmol) was mixed with N -methylpyrrolidone (30 mL), and the mixture was heated to 100 °C for 7 hours. Suction filtration, the filter cake was washed with ethyl acetate, water (100 mL) was added to the filtrate, the aqueous phase was separated, extracted with ethyl acetate (100 mL×3), the organic phases were combined and washed with water and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 1.5 g of the title compound (the ratio of methyl ester to ethyl ester was 1:1).

MS (ESI) m/z: 552.4 [M+H] ⁺ (methyl ester), 566.4 [M+H] ⁺ (ethyl ester).

Step 4: ( R )-6-(6- bromine -1-(2-(2- methoxyphenyl )-2 -(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- methyl formate /( R )-6-(6- bromine -1-(2-(2- methoxyphenyl )-2 -(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Synthesis of Ethyl Formate

( R )-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl Methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylate with ( R )-6-( 1-(2-(2-Methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo A mixture of ethyl substituted-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylate (1.1 g) was mixed with dichloromethane (30 mL), The temperature was cooled in an ice-water bath, bromosuccinimide (0.355 g, 1.994 mmol) was added, and the reaction was carried out at 0° C. for 1 hour. The reaction solution was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, dissolved in acetonitrile after concentration, and purified with a Biotage C18 120g reverse phase chromatography column (water:acetonitrile=2:3) to obtain the title compound 0.43g ( The ratio of methyl ester to ethyl ester is 1:1).

MS (ESI) m/z: 630.4 [M+H] ⁺ (methyl ester), 644.4 [M+H] ⁺ (ethyl ester).

Step 5: ( R )-6-(1-(2-(2- methoxyphenyl )-2 -(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Methyl formate (formula I-14 compound) /( R )-6-(1-(2-(2- methoxyphenyl )-2 -(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Pyridine -2- Ethyl formate (formula I-15 compound) synthesis

( R )-6-(6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl) -5-Methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylic acid methyl ester with ( R ) -6-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl A mixture of ethyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)pyridine-2-carboxylic acid ethyl esters (400 mg), bis (Triphenylphosphine)palladium dichloride (44.5 mg, 0.063 mmol), cuprous iodide (24.16 mg, 0.127 mmol) were mixed with N,N -dimethylformamide (10 mL). After purging with nitrogen, triethylamine (0.265 mL, 1.903 mmol) and propyne (1M tetrahydrofuran solution) (1.586 mL, 1.586 mmol) were added, and the reaction was carried out at 80° C. for 2 hours. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed with water and saturated brine successively. The organic phase was dried with anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:2) to obtain 326 mg of a mixture of compounds of formula I-14 and compound of formula I-15 (formula I The ratio of the -14 compound to the formula I-15 compound is 1:1).

Compound of formula 1-14: MS (ESI) m/z: 590.4 [M+H] ⁺ ; compound of formula 1-15: MS (ESI) m/z: 604.4 [M+H] ⁺ .

Step 6: Formula I-6 compound synthesis

The compound of formula I-14, a mixture of compounds of formula I-15 (300 mg), methanol (5 mL), and an aqueous solution (1.5 mL) of lithium hydroxide hydrate (64 mg, 1.526 mmol) were mixed and reacted at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6. Separate the aqueous phase, extract the aqueous phase with ethyl acetate (10 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, dissolve in tetrahydrofuran after concentration, and purify with a Biotage C18 120g reverse-phase chromatography column (water:acetonitrile= 1:1) to obtain 76 mg of the compound of formula I-6.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.34 (s, 1H), 8.12 (s, 1H), 7.54 (d, J =7.5Hz, 2H), 7.33 (t, J =7.8Hz, 1H) , 7.04 (t, J =7.3Hz, 1H), 6.90 (d, J =8.0Hz, 1H), 5.42 (dd, J ₁ =8.5Hz, J ₂ =4.0Hz, 1H), 4.26-4.20 (m, 1H), 4.08-4.05 (m, 1H), 3.88 (s, 3H), 3.85-3.81 (m, 2H), 3.52-3.47 (m, 3H), 2.51 (s, 3H), 2.17 (s, 3H) , 1.82-1.75 (m, 2H), 1.63-1.60 (m, 1H), 1.50-1.46 (m, 1H).

HRMS (ESI) m/z: 576.1783[M+H] ⁺ .

Example 7 : ( R )-5-(1-(2-(2 -methoxyphenyl )-2-(( tetrahydro - 2H - pyran- 4 -yl ) oxy ) ethyl )- 5 -Methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3- d ] pyrimidine -3( 2H )- base ) niacin (compound of formula I-7 )

step one: 5-(3-(3-( Ethoxycarbonyl )-4- methylthiophene -2- base ) Urea group ) Synthesis of Methyl Nicotinate

Ethyl 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (10 g, 32.7 mmol), methyl 5-aminonicotinate (5.98 g, 39.3 mmol), Triethylamine (6.85 mL, 49.1 mmol) and toluene (200 mL) were mixed, and the mixture was heated to 110°C for 10 hours. The reaction solution was cooled to room temperature, filtered with suction, and the filter cake was washed with water and dried. The obtained crude product was purified by beating with dichloromethane, suction filtered, and the filter cake was dried to obtain 9.9 g of the title compound.

