CN116745299A - Thienopyrimidine derivatives - Google Patents

Thienopyrimidine derivatives Download PDF

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Publication number
CN116745299A
CN116745299A CN202280012196.9A CN202280012196A CN116745299A CN 116745299 A CN116745299 A CN 116745299A CN 202280012196 A CN202280012196 A CN 202280012196A CN 116745299 A CN116745299 A CN 116745299A
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China
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membered
heterocyclic group
atom
nitrogen
oxygen
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CN202280012196.9A
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Chinese (zh)
Inventor
张寅生
刘保民
黄雨
陈正帮
朱炎
盖阔
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Publication of CN116745299A publication Critical patent/CN116745299A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Thienopyrimidine derivatives, in particular to a compound of formula I or pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application thereof in preparing medicines for treating diseases mediated by acetyl-CoA carboxylase (ACC) in individuals, such as insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, lung cancer, pancreatic cancer and the like.

Description

Thienopyrimidine derivatives Technical Field
The application belongs to the field of pharmaceutical chemistry, and relates to thienopyrimidine derivatives, in particular to a compound shown in a formula I or pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in medicines for treating diseases mediated by acetyl-CoA carboxylase (ACC) in individuals.
Background
Acetyl-coa carboxylase (ACC) is the rate-limiting enzyme for fatty acid synthesis, and is predominantly distributed in hepatocytes and adipocytes. It uses biotin as coenzyme, catalyzes acetyl coenzyme A to generate malonyl coenzyme A, and provides substrate for synthesizing fatty acid. In addition to the activity of ACC being regulated by various factors, insulin, glucagon, thyroid hormone, etc. have a certain regulatory effect on ACC. Initially, people's knowledge of ACC is mainly limited to fatty acid synthesis, and research has found that ACC is widely involved in the occurrence and development of metabolic diseases such as obesity, non-alcoholic steatohepatitis, diabetes and the like in recent years, so ACC is expected to become a potential target for the treatment of various metabolic diseases.
Metabolic diseases such as obesity, nonalcoholic steatohepatitis and diabetes are difficult and complicated diseases which always plague people, and no therapeutic drug with good curative effect exists clinically until now. With the improvement of the living standard of people, the obesity phenomenon is serious due to the eating of various high-fat foods, and a series of metabolic syndromes such as nonalcoholic steatohepatitis, diabetes, hyperuricemia, hypertension, stroke, atherosclerosis and the like are caused by the obesity, so that the development of medicines for treating the diseases is of great significance.
Detailed Description
The present application relates to compounds of formula I or a pharmaceutically acceptable salt thereof,
wherein,
R 1 and R is 2 Independently selected from hydrogen or C 1-6 Alkyl, optionally selected from hydroxy, -O-C 1-6 Alkyl, amino, halogen, cyano and nitro groups;
R 4 selected from hydrogen, -R ', -O-R'; r' is independently selected from the following groups optionally substituted with R: c (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 the group consisting of-O-C optionally substituted with R 1-6 An alkylene group, or a chemical bond;
l is selected from a bond, or a divalent group selected from 3-10 membered cycloalkyl, 6-10 membered aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with R;
Z is selected from-COOR 3 ；
R 3 Selected from hydrogen, or C optionally substituted by R 1-6 Alkyl, phenyl C 1-6 Alkyl, silyl;
wherein one of A and L is a 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, halo 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 C 1-6 Alkyl, halophenyl, cyanophenyl, 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms selected independently from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected independently from nitrogen, oxygen, and sulfur.
In some embodiments, when a is a bond, the attachment sites of a and Z are different from L.
In some embodiments, R 1 And R is 2 Independently selected from methyl, ethyl.
In some embodiments, R 4 Selected from hydrogen, -O-R ', wherein R' is independently selected from the following groups optionally substituted with R: c (C) 1-6 Alkyl, 3-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 6-10 membered aryl, 4-10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected independently from nitrogen, oxygen and sulfur, 5-8 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected independently from nitrogen, oxygen and sulfur.
In some embodiments, R 4 Selected from hydrogen, -O-R ', wherein R' is selected from the following groups optionally substituted with R: -C 1-4 Alkyl, 5, 6, 7 or 8 membered cycloalkyl, 5, 6, 7, 8, 9 or 10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected independently from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl having 1 or 2 heteroatoms selected independently from nitrogen, oxygen and sulfur.
In some embodiments, R 4 Selected from hydrogen, -O-R ', wherein R' is selected from a saturated 5-8 membered heterocyclyl optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, R 4 Selected from hydrogen, -O-R ', wherein R' is selected from an unsaturated 5-8 membered heterocyclyl optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, R 4 Selected from the group consisting of hydrogen, -O-R ', wherein R' is selected from the group consisting of a saturated 5-8 membered heterocyclic group having 1 nitrogen atom, an unsaturated 5-8 membered heterocyclic group having 1 nitrogen atom, a saturated 5-8 membered heterocyclic group having 1 oxygen atom, an unsaturated 5-8 membered heterocyclic group having 1 oxygen atom, a saturated 5-8 membered heterocyclic group having 1 sulfur atom, an unsaturated 5-8 membered heterocyclic group having 1 sulfur atom, a 5-6 membered saturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered unsaturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, A 5-6 membered saturated heterocyclic group having 2 oxygen atoms, a 5-6 membered unsaturated heterocyclic group having 2 oxygen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a saturated 5-6 membered heterocyclic group having 1 oxygen atom and 1 sulfur atom.
In some embodiments, R 4 Selected from hydrogen, -O-R ', wherein R' is selected from a 5-6 membered saturated heterocyclic group having 1 nitrogen atom, a 5-6 membered saturated heterocyclic group having 1 oxygen atom, a 5-6 membered saturated heterocyclic group having 1 sulfur atom, optionally substituted with R.
In some embodiments, R 4 A group selected from hydrogen, or optionally R-substituted: methoxy, ethoxy,
In some embodiments, R 4 Is that
In some embodiments, R 3 Selected from hydrogen, or C optionally substituted by R 1-4 Alkyl, phenyl C 1-4 Alkyl, C 1-6 A silane group;
in some embodiments, R 3 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, benzyl, methylphenyl, ethylphenyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl.
In some embodiments, R 3 Selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, benzyl, and t-butyldiphenylsilyl.
In some embodiments, A is selected from the group consisting of-O-C optionally substituted with R 1-6 An alkylene group.
In some embodiments, a is selected from the following groups: -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 )-、-O-C(CH 3 ) 2 -、-O-CH 2 CH 2 CH 2 -、-O-CH 2 CH 2 CH 2 CH 2 -、-O-CH 2 CH(CH 3 )CH 2 -、-O-CH(CH 3 )CH 2 CH 2 -、-O-CH 2 CH 2 CH(CH 3 )-、-O-CH 2 C(CH 3 ) 2 -、-O-C(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 )-、-O-C(CH 2 CH 3 )(CH 3 )-。
In some embodiments, a is selected from the following groups: -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 )-、-O-C(CH 3 ) 2 -、-O-CH 2 CH 2 CH 2 -。
In some embodiments, A is-O-C (CH 3 ) 2 -。
In some embodiments, L is selected from a divalent group of 3-to 10-membered cycloalkyl optionally substituted with R, phenyl, a 3-to 8-membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-to 6-membered heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, L is selected from the divalent group of a 3-8 membered cycloalkyl optionally substituted with R.
In some embodiments, L is selected from a divalent group of saturated 3-8 membered heterocyclyl optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur.
In some embodiments, L is selected from a divalent group of an unsaturated 3-8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with R.
In some embodiments, L is selected from the group consisting of saturated 3-8 membered heterocyclyl with 1 nitrogen atom, unsaturated 3-8 membered heterocyclyl with 1 nitrogen atom, saturated 3-8 membered heterocyclyl with 1 oxygen atom, unsaturated 3-8 membered heterocyclyl with 1 oxygen atom, saturated 3-8 membered heterocyclyl with 1 sulfur atom, unsaturated 3-8 membered heterocyclyl with 1 sulfur atom, 5-6 membered saturated heterocyclyl with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclyl with 2 nitrogen atoms, 5-6 membered saturated heterocyclyl with 1 nitrogen atom and 1 oxygen atom, 5-6 membered unsaturated heterocyclyl with 1 nitrogen atom and 1 oxygen atom, 5-6 membered saturated heterocyclyl with 2 oxygen atom, 5-6 membered unsaturated heterocyclyl with 1 nitrogen atom and 1 sulfur atom, and divalent 1-6 membered unsaturated heterocyclyl with 1-6 oxygen atom.
In some embodiments, L is selected from a divalent group of a 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 a divalent group optionally substituted with R selected from 4-6 membered heteroaryl having 1 nitrogen atom, 5-6 membered heteroaryl having 1 oxygen atom, 5-6 membered heteroaryl having 1 sulfur atom, 5-6 membered heteroaryl having 2 nitrogen atoms, 5-6 membered heteroaryl having 3 nitrogen atoms.
In some embodiments, L is selected from a divalent group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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, pyridinyl, piperidinyl, piperazinyl, pyrimidinyl, pyridazinyl, thienyl.
In some embodiments, L is selected from the group consisting of:
etc.
In some embodiments, L is selected from a divalent group selected from cyclobutyl, bicyclo [1.1.1] pentyl, phenyl, pyridinyl, optionally substituted with R.
In some embodiments, L is selected from the group consisting of the following optionally substituted with R
In some embodimentsR is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, halogenated C 1-4 Alkoxy, cyano C 1-4 Alkyl, hydroxy C 1-4 Alkyl, phenyl C 1-3 Alkyl, 3-6 membered cycloalkyl, phenyl C 1-3 Alkyl, halophenyl, cyanophenyl.
In some embodiments, R is selected from a 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 having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, R is selected from the group consisting of a saturated 3-8 membered heterocyclyl having 1 nitrogen atom, an unsaturated 3-8 membered heterocyclyl having 1 nitrogen atom, a saturated 3-8 membered heterocyclyl having 1 oxygen atom, an unsaturated 3-8 membered heterocyclyl having 1 oxygen atom, a saturated 3-8 membered heterocyclyl having 1 sulfur atom, an unsaturated 3-8 membered heterocyclyl having 1 sulfur atom, a 4-8 membered saturated heterocyclyl having 2 nitrogen atoms, a 4-8 membered unsaturated heterocyclyl having 2 nitrogen atoms, a 4-8 membered saturated heterocyclyl having 1 nitrogen atom and 1 oxygen atom, a 4-8 membered unsaturated heterocyclyl having 1 nitrogen atom and 1 oxygen atom, a 4-8 membered saturated heterocyclyl having 2 oxygen atoms, a 4-8 membered unsaturated heterocyclyl having 2 oxygen atoms, a 4-8 membered saturated heterocyclyl having 1 nitrogen atom and 1 sulfur atom, a 4-8 membered unsaturated heterocyclyl having 1 nitrogen atom and 1 oxygen atom.
