WO2021227439A1 - 一种芳基葡糖苷衍生物 - Google Patents

一种芳基葡糖苷衍生物 Download PDF

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WO2021227439A1
WO2021227439A1 PCT/CN2020/131248 CN2020131248W WO2021227439A1 WO 2021227439 A1 WO2021227439 A1 WO 2021227439A1 CN 2020131248 W CN2020131248 W CN 2020131248W WO 2021227439 A1 WO2021227439 A1 WO 2021227439A1
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alkyl
hydrogen
halogen
deuterium
substituted
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PCT/CN2020/131248
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English (en)
French (fr)
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王海波
杜锋田
张强
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上海喆邺生物科技有限公司
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Priority to CN202080073121.2A priority Critical patent/CN114599643B/zh
Priority to EP20935121.2A priority patent/EP4166547A1/en
Priority to US18/023,878 priority patent/US20230365610A1/en
Publication of WO2021227439A1 publication Critical patent/WO2021227439A1/zh

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    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical

Definitions

  • the present invention relates to a sodium-glucose cotransporter 1 (SGLT1) inhibitor, a drug synthesis method containing their composition, and their use in the treatment of metabolic diseases, especially type 2 diabetes.
  • SGLT1 sodium-glucose cotransporter 1
  • Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological effects, or both.
  • the long-term high blood sugar in diabetes causes chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves.
  • the incidence of diabetes in adults over 18 years of age was greater than 9%. As the population increases, ages, and life expectancy increases, the incidence of diabetes will increase. Among obese people, the incidence of diabetes is higher. According to forecasts, by 2030, diabetes will become the seventh leading cause of death.
  • Sodium-dependent glucose transporters (SGLT) inhibitors can inhibit the reabsorption of glucose by the kidneys, excrete excess glucose from the urine, and lower blood sugar. It provides a new way for the treatment of diabetes and has become a hot spot in the research of hypoglycemic drugs. Based on the structure of Plorizin, in the past decades, new target drugs have been developed for the treatment of diabetes.
  • SGLT Sodium-dependent glucose transporters
  • the SGLT family is composed of some subtypes, which act as the transport of sugars on the cell membrane. This process combines with sodium ion transporters.
  • SGLT1 is mainly expressed in the gastrointestinal tract and is mainly responsible for the absorption of glucose and galactose in the small intestine.
  • SGLT1 is also present in the proximal tubules of the kidney, where it contributes to the reabsorption of blood sugar. By inhibiting SGLT1, it prevents the absorption and utilization of blood sugar, thereby achieving the goal of lowering blood sugar levels.
  • SGLT1 inhibition may also provide an alternative therapy for blood sugar control. Improving blood sugar control through SGLT1 inhibition is very attractive because this effect can be independent of kidney function.
  • the current selective inhibitors of SGLT2 lack efficacy in patients with moderate to severe renal injury, and patients with moderate to severe renal injury account for about 30-40% of all diabetic patients. Inhibition of intestinal SGLT1 can achieve the potential effect of blood sugar control. Through this effect, the diabetes-related side effects of SGLT2 inhibitors, especially genital infections, can also be avoided.
  • the present invention provides a compound of formula (V), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • U, V, W and Q are each independently selected from nitrogen atom or CH;
  • Each R 1a , R 1b , R 1c is independently selected from halogen or -OR 1A , -NHR 1A , wherein each R 1A is independently hydrogen, C1-C6 alkyl or acyl;
  • R 2 is selected from -S(O) m -R 1A ;
  • Each of R 3 , R 4 , R 5 , R 6a , R 7a , R 6b , R 7b , R 6c , and R 7c is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl; or R 6a And R 7a , R 6b and R 7b , R 6c and R 7c can form a 3-8 membered carbocyclic ring together with the carbon atoms connected to them, respectively, wherein the carbocyclic ring can be hydrogen, halogen, C1-6 alkyl, halogen Substitute C1 ⁇ C6 alkyl substitution;
  • R A and R B are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo , C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -SR aa , -(CH 2 ) n1 C(O)R aa , -SR aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH 2 ) n1 S( O) m1 R aa , -NR aa R bb ,
  • R A and R B together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocyclic ring.
  • the heterocyclic ring may contain one or more carbon atoms, nitrogen atoms, oxygen atoms or sulfur atoms.
  • the heterocyclic ring may be further halogenated. , Alkyl, cycloalkyl, aryl, alkoxy, alkenyl, alkynyl or oxo substituted;
  • R aa and R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Alkyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy Alkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, silyl , Alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or un
  • Z is selected from oxygen atom or sulfur atom
  • n1 0,1,2,3,4;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y is a linking group, selected from the following structures:
  • R E , R F , R G , and R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • E and J are independently selected from chemical bonds, -CH 2 -, oxygen, -NH-;
  • the present invention provides a compound of formula (VA), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1a , R 1b , and R 1c are each independently selected from halogen or -OR 1A , -NHR 1A , wherein R 1A is independently hydrogen, C1-C6 alkyl or acyl;
  • R 2 is selected from -S(O) m -R 1A ;
  • R 3 , R 4 , R 5 , R 6b , R 7b , R 6c , R 7c is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl; or R 6b and R 7b , R 6c And R 7c can respectively form a 3-8 membered carbocyclic ring together with the carbon atoms to which they are connected, wherein the carbocyclic ring can be substituted by hydrogen, halogen, C1-6 alkyl, and halogenated C1-C6 alkyl;
  • R A and R B are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo , C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -SR aa , -(CH 2 ) n1 C(O)R aa , -SR aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH 2 ) n1 S( O) m1 R aa , -NR aa R bb ,
  • R A and R B together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocyclic ring.
  • the heterocyclic ring may contain one or more carbon atoms, nitrogen atoms, oxygen atoms or sulfur atoms.