¹ H-NMR (500 MHz, DMSO- d ₆ ): δ 10.80 (s, 1H), 10.70 (s, 1H), 8.75 (d, J = 2.6 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 6.57 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.29 (s, 3H), 1.34 ( t, J = 7.1 Hz, 3H).

¹³ C-NMR (125 MHz, DMSO- D ₆ ): Δ 165.94, 165.60, 151.94, 151.57, 143.95, 143.94, 136.54, 134.15, 125.93, 125.31, 110.64, 60.72, 52.94, 18.53.

MS (ESI) m/z: 364.4 [M+H] ⁺ .

Step 2: 3-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) methyl benzoate /3-(5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of Ethyl Benzoate

Combine methyl 5-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)nicotinate (5 g, 13.76 mmol) with N,N -dimethylformamide The amines (50 mL) were mixed, cooled in an ice-water bath, and under nitrogen purge, sodium hydride (0.660 g, 16.51 mmol) was added in portions, and the mixture was heated to 100° C. to react for 1 hour. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution was added, suction filtered, and the filter cake was washed with water and dried. The obtained crude product was purified by slurrying with dichloromethane and methanol, suction filtered, and the filter cake was dried to obtain 3.1 g of the title compound (a mixture of methyl ester and ethyl ester, the ratio of the two being 3:2).

MS (ESI) m/z: 318.4 [M+H] ⁺ (methyl ester).

Step 3: ( R )-5-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) methyl nicotinate /( R )-5-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of ethyl nicotinate

Combine ( R )-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro- 2H -pyran (1.093 g, 3.47 mmol), 3-(5-methyl) -2,4-Dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoic acid methyl ester/3-(5-methyl-2,4 - Mixture of ethyl dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)benzoate (1 g), cesium carbonate (1.540 g, 4.73 mmol) It was mixed with N -methylpyrrolidone (30 mL), and the mixture was heated to 100°C for 5 hours. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3:2) to obtain 740 mg of the title compound (methyl ester) The ratio to ethyl ester is 1.2:1).

MS (ESI) m/z: 552.4 [M+H] ⁺ (methyl ester).

Step 4: ( R )-5-(6- bromine -1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) methyl nicotinate /( R )-5-(6- bromine -1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Synthesis of ethyl nicotinate

( R )-5-(1-(2-(2-methoxyphenyl)-2((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl -2,4-Dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)nicotinic acid methyl ester with ( R )-5-(1-(2 -(2-Methoxyphenyl)-2((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1,4 The compound of -dihydrothieno[2,3- d ]pyrimidin-3( 2H )-yl)nicotinic acid ethyl ester (0.31 g) was mixed with dichloromethane (5 mL), cooled in an ice-water bath, and bromobutane was added Diimide (0.091 g, 0.513 mmol) was reacted at 0°C for 1 hour. Dichloromethane (50 mL) was added to dilute, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, suction filtered, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:1) to obtain the title Compound 280 mg (1.1:1 ratio of methyl ester to ethyl ester).

MS (ESI) m/z: 630.4 [M+H] ⁺ (methyl ester).

Step 5: ( R )-5-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H- Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Methyl nicotinate (formula I-16 compound) /( R )-5-(1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H- Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Ethyl nicotinate (formula I-17 compound) synthesis

( R )-5-(6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl) -5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3(2H)-yl)nicotinic acid methyl ester with ( R )-5-( 6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethyl)-5-methyl-2, Mixture of ethyl 4-dioxo-1,4-dihydrothieno[2,3- d ]pyrimidin-3(2H)-yl)nicotinate (200 mg), bis(triphenylphosphine)dichloro Palladium (22.26 mg, 0.032 mmol), cuprous iodide (12.08 mg, 0.063 mmol) were mixed with N,N -dimethylformamide (3 mL). After nitrogen purging, triethylamine (0.133 mL, 0.952 mmol), propyne (1M tetrahydrofuran solution) (0.824 mL, 0.824 mmol) were added, and the reaction was carried out at 80° C. for 24 hours. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, and washed with water and saturated brine successively. The organic phase was dried with anhydrous sodium sulfate, filtered with suction, concentrated and purified with a Biotage C18 120g reverse-phase chromatography column (water:acetonitrile=1:2) to obtain 100 mg of a compound of formula I-16 and a mixture of compounds of formula I-17 (formula I The ratio of the -16 compound to the formula I-17 compound is 1:1).

Compound of formula 1-16: MS (ESI) m/z: 590.4 [M+H] ⁺ .

