WO2022063205A1 - 芳基甲酰胺类化合物及其制备方法和医药用途 - Google Patents

芳基甲酰胺类化合物及其制备方法和医药用途 Download PDF

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WO2022063205A1
WO2022063205A1 PCT/CN2021/120150 CN2021120150W WO2022063205A1 WO 2022063205 A1 WO2022063205 A1 WO 2022063205A1 CN 2021120150 W CN2021120150 W CN 2021120150W WO 2022063205 A1 WO2022063205 A1 WO 2022063205A1
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alkyl
alkoxy
aryl
preparation
mmol
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PCT/CN2021/120150
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French (fr)
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WO2022063205A8 (zh
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殷惠军
闫旭
宗利斌
刘国标
张守良
陈彬
路嘉伟
王卓
栗睿
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中国医药研究开发中心有限公司
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Priority to CN202180049562.3A priority Critical patent/CN115884970A/zh
Publication of WO2022063205A1 publication Critical patent/WO2022063205A1/zh
Publication of WO2022063205A8 publication Critical patent/WO2022063205A8/zh

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to an aryl formamide compound, a preparation method thereof and a pharmaceutical composition containing the same, and as a P2X3 receptor antagonist in the treatment and/or prevention of P2X3 receptor activity-related use in disease.
  • ATP levels are elevated in pathological settings, suggesting that it plays an important role in the pathogenesis of many diseases.
  • ATP drives and modulates various sensory behaviors and related responses.
  • ATP has a greater effect on sensation when the body is stimulated (ultraviolet light and chemical damage, etc.) or in a pathological state (asthma, bladder pain syndrome, etc.).
  • P2X3 receptors are ATP-gated cation channels and belong to the P2X receptor family, which also includes P2X1, P2X2, P2X4, P2X5, P2X6, and P2X7.
  • P2X3 receptors function in vivo as homotrimeric P2X3 or heterotrimeric P2X2/3 (Neuro Report, 10, 1107-1111).
  • P2X3 and P2X2/3 receptors are mainly expressed in small and medium diameter C- and A ⁇ -fiber sensory neurons in dorsal root ganglia (DRG) and cranial sensory ganglia, as well as peripheral nerves in the receptive fields of tissues such as skin, joints, and internal organs tip.
  • DDG dorsal root ganglia
  • cranial sensory ganglia as well as peripheral nerves in the receptive fields of tissues such as skin, joints, and internal organs tip.
  • P2X3 receptor is a member of the purinergic receptor family and is a non-selective ligand-gated ion channel. After being activated by ATP, it allows the passage of Na + , K + , and Ca 2+ , especially the passage of Ca 2+ .
  • the permeability is the most obvious, and plays an important role in the generation and transmission of noxious information.
  • PKA protein kinase A
  • PKC protein kinase C
  • P2X3 receptors play an important role in the process of nociception. For example, P2X3 receptor knockout significantly reduced pain responses. P2X3 receptor antagonists have antinociceptive effects in multiple models of pain and inflammatory pain. In addition to prominent roles in nociception and acute and chronic pain, P2X3 receptors have also been shown to be involved in the pathological processes of urogenital, gastrointestinal, and respiratory diseases, especially overactive bladder and chronic cough. Therefore, P2X3 receptors play an important role in the pathological mechanisms of various diseases including pain, genitourinary diseases, gastrointestinal diseases and respiratory diseases, and are ideal targets for the treatment of these diseases.
  • P2X3 subunits form not only homotrimers, but also heterotrimers with P2X2 subunits.
  • P2X3 and P2X2 subunits are also expressed on nerve fibers of the tongue, and receptors containing P2X3 and/or P2X2 subunits are involved in taste transmission (bitter, sweet, salty, umami and sour).
  • Studies have shown that P2X3 homotrimers are mainly involved in mediating nociception, while P2X2/X3 heterotrimers are mainly involved in taste perception.
  • Knockout animals lacking P2X2 and P2X3 subunits exhibited reduced taste and even loss of taste, whereas P2X3 subunit knockout exhibited mild or no changes in phenotype (J. Physiol. 2015, 593, 1113–1125).
  • the object of the present invention is to provide a compound represented by the general formula (I) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salts,
  • Ring A is a 5-membered heteroaryl
  • B rings are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, Substitution of one or more groups of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • W 1 and W 2 are each independently selected from CR 6 or N;
  • L 2 is selected from single bond, -CO-, -O-, -S-, -SO-, -SO 2 - and -NR 6 -;
  • Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O p R a , -S(O) p NR a R b and -NHS(O) p R a , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optional is further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alky
  • R 2 is selected from aryl and heteroaryl; said aryl and heteroaryl are each independently optionally further selected from one or more groups of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy group replacement;
  • R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl base, -C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NHC(O)R a , -S(O) p R a , -S(O) p NR a R b and -NHS(O) p R a , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl,
  • R4 and R5 are each independently selected from hydrogen, alkyl and alkoxy, wherein said alkyl and alkoxy are each independently optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted with one or more groups;
  • Each of R4 ' and R5 ' is independently selected from hydrogen, alkyl and alkoxy, wherein each of said alkyl and alkoxy is independently optionally further selected from halogen, amino, nitro, cyano , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl substitution with one or more groups ;
  • R 6 is selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxy, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with one or more groups;
  • R a and R b are each independently selected from hydrogen, halogen, hydroxy, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally further selected from halogen, amino, nitro, One or more of cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups group replacement;
  • Ra and Rb together with the atoms to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, oxo, Substitution of one or more of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;
  • p 0, 1, 2;
  • n is an integer from 1 to 4.
  • n is an integer from 0 to 3.
  • Ring A is selected from pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,3,4-oxadiazolyl, 1,2 ,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, triazolyl and tetrazolyl, preferably pyrazolyl, thiazolyl, oxazolyl and 1,3,4-oxadiazolyl, more preferably thiazolyl.
  • the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (II) or a meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • B rings are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, Substitution of one or more groups of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • W 1 , W 2 , L 2 and R 3 are as defined in the general formula (I).
  • the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,
  • L 2 is selected from single bond, -(CH 2 ) m -, -(CH)CH 3 -, -CO-, -SO- and -SO 2 -;
  • n is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably 1 or 2.
  • R 3 is selected from hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 -cycloalkyl, 4- to 7-membered heterocyclyl, C6 - C10 -aryl and 5- to 10-membered heteroaryl, wherein the C1 - C6 alkyl, C1 - C6 alkoxy, C 2 -C6alkenyl, C2 - C6alkynyl , C3- C7cycloalkyl , 4- to 7 -membered heterocyclyl, C6 - C10 -aryl, and 5- to 10-membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, carboxyl, ester, C1 - C6 alkyl, C
  • R a is selected from C 1 -C 6 alkyl
  • p 1 or 2.
  • L 2 is selected from single bond, -(CH 2 ) m - and -CO-;
  • R 3 is selected from 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally further selected from halogen, oxo, C 1 -C 6 alkyl, -C(O)OR a One or more groups are substituted;
  • R a is selected from C 1 -C 6 alkyl
  • n 1 or 2.
  • L 2 is selected from single bond, -CH 2 - and -CO-;
  • R is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperidinyl, piperazinyl, optionally is further substituted with one or more groups selected from halogen, oxo, C 1 -C 6 alkyl, -C(O)OR a ;
  • R a is selected from C 1 -C 6 alkyl.
  • L 2 is a single bond, -CH 2 - and -CO-;
  • R 3 is selected from C 3 -C 6 cycloalkyl optionally further selected from one of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl , or Multiple group substitutions.
  • L 2 is a single bond, -CH 2 - and -CO-;
  • R 3 is selected from phenyl or 5- to 6-membered heteroaryl optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted with one or more groups of C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy.
  • L 2 is a single bond, -(CH 2 ) m - and -(CH)CH 3 -;
  • R 3 is selected from cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, the C 1 -C 6 alkane base, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl optionally further substituted with one or more groups selected from halogen, hydroxyl;
  • n is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably 1 or 2.
  • R 4 and R 5 are each independently selected from hydrogen and C 1 -C 6 alkyl
  • L 1 is N
  • each R 1 is independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 7 cycloalkyl and 5- to 7-membered heterocyclyl, preferably C 1 -C 6 alkyl or C 1 -C 6 haloalkyl .
  • R 2 is a C 6 -C 10 aryl group or a 5- to 10-membered heteroaryl group, preferably phenyl, pyridy
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention further provides a method for preparing the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a method of a pharmaceutically acceptable salt thereof, comprising the steps of:
  • compound Ig and compound Ih undergo a condensation reaction under basic conditions to obtain the compound represented by the general formula (I), wherein the reagent providing basic conditions is preferably DIPEA, and the condensing agent is preferably HATU;
  • a ring, B ring, W 1 , W 2 , R 1 , R 2 , R 3 , L 1 , L 2 , and n are as defined in the general formula (I).
  • the present invention also provides a method for preparing the compound represented by the general formula (II) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, a prodrug thereof, or a method of a pharmaceutically acceptable salt thereof, comprising the steps of:
  • compound IIg and compound IIh are subjected to a condensation reaction under basic conditions to obtain the compound represented by the general formula (II), wherein the reagent for providing basic conditions is preferably DIPEA, and the condensing agent is preferably HATU;
  • B ring, R 1 , R 2 , R 3 , L 1 , L 2 , and n are as defined in the general formula (II).
  • Another aspect of the present invention provides a pharmaceutical composition, which contains the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • the present invention further provides the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, diastereomer, Use of the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a P2X3 receptor antagonist.
  • the present invention further provides the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, diastereomer, Use of the form of a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a medicament for preventing and/or treating a disease associated with P2X3 receptor activity.
  • the present invention further provides the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a P2X3 receptor antagonist.
  • the present invention further provides the compound represented by general formula (I) or general formula (II) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for the prevention and/or treatment of diseases associated with P2X3 receptor activity.
  • the present invention further provides a method for preventing and/or treating a disease associated with P2X3 receptor activity, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of the general formula (I) or The compound represented by the general formula (II) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound containing the same pharmaceutical composition.
  • diseases associated with P2X3 receptor activity may be: respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, pulmonary fibrosis, acute cough, chronic cough, including chronic idiopathic and chronic refractory Treatment of cough, genitourinary, gastrointestinal, respiratory and pain related diseases, gynecological diseases including dysmenorrhea (primary and secondary), dyspareunia, dysuria or orchitis, endometriosis and uterine Adenomyosis, endometriosis-related pain, endometriosis-related symptoms, pelvic hypersensitivity, urinary tract disease states associated with bladder outlet obstruction, urinary incontinence symptoms such as decreased bladder capacity, increased frequency of urination, Urge urinary incontinence, stress urinary incontinence or overactive bladder, benign prostatic hypertrophy, benign prostatic hyperplasia, prostatitis, detrusor hyperreflexia, overactive bladder and symptoms
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid.
  • the acid includes inorganic and organic acids, particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid , trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base.
  • the bases include inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide, etc.
  • the present invention also includes prodrugs of the compounds represented by the general formula (I) of the present invention.
  • the prodrugs described in the present invention are derivatives of the compounds represented by the general formula (I). They may have weak activity or even no activity, but after administration, under physiological conditions (for example, through metabolism, solvolysis, etc.) or otherwise) into the corresponding biologically active form.
  • compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening, flavoring, coloring and preservative agents, to provide pleasing and palatable medicinal preparations.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • water soluble taste masking materials such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or time prolonging materials such as ethyl cellulose, cellulose acetate butyrate can be used.
  • Hard gelatin capsules are also available wherein the active ingredient is in admixture with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide an oral preparation.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or the condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetyl Wax alcohols (heptadecaethyleneoxy cetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • preservatives such as ethyl or n-propyl paraben
  • coloring agents such as ethyl or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents are those mentioned above. Other excipients such as sweetening, flavouring and colouring agents may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive or peanut oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then processed into a mixture of water and glycerol to form a microemulsion.
  • Injections or microemulsions can be injected into a patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device can be used.
  • compositions of the present invention may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can also be used in the preparation of injectables.
  • the compounds of the present invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the condition of the patient, the diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.
  • the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of the general formula, or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
  • the present invention can contain the compound represented by the general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared in a clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compounds of the present invention can be used as the sole active ingredient or in combination with other drugs for the treatment of diseases associated with P2X3 receptor activity. Combination therapy is accomplished by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg, ethynyl, propynyl, butynyl, and the like.
  • Alkynyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 4 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, oxadiazolyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydroimidazolyl Hydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxadiazolyl, pyridine alkyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • m is an integer from 0 to 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, such as benzene base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 to 7 membered, containing 1 to 3 heteroatoms; most preferably 5 membered or 6 membered, containing 1 to 2 heteroatoms ; preferably imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, pyridazine, isothiazolyl , isoxazolyl, oxadiazolyl, triazolyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl,
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • thiol refers to -SH.
  • esters refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • sulfonic acid refers to -S(O)2OH.
  • sulfonate refers to -S(O) 2O (alkyl) or -S(O) 2O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • sulfonyl refers to compounds of the -S(O ) 2R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • aminoacyl refers to -C(O)-NRR', wherein R, R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • aminosulfonyl or “sulfonamido” refers to -S(O) 2 -NRR', wherein R, R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl base.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.
  • the present invention adopts the following technical solutions.
  • the compound represented by the general formula (I) of the present invention or its salt can be prepared by the following scheme, and the specific preparation method is as follows.
  • Step 1 under high temperature and alkaline conditions, compound Ia and Ib are reacted to obtain compound Ic, wherein the high temperature condition is preferably 100°C, and the alkaline reagent is preferably cesium carbonate;
  • Step 2 In the presence of high temperature, alkalinity and a catalyst, compound Ic is reacted with bis-boronic acid pinacol ester to obtain compound Id, wherein the high temperature condition is preferably 100°C, the basic reagent is preferably potassium acetate, and the catalyst is preferably Pd(dppf) Cl 2 catalyst;
  • Step 3 in the presence of high temperature, alkalinity and catalyst, compound Id is reacted with compound Ie to obtain compound If, wherein, the high temperature condition is preferably 90° C., the basic reagent is preferably potassium carbonate, and the catalyst is preferably Pd(dppf)Cl 2 catalyst;
  • Step 4 Under alkaline conditions, compound If is hydrolyzed to obtain compound Ig, wherein the alkaline reagent is preferably lithium hydroxide;
  • Step 5 In the presence of a condensing agent, compound Ig and Ih are subjected to a condensation reaction under basic conditions to obtain a compound of general formula (I), wherein the reagent for providing basic conditions is preferably DIPEA, and the condensing agent is preferably HATU.
  • Step 1 Compound Ii is reacted with a halogenated reagent at room temperature to obtain compound Ij, wherein the halogenated reagent is preferably NBS;
  • Step 2 in the presence of high temperature, acidity and reducing agent, compound Ij is reduced to obtain compound Ik, wherein the high temperature condition is preferably 65°C, the acid reagent is preferably ammonium chloride, and the reducing agent is preferably zinc powder;
  • Step 3 In the presence of a high temperature and an alkaline reagent, compound Ik is subjected to a substitution reaction with a dihalide to obtain a compound Ia, wherein the high temperature condition is preferably 110 ° C, the alkaline reagent is preferably potassium carbonate, and the dihalide is preferably 1,2-Di Ethyl bromide;
  • Step 4 at room temperature, in the presence of a reducing agent and a catalyst, compound Ia is reacted with compound Il to obtain compound Ic, wherein the reducing agent is preferably sodium cyanoborohydride, and the catalyst is preferably anhydrous zinc chloride;
  • the reducing agent is preferably sodium cyanoborohydride
  • the catalyst is preferably anhydrous zinc chloride
  • Step 1 under low temperature and basic conditions, compound Ik is condensed with chloroacetyl chloride to obtain compound Im, wherein the low temperature condition is preferably 0°C, and the basic reagent is preferably potassium carbonate;
  • Step 2 under high temperature and alkaline conditions, compound Im undergoes a ring closure reaction to obtain compound Ia, wherein the high temperature condition is preferably 80°C, and the alkaline reagent is preferably potassium acetate;
  • Step 3 under room temperature and basic conditions, compound Ia and Ib are reacted to obtain Ic, wherein, the basic reagent is preferably cesium carbonate;
  • Step 1 Under high temperature conditions, compound In is reacted with cyclo()isopropyl malonate to obtain compound Io, wherein the high temperature conditions are preferably 100°C;
  • Step 2 under high temperature conditions, compound Io is dissolved in diphenyl ether to undergo self-ring-closing reaction to obtain compound Ip, wherein the high temperature conditions are preferably 210°C;
  • Step 3 Under high temperature conditions, compound Ip is reacted with phosphorus oxychloride to obtain compound Ia, wherein the high temperature conditions are preferably 80°C;
  • Step 4 Under the condition of high temperature and alkaline sealing tube, compound Ia and Iq are reacted to obtain compound Ic, wherein the high temperature condition is preferably 100°C, and the alkaline reagent is preferably DIPEA;
  • Step 1 Under high temperature conditions, compound Ir is reacted with glyoxylic acid to obtain compound Is, wherein the high temperature conditions are preferably 80°C;
  • Step 2 Under high temperature conditions, compound Is is reacted with phosphorus oxychloride to obtain compound Ia, wherein the high temperature conditions are preferably 80°C;
  • Step 3 Under the condition of high temperature and alkaline sealing tube, compound Ia and Iq are reacted to obtain compound Ic, wherein the high temperature condition is preferably 100°C, and the alkaline reagent is preferably DIPEA;
  • Step 1 at room temperature, compound It is reacted with NBS to obtain compound Iu;
  • Step 2 Under the condition of high temperature and alkaline sealing tube, compound Iu is reacted with CS 2 to obtain compound Ia, wherein the high temperature condition is preferably 80°C, and the alkaline reagent is preferably KOH;
  • Step 3 Under the condition of high temperature and alkaline sealing tube, compound Ia and Iq are reacted to obtain compound Ic, wherein the high temperature condition is preferably 150°C, and the alkaline reagent is preferably DIPEA;
  • Step 1 under high temperature and p-toluenesulfonic acid catalytic conditions, compound Iv and Iw are reacted to obtain compound Ix;
  • Step 2 Under high temperature conditions, compound Ix is reacted with NBS to obtain compound Ic;
  • W 1 , W 2 , A ring, B ring, R 1 , R 2 , R 3 , L 1 , L 2 , and n are as defined in the general formula (I).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was measured using a 1100 Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).
  • Preparative liquid phase used lc3000 high performance liquid chromatograph and lc6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng).
  • the chromatographic column is Daisogel C18 10 ⁇ m 60A (20mm ⁇ 250mm).
  • the thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm mm.
  • the known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Inoke, Nanjing Yaoshi, Anaiji Chemical and other companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the microwave reaction used a CEM Discover SP type microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), and the systems of the developing solvent used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum In the ether and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • ⁇ L microliter
  • ⁇ M micromolar
  • AIBN azobisisobutyronitrile
  • Boc tert-butoxycarbonyl
  • DIPEA Diisopropylethylamine
  • IC50 concentration that inhibits 50% activity
  • nM nanomoles
  • NBS N-bromosuccinimide
  • PE petroleum ether
  • THF tetrahydrofuran
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DCDMH 1,3-dichloro-5,5-dimethylhydantoin
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • Pd(dppf)Cl 2 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride
  • Step 1 Synthesis of methyl 4-bromo-1-(oxetan-3-yl)-1H-indazole-6-carboxylate (1b)
  • Step 3 Synthesis of methyl 4-(5-methylthiazol-2-yl)-1-(oxetan-3-yl)-1H-indazole-6-carboxylate (1d)
  • Step 4 Synthesis of 4-(5-Methylthiazol-2-yl)-1-(oxetan-3-yl)-1H-indazole-6-carboxylic acid (1e)
  • Step 5 (R)-4-(5-Methylthiazol-2-yl)-1-(oxetan-3-yl)-N-(1-(2-(trifluoromethyl)pyrimidine) Synthesis of -5-yl)ethyl)-1H-indazole-6-carboxamide (Compound 1)
  • reaction solution was poured into 100 mL of ice water, stirred for 10 minutes, filtered with suction, and the filter cake was purified by preparative liquid phase (eluent: 0%-100% acetonitrile: aqueous solution) to obtain 15 mg of the title compound as a white solid, Yield: 8.3%.
  • Step 1 Preparation of methyl 4-bromo-2-(1-(tert-butoxycarbonyl)azetidine-3-yl)-2H-indazole-6-carboxylate (3a)
  • reaction solution was concentrated under reduced pressure, diluted with EtOAc (40 mL) and washed with water (30 mL), the organic phase was separated, the aqueous phase was extracted with EtOAc (30 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , the residue was separated and purified by silica gel column chromatography to obtain 1.4 g of the title compound as a semi-oily white solid with a yield of 49%.
  • Step 2 2-(1-(tert-Butoxycarbonyl)azetidine-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Preparation of borolan-2-yl)-2H-indazole-6-methyl carboxylic acid (3b).
  • Step 4 2-(1-(tert-Butoxycarbonyl)azetidine-3-yl)-4-(5-methylthiazol-2-yl)-2H-indazole-6-carboxylic acid (Preparation of 3d).
  • Step 5 (R)-3-(4-(5-Methylthiazol-2-yl)-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)aminomethane
  • Step 6 (R)-2-(azetidin-3-yl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidine) Preparation of -5-yl)ethyl)-2H-indazole-6-carboxamide (compound 3).
  • the residue was separated by preparative liquid chromatography (chromatographic column type: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain 84 mg of the title compound as a white solid, which was collected Rate: 34%.
  • the title compound 4 was prepared in the same manner as in Example 2 except that 3-iodoazetidine was replaced with tert-butyl 3-iodoazetane-1-carboxylate.
  • Step 1 Preparation of methyl 3-bromo-4-hydroxy-5-nitrobenzoate (7b).
  • Step 2 Preparation of methyl 3-amino-5-bromo-4-hydroxybenzoate (7c).
  • Methyl 3-bromo-4-hydroxy-5-nitrobenzoate (13.5 g, 49.1 mmol), NH4Cl (13.5 g, 245 mmol) were dissolved in a mixture of EtOH (100 mL) and water (20 mL) at room temperature
  • Zn powder (15.9 g, 245 mmol) was slowly added in batches at 0 °C, and after the addition was completed, stirring was continued at 0 °C for 20 min, and then the temperature was raised to 80 °C and stirred for 5 h. Cooled to room temperature, suction filtered, the filter cake was washed with methanol and collected, and the obtained filtrate was concentrated to obtain a small amount of crude product.
  • the above-mentioned filter cake was dissolved in 100 mL of 6N aqueous sodium hydroxide solution, stirred for 10 min and filtered, the filter cake was washed with methanol, the filtrate was collected, the pH of the filtrate was adjusted to 5-6 with 6N aqueous hydrochloric acid solution, and the dry filtrate was concentrated under reduced pressure to obtain most of the crude product.
  • Step 3 Preparation of methyl 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (7d).
  • Step 4 8-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro-2H-benzo[ b] Preparation of methyl [1,4]oxazine-6-carboxylate (7e).
  • Step 5 Preparation of methyl 8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (7f) .
  • Step 6 Preparation of 8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (7 g).
  • reaction solution was concentrated under reduced pressure, 4 mL of water was added, the pH was adjusted to 4-5 with 6N aqueous hydrochloric acid solution, a large amount of yellow solid was precipitated, filtered, collected and dried to obtain 60 mg of the title compound as a yellow solid, yield: 79%.
  • Step 7 (R)-8-(5-Methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-di Preparation of Hydro-2H-benzo[b][1,4]oxazine-6-carboxamide (Compound 7).
  • Example 8 8-(5-Methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-N-((R)-1-(2-(trifluoromethyl) Preparation of pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (8)
  • Step 1 8-(5-Methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] Preparation of oxazine-6-carboxylate methyl ester (8a).
  • Step 2 8-(5-Methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] Preparation of oxazine-6-carboxylic acid (8b).
  • Step 3 8-(5-Methylthiazol-2-yl)-4-((tetrahydrofuran-3-yl)methyl)-N-((R)-1-(2-(trifluoromethyl)pyrimidine) Preparation of -5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (compound 8).
  • reaction solution was concentrated under reduced pressure, and 15 mL of water was added thereto, followed by extraction with ethyl acetate (20 mL x 3).
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (Column type: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient : 30%-80%) to obtain 128 mg of the title compound as a white solid, yield: 61%.
  • Step 1 (R)-3-((8-(5-Methylthiazol-2-yl)-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino Preparation of formyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (9a)
  • Compound 9a was prepared in the same manner as in Example 8, except that tert-butyl 3-formylazetidine-1-carboxylate was used instead of tetrahydrofuran-3-carbaldehyde in step 1.
  • Step 2 (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl) ) pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (9)
  • the residue was separated by preparative liquid chromatography (chromatographic column type: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain 56 mg of the title compound as a white solid, which was collected Rate: 51.4%.
  • Step 1 Preparation of methyl 3-bromo-5-(2-chloroacetamido)-4-hydroxybenzoate (11a).
  • methyl 3-amino-5-bromo-4-hydroxybenzoate (245 mg, 1.00 mmol) and K 2 CO 3 (414 mg, 3.00 mmol) were dissolved in MeCN (5 mL), and the dissolved solution was slowly added dropwise. A solution of chloroacetyl chloride (0.09 ml, 1.20 mmol) in acetonitrile was added and stirred. After the addition, the reaction solution was warmed to room temperature and stirred for 2 h.
  • Step 2 Preparation of methyl 8-bromo-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (11b).
  • Step 3 3-oxo-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,4-dihydro- Preparation of 2H-benzo[b][1,4]oxazine-6-carboxylic acid ethyl ester (11c).
  • Step 4 Methyl 8-(5-Methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate Preparation of (11d).
  • Step 5 8-(5-Methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (11e ) preparation.
  • Step 6 (R)-8-(5-Methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)- Preparation of 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (compound 11).
  • Step 2 8-(5-Methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydro-2H-benzo[b] Preparation of [1,4]oxazine-6-carboxylic acid (12b).
  • reaction solution was concentrated under reduced pressure, 2 mL of water was added, the pH was adjusted to 3-5 with 1N dilute aqueous HCl solution, and the resulting solution was concentrated under reduced pressure to obtain 130 mg of the crude title compound (containing LiCl salt, ⁇ 90 mg of product) as a yellow solid, yield: 85 %.
  • Step 3 8-(5-Methylthiazol-2-yl)-3-oxo-4-((tetrahydrofuran-2-yl)methyl)-N-((R)-1-(2-(tris) Preparation of fluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (compound 12).
  • reaction solution was concentrated under reduced pressure, and 10 mL of water was added thereto, followed by extraction with ethyl acetate (15 mL ⁇ 3).
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (Column type: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient : 30%-80%) to obtain 93 mg of the title compound as a white solid, yield: 71%.
  • the title compound 13 was prepared in the same manner as in Example 12 except that 4-(bromomethyl)tetrahydro-2H-pyran was used in step 1 instead of 2-(bromomethyl)tetrahydrofuran.
  • Step 1 (R)-3-((8-(5-Methylthiazol-2-yl)-3-oxo-6-((1-(2-(trifluoromethyl)pyrimidin-5-yl) )ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester
  • the title compound 14a was prepared in the same manner as in Example 12 except substituting 2-(bromomethyl)tetrahydrofuran with tert-butyl 3-(bromomethyl)azetidine-1-carboxylate.