  • the heterocyclic ring may be further halogenated. , Alkyl, cycloalkyl, aryl, alkoxy, alkenyl, alkynyl or oxo substituted;
  • R aa and R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Alkyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy Alkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, silyl , Alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or un
  • n1 0,1,2,3,4;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y is a linking group, selected from the following structures:
  • R E , R F , R G , and R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • E and J are independently selected from chemical bonds, -CH 2 -, oxygen, -NH-;
  • the present invention provides a compound of formula (VA-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • R 6b , R 7b , R 6c , and R 7c is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl; or R 6b and R 7b , R 6c and R 7c can be connected together with them, respectively The carbon atoms of together form a 3- to 8-membered carbocyclic ring, wherein the carbocyclic ring can be substituted by hydrogen, halogen, C1-6 alkyl, and halogenated C1-C6 alkyl;
  • R A and R B are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo , C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -SR aa , -(CH 2 ) n1 C(O)R aa , -SR aa , -C(O)OR aa , -C(O)R aa , -S(O) m1 R aa , -(CH 2 ) n1 S( O) m1 R aa , -NR aa R bb ,
  • R aa and R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino, alkene Alkyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy Alkyl, haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, silyl , Alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or un
  • n1 0,1,2,3,4;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y is a linking group, selected from the following structures:
  • the present invention provides the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts,
  • the present invention provides a compound of formula (VA-2), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • R 6b , R 7b , R 6c , and R 7c is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl; or R 6b and R 7b , R 6c and R 7c can be connected together with them, respectively The carbon atoms of together form a 3- to 8-membered carbocyclic ring, wherein the carbocyclic ring can be substituted by hydrogen, halogen, C1-6 alkyl, and halogenated C1-C6 alkyl;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Ring B is selected from the following structures:
  • Z 1 and Z 2 are selected from oxygen atom and sulfur atom;
  • T is a chemical bond, an oxygen atom, -NR 7h , a substituted or unsubstituted carbon atom, where the substituent includes hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • R d1 , R d2 , R e1 , R e2 , R f1 , R f2 , R g1 , R g2 , and R 7h is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • Y is a linking group, selected from the following structures:
  • the present invention provides the following compounds, their stereoisomers, tautomers, and pharmaceutically acceptable salts,
  • the present invention provides a compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • n2 0,1,2,3;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y is a linking group, which is 2-17 linking arms composed of carbon, oxygen, and nitrogen atoms;
  • Z is O or S.
  • the present invention provides a compound of formula (I-1), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1a , R 1b , and R 1c are each independently selected from F or -OR 1A , -NHR 1A , wherein R 1A is independently hydrogen, C1-C6 alkyl or acyl;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, cycloalkyl, cycloalkylalkyl or acyl , Alkynylalkyl;
  • n2 0,1,2,3;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y1 is a linking group, selected from the following structures:
  • R E , R F , R G , and R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • E and J are independently selected from chemical bonds, -CH 2 -, oxygen, -NH-;
  • the present invention provides the compound of formula (I), including the compound of the following general structure (II), its stereoisomers, tautomers or pharmaceutically acceptable salts,
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • n2 1;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y is a linking group, which is 2-17 linking arms composed of carbon, oxygen, and nitrogen atoms.
  • the present invention provides the compound of formula (I), including the compound of the following general structure (II-1), its stereoisomers, tautomers or pharmaceutically acceptable salts,
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl, cycloalkyl, cycloalkylalkyl or acyl, alkynylalkyl;
  • n2 1;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y1 is a linking group, selected from the following structures:
  • R E , R F , R G , and R H are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • E and J are independently selected from chemical bonds, -CH 2 -, oxygen, -NH-;
  • the present invention provides the compound of formula (II), including the compound of the following general structure (III), its stereoisomers, tautomers or pharmaceutically acceptable salts,
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • R 8 and R 9 are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;
  • n2 1;
  • X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;
  • Y 1 is a linking group, which is 2-17 linking arms composed of carbon, oxygen, and nitrogen atoms, and is selected from the following structures:
  • the present invention provides the compound of formula (III), wherein X is selected from hydrogen, deuterium, fluorine, bromine, iodine, methyl, ethyl, vinyl, and ethynyl.
  • the present invention provides the compound of formula (III), wherein R 9 is selected from hydrogen, deuterium, fluorine, bromine, iodine, methyl, ethyl, C3-C8 cycloalkyl, vinyl, and ethynyl.
  • the present invention provides the following compounds, including the following structural compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
  • the compound according to any one of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention is prepared for the treatment and improvement of diabetes, cardiovascular and cerebrovascular diseases, weight reduction, fatty liver, and metabolic related diseases. And application in tumor treatment.
  • the compound according to any one of the present invention or its pharmaceutically acceptable salt or the pharmaceutical composition according to the present invention is used in the preparation of drugs or drugs for the treatment of diseases related to the function of SGLT1/SGLT2.
  • the patient has taken or is currently taking other therapeutic drugs, including blood pressure lowering drugs, blood lipid lowering drugs, antidiabetic drugs, blood sugar lowering drugs, weight loss drugs or appetite suppressants.
  • blood pressure lowering drugs including blood pressure lowering drugs, blood lipid lowering drugs, antidiabetic drugs, blood sugar lowering drugs, weight loss drugs or appetite suppressants.
  • FIG. 1 Glucose tolerance (OGTT) test results after 14 days of continuous administration in rats
  • FIG. 1 Glucose tolerance (OGTT) test results on the 6th day after 5 consecutive days of administration in mice
  • halogen refers herein to -F, -Cl, -Br and -I.
  • fluorine refers to -F herein; the term “chloro” refers to -Cl herein; the term “bromo” refers to -Br herein; and the term “iodine” refers to -I herein.
  • cyano refers herein to -CN.
  • amino refers herein to -NH 2 .
  • hydroxyl refers herein to -OH.
  • nitro refers herein to -NO 2 .
  • linking arm refers to a chemical structure selected from 2-17 consisting of carbon, oxygen, and nitrogen atoms with a linking function. Specifically refers to linear or branched alkane structures (including saturated alkanes, alkenes and alkynes) or similar alkane structures with a carbonyl group at one end; where any carbon atom can be oxygen atom under the premise of forming a stable chemical structure.