Step 6: Formula I-7 compound synthesis

The compound of formula I-16, a mixture of compounds of formula I-17 (100 mg), methanol (6 mL), and an aqueous solution (2 mL) of lithium hydroxide hydrate (142 mg, 3.39 mmol) were mixed and reacted at room temperature for 1 hour. 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6, and a solid was precipitated. After suction filtration, the obtained crude product was purified by a Biotage C18 120 g reverse phase chromatography column (water:acetonitrile=1:1) to obtain 6 mg of the compound of formula I-7.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 13.56 (br, 1H), 9.12 (s, 1H), 8.66 (s, 1H), 8.21 (s, 1H), 7.48 (d, J = 7.5 Hz , 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.12 – 6.87 (m, 2H), 5.30 (d, J = 6.2 Hz, 1H), 4.11 (s, 1H), 3.95 (s, 1H) , 3.77 (s, 3H), 3.61 (s, 2H), 3.41 (s, 3H), 2.41 (s, 3H), 2.15 (s, 3H), 1.78–1.57 (m, 2H), 1.32 (d, J = 21.1 Hz, 2H).

HRMS (ESI) m/z: 576.1832 [M+H] ⁺ .

Example 8 : ( R )-2-((1-(2-(2 -methoxyphenyl )-2-(( tetrahydro -2H- pyran- 4 -yl ) oxy ) ethyl )- 5 -Methyl -2,4- dioxo- 6-( prop- 1 -yn- 1 -yl )-1,4- dihydrothieno [2,3-d] pyrimidin -3(2H) -yl ) oxy )-2- methylpropionic acid (compound of formula 1-8 )

step one: 2-((1,3- Dioxisoindole -2- base ) Oxygen )-2- Synthesis of tert-butyl methylpropionate

2-Bromo-2-methylpropionic acid tert-butyl ester (5 g, 22.41 mmol), N-hydroxyphthalimide (3.66 g, 22.41 mmol), potassium carbonate (3.72 g, 26.9 mmol), DMF (60 ml) was mixed and reacted at 90°C for 20 hours. The reaction solution was suction filtered, water and ethyl acetate were added to the filtrate, and the layers were separated. The aqueous phase was extracted with ethyl acetate (200mL*3), and the organic phases were combined, washed with water (200mL*3), washed with saturated brine (100mL), and anhydrous. Dry over sodium sulfate. After suction filtration, the filtrate was concentrated to obtain a yellow oil, which was purified by column chromatography (ethyl acetate:petroleum ether=2:3) to obtain 720 mg of the title compound.

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.86 - 7.84 (m, 2H), 7.78 - 7.76 (m, 2H), 1.60 (s, 6H), 1.53 (s, 9H).

MS (ESI) m/z: 328.3 [M+Na] ⁺ .

Step 2: 2-( Aminooxy )-2- Synthesis of tert-butyl methylpropionate

Dissolve 2-((1,3-dioxoisoindol-2-yl)oxy)-2-methylpropionic acid tert-butyl ester (7 g, 22.93 mmol) in dichloromethane (33 ml) and To the mixed solution of methanol (6 mL), hydrazine hydrate (4.59 g, 92 mmol) was added dropwise to it with stirring at room temperature, and the reaction was stirred for 1.5 hours after the dropwise addition. Suction filtration, the filter cake was washed with dichloromethane (30ml), the filtrate was concentrated, the residue was diluted with ethyl acetate (50ml), washed with water (50ml) and saturated brine (50ml) successively, dried over anhydrous sodium sulfate, and suction filtered , the filtrate was concentrated to obtain 3.4 g of the title compound.

¹ H NMR (500 MHz, CDCl ₃ ): δ 5.313 (s, 2H), 1.489 (s, 9H), 1.378 (s, 6H).

GCMS m/z: 119 [MC ₄ H ₈ ] ⁺

Step 3: 4- methyl -2-(( Phenoxycarbonyl ) Amine ) Thiophene -3- Synthesis of Ethyl Carboxylate

Ethyl 2-amino-4-methylthiophene-3-carboxylate (1 g, 5.40 mmol), ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate solution (15 mL) were mixed, stirred at room temperature, and added to it Phenyl chloroformate (0.845 g, 5.40 mmol) was added and the reaction was continued to stir at room temperature for 2 hours. The reaction solution was separated, the aqueous phase was washed with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the residual solid was slurried with petroleum ether (10 mL) to obtain the title Compound 1.25g.

Step 4: 2-(3-((1-( tertiary butoxy )-2- methyl -1- oxopropane -2- base ) Oxygen ) Urea group )-4- methylthiophene -3- Synthesis of Ethyl Carboxylate

4-Methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (0.5 g, 1.637 mmol), toluene (5 ml), 2-(aminooxy)-2 - tert-butyl methylpropionate (0.344 g, 1.965 mmol) and triethylamine (0.199 g, 1.965 mmol) were mixed, and the reaction was stirred at 90 °C for 7 hours. The reaction was stopped, the reaction solution was cooled to room temperature, toluene was removed under reduced pressure, and the remaining yellow oil was slurried with petroleum ether:methyl tertiary butyl ether=3:1 mixed solvent (10 mL) to obtain 0.376 g of the title compound.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 11.29(s, 1H), 10.10(s, 1H), 6.59(s, 1H), 4.31(q, J = 7.0 Hz, 2H), 2.31(s , 3H), 1.44(s, 6H), 1.30-1.33(m, 12H).