In some embodiments, R is selected from the group consisting of a 4-6 membered saturated heterocyclic group having 1 nitrogen atom, a 4-6 membered unsaturated heterocyclic group having 1 nitrogen atom, a 4-6 membered saturated heterocyclic group having 1 oxygen atom, a 4-6 membered unsaturated heterocyclic group having 1 oxygen atom, a 4-6 membered saturated heterocyclic group having 1 sulfur atom, a 4-6 membered unsaturated heterocyclic group having 1 sulfur atom, a 5-6 membered saturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered unsaturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 5-6 membered saturated heterocyclic group having 2 oxygen atoms, a 5-6 membered unsaturated heterocyclic group having 2 oxygen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen 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 the group consisting of 4-6 membered heteroaryl having 1 nitrogen atom, 5-6 membered heteroaryl having 1 oxygen atom, 5-6 membered heteroaryl having 1 sulfur atom, 5-6 membered heteroaryl having 2 nitrogen atoms, 5-6 membered heteroaryl having 3 nitrogen atoms.
In some embodiments, R is selected from hydrogen, fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, phenyl, benzyl, methylphenyl, ethylphenyl, furanyl, pyranyl, pyrrolidinyl, pyridinyl, piperidinyl, piperazinyl, pyrimidinyl, thienyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl.
In some embodiments, R is selected from hydrogen, methyl, ethyl, t-butyl, methoxy, ethoxy, phenyl, benzyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula II or pharmaceutically acceptable salts thereof,
therein A, L, Z, R 3 、R 4 R' and R are as defined above.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula III or pharmaceutically acceptable salts thereof,
therein A, L, R 1 、R 4 R' and R are as defined above.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula II-A or pharmaceutically acceptable salts thereof,
Therein A, L, Z, R 3 R' and R are as defined above.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula II-B or pharmaceutically acceptable salts thereof,
wherein A, L, R' and R are as defined above.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula III-A or pharmaceutically acceptable salts thereof,
therein L, R 1 R' and R are as defined above.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formulas III-A-1-III-A-6 or pharmaceutically acceptable salts thereof,
wherein R is 1 R' and R are as defined above.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula III-B or pharmaceutically acceptable salts thereof,
therein A, R 1 R' and R are as defined above.
In some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula IV or pharmaceutically acceptable salts thereof,
wherein A, L and R 1 As defined above.
In some embodiments, the compounds of formulSup>A I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formulSup>A IV-A or pharmaceutically acceptable salts thereof,
Wherein L and R 1 As defined above.
In some embodiments, the compounds of formulSup>A I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formulas IV-A-1-IV-A-6 or pharmaceutically acceptable salts thereof,
in some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula IV-B or pharmaceutically acceptable salts thereof,
wherein A and R 1 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 group consisting of a compound of formula V,
wherein A and L are as defined above.
In some embodiments, the compounds of formulSup>A I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formulSup>A V-A or pharmaceutically acceptable salts thereof,
wherein L is as defined above.
In some embodiments, the compounds of formulSup>A I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formulas V-A-1-V-A-6 or pharmaceutically acceptable salts thereof,
in some embodiments, the compounds of formula I of the present application or pharmaceutically acceptable salts thereof are selected from compounds of formula V-B or pharmaceutically acceptable salts 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 pharmaceutically acceptable salts thereof:
In another aspect, the present application relates to a pharmaceutical composition 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 comprise pharmaceutically acceptable excipients.
In another aspect, the 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
In another aspect, the application relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prevention or treatment of an acetyl-coa carboxylase (ACC) -mediated disease.
In another aspect, the 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 an acetyl-coa carboxylase (ACC) mediated disease.
In another aspect, the 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 an acetyl-coa carboxylase (ACC) -mediated disease.
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 steatohepatitis, lung cancer, pancreatic cancer.
The compound disclosed by the application can inhibit ACC1 enzyme and ACC2 enzyme with high activity, has a good inhibition effect on ACC-mediated diseases such as lung cancer and pancreatic cancer, and has good in vivo metabolic stability and good drug absorption.
Definition of the definition
The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (e.g. CH 2 CH 2 F) Polysubstituted (e.g. CHFCH 2 F、CH 2 CHF 2 Etc.) or fully substituted (CF) 2 CF 3 ). Those skilled in the art will appreciate that for inclusion of one or moreAny group of substituents does not introduce any substitution or substitution pattern that is sterically impossible and/or impossible to synthesize.
C herein m-n It is that the moiety has an integer number of carbon atoms in the given range. For example "C 1-6 By "is meant 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 (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if one group is substituted with 2R's, then each R has an independent option.
When the number of one linking group is 0, such as- (CH) 2 ) 0 -it is meant that the linking group is a chemical bond.
When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a bond, it is indicated that the structure is actually A-Z.
When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural units Meaning that it may be substituted at any one position on the cyclohexyl or cyclohexadiene.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to a-CN group.
The term "amino" refers to-NH 2 A group.
The term "nitro" refers to-NO 2 A group.
The term "alkyl" refers to a compound of the formula C n H 2n+1 Is a hydrocarbon group of (a). The alkyl group may be linear orBranched. For example, the term "C 1 - 6 Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms (e.g., 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 portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as above.
The term "silyl" refers to an alkyl-substituted silicon group, the alkyl group may be straight or branched. For example, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, the silyl groups may be further substituted with phenyl groups, such as t-butyldiphenylsilyl.
The term "alkylene" refers to a straight-chain or straight-chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is linked to the rest through two points of attachment. Non-limiting examples of this term include-CH 2 -、-CH(CH 3 )-、-CH 2 CH 2 -、-CH(CH 2 CH 3 )-、-CH 2 CH(CH 3 )-、-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 an-O-alkyl group.
The term "alkylamino" refers to an-NH-alkyl group.
The term "dialkylamino" refers to-N (alkyl) 2 。
The term "alkylsulfonyl" refers to-SO 2 -an alkyl group.
The term "alkylthio" refers to-S-alkyl.
The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond consisting of carbon atoms and hydrogen atoms. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) 2-propynyl (-CH) 2 -C.ident.CH), 1, 3-butadienyl (-C.ident.C-C.ident.CH), and the like.
The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to Adamantyl, and the like.
The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a single ring, bridged ring, or spiro 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 a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated, e.g., having 1 or 2 double bonds), and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically one containing 1, 2, 3 or 4 independently selected from sulfur S (O) n (wherein n is 0, 1 or 2), oxygen and/or nitrogen heteroatoms (preferably 1 or 2 heteroatoms), 3, 4, 5, 6, 7, 8, 9, 10 membered rings.
Examples of saturated 3-membered heterocyclyl groups include, but are not limited to, oxiranyl, thiiranyl, cyclic azetidinyl, non-limiting examples of saturated 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of saturated 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of saturated 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiazalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, examples of saturated 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepinyl, thietanyl.
Non-limiting examples of partially unsaturated heterocyclyl groups include, but are not limited to Etc.
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. For example, an aryl group may 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, anthryl, and 1,2,3, 4-tetrahydronaphthalene, and the like.
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or contain 6 to 14, especially 6 toA plurality of fused rings of 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to Etc.
The term "treating" means administering a compound or formulation of the application to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state, but has not been diagnosed as having the disease state;
(ii) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(iii) The disease or condition is alleviated, even if the disease or condition subsides.
The term "therapeutically effective amount" means an amount of a compound of the application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the 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 one of ordinary skill in the art based on his own knowledge and disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, 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, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person 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 words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
The compounds and intermediates of the application may also exist in different tautomeric forms and all such forms are included within the scope of the application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine isomerisation. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include tautomers by recombination of some bond-forming electrons.
The application also includes isotopically-labeled compounds of the application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such asSuch as respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 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 application (e.g., with 3 H is H 14 C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.
In addition, the use of heavier isotopes (such as deuterium (i.e. 2 H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.
The compounds of the application may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the application containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents. Exemplary stereoisomer compounds are shown below, but are not limited thereto.
The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing 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, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients 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, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.
In some embodiments, the compounds of formula IV of the present application can be prepared from the following route, including the steps of:
1) Reacting the compound of formula A and the compound of formula B with a condensing agent to obtain a compound of formula C;
2) The compound of the formula C undergoes a cyclization reaction to obtain a compound of the formula D;
3) Reacting a compound of formula D with a halide in the presence of a solvent to obtain a compound of formula E;
4) Compounds of formula E and R 1 C.ident.CH inversionReacting to obtain a compound of formula F;
5) Reacting a compound of formula F with 2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethan-1-ol to give a compound of formula G;
6) The compounds of formula G may be freed from R by methods conventional in the art 3 The group, a compound of formula IV is prepared.
Therein, A, L, R 1 、R 3 And R is 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 reacted with (R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethan-1-ol.
In some embodiments, the compounds of formula IV of the present application may also be prepared by a route comprising the steps of:
1) Reacting the compound of formula A and the compound of formula B with a condensing agent to obtain a compound of formula C;
2) The compound of the formula C undergoes a cyclization reaction to obtain a compound of the formula D;
3) Reacting a compound of formula D with a compound of formula H in the presence of a solvent to obtain a compound of formula J;
4) Reacting a compound of formula J with a halide to obtain a compound of formula K;
5) Compounds of formula K and R 1 C.ident.CH to give compounds of the formula G;
6) The compounds of formula G may be freed from R by methods conventional in the art 3 The group, a compound of formula IV is prepared.