  • the nitrogen atom can be replaced by a substituent, and the substituent includes: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide , Ester group, amino group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • the "connecting arm" described herein includes, but is not limited to, the following chemical structures:
  • aryl refers to a 6 to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic group with a conjugated ⁇ -electron system (i.e., with A ring) group with adjacent pairs of carbon atoms.
  • the aryl group can be covalently attached to the defined chemical structure on any carbon atom that results in a stable structure.
  • aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide Groups, ester groups, amino groups, sulfonyl groups, sulfinyl groups, cycloalkyl groups, cycloalkenyl groups, heterocycloalkyl groups, alkenyl groups, alkynyl groups and cycloalkoxy groups.
  • heteroaryl refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O or S.
  • the term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple condensed rings (non-limiting examples include benzothiophene, benzofuran , Indole, isoindole, etc.), where the fused ring may or may not be an aromatic group containing heteroatoms, assuming that the point of attachment is through an atom of the aromatic heteroaryl group.
  • heteroaryl groups described herein may be optionally substituted by one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy Group, amido group, ester group, amino group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • cycloalkyl herein refers to a cyclic alkyl group having 3 to 10 carbon atoms and having a single ring or multiple rings (including fused rings, bridged rings, and spiro ring systems).
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, oxo, alkoxy , Acyl, acyloxy, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl .
  • heterocyclic group refers to a substituted or unsubstituted saturated or unsaturated aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S.
  • the non-aromatic ring, the aromatic ring, and the non-aromatic ring may be 3- to 10-membered monocyclic ring, 4- to 20-membered spiro ring, concatenated or bridged ring, and optionally substituted N, S in heterocyclyl ring can be oxidized to various oxidation states. It is preferably a 3- to 12-membered heterocyclic ring.
  • Non-limiting examples include oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxanyl, oxetanyl, aziridinyl, azetidine Group, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1 ,3-dioxyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazoly
  • heterocycloalkyl refers to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N and S and optionally one or more double bonds or triple bonds.
  • the heterocycloalkyl group as a whole may have 3 to 10 ring atoms.
  • the heterocycloalkyl group can be covalently attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure.
  • Non-limiting examples of heterocycloalkyl groups include: pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl and the like.
  • heterocycloalkyl group can be oxidized (for example, morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide).
  • Heterocycloalkyl groups may also contain one or more oxo groups, such as phthalimido, piperidinonyl, oxazolidinonyl, 2,4(1H,3H)-dioxo-pyrimidinyl , Pyridine-2(1H)-keto and so on.
  • heterocycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxygen Generation, acyl, acyloxy, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl base.
  • alkenyl herein refers to an alkenyl group having 2 to 8 carbon atoms and having at least one site of alkenyl unsaturation.
  • alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, and the like.
  • alkenyl groups described herein may be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl , Amide group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, cycloalkoxy group, mercapto group, alkyl mercapto group, deuterated alkyl mercapto group, sulfone group, Sulfoxide, amino, silyl, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester group.
  • substituents deuterium, fluorine, chlorine, bromine, iodine,
  • alkynyl refers herein to an alkyl group in which two adjacent carbon atoms are connected by a triple bond, where the alkyl group is as defined herein.
  • Alkynyl refers to an unsaturated alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl , Carboxy, amino, alkyl, alkoxy, acyl, amide, ester, amino, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, Alkyl mercapto, deuterated alkyl mercapto, sulfone, sulfoxide, amino, silyl, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, aryl Alkyl, ester group.
  • groups which are independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl , Carboxy
  • alkyl herein refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and the term includes straight chain and branched chain hydrocarbon groups.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and the like.
  • alkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, acyl Oxy, oxo, amide, ester, amino, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, Aryloxy, heteroaryloxy, aryl or heteroaryl.
  • heteroalkyl refers herein to an alkyl group that includes at least one heteroatom.
  • alkoxy refers herein to an alkyl group attached to the rest of the molecule through an oxygen atom (-O-alkyl), where the alkyl group is as defined herein.
  • alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n Pentyloxy and so on.
  • amido herein refers to -NR 8 -C(O)-alkyl, -NR 8 -C(O)-cycloalkyl, -NR 8 -C(O)-cycloalkenyl, -NR 8 -C(O)-aryl, -NR 8 -C(O)-heteroaryl and -NR 8 -C(O)-heterocycloalkyl, where R 8 is hydrogen, cycloalkyl, cycloalkenyl , Aryl, heteroaryl, heterocycloalkyl and alkyl.
  • the hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl groups are as defined herein.
  • acyl refers herein to HC(O)-, R 9 R 10 NC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C( O)-, heterocycloalkyl-C(O)-, aryl-C(O)- and heteroaryl-C(O)-, wherein said R 9 and R 10 are each independently selected from hydrogen and hydroxyl , Alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • the hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, and cycloalkyl groups are as defined herein.
  • oxo group refers to the description of the oxidation state of an oxygen atom to a carbon atom, a nitrogen atom, a sulfur atom, etc.
  • the representative structure formed includes but not Limited to functional group structures such as hydroxyl, alkoxy, carbonyl, nitrogen oxide, sulfoxide, sulfone, etc.
  • sulfonyl refers herein to R 11 R 12 NS(O) 2 -, cycloalkyl-S(O) 2 -, cycloalkenyl-S(O) 2 -, aryl-S(O) 2 -, heteroaryl-S(O) 2 -, heterocycloalkyl-S(O) 2 -and alkyl-S(O) 2 -, wherein said R 11 and R 12 are each independently selected from hydrogen , Hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • the hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, and cycloalkyl groups are as defined herein.
  • sulfinyl refers herein to R 13 R 14 NS(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, aryl-S(O)-, Heteroaryl-S(O)-, heterocycloalkyl-S(O)- or alkyl-S(O)-, wherein said R 13 and R 14 are each independently selected from hydrogen, hydroxyl, alkyl, Heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • the hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl, and cycloalkyl groups are as defined herein.
  • acyloxy herein refers to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-cycloalkenyl, -OC(O)-aryl,- OC(O)-heteroaryl and -OC(O)-heterocycloalkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl groups are as described herein As defined in.