MS (ESI) m/z: 409.02 [M+Na] ⁺ .

Step 5: 5- bromine -2-(3-((1-( tertiary butoxy )-2- methyl -1- oxopropane -2- base ) Oxygen ) Urea group )-4- methylthiophene -3- Synthesis of Ethyl Carboxylate

2-(3-((1-(Third-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)ureido)-4-methylthiophene-3-carboxylic acid Ethyl ester (0.35 g, 0.906 mmol) and DMF (5 ml) were mixed, the mixture was stirred and cooled to 0 °C, N-bromosuccinimide (0.161 g, 0.906 mmol) was added to it, and the mixture was warmed to room temperature after the addition. The reaction was stirred for 1.5 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL), the organic phase was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the residue was washed with petroleum ether: methyl alcohol Base tert-butyl ether=3:1 mixed solvent (10 mL) was slurried to obtain 0.408 g of the title compound.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 11.34(s, 1H), 10.34(s, 1H), 4.32(q, J =7.0Hz, 2H), 2.29(s, 3H), 1.44(s , 6H), 1.31-1.33 (m, 12H).

MS (ESI) m/z: 486.87 [M+Na] ⁺ .

Step 6: 2-((6- bromine -5- methyl -2,4- Dioxy -1,4- dihydrothiophene [2,3- d ] Pyrimidine -3( 2H )- base ) Oxygen )-2- Synthesis of Methylpropionic Acid

5-Bromo-2-(3-((1-(tertiary-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)ureido)-4-methylthiophene- Ethyl 3-carboxylate (10 g, 21.49 mmol) was dispersed in absolute ethanol (120 mL), the mixture was stirred at room temperature under nitrogen atmosphere, and sodium methoxide 25% m/v methanol solution (16.24 mL) was added dropwise thereto. , 75 mmol), the dropwise addition was completed and the reaction was stirred at room temperature for 20 hours. The reaction solution was added to water (600 mL), the pH was adjusted to acidity with 2M hydrochloric acid, extracted with ethyl acetate (200 mL*2), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered with suction, The filtrate was concentrated and the residue was separated and purified with a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain 1.3 g of the title compound.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 12.85(br, 1H), 12.50(br, 1H), 2.31(s, 3H), 1.44(s, 6H).

MS (ESI) m/z: 364.8 [M+H] ⁺ .

Step seven: 2-((6- bromine -5- methyl -2,4- Dioxy -1,4- dihydrothiophene [2,3- d ] Pyrimidine -3(2H)- base ) Oxygen )-2- Synthesis of Benzyl Methylpropionate

2-((6-Bromo-5-methyl-2,4-dioxy-1,4-dihydrothiophen[2,3-d]pyrimidin-3(2H)-yl)oxy)-2 - Methylpropionic acid (7 g, 19.3 mmol), benzyl alcohol (14 g, 129.5 mmol), p-toluenesulfonic acid (6.65 g, 38.6 mmol) and toluene (50 mL) were mixed, and the mixture was heated to 120 °C by microwave for 1 hour. The reaction solution was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain 6.25 g of the title compound, which was directly used in the next step. reaction.

Step 8: ( R )-2-((6- bromine -1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxy -1,4- dihydrothiophene [2,3- d ] Pyrimidine -3( 2H )- base) oxy )-2- Synthesis of Benzyl Methylpropionate

( R )-2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4-yl)oxy)ethan-1-ol (6.01 g, 23.82 mmol) , 2-((6-bromo-5-methyl-2,4-dioxy-1,4-dihydrothiophene[2,3- d ]pyrimidin-3(2H)-yl)oxy)-2 - Benzyl methylpropionate (9 g, 19.85 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and tetrahydrofuran (120.000 mL) were mixed, stirred at 0°C under nitrogen protection, and azodicarboxylic acid was added dropwise to it A solution of di-tert-butyl ester (7.18 g, 31.2 mmol) in tetrahydrofuran (5 mL), the mixture was warmed to room temperature and stirred for 17 hours. The reaction solution was concentrated, and the residue was separated and purified by a C18 column (acetonitrile:water=60:40-90:10) to obtain 4.86 g of the title compound.

¹ H NMR (500 MHz, DMSO- d ₆ ): δ 7.31-7.47(m, 7H), 7.00-7.05(m, 2H), 5.16-5.25(m, 3H), 4.03-4.06(m, 1H), 3.83-3.85(m, 1H), 3.77(s, 3H), 3.59-3.61(m, 1H), 3.47-3.50(m, 1H), 3.34-3.36(m, 1H), 3.16-3.25(m, 2H) ), 2.30(m, 3H), 1.49-1.63(m, 8H), 1.32-1.34(m, 1H), 1.17-1.89(m, 1H).