  • Step 2 (R)-4-(azetidin-3-ylmethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-(1-(2- Preparation of (trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (14)
  • reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column type: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%) to obtain a white solid 56 mg of the title compound, yield: 44%.
  • Step 1 Methyl 3-bromo-4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)benzoate Preparation of (16b).
  • Step 2 Preparation of methyl 8-bromo-4-oxo-1,4-dihydroquinoline-6-carboxylate (16c).
  • Step 3 Preparation of methyl 8-bromo-4-chloro-1,4-dihydroquinoline-6-carboxylate (16d).
  • Step 4 Preparation of methyl 8-bromo-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (16e).
  • Step 5 Preparation of methyl 8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (16f).
  • Step 6 Preparation of 8-(5-methylthiazol-2-yl)-4-(pyrrolidin-1-yl)quinoline-6-carboxylic acid (16 g).
  • Step 7 (R)-8-(5-Methylthiazol-2-yl)-4-(pyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidine-5- Preparation of yl)ethyl)quinoline-6-carboxamide (compound 16).
  • Step 1 Preparation of methyl 8-bromo-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (17b).
  • Step 2 Preparation of methyl 8-bromo-2-chloroquinoxaline-6-carboxylate (17c).
  • Step 3 Preparation of methyl 8-bromo-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (17d).
  • Step 4 Preparation of (7-(methoxycarbonyl)-3-(pyrrolidin-1-yl)quinoxalin-5-yl)boronic acid (17e).
  • Step 5 Preparation of methyl 8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (17f).
  • Step 6 Preparation of 8-(5-methylthiazol-2-yl)-2-(pyrrolidin-1-yl)quinoxaline-6-carboxylic acid (17 g).
  • Step 7 (R)-8-(5-Methylthiazol-2-yl)-2-(pyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidine-5- Preparation of yl)ethyl)quinoxaline-6-carboxamide (compound 17).
  • the title compound 18 was prepared in the same manner as in Example 12 except that 3-(bromomethyl)-3-methyloxetane was used in step 1 instead of 2-(bromomethyl)tetrahydrofuran.
  • Step 1 Preparation of methyl 4-amino-3-bromo-5-hydroxybenzoate (19b).
  • methyl 4-amino-3-hydroxybenzoate (1.90 g, 11.40 mmol), NBS (1.90 g, 13.7 mmol), and dichloromethane (20 mL) were added to the reaction flask and reacted at room temperature for 1 hour.
  • Step 2 Preparation of (2-amino-3-hydroxy-5-(methoxycarbonyl)phenyl)boronic acid (19c).
  • Step 3 Preparation of methyl 4-amino-3-hydroxy-5-(5-methylthiazol-2-yl)benzoate (19d).
  • Step 4 Preparation of methyl 4-(5-methylthiazol-2-yl)-2-thio-2,3-dihydrobenzo[d]oxazole-6-carboxylate (19e).
  • Step 5 Preparation of 4-(5-methylthiazol-2-yl)-2-morpholinyl-benzo[d]oxazole-6-carboxylic acid methyl ester (19f).
  • Step 6 Preparation of 4-(5-methylthiazol-2-yl)-2-morpholinyl-benzo[d]oxazole-6-carboxylic acid (19 g).
  • Step 7 (R)-4-(5-Methylthiazol-2-yl)-2-morpholinyl-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl) Preparation of benzo[d]oxazole-6-carboxamide (19h).
  • the title compound 20 was prepared in the same manner as in Example 2 except that 3-iodotetrahydrofuran was used in place of 3-iodooxetane.
  • the title compound 20 was prepared in the same manner as in Example 1 except that 3-iodotetrahydrofuran was used in place of 3-iodooxetane.
  • the title compound 22 was prepared in the same manner as in Example 1 except that 4-iodotetrahydro-2H-pyran was used in place of 3-iodooxetane.
  • the title compound 23 was prepared in the same manner as in Example 1 except that 2-(bromomethyl)tetrahydrofuran was used in place of 3-iodooxetane.
  • the title compound 24 was prepared in the same manner as in Example 2, except that 2-(bromomethyl)tetrahydrofuran was used in place of 3-iodooxetane.
  • the title compound 25 was prepared in the same manner as in Example 1 except that 4-(bromomethyl)tetrahydro-2H-pyran was used in place of 3-iodooxetane.
  • the title compound 26 was prepared in the same manner as in Example 2, except that 4-(bromomethyl)tetrahydro-2H-pyran was used in place of 3-iodooxetane.
  • the title compound 27 was prepared in the same manner as in Example 1 except that 3-(bromomethyl)-1,1-difluorocyclobutane was used in place of 3-iodooxetane.
  • the title compound 28 was prepared in the same manner as in Example 2 except that 3-(bromomethyl)-1,1-difluorocyclobutane was used in place of 3-iodooxetane.
  • the preparation method was the same as in Example 4, except that tert-butyl 2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylate was used instead of tert-3-iodoazetidine-1-carboxylate butyl ester to give the title compound 29.
  • the preparation method was the same as in Example 3, except that tert-butyl 2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylate was used instead of tert-3-iodoazetidine-1-carboxylate butyl ester to give the title compound 30.
  • the title compound 32 was prepared in the same manner as in Example 2, except that methyl (1-methylpyrrolidin-3-yl)4-methylbenzenesulfonate (31c) was used instead of 3-iodooxetane .
  • the title compound 33 was prepared in the same manner as in Example 8, except that tetrahydro-4H-pyran-4-one was used in place of tetrahydrofuran-3-carbaldehyde.
  • Step 1 4-(2-Ethoxyethyl)-8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine Preparation of -6-Carboxylic acid 2-ethoxyethyl ester (34a)
  • Step 2 4-(2-Ethoxyethyl)-8-(5-methylthiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine Preparation of -6-carboxylic acid (34b)
  • Step 3 (R)-4-(2-Ethoxyethyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidine-5) Preparation of -yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (34)
  • reaction solution was concentrated under reduced pressure, and 10 mL of water was added thereto, followed by extraction with ethyl acetate (15 mL x 3).
  • the combined organic phases were dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, Gradient: 10%-100%), 51 mg of the title compound was obtained as a white solid, yield: 34%.
  • Step 1 (R)-8-(5-Methylthiazol-2-yl)-4-(tetrahydro-2H-pyran-4-carbonyl)-N-(1-(2-(trifluoromethyl) ) pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (35)
  • Example 36 (R)-4-(Cyclopropanecarbonyl)-8-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl) Preparation of ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (36).
  • the title compound 36 was prepared in the same manner as in Example 35, except that cyclopropanecarbonyl chloride was used in place of tetrahydro-2H-pyran-4-carbonyl chloride.
  • the title compound 37 was prepared in the same manner as in Example 12 except that 1-bromo-2-ethoxyethane was used in step 1 instead of 2-(bromomethyl)tetrahydrofuran.
  • Example 38 4-((((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3- Oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4] Preparation of oxazine-6-carboxamide (38)
  • Example 40 4-((((R)-3-Methyl-2-oxooxazolin-5-yl)methyl)-8-(5-methylthiazol-2-yl)-3- Oxo-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4] Preparation of oxazine-6-carboxamide (40)
  • Step 1 Preparation of (R)-3-(benzyl(methyl)amino)propane-1,2-diol (40b).
  • N-methyl-1-phenylmethanamine (10.0 g, 0.0826 mol) was dissolved in methanol (100 mL), and (R)-oxiran-2-ylmethanol (6.42 g, 0.0867 mmol), the addition was completed, and the reaction solution was stirred at 65 °C overnight. The reaction solution was concentrated under reduced pressure to obtain 15.0 g of the title compound as a colorless oil, yield: 98%.
  • Step 3 Preparation of (S)-5-(hydroxymethyl)-3-methyloxazolidin-2-one (40d).
  • Step 4 Preparation of (S)-5-(chloromethyl)-3-methyloxazolidin-2-one (40e).
  • Example 41 4-((1,4-dioxan-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)- 1-(2-(Trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (41) preparation
  • the title compound 43 was prepared in the same manner as in Example 12 except substituting (bromomethyl)cyclopropane for 2-(bromomethyl)tetrahydrofuran.
  • Example 44 4-(2,2-Difluorocyclopropane-1-carbonyl)-8-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoro) Preparation of methyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (44)
  • the title compound 44 was prepared in the same manner as in Example 35, except that 2,2-difluorocyclopropane-1-carbonyl chloride was used in place of tetrahydro-2H-pyran-4-carbonyl chloride.
  • the title compound 45 was prepared in the same manner as in Example 35, except that 3,3-difluorocyclobutane-1-carbonyl chloride was used in place of tetrahydro-2H-pyran-4-carbonyl chloride.
  • the title compound 46 was prepared in the same manner as in Example 35, except that benzoyl chloride was used in place of tetrahydro-2H-pyran-4-carbonyl chloride.
  • the title compound 47 was prepared in the same manner as in Example 8, except that cyclopropanecarbaldehyde was used in place of tetrahydrofuran-3-carbaldehyde.
  • Example 48 4-((2,2-Difluorocyclopropyl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1- Preparation of (2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (48)
  • the title compound 49 was prepared in the same manner as in Example 12 except substituting (bromomethyl)cyclobutane for 2-(bromomethyl)tetrahydrofuran.
  • the title compound 50 was prepared in the same manner as in Example 48, except that 1-methylcyclobutane-1-carboxylic acid was used in place of 2,2-difluorocyclopropane-1-carboxylic acid.
  • the title compound 51 was prepared in the same manner as in Example 12 except substituting (bromomethyl)cyclohexane for 2-(bromomethyl)tetrahydrofuran.
  • the preparation method was the same as that of Example 48, except that 1-methyl-5-oxopyrrolidine-3-carboxylate methyl ester was used instead of 2,2-difluorocyclopropane-1-carboxylic acid, NaBH 4 was used instead of LiAlH 4 , The title compound 52 was prepared.
  • Step 1 2-((8-(5-Methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl )ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester ( 53a) Preparation
  • the title compound 53a was prepared in the same manner as in Example 12, except substituting tert-butyl 2-((toluenesulfonyloxy)methyl)morpholine-4-carboxylate for 2-(bromomethyl)tetrahydrofuran.
  • Step 2 8-(5-Methylthiazol-2-yl)-4-(morpholin-2-ylmethyl)-3-oxo-N-((R)-1-(2-(trifluoro) Preparation of methyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide hydrochloride (53b)
  • Step 3 2-((8-(5-Methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl )ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)morpholine-4-carboxylic acid methyl ester (53) preparation
  • Example 55 3-((8-(5-Methylthiazol-2-yl)-3-oxo-6-(((R)-1-(2-(trifluoromethyl)pyrimidine-5- yl)ethyl)carbamoyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)pyrrolidine-1-carboxylate (55 ) preparation
  • Example 56 4-((4-Methylmorpholin-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1 of -(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (56) preparation
  • Step 1 4-((4-Methylmorpholin-2-yl)methyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1- Preparation of (2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (56) .
  • the title compound 57 was prepared in the same manner as in Example 12 except that methyl (R)-(tetrahydrofuran-2-yl)-4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.
  • Example 58 8-(5-Methylthiazol-2-yl)-3-oxo-4-(((S)-tetrahydrofuran-2-yl)methyl)-N-((R)-1- Preparation of (2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (58)
  • the title compound 58 was prepared in the same manner as in Example 12 except that methyl (S)-(tetrahydrofuran-2-yl)4-methylbenzenesulfonate was used instead of 2-(bromomethyl)tetrahydrofuran.
  • the title compound 59 was prepared in the same manner as in Example 12, except that bromoacetonitrile was used in place of 2-(bromomethyl)tetrahydrofuran.
  • Step 1 4-(2-Hydroxy-2-methylpropyl)-8-(5-methylthiazol-2-yl)-3-oxo-3,4-dihydro-2H-benzo[b ] Preparation of methyl [1,4]oxazine-6-carboxylate (60a).
  • the title compound 61 was prepared in the same manner as in Example 12 except that 3-bromoprop-1-yne was used in place of 2-(bromomethyl)tetrahydrofuran.
  • the title compound 62 was prepared in the same manner as in Example 48 except that 2-(tetrahydro-2H-pyran-4-yl)acetic acid was used in place of 2,2-difluorocyclopropane-1-carboxylic acid.
  • the title compound was prepared in the same manner as in Example 48, except that tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide was used in place of 2,2-difluorocyclopropane-1-carboxylic acid 63.
  • Example 64 2-Methyl-7-(5-methylthiazol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-N-((R)-1-(2 Preparation of -(trifluoromethyl)pyrimidin-5-yl)ethyl)benzo[d][1,3]bisoxazole-5-carboxamide (64)
  • Step 1 Preparation of methyl 2-methyl-2-(tetrahydro-2H-pyran-4-yl)benzo[d][1,3]dioxazole-5-carboxylate (64b)
  • Step 2 Methyl 7-bromo-2-methyl-2-(tetrahydro-2H-pyran-4-yl)benzo[d][1,3]dioxazole-5-carboxylate (64c) preparation.
  • Example 65 (R)-1-(4-Methoxyphenyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidine- Preparation of 5-yl)ethyl)-lH-indazole-6-carboxamide (65).
  • the title compound 65 was prepared in the same manner as in Example 1 except that 1-iodo-4-methoxybenzene was used in place of 3-iodooxetane.
  • Example 66 (R)-1-(4-Fluorophenyl)-4-(5-methylthiazol-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidine-5- Preparation of yl)ethyl)-1H-indazole-6-carboxamide (66).
  • the title compound 66 was prepared in the same manner as in Example 1 except that 1-fluoro-4-iodobenzene was used in place of 3-iodooxetane.
  • the title compound was prepared in the same manner as in Example 1, except that (3-fluorooxetan-3-yl)methyl-4-methylbenzenesulfonate was used instead of 3-iodooxetane 67.
  • Example 68 (R)-2-((3-Fluoroxetan-3-yl)methyl)-4-(5-methylthiazol-2-yl)-N-(1-(2 - Preparation of (trifluoromethyl)pyrimidin-5-yl)ethyl)-2H-indazole-6-carboxamide (68).
  • the title compound 70 was prepared in the same manner as in Example 1 except that 4-iodotetrahydro-2H-pyran was used in place of 3-iodooxetane.
  • the title compound 71 was prepared in the same manner as in Example 2, except that 4-iodotetrahydro-2H-pyran was used in place of 3-iodooxetane.
  • the title compound 72 was prepared in the same manner as in Example 1 except that 4-(bromomethyl)tetrahydro-2H-pyran was used in place of 3-iodooxetane.
  • the title compound 73 was prepared in the same manner as in Example 2, except that 4-(bromomethyl)tetrahydro-2H-pyran was used in place of 3-iodooxetane.
  • the title compound 74 was prepared in the same manner as in Example 1, except that (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 75 was prepared in the same manner as in Example 2 except that (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 76 was prepared in the same manner as in Example 1 except that (1-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 77 was prepared in the same manner as in Example 2 except that (1-methylpyrrolidin-3-yl)methyl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 78 was prepared in the same manner as in Example 12, except that 1-fluoro-2-iodoethane was used in place of 2-(bromomethyl)tetrahydrofuran.
  • the title compound 79 was prepared in the same manner as in Example 12, except that 1-fluoro-3-iodopropane was used in place of 2-(bromomethyl)tetrahydrofuran.
  • Example 80 (R)-8-(5-Methylthiazol-2-yl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl) Preparation of -4-(3,3,3-trifluoropropyl))-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (80)
  • the title compound 80 was prepared in the same manner as in Example 12, except that 1,1,1-trifluoro-3-iodopropane was used in place of 2-(bromomethyl)tetrahydrofuran.
  • Example 81 4-(1-Cyanoethyl)-8-(5-methylthiazol-2-yl)-3-oxo-N-((R)-1-(2-(trifluoromethyl) ) pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (81)
  • the title compound 81 was prepared in the same manner as in Example 12, except that 2-bromopropionitrile was used in place of 2-(bromomethyl)tetrahydrofuran.
  • the title compound 82 was prepared in the same manner as in Example 1 except that 4,4-difluorocyclohexyl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • Example 83 4-(5-Methylthiazol-2-yl)-1-((S)-tetrahydrofuran-3-yl)-N-((R)-1-(2-(trifluoromethyl) Preparation of pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (83)
  • the title compound 83 was prepared in the same manner as in Example 1 except that (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • Example 84 4-(5-Methylthiazol-2-yl)-1-((R)-tetrahydrofuran-3-yl)-N-((R)-1-(2-(trifluoromethyl) Preparation of pyrimidin-5-yl)ethyl)-1H-indazole-6-carboxamide (84)
  • the title compound 84 was prepared in the same manner as in Example 1 except that (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 85 was prepared in the same manner as in Example 1 except that 3-bromopropionitrile was used in place of 3-iodooxetane.
  • the title compound 86 was prepared in the same manner as in Example 2, except that 3-bromopropionitrile was used in place of 3-iodooxetane.
  • the title compound 87 was prepared in the same manner as in Example 1 except that 2-bromoacetonitrile was used in place of 3-iodooxetane.
  • the title compound 88 was prepared in the same manner as in Example 2 except that 2-bromoacetonitrile was used in place of 3-iodooxetane.
  • the title compound 89 was prepared in the same manner as in Example 1 except that 2,2-dimethyloxirane was used in place of 3-iodooxetane.