Therein, A, L, R 1 、R 3 And R is 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 application adopts the following abbreviations:
cbz represents benzyloxycarbonyl; TMS represents trimethylsilyl; TES represents triethylsilyl; TIPS represents triisopropylsilyl; TBS represents tert-butyldimethylsilyl; TBDPS represents tert-butyldiphenylsilyl; MS represents methanesulfonyl; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; etOAc represents ethyl acetate; i-PrOH represents isopropanol; etOH stands for ethanol; meOH is methanol; THF represents tetrahydrofuran.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The application is further illustrated by examples, which are not intended to limit the scope of the application, for clarity. All reagents used in the present application are commercially available and can be 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 ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylic acid (compound of formula I-1)
Step one: synthesis of methyl 3- (((benzyloxy) carbonyl) amino) bicyclo [1.1.1] pentane-1-carboxylate
3- (methoxycarbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid (22 g,129 mmol), toluene (660 mL) and triethylamine (54.1 mL, 385 mmol) were mixed, diphenylphosphoryl hydrazine (57.4 mL, 319 mmol) was added to the mixture after heating and refluxing for 3 hours, and the refluxing reaction was continued for 4 hours. The reaction mixture was cooled to room temperature, concentrated, and the crude product was dissolved in ethyl acetate (200 mL), washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration and purification of the crude product by column chromatography (petroleum ether: ethyl acetate=5:1) gave 24.5g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ8.10(s,1H),7.50-7.27(m,5H),5.01(s,2H),3.61(s,3H),2.19(s,6H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ169.87,155.51,137.37,128.84,128.31,65.66,54.05,51.97,45.86,35.43。
MS(ESI)m/z:276.4[M+H] + 。
Step two: synthesis of methyl 3-aminobicyclo [1.1.1] pentane-1-carboxylate hydrochloride
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 and reacted at room temperature under hydrogen atmosphere for 7 hours, filtered through celite, concentrated, the residue was dissolved in ethyl acetate (200 mL), 4M dioxane hydrochloride solution (22.25 mL,89 mmol) was added thereto, and suction filtration gave 14.3g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ9.21(s,3H),3.62(s,3H),2.24(s,6H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ168.48,53.18,52.31,43.68,35.31。
Step three: synthesis of ethyl 2- (3- (3- (methoxycarbonyl) bicyclo [1.1.1] pent-1-yl) ureido) -4-methylthiophene-3-carboxylate
Ethyl 2-amino-4-methylthiophene-3-carboxylate (12 g,64.8 mmol) was dissolved in methylene chloride (120 mL), N-carbonyldiimidazole (11.55 g,71.3 mmol) was added thereto in portions at 0℃and reacted at room temperature for 12 hours, triethylamine (9.93 mL,71.3 mmol) and methyl 3-aminobicyclo [1.1.1] pentane-1-carboxylate hydrochloride (12.66 g,71.3 mmol) were added in sequence and reacted at room temperature for 2 hours. To the reaction mixture was added water (200 mL), and the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration and beating of the residue with petroleum ether (800 mL) gave 21.5g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ10.29(s,1H),8.64(s,1H),6.46(s,1H),4.30(q,J＝7.0Hz,2H),3.63(s,3H),2.27(s,3H),2.26(s,6H),1.31(t,J＝7.0Hz,3H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ169.81,165.76,153.29,152.83,133.93,112.03,109.57,60.48,54.22,52.02,45.79,35.73,18.22,14.58。
MS(ESI)m/z:351.1[M-H] - 。
Step four: synthesis of methyl 3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-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 ℃ for 1 hour. The reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (500 mL) and ethyl acetate (500 mL) were added, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration, concentration and beating of the residue with a mixed solvent of petroleum ether and ethyl acetate (100 mL, petroleum ether: ethyl acetate=10:1) gave 16g of the title compound.
MS(ESI)m/z:305.2[M-H] - 。
Step five: synthesis of methyl 3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylate
N-bromosuccinimide (9.47 g,53.2 mmol) was added in three portions to a solution of methyl 3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3] -d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylate (16.3 g,53.2 mmol) in methylene chloride (380 mL) at 0deg.C, reacted for 30 min at 0deg.C, the reaction solution diluted with methylene chloride (200 mL), the organic phase washed with water and saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (360 mL, petroleum ether: ethyl acetate=5:1), affording 20.67g of the title compound.
MS(ESI)m/z:383.2[M-H] - 。
Step six: synthesis of methyl 3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylate
Methyl 3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylate (0.5 g,1.298 mmol), triethylamine (5.23 mL,37.5 mmol), N, N-dimethylformamide (5 mL), bis (triphenylphosphine) 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 the pressure-resistant tube and the mixture was sealed at 80℃for 4 hours. The reaction mixture was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate, respectively. Suction filtration, concentration and purification of the crude product by column chromatography (dichloromethane: methanol=20:1) gave the title compound 0.147g.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.05(s,1H),3.64(s,3H),2.62(s,6H),2.36(s,3H),2.11(s,3H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ169.25,159.73,150.48,138.67,112.70,108.88,94.56,71.51,56.01,52.09,48.04,37.12,15.15,4.75。
MS(ESI)m/z:343.2[M-H] - 。
Step seven: synthesis of 3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylic acid
Methyl 3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylate (3.1 g,9.00 mmol), methanol (30 mL), water (6 mL) were mixed, lithium hydroxide (1.889 g,45.0 mmol) was added under ice bath, and the reaction was carried out at room temperature for 1 hour. The reaction mixture was adjusted to pH with 1N hydrochloric acid solution, ethyl acetate (100 mL) was added, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration gave 2.652g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.40(brs,2H),2.57(s,6H),2.35(s,3H),2.10(s,3H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ170.58,159.75,150.40,138.54,112.68,108.99,94.46,71.56,55.80,47.94,37.43,15.13,4.76。
MS(ESI)m/z:329.2[M-H] - 。
Step eight: synthesis of tert-butyldiphenylsilyl 3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylate
3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylic acid (1 g,3.03 mmol), 1H-imidazole (0.495 g,7.26 mmol), N, N-dimethylformamide (30 mL), N, N-dimethylpyridin-4-amine (0.037 g,0.303 mmol) and t-butylchlorodiphenylsilane (0.998 g,3.63 mmol) were mixed and reacted at room temperature for 4 hours. To the reaction solution were added water (100 mL) and ethyl acetate (100 mL), and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration, concentration and purification of the crude product by column chromatography (dichloromethane: methanol=20:1) gave the title compound 1.19g.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.12(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(125MHz,DMSO-d 6 ):δ168.07,159.74,150.50,150.35,138.66,135.11,131.57,130.76,128.43,112.75,108.98,94.55,71.50,56.12,48.06,38.53,26.84,19.13,15.13,4.76。
MS(ESI)m/z:567.4[M-H] - 。
Step nine: synthesis of tert-butyldiphenylsilyl (formula I-9) of (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 ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylate
3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) bicyclo [1.1.1] pentane-1-carboxylic acid tert-butyldiphenylsilyl ester (0.6 g,1.055 mmol), (R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethan-1-ol (0.399 g,1.582 mmol), tetrahydrofuran (6 mL), triphenylphosphine (0.830 g,3.16 mmol) and diisopropyl azodicarboxylate (0.615mL, 3.16 mmol) were mixed and reacted at room temperature for 12 hours. To the reaction solution were added water (50 mL) and ethyl acetate (50 mL), and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration, concentration and purification of the crude product obtained by separation with a C18 column (water: acetonitrile=1:20) gives 0.1g of the compound of formula I-9.
MS(ESI)m/z:803.7[M+H] + 。
Step ten: synthesis of Compounds of formula I-1
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. To the reaction solution were added water (50 mL) and ethyl acetate (50 mL), and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration, concentration and purification of the crude product by column chromatography (dichloromethane: methanol=40:1) gave 0.025g of the compound of formula I-1.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.53(s,1H),7.47-7.43(m,1H),7.32-7.27(m,1H),7.04-6.99(m,1H),6.97(d,J＝8.0Hz,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[M-H] - 。
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 ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid (compound of formula I-2)
Step one: synthesis of tert-butyl (1S, 3S) -3-hydroxycyclobutane-1-carboxylate
Tert-butyl 3-oxocyclobutane-1-carboxylate (45 g,264 mmol), tetrahydrofuran (432 mL) and methanol (54 mL) were mixed, sodium borohydride (5.00 g,132 mmol) was added thereto in portions at 0℃and the reaction was continued at 0℃for 1 hour. To the reaction mixture were added 20% potassium carbonate solution (500 mL) and ethyl acetate (500 mL), and the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration and concentration gave 44.96g of the title compound.
1 H-NMR(500MHz,CDCl 3 ):δ4.16-4.08(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(125MHz,CDCl 3 ):δ174.42,80.42,63.16,36.86,30.04,28.02。
MS(EI)m/z:172[M] + 。
Step two: synthesis of tert-butyl ((1R, 3R) -3- (1, 3-dioxoisoindolin-2-yl) cyclobutane-1-carboxylate)
(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℃and reacted at room temperature for 18 hours. To the reaction mixture were added water (300 mL) and ethyl acetate (300 mL), and the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, concentration and purification of the crude product by column chromatography (petroleum ether: ethyl acetate=20:1) gave 29.2g of the title compound.
1 H-NMR(500MHz,CDCl 3 ):δ7.85-7.80(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(125MHz,CDCl 3 ):δ174.86,168.25,133.97,131.89,123.15,80.44,42.62,33.75,30.31,28.08。
MS(ESI)m/z:302.3[M+H] + 。
Step three: synthesis of (1R, 3R) -3-aminocyclobutane-1-carboxylic acid tert-butyl ester hydrochloride
Tert-butyl ((1R, 3R) -3- (1, 3-dioxoisoindolin-2-yl) cyclobutane-1-carboxylate (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, filtered, concentrated, the residue was dissolved in ethyl acetate (500 mL) to which 4M dioxane hydrochloride solution (25.00 mL,100 mmol) was added and suction filtered to give 17.69g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ8.53(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(125MHz,DMSO-d 6 ):δ174.02,80.52,43.54,34.05,29.87,28.12。
Step four: synthesis of ethyl 2- (3- ((1R, 3R) -3- (tert-butoxycarbonyl) cyclobutyl) ureido) -4-methylthiophene-3-carboxylate
Ethyl 2-amino-4-methylthiophene-3-carboxylate (14 g,76 mmol) was dissolved in methylene chloride (140 mL), N-carbonyldiimidazole (13.76 g,83 mmol) was added thereto in portions at 0℃and reacted at room temperature for 12 hours, triethylamine (1.59 mL,83 mmol) and tert-butyl (1R, 3R) -3-aminocyclobutane-1-carboxylate hydrochloride (17.27 g,83 mmol) were added thereto in sequence, 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, and dried over anhydrous sodium sulfate. Suction filtration, concentration and beating of the residue with petroleum ether (800 mL) gave 27.85g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ10.31(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＝7.0Hz,3H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ174.77,165.91,153.47,152.99,133.83,111.81,109.18,80.18,60.44,43.57,33.58,33.41,28.15,18.26,14.58。
MS(ESI)m/z:383.4[M+H] + 。
Step five: synthesis of tert-butyl (1R, 3R) -3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylate
Ethyl 2- (3- ((1 r,3 r) -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 ℃ for 1 hour. The reaction mixture was cooled to room temperature, a saturated ammonium chloride solution (500 mL) and ethyl acetate (500 mL) were added, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration, concentration and beating of the residue with a mixed solvent of petroleum ether and ethyl acetate (100 mL, petroleum ether: ethyl acetate=10:1) gave 16.21g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.06(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(125MHz,DMSO-d 6 ):δ175.12,159.93,151.91,150.87,134.66,113.34,111.89,80.15,44.30,33.39,29.92,28.18,16.27。
Step six: synthesis of (1R, 3R) -3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid tert-butyl ester
N-bromosuccinimide (8.58 g,48.2 mmol) was added in three portions to a solution of tert-butyl (1R, 3R) -3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylate (16.21 g,48.2 mmol) in methylene chloride (350 mL) at 0deg.C, reacted for 30 min at 0deg.C, the reaction solution was diluted with methylene chloride (200 mL), the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (150 mL, petroleum ether: ethyl acetate=5:1), suction filtered to give 21g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.06(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(125MHz,DMSO-d 6 ):δ179.82,159.05,151.19,150.32,134.23,112.84,99.95,80.20,44.56,33.42,29.99,28.18,14.92。
Step seven: synthesis of (1R, 3R) -3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylic acid
Trifluoroacetic acid (45 mL, 284 mmol) was slowly added to a solution of tert-butyl (1R, 3R) -3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclobutane-1-carboxylate (18 g,43.3 mmol) in dichloromethane (225 mL) at 0deg.C and the mixture was reacted at room temperature for 12H. The reaction solution was poured into ice water (1500 mL) and suction-filtered to obtain 13.5g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.06(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(125MHz,DMSO-d 6 ):δ177.28,159.01,151.14,150.31,134.19,112.78,99.93,44.58,32.39,29.96,14.89。
MS(ESI)m/z:357.1[M-H] - 。
Step eight: synthesis of methyl (1R, 3R) -3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3- (2H) -yl) cyclobutane-1-carboxylate
(1R, 3R) -3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3- (2H) -yl) cyclobutane-1-carboxylic acid (5.0 g,13.92 mmol) and dichloromethane (50 mL) were mixed, N-carbonyldiimidazole (2.7 g,16.70 mmol) was added thereto in portions at 0℃and the reaction was carried out at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added to the residue and stirred for 30 minutes, followed by suction filtration, washing the cake with water, and drying to obtain 4.1g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.18(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: synthesis of methyl (1R, 3R) -3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3- (2H) -yl) cyclobutane-1-carboxylate
Methyl (1R, 3R) -3- (6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3- (2H) -yl) cyclobutane-1-carboxylate (4.0 g,10.72 mmol), triethylamine (43.2 mL,310 mmol), N-dimethylformamide (50 mL), bis (triphenylphosphine) 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) was added to the pressure-resistant tube and the mixture was sealed at 80℃for 6 hours. The reaction solution was cooled to room temperature, the reaction solution was poured into water (300 mL), extracted with ethyl acetate (3×100 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, suction-filtered, and the crude product obtained was concentrated and purified by silica gel column chromatography (dichloromethane: methanol=50:1) to give 870mg of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.13(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[M-H] - 。
Step ten: synthesis of (1R, 3R) -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 (1R, 3R) -3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3- (2H) -yl) cyclobutane-1-carboxylate (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 reaction solution was adjusted to pH 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, the filtrate was concentrated, and the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (15 mL, petroleum ether: ethyl acetate=1:1) to give 0.73g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.18(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[M-H] - 。
Step eleven: synthesis of tert-butyldiphenylsilyl (1R, 3R) -3- (5-methyl-2, 4-dioxo-6- (prop-1-yn-1-yl) -1, 4-dihydrothieno [2,3-d ] pyrimidin-3- (2H) -yl) cyclobutane-1-carboxylate
(1R, 3R) -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), t-butyldiphenylchlorosilane (0.71 g, 0.578 mL,2.56 mmol) were mixed and reacted at room temperature for 4 hours. The reaction solution was filtered with suction, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=8:1) to give the title compound (0.9 g).