  • ester group refers herein to alkyl-OC(O)-, cycloalkyl-OC(O)-, cycloalkenyl-OC(O)-, heterocycloalkyl-OC(O)-, Aryl-OC(O)- and heteroaryl-OC(O)-, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups are as described herein Defined.
  • any substituent is mono- or poly-substituted by a designated substituent to the degree that such mono- or poly-substitution (including multiple substitutions in the same part) is chemically permissible, and each substituent may It is located at any available position on the group, and can be connected through any available atom on the substituent.
  • Any available position refers to any position on the group that can be chemically obtained by methods known in the art or methods taught herein, and does not produce excessively unstable molecules.
  • the substituents of the compounds of the present invention are disclosed in the form of groups or ranges. This specifically means that the present invention includes each member of such groups and ranges or subcombinations of each individual in the members.
  • C 1-6 alkyl specifically means that a methyl group, an ethyl group, a C 3 alkyl group, a C 4 alkyl group, a C 5 alkyl group and a C 6 alkyl group are separately disclosed.
  • compounds of the present invention refers to compounds of formula (I) and formula (II) and all pure and mixed stereoisomers, geometric isomers, tautomers Body, solvate, prodrug and isotope-labeled compound and any pharmaceutically acceptable salt.
  • the solvate of the compound of the present invention refers to a compound or a salt thereof combined with a stoichiometric and non-stoichiometric solvent, such as hydrate, ethanolate, methanolate, acetonate and the like.
  • Compounds can also exist in one or more crystalline states, i.e. as co-crystals, polymorphs, or they can exist as amorphous solids. All such forms are covered by the claims.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal to be treated with it.
  • stereoisomers herein refers to compounds having one or more stereocenters with different chirality, including enantiomers and diastereomers.
  • tautomers in this context means that structural isomers with different energies can cross the low energy barrier and thus convert into each other.
  • Valence tautomers include some bond-forming electrons that recombine and undergo interconversion.
  • prodrug herein refers to any derivative of the compound of the present invention that can directly or indirectly provide the compound of the present invention, its active metabolite or residue when administered to a subject. Especially preferred are those derivatives or prodrugs that can increase the bioavailability of the compounds of the present invention, improve metabolic stability and tissue targeting.
  • the compounds of the present invention can be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, ethanesulfonate, hydrogen sulfate Salt, butyrate, camphorate, camphor sulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, half Sulfate, heptanoate, caproate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, Ethylsulfonate, hydrochloride, 2-naphthalenes
  • basic nitrogen-containing groups can undergo quaternization with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including methyl, ethyl, propyl and butyl chlorides, bromides and iodine Compounds; such as dialkyl sulfates, including dimethyl, diethyl, dibutyl and dipentyl sulfates; such as long-chain halides, including decyl, lauryl, myristyl and stearyl Chlorides, bromides and iodides; such as aralkyl halides, such as benzyl and phenethyl bromides.
  • lower alkyl halides including methyl, ethyl, propyl and butyl chlorides, bromides and iodine Compounds
  • dialkyl sulfates including dimethyl, diethyl, dibutyl and dipentyl sulfates
  • the present invention also includes isotopically labeled compounds of the present invention, which have the same structure as disclosed above, but one or more atoms in the structure are replaced by atoms having the same number of protons but different numbers of neutrons.
  • isotopes incorporating the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I and so on.
  • the compounds of the present invention are all within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as those labeled with 3 H or 14 C, can be used in drug tissue distribution tests. Therefore, these 3 H or 14 C isotopes are particularly preferred due to their ease of preparation and detection.
  • some of the compounds of the present invention replaced by heavier isotopes such as 2 H have certain therapeutic advantages due to their better metabolic stability, such as increased half-life in the body and lower doses. Therefore, 2 H is in a certain It is also preferable in some cases.
  • a method for preparing a compound of formula (I) according to any one of claims 1 to 6, its stereoisomer, tautomer or pharmaceutically acceptable salt comprises the following steps, Scheme 2 :
  • the compounds provided by the present invention can be prepared by standard synthetic methods known in the art, and this specification provides general methods for preparing the compounds of the present invention.
  • Starting materials are usually commercially available, for example through Alfa TCI, It can be purchased from Shaoyuan Chemical, Anaiji Chemical and other companies, or prepared by methods well known to those skilled in the art.
  • the structures of the following example compounds were characterized by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the starting materials, intermediates and the example compounds can be separated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (such as column chromatography, TLC separation and purification, etc.).
  • TLC uses HSGF254 thin-layer chromatography silica gel plates (0.2 ⁇ 0.03mm), and TLC separation and purification uses HSGF254 thin-layer chromatography thick preparation plates (0.9-1mm).
  • Column chromatography uses 300-400 mesh silica gel as a carrier.
  • reaction conditions reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration
  • reaction temperature reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration
  • reaction solvent molar ratio of reactants or/and reaction duration
  • the progress of the reaction can be monitored by TLC, and an appropriate time can be selected accordingly to terminate the reaction and carry out post-treatment.
  • the purification conditions of the compound may also change.
  • an appropriate column chromatography eluent is selected according to the R f value of TLC, or the corresponding compound is separated and purified by preparative TLC.
  • reaction solution was poured into 1M dilute hydrochloric acid, separated, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was passed through the column layer After purification, 23.1 g of colorless liquid was obtained.
  • reaction solution was cooled to 0°C, saturated aqueous sodium bicarbonate solution was slowly added until no bubbles were generated, ethyl acetate extracted 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Column chromatography (petroleum ether elution) to obtain 18.5 g of white solid.
  • reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 14.2 g White solid.
  • reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 13.0 g of light yellow solid, which was used directly for the next One step response.
  • reaction solutions were combined, diluted with ethyl acetate, water was added, and the layers were separated.
  • the aqueous phase was extracted three times with ethyl acetate.
  • the organic phases were combined, washed with dilute hydrochloric acid and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and reduced pressure. Concentrate and purify by column chromatography to obtain 6.4 g of light yellow solid.
  • reaction solution was diluted with water, extracted with ethyl acetate 3 times, the organic phase was discarded, the aqueous phase was adjusted to pH 1 with dilute hydrochloric acid, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine once, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.8 g of white solid.
  • reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 4.0 g of white solid .
  • reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3.0 g of light yellow solid.
  • Acetic anhydride (9.0ml) in acetonitrile (18ml) was slowly added dropwise at 35°C. After completion, it was cooled to room temperature and stirred for 15 hours.
  • the reaction solution was diluted with ethyl acetate, water was added, and the layers were separated. The aqueous phase was extracted 3 times with ethyl acetate.
  • the organic phases were combined, washed once with dilute hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4.6g of brown oil. Thing, directly cast the next reaction.
  • aqueous phase was extracted 3 times with ethyl acetate.
  • the organic phases were combined, washed once with dilute hydrochloric acid and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. , Purified by column chromatography to obtain 2.4 g of light yellow solid.
  • reaction solution was poured into 1N HCl aqueous solution, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine once, dried with anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain 620 mg of colorless liquid.
  • reaction solution was diluted with water, extracted with ethyl acetate 3 times, the organic phase was discarded, the aqueous phase was adjusted to pH 1 with dilute hydrochloric acid, extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, dried with anhydrous sodium sulfate, filtered The filtrate was concentrated to dryness to obtain 300 mg of colorless foam.
  • reaction solution was diluted with dichloromethane, water was added, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, washed once with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain 1.04 g of light yellow liquid.
  • the reaction solution was diluted with dichloromethane, water was added for liquid separation, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 3.2 g of light yellow oil.
  • the product was dissolved in acetonitrile (15ml), slowly dropped into concentrated hydrochloric acid (5ml), and stirred at room temperature for 1h.
  • the reaction solution was concentrated, acetonitrile (15ml) was added to dissolve, potassium carbonate (6.24g) was added, and the mixture was stirred at 35°C for 3h.
  • the reaction solution was cooled to room temperature, filtered through a pad of Celite, washed with acetonitrile, and the filtrate was concentrated to obtain 1.67 g of light yellow liquid.
  • N-tert-butoxycarbonyl-2-methylalanine (5g) and dichloromethane (35ml) into a 100ml single-neck flask add N,N'-carbonyldiimidazole (4.4g) in batches at room temperature, and stir at room temperature 30 minutes. The temperature was lowered to 0°C, and a dichloromethane solution (10 ml) of N-(2-aminoethyl)pyrrolidine (3.4 g) was added dropwise. After the dropping, the mixture was returned to room temperature and stirred for 1 hour.
  • N-tert-butoxycarbonyl-2-methylalanine (5g) and dichloromethane (35ml) into a 100ml single-neck flask add N,N'-carbonyldiimidazole (4.4g) in batches at room temperature, and stir at room temperature 30 minutes. The temperature was lowered to 0° C., the dichloromethane solution (10 mL) of 4-methyl-1-piperazine ethylamine (4.2 g) was added dropwise, and the dripping was completed, and the mixture was returned to room temperature and stirred for 1 hour.
  • N-tert-butoxycarbonyl-2-methylalanine (2g) and dichloromethane (14ml) into a 50ml single-neck flask add N,N'-carbonyldiimidazole (1.75g) in batches at room temperature, and stir at room temperature 30 minutes. The temperature was lowered to 0°C, and the dichloromethane solution (5 ml) of N 1 -benzyl-N 1 -methylethane-1,2-diamine (1.94 g) was added dropwise, and the dropping was completed, and the mixture was returned to room temperature and stirred for 1 hour.
  • reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a white solid ( 42mg).
  • the specific preparation method is as follows:
  • reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a pale yellow solid 30mg.
  • the specific preparation method is as follows;
  • reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain 32 mg of white solid.
  • the specific preparation method is as follows:
  • reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain an off-white solid 32mg.
  • the specific preparation method is as follows:
  • reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a pale yellow solid 26mg.
  • the specific preparation method is as follows:
  • reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a pale yellow solid 22mg.
  • the specific preparation method is as follows:
  • reaction solution was diluted with dichloromethane, washed with water, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and purified by column chromatography to obtain a pale yellow solid 26mg.
  • alkyne functional groups can be linked to bioluminescent markers by "Click chemistry", which is conducive to accurately determining the distribution of compounds in the body. Under the catalysis of the salt, the “Click chemistry” occurs to generate fluorescent compounds with a "triazole structure".
  • the compounds of the present invention can also be connected with other chemical substances with biomarker functions to form new chemical substances that are easy to detect. It is of great significance to fully study the effectiveness and safety of such compounds.
  • alkyne is connected to other pharmacophore groups through “Click chemistry", which is conducive to finding candidate compounds with better comprehensive performance. Examples are as follows:
  • A means: activity IC50 ⁇ 50nM
  • B means 50nM ⁇ IC50 ⁇ 1000nM
  • C means IC50>1000nM
  • the experimental results show that the compound of the present invention has a significant inhibitory activity of SGLT1.
  • the compound of the present invention has the effect of improving the blood sugar level of the test animal.
  • the compound of the present invention helps to reduce body weight. In the study of in vivo pharmacodynamics, the compound of the present invention reduces the body weight of experimental animals.
  • the compound of the present invention has low or no absorption in vivo. Pharmacokinetic studies show that the compound of the present invention is almost undetectable in experimental animals and has almost no side effects on other organs in the body.
  • the in vitro activity determination of this test uses human embryonic kidney epithelial cells (HEK293, stably expressing human SGLT1) to 2-NBDG(2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino] -D-glucose, CAS NO: 186689-07-6 ) uptake was evaluated to determine the target compound by measuring the half maximal inhibitory concentration (IC 50) SGLT1 inhibitory activity.
  • IC 50 half maximal inhibitory concentration
  • HEK293 cells capable of stably expressing the human SGLT1 gene were seeded in a 96-well transparent bottom blackboard containing DMEM medium. Incubate in a cell culture incubator at 37°C and 5% CO 2. Aspirate the medium in the 96-well plate, treat it with low-sugar and serum-free DMEM medium, and then wash it with non-specific uptake buffer and Na + dependent uptake buffer. Add the uptake buffer containing the test compound to each well of the cells, and then add the uptake solution containing 2-NBDG for glucose uptake, and incubate the cell plate at 37° C. under 5% CO 2. The compound is diluted in a gradient.