MS (ESI) m/z: 709.3 [M+Na] ⁺

Step nine: ( R )-2-(((1-(2-(2- methoxyphenyl )-2-(( tetrahydro -2H - Pyran -4- base ) Oxygen ) Ethyl )-5- methyl -2,4- Dioxo -6-( C -1- Alkyne -1- base )-1,4- dihydrothieno [2,3- d ] Pyrimidine -3( 2H )- base ) Oxygen )-2- Benzyl methylpropionate (formula I-18 compound) synthesis

Add benzyl ( R )-2-((6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro- 2H -pyran-4) to the 48mL pressure bottle in turn -yl)oxy)ethyl)-5-methyl-2,4-dioxy-1,4-dihydrothiophene[2,3- d ]pyrimidin-3( 2H )-yl)oxy) -2-Methylpropionate (0.5 g, 0.727 mmol), propyne (0.146 g, 3.64 mmol), bistriphenylphosphine palladium dichloride (0.051 g, 0.073 mmol) and cuprous iodide (0.014 g) , 0.073 mmol), triethylamine (10 mL) under nitrogen, and the mixture was heated to 80 °C for overnight reaction. The reaction solution was cooled to room temperature, diatomaceous earth was suction filtered, the filtrate was added to water (100 mL), extracted with ethyl acetate (50 mL*2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered with suction, The filtrate was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate=4:1) to obtain 0.412g of the compound of formula I-18.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 7.45-7.47(m, 1H), 7.40-7.41(m, 2H), 7.31-7.37(m, 4H), 7.00-7.05(m, 2H), 5.24-5.27(m, 1H), 5.13-5.18(m, 2H), 4.03-4.06(m, 1H), 3.82-3.86(m, 1H), 3.76(s, 3H), 3.58-3.60(m, 1H) ), 3.46-3.48(m, 1H), 3.15-3.24(m, 2H), 2.37(s, 3H), 2.14(s, 3H), 1.61-1.64(m, 2H), 1.52(s, 3H), 1.49(s, 3H), 1.24-1.34(m, 2H), 1.14-1.16(m, 1H).

MS (ESI) m/z: 669.5 [M+Na] ⁺ .

Step ten: formula I-8 compound synthesis

The compound of formula I-18 (0.3 g, 0.464 mmol) was mixed with lithium hydroxide (0.012 g, 0.510 mmol), tetrahydrofuran (6 mL) and water (3 mL), and the mixture was reacted at room temperature overnight. The pH of the reaction solution was adjusted to neutrality with 1M dilute hydrochloric acid, extracted with ethyl acetate (50 mL*2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the residue was placed on a silica gel column. Separation and purification (petroleum ether:ethyl acetate=1:1) gave 38 mg of the compound of formula I-8.

¹ H NMR (500 MHz, CDCl ₃ ) δ 13.13 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.03 (t, J = 7.5 Hz , 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.41 (t, J = 6.5 Hz, 1H), 4.24–4.01 (m, 2H), 3.87 (s, 3H), 3.80 (d, J = 11.9 Hz, 1H), 3.76 – 3.66 (m, 1H), 3.44 (s, 1H), 3.38 – 3.26 (m, 2H), 2.55 (s, 3H), 2.16 (s, 3H), 1.82–1.51 (m , 10H).

MS (ESI) m/z: 579.5 [M+Na] ⁺ .

Example 9

In vitro enzyme inhibitory activity

1.1 Screening of ACC1 inhibitory activity

Prepare matrix mix 0.84 μl 5x concentration of enzyme buffer (150 mM HEPES, 10 mM MgCl ₂ , 5 mM DTT, 10 mM sodium citrate) + 1.2 μl ATP (100 μM) + 0.06 μl Acetyl-CoA (2 mM) + 0.18 μl NaHCO ₃ ( 1M) + 1.92 μl water, 4.2 μL/well was added to the 96 half-well plate, the test compound dissolved in DMSO was added to the well with a nanoliter sampler, and centrifuged to make the final compound concentration 4-fold dilution, 7 concentrations Gradient, the highest concentration is 500nM, the lowest concentration is 0.12nM, and 2 replicate wells are set for each concentration. At the same time, a blank control well (without enzyme) and a negative control well (with enzyme) were set, and 5 duplicate wells were set. Dilute ACC1 enzyme to 8.25 ng/μL with 1x concentration of enzyme buffer (30 mM HEPES, 2 mM MgCl ₂ , 1 mM DTT, 2 mM sodium citrate), add 1.8 μL to each well, and add 1.8 μL to blank control wells 1 times the concentration of enzyme buffer, centrifuge, and react at room temperature for 60 minutes. Add 5 μL of ADP-Glo reagent to each well, centrifuge, and react at room temperature for 40 minutes; add 10 μL of kinase detection reagent to each well, centrifuge, and incubate in the dark at room temperature for 30 minutes; read by PE Envision multifunctional enzyme label reader Chemiluminescence data, using a four-parameter fit, calculate _IC50 .