1 H-NMR(500MHz,DMSO-d 6 ):δ12.16(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 twelve: synthesis of Compounds of formula I-2
(1R, 3R) -3- (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 tert-butyldiphenylsilyl ester (0.83 g,1.491 mmol), (R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethan-1-ol (0.38 g,1.491 mmol), tetrahydrofuran (2.5 mL) and triphenylphosphine (1.17 g,4.47 mmol) were mixed, nitrogen was replaced three times, the ice salt bath was cooled to below 0 ℃, diisopropyl azodicarboxylate (0.91 g,4.47 mmol) was added dropwise and the reaction was reacted at room temperature for 5 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated, and the residue was separated and purified by a Biotage C18 g reverse phase chromatography column (water: acetonitrile=1:1) to give the title compound 70mg.
1 H-NMR(500MHz,DMSO-d 6 ):δ12.27(s,1H),7.46(dd,J＝7.5,1.4Hz,1H),7.34-7.25(m,1H),7.03(t,J＝7.3Hz,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[M-H] - 。
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 ] pyrimidin-3 (2H) -yl) benzoic acid (compound of formula I-3)
Step one: synthesis of ethyl 2- (3- (4- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate
Ethyl 2-amino-4-methylthiophene-3-carboxylate (10 g,54 mmol) was dissolved in dichloromethane (70 mL), cooled in an ice-water bath, N-carbonyldiimidazole (9.63 g,59.4 mmol) was added slowly in portions, the ice bath was removed after the addition, and the reaction was carried out overnight at room temperature. Triethylamine (8.25 ml,59.4 mmol) and ethyl 4-aminobenzoate (9.81 g,59.4 mmol) were added sequentially to the reaction solution, and the mixture was reacted overnight at room temperature. Water (100 mL) was added to the reaction mixture, and a solid was precipitated, suction filtration and drying of the cake gave the title compound (5.7 g). The organic phase was separated from the filtrate, dried over anhydrous sodium sulfate, suction-filtered, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=4:1) to give 3.8g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ10.77(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(125MHz,DMSO-d 6 ):δ165.92,165.83,152.08,151.37,144.12,134.16,130.87,123.93,118.05,112.82,110.60,60.83,60.70,18.24,14.70,14.56。
MS(ESI)m/z:377.3[M+H] + 。
Step two: synthesis of ethyl 4- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) benzoate
Ethyl 2- (3- (4- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate (7.5 g,19.92 mmol) was mixed with N, N-dimethylformamide (75 mL), sodium hydride (1.20 g,29.9 mmol) was added in three portions under nitrogen protection, and the mixture was heated to 100 ℃ for 2 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution (225 mL) was added, and a solid was precipitated. Suction filtration and drying of the filter cake gave 3.6g of the title compound.
MS(ESI)m/z:329.2[M-H] - 。
Step three: synthesis of ethyl (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) 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 and heated to 100deg.C for 20 hours. To the reaction solution were added water (100 mL) and ethyl acetate (100 mL), the aqueous phase was extracted with ethyl acetate (100 ml×2), and the organic phases were combined, washed successively with water, saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give 2.1g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ8.09(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(125MHz,DMSO-d 6 ):δ165.71,158.66,157.08,156.11,150.29,140.80,135.28,130.32,130.26,130.03,129.73,127.69,127.05,121.28,113.66,113.20,111.45,71.91,69.61,64.59,64.29,61.45,55.98,53.45,33.31,31.41,16.45,14.64。
MS(ESI)m/z:565.4[M+H] + 。
Step four: synthesis of ethyl (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) benzoate
Ethyl (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) benzoate (1.5 g,2.66 mmol) was mixed with dichloromethane (15 mL), cooled in an ice water bath, and bromosuccinimide (0.52 g,2.92 mmol) was added and reacted at 0℃for 1 hour. The reaction solution was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered off with suction, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=9:1) to give the title compound 1.45g.
1 H-NMR(500MHz,DMSO-d 6 ):δ8.10(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 five: synthesis of ethyl (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 ] pyrimidin-3 (2H) -yl) benzoate (Compound of formula I-10)
Ethyl (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) benzoate (750 mg,1.165 mmol), bis triphenylphosphine 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 in tetrahydrofuran) (2.91 mL,2.91 mmol) were added and the reaction was blocked at 80℃for 10 hours. To the reaction solution was added water (20 mL), the aqueous phase was extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, suction-filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give 456mg of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ8.10(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 six: synthesis of I-3 Compounds
Methyl (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 ] pyrimidin-3 (2H) -yl) benzoate (400 mg,0.664 mmol) was mixed with an aqueous solution (0.5 mL) of methanol (1.5 mL), tetrahydrofuran (1 mL), lithium hydroxide hydrate (178 mg,6.64 mmol) and reacted at room temperature for 5 hours. 2N diluted hydrochloric acid was added to the mixture in an ice bath to adjust the 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. Times.4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, concentrated and purified by column chromatography on silica gel (dichloromethane: methanol=10:1) to give 75mg of the I-3 compound.
1 H-NMR(500MHz,CDCl 3 ):δ8.25(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(125MHz,CDCl 3 ):δ169.82,158.38,156.95,154.21,150.29,140.17,140.00,131.38,129.70,129.37,129.00,127.29,127.07,120.99,113.46,110.96,110.35,94.03,72.12,70.87,69.70,65.34,65.02,55.45,53.85,33.19,31.38,15.06,4.84。
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 ] pyrimidin-3 (2H) -yl) benzoic acid (compound of formula I-4)
Step one: synthesis of ethyl 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate
Ethyl 2-amino-4-methylthiophene-3-carboxylate (15 g,81 mmol) was mixed with dichloromethane (140 mL), cooled in an ice-water bath, carbonyldiimidazole (14.44 g,89 mmol) was added in portions, the ice-bath was removed after the addition, and the reaction was carried out overnight at room temperature. Triethylamine (12.42 mL,89 mmol) and ethyl 3-aminobenzoate (14.71 g,89 mmol) were added sequentially to the reaction solution, and the mixture was reacted overnight at room temperature. To the reaction solution was added water (100 mL), extracted with dichloromethane (100 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and purified by silica gel column chromatography (dichloromethane) to give 4.3g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ10.72(s,1H),10.50(s,1H),8.16(d,J＝2.5Hz,1H),7.76(d,J＝8.2Hz,1H),7.61(d,J＝7.8Hz,1H),7.46(t,J＝8.0Hz,1H),6.55(s,1H),4.33(q,J＝7.2Hz,4H),2.30(s,3H),1.34(td,J＝7.2,3.5Hz,6H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ166.04,165.94,152.32,151.53,140.01,134.10,130.99,129.78,123.55,123.11,119.08,112.61,110.33,61.27,60.65,18.24,14.65,14.56。
MS(ESI)m/z:377.4[M+H] + 。
Step two: synthesis of ethyl 3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) benzoate
Ethyl 2- (3- (3- (ethoxycarbonyl) phenyl) ureido) -4-methylthiophene-3-carboxylate (4 g,10.63 mmol) was mixed with N, N-dimethylformamide (40 mL), cooled in an ice-water bath, and sodium hydride (0.428 g,15.94 mmol) was added in three portions under nitrogen purge, and the mixture was heated to 100 ℃ for reaction for 1h. After cooling to room temperature, a saturated aqueous ammonium chloride solution (100 mL) was added, and a solid was precipitated. Suction filtration and filter cake drying gave the title compound 2.3g.
MS(ESI)m/z:329.2[M-H] - 。
Step three: synthesis of ethyl (R) -3- (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) 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) and N-methylpyrrolidone (20 mL) were mixed and heated to 100 ℃ under nitrogen protection overnight. To the reaction solution were added water (100 mL) and ethyl acetate (100 mL), and the aqueous phase was separated and extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give 550mg of the title compound.