  • the uptake reaction is stopped by removing the culture solution, and after washing the cells with ice-cold uptake buffer, the washing solution is removed. NaOH was added to lyse the cells, and a fluorescence microplate reader was used to detect the content of 2-NBDG in the cells.
  • the protein concentration of the lysate was measured by the BCA method, the intake of 2-NBDG was quantified by fluorescence intensity/protein content, and the obtained data was analyzed using GraphPad Prism to determine the half inhibitory concentration (IC 50 ) of the test compound.
  • Comparative compound 18 is the number in the literature (Journal of Medicinal Chemistry 2017, 60,710-721, Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1(SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of “Diabetes”) Compound. Its preparation was prepared and identified according to the synthetic method described in the literature.
  • Example 1 Example 2, Example 3, and Example 4 have significant SGLT1 inhibitory activity.
  • Compound preparation Weigh an appropriate amount of the compound of Example 1, Example 3, and Example 4, and suspend it evenly with an appropriate amount of 0.5% CMC-Na solution;
  • Glucose solution preparation Weigh an appropriate amount of glucose powder and dissolve it in an appropriate amount of pure water;
  • Dosage and method of administration 0.009mg/kg, oral gavage
  • Compound preparation Weigh an appropriate amount of the compound of Example 4, and suspend it evenly with an appropriate amount of 0.5% CMC-Na solution;
  • Glucose solution preparation Weigh an appropriate amount of glucose powder and dissolve it in an appropriate amount of pure water;
  • Administration method and dosage oral gavage; blank vehicle group, high-dose group (1.5mg/kg), low-dose group (0.1mg/kg).
  • mice Feed the mice on a high-sugar diet for 6 days, then divide them into groups (10 in each group) and enter the administration phase;
  • Example compound 4 was administered at 5 pm every day from the 1st to the 5th day, once a day, and then the animal had a high-sugar free diet, and the animal's defecation was observed.
  • Glucose tolerance test was performed on the 6th day, and glucose solution (2g/kg) was orally administered.
  • the blood glucose was measured before the administration of glucose (0 min) and 10, 30, and 60 min after administration of the glucose solution.
  • the data in the table represents the total number of animals with "loose stools” and the total number of animals in this group. For example, “3/10" means that 3 out of 10 animals in each group have "loose symptoms”.
  • Example Compound 4 was continuously administered, high-dose group (1.5 mg/kg), on day 1 and day 2, only a few animals had loose stools, and from day 3 to day 2. After 5 days, the animals did not have loose stools; in the low-dose group (0.1 mg/kg), after continuous administration for 5 days, the animals did not appear loose stools.
  • Dosage and method of administration 10mg/kg, oral gavage;
  • Test method Before administration (0) and 1, 4, 8, and 24 hours after administration, 0.2ml of blood was collected from the orbital venous plexus, heparin was used for anticoagulation, and plasma was collected.
  • Comparative compound 6 is the literature (Journal of Medicinal Chemistry 2017, 60,710-721, Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes) "compound of. Its preparation was prepared and identified according to the synthetic method described in the literature.
  • N/A Because the drug concentration in plasma is lower than the detection limit, the drug concentration in plasma cannot be detected, and the F% value cannot be calculated.
  • the experimental results show that the plasma drug concentration did not reach the detection limit during the in vivo detection of Example 4 and Example 6, and the amount of the compound of Example 4 and Example 6 entering the body could not be quantitatively detected, indicating that Example 4 and Example 6 almost did not
  • the absolute bioavailability of comparative compound 6 is 23%, and the absolute bioavailability of dapagliflozin is 73%. Therefore, the comparative compound 6 and dapagliflozin, after oral administration, are both absorbed into the blood, and their exposure to internal organs (for example, brain, heart and other organs) is high, and they have potential and unpredictable toxicity.
  • SGLT1 is also present in intestinal epithelial cells, heart, brain and other organs.
  • the compounds of Example 4 and Example 6 of the present invention after oral administration, the in vivo It is almost undetected. Therefore, preliminary experimental evidence infers that the compounds of Example 4 and Example 6 of the present invention have no side effects on various organs such as the heart and brain.
  • Example Compound 4 significantly reduces the blood glucose level of diabetic model animals, and has a dose-effect relationship.
  • the collected rat feces were processed, and the fecal suspension was obtained for the determination of metabolic stability.
  • the mixed reaction system composed of the rat stool suspension and the compound of Example 5 was incubated at 37° C. for 3 h, 6 h, 12 h, and 24 h.
  • the Example Compound 4 in the incubation system was analyzed to determine the total amount of remaining compounds. Among them, "+” represents the percentage of remaining amount: ⁇ 50%; “++” represents the percentage of remaining amount: 50% to 70%; “+++” represents the percentage of remaining amount: 70% to 90%; “++ ++” represents the percentage of remaining amount: >90%.
  • test results show that after about 24 hours of incubation of the compound of Example 4 with the microorganisms in the feces of rats, the remaining compound of Example 4 is still relatively large (>70%). It shows that the compound of Example 4 can still maintain high stability under the effect of intestinal microbial metabolism.
  • the compound of the present invention has an anti-tumor effect.
  • the compound of the present invention can inhibit the growth of tumor; the test on the animal model induced by high-fat diet suggests that the compound of the present invention is beneficial to non-alcohol Relief of fatty liver disease and non-alcoholic steatohepatitis, as well as treatment of liver and kidney diseases related to energy absorption and metabolism.