1.2 Screening of ACC2 inhibitory activity

Prepare matrix mix 0.84 μl 5x concentration of enzyme buffer (150 mM HEPES, 10 mM MgCl ₂ , 5 mM DTT, 10 mM sodium citrate) + 1.2 μl ATP (100 μM) + 0.06 μl Acetyl-CoA (2 mM) + 0.18 μl NaHCO ₃ ( 400mM) + 1.92μl water, 4.2μL/well was added to a 96 half-well plate, the test compound dissolved in DMSO was added to the well with a nanoliter sampler, and centrifuged, so that the final concentration of the compound was diluted 4 times, with 8 concentrations. Gradient, the highest concentration is 5000 nM, the lowest concentration is 0.31 nM, and 2 replicate wells are set for each concentration. At the same time, a blank control well (without enzyme) and a negative control well (with enzyme) were set, and 5 duplicate wells were set. Dilute ACC2 enzyme to 5.4 ng/μL with 1x concentration of enzyme buffer (30 mM HEPES, 2 mM MgCl ₂ , 1 mM DTT, 2 mM sodium citrate), add 1.8 μL to each well, and add 1.8 μL to blank control wells 1 times the concentration of enzyme buffer, centrifuge, and react at room temperature for 60 minutes. Add 5 μL of ADP-Glo reagent to each well, centrifuge, and react at room temperature for 40 minutes; add 10 μL of kinase detection reagent to each well, centrifuge, and incubate in the dark at room temperature for 30 minutes; read by PE Envision multifunctional enzyme label reader Chemiluminescence data, using a four-parameter fit, calculate _IC50 .

In vitro cell-level antitumor activity screening

2.1 The proliferation inhibitory effect of compounds on A549 and NCI-H460

The A549 (adenocarcinoma human alveolar basal epithelial cell line) and NCI-H460 (large cell lung cancer cell line) cells in the logarithmic growth phase were digested and collected, and a single cell suspension was prepared in complete medium containing 5% FBS, at 1 × 10 The density of ⁴ cells/mL was inoculated in a 96-well plate, 100 μL per well, and placed in a cell incubator at 37°C with a saturated humidity of 5% CO ₂ for overnight incubation. The final concentrations were 10000.0, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, and 4.6 nM, respectively, and two replicate wells were set for each concentration. At the same time, the groups with and without palmitic acid were set. The cells without compound were used as negative control, and the blank group without cells was used as blank control. The cells were placed in a cell incubator at 37°C with 5% CO ₂ saturated humidity for 6 days. After 6 days of culture, 10 μL of CCK-8 was added to each well, and the culture was continued for 2-4 h. The absorbance value A of each well was measured at 450nm of the enzyme label reader, and the inhibition rate was calculated according to the following formula: Inhibition rate (%)=(average A value of negative control group-average A value of experimental group)/(negative control group) The average A value - the average A value of the blank control group) × 100%, and the IC ₅₀ was calculated from the obtained data.

The results of the in vitro ACC enzyme inhibitory activity and the proliferation inhibitory activity at the cell level measured are shown in Table 1.

  6.6 33 / / 注：“/”表示未測量。 Table 1 _IC50 (nM) compound ACC2 ACC1 A549 without palmitic acid NCI-H460 without palmitic acid I-1 1.6 2.3 0.94 0.73 I-2 2.1 2.2 0.77 0.88 I-3 1.8 1.4 2.64 1.58 I-4 2.5 3.0 5.78 3.00 I-5 1.9 1.8 20.7 9.40 I-6 2.0 1.4 37.6 17.4 I-8 1.7 1.8 6.39 5.39 control compound

6.6 33 / / Note: "/" means not measured.

Example 10 In vitro pharmacokinetics

In vitro liver microsome stability:

Preparation of liver microsome body temperature incubation sample: mix PBS buffer (pH 7.4), liver microsome solution (0.5mg/mL), test compound and NADPH + MgCl ₂ solution, incubate at 37°C and 300rpm for 60min.

0-hour sample preparation: mix PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), and test compound.

The samples were added to the acetonitrile solution containing the internal standard, and the supernatant was prepared by protein precipitation. After dilution, it was used for LC/MS/MS determination. The test results are shown in Table 2.

  0.12% / / /   注：“/”表示未測量。 Table 2 Liver microsome stability remaining % 60min compound people dog rat mouse I-1 103.04% 48.24% 30.51% 87.8% I-2 92.22% 37.38% 8.55% 65.69% I-3 102.26% 97.14% 92.63% 95.89% I-4 95.93% 98.38% 89.35% 90.82% I-5 87.40% 103.19% 74.18% 103.16% I-6 81.90% 100.91% 98.74% 98.87% I-8 97.53% 74.92% 82.43% 80.82% control compound

0.12% / / / Note: "/" means not measured.

none.