  • the title compound 90 was prepared in the same manner as in Example 2 except that 2,2-dimethyloxirane was used in place of 3-iodooxetane.
  • the title compound 91 was prepared in the same manner as in Example 1 except that (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 3-iodooxetane.
  • the title compound 92 was prepared in the same manner as in Example 2, except that (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 93 was prepared in the same manner as in Example 12, except substituting (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate for 2-(bromomethyl)tetrahydrofuran.
  • the title compound 94 was prepared in the same manner as in Example 1 except that tetrahydrofuran-2-yl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 95 was prepared in the same manner as in Example 2, except that tetrahydrofuran-2-yl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 96 was prepared in the same manner as in Example 1 except that (4-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate was used in place of 3-iodooxetane.
  • the title compound 97 was prepared in the same manner as in Example 2 except substituting (4-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate for 3-iodooxetane.
  • the title compound 98 was prepared in the same manner as in Example 1 except that 1-fluoro-2-iodoethane was used in place of 3-iodooxetane.

Abstract

一类芳基甲酰胺类化合物及其制备方法和医药用途。特别地，涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物，及其作为P2X3受体拮抗剂的用途，和用于治疗和/或预防与P2X3受体活性相关的疾病例如慢性咳嗽、疼痛、子宫内膜异位、膀胱过度活动症等的用途。其中通式(I)中的各取代基的定义与说明书中的定义相同。

Description

芳基甲酰胺类化合物及其制备方法和医药用途 技术领域
本发明属于医药技术领域，具体涉及一种芳基甲酰胺类化合物、其制备方法及含有其的药物组合物，以及其作为P2X3受体拮抗剂在治疗和/或预防与P2X3受体活性相关的疾病中的用途。
背景技术
ATP在病理环境中水平升高，表明其在许多疾病的发病机制中扮演重要角色。特别地，ATP可驱动和调节各种感觉行为和相关反应。当机体受到刺激(紫外线和化学损伤等)或处于病理学状态(哮喘、膀胱疼痛综合征等)时，ATP对感觉影响更大。
许多细胞表面受体(嘌呤能受体)参与介导ATP的感觉信号功能，其中，P2X3受体是介导ATP的感觉效应的主要受体。P2X3受体是ATP门控阳离子通道，属于P2X受体家族成员，P2X受体家族还包括P2X1、P2X2、P2X4、P2X5、P2X6、P2X7。P2X3受体在体内以同源三聚体P2X3或异三聚体P2X2/3的形式发挥作用(NeuroReport,10,1107–1111)。
P2X3和P2X2/3受体主要表达于背根神经节(DRG)和颅感觉神经节内的中小直径C-和Aδ-纤维感觉神经元，以及皮肤、关节和内脏等组织的感受野中的周围神经末梢。
P2X3受体是嘌呤类受体家族中的一员，是非选择性的配体门控离子通道，ATP将其激活后，允许Na +、K +、Ca 2+通过，尤以Ca 2+的通透性最为明显，在伤害性信息的产生、传递中起着重要的作用。当机体受到伤害或神经损伤后释放大量ATP，激活突触前膜P2X3受体，引起大量Ca 2+内流，细胞内钙浓度增加激活蛋白激酶A(protein kinase A，PKA)、蛋白激酶C(protein kinase C，PKC)，使得PKA、PKC磷酸化，同时促进了谷氨酸释放，进一步激活NMDA受体，导致兴奋性突触后电流的产生，引起中枢敏感化。
多种动物模型研究显示P2X3受体在伤害感受过程中具有重要作用。例如，P2X3受体敲除显著减轻疼痛反应。P2X3受体拮抗剂在疼痛和炎性疼痛的多种模型中具有抗伤害作用。除在伤害感受和急慢性疼痛中的突出作用外，P2X3受体还被证明参与泌尿生殖系统、胃肠道和呼吸系统疾病的病理过程，特别是膀胱过度活动症和慢性咳嗽。因此，P2X3受体在包括疼痛、泌尿生殖系统疾病、胃肠道疾病和呼吸系统疾病在内的多种疾病的病理机制中扮演重要角色，是治疗这些疾病的理想靶点。
P2X3亚基不仅形成同源三聚体，还形成具有P2X2亚基的异源三聚体。P2X3亚基和P2X2亚基也在舌头的神经纤维上表达，含有P2X3和/或P2X2亚基的受体 参与味觉传递(苦味、甜味、咸味、鲜味和酸味)。研究表明，P2X3同三聚体主要参与介导伤害感受，而P2X2/X3异三聚体主要参与味觉感受。缺乏P2X2和P2X3亚基的敲除动物表现出降低的味觉和甚至味觉丧失，而P2X3亚单位敲除表现出表型的温和或无变化(J.Physiol.2015,593,1113–1125)。
目前，在P2X3受体拮抗剂领域研究最快的是Merck和Afferent公司研发的化合物Gefapixant(AF-219)(PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,115(19),4939-4944.)，该化合物是P2X3和P2X2/X3受体非选择性拮抗剂，在针对慢性咳嗽的临床II期研究中表现出显著疗效，但也表现出味觉干扰的副作用。这种副作用主要归因于P2X2/3异三聚体阻断。因此，持续地需要新型或改进的P2X3受体拮抗剂，以用于开发新的、更有效的药物来治疗慢性咳嗽或其它与P2X3受体相关的疾病。
发明内容
本发明人经过潜心研究，设计合成了一系列取代的芳基甲酰胺类化合物，并对其进行了P2X3受体活性的筛选，研究结果显示该类化合物具有突出的P2X3受体拮抗活性，并且可以被开发为治疗和/或预防与P2X3受体活性相关的疾病的药物。
因此，本发明的目的为提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2021120150-appb-000001
其中：
A环为5元杂芳基；
Figure PCTCN2021120150-appb-000002
选自：
Figure PCTCN2021120150-appb-000003
Figure PCTCN2021120150-appb-000004
Figure PCTCN2021120150-appb-000005
其中所述B环各自独立地任选进一步被选自卤素、氨基、硝基、氰 基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基中的一个或多个基团取代；
W 1和W 2各自独立地选自CR 6或N；
L 1为
Figure PCTCN2021120150-appb-000006
L 2选自单键、
Figure PCTCN2021120150-appb-000007
-CO-、-O-、-S-、-SO-、-SO 2-和-NR 6-；
每一个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O pR a、-S(O) pNR aR b和-NHS(O) pR a，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
R 2选自芳基和杂芳基；所述芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基中的一个或多个基团取代；
R 3选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) pR a、-S(O) pNR aR b和-NHS(O) pR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) pR a、-S(O) pNR aR b和-NHS(O) pR a中的一个或多个基团取代；
R 4和R 5各自独立地选自氢、烷基和烷氧基，其中所述烷基和烷氧基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
每一个R 4’和R 5’各自独立地选自氢、烷基和烷氧基，其中所述烷基和烷氧基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
R 6选自氢、卤素、羟基、氰基、氨基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、 杂环基、芳基和杂芳基中的一个或多个基团取代；
R a和R b各自独立地选自氢、卤素、羟基、氰基、氨基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
p为0、1、2；
m为1至4的整数；且
n为0至3的整数。
在本发明一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
A环选自吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噻唑基、噁唑基、异噻唑基、异噁唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、1,3,4-噻二唑基、1,2,4-噻二唑基、三唑基和四唑基，优选吡唑基、噻唑基、噁唑基和1,3,4-噁二唑基，更优选噻唑基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2021120150-appb-000008
其中，B环、R 1、R 2、R 3、L 1、L 2和n如通式(I)所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
其中，
Figure PCTCN2021120150-appb-000009
选自：
Figure PCTCN2021120150-appb-000010
Figure PCTCN2021120150-appb-000011
其中所述B环各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基中的一个或多个基团取代；
其中，W 1、W 2、L 2、R 3如通式(I)所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
L 2选自单键、-(CH 2) m-、-(CH)CH 3-、-CO-、-SO-和-SO 2-；
m为1至4的整数，优选1至3的整数，更优选1或2。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
R 3选自氢、卤素、氰基、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7环烷基、4至7元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7环烷基、4至7元杂环基、C 6-C 10芳基和5至10元杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、4至6元杂环基、C 6-C 10芳基、5至10元杂芳基、-C(O)R a、-C(O)OR a、-S(O) pR a中的一个或多个基团取代；
R a选自C 1-C 6烷基；
p为1或2。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
L 2选自单键、-(CH 2) m-和-CO-；
R 3选自4至6元杂环基，其中所述4至6元杂环基任选进一步被选自卤素、氧代基、C 1-C 6烷基、-C(O)OR a的一个或多个基团取代；
R a选自C 1-C 6烷基；
m为1或2。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
L 2选自单键、-CH 2-和-CO-；
R 3选自氧杂环丁基、氮杂环丁基、四氢呋喃基、吡咯烷基、四氢吡喃基、四氢噻喃基、吗啉基、哌啶基、哌嗪基，其任选进一步被选自卤素、氧代基、C 1-C 6烷基、-C(O)OR a的一个或多个基团取代；
R a选自C 1-C 6烷基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
L 2为单键、-CH 2-和-CO-；
R 3选自C 3-C 6环烷基，所述C 3-C 6环烷基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基中的一个或多个基团取代。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
L 2为单键、-CH 2-和-CO-；
R 3选自苯基或5至6元杂芳基，所述苯基或5至6元杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
L 2为单键、-(CH 2) m-和-(CH)CH 3-；
R 3选自氰基、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基，所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基任选进一步被选自卤素、羟基中的一个或多个基团取代；
m为1至4的整数，优选1至3的整数，更优选1或2。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，
L 1为
Figure PCTCN2021120150-appb-000012
R 4和R 5各自独立地选自氢和C 1-C 6烷基；
优选地，L 1为
Figure PCTCN2021120150-appb-000013
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，每一个R 1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 7环烷基和5至7元杂环基，优选C 1-C 6烷基或C 1-C 6卤代烷基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其中，R 2为C 6-C 10芳基或5至10元杂芳基，优选苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基，更优选嘧啶基，所述芳基或杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基和C 1-C 6卤代烷氧基中的一个或多个基团取代。
本发明的典型化合物，包括但不限于：
Figure PCTCN2021120150-appb-000014
Figure PCTCN2021120150-appb-000015
Figure PCTCN2021120150-appb-000016
Figure PCTCN2021120150-appb-000017
Figure PCTCN2021120150-appb-000018
Figure PCTCN2021120150-appb-000019
Figure PCTCN2021120150-appb-000020
Figure PCTCN2021120150-appb-000021
Figure PCTCN2021120150-appb-000022
Figure PCTCN2021120150-appb-000023
Figure PCTCN2021120150-appb-000024
Figure PCTCN2021120150-appb-000025
Figure PCTCN2021120150-appb-000026
Figure PCTCN2021120150-appb-000027
Figure PCTCN2021120150-appb-000028
Figure PCTCN2021120150-appb-000029
Figure PCTCN2021120150-appb-000030
Figure PCTCN2021120150-appb-000031
Figure PCTCN2021120150-appb-000032
Figure PCTCN2021120150-appb-000033
Figure PCTCN2021120150-appb-000034
Figure PCTCN2021120150-appb-000035
Figure PCTCN2021120150-appb-000036
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用盐。
本发明进一步提供一种制备根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
Figure PCTCN2021120150-appb-000037
在缩合剂存在下，化合物Ig与化合物Ih在碱性条件下进行缩合反应得到通式(I)所示的化合物，其中，提供碱性条件的试剂优选DIPEA，缩合剂优选为HATU；
其中，A环、B环、W 1、W 2、R 1、R 2、R 3、L 1、L 2、n如通式(I)所定义。
本发明还提供一种制备根据本发明所述的通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法，其包括以下步骤：
Figure PCTCN2021120150-appb-000038
在缩合剂存在下，化合物IIg与化合物IIh在碱性条件下进行缩合反应得到通式(II)所示的化合物，其中，提供碱性条件的试剂优选DIPEA，缩合剂优选为HATU；
其中，B环、R 1、R 2、R 3、L 1、L 2、n如通式(II)所定义。
本发明另一方面提供一种药物组合物，其含有根据本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体。
本发明进一步提供根据本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物在制备P2X3受体拮抗剂中的用途。
本发明进一步提供根据本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物在制备预防和/或治疗与P2X3受体活性相关的疾病的药物中的用途。
本发明进一步提供根据本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物，其用作P2X3受体拮抗剂。
本发明进一步提供根据本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者含有其的药物组合物，其用于预防和/或治疗与P2X3受体活性相关的疾病。
本发明进一步提供一种预防和/或治疗与P2X3受体活性相关的疾病的方法，其包括向有需要的受试者施用预防或治疗有效量的根据本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，或者含有其的药物组合物。
在本文中，与P2X3受体活性相关的疾病可以为：呼吸系统疾病包括慢性阻塞性肺病(COPD)，哮喘，支气管痉挛，肺纤维化，急性咳嗽，慢性咳嗽，包括慢性特发性和慢性难治性咳嗽，泌尿生殖系统，胃肠道，呼吸和疼痛相关疾病，妇科疾病包括痛经(原发性和继发性痛经)，性交困难，排尿困难或睾丸炎，子宫内膜异位症和子宫腺肌症，子宫内膜异位症相关疼痛，子宫内膜异位症相关症状，盆腔超敏反应，泌尿道疾病状态与膀胱出口梗阻有关，尿失禁症状，如膀胱容量减少，排尿频率增加，急迫性尿失禁，压力性尿失禁或膀胱过度反应，良性前列腺肥大，前列腺增生，前列腺炎，逼尿肌反射亢进，膀胱过度活动症和与膀胱过度活动症有关的症状，其中所述症状尤其是尿频，夜尿，尿急或急迫性尿失禁，盆腔超敏反应，尿道炎，前列腺炎，前列腺痛，膀胱炎，特别是间质性膀胱炎，特发性膀胱过敏症，癫痫，部分和全身性癫痫发作，胃肠道疾病包括肠易激综合征(IBS)，炎性肠病(IBD)，胆绞痛和其他胆道疾病，肾绞痛，腹泻占优势的IBS，胃食管反流，胃肠道扩张，克罗恩病，神经退行性疾病，如阿尔茨海默病，多发性硬化症，帕金森病，脑缺血和创伤性脑损伤，心肌梗塞，脂质紊乱，与疼痛相关的疾病或病症选自痛觉过敏，异常性疼痛，功能性肠病，痛风，关节炎(如 骨关节炎，类风湿性关节炎和强直性脊柱炎)，灼口综合征，烧伤，偏头痛或丛集性头痛，神经损伤，创伤后损伤(包括骨折和运动损伤)，神经炎，神经痛，中毒，缺血性损伤，间质性膀胱炎，癌症，三叉神经痛，小纤维神经病变，糖尿病神经病变，慢性关节炎和相关神经病，HIV和HIV治疗引起的神经病，瘙痒症，伤口愈合受损和骨骼疾病如关节退化等。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸，特别优选盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。
此外，本发明还包括本发明通式(I)所示的化合物的前药。本发明所述的前药是通式(I)所示的化合物的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链 脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植 物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分使用，也可以与其它治疗与P2X3受体活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基 或羧酸酯基。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021120150-appb-000039
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021120150-appb-000040
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电 子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021120150-appb-000041
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含4至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括氧杂环丁基、氮杂环丁基、噁二唑基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021120150-appb-000042
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m (其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021120150-appb-000043
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021120150-appb-000044
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021120150-appb-000045
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021120150-appb-000046
Figure PCTCN2021120150-appb-000047
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5至7元，含1至3个杂原子；最优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、哒嗪、异噻唑基、异噁唑基、噁二唑基、三唑基等，优选为咪唑基、噻唑基、吡唑基、嘧啶基、噻唑基、哒嗪或噁唑基；更优选噻唑基、吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021120150-appb-000048
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。
术语“磺酸基”指-S(O) 2OH。
术语“磺酸酯基”指-S(O) 2O(烷基)或-S(O) 2O(环烷基)，其中烷基和环烷基如上所定义。
术语“磺酰基”指-S(O) 2R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。
术语“氨基酰基”指-C(O)-NRR’，其中R、R’各自独立地为氢、烷基、环烷基、杂环基、芳基、杂芳基。
术语“氨基磺酰基”或“磺酰氨基”指-S(O) 2-NRR’，其中R、R’各自独立地为氢、烷基、环烷基、杂环基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案。
本发明通式(I)所示的化合物或其盐可通过以下方案制备，具体制备方法如下。
(1)方案1：当
Figure PCTCN2021120150-appb-000049
为
Figure PCTCN2021120150-appb-000050
时，按照方案1的方法，由化合物Ia作为起始原料，得到通式(I)化合物。
Figure PCTCN2021120150-appb-000051
方案1
方案1的合成：
步骤1：在高温、碱性条件下，将化合物Ia与Ib反应得到化合物Ic，其中，高温条件优选100℃，碱性试剂优选碳酸铯；
步骤2：在高温、碱性和催化剂存在下，将化合物Ic与双联硼酸频哪醇酯反应得到化合物Id，其中，高温条件优选100℃，碱性试剂优选乙酸钾，催化剂优选Pd(dppf)Cl 2催化剂；
步骤3：在高温、碱性和催化剂存在下，将化合物Id与化合物Ie反应得到化合物If，其中，高温条件优选90℃，碱性试剂优选碳酸钾，催化剂优选Pd(dppf)Cl 2催化剂；
步骤4：在碱性条件下，将化合物If水解得到化合物Ig，其中，碱性试剂优选氢氧化锂；
步骤5：在缩合剂存在下，将化合物Ig与Ih在碱性条件下进行缩合反应，得到通式(I)化合物，其中，提供碱性条件的试剂优选DIPEA，缩合剂优选HATU。
(2)方案2：当
Figure PCTCN2021120150-appb-000052
为
Figure PCTCN2021120150-appb-000053
时，按照方案2的方法，由化合物Ii作为起始原料，得到化合物Ic。再参考方案1的合成方法，以化合物Ic作为起始原料，得到通式(I)化合物。
Figure PCTCN2021120150-appb-000054
方案2
方案2的合成：
步骤1：将化合物Ii在室温条件下与卤代试剂反应得到化合物Ij，其中，卤代试剂优选NBS；
步骤2：在高温、酸性和还原剂存在下，将化合物Ij还原得到化合物Ik，其中，高温条件优选65℃，酸性试剂优选氯化铵，还原剂优选锌粉；
步骤3：在高温、碱性试剂存在下，将化合物Ik与二卤代物发生取代反应得到化合物Ia，其中，高温条件优选110℃，碱性试剂优选碳酸钾，二卤代物优选1,2-二溴乙烷；
步骤4：在室温、还原剂和催化剂存在下，将化合物Ia与化合物Il反应得到化合物Ic，其中还原剂优选氰基硼氢化钠，催化剂优选无水氯化锌；
(3)方案3：当
Figure PCTCN2021120150-appb-000055
为
Figure PCTCN2021120150-appb-000056
时，按照方案3的方法，由化合物Ik作为起始原料，得到化合物Ic。再参考方案1的合成方法，以化合物Ic作为起始原料，得到通式(I)化合物。
Figure PCTCN2021120150-appb-000057
方案3
方案3的合成：
步骤1：在低温和碱性条件下，将化合物Ik与氯乙酰氯缩合得到化合物Im，其中，低温条件优选0℃，碱性试剂优选碳酸钾；
步骤2：在高温和碱性条件下，化合物Im发生关环反应得到化合物Ia，其中，高温条件优选80℃，碱性试剂优选醋酸钾；
步骤3：在室温和碱性条件下，将化合物Ia与Ib反应得到Ic，其中，碱性试剂优选碳酸铯；
(4)方案4：当
Figure PCTCN2021120150-appb-000058
为
Figure PCTCN2021120150-appb-000059
时，按照方案4的方法，由化合物In作为起始原料，到化合物Ic。再参考方案1的合成方法，以化合物Ic作为起始原料，得 到通式(I)化合物。
Figure PCTCN2021120150-appb-000060
方案4
方案4的合成：
步骤1：在高温条件下，将化合物In与丙二酸环(亚)异丙酯反应得到化合物Io，其中，高温条件优选100℃；
步骤2：在高温条件下，将化合物Io溶解于二苯醚中发生自身关环反应得到化合物Ip，其中，高温条件优选210℃；
步骤3：在高温条件下，将化合物Ip与三氯氧磷反应得到化合物Ia，其中，高温条件优选80℃；
步骤4：在高温、碱性封管条件下，将化合物Ia与Iq反应得到化合物Ic，其中，高温条件优选100℃，碱性试剂优选DIPEA；
(5)方案5：当
Figure PCTCN2021120150-appb-000061
为
Figure PCTCN2021120150-appb-000062
时，按照方案5的方法，由化合物Ir作为起始原料，到化合物Ic。再参考方案1的合成方法，以化合物Ic作为起始原料，得到通式(I)化合物。
Figure PCTCN2021120150-appb-000063
方案5
方案5的合成：
步骤1：在高温条件下，将化合物Ir与乙醛酸反应得到化合物Is，其中，高温条件优选80℃；
步骤2：在高温条件下，将化合物Is与三氯氧磷反应得到化合物Ia，其中，高温条件优选80℃；
步骤3：在高温、碱性封管条件下，将化合物Ia与Iq反应得到化合物Ic，其中，高温条件优选100℃，碱性试剂优选DIPEA；
(6)方案6：当
Figure PCTCN2021120150-appb-000064
为
Figure PCTCN2021120150-appb-000065
时，按照方案6的方法，由化合物It作为起始原料，到化合物Ic。再参考方案1的合成方法，以化合物Ic作为起始原料，得 到通式(I)化合物。
Figure PCTCN2021120150-appb-000066
方案6
方案6的合成：
步骤1：在室温条件下，将化合物It与NBS反应得到化合物Iu；
步骤2：在高温、碱性封管条件下，将化合物Iu与CS 2反应得到化合物Ia，其中，高温条件优选80℃，碱性试剂优选KOH；
步骤3：在高温、碱性封管条件下，将化合物Ia与Iq反应得到化合物Ic，其中，高温条件优选150℃，碱性试剂优选DIPEA；
(7)方案7：当
Figure PCTCN2021120150-appb-000067
为
Figure PCTCN2021120150-appb-000068
时，按照方案7的方法，由化合物Iv作为起始原料，到化合物Ic。再参考方案1的合成方法，以化合物Ic作为起始原料，得到通式(I)化合物。
Figure PCTCN2021120150-appb-000069
方案7
方案7的合成：
步骤1：在高温、对甲苯磺酸催化条件下，将化合物Iv与Iw反应得到化合物Ix；
步骤2：在高温条件下，将化合物Ix与NBS反应得到化合物Ic；
其中，W 1、W 2、A环、B环、R 1、R 2、R 3、L 1、L 2、n如通式(I)所定义。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用1100 Series LC/MSD Trap(ESI)质谱仪(生产商：Agilent)。
制备液相使用lc3000高效液相色谱仪以及lc6000高效液相色谱仪(生产商： 创新通恒)。色谱柱为Daisogel C18 10μm 60A(20mm×250mm)。
HPLC的测定使用岛津LC-20AD高压液相色谱仪(Agilent TC-C18 250×4.6mm5μm色谱柱)和岛津LC-2010AHT高压液相色谱仪(Phenomenex C18 250×4.6mm5μm色谱柱)。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用青岛海洋硅胶100～200目、200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京耦合、Sigma、百灵威、易世明、上海书亚、伊诺凯、南京药石、安耐吉化学等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
微波反应使用CEM Discover SP型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚、乙酸乙酯和二氯甲烷体系，C：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
缩略语
μL＝微升；
μM＝微摩尔；
NMR＝核磁共振；
AIBN＝偶氮二异丁腈
Boc＝叔丁氧基羰基
br＝宽峰
d＝双峰
δ＝化学位移
℃＝摄氏度
dd＝双双峰
DIPEA＝二异丙基乙基胺
DMAP＝4-二甲氨基吡啶
DMF＝N,N-二甲基甲酰胺
DMSO＝二甲亚砜
DCM＝二氯甲烷
EA＝乙酸乙酯
HPLC＝高效液相
Hz＝赫兹
IC 50＝抑制50％活性的浓度
J＝偶合常数(Hz)
LC-MS＝液相色谱-质普联用
m＝多重峰
M+H +＝母体化合物质量+一质子
mg＝毫克
mL＝毫升
mmol＝毫摩尔
mol＝摩尔
Ms＝甲磺酰基
MS＝质谱
MsCl＝甲基磺酰氯
m/z＝质荷比
nM＝纳摩尔
NBS＝N-溴代琥珀酰亚胺
NIS＝N-碘代丁二酰亚胺
PE＝石油醚
ppm＝每百万分
Pro＝保护基
s＝单峰
t＝三重峰
TEA＝三乙胺
TFA＝三氟乙酸
THF＝四氢呋喃。
BPD＝双联硼酸频那醇酯
HATU＝2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐
DCDMH＝1,3-二氯-5,5-二甲基海因
Pd 2(dba) 3＝三(二亚苄基丙酮)二钯
Pd(dppf)Cl 2＝1,1'-二(二苯膦基)二茂铁二氯化钯(II)
Xantphos＝4,5-双(二苯基膦)-9,9-二甲基氧杂蒽
实施例1：(R)-4-(5-甲基噻唑-2-基)-1-(氧杂环丁烷-3-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(1)的制备
Figure PCTCN2021120150-appb-000070
步骤1：4-溴-1-(氧杂环丁烷-3-基)-1H-吲唑-6-羧酸甲酯的合成(1b)
于室温，将4-溴-1H-吲唑-6-甲酸甲酯(2.0g，7.8mmol)、3-碘氧杂环丁烷(2.0g，11.7mmol)、Cs 2CO 3(7.6g，23.4mmol)、DMF(20mL)加到反应瓶中，100℃反应16小时。反应结束后，加100mL水，100mL乙酸乙酯萃取，有机相用水洗涤三次，无水硫酸钠干燥，浓缩，制备纯化(洗脱剂：石油醚：乙酸乙酯＝2：1)，得到0.5g类白色固体状的标题化合物，收率：20.6％。
步骤2：1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑-6-羧酸甲酯的合成(1c)
于室温，将4-溴-1-(氧杂环丁烷-3-基)-1H-吲唑-6-羧酸甲酯(0.5g，1.6mmol)、联硼酸频那醇酯(0.6g，2.4mmol)、乙酸钾(0.3g,3.2mmol)、Pd(dppf)Cl 2(59mg，0.08mmol)、DMF(10mL)加到反应瓶中，排空气，氮气保护，110℃搅拌反应3小时。反应结束后，抽滤，滤液浓缩至干，制备纯化(洗脱剂：石油醚：乙酸乙酯＝2：1)，得到0.5g白色固体状的标题化合物，收率：86.6％。
步骤3：4-(5-甲基噻唑-2-基)-1-(氧杂环丁烷-3-基)-1H-吲唑-6-羧酸甲酯的合成(1d)
于室温，将1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑-6-羧酸甲酯(0.43g，1.2mmol)、2-溴-5-甲基噻唑(0.26g,1.44mmol)、碳酸钾(0.40g，2.88mmol)、Pd(dppf)Cl 2(132mg，0.18mmol)、THF(20mL)、水(3mL)加到反应瓶中，排空气，氮气保护，90℃搅拌反应16小时。反应结束后，抽滤，滤液加100mL乙酸乙酯、100mL水萃取，有机相用水洗涤一次，无水硫酸钠干燥，浓缩至干，制备纯化(洗脱剂：二氯甲烷)，得到0.5g黄色油状物的标题化合物，收率：126.5％。
步骤4：4-(5-甲基噻唑-2-基)-1-(氧杂环丁烷-3-基)-1H-吲唑-6-羧酸的合成(1e)
于室温，将4-(5-甲基噻唑-2-基)-1-(氧杂环丁烷-3-基)-1H-吲唑-6-羧酸甲酯(0.5g，2mmol)、THF(5mL)、甲醇(5mL)、1N氢氧化锂(4mL)加到反应瓶中，室温搅拌反应16小时。反应结束后，用1N盐酸调pH至3-4，加20mL水、20mL乙酸乙酯萃取，有机相用水、饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩，得到0.4g灰色固体状的标题化合物，收率：83.6％。
步骤5：(R)-4-(5-甲基噻唑-2-基)-1-(氧杂环丁烷-3-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺的合成(化合物1)
于室温，将4-(5-甲基噻唑-2-基)-1-(氧杂环丁烷-3-基)-1H-吲唑-6-羧酸(117mg,0.37mmol)、DMF(10mL)、HATU(197mg，0.52mmol)、DIPEA(191mg，1.48mmol)、(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(根据文献WO2010111059制备)(93mg，0.41mmol)加到反应瓶中，室温反应16小时。反应结束后，将反应液倒入100mL冰水中，搅拌10分钟，抽滤，滤饼通过制备液相(洗脱剂：0％-100％乙腈：水溶液)纯化，得到15mg白色固体的标题化合物，收率：8.3％。
MS:m/z＝489.18[M+H] +。
1H NMR(400MHz,DMSO-d6):δppm 9.23(d,J＝7.1Hz,1H),9.16(s,2H),9.01(s,1H),8.48(s,1H),7.99(s,1H),7.73(s,1H),6.11-6.04(m,1H),5.38-5.31(m,1H),5.07-5.03(m,4H),2.50(s,3H),1.64(d,J＝7.1Hz,3H)。