1 H NMR(500MHz,DMSO-d 6 ):δ8.04(d,J＝7.9Hz,1H),7.81(s,1H),7.68(t,J＝7.9Hz,1H),7.54(d,J＝8.0Hz,1H),7.47(d,J＝7.6Hz,1H),7.32(t,J＝8.0Hz,1H),7.08-6.98(m,2H),6.89(s,1H),5.34(t,J＝6.7Hz,1H),4.36(q,J＝7.4Hz,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＝8.8Hz,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 four: synthesis of ethyl (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) benzoate
Ethyl (R) -3- (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) benzoate (0.53 g,0.939 mmol) was mixed with dichloromethane (5 mL), cooled in an ice-water bath, and bromosuccinimide (0.184 g,1.032 mmol) was added and reacted at 0℃for 3 hours. The reaction solution was washed with water and saturated brine in this order, and the organic phases were combined, dried over anhydrous sodium sulfate, suction-filtered, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give 475mg of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ8.05(d,J＝7.9Hz,1H),7.82(s,1H),7.68(t,J＝7.9Hz,1H),7.54(d,J＝7.9Hz,1H),7.51-7.45(m,1H),7.32(t,J＝7.7Hz,1H),7.08-6.97(m,2H),5.29(dd,J＝8.5,4.6Hz,1H),4.35(q,J＝7.2Hz,2H),4.08(d,J＝13.3Hz,1H),3.93(s,1H),3.83(s,1H),3.78(s,3H),3.62(dd,J＝11.9,5.8Hz,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＝7.0Hz,3H)。
MS(ESI)m/z:643.4[M+H] + 。
Step five: synthesis of ethyl (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 ] pyrimidin-3 (2H) -yl) benzoate (Compound of formula I-11)
Ethyl (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) benzoate (213 mg,0.331 mmol), bis triphenylphosphine 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) and propyne (1M tetrahydrofuran solution) (0.284 mL, 0.284 mmol) were added and the reaction was blocked at 80℃overnight. Water (20 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give 77mg of the compound of formula I-11.
MS(ESI)m/z:603.4[M+H] + 。
Step six: synthesis of Compound of formula I-4
A compound of formula I-11 (77 mg,0.128 mmol), methanol (6 mL), tetrahydrofuran (2 mL) and an aqueous solution of lithium hydroxide hydrate (107 mg,2.56 mmol) (2 mL) were mixed and reacted at room temperature for 1 hour. 2N hydrochloric acid solution was added to adjust pH to 5-6 under ice bath, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was extracted with ethyl acetate (10 mL. Times.2). The organic phases were combined, washed successively with water, saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:2) to give 44mg of the compound of formula I-4.
1 H NMR(500MHz,DMSO-d 6 ):13.22(br,1H),8.02(d,J＝7.8Hz,1H),7.79(s,1H),7.65(t,J＝7.8Hz,1H),7.49(t,J＝7.9Hz,2H),7.32(t,J＝7.8Hz,1H),7.10–6.94(m,2H),5.30(dd,J＝8.5,4.9Hz,1H),4.08(s,1H),3.93(s,1H),3.77(s,3H),3.60(dt,J＝10.8,5.7Hz,2H),3.47–3.39(m,3H),2.40(s,3H),2.15(s,3H),1.68(t,J＝15.8Hz,2H),1.41–1.32(m,1H),1.28(s,1H)。
MS(ESI)m/z:573.4[M-H] - 。
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 ] pyrimidin-3 (2H) -yl) pyridine-2-carboxylic acid (compound of formula I-5)
Step one: synthesis of ethyl 4-methyl-2- ((phenoxycarbonyl) amino) thiophene-3-carboxylate
Ethyl 2-amino-4-methylthiophene-3-carboxylate (60.2 g,325 mmol) was mixed with ethyl acetate (500 mL), a saturated aqueous sodium hydrogencarbonate solution (500 mL), and phenyl chloroformate (61.1 g,390 mmol) was added thereto and reacted at room temperature for 17 hours. Ethyl acetate (1L) was added to the reaction mixture until the solid was completely dissolved, and an aqueous phase was separated and extracted with ethyl acetate (200 mL. Times.2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the resulting crude product was slurried with petroleum ether, suction filtered, and the cake was dried to give 88.3g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ10.74(s,1H),7.45-7.48(m,2H),7.29-7.33(m,3H),6.74(s,1H),4.33(q,J＝7.0Hz,2H),2.32(s,3H),1.34(t,J＝7.0Hz,3H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ165.6,151.3,150.6,150.2,135.1,130.1,126.6,122.1,113.7,61.2,17.9,14.5。
MS(ESI)m/z:327.9[M+Na] + 。
Step two: synthesis of methyl 4- (3- (3- (ethoxycarbonyl) -4-methylthiophene-2-yl) ureido) pyridine-2-carboxylate
Methyl 4-aminopyridine-2-carboxylate (10 g,65.7 mmol), ethyl 4-methyl-2- ((phenoxycarbonyl) amino) thiophene-3-carboxylate (24.08 g,79 mmol), triethylamine (12.83 mL,92 mmol) were mixed with toluene (100 mL), and the mixture was heated to 110 ℃ for reaction for 5 hours. The reaction solution was cooled to room temperature, suction-filtered, and the cake was slurried with petroleum ether and ethyl acetate, suction-filtered, and the cake was dried to give 17.6g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ10.93(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＝7.0Hz,3H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ165.94,165.74,151.53,151.27,150.97,148.80,147.56,134.27,115.55,113.96,113.09,111.07,60.81,52.88,18.18,14.54。
MS(ESI)m/z:364.4[M+H] + 。
Step three: synthesis of methyl 4- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) pyridine-2-carboxylate/ethyl 4- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) pyridine-2-carboxylate
Methyl 4- (3- (3- (ethoxycarbonyl) -4-methylthiophene-2-yl) carbamate (9 g,24.77 mmol) was mixed with N, N-dimethylformamide (140 mL), sodium hydride (1.19 g,29.7 mmol) was added in three portions under nitrogen protection, and the mixture was heated to 60℃for 1 hour. The reaction mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution (420 mL) was added to precipitate a solid. Suction filtration and drying of the filter cake gave 4.1g of the title compound (mixture of methyl ester and ethyl ester in a ratio of 3:2).
MS(ESI)m/z:316.1[M-H] - (methyl ester), 330.2[ M-H] - (ethyl ester).
Step four: synthesis of methyl (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-carboxylate/(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-carboxylate
Methyl 4- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) pyridine-2-carboxylate was mixed with ethyl 4- (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) and N-methylpyrrolidone (30 ml) and the mixture was heated to 100℃for reaction for 7 hours. Suction filtration, filter cake washing with ethyl acetate, adding water (100 mL) to the filtrate, separating the aqueous phase, extracting with ethyl acetate (100 mL. Times.3), combining the organic phases, washing with water, saturated brine in this order. The organic phase was dried over anhydrous sodium sulfate, filtered off with suction, concentrated and purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:1) to give 2.7g of the title compound (methyl ester to ethyl ester ratio 1:1).
MS(ESI)m/z:552.4[M+H] + (methyl ester), 566.4[ M+H ]] + (ethyl ester).
Step five: synthesis of methyl (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-carboxylate/(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-carboxylate
A mixture of (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 methyl ester and (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 (2.7 g) was mixed with dichloromethane (30 mL), cooled in an ice water bath, and bromosuccinimide (0.871 g,4.89 mmol) was added and reacted at 0℃for 1 hour. The reaction solution was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered off with suction, concentrated and dissolved in acetonitrile, and purified by a Biotage C18 g reverse phase chromatography column (water: acetonitrile=2:3) to give 0.89g of the title compound (ratio of methyl ester to ethyl ester 1:1).
MS(ESI)m/z:630.3[M+H] + (methyl ester), 644.4[ M+H] + (ethyl ester).
Step six: synthesis of methyl (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 ] pyrimidin-3 (2H) -yl) pyridine-2-carboxylate (Compound of formula I-12)/(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 ] pyrimidin-3 (2H) -yl) pyridine-2-carboxylate (Compound of formula I-13)
Methyl (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-carboxylate was mixed with ethyl (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-carboxylate mixture (700 mg), bis (triphenylphosphine) palladium dichloride (78 mg,0.111 mmol), cuprous iodide (42.3 mg,0.222 mmol) and N, N-dimethylformamide (10 mL). After purging with nitrogen, triethylamine (0.460 mL,3.33 mmol) and propyne (1M tetrahydrofuran solution) (2.78 mL,2.78 mmol) were added and the reaction was blocked at 80℃for 2 hours. To the reaction mixture was added water (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with water and saturated brine in this order. The organic phase is dried over anhydrous sodium sulfate, filtered off with suction, concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:2) to give 456mg of a mixture of compounds of formula I-12 and of formula I-13 (ratio of methyl ester to ethyl ester 1:1).
A compound of formula I-12: MS (ESI) m/z 590.5[ M+H ]] + The method comprises the steps of carrying out a first treatment on the surface of the A compound of formula I-13: MS (ESI) m/z 604.5[ M+H ]] + 。
Step seven: synthesis of Compound of formula I-5
A mixture of the compound of formula I-12 and the compound of formula I-13 (250 mg), methanol (1.5 mL), and an aqueous solution of lithium hydroxide hydrate (49.7 mg,1.185 mmol) (0.5 mL) were mixed and reacted at room temperature for 2 hours. To the reaction mixture were added water (10 mL) and ethyl acetate (10 mL), and a 2N hydrochloric acid solution was added under an ice bath to adjust the pH to 5-6. The aqueous phase was separated, extracted with ethyl acetate (10 ml×4), the organic phases combined, dried over anhydrous sodium sulfate, filtered off with suction, concentrated and dissolved in tetrahydrofuran, and purified by Biotage C18 g reverse phase chromatography (water: acetonitrile=2:3) to give 87mg of the compound of formula I-5.
1 H-NMR(500MHz,CDCl 3 ):δ8.77(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(125MHz,CDCl 3 ):δ157.40,156.95,154.35,149.53,139.77,129.51,127.12,127.04,121.00,113.20,110.43,94.26,72.04,70.70,69.69,65.40,65.10,55.50,53.90,33.23,31.52,14.99,4.81。
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 ] pyrimidin-3 (2H) -yl) pyridine-2-carboxylic acid (compound of formula I-6)
Step one: synthesis of methyl 6- (3- (3- (ethoxycarbonyl) -4-methylthiophene-2-yl) ureido) pyridine-2-carboxylate
Methyl 6-aminopyridine-2-carboxylate (10 g,65.7 mmol), ethyl 4-methyl-2- ((phenoxycarbonyl) amino) thiophene-3-carboxylate (24.08 g,79 mmol), triethylamine (12.83 mL,92 mmol) were mixed with toluene (100 mL), and the mixture was heated to 110 ℃ for reaction for 12 hours. The reaction solution was cooled to room temperature, suction-filtered, and the cake was slurried with petroleum ether and ethyl acetate, suction-filtered, and the cake was dried to give 16.6g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ11.23(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(125MHz,DMSO-d 6 ):δ165.34,164.82,152.83,151.69,150.80,146.19,140.08,134.49,119.79,116.60,113.16,111.58,60.49,52.80,18.18,14.66。
MS(ESI)m/z:364.4[M+H] + .