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Abstract

本发明提供了抑制钠葡萄糖协同转运蛋白1的化合物及其药学上可接受的盐和立体异构体。该化合物用于药物组合物，以及制备和使用的方法，包括药物及其组合物在制备用于治疗和改善糖尿病，心脑血管疾病，降低体重，脂肪肝，便秘，代谢相关疾病和肿瘤治疗中应用。

Description

一种芳基葡糖苷衍生物 技术领域
本发明涉及一种钠-葡萄糖协同转运蛋白1(SGLT1)抑制剂，包含它们组合物的药物合成方法以及它们在治疗代谢类疾病尤其是2型糖尿病的用途。
背景技术
糖尿病是一组以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损，或两者兼有引起。糖尿病时长期存在的高血糖，导致各种组织，特别是眼，肾，心脏，血管，神经的慢性损害，功能障碍。2012年，据世界卫生组织报道，糖尿病在18周岁以上成年人中的发病率大于为9％。随着人口增加、老龄化和人寿命的延长，糖尿病发病率还会上升。在肥胖人群中，糖尿病发病率更高。根据预测，到2030年，糖尿病将成为第七大致死疾病。
钠-葡萄糖协同转运蛋白(Sodium-dependent glucose transporters，SGLT)抑制剂可以抑制肾脏对葡萄糖的重吸收，使过量的葡萄糖从尿液中排出，降低血糖。为糖尿病的治疗提供了一条新的途径，成为降糖药物研究的热点。基于根皮苷(Plorizin)的结构，在过去数十年来，已经开发出新的靶点药物用于治疗糖尿病。
Figure PCTCN2020131248-appb-000001
SGLT家族由一些亚型组成，在细胞膜上起转运糖类的作用，这个过程与钠离子转运体结合。SGLT1主要在胃肠通道中表达，主要负责葡萄糖和半乳糖在小肠中的吸收。SGLT1也存在于肾近直小管，此处有助于血糖的重吸收。通过抑制SGLT1来阻碍血糖的吸收利用回血，从而达到降低血糖水平的目标。
SGLT1抑制作用对于血糖控制也可能提供一种替代疗法，通过SGLT1抑制作用来提高血糖控制能力具有很大吸引力，因为这种作用可以不依赖肾脏功能。目前的SGLT2选择性抑制剂对于中重度肾损伤患者缺乏疗效，中重度肾损伤患者在所有糖尿病患者中约占30～40％。抑制肠道SGLT1，能够达到血糖控制的潜在功效。通过这种作用，也可以避免SGLT2抑制剂的糖尿相关副作用，尤其是生殖器感染。
尽管目前针对肠道SGLT1抑制剂的开发已经取得了进步，仍然需要开发新的具有更好药效的化合物，经过不断努力，本发明设计具有通式(V)结构的化合物，并发现具有此 类结构的化合物表现出优异的效果和作用，在更大范围内，更加深入和全面地揭示和阐明了结构和活性效能的关系，具有重要的应用价值。
发明内容
本发明提供一种式(V)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000002
其中，U，V，W和Q分别独立地选自氮原子或者CH；
每个R 1a，R 1b，R 1c分别独立地选自卤素或者-OR 1A，-NHR 1A，其中每个R 1A独立的是氢，C1～C6烷基或者酰基；
R 2选自-S(O) m-R 1A；
每个R 3，R 4，R 5，R 6a，R 7a，R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6a和R 7a，R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
R A，R B分别独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，卤代烷氧基，卤素，氨基，巯基，硝基，羟基，氰基，氧代基，C2～C8烯基，C2～C8炔基，环烷基，杂环基，芳基，杂芳基，-(CH 2) n1R aa，-(CH 2) n1OR aa，-SR aa，-(CH 2) n1C(O)R aa，-SR aa，-C(O)OR aa，-C(O)R aa，-S(O) m1R aa，-(CH 2) n1S(O) m1R aa，-NR aaR bb，-C(O)NR aaR bb，-NR aaC(O)R bb，-NR aaS(O) m1R bb；
或者R A，R B连同与它们相连的氮原子一起形成3至8元杂环，该杂环可以包含一个或多个碳原子，氮原子，氧原子或硫原子，该杂环可以进一步被卤素，烷基，环烷基，芳基，烷氧基，烯基，炔基或氧代基取代；
R aa，R bb各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，卤素，氰基，硝基，羟基，氨基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，其中所述的烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，任选进一步被选自氢，氘，硅基，烷基硅基，取代或未取代的烷基，卤素，羟基，取代或未取代的氨基，氧代基，硝基，氰基，取代或未取代烯基，取代或未取代炔基，取代或未取代烷氧基，取代或未取代羟烷基，取代或未取代的环烷基，取代或未取代的杂环基，取代或未取代的芳基和取代或未取代的杂芳基中一个或多个取代基所取代；
Z选自氧原子，或者硫原子；
n1＝0，1，2，3，4；
m1＝0，1，2，3，4；
m＝0，1，2；
p＝0，1，2，3；
q＝0，1，2，3；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y为连接基团，选自以下结构：
Figure PCTCN2020131248-appb-000003
其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
s1＝0，1，2，3，4，5；
s2＝0，1，2，3，4，5
s3＝0，1，2，3，4，5。
本发明提供一种式(VA)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000004
其中，R 1a，R 1b，R 1c分别独立地选自卤素或者-OR 1A，-NHR 1A，其中R 1A独立的是氢，C1～C6烷基或者酰基；
R 2选自-S(O) m-R 1A；
每个R 3，R 4，R 5，R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被选自氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
R A，R B分别独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，卤代烷氧基，卤素，氨基，巯基，硝基，羟基，氰基，氧代基，C2～C8烯基，C2～C8炔基，环烷基，杂环基，芳基，杂芳基，-(CH 2) n1R aa，-(CH 2) n1OR aa，-SR aa，-(CH 2) n1C(O)R aa，-SR aa，-C(O)OR aa，-C(O)R aa，-S(O) m1R aa，-(CH 2) n1S(O) m1R aa，-NR aaR bb，-C(O)NR aaR bb，-NR aaC(O)R bb， -NR aaS(O) m1R bb；
或者R A，R B连同与它们相连的氮原子一起形成3至8元杂环，该杂环可以包含一个或多个碳原子，氮原子，氧原子或硫原子，该杂环可以进一步被卤素，烷基，环烷基，芳基，烷氧基，烯基，炔基或氧代基取代；
R aa，R bb各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，卤素，氰基，硝基，羟基，氨基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，其中所述的烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，任选进一步被选自氢，氘，硅基，烷基硅基，取代或未取代的烷基，卤素，羟基，取代或未取代的氨基，氧代基，硝基，氰基，取代或未取代烯基，取代或未取代炔基，取代或未取代烷氧基，取代或未取代羟烷基，取代或未取代的环烷基，取代或未取代的杂环基，取代或未取代的芳基和取代或未取代的杂芳基中一个或多个取代基所取代；
n1＝0，1，2，3，4；
m1＝0，1，2，3，4；
m＝0，1，2；
p＝0，1，2，3；
q＝0，1，2，3
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y为连接基团，选自以下结构：
Figure PCTCN2020131248-appb-000005
其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
s1＝0，1，2，3，4，5；
s2＝0，1，2，3，4，5
s3＝0，1，2，3，4，5。