实施例2：(R)-4-(5-甲基噻唑-2-基)-2-(氧杂环丁烷-3-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(2)的制备
Figure PCTCN2021120150-appb-000071
Figure PCTCN2021120150-appb-000072
步骤1：4-溴-2-(氧杂环丁-3-基)-2H-吲唑-6-羧酸甲酯的合成(2a)
于室温，将4-溴-1H-吲唑-6-甲酸甲酯(2.0g，7.8mmol)、3-碘氧杂环丁烷(2.0g，11.7mmol)、Cs 2CO 3(7.6g，23.4mmol)、DMF(20mL)加到反应瓶中，100℃反应16小时。反应结束后，加100mL水，100mL乙酸乙酯萃取，有机相用水洗涤三次，无水硫酸钠干燥，浓缩，制备纯化(洗脱剂：石油醚：乙酸乙酯＝2：1)，得到0.5g类白色固体状的标题化合物，收率：20.6％。
后续步骤与实施例1的制备方法相同，除了用2a替代1b，制得标题化合物2。
MS:m/z＝489.18[M+H] +。
1H NMR(400MHz,DMSO-d6):δppm 9.27(d,J＝7.1Hz,1H),9.16(s,2H),8.81(s,1H),8.34(s,1H),8.07(s,1H),7.79(s,1H),6.22-6.15(m,1H),5.37-5.32(m,1H),5.10-5.04(m,4H),2.56(s,3H),1.65(d,J＝7.1Hz,3H)。
实施例3：(R)-2-(氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(3)的制备
Figure PCTCN2021120150-appb-000073
步骤1：4-溴-2-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-2H-吲唑-6-羧酸甲酯(3a)的制备
于室温，将4-溴-1H-吲唑-6-甲酸甲酯(2.00g，7.87mmol)、3-碘代氮杂环丁烷-1-羧酸叔丁酯(6.68g，23.6mmol)和Cs 2CO 3(7.74g，23.6mmol)溶于DMF (30mL)中，反应液在室温下搅拌过夜。反应液减压浓缩，用EtOAc(40mL)稀释并用水(30mL)洗涤，分离有机相，水相用EtOAc(30mL x 2)萃取，合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化，得1.4g半油状白色固体状标题化合物，收率49％。
步骤2：2-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2H-吲唑-6-甲酯羧酸(3b)的制备。
于室温，将4-溴-2-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-2H-吲唑-6-羧酸甲酯(1.20g，2.93mmol)，双联频哪醇硼酸酯(1.12g，4.40mmol)和KOAc(0.862g，8.80mmol)溶于1,4-二氧六环(20mL)中，加入Pd(dppf)Cl 2(0.297g，0.406mmol)，反应液在N 2保护下置换气体三次，加热到90℃搅拌过夜。反应液降至室温，不需作进一步处理可直接用于下一步。
步骤3：2-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-2H-吲唑-6-羧酸甲酯(3c)的制备。
于室温，向上述反应液中加入4mL水，2-溴-5-甲基噻唑(0.942g，5.29mmol)和K 2CO 3(1.10g，7.94mmol)，再加入Pd(dppf)Cl 2(0.194g，0.265mmol)，反应液在N 2保护下置换气体三次，在80℃下搅拌过夜。向反应液中加入20mL水，用乙酸乙酯(20mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚：乙酸乙酯＝2/1～1/1)，得白色固体状标题化合物1.30g，收率：87％。
步骤4：2-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-2H-吲唑-6-羧酸(3d)的制备。
于室温，将2-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-2H-吲唑-6-羧酸甲酯(1.30g，3.04mmol)和LiOH·H 2O(511mg，12.1mmol)溶于EtOH(10mL)，H 2O(4mL)和MeOH(2mL)的混合溶剂中，反应液加热到60℃并搅拌5h。反应液减压浓缩，用1N盐酸水溶液调节pH＝4～6，析出大量黄色固体，过滤、收集并干燥得黄色固体状标题化合物930mg，收率：74％。
步骤5：(R)-3-(4-(5-甲基噻唑-2-基)-6-((1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2H-吲唑-2-(叔丁基)基)氮杂环丁烷-1-羧酸叔丁酯(3e)的制备。
于室温，将2-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-2H-吲唑-6-羧酸(300mg，0.725mmol)，(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(198mg，0.870mmol)和DIPEA(281mg，2.17mmol)溶于DMF(6mL)中，加入HATU(551mg，1.45mmol)，反应液在室温下搅拌过夜。向反应液中加入水(20mL)，用乙酸乙酯(25mL x 3)萃取。合并的有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥，过滤并减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2/1～1/1)，得黄色油状标题化合物300mg，收率：71％。
步骤6：(R)-2-(氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶 -5-基)乙基)-2H-吲唑-6-甲酰胺(化合物3)的制备。
于室温，将(R)-3-(4-(5-甲基噻唑-2-基)-6-((1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2H-吲唑-2-(叔丁基)基)氮杂环丁烷-1-羧酸叔丁酯(300mg，0.511mmol)溶于DCM(5mL)中，室温下滴加TFA(291mg，2.56mmol)，反应液在室温搅拌4h。反应液减压浓缩，加入碳酸氢钠水溶液，调节pH＝6～7，用EtOAc(20mL x 2)萃取，合并的有机相用无水硫酸钠干燥，浓缩得粗品。残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得白色固体状标题化合物84mg，收率：34％。
MS：m/z＝488.50[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.35(d,J＝7.4Hz,1H),9.16(s,2H),8.88(s,1H),8.33(s,1H),8.11(s,1H),7.81(s,1H),5.97-5.95(m,1H),5.36(t,J＝6.9Hz,1H),4.52-4.49(m,4H),2.57(s,3H),1.66(d,J＝7.1Hz,3H)。
实施例4：(R)-1-(氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(4)的制备
Figure PCTCN2021120150-appb-000074
与实施例2的制备方法相同，除了用3-碘代氮杂环丁烷-1-羧酸叔丁酯代替3-碘氧杂环丁烷，制得标题化合物4。
MS：m/z＝488.43[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.29(d,J＝7.1Hz,1H),9.16(s,2H),9.09(s,1H),8.44(s,1H),8.02(s,1H),7.75(s,1H),5.93-5.90(m,1H),5.36-5.33(m,1H),4.53-4.50(m,4H),2.55(s,3H),1.65(d,J＝7.1Hz,3H)。
实施例5：(R)-2-(1-甲基氮杂-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(5)的制备
Figure PCTCN2021120150-appb-000075
Figure PCTCN2021120150-appb-000076
将(R)-2-(氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(84.0mg，0.173mmol)、MeOH(5mL)、37％HCHO水溶液(65.2mg，0.863mmol)加到反应瓶中，于室温搅拌1小时，再加入NaBH 3CN(21.7mg，0.345mmol)，反应液继续搅拌过夜。反应结束后，将反应液减压浓缩，残余物用乙酸乙酯(15mL)稀释，用水(15mL x 2)洗涤。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过制备液相色谱法(色谱柱：Hedea ODS-2C18，300mm*250mm，10μm；洗脱剂：0％-100％乙腈：水溶液)纯化，得到55mg白色固体的标题产物，收率：63.9％。
MS：m/z＝502.74[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.38(d,J＝7.4Hz,1H),9.17(s,2H),8.90(s,1H),8.35(s,1H),8.10(s,1H),7.84(s,1H),5.99-5.96(m,1H),5.38(t,J＝6.9Hz,1H),4.55-4.50(m,4H),2.59(s,3H),2.20(s,3H),1.68(d,J＝7.1Hz,3H)。
实施例6：(R)-1-(1-甲基氮杂-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(6)的制备
Figure PCTCN2021120150-appb-000077
与实施例5的制备方法相同，除了用化合物4替代化合物3，制得标题化合物6。
MS：m/z＝502.05[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.30(d,J＝7.1Hz,1H),9.17(s,2H),9.11(s,1H),8.46(s,1H),8.03(s,1H),7.75(s,1H),5.95-5.91(m,1H),5.36-5.33(m,1H),4.54-4.51(m,4H),2.55(s,3H),2.18(s,3H),1.65(d,J＝7.1Hz,3H)。
实施例7：(R)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]嗪-6-甲酰胺(7)的制备
Figure PCTCN2021120150-appb-000078
Figure PCTCN2021120150-appb-000079
步骤1：3-溴-4-羟基-5-硝基苯甲酸甲酯(7b)的制备。
于室温，将4-羟基-3-硝基苯甲酸甲酯(10.0g，50.7mmol)溶于DMF(100mL)中，于0℃，分批缓慢加入NBS(9.88g，55.8mmol)，加毕，反应液升至室温搅拌2h。反应结束后，减压浓缩，向残余物中加入70mL水，析出大量黄色固体，静置5min，过滤，用水(10mL x 3)洗涤并收集滤饼，得黄色固体状标题化合物14g，收率：99％。
步骤2：3-氨基-5-溴-4-羟基苯甲酸甲酯(7c)的制备。
于室温，将3-溴-4-羟基-5-硝基苯甲酸甲酯(13.5g，49.1mmol)、NH 4Cl(13.5g，245mmol)溶于EtOH(100mL)和水(20mL)的混合溶剂中，于0℃，分批缓慢加入Zn粉(15.9g，245mmol)，加完后0℃继续搅拌20min，然后升温至80℃搅拌5h。冷却至室温，抽滤，滤饼用甲醇洗涤并收集，所得滤液浓缩得少部分粗产物。上述滤饼溶于100mL 6N的氢氧化钠水溶液中，搅拌10min过滤，滤饼用甲醇洗涤，收集滤液，滤液用6N盐酸水溶液调节pH至5～6，减压浓缩干滤液得大部分粗产物。两部分粗产物合并，用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20/1-10:1)，得浅黄色固体状标题化合物7.0g，收率：58％。
步骤3：8-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(7d)的制备。
于室温，将3-氨基-5-溴-4-羟基苯甲酸甲酯(2.00g，8.20mmol)和K 2CO 3(2.26g，16.4mmol)溶于DMF(15mL)中，加入1,2-二溴乙烷(0.845mL，9.86mmol)，反应液在100℃油浴中搅拌2h。反应液减压浓缩，向残余物中加入30mL水，用乙酸乙酯(30mL x 3)萃取。合并有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2/1-1:1)，得浅黄色固体状标题化合物1.5g，收率：68％。
步骤4：8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(7e)的制备。
于室温，将8-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(1.10g，4.06mmol)，双联频哪醇硼酸酯(1.55g，6.09mmol)和KOAc(1.20g，12.2mmol)溶于1,4-二氧六环(15mL)中，加入Pd(dppf)Cl 2(0.297g，0.406mmol)，反应液在N 2保护下置换气体三次，在90℃油浴中搅拌过夜。反应液降至室温，不需作进一步处理可直接用于下一步。
步骤5：8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(7f)的 制备。
于室温，向上步反应液中加入3mL水，2-溴-5-甲基噻唑(836mg，4.70mmol)和K 2CO 3(1.49g，10.8mmol)，再加入Pd(dppf)Cl 2(0.263g，0.360mmol)，反应液在N 2保护下置换气体三次，80℃搅拌过夜。向反应液中加入20mL水，用乙酸乙酯(20mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2/1-1:1)，得黄色固体状标题化合物820mg，收率：77％。
步骤6：8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(7g)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(80.0mg，0.275mmol)和LiOH·H 2O(50.0mg，1.10mmol)溶于EtOH(5mL)和THF(2mL)的混合溶剂中，反应液80℃搅拌3h。反应液减压浓缩，加入4mL水，用6N盐酸水溶液调节pH至4～5，析出大量黄色固体，过滤、收集并干燥得黄色固体状标题化合物60mg，收率：79％。
LC-MS：m/z 277.22[M+H] +。
步骤7：(R)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(化合物7)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(35.0mg，0.127mmol)，(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(34.7mg，0.152mmol)和DIPEA(49.1mg，0.381mmol)溶于DMF(3mL)中，加入HATU(96.5mg，0.245mmol)，反应液在室温下搅拌过夜。向反应液中加入10mL水，用乙酸乙酯(15mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm,C18,10um,100A,流动相：乙腈/水，梯度：30％-80％)，得黄色固体状标题化合物32mg，收率：56％。
MS:m/z＝450.49[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.08(s,2H),8.95(d,J＝6.3Hz,1H),7.98(s,1H),7.52(s,1H),7.13(s,1H),6.22(s,1H),5.29-5.25(m,1H),4.39-4.36(m,2H),3.41-3.37(m,2H),2.48(s,3H),1.58(d,J＝7.2Hz,3H)。
实施例8：8-(5-甲基噻唑-2-基)-4-((四氢呋喃-3-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(8)的制备
Figure PCTCN2021120150-appb-000080
Figure PCTCN2021120150-appb-000081
步骤1：8-(5-甲基噻唑-2-基)-4-((四氢呋喃-3-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(8a)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(100mg，0.344mmol)，四氢呋喃-3-甲醛(101mg，1.03mmol)和ZnCl 2(83.6mg，0.688mmol)溶于无水DCM(20mL)中，反应液在室温下搅拌10min。加入NaBH 3CN(66.0mg，1.03mmol)，反应液在N 2保护下于室温搅拌过夜。向反应液中加入20mL水，搅拌5min，分离有机相，水相用DCM(15mL x 2)萃取。合并的有机相用无水硫酸钠干燥，过滤，浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1/1)，得黄色油状标题化合物150mg，收率：47％。
步骤2：8-(5-甲基噻唑-2-基)-4-((四氢呋喃-3-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(8b)的制备。
于室温，将8-(5-甲基噻唑-2-基)-4-((四氢呋喃-3-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(150mg，0.401mmol)和LiOH·H 2O(67.4mg，1.60mmol)溶于EtOH(5mL)和THF(2mL)的混合溶剂中，反应液在60℃下搅拌4h。反应液减压浓缩，加入2mL水，用1N稀HCl水溶液调节pH＝3～5，析出大量黄色固体，过滤、收集并干燥得黄色固体状标题化合物140mg，收率：96％。
步骤3：8-(5-甲基噻唑-2-基)-4-((四氢呋喃-3-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(化合物8)的制备。
于室温，将8-(5-甲基噻唑-2-基)-4-((四氢呋喃-3-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(140mg，0.389mmol)，(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(106mg，0.467mmol)和DIPEA(150mg，1.17mmol)溶于DMF(5mL)中，加入HATU(296mg，0.778mmol)，反应液在室温下搅拌过夜。反应液减压浓缩，向其中加入15mL水，用乙酸乙酯(20mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得白色固体状标题化合物128mg，收率：61％。
MS:m/z＝534.57[M+H] +。
1H NMR(400MHz,DMSO-d6)δ9.11-8.99(m,3H),8.30-8.07(m,1H),7.67-7.64(m,1H),7.55-7.21(m,1H),5.27-5.10(m,1H),4.44-4.10(m,2H),3.82-3.63(m,4H),3.48-3.44(m,3H),3.30-3.11(m,1H),2.65-2.58(m,1H),2.50(s,3H),2.01-1.98(m,1H),1.64-1.59(m,4H)。
实施例9：(R)-4-(氮杂环丁烷-3-基甲基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(9)的制备
Figure PCTCN2021120150-appb-000082
步骤1：(R)-3-((8-(5-甲基噻唑-2-基)-6-((1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(9a)的制备
与实施例8的制备方法相同，除了在步骤1用3-甲酰基氮杂环丁烷-1-羧酸叔丁酯替代四氢呋喃-3-甲醛，制得化合物9a。
步骤2：(R)-4-(氮杂环丁烷-3-基甲基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(9)的制备
于室温，将(R)-3-((8-(5-甲基噻唑-2-基)-6-((1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(130mg，0.210mmol)溶于DCM(10mL)中，室温滴加TFA(192mg，1.68mmol)，反应液在室温搅拌4h。反应液减压浓缩，加入氨水溶液，调节pH＝6～7，用EtOAc(15mL x 2)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得白色固体状标题化合物56mg，收率：51.4％。
MS:m/z＝519.13[M+H] +。
1H NMR(300MHz,CDCl 3)δ9.10(s,1H),9.04(s,1H),8.57(s,1H),8.29(s,1H),7.68(s,1H),7.54(s,1H),5.41-5.38(m,1H),4.86-4.84(m,2H),4.43-4.42(m,2H),4.39-4.36(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2H),3.48-3.47(m,1H),2.58(s,3H),1.75(d,J＝7.2Hz,3H)。
实施例10：(R)-4-((1-甲基氮杂-3-基)甲基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(10)的制备
Figure PCTCN2021120150-appb-000083
与实施例5的制备方法相同，除了用(R)-4-(氮杂环丁烷-3-基甲基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(化合物9)替代(R)-2-(氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(化合物3)，制得标题化合物10。
MS:m/z＝532.20[M+H] +。
1H NMR(300MHz,CDCl 3)δ9.10(s,1H),9.04(s,1H),8.57(s,1H),8.29(s,1H),7.68(s,1H),7.54(s,1H),5.41-5.38(m,1H),4.86-4.84(m,2H),4.43-4.42(m,2H),4.39-4.36(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2H),3.48-3.47(m,1H),2.58(s,3H),2.20(s,3H),1.75(d,J＝7.2Hz,3H)。
实施例11：(R)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(11)的制备
Figure PCTCN2021120150-appb-000084
步骤1：3-溴-5-(2-氯乙酰氨基)-4-羟基苯甲酸甲酯(11a)的制备。
于0℃，将3-氨基-5-溴-4-羟基苯甲酸甲酯(245mg，1.00mmol)和K 2CO 3(414mg，3.00mmol)溶于MeCN(5mL)中，缓慢滴加溶有氯乙酰氯(0.09ml，1.20mmol)的乙腈溶液，边加边搅拌，加毕，反应液升至室温搅拌2h。反应液减压浓缩，向残余物中加入10mL水，用EtOAc(15mL x 3)萃取，合并的有机相用无水Na 2SO 4干燥，过滤，滤液减压浓缩得黄色固体状标题化合物160mg，直接用于下一步。收率：49％。
步骤2：8-溴-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(11b)的制备。
于室温，将3-溴-5-(2-氯乙酰氨基)-4-羟基苯甲酸甲酯(120mg，0.374mmol)溶于无水EtOH(5mL)中，加入KOAc(110mg,1.12mmol)，反应液升温至80℃搅拌1h。反应液减压浓缩，残余物用EtOAc(20mL)稀释，用水(15mL x 2) 洗涤，分离的有机相用无水Na 2SO 4干燥，过滤、浓缩得白色固体状标题化合物100mg，收率：94％。
步骤3：3-氧代-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸乙酯(11c)的制备。
于室温，将8-溴-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(2.50g，8.77mmol)，双联频哪醇硼酸酯(3.35g，13.2mmol)和KOAc(2.58g，26.3mmol)溶于1,4-二氧六环(30mL)中，加入Pd(dppf)Cl 2(641mg，0.877mmol)，反应液在N 2保护下置换气体三次，升温至90℃搅拌过夜。反应液降至室温，不需作进一步处理可直接用于下一步。
步骤4：8-(5-甲基噻唑-2-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(11d)的制备。
于室温，向上述反应液中加入5mL水，2-溴-5-甲基噻唑(3.10g，17.4mmol)和K 2CO 3(3.61g，26.1mmol)，再加入Pd(dppf)Cl 2(630mg，0.871mmol)，反应液在N 2保护下置换气体三次，在80℃加热下搅拌过夜。向反应液中加入30mL水，用乙酸乙酯(30mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2/1-1/1)，得黄色固体状标题化合物980mg，收率：37％。
步骤5：8-(5-甲基噻唑-2-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(11e)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(50.0mg，0.164mmol)和LiOH·H 2O(27.5mg，0.656mmol)溶于EtOH(5mL)和THF(2mL)的混合溶剂中，反应液在60℃下搅拌3h。反应液减压浓缩，加入2mL水，用1N稀HCl水溶液调节pH＝4～5，析出大量黄色固体，过滤、收集并干燥得黄色固体状标题化合物32mg，收率：66％。
步骤6：(R)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(化合物11)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(63.0mg，0.217mmol)，(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(59.3mg，0.260mmol)和DIPEA(83.8mg，0.650mmol)溶于DMF(5mL)中，加入HATU(164mg，0.433mmol)，反应液在室温下搅拌过夜。向反应液中加入10mL水，用乙酸乙酯(15mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得黄色固体状标题化合物30mg，收率：30％。
MS:m/z＝464.36[M+H] +。
1H NMR(300MHz,DMSO-d6)δ11.015(s,1H),9.20(d,J＝4.2Hz,1H),9.10 (s,2H),8.38(s,1H),7.70(s,1H),7.43(s,1H),5.29(t,J＝6.9Hz,1H),4.87(s,2H),2.50(s,3H),1.60(d,J＝6.9Hz,3H)。
实施例12：8-(5-甲基噻唑-2-基)-3-氧代-4-((四氢呋喃-2-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(12)的制备
Figure PCTCN2021120150-appb-000085
步骤1：8-(5-甲基噻唑-2-基)-3-氧代-4-((四氢呋喃-2-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(12a)的制备
于室温，将8-(5-甲基噻唑-2-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(50.0mg，0.164mmol)、2-(溴甲基)四氢呋喃(54.3mg，0.329mmol)和Cs 2CO 3(162mg，0.492mmol)溶于DMF(3mL)中，反应液在室温下搅拌过夜。反应液减压浓缩，向残余物中加入10mL水，用乙酸乙酯(15mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，浓缩得黄色油状标题化合物120mg，收率：93％。
步骤2：8-(5-甲基噻唑-2-基)-3-氧代-4-((四氢呋喃-2-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(12b)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3-氧代-4-((四氢呋喃-2-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(110mg，0.284mmol)和LiOH·H 2O(47.6mg，1.13mmol)溶于EtOH(5mL)和THF(2mL)的混合溶剂中，反应液在60℃下搅拌6h。反应液减压浓缩，加入2mL水，用1N稀HCl水溶液调节pH＝3～5，所得溶液减压浓缩，得黄色固体状标题化合物130mg粗品(含LiCl盐，～90mg产品)，收率：85％。
步骤3：8-(5-甲基噻唑-2-基)-3-氧代-4-((四氢呋喃-2-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(化合物12)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3-氧代-4-((四氢呋喃-2-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(90.0mg，0.241mmol)，(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(83.1mg，0.289mmol)和DIPEA(93.3mg，0.723mmol)溶于DMF(5mL)中，加入HATU(183mg，0.482mmol)，反应液在室温下搅拌过夜。反应 液减压浓缩，向其中加入10mL水，用乙酸乙酯(15mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得白色固体状标题化合物93mg，收率：71％。
MS:m/z＝548.43[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.19(d,J＝7.2Hz,1H),9.11(s,2H),8.47(s,1H),7.82(s,1H),7.71(s,1H),5.33-5.29(m,1H),4.94(s,2H),4.12-4.02(m,3H),3.75-3.71(m,1H),3.63-3.59(m,1H),2.50(s,3H),1.94-1.79(m,3H),1.79-1.61(m,4H)。
实施例13：(R)-8-(5-甲基噻唑-2-基)-3-氧代-4-((四氢-2H-吡喃-4-基)甲基)-N-(1-(2-(三氟甲基)嘧啶嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(13)的制备
Figure PCTCN2021120150-appb-000086
与实施例12的制备方法相同，除了在步骤1用4-(溴甲基)四氢-2H-吡喃替代2-(溴甲基)四氢呋喃，制得标题化合物13。
MS:m/z＝562.36[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.23(d,J＝7.2Hz,1H),9.12(s,2H),8.49(s,1H),7.72(s,1H),7.68(s,1H),5.31(t,J＝6.9Hz,1H),3.97-3.94(m,2H),3.83-3.79(m,2H),3.25-3.17(m,2H),2.50(s,3H),1.94-1.93(m,1H),1.62(d,J＝7.2Hz,3H),1.55-1.51(m,1H),1.29-1.26(m,1H)。
实施例14：(R)-4-(氮杂环丁烷-3-基甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(14)的制备
Figure PCTCN2021120150-appb-000087
Figure PCTCN2021120150-appb-000088
步骤1：(R)-3-((8-(5-甲基噻唑-2-基)-3-氧代-6-((1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(14a)的制备
与实施例12的制备方法相同，除了用3-(溴甲基)氮杂环丁烷-1-羧酸叔丁酯替代2-(溴甲基)四氢呋喃，制得标题化合物14a。
步骤2：(R)-4-(氮杂环丁烷-3-基甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(14)的制备
于室温，将(R)-3-((8-(5-甲基噻唑-2-基)-3-氧代-6-((1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(150mg，0.237mmol)溶于1,4-二氧六环(5mL)中，加入HCl·1,4-二氧六环(1.00mL，4.00mmol)，反应液在室温搅拌过夜。反应液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得白色固体状标题化合物56mg，收率：44％。
MS:m/z＝533.56[M+H] +。
1H NMR(300MHz,CDCl 3)δ9.54(s,1H),9.03(s,1H),8.55(s,1H),8.27(s,1H),7.66(s,1H),7.55(s,1H),5.39-5.37(m,1H),4.86-4.84(m,2H),4.43-4.42(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2H),3.48-3.47(m,1H),2.58(s,3H),1.75(d,J＝7.2Hz,3H)。
实施例15：(R)-4-((1-甲基氮杂-3-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(15)的制备
Figure PCTCN2021120150-appb-000089
与实施例5的制备方法相同，除了用(R)-4-(氮杂环丁烷-3-基甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(化合物14)替代(R)-2-(氮杂环丁烷-3-基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三 氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(化合物3)，制得标题化合物15。
MS:m/z＝547.23[M+H] +。
1H NMR(300MHz,CDCl 3)δ9.54(s,1H),9.03(s,1H),8.55(s,1H),8.27(s,1H),7.66(s,1H),7.55(s,1H),5.39-5.37(m,1H),4.86-4.84(m,2H),4.43-4.42(m,2H),4.20-4.18(m,2H),4.04-4.03(m,2H),3.48-3.47(m,1H),2.58(s,3H),2.17(s,3H),1.75(d,J＝7.2Hz,3H)。
实施例16：(R)-8-(5-甲基噻唑-2-基)-4-(吡咯烷-1-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)喹啉-6-甲酰胺(16)的制备
Figure PCTCN2021120150-appb-000090
步骤1：3-溴-4-(((2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚基)甲基)氨基)苯甲酸甲酯(16b)的制备。
于室温，将4-氨基-3-溴苯甲酸甲酯(3.00g，13.0mmol)、丙二酸环(亚)异丙酯(2.38g，17.0mmol)、原甲酸三乙酯(7.72g，52.2mmol)、异丙醇(30mL)加入反应瓶中，升温至100℃反应2小时。反应结束后，将反应液过滤，滤饼用正己烷洗涤，干燥得4.7g白色固体状标题产物，收率94.0％。
步骤2：8-溴-4-氧代-1,4-二氢喹啉-6-羧酸甲酯(16c)的制备。
于室温，将3-溴-4-(((2,2-二甲基-4,6-二氧代-1,3-二噁烷-5-亚基)甲基)氨基)苯甲酸甲酯(4.7g，12.2mmol)、二苯醚(30mL)加入反应瓶中，然后放入已经预热到180℃的油浴锅中，升温至210℃反应1小时。反应结束后冷却至室温，加入正己烷(50mL)，有固体析出，过滤，干燥得3.8g黑色固体状标题产物，收率93.2％。
步骤3：8-溴-4-氯-1,4-二氢喹啉-6-羧酸甲酯(16d)的制备。
于室温，将8-溴-4-氧代-1,4-二氢喹啉-6-羧酸甲酯(3.00g，10.7mmol)、三氯氧磷(30mL)加入反应瓶中，升温至80℃反应1小时。反应结束后冷却至室温， 减压浓缩，向残余物中加入60mL乙酸乙酯和60mL水，加入碳酸氢钠饱和溶液调PH至中性，分液得有机相，无水硫酸钠干燥，浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得2.12g灰色固体状标题产物，收率66.0％。
步骤4：8-溴-4-(吡咯烷-1-基)喹啉-6-羧酸甲酯(16e)的制备。
于室温，将8-溴-4-氯-1,4-二氢喹啉-6-羧酸甲酯(260mg，0.870mmol)、吡咯烷(390mg，4.35mmol)、DIPEA(339mg，42.0mmol)、DMF(10mL)加入反应封管中，升温至100℃反应1小时。反应结束后冷却至室温，减压浓缩，得330mg黄色固体状标题产物，直接用于下一步。
步骤5:8-(5-甲基噻唑-2-基)-4-(吡咯烷-1-基)喹啉-6-羧酸甲酯(16f)的制备。
于室温，将8-溴-4-(吡咯烷-1-基)喹啉-6-羧酸甲酯(200mg，0.599mmol)、5-甲基噻唑(119mg，1.20mmol)、CuI(114mg，0.599mmol)、Pd(OAc)2(0.328g，0.449mmol)、DMF(7.00mL)加入反应瓶中，在氮气氛下，升温至140℃反应8小时。反应结束后，减压浓缩，加50mL乙酸乙酯和50mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残余物通过硅胶柱层析色谱法(流动相：DCM：MeOH＝20:1)纯化，得0.19g黄色固体状标题产物，收率90.1％。