Step two: synthesis of methyl 6- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) pyridine-2-carboxylate/ethyl 6- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) pyridine-2-carboxylate
Methyl 6- (3- (3- (ethoxycarbonyl) -4-methylthiophene-2-yl) carbamate (8 g,22.02 mmol) was mixed with N, N-dimethylformamide (50 mL), sodium hydride (1.23 g,30.8 mmol) was added in three portions under nitrogen protection, and the mixture was heated to 60℃for 1 hour. The reaction mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution (250 mL) was added to precipitate a solid. Suction filtration and drying of the filter cake gave 3.5g of the title compound (mixture of methyl ester and ethyl ester in a ratio of 3:2).
MS(ESI)m/z:316.1[M-H] - (methyl ester), 330.2[ M-H] - (ethyl ester).
Step three: synthesis of methyl (R) -6- (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-carboxylate/(R) -6- (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-carboxylate
Methyl 6- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidine-3 (2H) -yl) pyridine-2-carboxylate was mixed with 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) and N-methylpyrrolidone (30 mL), and the mixture was heated to 100℃for 7 hours. Suction filtration, filter cake washing with ethyl acetate, adding water (100 mL) to the filtrate, separating the aqueous phase, extracting with ethyl acetate (100 mL. Times.3), combining the organic phases, washing with water, saturated brine in this order. The organic phase was dried over anhydrous sodium sulfate, filtered off with suction, concentrated and purified by column chromatography on silica gel (ethyl acetate: petroleum ether=1:1) to give 1.5g of the title compound (1:1 ratio of methyl ester to ethyl ester).
MS(ESI)m/z:552.4[M+H] + (methyl ester), 566.4[ M+H ]] + (ethyl ester).
Step four: synthesis of methyl (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-carboxylate/(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-carboxylate
A mixture (1.1 g) of (R) -6- (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 and (R) -6- (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 (1.1 g) were mixed with dichloromethane (30 mL), cooled in an ice water bath, and bromosuccinimide (0.355 g,1.994 mmol) was added and reacted at 0℃for 1 hour. The reaction solution was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered off with suction, concentrated and dissolved in acetonitrile, and purified by a Biotage C18 g reverse phase chromatography column (water: acetonitrile=2:3) to give 0.43g of the title compound (ratio of methyl ester to ethyl ester 1:1).
MS(ESI)m/z:630.4[M+H] + (methyl ester), 644.4[ M+H] + (ethyl ester).
Step five: synthesis of methyl (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 ] pyrimidin-3 (2H) -yl) pyridine-2-carboxylate (Compound of formula I-14)/(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 ] pyrimidin-3 (2H) -yl) pyridine-2-carboxylate (Compound of formula I-15)
Methyl (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-carboxylate was mixed with a mixture (400 mg) of ethyl (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-carboxylate, bis (triphenylphosphine) palladium dichloride (44.5 mg,0.063 mmol), cuprous iodide (24.16 mg,0.127 mmol) and N, N-dimethylformamide (10 mL). After purging with nitrogen, triethylamine (0.265 mL,1.903 mmol) and propyne (1M in tetrahydrofuran) were added (1.586 mL,1.586 mmol) and the reaction was capped at 80℃for 2 hours. To the reaction mixture was added water (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with water and saturated brine in this order. The organic phase is dried over anhydrous sodium sulfate, filtered off with suction, concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:2) to give 326mg of a mixture of the compounds of formula I-14 and of the compounds of formula I-15 (the ratio of the compounds of formula I-14 to the compounds of formula I-15 is 1:1).
A compound of formula I-14: MS (ESI) m/z 590.4[ M+H ]] + The method comprises the steps of carrying out a first treatment on the surface of the A compound of formula I-15: MS (ESI) m/z 604.4[ M+H ]] + . Step six: synthesis of Compounds of formula I-6
A mixture of the compound of formula I-14 and the compound of formula I-15 (300 mg), methanol (5 mL), and an aqueous solution of lithium hydroxide hydrate (64 mg,1.526 mmol) (1.5 mL) were mixed and reacted at room temperature for 2 hours. To the reaction mixture were added water (10 mL) and ethyl acetate (10 mL), and a 2N hydrochloric acid solution was added under an ice bath to adjust the pH to 5-6. The aqueous phase was separated, extracted with ethyl acetate (10 ml×3), the organic phases combined, dried over anhydrous sodium sulfate, filtered off with suction, concentrated and dissolved in tetrahydrofuran, and purified by Biotage C18 g reverse phase chromatography (water: acetonitrile=1:1) to give 76mg of the compound of formula I-6.
1 H-NMR(500MHz,CDCl 3 ):δ8.34(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 ] pyrimidin-3 (2H) -yl) nicotinic acid (compound of formula I-7)
Step one: synthesis of methyl 5- (3- (3- (ethoxycarbonyl) -4-methylthiophene-2-yl) 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℃for 10 hours. The reaction solution was cooled to room temperature, filtered with suction, and the cake was washed with water and dried. The crude product was purified by beating with methylene chloride, suction filtration and drying of the filter cake to give 9.9g of the title compound.
1 H-NMR(500MHz,DMSO-d 6 ):δ10.80(s,1H),10.70(s,1H),8.75(d,J＝2.6Hz,1H),8.72(d,J＝2.4Hz,1H),8.56(d,J＝2.4Hz,1H),6.57(s,1H),4.32(q,J＝7.1Hz,2H),3.90(s,3H),2.29(s,3H),1.34(t,J＝7.1Hz,3H)。
13 C-NMR(125MHz,DMSO-d 6 ):δ165.94,165.60,151.94,151.57,143.95,143.94,136.54,134.15,125.93,125.31,112.80,110.64,60.72,52.94,18.19,14.53。
MS(ESI)m/z:364.4[M+H] + .
Step two: synthesis of methyl 3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) benzoate/ethyl 3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) benzoate
Methyl 5- (3- (3- (ethoxycarbonyl) -4-methylthiophene-2-yl) nicotinate (5 g,13.76 mmol) was mixed with N, N-dimethylformamide (50 mL), cooled in an ice-water bath, sodium hydride (0.660 g,16.51 mmol) was added in portions under a nitrogen purge, and the mixture was heated to 100℃for reaction for 1 hour. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution was added, suction filtration was performed, and the cake was washed with water and dried. The crude product obtained was purified by beating with methylene chloride and methanol, suction filtration and drying of the filter cake to give 3.1g of the title compound (mixture of methyl ester and ethyl ester, ratio of 3:2).
MS(ESI)m/z:318.4[M+H] + (methyl ester).
Step three: synthesis of methyl (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/(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 ethyl ester
Methyl (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) benzoate/ethyl 3- (5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) benzoate (1 g), cesium carbonate (1.540 g,4.73 mmol) and N-methylpyrrolidone (30 mL) were mixed and the mixture was heated to 100℃for reaction for 5 hours. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined, washed successively with water, saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate: petroleum ether=3:2) to give 740mg of the title compound (methyl ester to ethyl ester ratio 1.2:1).
MS(ESI)m/z:552.4[M+H] + (methyl ester).
Step four: synthesis of methyl (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/(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 ethyl ester
A compound (0.31 g) of (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 was mixed with (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 ethyl ester (0.31 g) and dichloromethane (5 mL), cooled in an ice water bath, and bromosuccinimide (0.091 g,0.513 mmol) was added and reacted at 0℃for 1 hour. Dichloromethane (50 mL) was added for dilution, followed by washing with water, saturated brine, drying over anhydrous sodium sulfate, suction filtration, concentration and purification by silica gel column chromatography (ethyl acetate: petroleum ether=4:1) gave 280mg (methyl ester to ethyl ester ratio 1.1:1) of the title compound.
MS(ESI)m/z:630.4[M+H] + (methyl ester).
Step five: synthesis of methyl (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 ] pyrimidin-3 (2H) -yl) nicotinate (Compound of formula I-16)/(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 ] pyrimidin-3 (2H) -yl) nicotinate ethyl ester (Compound of formula I-17)
Methyl (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 was mixed with a mixture of ethyl (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 (200 mg), bis (triphenylphosphine) palladium dichloride (22.26 mg,0.032 mmol), cuprous iodide (12.08 mg,0.063 mmol) and N, N-dimethylformamide (3 mL). After purging with nitrogen, triethylamine (0.133 mL,0.952 mmol), propyne (1M tetrahydrofuran solution) (0.284 mL, 0.284 mmol) was added and the reaction was capped at 80℃for 24 hours. To the reaction mixture was added water (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined and washed with water and saturated brine in this order. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by Biotage C18 g reverse phase chromatography (water: acetonitrile=1:2) to give 100mg of a compound of formula I-16, a compound mixture of formula I-17 (ratio of compound of formula I-16 to compound of formula I-17: 1:1).
A compound of formula I-16: MS (ESI) m/z 590.4[ M+H ]] + 。
Step six: synthesis of Compounds of formula I-7
A mixture of the compound of formula I-16 and the compound of formula I-17 (100 mg), methanol (6 mL), and an aqueous solution of lithium hydroxide hydrate (142 mg,3.39 mmol) (2 mL) were mixed and reacted at room temperature for 1 hour. Adding 2N hydrochloric acid solution under ice bath to adjust pH to 5-6, and separating out solid. Suction filtration and purification of the crude product by Biotage C18 g reverse phase chromatography column (water: acetonitrile=1:1) gives 6mg of the compound of formula I-7.
1 H NMR(500MHz,DMSO-d 6 ):δ13.56(br,1H),9.12(s,1H),8.66(s,1H),8.21(s,1H),7.48(d,J＝7.5Hz,1H),7.32(t,J＝7.8Hz,1H),7.12–6.87(m,2H),5.30(d,J＝6.2Hz,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＝21.1Hz,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-methylpropanoic acid (compound of formula I-8)
Step one: synthesis of tert-butyl 2- ((1, 3-dioxoisoindol-2-yl) oxy) -2-methylpropionate
Tert-butyl 2-bromo-2-methylpropionate (5 g,22.41 mmol), N-hydroxyphthalimide (3.66 g,22.41 mmol), potassium carbonate (3.72 g,26.9 mmol) and DMF (60 ml) were mixed and reacted at 90℃for 20 hours. The reaction solution was filtered by suction, the filtrate was added with water and ethyl acetate, the solution was separated, the aqueous phase was extracted with ethyl acetate (200 ml×3), the organic phases were combined, washed with water (200 ml×3), saturated brine (100 mL), and dried over anhydrous sodium sulfate, respectively. Suction filtration and concentration of the filtrate gave a yellow oil which was purified by column chromatography (ethyl acetate: petroleum ether=2:3) to give 720mg of the title compound.