Claims (14)

A compound of formula I or a pharmaceutically acceptable salt thereof,

Wherein, R ¹ and R ² are independently selected from hydrogen or C _1-6 alkyl, which may be optionally substituted by groups selected from hydroxyl, -OC _1-6 alkyl, amino, halogen, cyano and nitro ; R ⁴ is selected from hydrogen, -R', -O-R';R' is independently selected from the following groups optionally substituted by R: C _1-6 alkyl, 3-8 membered cycloalkyl , 3-8-membered cycloalkenyl, 6-10-membered aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl; A is selected from -OC _1-6 alkylene optionally substituted by R, or chemical bond; L is selected from chemical bond, or optionally substituted by R and is selected from 3-10-membered cycloalkyl, 6-10-membered aryl, 3-10-membered heterocyclic group, 5-10-membered divalent heteroaryl group; Z is selected from -COOR ³ ; R ³ is selected from hydrogen, or optionally R-substituted C _1-6 alkyl, phenyl C _1-6 alkyl, silyl; One of A and L is a chemical bond ; R is independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano, silyl, C _1-6 alkyl, C _1-6 alkoxy, C _2-5 alkenyl , C _2-5 alkynyl, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, cyano C _1-6 alkyl, hydroxy C _1-6 alkyl, phenyl C _1-6 Alkyl, 3-8 membered cycloalkyl, phenyl, phenyl C _1-6 alkyl, halophenyl, cyanophenyl, with 1, 2 or 3 independently selected from nitrogen, oxygen and sulfur 3-8 membered heterocyclyl with heteroatoms, 5-6 membered heteroaryl with 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein when A is a chemical bond, the attachment sites of A and Z to L are different. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein L is selected from 3-10 membered cycloalkyl, phenyl, optionally substituted by R, having 1, 2 or 3 independent 3-8 membered heterocyclyl with heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl with 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur divalent group; Preferably, L is selected from 3-8 membered cycloalkyl optionally substituted by R, phenyl, saturated 3-8 membered heterocycle with 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur radicals or unsaturated 3-8 membered heterocyclic groups having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, unsaturated 3-8 membered heterocyclic groups having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur Divalent group of 5-6 membered heteroaryl; Further preferably, L is selected from the group consisting of 3-8 membered cycloalkyl, phenyl, saturated 3-8 membered heterocyclic group with 1 nitrogen atom, unsaturated 3 with 1 nitrogen atom optionally substituted by R. -8-membered heterocyclic group, saturated 3-8-membered heterocyclic group with 1 oxygen atom, unsaturated 3-8-membered heterocyclic group with 1 oxygen atom, saturated 3-8-membered heterocyclic group with 1 sulfur atom Ring group, unsaturated 3-8 membered heterocyclic group with 1 sulfur atom, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered with 2 oxygen atoms Member saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group with 2 oxygen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 nitrogen atom and 1 5-6 membered unsaturated heterocyclic group with sulfur atom, saturated 5-6 membered heterocyclic group with 1 oxygen atom and 1 sulfur atom, 4-6 membered heteroaryl group with 1 nitrogen atom, with 1 5-6-membered heteroaryl with oxygen atom, 5-6-membered heteroaryl with 1 sulfur atom, 5-6-membered heteroaryl with 2 nitrogen atoms, 5-6-membered heteroaryl with 3 nitrogen atoms The divalent group of an aryl group. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, optionally substituted by R Heptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2 .2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.2]decyl, bicyclo[3.3.2]decyl, phenyl, Epoxy, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, furanyl, tetrahydropyranyl, pyrrolyl, 2,3-dihydropyrrolyl, 2,5- Dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, tetrahydropyrazolyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, pyridyl, piperidinyl, piperazinyl , pyrimidinyl, pyridazinyl, thienyl, thienyl, thiazolyl divalent groups; preferably, L is selected from the following groups optionally substituted by R:

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. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein L is selected from the group consisting of cyclobutyl, bicyclo[1.1.1]pentyl, phenyl optionally substituted by R , a divalent group of pyridyl; preferably, L is selected from the following groups optionally substituted by R