步骤6：8-(5-甲基噻唑-2-基)-4-(吡咯烷-1-基)喹啉-6-羧酸(16g)的制备。
于室温，将8-(5-甲基噻唑-2-基)-4-(吡咯烷-1-基)喹啉-6-羧酸甲酯(0.19g，0.538mmol)、氢氧化锂(225mg，5.38mmol)、四氢呋喃(15.0mL)、甲醇(15.0mL)、H 2O(5.00mL)加入反应瓶中，室温搅拌14小时。反应结束后，减压浓缩，用1N盐酸溶液调pH至3-4，有固体析出，过滤，干燥得0.12g棕色固体状标题产物，收率62.4％。
步骤7：(R)-8-(5-甲基噻唑-2-基)-4-(吡咯烷-1-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)喹啉-6-甲酰胺(化合物16)的制备。
于室温，将8-(5-甲基噻唑-2-基)-4-(吡咯烷-1-基)喹啉-6-羧酸(120mg，0.353mmol)、(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(96.8mg，0.424mmol)、DIPEA(183mg，1.41mmol)、HATU(187mg，0.494mmol)、DMF(5.0mL)加入反应瓶中，室温搅拌2小时。反应结束后，加30mL乙酸乙酯和30mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm,C18,10μm,100A，流动相：乙腈/水＝0％-100％)得到30mg黄色固体状标题产物，收率16.6％。
MS:m/z＝513.45[M+H] +。
1HNMR(300MHz，DMSO-d6):δppm:14.38(s,1H),9.45(d,1H),9.16(s,2H),8.98(s,1H),8.74(s,1H),8.56(d,1H),7.91(s,1H),6.97(d,1H),5.35(m,1H),4.01(m,4H),2.62(s,3H),2.07(m,4H),1.67(d,3H)。
实施例17：(R)-8-(5-甲基噻唑-2-基)-2-(吡咯烷-1-基)-N-(1-(2-(三氟甲基)嘧啶-5- 基)乙基)喹喔啉-6-甲酰胺(17)的制备
Figure PCTCN2021120150-appb-000091
步骤1：8-溴-2-氧代-1,2-二氢喹喔啉-6-羧酸甲酯(17b)的制备。
于室温，将3,4-二氨基-5-溴苯甲酸甲酯(5.00g，20.4mmol)、乙醛酸(2.26g，30.6mmol)、无水乙醇(80mL)加入反应瓶中，升温至80℃反应2小时。将反应液直接浓缩得7.2g黄色固体状标题产物，直接用于下一步。
步骤2：8-溴-2-氯喹喔啉-6-羧酸甲酯(17c)的制备。
于室温，将8-溴-2-氧代-1,2-二氢喹喔啉-6-羧酸甲酯(7.2g)、三氯氧磷(35mL)加入反应瓶中，升温至80℃反应1小时。反应结束后冷却至室温，减压浓缩，向残余物中加入60mL乙酸乙酯和60mL水，加入碳酸氢钠饱和溶液调PH至中性，分液得有机相，无水硫酸钠干燥，浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得5.12g黄色固体状标题产物，两步总收率83.2％。
步骤3：8-溴-2-(吡咯烷-1-基)喹喔啉-6-羧酸甲酯(17d)的制备。
于室温，将8-溴-2-氯喹喔啉-6-羧酸甲酯(4.20g，14.0mmol)、吡咯烷(4.97g，70.0mmol)、DIPEA(5.46g，42.0mmol)、DMF(30mL)加入反应封管中，升温至100℃反应2小时。反应结束后冷却至室温，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得1.66g黄色固体状标题产物，收率35.3％。
步骤4：(7-(甲氧基羰基)-3-(吡咯烷-1-基)喹喔啉-5-基)硼酸(17e)的制备。
于室温，将8-溴-2-(吡咯烷-1-基)喹喔啉-6-羧酸甲酯(1.45g，4.30mmol)、双联硼酸频哪醇酯(2.18g，8.60mmol)、乙酸钾(1.26g，12.9mmol)、1,4-二氧六环(25mL)、Pd(dppf)Cl 2(0.157g，0.215mmol)加入反应瓶中，在氮气氛下，升温至90℃反应12小时。反应结束冷却至室温，减压浓缩，加50mL乙酸乙酯和50mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残余物通过硅胶柱层析色谱法(流动相：DCM：MeOH＝20:1)纯化，得到0.90g黄色固 体状标题产物，收率69.8％。
步骤5:8-(5-甲基噻唑-2-基)-2-(吡咯烷-1-基)喹喔啉-6-羧酸甲酯(17f)的制备。
于室温，将(7-(甲氧基羰基)-3-(吡咯烷-1-基)喹喔啉-5-基)硼酸(0.90g，2.99mmol)、2-溴-5-甲基噻唑(0.532g，2.99mmol)、碳酸钾(0.825g，5.98mmol)、水(5mL)、四氢呋喃(25mL)、Pd(dppf)Cl 2(0.328g，0.449mmol)加入反应瓶中，在氮气氛下，升温至90℃反应16小时。反应结束后，减压浓缩，加50mL乙酸乙酯和50mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残余物通过硅胶柱层析色谱法(流动相：石油醚：乙酸乙酯＝2:1)纯化，得到0.40g黄色固体状标题产物，收率37.7％。
步骤6：8-(5-甲基噻唑-2-基)-2-(吡咯烷-1-基)喹喔啉-6-羧酸(17g)的制备。
于室温，将8-(5-甲基噻唑-2-基)-2-(吡咯烷-1-基)喹喔啉-6-羧酸甲酯(0.35g，0.989mmol)、1N氢氧化锂溶液(10mL)、四氢呋喃(20mL)、甲醇(20mL)加入反应瓶中，室温搅拌14小时。反应结束后，减压浓缩，用1N盐酸溶液调pH至3-4，有固体析出，过滤得到0.25g橙黄色固体状标题产物，收率74.4％。
步骤7：(R)-8-(5-甲基噻唑-2-基)-2-(吡咯烷-1-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)喹喔啉-6-甲酰胺(化合物17)的制备。
于室温，将8-(5-甲基噻唑-2-基)-2-(吡咯烷-1-基)喹喔啉-6-羧酸(50.0mg，0.147mmol)、(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(36.9mg，0.160mmol)、DIPEA(76.5mg，4.00mmol)、HATU(78.2mg，0.210mmol)、DMF(5mL)加入反应瓶中，室温搅拌2小时。反应结束后，加30mL乙酸乙酯和30mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm,C18,10μm,100A，流动相：乙腈/水＝0％-100％)得到22mg黄色固体状标题产物，收率29.0％。
MS:m/z＝514.52[M+H] +。
1HNMR(300MHz,DMSO-d6):δppm:9.28(d,1H),9.16(s,2H),9.09(s,1H),8.66(s,1H),8.47(s,1H),7.70(s,1H),5.37(m,1H),3.74(m,4H),2.50(m,3H),2.07(m,4H),1.65(d,3H)。
实施例18：(R)-4-((3-甲基氧杂环丁-3-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(18)的制备
Figure PCTCN2021120150-appb-000092
与实施例12的制备方法相同，除了在步骤1用3-(溴甲基)-3-甲基氧杂环丁烷 替代2-(溴甲基)四氢呋喃，制得标题化合物18。
MS:m/z＝548.18[M+H] +。
1H NMR(300MHz,CDCl 3)δ8.92(s,2H),8.35(s,1H),7.60(d,J＝7.2Hz,2H),6.94(d,J＝6.9Hz,1H),5.36-5.32(m,1H),4.84(s,2H),4.67-4.64(m,2H),4.25-4.22(m,2H),4.21-4.08(m,2H),2.55(s,3H),1.71(d,J＝7.2Hz,2H),1.40(s,3H)。
实施例19：(R)-4-(5-甲基噻唑-2-基)-2-吗啉基-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)苯并[d]噁唑-6-甲酰胺(19)的制备
Figure PCTCN2021120150-appb-000093
步骤1：4-氨基-3-溴-5-羟基苯甲酸甲酯(19b)的制备。
于室温，将4-氨基-3-羟基苯甲酸甲酯(1.90g，11.40mmol)、NBS(1.90g，13.7mmol)、二氯甲烷(20mL)加入反应瓶中，室温反应1小时。反应结束后，加50mL二氯甲烷和50mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(流动相：DCM：MeOH＝20:1)纯化，得到2.0g棕色油状标题产物，收率71.7％。
LC-MS:m/z 246.01[M+H] +。
步骤2：(2-氨基-3-羟基-5-(甲氧基羰基)苯基)硼酸(19c)的制备。
于室温，将4-氨基-3-溴-5-羟基苯甲酸甲酯(2.00g，8.13mmol)、双联硼酸频哪醇酯(BPD)(4.13g，16.26mmol)、乙酸钾(2.39g，24.39mmol)、1,4-二氧六环(25mL)、Pd(dppf)Cl 2(298mg，0.407mmol)加入反应瓶中，在氮气氛下，升温至90℃反应12小时。反应结束冷却至室温，减压浓缩，加50mL乙酸乙酯和50mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(流动相：DCM：MeOH＝20:1)纯化，得到2.27g棕色固体状标题产物粗品，直接用于下一步。
步骤3：4-氨基-3-羟基-5-(5-甲基噻唑-2-基)苯甲酸甲酯(19d)的制备。
于室温，将(2-氨基-3-羟基-5-(甲氧基羰基)苯基)硼酸(2.27g，7.70mmol)、2-溴-5-甲基噻唑(1.37g，7.70mmol)、碳酸钾(2.12g，15.4mmol)、水(5mL)、四氢呋喃(25mL)、Pd(dppf)Cl 2(845mg，1.16mmol)加入反应瓶中，在氮气氛下，升温至90℃反应16小时。反应结束后，减压浓缩，加50mL乙酸乙酯和50mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(流动相：石油醚：乙酸乙酯＝2:1)纯化，得到1.05g黄色固体状标题产物，收率51.7％。
步骤4：4-(5-甲基噻唑-2-基)-2-硫代-2,3-二氢苯并[d]噁唑-6-羧酸甲酯(19e)的制备。
于室温，将4-氨基-3-羟基-5-(5-甲基噻唑-2-基)苯甲酸甲酯(730mg，2.80mmol)、二硫化碳(5.0mL)、KOH(0.19g，3.4mmol)、乙醇(10mL)加入反应封管中，升温至80℃反应2小时，反应结束后过滤，干燥滤饼，得0.42g黄色固体状标题产物，收率49.0％。
步骤5：4-(5-甲基噻唑-2-基)-2-吗啉基-苯并[d]噁唑-6-羧酸甲酯(19f)的制备。
于室温，将4-(5-甲基噻唑-2-基)-2-硫代-2,3-二氢苯并[d]噁唑-6-羧酸甲酯(200mg，0.654mmol)、吗啉(227mg，2.61mmol)、DIPEA(339mg，2.61mmol)、DMF(10.0mL)加入反应封管中，升温至150℃反应12小时。反应结束后冷却至室温，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10μm，100A，流动相：乙腈/水＝0％-100％)得到100mg灰色固体状标题产物。
步骤6：4-(5-甲基噻唑-2-基)-2-吗啉基-苯并[d]噁唑-6-羧酸(19g)的制备。
于室温，将4-(5-甲基噻唑-2-基)-2-吗啉基-苯并[d]噁唑-6-羧酸甲酯(100mg，0.279mmol)、1N氢氧化锂溶液(5mL)、四氢呋喃(10mL)、甲醇(10mL)加入反应瓶中，室温搅拌14小时。反应结束后，用1N盐酸溶液调pH至3-4，有固体析出，过滤得到50mg褐色固体状标题产物，收率40.4％。
步骤7：(R)-4-(5-甲基噻唑-2-基)-2-吗啉基-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)苯并[d]噁唑-6-甲酰胺(19h)的制备。
于室温，将4-(5-甲基噻唑-2-基)-2-吗啉基-苯并[d]噁唑-6-羧酸(50.0mg，0.145mmol)、(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(36.3mg，0.159mmol)、DIPEA(82.7mg，0.636mmol)、HATU(77.1mg，0.203mmol)、DMF(5.0mL)加入反应瓶中，室温搅拌2小时。反应结束后，加30mL乙酸乙酯和30mL水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10μm，100A，流动相：乙腈/水＝0％-100％)得到17mg白色固体状标题产物，收率22.7％。
MS:m/z＝519.44[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.05(s,2H),8.53(s,1H),7.83(s,1H),7.60(s,1H),5.35-5.38(m,1H),3.84(s,8H),2.57(m,3H),1.72(m,J＝7.14Hz,2H)。
实施例20：4-(5-甲基噻唑-2-基)-2-(四氢呋喃-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺的制备(20)的制备
Figure PCTCN2021120150-appb-000094
与实施例2的制备方法相同，除了用3-碘四氢呋喃替代3-碘氧杂环丁烷，制得标题化合物20。
MS:m/z＝503.00[M+H] +。
1H NMR(400MHz,DMSO-d6):δppm 9.21(s,1H),9.17(s,2H),8.67(s,1H),8.40(s,1H),8.08(s,1H),7.78(s,1H),5.60(s,1H),5.34-5.30(m,1H),4.10(m,2H),3.93(m,2H)，2.55(s,3H),2.50(s,1H),1.65(d,J＝7.1Hz,3H)。
实施例21：4-(5-甲基噻唑-2-基)-1-(四氢呋喃-3-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(21)的制备
Figure PCTCN2021120150-appb-000095
与实施例1的制备方法相同，除了用3-碘四氢呋喃替代3-碘氧杂环丁烷，制得标题化合物20。
MS:m/z＝503.00[M+H] +。
1H NMR(400MHz,DMSO-d6):δppm 9.21(s,1H),9.16(s,2H),8.93(s,1H),8.44(s,1H),7.97(s,1H),7.74(s,1H),5.54-5.35(m,1H),5.33-5.30(m,1H),4.16-4.10(m,3H),3.93-3.90(m,1H)，2.54(s,3H),2.40(s,1H),1.62(d,J＝7.1Hz,3H)。
实施例22：(R)-4-(5-甲基噻唑-2-基)-1-(四氢-2H-吡喃-4-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(22)的制备
Figure PCTCN2021120150-appb-000096
与实施例1的制备方法相同，除了用4-碘四氢-2H-吡喃替代3-碘氧杂环丁烷，制得标题化合物22。
MS:m/z＝517.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.99(s,2H),8.60(s,1H),8.15(s,2H),7.67(s,1H),7.16(s,1H),5.45-5.41(m,1H),4.79-4.73(m,1H),4.20-4.17(m,2H),3.66-3.60(m,2H),2.61(s,3H),2.47-2.39(m,2H),2.01-1.98(m,2H),1.78(d,J＝5.4Hz,3H)。
实施例23：4-(5-甲基噻唑-2-基)-1-((四氢呋喃-2-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(23)的制备
Figure PCTCN2021120150-appb-000097
与实施例1的制备方法相同，除了用2-(溴甲基)四氢呋喃替代3-碘氧杂环丁烷，制得标题化合物23。
MS:m/z＝517.10[M+H] +。
1H NMR(400MHz,DMSO-d6):δppm 9.27(d,J＝6.9Hz,1H),9.16(s,2H),8.64(s,1H),8.34(s,1H),8.08(s,1H),7.77(s,1H),5.38-5.33(m,1H),4.58-4.56(m,2H),4.33-4.30(m,1H),3.69-3.65(m,1H)，3.62-3.57(m,1H),2.56(s,3H),1.97-1.95(m,1H),1.80-1.74(m,3H),1.73-1.65(m,3H)。
实施例24：4-(5-甲基噻唑-2-基)-2-((四氢呋喃-2-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(24)的制备
Figure PCTCN2021120150-appb-000098
与实施例2的制备方法相同，除了用2-(溴甲基)四氢呋喃替代3-碘氧杂环丁烷， 制得标题化合物24。
MS:m/z＝517.10[M+H] +。
1H NMR(400MHz,DMSO-d6):δppm 9.24(d,J＝9.0Hz,1H),9.15(s,2H),8.89(s,1H),8.40(s,1H),7.97(s,1H),7.74(s,1H),5.38-5.33(m,1H),4.62-4.58(m,2H),4.37-4.35(m,1H),3.77-3.75(m,1H)，3.65-3.63(m,1H),2.59(s,3H),1.81-1.79(m,1H),1.77-1.74(m,3H),1.64(d,J＝7.2Hz,3H)。
实施例25：(R)-4-(5-甲基噻唑-2-基)-1-((四氢-2H-吡喃-4-基)甲基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(25)的制备
Figure PCTCN2021120150-appb-000099
与实施例1的制备方法相同，除了用4-(溴甲基)四氢-2H-吡喃替代3-碘氧杂环丁烷，制得标题化合物25。
MS:m/z＝531.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.98(s,2H),8.53(s,1H),8.04-8.01(m,2H),7.55(s,1H),6.90-6.88(m,1H),5.45-5.41(m,1H),4.34(d,J＝4.8Hz,2H),3.96-3.93(m,2H),3.37-3.31(m,2H),2.60(s,3H),2.36-2.31(m,1H),1.77(d,J＝5.2Hz,3H),1.49-1.41(m,4H)。
实施例26：(R)-4-(5-甲基噻唑-2-基)-2-((四氢-2H-吡喃-4-基)甲基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(26)的制备
Figure PCTCN2021120150-appb-000100
与实施例2的制备方法相同，除了用4-(溴甲基)四氢-2H-吡喃替代3-碘氧杂环丁烷，制得标题化合物26。
MS:m/z＝531.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.96(s,2H),8.74(s,1H),8.14(s,1H),7.93(s,1H),7.55(s,1H),6.66-6.64(m,1H),5.43-5.38(m,1H),4.35(d,J＝4.5Hz,2H),3.99-3.95(m,2H),3.41-3.31(m,2H),2.56(s,3H),2.37-2.32(m,1H),1.75(d,J＝ 5.2Hz,3H),1.50-1.43(m,4H)。
实施例27：(R)-1-(((3,3-二氟环丁基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(27)的制备
Figure PCTCN2021120150-appb-000101
与实施例1的制备方法相同，除了用3-(溴甲基)-1,1-二氟环丁烷替代3-碘氧杂环丁烷，制得标题化合物27。
MS:m/z＝537.00[M+H] +。
1H NMR(300MHz,CDCl3):δppm 8.99(s,2H),8.62(s,1H),8.06(s,2H),7.65(s,1H),6.98(s,1H),5.47-5.40(m,1H),4.56(d,J＝5.4Hz 1H),2.68(s,1H),2.65-2.61(m,2H),2.60(s,3H),2.52-2.40(m,2H),1.77(d,J＝5.4Hz,3H)。
实施例28：(R)-2-(((3,3-二氟环丁基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(28)的制备
Figure PCTCN2021120150-appb-000102
与实施例2的制备方法相同，除了用3-(溴甲基)-1,1-二氟环丁烷替代3-碘氧杂环丁烷，制得标题化合物28。
MS:m/z＝537.00[M+H] +。
1H NMR(300MHz,CDCl3):δppm 8.99(s,2H),8.70(s,1H),8.20(s,1H),8.11(s,1H),7.61(s,1H),6.91(s,1H),5.44-5.37(m,1H),4.59(d,J＝5.4Hz 1H),2.75(s,1H),2.61-2.50(m,2H),2.49(s,3H),2.47-2.42(m,2H),1.76(d,J＝5.4Hz,3H)。
实施例29：1-((4-甲基吗啉-2-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(29)的制备
Figure PCTCN2021120150-appb-000103
与实施例4的制备方法相同，除了用2-((甲苯磺酰氧基)甲基)吗啉-4-羧酸叔丁酯替代3-碘代氮杂环丁烷-1-羧酸叔丁酯，制得标题化合物29。
MS:m/z＝546.10[M+H] +。
1HNMR(300MHz,CDCl3):δppm 9.05(s,2H),8.73(s,1H),8.12-8.09(m,2H),7.69-7.57(m,2H),5.51-5.45(m,1H),4.61-4.53(m,1H),4.35(s,1H),3.93(d,J＝8.3Hz,1H),3.73(t,J＝9.0Hz,1H),2.98-2.90(m,1H),2.83-2.78(m,1H),2.62(s,3H),2.42(d,J＝6.0Hz,3H),2.33(s,1H)，2.18-2.06(m,1H)，1.80(d,J＝6.0Hz,3H)。
实施例30：1-((4-甲基吗啉-2-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(30)的制备
Figure PCTCN2021120150-appb-000104
与实施例3的制备方法相同，除了用2-((甲苯磺酰氧基)甲基)吗啉-4-羧酸叔丁酯替代3-碘代氮杂环丁烷-1-羧酸叔丁酯，制得标题化合物30。
MS:m/z＝546.10[M+H] +。
1HNMR(300MHz,CDCl3):δppm 9.04(s,2H),8.80(s,1H),8.19(d,J＝6.0Hz,1H),7.95(s,1H),7.61(s,2H),7.04-7.00(m,1H),5.49-5.44(m,1H),4.64-4.56(m,2H),4.25(s,1H),3.95(d,J＝9.0Hz,1H),3.81-3.79(m,1H),2.99-2.96(m,1H),2.79-2.77(m,1H),2.52(s,3H),2.41(s,3H),2.26-2.24(m,1H)，2.08-2.06(m,1H)，1.80(d,J＝9.0Hz,3H)。
实施例31：1-((1-甲基吡咯烷-3-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(31)的制备
Figure PCTCN2021120150-appb-000105
步骤1：(1-甲基吡咯烷-3-基)甲醇(31b)的制备
于0℃，将1-甲基-5-氧代吡咯烷-3-羧酸甲酯(1.00g，6.37mmol)溶于THF(15mL)中，缓慢分批加入LiAlH 4(535mg，12.7mmol)，加毕，反应液在氮气氛下室温搅拌过夜。于冰浴，向反应液中慢慢滴加水(～15mL)，用乙酸乙酯(40mL)稀释。反应液用硅藻土过滤并用EtOAc(10mL x 2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物450mg，收率：61.4％。
步骤2：(1-甲基吡咯烷-3-基)4-甲基苯磺酸甲酯(31c)的制备
于室温，将(1-甲基吡咯烷-3-基)甲醇(450mg，3.91mmol)、TEA(790mg，7.82mmol)溶于DCM(10mL)中，加入DMAP(477mg，3.91mmol)，反应液在室温搅拌过夜。反应液减压浓缩，残余物用硅胶柱层析色谱法分离(PE：EtOAc＝4:1)，得黄色油状标题化合物720mg，收率：68.6％。
MS:m/z＝270.00[M+H] +。
后续步骤与实施例1的制备方法相同，除了用31c替代3-碘氧杂环丁烷，制得标题化合物31。
MS:m/z＝530.00[M+H] +。
1H NMR(400MHz,CDCl 3):δppm 9.07(s,2H),8.77(s,1H),8.14(s,1H),7.59(s,1H),7.26-7.25(m,1H),5.44-5.37(m,1H),4.57-4.28(m,3H),3.53-3.52(m,2H),2.94-2.88(m,3H),2.54(s,3H),2.33-2.26(m,2H),2.13-2.09(m,2H),1.78(d,J＝5.2Hz,3H)。
实施例32：2-((1-甲基吡咯烷-3-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(32)的制备
Figure PCTCN2021120150-appb-000106
与实施例2的制备方法相同，除了用(1-甲基吡咯烷-3-基)4-甲基苯磺酸甲酯(31c)替代3-碘氧杂环丁烷，制得标题化合物32。
MS:m/z＝530.00[M+H] +。
1H NMR(400MHz,CDCl 3):δppm 9.06(s,1H),9.03(s,1H),8.77(s,1H),8.22-8.18(m,1H),7.94(s,1H),7.74-7.72(m,1H),7.49(s,1H),5.39-5.34(m,1H),4.66-4.58(m,3H),3.99-3.95(m,2H),3.16-3.13(m,1H),3.05(m,3H),2.95-2.88(m,1H),2.52(s,3H),2.40-2.37(m,1H),1.85-1.82(m,1H),1.75-1.74(m,3H)。
实施例33：(R)-8-(5-甲基噻唑-2-基)-4-(四氢-2H-吡喃-4-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(33)的制备
Figure PCTCN2021120150-appb-000107
与实施例8的制备方法相同，除了用四氢-4H-吡喃-4-酮替代四氢呋喃-3-甲醛，制得标题化合物33。
MS:m/z＝534.44[M+H] +。
1H NMR(300MHz,CD 3Cl):δppm 8.92(s,2H),7.97(s,1H),7.54(s,1H),7.26(s,1H),6.92(d,J＝5.7Hz,1H),5.34-5.30(m,1H),4.46(s,2H),4.09-3.99(m,3H),3.57-3.50(m,2H),3.41(s,2H),2.53(s,3H),1.83-1.67(m,7H)。
实施例34：(R)-4-(2-乙氧基乙基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(34)的制备
Figure PCTCN2021120150-appb-000108
步骤1：4-(2-乙氧基乙基)-8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸2-乙氧基乙酯(34a)的制备
于室温，将8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(7f)(150mg，0.516mmol)和1-溴-2-乙氧基乙烷(711mg，4.65mmol)溶于DMF(3mL)中，缓慢加入NaH(60％溶于矿物油中)(31.2mg，0.773mmol)，反应液在60℃搅拌过夜。反应结束后，向其中加入5mL MeOH淬灭反应，减压浓 缩得黄色粗品可直接用于下一步。
MS:m/z＝421.23[M+H] +。
步骤2：4-(2-乙氧基乙基)-8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(34b)的制备
于室温，将4-(2-乙氧基乙基)-8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸2-乙氧基乙酯(160mg，0.381mmol)和LiOH·H 2O(64.0mg，1.52mmol)溶于EtOH(5mL)、THF(2mL)和水(1mL)的混合溶剂中，反应液在60℃搅拌过夜。反应液减压浓缩，向其中加入2mL水，用1N稀盐酸水溶液调节pH 5～6。析出大量黄色固体，过滤并收集滤饼，干燥得黄色固体状标题化合物100mg，收率：75％。
MS:m/z＝349.33[M+H] +。
步骤3：(R)-4-(2-乙氧基乙基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(34)的制备
于室温，将4-(2-乙氧基乙基)-8-(5-甲基噻唑-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸(100mg，0.286mmol)，(R)-1-(2-(三氟甲基)嘧啶-5-基)乙-1-胺(78.4mg，0.344mmol)和DIPEA(111mg，0.860mmol)溶于DMF(5mL)中，加入HATU(218mg，0.573mmol)，反应液在室温搅拌过夜。反应液减压浓缩，向其中加入10mL水，用乙酸乙酯(15mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-100％)，得白色固体状标题化合物51mg，收率：34％。
MS:m/z＝522.34[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.91(s,2H),7.95(s,1H),7.53(s,1H),6.91(d,J＝6.6Hz,1H),5.35-5.30(m,1H),4.61-4.32(m,2H),3.66-3.55(m,6H),3.47(q,J＝6.9Hz,2H),2.51(s,3H),1.67(d,J＝7.2Hz,3H),1.17(t,J＝6.9Hz,3H)。
实施例35：(R)-8-(5-甲基噻唑-2-基)-4-(四氢-2H-吡喃-4-羰基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(35)的制备
Figure PCTCN2021120150-appb-000109
Figure PCTCN2021120150-appb-000110
步骤1：(R)-8-(5-甲基噻唑-2-基)-4-(四氢-2H-吡喃-4-羰基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(35)的制备
于冰浴，将(R)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(7)(100mg，0.223mmol)和DIPEA(57.4mg，0.445mmol)溶于DCM(5mL)中，缓慢滴加四氢-2H-吡喃-4-甲酰氯(49.7mg，0.334mmol)，反应液在室温搅拌过夜。反应结束后，向其中加入10mL水和10mL DCM，分离的水相再用DCM(15mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：10％-100％)，得白色固体状标题化合物105mg，收率：84％。
MS:m/z＝562.49[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.95(s,2H),8.51(s,1H),7.91(s,1H),7.56(s,1H),7.38(s,1H),5.40-5.36(m,1H),4.56-4.49(m,2H),4.09-3.97(m,4H),3.45-3.38(m,2H),3.15(s,1H),2.54(s,3H),2.01-1.91(m,4H),1.65(d,J＝7.2Hz,3H)。
实施例36：(R)-4-(环丙烷羰基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(36)的制备。
Figure PCTCN2021120150-appb-000111
与实施例35的制备方法相同，除了用环丙烷甲酰氯替代四氢-2H-吡喃-4-甲酰氯，制得标题化合物36。
MS:m/z＝518.50[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.93(s,2H),8.44(s,1H),8.14(s,1H),7.58(s,1H),6.92(d,J＝6.3Hz,1H),5.38-5.33(m,1H),4.60-4.57(m,2H),4.11-4.06(m,2H),2.55(s,3H),2.12-1.95(m,1H),1.70(d,J＝7.2Hz,3H),1.23-1.18(m,2H),0.99-0.95(m,2H)。
实施例37：(R)-4-(2-乙氧基乙基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲 基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(37)的制备
Figure PCTCN2021120150-appb-000112
与实施例12的制备方法相同，除了在步骤1用1-溴-2-乙氧基乙烷替代2-(溴甲基)四氢呋喃，制得标题化合物37。
MS:m/z＝536.52[M+H] +。
1H NMR(300MHz,DMSO-d 6):δppm 9.20(d,J＝4.2Hz,1H),9.11(s,2H),8.46(s,1H),7.80(s,1H),7.71(s,1H),5.33-5.29(m,1H),4.93(s,2H),4.18-4.14(m,2H),3.62-3.59(m,2H),3.44(q,J＝6.9Hz,2H),2.51(s,3H),1.62(d,J＝7.2Hz,3H),1.01(t,J＝6.9Hz,3H)。
实施例38：4-((((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(38)的制备
Figure PCTCN2021120150-appb-000113
步骤1：(2S,4R)-4-氟-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(38b)的制备
于0℃，将2-((2R,4R)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)乙酸(5.00g，0.0215mol)溶于THF(60mL)中，缓慢分批加入LiAlH 4(2.45g，0.0645mmol)，加毕，反应液在氮气氛下室温搅拌过夜。于冰浴，向反应液中慢慢滴加水(～15mL)，用乙酸乙酯(40mL)稀释。反应液用硅藻土过滤并用EtOAc(10mL x 2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物3.60g， 收率：76％。
MS:m/z＝220.04[M+H] +。
步骤2：((2S,4R)-4-氟吡咯烷-2-基)甲醇(38c)的制备
于室温，将(2S,4R)-4-氟-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(3.60g，0.0164mol)溶于DCM(40mL)中，加入TFA(21.5mL，0.164mmol)，反应液在室温搅拌过夜。反应液减压浓缩，用饱和NaHCO 3溶液调节pH＝8～9，减压浓缩，粗品用硅胶柱层析色谱法分离(DCM：MeOH＝10:1)，得黄色油状标题化合物1.81g，收率：92％。
MS:m/z＝120.01[M+H] +。
步骤3：((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(38d)的制备
于室温，将((2S,4R)-4-氟吡咯烷-2-基)甲醇(1.25g，0.0105mmol)和37％甲醛水溶液(3.94g，0.0525mmol)溶于MeOH(20mL)中，于室温搅拌30min，加入NaBH 3CN(1.32g，0.0210mmol)，反应液在室温搅拌过夜。反应液减压浓缩，粗品用硅胶柱层析色谱法分离(DCM：MeOH＝10:1)，得710mg黄色油状标题化合物，收率：50％。
MS:m/z＝133.95[M+H] +。
步骤4：(2S,4R)-2-(氯甲基)-4-氟-1-甲基吡咯烷(38e)的制备
于室温，将((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(700mg，5.22mmol)溶于DCM(10mL)中，加入SOCl 2(1.14mL，15.7mmol)，反应液在室温搅拌过夜。反应液减压浓缩，粗品用硅胶柱层析色谱法分离(DCM：MeOH＝10:1)，得550mg黄色油状标题化合物，收率：69％。
MS:m/z＝151.92[M+H] +。
后续步骤与实施例12的制备方法相同，除了用38e替代2-(溴甲基)四氢呋喃，制得标题化合物38。
MS:m/z＝579.50[M+H] +。
1H NMR(300MHz,DMSO-d 6):δppm 9.38-9.34(m,1H),9.24(s,2H),8.52(d,J＝9.0Hz 1H),5.43-5.28(m,2H),4.98-4.78(m,2H),4.55-4.43(m,1H),3.95-3.76(m,2H),3.59-3.57(m,1H),3.04-3.02(m,1H),2.90(s,3H),2.51(s,3H),2.39-2.27(m,1H),1.62(t,J＝6.9Hz,3H)。
实施例39：4-(((S)-4-甲基-5-氧代吗啉-2-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(39)的制备
Figure PCTCN2021120150-appb-000114
步骤1：(S)-2-氯-N-(2,3-二羟丙基)-N-甲基乙酰胺(39b)的制备