1 H NMR(500MHz,CDCl 3 ):δ7.86-7.84(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 two: synthesis of tert-butyl 2- (aminooxy) -2-methylpropionate
Tert-butyl 2- ((1, 3-dioxoisoindol-2-yl) oxy) -2-methylpropionate (7 g,22.93 mmol) was dissolved in a mixed solution of dichloromethane (33 mL) and methanol (6 mL), and hydrazine hydrate (4.59 g,92 mmol) was added dropwise thereto with stirring at room temperature, and the reaction was stirred for 1.5 hours after the addition. The mixture was filtered off with suction, the cake was washed with dichloromethane (30 mL), the filtrate was concentrated, the residue was diluted with ethyl acetate (50 mL), and then washed with water (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate was concentrated to give the title compound 3.4g.
1 H NMR(500MHz,CDCl 3 ):δ5.313(s,2H),1.489(s,9H),1.378(s,6H)。
GCMS m/z:119[M-C 4 H 8 ] +
Step three: synthesis of ethyl 4-methyl-2- ((phenoxycarbonyl) amino) thiophene-3-carboxylate
Ethyl 2-amino-4-methylthiophene-3-carboxylate (1 g,5.40 mmol), ethyl acetate (15 mL) and saturated aqueous sodium hydrogencarbonate solution (15 mL) were mixed and stirred at room temperature, phenyl chloroformate (0.845 g,5.40 mmol) was added thereto, and after the addition was completed, the reaction was continued at room temperature with stirring for 2 hours. The reaction mixture 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 off with suction, the filtrate was concentrated, and the residual solid was slurried with petroleum ether (10 mL) to give the title compound 1.25g.
Step four: synthesis of ethyl 2- (3- ((1- (tert-butoxy) -2-methyl-1-oxopropan-2-yl) oxy) ureido) -4-methylthiophene-3-carboxylate
Ethyl 4-methyl-2- ((phenoxycarbonyl) amino) thiophene-3-carboxylate (0.5 g,1.637 mmol), toluene (5 ml), tert-butyl 2- (aminooxy) -2-methylpropionate (0.344 g,1.965 mmol) and triethylamine (0.199g, 1.965 mmol) were mixed and reacted at 90℃with stirring for 7 hours. After the reaction was stopped, the reaction mixture was cooled to room temperature, toluene was removed under reduced pressure, and petroleum ether was used as a residual yellow oil: methyl tertiary butyl ether = 3:1 mixed solvent (10 mL) was slurried to afford the title compound 0.376g.
1 H NMR(500MHz,DMSO-d 6 ):δ11.29(s,1H),10.10(s,1H),6.59(s,1H),4.31(q,J＝7.0Hz,2H),2.31(s,3H),1.44(s,6H),1.30-1.33(m,12H)。
MS(ESI)m/z:409.02[M+Na] + 。
Step five: synthesis of ethyl 5-bromo-2- (3- ((1- (tert-butoxy) -2-methyl-1-oxopropan-2-yl) oxy) ureido) -4-methylthiophene-3-carboxylate
Ethyl 2- (3- ((1- (tert-butoxy) -2-methyl-1-oxopropan-2-yl) oxy) ureido) -4-methylthiophene-3-carboxylate (0.35 g,0.906 mmol) and DMF (5 ml) were mixed, the mixture was stirred and cooled to 0℃and N-bromosuccinimide (0.161 g,0.906 mmol) was added thereto, and after the addition was completed, the mixture was allowed to stand at room temperature with stirring for 1.5 hours. The reaction was diluted with water (20 mL), extracted with ethyl acetate (20 mL), the organic phase was washed successively with water (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the residue was concentrated with petroleum ether: methyl tertiary butyl ether = 3:1 mixed solvent (10 mL) was slurried to afford the title compound 0.408g.
1 H NMR(500MHz,DMSO-d 6 ):δ11.34(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 six: synthesis of 2- ((6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothiophene [2,3-d ] pyrimidin-3 (2H) -yl) oxy) -2-methylpropanoic acid
Ethyl 5-bromo-2- (3- ((1- (tert-butoxy) -2-methyl-1-oxopropan-2-yl) oxy) ureido) -4-methylthiophene-3-carboxylate (10 g,21.49 mmol) was dispersed in absolute ethanol (120 mL), and the mixture was stirred under nitrogen atmosphere at room temperature, to which was added dropwise sodium methoxide 25% m/v methanol solution (16.24 mL,75 mmol) and the reaction was stirred at room temperature for 20 hours after the addition. The reaction solution was added to water (600 mL), pH was adjusted to acidity with 2M hydrochloric acid, extracted with ethyl acetate (200 mL x 2), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated residue was separated and purified by silica gel column (petroleum ether: ethyl acetate=2:1) to give the title compound 1.3g.
1 H NMR(500MHz,DMSO-d 6 ):δ12.85(br,1H),12.50(br,1H),2.31(s,3H),1.44(s,6H)。
MS(ESI)m/z:364.8[M+H] + 。
Step seven: synthesis of benzyl 2- ((6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothiophene [2,3-d ] pyrimidin-3 (2H) -yl) oxy) -2-methylpropionate
2- ((6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) oxy) -2-methylpropanoic 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℃with microwaves for 1 hour. The reaction solution was diluted with ethyl acetate (150 mL), washed successively with a saturated aqueous sodium hydrogencarbonate solution (100 mL) and a saturated brine (100 mL), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated to give the title compound 6.25g, which was used directly in the next reaction.
Step eight: synthesis of benzyl (R) -2- ((6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothiophen [2,3-d ] pyrimidin-3 (2H) -yl) oxy) -2-methylpropionate
(R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethan-1-ol (6.01 g,23.82 mmol), benzyl 2- ((6-bromo-5-methyl-2, 4-dioxo-1, 4-dihydrothiophene [2,3-d ] pyrimidin-3 (2H) -yl) oxy) -2-methylpropionate (9 g,19.85 mmol), triphenylphosphine (8.18 g,31.2 mmol) and tetrahydrofuran (120.000 mL) were mixed, stirred at 0℃under nitrogen, and a solution of di-tert-butyl azodicarboxylate (7.18 g,31.2 mmol) in tetrahydrofuran (5 mL) was added dropwise thereto and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated, and the residue was purified by C18 column separation (acetonitrile: water=60:40-90:10) to obtain 4.86g of the title compound.
1 H NMR(500MHz,DMSO-d 6 ):δ7.31-7.47(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: synthesis of benzyl (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-methylpropionate (Compound of formula I-18)
To a 48mL pressure flask was added successively benzyl (R) -2- ((6-bromo-1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothiophen [2,3-d ] pyrimidin-3 (2H) -yl) oxy) -2-methylpropionate (0.5 g,0.727 mmol), propyne (0.146 g,3.64 mmol), bis triphenylphosphine palladium dichloride (0.051 g,0.073 mmol) and cuprous iodide (0.014 g,0.073 mmol), and triethylamine (10 mL) under nitrogen, and the mixture was heated to 80℃to react overnight. The reaction was cooled to room temperature, celite was suction filtered, the filtrate was added to water (100 mL), ethyl acetate (50 mL x 2) was extracted, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the residue was purified by silica gel column separation (petroleum ether: ethyl acetate=4:1) to give 0.412g of the compound of formula I-18.
1 H NMR(500MHz,DMSO-d 6 ):δ7.45-7.47(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: synthesis of Compound of formula I-8
The compound of formula I-18 (0.3 g, 0.460 mmol) was mixed with lithium hydroxide (0.012 g,0.510 mmol), tetrahydrofuran (6 mL) and water (3 mL) and the mixture was reacted overnight at room temperature. The reaction was brought to neutral pH with 1M dilute hydrochloric acid, extracted with ethyl acetate (50 mL. Times.2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered off with suction, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 38mg of the compound of formula I-8.
1 H NMR(500MHz,CDCl 3 )δ13.13(s,1H),7.52(d,J＝7.6Hz,1H),7.33(t,J＝7.9Hz,1H),7.03(t,J＝7.5Hz,1H),6.89(d,J＝8.3Hz,1H),5.41(t,J＝6.5Hz,1H),4.24–4.01(m,2H),3.87(s,3H),3.80(d,J＝11.9Hz,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
1. In vitro enzyme inhibition Activity
1.1 ACC1 inhibitory Activity screening
Preparation of substrate mixture 0.84. Mu.l 5-fold concentration of enzyme buffer (150 mM HEPES, 10mM MgCl) 2 5mM DTT, 10mM sodium citrate) +1.2. Mu.l ATP (100. Mu.M) +0.06. Mu.l Acetyl-CoA (2 mM) +0.18. Mu.l NaHCO 3 (1M) +1.92. Mu.l of water, 4.2. Mu.l/well were added to the 96-half-well plate, the test compound dissolved in DMSO was added to the well using a nanoliter loading apparatus, and centrifuged to give a final compound concentration of 4-fold dilution, 7 concentration gradients, 500nM maximum, 0.12nM minimum, and 2 multiplex wells were set for each concentration. Blank control wells (without enzyme) and negative control wells (with enzyme) were simultaneously set, with 5 multiplex wells. With 1-fold concentration of enzyme buffer (30 mM HEPES, 2mM MgCl) 2 1mM DTT, 2mM sodium citrate) to 8.25 ng/. Mu.L, 1.8. Mu.L per well, 1.8. Mu.L of 1-fold concentration enzyme buffer per well, centrifugation, and room temperature reaction for 60 minutes. Add 5. Mu.L of ADP-Glo reagent to each well, centrifuge, react for 40 minutes at room temperature; adding 10 mu L of kinase detection reagent into each hole, centrifuging, and incubating for 30 minutes at room temperature in a dark place;the PE Envision multifunctional enzyme-labeled instrument reads chemiluminescence data, and adopts four-parameter fitting to calculate IC 50 。
1.2 ACC2 inhibitory Activity screening
Preparation of substrate mixture 0.84. Mu.l 5-fold concentration of enzyme buffer (150 mM HEPES, 10mM MgCl) 2 5mM DTT, 10mM sodium citrate) +1.2. Mu.l ATP (100. Mu.M) +0.06. Mu.l Acetyl-CoA (2 mM) +0.18. Mu.l NaHCO 3 (400 mM) +1.92. Mu.l of water, 4.2. Mu.l/well was added to the 96-half well plate, the DMSO-dissolved test compound was added to the well using a nanoliter applicator, and centrifuged to give a final compound concentration of 4-fold dilution, 8 concentration gradients, a maximum concentration of 5000nM, a minimum concentration of 0.31nM, and 2 multiplex wells were set for each concentration. Blank control wells (without enzyme) and negative control wells (with enzyme) were simultaneously set, with 5 multiplex wells. With 1-fold concentration of enzyme buffer (30 mM HEPES, 2mM MgCl) 2 1mM DTT, 2mM sodium citrate) to 5.4 ng/. Mu.L, 1.8. Mu.L per well, 1.8. Mu.L of 1-fold concentration enzyme buffer per well, centrifugation, and room temperature reaction for 60 minutes. Add 5. Mu.L of ADP-Glo reagent to each well, centrifuge, react for 40 minutes at room temperature; adding 10 mu L of kinase detection reagent into each hole, centrifuging, and incubating for 30 minutes at room temperature in a dark place; the PE Envision multifunctional enzyme-labeled instrument reads chemiluminescence data, and adopts four-parameter fitting to calculate IC 50 。
2. In vitro cell level antitumor activity screening
2.1 proliferation inhibition of Compounds on A549, NCI-H460
Taking logarithmic phase A549 (adenocarcinoma human alveolar basal epithelium cell line) and NCI-H460 (large cell lung cancer cell line) cells, digesting and collecting, preparing single cell suspension from complete medium containing 5% FBS, and preparing 1×10 cell suspension 4 The density of each mL is inoculated into a 96-well plate, 100 mu L of each well is placed at 37 ℃ and contains 5% CO 2 The cells were incubated overnight in a saturated humidity cell incubator, and compound loading was performed using a nanoliter loading instrument with final concentrations of 10000.0, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6nM of test compound, each concentration being provided with 2 duplicate wells. The groups treated with and without palmitic acid were set at the same time. To be free of compoundAs negative control, a blank group without cells was used as a blank control. The cells were placed at 37℃and 5% CO 2 The cell culture is continued for 6 days in a saturated humidity cell incubator, 10 mu L of CCK-8 is added to each hole after the 6 days of culture, and the culture is continued for 2 to 4 hours. The absorbance value a of each well was measured at 450nm on a microplate reader and the inhibition ratio was calculated according to the following formula: inhibition ratio (%) = (average a value of negative control group-average a value of experimental group)/(average a value of negative control group-average a value of blank control group) ×100%, and the obtained data was calculated to obtain IC 50 。
The results of measuring the in vitro accase inhibitory activity and the proliferation inhibitory activity at the cellular level are shown in table 1.