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. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from -OC _1-6 alkylene optionally substituted by R, preferably -O-CH ₂ -, -O-CH ( CH ₃ )-, -O-CH ₂ CH ₂ -, -O-CH(CH ₂ CH ₃ )-, -O-CH(CH ₃ )CH ₂ -, -O-CH ₂ CH(CH ₃ )-, -OC( _CH3 ) _2- , -O _{- CH2CH2CH2-} , _{-O - CH2CH2CH2CH2-} , _{-O -} CH2CH _{( CH3 )} CH2-, -O- CH(CH ₃ )CH ₂ CH ₂ -, -O-CH ₂ CH ₂ CH(CH ₃ )-, -O-CH ₂ C(CH ₃ ) ₂ -, -OC(CH ₃ ) ₂ CH ₂ -, - O-CH ₂ CH(CH ₂ CH ₃ )-, -O-CH(CH ₂ CH ₃ )CH ₂ -, -O-CH(CH ₂ CH ₂ CH ₃ )-, -OC(CH ₂ CH ₃ )( CH ₃ )-, more preferably -O-CH ₂ -, -O-CH(CH ₃ )-, -O-CH ₂ CH ₂ -, -O-CH(CH ₂ CH ₃ )-, -O-CH (CH ₃ )CH ₂ -, -O-CH ₂ CH(CH ₃ )-, -OC(CH ₃ ) ₂ -, -O-CH ₂ CH ₂ CH ₂ -, more preferably -OC(CH ₃ ) _2- . The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are independently selected from methyl, ethyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R ³ is selected from hydrogen, or C _1-4 alkyl optionally substituted by R, phenyl C _1-4 alkane group, C _1-6 silyl group; preferably, R ³ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, methylphenyl, ethyl phenyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; further preferably, R ³ is selected From hydrogen, methyl, ethyl, tert-butyl, benzyl, tert-butyldiphenylsilyl. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, -O ^- R', wherein R' is independently selected from each of the following optionally substituted by R Item groups: C _1-6 alkyl, 3-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 6-10 membered aryl, with 1, 2 or 3 independently selected from nitrogen, oxygen and sulfur A 4-10-membered heterocyclic group of heteroatoms, a 5-8-membered heteroaryl group with 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; preferably, R' is selected from optional Groups of the following substituted by R: -C _1-4 alkyl, 5, 6, 7 or 8 membered cycloalkyl, having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 5, 6, 7, 8, 9 or 10 membered heterocyclic group, 5-6 membered heteroaryl group with 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; further preferably, R' is selected from any Saturated 5-8 membered heterocyclyl substituted by R with 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur or with 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated 5-8-membered heterocyclic group; More preferably, R' is selected from a saturated 5-8-membered heterocyclic group with 1 nitrogen atom optionally substituted by R, an unsaturated 5-membered heterocyclic group with 1 nitrogen atom 8-membered heterocyclic group, saturated 5-8-membered heterocyclic group with 1 oxygen atom, unsaturated 5-8-membered heterocyclic group with 1 oxygen atom, saturated 5-8-membered heterocyclic group with 1 sulfur atom base, unsaturated 5-8 membered heterocyclic group with 1 sulfur atom, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, with 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered with 2 oxygen atoms Saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group with 2 oxygen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 nitrogen atom and 1 sulfur atom Atomic 5-6 membered unsaturated heterocyclic group, saturated 5-6 membered heterocyclic group having 1 oxygen atom and 1 sulfur atom. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen, or a group optionally substituted by R of the following: methoxy, ethoxy ,

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,

, preferably

. The compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, R is selected from saturated 3-8 membered having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur Heterocyclyl, or unsaturated 3-8 membered heterocyclyl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen 5-6 membered heteroaryl with heteroatom of sulfur; Preferably, R is selected from saturated 3-8 membered heterocyclic groups having 1 nitrogen atom, unsaturated 3-8 membered heterocyclic groups having 1 nitrogen atom, saturated 3-8 membered heterocyclic groups having 1 oxygen atom base, unsaturated 3-8 membered heterocyclic group with 1 oxygen atom, saturated 3-8 membered heterocyclic group with 1 sulfur atom, unsaturated 3-8 membered heterocyclic group with 1 sulfur atom, with 4-8 membered saturated heterocyclic group with 2 nitrogen atoms, 4-8 membered unsaturated heterocyclic group with 2 nitrogen atoms, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 4-8-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 4-8-membered saturated heterocyclic group having 2 oxygen atoms, 4-8-membered unsaturated heterocyclic group having 2 oxygen atoms base, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 4-8 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen atom and 1 Saturated 4-8-membered heterocyclic group with 1 sulfur atom, or 4-6-membered heteroaryl with 1 nitrogen atom, 5-6-membered heteroaryl with 1 oxygen atom, 5-membered heteroaryl with 1 sulfur atom 6-membered heteroaryl, 5-6 membered heteroaryl with 2 nitrogen atoms, 5-6 membered heteroaryl with 3 nitrogen atoms; Further preferably, R is selected from a 4-6 membered saturated heterocyclic group with 1 nitrogen atom, a 4-6 membered unsaturated heterocyclic group with 1 nitrogen atom, and a 4-6 membered saturated heterocyclic group with 1 oxygen atom. Ring group, 4-6 membered unsaturated heterocyclic group with 1 oxygen atom, 4-6 membered saturated heterocyclic group with 1 sulfur atom, 4-6 membered unsaturated heterocyclic group with 1 sulfur atom, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom , 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered saturated heterocyclic group with 2 oxygen atoms, 5-6 membered unsaturated heterocyclic group with 2 oxygen atoms Ring group, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen atom and A saturated 5-6 membered heterocyclic group with 1 sulfur atom. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, R is selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tributyl, methoxy, ethoxy, phenyl, benzyl, methylphenyl, ethylphenyl, furyl, pyranyl, pyrrolidinyl, pyridyl, piperidinyl, piperazinyl, Pyrimidyl, thienyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, preferably hydrogen, methyl base, ethyl, tert-butyl, methoxy, ethoxy, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl. The compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, the compound has one of the following structures:

. Use of the compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating acetyl-CoA carboxylase-mediated diseases, including but not limited to insulin Resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, lung cancer, pancreatic cancer.