于室温，将(S)-3-(甲氨基)丙烷-1,2-二醇(1.00g，9.52mmol)、三乙胺(2.08mL，11.4mmol)溶于MeCN(20mL)和MeOH(3mL)的混合溶剂中，缓慢滴加氯乙酰氯(0.728mL，10.5mmol)，反应液在室温搅拌过夜。反应结束后，减压浓缩，粗品可直接用于下一步，为无色油状标题化合物1.70g，收率：98％。
MS：m/z＝181.88[M+H] +。
步骤2：(S)-6-(羟甲基)-4-甲基吗啉-3-酮(39c)的制备
于室温，将(S)-2-氯-N-(2,3-二羟丙基)-N-甲基乙酰胺(1.70g，9.34mmol)溶于2-甲基-2-叔丁醇(15mL)中，再加入t-BuOK(2.09g，18.7mmol)，反应液在室温搅拌15h。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离(DCM：MeOH＝20：1)，得无色油状标题化合物370mg，收率：27％。
MS：m/z＝146.00[M+H] +。
步骤3：(S)-4-(甲基-5-氧代吗啉-2-基)甲基4-甲基苯磺酸酯(39d)的制备
于室温，将(S)-6-(羟甲基)-4-甲基吗啉-3-酮(370mg，2.04mmol)、三乙胺(1.60mL，11.4mmol)和DMAP(25mg)溶于DCM(15mL)中，再加入TsCl(1.12g，5.73mmol)，反应液在室温搅拌15h。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离(PE/EtOAc＝3/1)，得无色油状标题化合物550mg，收率：72％。
后续步骤与实施例12的制备方法相同，除了用39d替代2-(溴甲基)四氢呋喃，制得标题化合物39。
MS:m/z＝591.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.96(s,2H),8.56(s,1H),7.91(s,1H),7.65(s,1H),7.18(s,1H),5.37-5.34(m,1H),4.95-4.82(m,2H),4.28-4.05(m,5H), 3.48-3.43(m,1H),3.31-3.29(m,1H),2.98(s,3H),2.58(s,3H),1.75(d,J＝5.4Hz,3H)。
实施例40：4-((((R)-3-甲基-2-氧代噁唑啉-5-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(40)的制备
Figure PCTCN2021120150-appb-000115
步骤1：(R)-3-(苄基(甲基)氨基)丙烷-1,2-二醇(40b)的制备。
于室温，将N-甲基-1-苯基甲胺(10.0g，0.0826mol)溶于甲醇(100mL)中，分批加入(R)-环氧乙烷-2-基甲醇(6.42g，0.0867mmol)，加毕，反应液在65℃搅拌过夜。反应液减压浓缩，得无色油状标题化合物15.0g，收率：98％。
MS：m/z＝196.01[M+H] +。
步骤2：(R)-3-(甲氨基)丙烷-1,2-二醇(40c)的制备。
于室温，将(R)-3-(苄基(甲基)氨基)丙烷-1,2-二醇(12.0g，0.0615mol)溶于MeOH(150mL)中，加入10％湿Pd/C(1.71g)，反应液在氢气氛下，在室温搅拌过夜。反应液用硅藻土过滤，用MeOH(20mL x 3)洗涤滤饼，收集滤液，有机相减压浓缩，干燥，得无色油状标题化合物6.10g，收率：92％。
MS：m/z＝106.06[M+H] +。
步骤3：(S)-5-(羟甲基)-3-甲基噁唑烷-2-酮(40d)的制备。
于室温，将(R)-3-(甲氨基)丙烷-1,2-二醇(3.00g，0.0286mmol)和t-BuOK(157mg，0.00143mmol)溶于碳酸二乙酯(21mL)中，反应液在100℃搅拌过夜。减压浓缩，粗品用硅胶柱层析色谱法分离(DCM：MeOH＝20:1)，得1.70g无色油状标题化合物，收率：46％。
MS：m/z＝131.86[M+H] +。
步骤4：(S)-5-(氯甲基)-3-甲基噁唑烷-2-酮(40e)的制备。
于室温，将(S)-5-(羟甲基)-3-甲基噁唑烷-2-酮(500mg，3.82mmol)溶于THF(15mL)中，加入SOCl 2(0.831mL，11.4mmol)，反应液在50℃搅拌过夜。反应液减压浓缩，粗品用硅胶柱层析色谱法分离(DCM：MeOH＝10:1)，得330mg黄色油状标题化合物，收率：53％。
MS：m/z＝149.84[M+H] +。
后续步骤与实施例12的制备方法相同，除了用40e替代2-(溴甲基)四氢呋喃，制得标题化合物40。
MS:m/z＝577.10[M+H] +。
1H NMR(300MHz,DMSO-d 6):δppm 9.14-9.10(m,3H),8.47(s,1H),7.77(s,1H),7.72(s,1H),5.32-5.27(m,1H),5.03-4.92(m,2H),4.65-4.53(m,1H),4.46-4.38(m,1H),4.26-4.19(m,1H),3.67(t,J＝8.1Hz,1H),3.37-3.35(m,1H),2.74(s,3H),1.62(t,J＝6.9Hz,3H)。
实施例41：4-((1,4-二噁烷-2-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(41)的制备
Figure PCTCN2021120150-appb-000116
步骤1：2-((苄氧基)甲基)-1,4-二噁烷(41b)的制备
于室温，将3-(苄氧基)丙烷-1,2-二醇(1.00g，5.49mmol)溶于NaOH(5.48g,137mmol)的水(15mL)溶液中，加入四丁基碘化铵(402mg，1.09mmol)和1,2-二氯乙烷(13.8g，137mmol)，反应液在50℃搅拌72h。反应液中加入水(40mL)和DCM(20mL)，分层，水相再用DCM(30mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物经硅胶柱层析色谱法分 离(PE：EA＝5：1)得无色油状标题化合物360mg，收率：31％。
步骤2：(1,4-二噁烷-2-基)甲醇(41c)的制备
于0℃，将2-((苄氧基)甲基)-1,4-二噁烷(360mg，1.73mmol)溶于MeOH(10mL)中，加入Pd(OH) 2/C(50mg)和3滴浓盐酸，反应液在氢气氛下置换气体三次，并在50℃搅拌15h。反应结束后，用硅藻土过滤，滤液减压浓缩得无色油状标题化合物200mg，收率：98％。
MS:m/z＝119.10[M+H] +。
步骤3：(1,4-二噁烷-2-基)4-甲基苯磺酸甲酯(41d)的制备
于室温，将(1,4-二噁烷-2-基)甲醇(200mg，1.69mmol)、三乙胺(1.60mL，11.4mmol)和吡啶(0.5mL)溶于DCM(15mL)中，再加入TsCl(1.12g，5.73mmol)，反应液在室温搅拌15h。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离(PE/EtOAc＝3/1)，得无色油状标题化合物100mg，收率：21％。
后续步骤与实施例12的制备方法相同，除了用41d替代2-(溴甲基)四氢呋喃，制得标题化合物41。
MS:m/z＝564.10[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.93(s,2H),8.34(s,1H),7.90(s,1H),7.56(s,1H),6.90(s,1H),5.38-5.34(m,1H),4.90-4.76(m,2H),3.94-3.64(m,8H),3.45-3.38(m,1H),2.54(s,3H),1.71(d,J＝6.9Hz,3H)。
实施例42：(R)-4-((3,3-二氟环丁基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(42)的制备
Figure PCTCN2021120150-appb-000117
步骤1：4-甲基苯磺酸(3,3-二氟环丁基)甲酯(42b)的制备
于室温，将(3,3-二氟环丁基)甲醇(500mg，3.82mmol)、三乙胺(1.60mL，11.4mmol)和吡啶(0.5mL)溶于DCM(15mL)中，再加入TsCl(1.12g，5.73mmol)，反应液在室温搅拌15h。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离(PE/EtOAc＝3/1)，得无色油状标题化合物700mg，收率：66％。
后续步骤与实施例12的制备方法相同，除了用42b替代2-(溴甲基)四氢呋喃，制得标题化合物42。
MS:m/z＝568.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.98(s,2H),8.52(s,1H),7.69-7.67(m,2H),7.04(s,1H),5.39-5.35(m,1H),4.87(s,2H),4.29-4.18(m,2H),2.69-2.47(m,8H),1.77(d,J＝5.4Hz,3H)。
实施例43：(R)-4-(环丙基甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(43)的制备
Figure PCTCN2021120150-appb-000118
与实施例12的制备方法相同，除了用(溴甲基)环丙烷替代2-(溴甲基)四氢呋喃，制得标题化合物43。
MS：m/z＝518.00[M+H] +。
1H NMR(300MHz,DMSO-d 6):δppm 9.20(d,J＝4.2Hz,1H),9.11(s,2H),8.46(s,1H),7.80(s,1H),7.71(s,1H),5.33-5.29(m,1H),4.93(s,2H),4.18-4.14(m,2H),3.62-3.59(m,2H),3.44(q,J＝6.9Hz,2H),2.51(s,3H),1.62(d,J＝7.2Hz,3H),1.01(t,J＝6.9Hz,3H)。
实施例44：4-(2,2-二氟环丙烷-1-羰基)-8-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(44)的制备
Figure PCTCN2021120150-appb-000119
与实施例35的制备方法相同，除了用2,2-二氟环丙烷-1-甲酰氯替代四氢-2H-吡喃-4-甲酰氯，制得标题化合物44。
MS:m/z＝554.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.95(d,J＝4.2Hz,2H),8.69(s,1H),7.90(s,1H),7.63(s,1H),6.95(s,1H),5.43-5.35(m,1H),4.75-4.72(m,2H),4.53-4.50(m,2H),3.59(s,1H),2.83-2.79(m,1H),2.56(s,3H),2.37-2.35(m,1H),1.71(d,J＝5.4Hz,3H)。
实施例45：(R)-4-(3,3-二氟环丁烷-1-羰基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(45)的制备
Figure PCTCN2021120150-appb-000120
与实施例35的制备方法相同，除了用3,3-二氟环丁烷-1-甲酰氯替代四氢-2H-吡喃-4-甲酰氯，制得标题化合物45。
MS:m/z＝568.10[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.97(s,2H),8.55(s,1H),7.72(s,1H),7.54(s,1H),7.12-7.01(m,1H),5.43-5.36(m,1H),4.63-4.57(m,2H),4.24-4.19(m,1H),4.02-3.97(m,1H),4.45-3.40(m,1H),3.03-2.90(m,2H),2.87-2.82(m,2H),2.57(s,3H),1.75(d,J＝5.4Hz,3H)。
实施例46：(R)-4-苯甲酰基-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(46)的制备
Figure PCTCN2021120150-appb-000121
与实施例35的制备方法相同，除了用苯甲酰氯替代四氢-2H-吡喃-4-甲酰氯，制得标题化合物46。
MS:m/z＝554.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.90(s,2H),8.43(s,1H),7.91(s,1H),7.58-7.44(m,6H),7.01(s,1H),5.36-5.29(m,1H),4.57-4.54(m,1H),4.36-4.33(m,1H),4.12-4.11(m,1H),4.10-3.99(m,1H),2.56(s,3H),1.67(d,J＝5.4Hz,3H)。
实施例47：(R)-4-(环丙基甲基)-8-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(47)的制备
Figure PCTCN2021120150-appb-000122
与实施例8的制备方法相同，除了用环丙烷甲醛替代四氢呋喃-3-甲醛，制得标题化合物47。
MS:m/z＝504.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.91(s,2H),7.96(s,1H),7.53(s,1H),7.38(s,1H),6.88(s,1H),5.35-5.31(s,1H),4.51(s,2H),3.56-3.54(m,2H),3.23-3.21(m,2H),2.52(s,3H),1.68-1.66(m,3H),1.05-1.04(m,1H),0.57-0.55(m,2H),0.23-0.21(m,2H)。
实施例48：4-((2,2-二氟环丙基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(48)的制备
Figure PCTCN2021120150-appb-000123
步骤1：(2,2-二氟环丙基)甲醇(48b)的制备
于0℃，将2,2-二氟环丙烷-1-羧酸(1.00g，8.19mmol)溶于THF(15mL)中，分批缓慢加入LiAlH 4(623mg，16.4mmol)，反应液在0℃搅拌1h，随后升至室温搅拌过夜。反应结束后，滴加冰水(15mL)淬灭反应，析出胶体，用硅藻土过滤，滤液中加入EtOAc(20mL)稀释，分层，水相用EtOAc(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤、浓缩得无色油状标题化合物412mg，收率：46.5％。
步骤2：(2,2-二氟环丙基)-4-甲基苯磺酸甲酯(48c)的制备
于室温，将(2,2-二氟环丙基)甲醇(412mg，3.82mmol)、三乙胺(1.60mL，11.4mmol)和吡啶(0.5mL)溶于DCM(15mL)中，再加入TsCl(1.12g，5.73mmol)，反应液在室温搅拌15h。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离(PE/EtOAc＝3/1)，得无色油状标题化合物200mg，收率：20％。
后续步骤与实施例12的制备方法相同，除了用48c替代2-(溴甲基)四氢呋喃，制得标题化合物48。
MS:m/z＝554.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.94(s,2H),8.37(s,1H),7.71-7.70(m,1H),7.59(s,1H),6.93-6.91(m,1H),5.38-5.35(m,1H),4.85(s,2H),4.35-4.31(m,1H),4.05-3.96(m,1H),2.55(s,3H),1.81-1.72(m,4H),1.51-1.47(m,1H),1.38-1.36(m,1H)。
实施例49：(R)-4-(环丁基甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(49)的制备
Figure PCTCN2021120150-appb-000124
与实施例12的制备方法相同，除了用(溴甲基)环丁烷替代2-(溴甲基)四氢呋喃，制得标题化合物49。
MS：m/z＝532.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.92(s,2H),8.29(s,1H),7.64(s,1H),7.57(s,1H),6.84(d,J＝6.3Hz,1H),5.36-5.32(m,1H),4.81(s,2H),4.08(d,J＝7.2Hz,2H),2.73-2.68(m,1H),2.55(s,3H),2.03-2.01(m,2H),1.87-1.85(m,4H),1.72(d,J＝7.2Hz,3H)。
实施例50：(R)-4-((1-甲基环丁基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(50)的制备
Figure PCTCN2021120150-appb-000125
与实施例48的制备方法相同，除了用1-甲基环丁烷-1-羧酸替代2,2-二氟环丙烷-1-羧酸，制得标题化合物50。
MS:m/z＝546.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.93(s,2H),8.32(s,1H),7.74(s,1H),7.59(s,1H),6.88(d,J＝6.0Hz,1H),5.39-5.30(m,1H),4.83(s,2H),4.08-3.95(dd,J 1＝24.3Hz,J 2＝14.7Hz,2H),2.55(s,3H),1.99-1.77(m,4H),1.68(d,J＝5.4Hz,3H),1.62-1.59(m,2H),1.10(s,3H)。
实施例51：(R)-4-(环己基甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(51)的制备
Figure PCTCN2021120150-appb-000126
与实施例12的制备方法相同，除了用(溴甲基)环己烷替代2-(溴甲基)四氢呋喃，制得标题化合物51。
MS:m/z＝560.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.94(s,2H),8.31(s,1H),7.68(s,1H),7.58(s,1H),6.91-6.89(m,1H),5.39-5.32(m,1H),4.87(s,2H),3.94-3.83(m,1H),2.55(s,3H),1.77-1.62(m,9H),1.16-1.04(m,5H)。
实施例52：4-((1-甲基-5-氧代吡咯烷-3-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(52)的制备
Figure PCTCN2021120150-appb-000127
与实施例48的制备方法相同，除了用1-甲基-5-氧代吡咯烷-3-羧酸甲酯替代2,2-二氟环丙烷-1-羧酸，NaBH 4替代LiAlH 4，制得标题化合物52。
MS:m/z＝575.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.98(s,2H),8.42-8.39(m,1H),7.60-7.50(m,2H),7.24(s,1H),5.41-5.32(m,1H),4.84(s,2H),4.27-4.23(m,1H),3.96-3.88(m,1H),3.48-3.45(m,1H),3.25-3.15(m,1H),2.83-2.74(m,4H),2.57(s,3H),2.56-2.55(m,1H),2.22-2.17(m,1H),1.76-1.73(m,3H)。
实施例53：2-((8-(5-甲基噻唑-2-基)-3-氧代-6-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)吗啉-4-甲酸甲酯(53)的制备
Figure PCTCN2021120150-appb-000128
步骤1：2-((8-(5-甲基噻唑-2-基)-3-氧代-6-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)吗啉-4-羧酸叔丁基酯(53a)的制备
与实施例12的制备方法相同，除了用2-((甲苯磺酰氧基)甲基)吗啉-4-羧酸叔丁酯替代2-(溴甲基)四氢呋喃，制得标题化合物53a。
步骤2：8-(5-甲基噻唑-2-基)-4-(吗啉-2-基甲基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺盐酸盐(53b)的制备
于室温，将2-((8-(5-甲基噻唑-2-基)-3-氧代-6-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)吗啉-4-羧酸叔丁基酯(100mg，0.151mmol)加入到二氯甲烷(3mL)中，再加入4M盐酸二氧六环溶液(1mL)，室温搅拌2小时。减压浓缩，得白色固体状标题化合物90mg，粗品直接用于下步反应。
MS:m/z＝563.0[M+H] +。
步骤3：2-((8-(5-甲基噻唑-2-基)-3-氧代-6-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)吗啉-4-甲酸甲酯(53)的制备
于室温，将8-(5-甲基噻唑-2-基)-4-(吗啉-2-基甲基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(30.0mg，0.0500mmol)和三乙胺(15.2mg，0.150mmol)加入到二氯甲烷(3mL)中，再加入氯甲酸甲酯(9.40mg，0.100mmol)，反应液室温搅拌2小时。加入水(5mL)，二氯甲烷萃取(10mL×2)，合并有机相，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Gemini-C18 150 x 21.2mm，5μm，流动相：乙腈/水，0.1％FA，梯度：40％-70％)，得到白色固体状标题化合物14.8mg，收率：43.5％。
MS:m/z＝620.5[M+H] +。
1H NMR(400MHz,CDCl 3):δppm 8.95(s,2H),8.35(d,J＝1.6Hz,1H),7.90(s,1H),7.60(d,J＝0.8Hz,1H),6.94-6.88(m,1H),5.40-5.33(m,1H),4.90(d,J＝15.2Hz,1H),4.81(dd,J＝14.8,1.2Hz,1H),4.20-4.03(m,2H),4.02-3.84(m,3H),3.81-3.74(m,1H),3.70(s,3H),3.49-3.41(m,1H),3.07-2.95(m,1H),2.86-2.76(m,1H),2.56(d,J＝0.8Hz,3H),1.73(d,J＝7.2Hz,3H)。
实施例54：2-((8-(5-甲基噻唑-2-基)-3-氧代-6-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)哌啶-4-甲酸甲酯(54)的制备
Figure PCTCN2021120150-appb-000129
与实施例53的制备方法相同，除了用3-((甲苯磺酰氧基)甲基)哌啶-1-甲酸叔丁酯替代2-((甲苯磺酰氧基)甲基)吗啉-4-羧酸叔丁酯，制得标题化合物54。
MS:m/z＝619.0[M+H] +。
1H NMR(400MHz,CDCl 3):δppm 8.96(s,2H),8.42(s,1H),7.61(s,2H),5.40-5.33(m,1H),4.85(d,J＝1.8Hz,2H),4.02-3.84(m,4H),3.62(s,3H),2.91(t,J＝12.0Hz,1H),2.83-2.75(m,1H),2.56(s,3H),1.99(s,2H),1.74(d,J＝7.2Hz,3H),1.70-1.52(s,2H)。
实施例55：3-((8-(5-甲基噻唑-2-基)-3-氧代-6-(((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)氨基甲酰基)-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)吡咯烷-1-羧酸甲酯(55)的制备
Figure PCTCN2021120150-appb-000130
与实施例53的制备方法相同，除了用3-((甲苯磺酰氧基)甲基)吡咯烷-1-羧酸叔丁酯替代2-((甲苯磺酰氧基)甲基)吗啉-4-羧酸叔丁酯，制得标题化合物55。
MS:m/z＝605.1[M+H] +。
1H NMR(400MHz,DMSO-d6):δppm 9.23-9.21(d,J＝7.2Hz,1H),9.11(s,2H),8.50(s,1H),7.72(s,1H),7.69(s,1H),5.32-5.28(m,1H),4.96(s,2H),4.09-4.07(d,J＝8.0Hz,2H),3.55-3.53(m,3H),3.40-3.36(m,2H),3.26-3.20(m,1 H),3.12-3.06(m,1H),2.62-2.55(m,1H),2.52(s,3H),1.99-1.88(m,1H),1.71-1.66(m,1H),1.63-1.62(d,J＝4.0Hz,3H)。
实施例56：4-((4-甲基吗啉-2-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(56)的制备
Figure PCTCN2021120150-appb-000131
步骤1：4-((4-甲基吗啉-2-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(56)的制备。
于室温，将8-(5-甲基噻唑-2-基)-4-(吗啉-2-基甲基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酰胺盐酸盐(53b)(50.0mg，0.0830mmol)和碳酸钾(28.7mg，0.207mmol)加入到乙腈(5mL)中，再加入碘甲烷(14.0mg，0.0100mmol)，反应液加热至60℃搅拌2小时。反应结束后过滤，滤液减压浓缩，残余物用制备TLC板分离(二氯甲烷：甲醇＝40:1)，得到白色固体状标题化合物18.7mg，收率：38.9％。
MS：m/z＝577.1[M+H] +。
1H NMR(400MHz,CDCl3):δppm 8.95(d,J＝2.8Hz,2H),8.34(dd,J＝3.8,2.0Hz,1H),7.85(d,J＝2.0Hz,1H),7.59(s,1H),7.02-6.92(m,1H),5.41-5.33(m,1H),4.88(dd,J＝14.8,2.4Hz,1H),4.79(d,J＝14.8Hz,1H),4.13-4.03(m,2H),3.96-3.85(m,2H),3.66-3.56(m,1H),2.86(d,J＝10.6Hz,1H),2.69-2.61(m,1H),2.55(d,J＝0.8Hz,3H),2.32(s,3H),2.25-2.17(m,1H),2.06-1.99(m,1H),1.73(d,J＝7.2Hz,3H)。
实施例57：8-(5-甲基噻唑-2-基)-3-氧代-4-(((R)-四氢呋喃-2-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(57)的制备
Figure PCTCN2021120150-appb-000132
与实施例12的制备方法相同，除了用(R)-(四氢呋喃-2-基)-4-甲基苯磺酸甲酯替代2-(溴甲基)四氢呋喃，制得标题化合物57。
MS:m/z＝548.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.94(s,2H),8.32(s,1H),7.93(s,1H),7.59(s,1H),6.91-6.88(m,1H),5.39-5.35(m,1H),4.92-4.75(m,2H),4.16-4.14(m,2H),4.00-3.92(m,2H),3.77-3.75(m,1H),2.55(s,3H),2.20-1.95(m,4H),1.72(d,J＝5.2Hz,3H)。
实施例58：8-(5-甲基噻唑-2-基)-3-氧代-4-(((S)-四氢呋喃-2-基)甲基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(58)的制备
Figure PCTCN2021120150-appb-000133
与实施例12的制备方法相同，除了用(S)-(四氢呋喃-2-基)4-甲基苯磺酸甲酯替代2-(溴甲基)四氢呋喃，制得标题化合物58。
MS：m/z＝548.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.94(s,2H),8.33(s,1H),7.90(s,1H),7.58(s,1H),6.91-6.89(m,1H),5.39-5.35(m,1H),4.91-4.76(m,2H),4.12-4.11(m,1H),4.07-4.05(m,1H),3.93-3.90(m,2H),3.75-3.73(m,1H),2.55(s,3H),2.18-1.94(m,4H),1.72(d,J＝5.2Hz,3H)。
实施例59：(R)-4-(氰基甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(59)的制备
Figure PCTCN2021120150-appb-000134
与实施例12的制备方法相同，除了用溴乙腈替代2-(溴甲基)四氢呋喃，制得标题化合物59。
MS:m/z＝503.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.96(s,2H),8.49(s,1H),7.72(s,1H),7.62(s,1H),7.15-7.14(m,1H),5.41-5.34(m,1H),5.07-5.03(m,1H),4.91(s,2H),4.83-4.79(m,1H),2.57(s,3H),1.73(d,J＝5.4Hz,3H)。
实施例60：(R)-4-(2-羟基-2-甲基丙基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(60)的制备
Figure PCTCN2021120150-appb-000135
步骤1：4-(2-羟基-2-甲基丙基)-8-(5-甲基噻唑-2-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(60a)的制备。
于室温，将8-(5-甲基噻唑-2-基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-羧酸甲酯(100mg，0.329mmol)、2,2-二甲基环氧乙烷(47.4mg，0.658mmol)和碳酸铯(215mg，0.658mmol)溶于DMF(3mL)中，反应液在50℃搅拌15h。反应结束后，减压浓缩，残余物用硅胶柱层析色谱法分离(PE/EtOAc＝3/1)，得黄色固体状标题化合物55mg，收率：44％。
MS:m/z＝377.00[M+H] +。
后续步骤与实施例12的制备方法相同，除了用化合物60a代替化合物12a制得标题化合物60。
MS:m/z＝536.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.94(s,2H),8.16(s,1H),7.92(s,1H),7.57(s,1H),7.17-7.16(m,1H),5.38-5.31(m,1H),4.75(s,2H),4.24-4.20(m,1H),4.05-4.01(m,1H),2.56(s,3H),1.75(d,J＝5.4Hz,3H),1.38(s,3H),1.34(s,3H)。
实施例61：(R)-8-(5-甲基噻唑-2-基)-3-氧代-4-(丙-2-炔-1-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(61)的制备
Figure PCTCN2021120150-appb-000136
与实施例12的制备方法相同，除了用3-溴丙-1-炔替代2-(溴甲基)四氢呋喃，制得标题化合物61。
MS:m/z＝502.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.95(s,2H),8.37(s,1H),7.86(s,1H),7.59(s,1H),6.98-6.96(m,1H),5.39-5.35(m,1H),4.87(s,2H),4.85-4.73(m,2H),2.55(s,3H),2.29(s,1H),1.72(d,J＝5.2Hz,3H)。
实施例62：(R)-8-(5-甲基噻唑-2-基)-3-氧代-4-(2-(四氢-2H-吡喃-4-基)乙基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(62)的制备
Figure PCTCN2021120150-appb-000137
与实施例48的制备方法相同，除了用2-(四氢-2H-吡喃-4-基)乙酸替代2,2-二氟环丙烷-1-羧酸，制得标题化合物62。
MS：m/z＝576.10[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.96(s,2H),8.49(s,1H),7.68(s,1H),7.63(s,1H),7.20-7.18(m,1H),5.40-5.33(m,1H),4.10-3.94(m,4H),3.41-3.34(m,2H),2.57(s,3H),1.67-1.33(m,8H),1.41-1.33(m,1H)。
实施例63：(R)-4-(((1,1-二氧代四氢-2H-噻喃-4-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(63)的制备
Figure PCTCN2021120150-appb-000138
与实施例48的制备方法相同，除了用四氢-2H-硫代吡喃-4-甲酸1,1-二氧化物替代2,2-二氟环丙烷-1-羧酸，制得标题化合物63。
MS:m/z＝610.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.97(s,2H),8.59(s,1H),7.66(s,2H),7.34-7.33(m,1H),5.38-5.31(m,1H),4.86(s,2H),4.09-4.00(m,2H),3.09-3.05(m,2H),2.94-2.88(m,2H),2.58(s,3H),2.06-2.01(m,5H),1.75(d,J＝5.4Hz,3H)。
实施例64：2-甲基-7-(5-甲基噻唑-2-基)-2-(四氢-2H-吡喃-4-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)苯并[d][1,3]二噁唑-5-甲酰胺(64)的制备
Figure PCTCN2021120150-appb-000139
步骤1：2-甲基-2-(四氢-2H-吡喃-4-基)苯并[d][1,3]二噁唑-5-羧酸甲酯(64b)的制备
于室温，将3,4-二羟基苯甲酸甲酯(1.00g，5.95mmol)、1-(四氢-2H-吡喃-4-基)乙-1-酮(1.14g，8.93mmol)和TsOH(204mg，1.19mmol)溶于甲苯(10mL)中，反应液在110℃搅拌过夜。反应结束后，减压浓缩，向残余物中加入10mL水和10mL EtOAc，分离的水相再用EtOAc(15mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离(PE:EtOAc＝3:1)，得无色油状物标题化合物1.50g，收率：89％。
MS:m/z＝279.00[M+H] +。
步骤2：7-溴-2-甲基-2-(四氢-2H-吡喃-4-基)苯并[d][1,3]二噁唑-5-羧酸甲酯(64c)的制备。
于室温，将2-甲基-2-(四氢-2H-吡喃-4-基)苯并[d][1,3]二恶唑-5-羧酸甲酯(1.40g，5.04mmol)溶于DMF(15mL)中，加入NBS(1.78g，10.1mmol)，反应 液在50℃搅拌过夜。反应结束后，减压浓缩，向残余物中加入10mL水和20mL EtOAc，分离的水相再用EtOAc(15mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离(PE:EtOAc＝2:1)，得无色油状物标题化合物1.60g，收率：89％。
MS：m/z＝258.00[M+H] +。
后续步骤与实施例1的制备方法相同，除了用64c替代1b，制得标题化合物64。
MS:m/z＝535.00[M+H] +。
1H NMR(400MHz,CDCl 3):δppm 8.77(s,2H),7.87-7.83(m,1H),7.40(s,1H),7.13(s,1H),6.85(s,1H),5.20-5.17(m,1H),4.05-4.02(m,2H),3.40-3.35(m,2H),2.49(s,3H),2.13-2.08(m,1H),1.70-1.62(m,2H),1.61-1.56(m,5H),1.53(d,J＝6.8Hz,3H)。
实施例65：(R)-1-(4-甲氧基苯基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(65)的制备。
Figure PCTCN2021120150-appb-000140
与实施例1的制备方法相同，除了用1-碘-4-甲氧基苯替代3-碘氧杂环丁烷，制得标题化合物65。
MS：m/z m/z 539.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm:9.00(s,2H),8.74(s,1H),8.43(s,1H),8.21(s,1H),7.71(s,1H),7.60(s,1H),7.55(s,1H)，7.41(s,1H)，7.09-7.05(m,1H)，5.43-5.36(m,1H),3.89(s,3H),2.64(s,3H),1.78(d,J＝7.2Hz,3H)。
实施例66：(R)-1-(4-氟苯基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(66)的制备。
Figure PCTCN2021120150-appb-000141
与实施例1的制备方法相同，除了用1-氟-4-碘苯替代3-碘氧杂环丁烷，制得 标题化合物66。
MS：m/z m/z 526.90[M+H] +。
1H NMR(400MHz,CDCl 3)δppm:9.00(s,2H),8.77(s,1H),8.51(s,1H),8.28(s,1H),7.67(s,1H),7.66-7.65(m,2H),7.48(s,1H)，7.29(s,1H)，5.42-5.39(m,1H),2.66(s,3H),1.78(d,J＝7.2Hz,3H)。
实施例67：(R)-1-((3-氟氧杂环丁烷-3-基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(67)的制备
Figure PCTCN2021120150-appb-000142
与实施例1的制备方法相同，除了用(3-氟氧杂环丁烷-3-基)甲基-4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物67。
MS：m/z＝521.00[M+H] +。
1H NMR(300MHz,CDCl 3)δ9.03(s,2H),8.59(s,1H),8.47(s,1H),8.15(s,1H),7.71(s,1H),7.59-7.51(m,1H),5.44-5.40(m,1H),4.98(s,1H),4.93(s,1H),4.89-4.78(m,4H),2.63(s,3H),1.80-1.79(d,J＝5.1Hz,3H).