TABLE 1
Note that: "/" indicates not measured.
EXAMPLE 10 in vitro pharmacokinetics
In vitro liver microsomal stability:
preparation of liver microparticle body temperature incubation samples: PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), test compound and NADPH+MgCl were mixed 2 The solution was incubated at 37℃and 300rpm for 60min.
Sample preparation at 0 hours: PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL) and test compound were mixed. The sample is added into acetonitrile solution containing internal standard, protein precipitation is carried out to prepare supernatant, and the supernatant is used for LC/MS/MS determination after dilution. The test results are shown in Table 2.
TABLE 2
Note that: "/" indicates not measured.

Claims (14)

  1. A compound of formula I or a pharmaceutically acceptable salt thereof,
    wherein,
    R 1 and R is 2 Independently selected from hydrogen or C 1-6 Alkyl, optionally selected from hydroxy, -O-C 1-6 Alkyl, amino, halogen, cyano and nitro groups;
    R 4 selected from hydrogen, -R ', -O-R'; r' is independently selected from the following groups optionally substituted with R: c (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 the group consisting of-O-C optionally substituted with R 1-6 An alkylene group, or a chemical bond;
    l is selected from a bond, or a divalent group selected from 3-10 membered cycloalkyl, 6-10 membered aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with R;
    z is selected from-COOR 3 ；
    R 3 Selected from hydrogen, or C optionally substituted by R 1-6 Alkyl, phenyl C 1-6 Alkyl, silyl;
    wherein one of A and L is a 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, halo 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 C 1-6 Alkyl, halophenyl, cyanophenyl, 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms selected independently from nitrogen, oxygen, and sulfur, and 5-6 membered heteroaryl having 1, 2, 3, or 4 heteroatoms selected independently from nitrogen, oxygen, and sulfur.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein when a is a bond, the attachment sites of a and Z are different from L.
  3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is selected from a divalent group of 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-6 membered heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with R;
    Preferably, L is a divalent radical selected from 3-8 membered cycloalkyl optionally substituted with R, phenyl, saturated 3-8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, unsaturated 3-8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;
    further preferably, L is selected from the group consisting of 3-8 membered cycloalkyl optionally substituted with R, phenyl, saturated 3-8 membered heterocyclic group having 1 nitrogen atom, unsaturated 3-8 membered heterocyclic group having 1 nitrogen atom, saturated 3-8 membered heterocyclic group having 1 oxygen atom, unsaturated 3-8 membered heterocyclic group having 1 oxygen atom, saturated 3-8 membered heterocyclic group having 1 sulfur atom, unsaturated 3-8 membered heterocyclic group having 1 sulfur atom, 5-6 membered saturated heterocyclic group having 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group having 2 nitrogen atoms, 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, 5-6 membered saturated heterocyclic group having 2 oxygen atom, 5-6 membered unsaturated heterocyclic group having 2 oxygen atom, 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1-6 membered saturated heterocyclic group having 1-6 nitrogen atom, 1-4 membered saturated heterocyclic group having 1-6 nitrogen atom, a divalent group of a 5-6 membered heteroaryl group having 1 oxygen atom, a 5-6 membered heteroaryl group having 1 sulfur atom, a 5-6 membered heteroaryl group having 2 nitrogen atoms, a 5-6 membered heteroaryl group having 3 nitrogen atoms.
  4. A compound according to 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, cycloheptyl, 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, thio, pyridinyl, pyrimidinyl, thiophenyl, and divalent groups;
    preferably, L is selected from the following groups optionally substituted with R:
  5. the compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L is selected from cyclobutyl, bicyclo [1.1.1]Divalent radicals of pentyl, phenyl, pyridyl; preferably, L is selected from the group consisting of optionally R-substituted groups
  6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is selected from-O-C optionally substituted with R 1-6 Alkylene, 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 )-、-O-C(CH 3 ) 2 -、-O-CH 2 CH 2 CH 2 -、-O-CH 2 CH 2 CH 2 CH 2 -、-O-CH 2 CH(CH 3 )CH 2 -、-O-CH(CH 3 )CH 2 CH 2 -、-O-CH 2 CH 2 CH(CH 3 )-、-O-CH 2 C(CH 3 ) 2 -、-O-C(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 )-、-O-C(CH 2 CH 3 )(CH 3 ) -, go toThe step is 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 )-、-O-C(CH 3 ) 2 -、-O-CH 2 CH 2 CH 2 -, still more preferably-O-C (CH 3 ) 2 -。
  7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Independently selected from methyl, ethyl.
  8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, or C optionally substituted by R 1-4 Alkyl, phenyl C 1-4 Alkyl, C 1-6 A silane group; preferably, R 3 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, benzyl, methylphenyl, ethylphenyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl; further preferably, R 3 Selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, benzyl, and t-butyldiphenylsilyl.
  9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen, -O-R ', wherein R' is independently selected from the following groups optionally substituted with R: c (C) 1-6 Alkyl, 3-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 6-10 membered aryl, 4-10 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-8 membered heteroaryl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
    preferably, R' is selected from the group consisting of the following optionally substituted with R: -C 1-4 Alkyl, 5, 6, 7 or 8 membered cycloalkyl, 5, 6, 7, 8, 9 or 10 membered heterocyclyl having 1, 2 or 3 heteroatoms selected independently from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl having 1 or 2 heteroatoms selected independently from nitrogen, oxygen and sulfur;
    further preferably, R' is selected from a saturated 5-8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur or an unsaturated 5-8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted with R;
    still more preferably, R' is selected from the group consisting of a saturated 5-8 membered heterocyclic group having 1 nitrogen atom, an unsaturated 5-8 membered heterocyclic group having 1 nitrogen atom, a saturated 5-8 membered heterocyclic group having 1 oxygen atom, an unsaturated 5-8 membered heterocyclic group having 1 oxygen atom, a saturated 5-8 membered heterocyclic group having 1 sulfur atom, an unsaturated 5-8 membered heterocyclic group having 1 sulfur atom, a 5-6 membered saturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered unsaturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 5-6 membered saturated heterocyclic group having 2 oxygen atoms, a 5-6 membered unsaturated heterocyclic group having 2 oxygen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, and a 5-6 membered saturated heterocyclic group having 1-6 sulfur atom, which are optionally substituted by R.
  10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 4 A group selected from hydrogen, or optionally R-substituted: methoxy, ethoxy, Preferably is
  11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, R is selected from a saturated 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an unsaturated 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
    preferably, R is selected from the group consisting of a saturated 3-8 membered heterocyclic group having 1 nitrogen atom, an unsaturated 3-8 membered heterocyclic group having 1 nitrogen atom, a saturated 3-8 membered heterocyclic group having 1 oxygen atom, an unsaturated 3-8 membered heterocyclic group having 1 oxygen atom, a saturated 3-8 membered heterocyclic group having 1 sulfur atom, an unsaturated 3-8 membered heterocyclic group having 1 sulfur atom, a 4-8 membered saturated heterocyclic group having 2 nitrogen atoms, a 4-8 membered unsaturated heterocyclic group having 2 nitrogen atoms, a 4-8 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 4-8 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 4-8 membered saturated heterocyclic group having 2 oxygen atoms, a 4-8 membered unsaturated heterocyclic group having 2 oxygen atoms, a 4-8 membered saturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 4-8 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 4-8 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 4-8 membered saturated heterocyclic group having 1-6-membered nitrogen atom, a 5-membered heteroaryl group having 1-6 atoms, a 5 membered heteroaryl group having 1-6 membered nitrogen atom;
    Further preferably, R is selected from the group consisting of a 4-6 membered saturated heterocyclic group having 1 nitrogen atom, a 4-6 membered unsaturated heterocyclic group having 1 nitrogen atom, a 4-6 membered saturated heterocyclic group having 1 oxygen atom, a 4-6 membered unsaturated heterocyclic group having 1 oxygen atom, a 4-6 membered saturated heterocyclic group having 1 sulfur atom, a 4-6 membered unsaturated heterocyclic group having 1 sulfur atom, a 5-6 membered saturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered unsaturated heterocyclic group having 2 nitrogen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, a 5-6 membered saturated heterocyclic group having 2 oxygen atoms, a 5-6 membered unsaturated heterocyclic group having 2 oxygen atoms, a 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 sulfur atom, a 5-6 membered saturated heterocyclic group having 1 oxygen atom and a 5-6 membered saturated heterocyclic group having 1 oxygen atom.
  12. A compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, R is selected from hydrogen, fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, phenyl, benzyl, methylphenyl, ethylphenyl, furyl, pyranyl, pyrrolidinyl, pyridyl, piperidinyl, piperazinyl, pyrimidinyl, thienyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, preferably hydrogen, methyl, ethyl, t-butyl, methoxy, ethoxy, phenyl, benzyl, trimethylsilyl, t-butyldiphenylsilyl.
  13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, said compound having the structure of one of:
  14. use of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of an acetyl-coa carboxylase mediated disease, 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.
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