实施例68：(R)-2-((3-氟氧杂环丁烷-3-基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(68)的制备。
Figure PCTCN2021120150-appb-000143
与实施例2的制备方法相同，除了用(3-氟氧杂环丁烷-3-基)甲基-4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物68。
MS：m/z＝521.13[M+H] +。
1H NMR(300MHz,CDCl 3)δ9.15(s,1H),9.08(s,2H),8.46-8.41(m,2H),8.33(s,1H),7.85(s,1H),5.44-5.40(m,1H),5.01(s,1H),4.96(s,1H),4.86-4.78(m,4H),2.71(s,3H),1.85-1.83(d,J＝5.4Hz,3H).
实施例69：(R)-4-((3-氟氧杂环丁烷-3-基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基))嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(69)的制备
Figure PCTCN2021120150-appb-000144
与实施例12的制备方法相同，除了用(3-氟氧杂环丁烷-3-基)甲基-4-甲基苯磺酸酯替代2-(溴甲基)四氢呋喃，制得标题化合物69。
MS：m/z 552.13[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.95(s,2H),8.52(s,1H),7.82(s,1H),7.63(s,1H),7.11(s,1H),5.35-5.32(m,1H),4.87(m,2H),4.82-4.75(m,4H),4.68-4.47(m,2H),2.58(s,3H),1.74(d,J＝7.1Hz,3H).
实施例70：(R)-4-(5-甲基噻唑-2-基)-1-(四氢-2H-吡喃-4-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(70)的制备
Figure PCTCN2021120150-appb-000145
与实施例1的制备方法相同，除了用4-碘四氢-2H-吡喃替代3-碘氧杂环丁烷，制得标题化合物70。
MS：m/z＝517.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 8.99(s,2H),8.60(s,1H),8.15(s,2H),7.67(s,1H),7.16(s,1H),5.45-5.41(m,1H),4.79-4.73(m,1H),4.20-4.17(m,2H),3.66-3.60(m,2H),2.61(s,3H),2.47-2.39(m,2H),2.01-1.98(m,2H),1.78(d,J＝5.4Hz,3H)。
实施例71：(R)-4-(5-甲基噻唑-2-基)-2-(四氢-2H-吡喃-4-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(71)的制备
Figure PCTCN2021120150-appb-000146
与实施例2的制备方法相同，除了用4-碘四氢-2H-吡喃替代3-碘氧杂环丁烷，制得标题化合物71。
MS：m/z＝517.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.99(s,2H),8.74(s,1H),8.24(s,1H),8.17(s,1H),7.63(s,1H),6.99(s,1H),5.43-5.37(m,1H),4.76-4.70(m,1H),4.18-4.17(m,2H),3.66-3.59(m,2H),2.58(s,3H),2.35-2.25(m,4H),1.76(d,J＝5.1Hz,3H)。
实施例72：(R)-4-(5-甲基噻唑-2-基)-1-((四氢-2H-吡喃-4-基)甲基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(72)的制备
Figure PCTCN2021120150-appb-000147
与实施例1的制备方法相同，除了用4-(溴甲基)四氢-2H-吡喃替代3-碘氧杂环丁烷，制得标题化合物72。
MS：m/z＝531.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 8.98(s,2H),8.53(s,1H),8.04-8.01(m,2H),7.55(s,1H),6.90-6.88(m,1H),5.45-5.41(m,1H),4.34(d,J＝4.8Hz,2H),3.96-3.93(m,2H),3.37-3.31(m,2H),2.60(s,3H),2.36-2.31(m,1H),1.77(d,J＝5.2Hz,3H),1.49-1.41(m,4H)。
实施例73：(R)-4-(5-甲基噻唑-2-基)-2-((四氢-2H-吡喃-4-基)甲基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(73)的制备
Figure PCTCN2021120150-appb-000148
与实施例2的制备方法相同，除了用4-(溴甲基)四氢-2H-吡喃替代3-碘氧杂环丁烷，制得标题化合物73。
MS：m/z＝531.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.96(s,2H),8.74(s,1H),8.14(s,1H),7.93(s,1H),7.55(s,1H),6.66-6.64(m,1H),5.43-5.38(m,1H),4.35(d,J＝4.5Hz,2H),3.99-3.95(m,2H),3.41-3.31(m,2H),2.56(s,3H),2.37-2.32(m,1H),1.75(d,J＝5.2Hz,3H),1.50-1.43(m,4H)。
实施例74：(R)-1-((3,3-二氟环丁基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(74)的制备
Figure PCTCN2021120150-appb-000149
与实施例1的制备方法相同，除了用(3,3-二氟环丁基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物74。
MS：m/z＝537.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 8.99(s,2H),8.62(s,1H),8.06(s,2H),7.65(s,1H),6.98(s,1H),5.47-5.40(m,1H),4.56(d,J＝5.4Hz 1H),2.68(s,1H),2.65-2.61(m,2H),2.60(s,3H),2.52-2.40(m,2H),1.77(d,J＝5.4Hz,3H)。
实施例75：(R)-2-((3,3-二氟环丁基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(75)的制备
Figure PCTCN2021120150-appb-000150
与实施例2的制备方法相同，除了用(3,3-二氟环丁基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物75。
MS：m/z＝537.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 8.99(s,2H),8.70(s,1H),8.20(s,1H),8.11(s,1H),7.61(s,1H),6.91(s,1H),5.44-5.37(m,1H),4.59(d,J＝5.4Hz 1H),2.75(s,1H),2.61-2.50(m,2H),2.49(s,3H),2.47-2.42(m,2H),1.76(d,J＝5.4Hz,3H)。
实施例76：1-((1-甲基吡咯烷-3-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(76)的制备
Figure PCTCN2021120150-appb-000151
与实施例1的制备方法相同，除了用(1-甲基吡咯烷-3-基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物76。
MS：m/z＝530.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 9.07(s,2H),8.77(s,1H),8.14(s,1H),7.59(s,1H),7.26-7.25(m,1H),5.44-5.37(m,1H),4.57-4.28(m,3H),3.53-3.52(m,2H),2.94-2.88(m,3H),2.54(s,3H),2.33-2.26(m,2H),2.13-2.09(m,2H),1.78(d,J＝5.2Hz,3H)。
实施例77：2-((1-甲基吡咯烷-3-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(77)的制备
Figure PCTCN2021120150-appb-000152
与实施例2的制备方法相同，除了用(1-甲基吡咯烷-3-基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物77。
MS：m/z＝530.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 9.06(s,1H),9.03(s,1H),8.77(s,1H),8.22-8.18(m,1H),7.94(s,1H),7.74-7.72(m,1H),7.49(s,1H),5.39-5.34(m,1H),4.66-4.58(m,3H),3.99-3.95(m,2H),3.16-3.13(m,1H),3.05(m,3H),2.95-2.88(m,1H),2.52(s,3H),2.40-2.37(m,1H),1.85-1.82(m,1H),1.75-1.74(m,3H)。
实施例78：(R)-4-(2-氟乙基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(78)的制备
Figure PCTCN2021120150-appb-000153
与实施例12的制备方法相同，除了用1-氟-2-碘乙烷替代2-(溴甲基)四氢呋喃，制得标题化合物78。
MS：m/z＝510.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 8.97(s,2H),8.67(s,1H),7.84(s,1H),7.68(s,1H),7.31(m,1H),5.36-5.34(m,1H),4.88(s,2H),4.88-4.87(m,1H),4.68-4.66(m,1H),4.36-4.30(m,2H),2.60(s,3H),1.75(d,J＝5.1Hz,3H)。
实施例79：(R)-4-(3-氟丙基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(79)的制备
Figure PCTCN2021120150-appb-000154
与实施例12的制备方法相同，除了用1-氟-3-碘丙烷替代2-(溴甲基)四氢呋喃，制得标题化合物79。
MS：m/z＝524.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 8.96(s,2H),8.55(s,1H),7.72(s,1H),7.64(s,1H),7.12(s,1H),5.39-5.32(m,1H),4.85(s,2H),4.61-4.59(m,1H),4.48-4.47(m,1H),4.20-4.17(m,2H),2.57(s,3H),2.15-2.05(m,2H),1.74(d,J＝5.4Hz,3H)。
实施例80：(R)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-4-(3,3,3-三氟丙基))-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(80)的制备
Figure PCTCN2021120150-appb-000155
与实施例12的制备方法相同，除了用1,1,1-三氟-3-碘丙烷替代2-(溴甲基)四氢呋喃，制得标题化合物80。
MS：m/z＝560.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 8.97(s,2H),8.66(s,1H),7.70-7.67(m,2H),7.27(s,1H),5.37-5.35(m,1H),4.86(s,2H),4.32-4.278(m,2H),2.59-2.48(m,5H),1.76(d,J＝5.1Hz,3H)。
实施例81：4-(1-氰乙基)-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(81)的制备
Figure PCTCN2021120150-appb-000156
与实施例12的制备方法相同，除了用2-溴丙腈替代2-(溴甲基)四氢呋喃，制得标题化合物81。
MS：m/z＝517.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 8.96(s,2H),8.56(s,1H),7.96-7.91(m,1H),7.65(s,1H),7.12(s,1H),5.99-5.79(m,1H),5.37(s,1H),4.91-4.78(m,2H),2.59(s,3H),1.84-1.81(m,3H),1.74(d,J＝5.4Hz,3H)。
实施例82：(R)-1-(4,4-二氟环己基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(82)的制备
Figure PCTCN2021120150-appb-000157
与实施例1的制备方法相同，除了用4,4-二氟环己基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物82。
MS：m/z＝551.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 8.97(s,2H),8.60(s,1H),8.06(s,2H),7.64(s,1H),7.02-7.00(m,1H),5.44-5.41(m,1H),4.65-4.64(m,1H),2.59(s,3H),2.34-2.27(m,4H),2.04-1.90(m,4H),1.77(d,J＝5.1Hz,3H)。
实施例83：4-(5-甲基噻唑-2-基)-1-((S)-四氢呋喃-3-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(83)的制备
Figure PCTCN2021120150-appb-000158
与实施例1的制备方法相同，除了用(R)-四氢呋喃-3-基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物83。
MS：m/z＝503.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 9.07(s,2H),8.96(s,1H),8.47(s,1H),8.35(s,1H),8.17(s,1H),7.82(s,1H),5.45-5.41(m,2H),4.31-4.28(m,1H),4.29-4.26(m,2H),4.20-4.19(m,1H),2.88(s,3H),2.55-2.52(m,2H),1.83(d,J＝5.4Hz,3H)。
实施例84：4-(5-甲基噻唑-2-基)-1-((R)-四氢呋喃-3-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(84)的制备
Figure PCTCN2021120150-appb-000159
与实施例1的制备方法相同，除了用(S)-四氢呋喃-3-基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物84。
MS：m/z＝503.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 8.99(s,2H),8.62(s,1H),8.18-8.15(m,2H),7.67(s,1H),7.04(s,1H),5.43-5.37(m,2H),4.29-4.21(m,3H),4.04-4.02(m,1H),2.61(s,3H),2.53-2.51(m,2H),1.78(d,J＝5.4Hz,3H)。
实施例85：(R)-1-(2-氰乙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(85)的制备
Figure PCTCN2021120150-appb-000160
与实施例1的制备方法相同，除了用3-溴丙腈替代3-碘氧杂环丁烷，制得标题化合物85。
MS：m/z＝486.10[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 9.05(s,2H),8.72(s,1H),8.60(s,1H),8.24(s,1H),7.86(s,1H),7.76(s,1H),5.44-5.41(m,1H),4.78(t,J＝4.8Hz,2H),3.07(t,J＝4.8Hz,2H),2.66(s,3H),1.80(d,J＝4.8Hz,3H)。
实施例86：(R)-2-(2-氰乙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(86)的制备
Figure PCTCN2021120150-appb-000161
与实施例2的制备方法相同，除了用3-溴丙腈替代3-碘氧杂环丁烷，制得标题化合物86。
MS：m/z＝486.10[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 9.47(s,1H),9.13(s,2H),8.82(s,1H),8.68(s,1H),8.45(s,1H),7.87(s,1H),5.43-5.42(m,1H),4.83(t,J＝4.5Hz,2H),3.21(t,J＝4.5Hz,2H),2.72(s,3H),1.86(d,J＝5.1Hz,3H)。
实施例87：(R)-1-(氰基甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(87)的制备
Figure PCTCN2021120150-appb-000162
与实施例1的制备方法相同，除了用2-溴乙腈替代3-碘氧杂环丁烷，制得标题化合物87。
MS：m/z＝472.10[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 9.04(s,2H),8.67(s,1H),8.53(s,1H),8.18(s,1H),7.75(s,1H),7.52(s,1H),5.43-5.41(m,3H),2.66(s,3H),1.81(d,J＝4.8Hz,3H)。
实施例88：(R)-2-(氰基甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(88)的制备
Figure PCTCN2021120150-appb-000163
与实施例2的制备方法相同，除了用2-溴乙腈替代3-碘氧杂环丁烷，制得标题化合物88。
MS：m/z＝472.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 9.04(s,2H),8.80(s,1H),8.43(s,1H),8.30(s,1H),7.68(s,1H),7.44(s,1H),5.47-5.42(m,3H),2.62(s,3H),1.80(d,J＝4.2 Hz,3H)。
实施例89：(R)-1-(2-羟基-2-甲基丙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(89)的制备
Figure PCTCN2021120150-appb-000164
与实施例1的制备方法相同，除了用2,2-二甲基环氧乙烷替代3-碘氧杂环丁烷，制得标题化合物89。
MS：m/z＝505.10[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 8.99(s,2H),8.66(s,1H),8.16(s,1H),8.11(s,1H),7.66(s,1H),7.15(s,1H),5.43-5.41(m,1H),4.41(s,2H),2.61(s,3H),1.77(d,J＝5.1Hz,3H),1.24(s,6H)。
实施例90：(R)-2-(2-羟基-2-甲基丙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(90)的制备
Figure PCTCN2021120150-appb-000165
与实施例2的制备方法相同，除了用2,2-二甲基环氧乙烷替代3-碘氧杂环丁烷，制得标题化合物90。
MS：m/z＝505.10[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 9.01(s,2H),8.73(s,1H),8.24(s,1H),8.20(s,1H),7.61(s,1H),7.06(s,1H),5.43-5.40(m,1H),4.44(s,2H),2.57(s,3H),1.77(d,J＝5.4Hz,3H),1.23(s,6H)。
实施例91：(R)-1-((1-氟环丙基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(91)的制备
Figure PCTCN2021120150-appb-000166
与实施例1的制备方法相同，除了用(1-氟环丙基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物91。
MS：m/z＝505.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm 8.99(s,2H),8.68(s,1H),8.11(s,1H),8.07(s,1H),7.65(s,1H),6.89(s,1H),5.45-5.41(m,1H),4.84(s,1H),4.79(s,1H),2.60(s,3H),1.76(d,J＝5.4Hz,3H),1.16-1.10(m,2H),0.97-0.92(m,2H)。
实施例92：(R)-2-((1-氟环丙基)甲基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(92)的制备
Figure PCTCN2021120150-appb-000167
与实施例2的制备方法相同，除了用(1-氟环丙基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物92。
MS：m/z＝505.00[M+H] +。
1H NMR(300MHz,CDCl 3):δppm 9.02(s,2H),8.77(s,1H),8.34(s,1H),8.30(s,1H),7.63(s,1H),5.45-5.38(m,1H),4.85(s,1H),4.79(s,1H),2.58(s,3H),1.76(d,J＝5.4Hz,3H),1.27-1.21(m,2H),1.04-0.94(m,2H)。
实施例93：(R)-4-((1-氟环丙基)甲基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(93)的制备
Figure PCTCN2021120150-appb-000168
与实施例12的制备方法相同，除了用(1-氟环丙基)甲基4-甲基苯磺酸酯替代2-(溴甲基)四氢呋喃，制得标题化合物93。
MS：m/z＝536.10[M+H] +。
1H NMR(400MHz,CDCl 3)δppm 8.96(s,2H),9.56(s,1H),7.99(s,1H),7.65(s,1H),7.17(s,1H),5.38-5.32(m,1H),4.88(s,2H),4.47(s,1H),4.38(s,1H),2.58(s,3H),1.73(d,J＝5.4Hz,3H),1.14-1.08(m,2H),0.96-0.94(m,2H)。
实施例94：4-(5-甲基噻唑-2-基)-1-(四氢呋喃-3-基)-N-((R)-1-(2-(三氟甲基)嘧啶 -5-基)乙基)-1H-吲唑-6-甲酰胺(94)的制备
Figure PCTCN2021120150-appb-000169
与实施例1的制备方法相同，除了用四氢呋喃-2-基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物94。
MS：m/z 503.00[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.27(d,J＝5.4Hz,1H),9.18(s,2H),8.68(s,1H),8.41(s,1H),8.09(s,1H),7.78(s,1H),5.67-5.61(m,1H),5.41-5.39(m,1H),4.11-3.98(m,2H),3.96-3.91(m,2H),2.43-2.40(m,3H),2.29-2.33(m,2H),1.67(d,J＝5.1Hz,3H)。
实施例95：4-(5-甲基噻唑-2-基)-2-(四氢呋喃-3-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(95)的制备
Figure PCTCN2021120150-appb-000170
与实施例2的制备方法相同，除了用四氢呋喃-2-基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物95。
MS：m/z 503.00[M+H] +。
1H NMR(300MHz,DMSO-d6)δ9.21(d,J＝7.14Hz,1H),9.16(s,2H),8.94(s,1H),8.44(s,1H),7.97(s,1H),7.73(s,1H),5.54(s,1H),5.45-5.31(m,1H),4.16-4.08(m,3H),3.93-3.90(m,1H),2.54(m,4H),2.51-2.49(m,1H),1.67(d,J＝7.1Hz,3H)。
实施例96：1-((4-甲基吗啉-2-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(96)的制备
Figure PCTCN2021120150-appb-000171
与实施例1的制备方法相同，除了用(4-甲基吗啉-2-基)甲基4-甲基苯磺酸酯替 代3-碘氧杂环丁烷，制得标题化合物96。
MS：m/z＝546.10[M+H] +。
1H NMR(300MHz,CDCl 3):δppm:9.05(s,2H),8.73(s,1H),8.12-8.09(m,2H),7.69-7.57(m,2H),5.51-5.45(m,1H),4.61-4.53(m,1H),4.35(s,1H),3.93(d,1H,J＝8.3Hz),3.73(t,J＝9.0Hz,1H),2.98-2.90(m,1H),2.83-2.78(m,1H),2.62(s,3H),2.42(d,J＝6.0Hz,3H),2.33(s,1H)，2.18-2.06(m,1H)，1.80(d,J＝6.0Hz,3H)。
实施例97：2-((4-甲基吗啉-2-基)甲基)-4-(5-甲基噻唑-2-基)-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(97)的制备
Figure PCTCN2021120150-appb-000172
与实施例2的制备方法相同，除了用(4-甲基吗啉-2-基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物97。
MS：m/z＝546.10[M+H] +。
1H NMR(300MHz,CDCl 3):δppm:9.04(s,2H),8.80(s,1H),8.19(d,J＝6.0Hz,1H),7.95(s,1H),7.61(s,2H),7.04-7.00(m,1H),5.49-5.44(m,1H),4.64-4.56(m,2H),4.25(s,1H),3.95(d,J＝9.0Hz,1H,),3.81-3.79(m,1H),2.99-2.96(m,1H),2.79-2.77(m,1H),2.52(s,3H),2.41(s,3H),2.26-2.24(m,1H)，2.08-2.06(m,1H)，1.80(d,J＝9.0Hz,3H)。
实施例98：(R)-1-(2-氟乙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(98)的制备
Figure PCTCN2021120150-appb-000173
与实施例1的制备方法相同，除了用1-氟-2-碘乙烷替代3-碘氧杂环丁烷，制得标题化合物98。
MS：m/z 479.00[M+H] +。
1H NMR(300MHz,CDCl3)δppm:9.01(s,2H)，8.65(s,1H),8.24(s,1H),8.09(s,1H),7.65(s,1H),7.20(s,1H),5.46-5.39(m,1H),4.95-4.71(m,4H),2.60(s,3H),1.78(d,J＝5.4Hz,3H)。
实施例99：(R)-2-(2-氟乙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(99)的制备
Figure PCTCN2021120150-appb-000174
与实施例2的制备方法相同，除了用1-氟-2-碘乙烷替代3-碘氧杂环丁烷，制得标题化合物99。
MS：m/z 479.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:9.00(s,2H)，8.76(s,1H),8.21(s,1H),8.10(s,1H),7.59(s,1H),7.00(s,1H),5.43-5.39(m,1H),5.02-4.74(m,4H),2.56(s,3H),1.76(d,J＝5.4Hz,3H)。
实施例100：(R)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1-(3,3,3-三氟丙基)-1H-吲唑-6-甲酰胺(100)的制备
Figure PCTCN2021120150-appb-000175
与实施例1的制备方法相同，除了用1,1,1-三氟-3-碘丙烷替代3-碘氧杂环丁烷，制得标题化合物100。
MS：m/z 529.10[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:9.05(s,2H)，8.75(s,1H),8.55(s,1H),8.21(s,1H),7.89(s,1H),7.77(s,1H),5.45-5.41(m,1H),4.72(t,J＝5.4Hz,2H),2.87-2.81(m,2H),2.67(s,3H),1.82(d,J＝5.4Hz,3H)。
实施例101：(R)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2-(3,3,3-三氟丙基)-2H-吲唑-6-甲酰胺(101)的制备
Figure PCTCN2021120150-appb-000176
与实施例2的制备方法相同，除了用1,1,1-三氟-3-碘丙烷替代3-碘氧杂环丁烷，制得标题化合物101。
MS：m/z 529.10[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:9.02(s,2H)，8.67(s,1H),8.34(s,1H),8.27(s,1H),7.65(s,1H),5.45-5.39(m,1H),4.74(t,J＝5.4Hz,2H),3.02-2.91(m,2H),2.60(s,3H),1.78(d,J＝5.4Hz,3H)。
实施例102：(R)-1-(3-氟丙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(102)的制备
Figure PCTCN2021120150-appb-000177
与实施例1的制备方法相同，除了用1-氟-3-碘丙烷替代3-碘氧杂环丁烷，制得标题化合物102。
MS：m/z 493.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:8.99(s,2H)，8.65(s,1H),8.12(s,1H),8.04(s,1H),7.66(s,1H),6.96(s,1H),5.46-5.39(m,1H),4.63-4.36(m,4H),2.60(s,3H),2.42-2.29(m,2H),1.78(d,J＝5.4Hz,3H)。
实施例103：(R)-2-(3-氟丙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(103)的制备
Figure PCTCN2021120150-appb-000178
与实施例2的制备方法相同，除了用1-氟-3-碘丙烷替代3-碘氧杂环丁烷，制得标题化合物103。
MS：m/z 493.10[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:8.98(s,2H)，8.73(s,1H),8.19(s,1H),8.06(s,1H),7.60(s,1H),6.88(s,1H),5.44-5.37(m,1H),4.67-4.40(m,4H),2.56(s,3H),2.52-2.39(m,2H),1.75(d,J＝5.4Hz,3H)。
实施例104：(R)-1-(2-氟-2-甲基丙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(104)的制备
Figure PCTCN2021120150-appb-000179
与实施例1的制备方法相同，除了用2-氟-2-甲基丙基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物104。
MS：m/z 507.20[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:9.03(s,2H),8.59(s,1H),8.48(s,1H),8.19(s,1H),7.72(s,1H),7.52(s,1H),5.43-5.38(m,1H),4.63(d,J＝15.9Hz,2H),2.63(s,3H),1.79(d,J＝5.4Hz,3H),1.40(dd,J 1＝15.9Hz,J 2＝2.1Hz,6H)。
实施例105：(R)-2-(2-氟-2-甲基丙基)-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(105)的制备
Figure PCTCN2021120150-appb-000180
与实施例2的制备方法相同，除了用2-氟-2-甲基丙基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物105。
MS：m/z 507.10[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:8.99(s,2H)，8.77(s,1H),8.22(s,1H),8.10(s,1H),7.61(s,1H),6.89(s,1H),5.45-5.38(m,1H),4.63(d,J＝15.9Hz,2H),2.57(s,3H),1.76(d,J＝5.1Hz,3H),1.40(d,J＝15.9Hz,6H)。
实施例106：(R)-4-(2-氟-2-甲基丙基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基))-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(106)的制备
Figure PCTCN2021120150-appb-000181
与实施例12的制备方法相同，除了用2-氟-2-甲基丙基4-甲基苯磺酸酯替代2-(溴甲基)四氢呋喃，制得标题化合物106。
MS：m/z 538.10[M+H] +。
1H NMR(300MHz,CDCl3)δppm:8.95(s,2H),8.51(s,1H),7.96(s,1H),7.63(s,1H),7.06(s,1H),5.38-5.31(m,1H),4.86(s,2H),4.33-4.16(m,2H),2.57(s,3H),1.73(d,J＝5.4Hz,3H)，1.43(dd,J 1＝15.9Hz,J 2＝4.8Hz,6H)。
实施例107：(R)-4-(5-甲基噻唑-2-基)-1-(2,2,2-三氟乙基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(107)的制备
Figure PCTCN2021120150-appb-000182
与实施例1的制备方法相同，除了用1,1,1-三氟-2-碘乙烷替代3-碘氧杂环丁烷，制得标题化合物107。
MS：m/z m/z 515.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm:9.00(s,2H),8.72(s,1H),8.23(s,1H),8.07(s,1H),7.67(s,1H),7.20(s,1H),5.46-5.41(m,1H),5.07-5.01(m,1H),2.61(s,3H),1.78(d,J＝6.8Hz,3H)。
实施例108：(R)-4-(5-甲基噻唑-2-基)-2-(2,2,2-三氟乙基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(108)的制备
Figure PCTCN2021120150-appb-000183
与实施例2的制备方法相同，除了用1,1,1-三氟-2-碘乙烷替代3-碘氧杂环丁烷，制得标题化合物108。
MS：m/z 515.00[M+H] +。
1H NMR(400MHz,CDCl3)δppm:9.02(s,2),8.70(s,1),8.37(s,1),8.12(s,1),7.72(s,1),7.36(s,1),5.45-5.42(m,1),5.06-5.02(m,2),2.63(s,3),1.79(d,J＝7.2Hz,3)。
实施例109：(R)-1-异丁基-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(109)的制备
Figure PCTCN2021120150-appb-000184
与实施例1的制备方法相同，除了用1-碘-2-甲基丙烷替代3-碘氧杂环丁烷，制得标题化合物109。
MS：m/z m/z 489.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm:9.04(s,2),8.59(s,1),8.50(s,1),8.40(s,1),7.70(s,1),7.52(s,1),5.51-5.34(m,1H),4.30(d,J＝7.3Hz,2H),2.62(s,3H),2.45(s,1H),1.79(d,J＝7.1Hz,3H),0.98(d,J＝7.2Hz,6H)。
实施例110：(R)-2-异丁基-4-(5-甲基噻唑-2-基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(110)的制备
Figure PCTCN2021120150-appb-000185
与实施例2的制备方法相同，除了用1-碘-2-甲基丙烷替代3-碘氧杂环丁烷，制得标题化合物110。
MS：m/z 489.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm:8.97(s,2H),8.59(s,1H),8.10(s,1H),8.05(s,1H),7.64(s,1H),7.09-7.07(m,1H),5.46-5.39(m,1H),4.25(d,J＝3.6Hz,2H),2.59(s,3H),2.42-2.32(m,1H),1.76(d,J＝7.2Hz,3H),0.92(d,J＝6.8Hz,6H)。
实施例111：(R)-8-(5-甲基噻唑-2-基)-3-氧代-4-(2,2,2-三氟乙基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基))-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(111)的制备
Figure PCTCN2021120150-appb-000186
与实施例12的制备方法相同，除了用1,1,1-三氟-2-碘乙烷替代2-(溴甲基)四氢呋喃，制得标题化合物111。
MS：m/z 545.90[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:9.14(s,1H),9.02(s,2H),7.94(s,1H),7.89(s,1H),7.78(s,1H),5.39-5.32(m,1H),4.95(s,2H),4.76-4.69(m,1H),4.67-4.59(m,1H),2.64(s,3H),1.80(d,J＝5.4Hz,3H)。
实施例112：(R)-4-异丁基-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(112)的制备
Figure PCTCN2021120150-appb-000187
与实施例12的制备方法相同，除了用1-碘-2-甲基丙烷替代2-(溴甲基)四氢呋喃，制得标题化合物112。
MS：m/z 520.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:8.98(s,2H),8.71(s,1H),7.74(s,1H),7.68(s,1H),7.44(s,1H),5.38-5.31(m,1H),4.86(s,2H),3.89(d,J＝6.0Hz,2H),2.60(s,3H),2.13-2.08(m,1H),1.77(d,J＝5.4Hz,2H),0.96(d,J＝4.8Hz,6H)。
实施例113：(R)-4-(5-甲基噻唑-2-基)-1-((1-(三氟甲基)环丙基)甲基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-1H-吲唑-6-甲酰胺(113)的制备
Figure PCTCN2021120150-appb-000188
与实施例1的制备方法相同，除了用(1-(三氟甲基)环丙基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物113。
MS：m/z m/z 555.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm:9.00(s,2H),8.63(s,1H),8.19(s,1H),8.08(s,1H),7.67(s,1H),7.1(s,1H),5.44-5.41(m,1H),4.77-4.67(m,2H),2.61(s,3H),1.78(d,J＝7.2Hz,3H),1.11-1.00(m,2H),0.86-0.84(m,2H)。
实施例114：(R)-4-(5-甲基噻唑-2-基)-2-((1-(三氟甲基)环丙基)甲基)-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-2H-吲唑-6-甲酰胺(114)的制备
Figure PCTCN2021120150-appb-000189
与实施例2的制备方法相同，除了用(1-(三氟甲基)环丙基)甲基4-甲基苯磺酸酯替代3-碘氧杂环丁烷，制得标题化合物114。
MS：m/z 555.00[M+H] +。
1H NMR(400MHz,CDCl 3)δppm:9.00(s,2H),8.72(s,1H),8.23(s,1H),8.19(s,1H),7.63(s,1H),7.04(s,1H),5.44-5.37(m,1H),4.71(s,2H),2.58(s,3H),1.76(d,J＝7.2Hz,3H),1.19-1.09(m,2H),0.88-0.83(m,2H)。
实施例115：(R)-8-(5-甲基噻唑-2-基)-3-氧代-4-((1-(三氟甲基)环丙基)甲基)-N-(1-(2-(三氟甲基)嘧啶-5-基))乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(115)的制备
Figure PCTCN2021120150-appb-000190
与实施例12的制备方法相同，除了用(1-(三氟甲基)环丙基)甲基4-甲基苯磺酸酯替代2-(溴甲基)四氢呋喃，制得标题化合物115。
MS：m/z 585.90[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:9.67(s,1H),9.07(s,2H),8.96(s,1H),8.09(s,1H),7.92(s,1H),5.36-5.35(m,1H),4.90(s,2H),4.43-4.33(m,2H),2.69(s,3H),1.82(d,J＝5.1Hz,3H),1.08-1.07(m,2H),0.92-0.90(m,2H)。
实施例116：(R)-4-(2,2-二氟丙基)-8-(5-甲基噻唑-2-基)-3-氧代-N-(1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(116)的制备
Figure PCTCN2021120150-appb-000191
与实施例12的制备方法相同，除了用2,2-二氟丙基4-甲基苯磺酸酯替代2-(溴甲基)四氢呋喃，制得标题化合物116。
MS：m/z 541.90[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:8.97(s,2H),8.63(s,1H),7.87(s,1H),7.65(s,1H),7.30-7.29(m,1H),5.39-5.32(m,1H),4.89(s,2H),4.54-4.34(m,2H),2.58(s,3H),1.75-1.64(m,6H)。
实施例117：4-(2-氟乙基)-2-甲基-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(117)的制备
Figure PCTCN2021120150-appb-000192
步骤1：4-(2-氟乙基)-2-甲基-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(117)的制备
于室温，将2-甲基-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(117a)(100mg，0.210mmol)(制备方法与实施例11的制备方法相同，除了用2-氯丙酰氯替代氯乙酰氯，制得中间体117a)、1-氟-2-碘乙烷(72.9mg，0.420mmol)和Cs 2CO 3(138mg，0.420mmol)溶于DMF(3mL)中，反应液在50℃搅拌过夜。反应液减压浓缩，向残余物中加入10mL水，用乙酸乙酯(15mL x 3)萃取。合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用制备液相色谱法分离(色谱柱型号：Daisogei30mm×250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得白色固体状标题化合物50.0mg，收率：45％。
MS：m/z 523.90[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:8.99(s,2H),8.79(s,1H),7.84(s,1H),7.70(s,1H),7.46(s,1H),5.37-5.34(m,1H),4.77-4.76(m,1H),4.67-4.66(m,1H),4.65-4.64(m,1H),4.36-4.22(m,2H),2.61(s,3H),1.77-1.72(m,6H)。
实施例118：4-(3-氟丙基)-2-甲基-8-(5-甲基噻唑-2-基)-3-氧代-N-((R)-1-(2-(三氟甲基)嘧啶-5-基)乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺(118)的制备
Figure PCTCN2021120150-appb-000193
与实施例117的制备方法相同，除了用1-氟-3-碘丙烷替代1-氟-2-碘乙烷，制得标题化合物118。
MS：m/z 538.00[M+H] +。
1H NMR(300MHz,CDCl 3)δppm:9.37(s,1H),9.05(s,2H),8.33(s,1H), 7.85-7.83(m,2H),5.36-5.34(m,1H),4.96-4.95(m,1H),4.60-4.58(m,1H),4.50-4.47(m,1H),4.20-4.17(m,2H),2.66(s,3H),2.13-2.25(m,2H),1.81(d,J＝5.1Hz,3H),1.71(d,J＝4.8Hz,3H)。
生物学评价
测试例1：本发明化合物对人P2X3受体抑制活性的评价
采用荧光成像读板仪(Fluorescence Image Plate Reader，FLIPR，Molecular Devices，0296)监测细胞内钙水平变化以评价本发明化合物对人P2X3受体抑制活性。
实验过程：复苏HEK293-pCMV6-P2X3细胞株(Pharmaron，Clone#34)，将其接种于完全培养基(DMEM，高葡萄糖(high glucose)(31053028，Gibco)+10％胎牛血清(FBS)(Gibco，10099141)+4mM GlutaMAX(Gibco，35050-061)+1×青霉素-链霉素，液体(100×，Gibco，15140-122)+350μg/ml遗传霉素(invitrogen，10131-027)中，在37℃，5％CO 2的培养箱中培养。待细胞培养至70％～90％融合度时，用胰蛋白酶(Thermofisher，12604021)消化细胞并重悬于细胞接种培养基(DMEM，高葡萄糖(31053028，Gibco)+2％胎牛血清(FBS)(Gibco，10099141)+4mM GlutaMAX(Gibco，35050-061))中，接种11000个细胞/孔/25μL至384孔细胞培养板(Corning，3845)中，在37℃，5％CO 2的培养箱中培养22小时。用实验缓冲液(1×HBSS(Gibco，14025076)+20mM HEPES(Gibco，15630080))将组分A(Component A)粉末(FLIPR Calcium 6 Assay Kit，Molecular Devices，R8191)稀释至2×工作浓度，平衡至室温待用。将384孔细胞培养板置于室温平衡10分钟，去除培养基，加入25μL实验缓冲液和25μL 2×组分A，室温200g离心3-5秒后，于37℃静置2小时。用实验缓冲液将α,β-MeATP(Sigma，M6517)稀释至2.1μΜ，转移50μL至384孔板中，置于室温待用。取出细胞培养板于室温静置10分钟，将待测化合物工作液(检测起始浓度为10000nM，利用细胞接种培养基3倍稀释，使DMSO终浓度为0.1％)加至384孔细胞培养板的相应实验孔中，于室温孵育30分钟。利用FLIPR Tetra(Molecular Devices，0296)将10μL稀释后的α,β-MeATP加入相应待测实验孔中，设置激发波长为470-495nm，发射波长为515-575nm检测荧光值，收集数据。
利用GraphPad四参数非线性拟合公式计算化合物IC 50：
Figure PCTCN2021120150-appb-000194
X：化合物浓度log值；Y：比例。
本发明化合物对P2X3受体的抑制活性如下表1所示。其中，A代表IC 50<200nM；B代表IC 50＝200-500nM；C代表IC 50＝500-1000nM；D代表IC 50>1000nM。
表1.本发明化合物对P2X3受体抑制IC 50值
化合物 P2X3 IC 50(nM)
实施例1 A
实施例2 B
实施例3 D
实施例4 D
实施例5 C
实施例6 C
实施例7 C
实施例8 A
实施例11 D
实施例12 A
实施例13 A
实施例14 D
实施例15 D
实施例16 C
实施例17 C
实施例18 A
实施例19 C
实施例20 A
实施例21 B
实施例22 A
实施例23 A
实施例24 A
实施例25 B
实施例26 B
实施例27 A
实施例28 A
实施例29 B
实施例30 C
实施例31 D
实施例32 D
实施例33 B
实施例34 B
实施例35 B
实施例36 A
实施例37 A
实施例38 B
实施例39 B
实施例40 A
实施例41 B
实施例42 A
实施例43 A
实施例44 B
实施例45 A
实施例46 B
实施例47 B
实施例48 A
实施例49 B
实施例50 A
实施例51 B
实施例52 B
实施例53 B
实施例54 B
实施例55 B
实施例56 C
实施例57 A
实施例58 A
实施例59 A
实施例60 A
实施例61 B
实施例62 B
实施例63 B
实施例64 D
实施例65 B
实施例66 B
实施例67 A
实施例68 A
实施例69 A
实施例70 B
实施例71 B
实施例72 B
实施例73 B
实施例74 A
实施例75 A
实施例76 D
实施例77 D
实施例78 A
实施例79 A
实施例80 A
实施例81 A
实施例82 B
实施例83 A
实施例84 A
实施例85 A
实施例86 A
实施例87 A
实施例88 B
实施例89 A
实施例90 A
实施例91 A
实施例92 A
实施例93 A
实施例94 A
实施例95 B
实施例96 B
实施例97 C
实施例98 A
实施例99 A
实施例100 A
实施例101 A
实施例102 A
实施例103 A
实施例104 A
实施例105 B
实施例106 B
实施例107 A
实施例108 A
实施例109 B
实施例110 A
实施例111 A
实施例112 A
实施例113 B
实施例114 B
实施例115 B
实施例116 A
实施例117 A
实施例118 A
结论：如上表1所述，本发明化合物显示出显著的P2X3受体拮抗活性。
测试例2：体外P2X2/3受体选择性评价
利用荧光成像读板仪(Fluorescence image plate reader，FLIPR，Molecular Devices，0296)法进行本发明中化合物对P2X2/3受体的选择性测定，监测细胞内钙水平变化以评价本发明化合物对人P2X2/3受体抑制活性。
实验过程：复苏HEK293/hP2X2/X3细胞株(Bioduro clone#164)，将细胞接种于用1X基质胶(BD Bioscience，354230)5μL/孔包被的384孔板中。37℃，5％CO2培养箱孵育30分钟。然后处理细胞，去除培养液(DMEM，高葡萄糖(31053028，Gibco)+10％FBS+4mM GlutaMAX+1X PS+350μg/ml G418)，PBS洗涤一次，用0.25％Trypsin-EDTA(Invitrogen，25200056)消化细胞，调整细胞密度为7.5X10 5/mL。将稀释好的细胞加入384孔检测板(Corning，3709)中，20μL/孔。将板子置于37℃，5％CO 2培养箱中孵育过夜。弃去384孔检测板中细胞培养基，加入20μ0/孔新鲜制备的Fluo-8缓冲液(AAT Bioquest，21080)。37℃、5％CO 2培养箱中避光孵育1小时。
制备不同浓度的化合物(10μM为起始浓度，3倍连续倍比稀释，共10个浓度)，向384孔检测板中加入5μL/孔。37℃，5％CO 2培养箱中孵育30分钟。制备6X EC80的αββC80入化(TOCRIS，3209)，利用FLIPR将5μL/孔加入384孔检测板，收集数据。
本发明化合物对P2X3/3受体的抑制活性如下表2所示。其中，A代表IC 50＞10000nM；B代表IC 50＝10000-1000nM；C代表IC 50＝1000-100nM；D代表IC 50＜100nM。
表2.本发明化合物对P2X2/3受体抑制IC 50值
化合物 P2X2/3 IC 50(nM)
实施例21 A
实施例60 A
结论：如上表2所述，本发明化合物显示出对P2X2/3受体没有明显的拮抗活性，本发明中其他实施例也未见对P2X2/3具有明显拮抗作用。
测试例3：本发明化合物对ATP-柠檬酸豚鼠急性咳嗽模型的疗效
动物：Dunkin Hartley豚鼠，雄性，250-400g。购于北京市芳缘源养殖场，普通级，动物生产许可证号：SCXK(京)2020-0001。
实验过程：选用雄性豚鼠56只，分为模型对照组、实施例21组、实施例80组、实施例81组、实施例93组、实施例98组、实施例116组，每组8只。激发豚鼠咳嗽前45分钟，各组给予40mg/kg相应药物。首先采用2mg/mL ATP(Sigma)溶液超声雾化吸入致敏豚鼠1分钟，待其出现咳嗽后迅速拿出，自由活动3分钟。5分钟后用2M柠檬酸溶液雾化吸入引咳5分钟。自柠檬酸雾化开始，观察豚鼠5分钟内的咳嗽潜伏期及咳嗽次数，根据豚鼠咳嗽潜伏期及咳嗽次数，评价本发明化合物对豚鼠咳嗽模型的镇咳作用。
本发明化合物对ATP-柠檬酸豚鼠急性咳嗽模型疗效如下表3所示。
表3.豚鼠咳嗽潜伏期变化表
Figure PCTCN2021120150-appb-000195
注： *：P<0.05v.s模型组； **：P<0.01v.s模型组，T-test。咳嗽抑制率(％)＝(模型组平均咳嗽次数-给药组平均咳嗽次数)/模型组平均咳嗽次数*100％。
结论：如上表3所述，本发明化合物均可明显降低咳嗽次数，延长平均咳嗽潜伏期。
测试例4：药代动力学
动物：Wistar雄性大鼠，180-220g，7-8周龄，购于北京市维通利华实验动物技术有限公司，SPF级，动物生产许可证号：SCXK(京)2016-0011。
实验过程：口服剂量为3mg/kg。动物采用吸入麻醉，麻醉参数：流速：1.0L/min， 氧气压力：0.1MPa，溶度：4.5％，麻醉用时：3分钟。动物麻醉后眼眶采血0.5mL，采血管预先按10mg/mL肝素锂与血浆体积比为1：10加入，抗凝。将血液与抗凝剂混合均匀后，3000rpm/min离心，离心10分钟，取上层血浆，冻存到-20℃冰箱内，备用。取动物血浆样品50μL置于1.5ml EP管中，加入内标工作液5μL，涡旋60秒充分混匀。涡旋后加入0.2mL乙腈，涡旋剧烈震荡1分钟，16000rpm离心10分钟。移取上清液0.2mL，用0.22μm滤膜过滤后加入进样小瓶中待测。质谱条件(Waters，TQ-S micro)下分离测定，记录各待测样品及内标峰面积。
LC/MS/MS参数：
流动相A：0.1％甲酸乙腈
流动相B：0.1％甲酸水
色谱柱：Waters UPLC C18 1.7μm，2.1*50mm
梯度：
Figure PCTCN2021120150-appb-000196
应用数据处理软件，对待测物和内标物进行积分，得出峰面积。以待测物浓度(x)为横坐标，待测物与内标物的峰面积比值(y)为纵坐标，用加权最小二乘法(权重为1/x 2)进行回归运算，求得的直线回归方程即为血浆校正曲线。采用DAS进行统计分析。获得各种药代参数、药时曲线。
表4.本发明化合物药代动力学参数
Figure PCTCN2021120150-appb-000197
Figure PCTCN2021120150-appb-000198
结论：如上表4所述，本发明化合物具有良好的药代动力学性质。

Claims (19)

  1. 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2021120150-appb-100001
    其中：
    A环为5元杂芳基；
    Figure PCTCN2021120150-appb-100002
    选自：
    Figure PCTCN2021120150-appb-100003
    Figure PCTCN2021120150-appb-100004
    Figure PCTCN2021120150-appb-100005
    其中B环各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基中的一个或多个基团取代；
    W 1和W 2各自独立地选自CR 6或N；
    L 1为
    Figure PCTCN2021120150-appb-100006
    L 2选自单键、
    Figure PCTCN2021120150-appb-100007
    -CO-、-O-、-S-、-SO-、-SO 2-和-NR 6-；
    每一个R 1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O pR a、-S(O) pNR aR b和-NHS(O) pR a，其中所述烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔 基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
    R 2选自芳基和杂芳基；所述芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基中的一个或多个基团取代；
    R 3选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) pR a、-S(O) pNR aR b和-NHS(O) pR a，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NHC(O)R a、-S(O) pR a、-S(O) pNR aR b和-NHS(O) pR a中的一个或多个基团取代；
    R 4和R 5各自独立地选自氢、烷基和烷氧基，其中所述烷基和烷氧基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
    每一个R 4’和R 5’各自独立地选自氢、烷基和烷氧基，其中所述烷基和烷氧基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
    R 6选自氢、卤素、羟基、氰基、氨基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
    R a和R b各自独立地选自氢、卤素、羟基、氰基、氨基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
    或者R a和R b与他们连接的原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代；
    p为0、1、2；
    m为1至4的整数；且
    n为0至3的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，
    A环选自吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噻唑基、噁唑基、异噻唑基、异噁唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、1,3,4-噻二唑基、1,2,4-噻二唑基、三唑基和四唑基，优选吡唑基、噻唑基、噁唑基和1,3,4-噁二唑基，更优选噻唑基。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2021120150-appb-100008
    其中，B环、R 1、R 2、R 3、L 1、L 2和n如权利要求1所定义。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
    其中，
    Figure PCTCN2021120150-appb-100009
    选自：
    Figure PCTCN2021120150-appb-100010
    Figure PCTCN2021120150-appb-100011
    其中所述B环各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基中的一个或多个基团取代；
    其中，W 1、W 2、L 2、R 3如权利要求1所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，L 2选自单键、-(CH 2) m-、-(CH)CH 3-、-CO-、-SO-和-SO 2-；
    m为1至4的整数，优选1至3的整数，更优选1或2。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，
    R 3选自氢、卤素、氰基、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7环烷基、4至7元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7环烷基、4至7元杂环基、C 6-C 10芳基和5至10元杂芳基各自独立地任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 6环烷基、4至6元杂环基、C 6-C 10芳基、5至10元杂芳基、-C(O)R a、-C(O)OR a、-S(O) pR a中的一个或多个基团取代；
    R a选自C 1-C 6烷基；
    p为1或2。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    L 2选自单键、-(CH 2) m-和-CO-；
    R 3选自4至6元杂环基，其中所述4至6元杂环基任选进一步被选自卤素、氧代基、C 1-C 6烷基、-C(O)OR a的一个或多个基团取代；
    R a选自C 1-C 6烷基；
    m为1或2。
  8. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    L 2选自单键、-CH 2-和-CO-；
    R 3选自C 3-C 6环烷基，所述C 3-C 6环烷基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基中的一个或多个基团取代。
  9. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    L 2选自单键、-CH 2-和-CO-；
    R 3选自苯基或5至6元杂芳基，所述苯基或5至6元杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代。
  10. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    L 2选自单键、-(CH 2) m-和-(CH)CH 3-；
    R 3选自氰基、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 2-C 6烯基、C 2-C 6炔基，所述C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基任选进一步被选自卤素、羟基中的一个或多个基团取代；
    m为1至4的整数，优选1至3的整数，更优选1或2。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，
    L 1为
    Figure PCTCN2021120150-appb-100012
    R 4和R 5各自独立地选自氢和C 1-C 6烷基；
    优选地，L 1为
    Figure PCTCN2021120150-appb-100013
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，
    每一个R 1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基、C 3-C 7环烷基和5至7元杂环基，优选C 1-C 6烷基或C 1-C 6卤代烷基。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，
    R 2为C 6-C 10芳基或5至10元杂芳基，优选苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基，更优选嘧啶基，所述芳基或杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基和C 1-C 6卤代烷氧基中的一个或多个基团取代。
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中所述化合物选自：
    Figure PCTCN2021120150-appb-100014
    Figure PCTCN2021120150-appb-100015
    Figure PCTCN2021120150-appb-100016
    Figure PCTCN2021120150-appb-100017
    Figure PCTCN2021120150-appb-100018
    Figure PCTCN2021120150-appb-100019
  15. 一种制备根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
    Figure PCTCN2021120150-appb-100020
    在缩合剂存在下，化合物Ig与化合物Ih在碱性条件下进行缩合反应得到通式(I)所示的化合物，其中，提供碱性条件的试剂优选DIPEA，缩合剂优选为HATU；
    其中，A环、B环、W 1、W 2、R 1、R 2、R 3、L 1、L 2、n如前述权利要求中任一项所定义。
  16. 一种药物组合物，其含有根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体。
  17. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或 者根据权利要求16所述的药物组合物在制备P2X3受体拮抗剂中的用途。
  18. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求16所述的药物组合物在制备预防和/或治疗与P2X3受体活性相关的疾病的药物中的用途。
  19. 根据权利要求18所述的用途，其中所述与P2X3受体活性相关的疾病选自呼吸系统疾病、泌尿生殖系统疾病、消化系统疾病、神经系统疾病、肌肉骨骼系统疾病、循环系统疾病和疼痛；所述呼吸系统疾病优选选自慢性阻塞性肺病、肺气肿、哮喘、支气管痉挛、肺纤维化、急性咳嗽和慢性咳嗽；所述泌尿生殖系统疾病优选选自子宫内膜异位症、子宫肌瘤、痛经、盆腔炎性疾病、尿道炎、膀胱炎、膀胱过度活动症、尿失禁、前列腺增生、前列腺炎、睾丸炎和性交困难；所述消化系统疾病优选选自肠易激综合征、溃疡性结肠炎、克罗恩病、胆绞痛和其他胆道疾病、功能性肠病、胃食管反流、胃扩张和结肠扩张；所述神经系统疾病优选选自癫痫、神经炎、神经病、阿尔茨海默病和帕金森病；所述肌肉骨骼系统疾病优选选自痛风、关节炎如骨关节炎、类风湿关节炎和强直性脊柱炎；所述循环系统疾病优选选自脑缺血、创伤性脑损伤和心肌梗塞。
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