本发明提供一种式(VA-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000006
其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
每个R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被选自氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
R A，R B分别独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，卤代烷氧基，卤素，氨基，巯基，硝基，羟基，氰基，氧代基，C2～C8烯基，C2～C8炔基，环烷基，杂环基，芳基，杂芳基，-(CH 2) n1R aa，-(CH 2) n1OR aa，-SR aa，-(CH 2) n1C(O)R aa，-SR aa，-C(O)OR aa，-C(O)R aa，-S(O) m1R aa，-(CH 2) n1S(O) m1R aa，-NR aaR bb，-C(O)NR aaR bb，-NR aaC(O)R bb，-NR aaS(O) m1R bb；
R aa，R bb各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，卤素，氰基，硝基，羟基，氨基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，其中所述的烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，任选进一步被选自氢，氘，硅基，烷基硅基，取代或未取代的烷基，卤素，羟基，取代或未取代的氨基，氧代基，硝基，氰基，取代或未取代烯基，取代或未取代炔基，取代或未取代烷氧基，取代或未取代羟烷基，取代或未取代的环烷基，取代或未取代的杂环基，取代或未取代的芳基和取代或未取代的杂芳基中一个或多个取代基所取代；
n1＝0，1，2，3，4；
m1＝0，1，2，3，4；
p＝0，1，2，3；
q＝0，1，2，3；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y为连接基团，选自以下结构：
Figure PCTCN2020131248-appb-000007
本发明提供下列化合物，其立体异构体，互变异构体，药学上可接受的盐，
Figure PCTCN2020131248-appb-000008
本发明提供一种式(VA-2)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000009
其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
每个R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被选自氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
p＝0，1，2，3；
q＝0，1，2，3；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
环B选自以下结构：
Figure PCTCN2020131248-appb-000010
其中，Z 1，Z 2选自氧原子，硫原子；
T为化学键，氧原子，-NR 7h，取代或者未取代的碳原子，其中取代基包括氢，氘，卤素，C1～C6烷基或者酰基；
每个R d1，R d2，R e1，R e2，R f1，R f2，R g1，R g2，R 7h分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
r＝0，1，2，3；
Y为连接基团，选自以下结构：
Figure PCTCN2020131248-appb-000011
Figure PCTCN2020131248-appb-000012
本发明提供下列化合物，其立体异构体，互变异构体，药学上可接受的盐，
Figure PCTCN2020131248-appb-000013
Figure PCTCN2020131248-appb-000014
本发明提供一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000015
其中，R 1选自F或者-OR 1A，-NHR 1A，其中R 1A独立的是氢，C1～C6烷基或者酰基；R 2选自-S(O) m-R 1A，m＝0，1，2；
R 3，R 4，R 5，R 6，R 7，R 8，R 9选自氢，氘，卤素，C1～C6烷基或者酰基；
m2＝0，1，2，3；
n2＝0，1，2，3；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y为连接基团，为2～17个由碳，氧，氮原子组成的连接臂；
Z为O或者S。
本发明提供一种式(I-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000016
其中，R 1a，R 1b，R 1c分别独立地选自F或者-OR 1A，-NHR 1A，其中R 1A独立的是氢，C1～C6烷基或者酰基；
R 2选自-S(O) m-R 1A，m＝0，1，2；
每个R 3，R 4，R 5，R 6，R 7，R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基，环烷基，环烷基烷基或者酰基，炔基烷基；
m2＝0，1，2，3；
n2＝0，1，2，3；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y1为连接基团，选自以下结构：
Figure PCTCN2020131248-appb-000017
其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
s1＝0，1，2，3，4，5；
s2＝0，1，2，3，4，5
s3＝0，1，2，3，4，5。
本发明提供所述的式(I)化合物，包括以下通式结构(II)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000018
其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
m2＝0，1，2，3；
n2＝1；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y为连接基团，为2～17个由碳，氧，氮原子组成的连接臂。
本发明提供所述的式(I)化合物，包括以下通式结构(II-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000019
其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基，环烷基，环烷基烷基或者酰基，炔基烷基；
m2＝0，1，2，3；
n2＝1；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y1为连接基团，选自以下结构：
Figure PCTCN2020131248-appb-000020
其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
s1＝0，1，2，3，4，5；
s2＝0，1，2，3，4，5
s3＝0，1，2，3，4，5。
本发明提供所述的式(II)化合物，包括以下通式结构(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000021
其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
m2＝0，1，2，3；
n2＝1；
X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
Y 1为连接基团，为2～17个由碳，氧，氮原子组成的连接臂，选自以下结构：
Figure PCTCN2020131248-appb-000022
本发明提供所述的式(III)化合物，其中，X选自氢，氘，氟，溴，碘，甲基，乙基，乙烯基，乙炔基。
本发明提供所述的式(III)化合物，其中，R 9选自氢，氘，氟，溴，碘，甲基，乙基，C3～C8环烷基，乙烯基，乙炔基。
本发明提供下列化合物，包括以下结构化合物，其立体异构体，互变异构体或药学上可接受的盐，
Figure PCTCN2020131248-appb-000023
Figure PCTCN2020131248-appb-000024
Figure PCTCN2020131248-appb-000025
Figure PCTCN2020131248-appb-000026
本发明提供一种药物组合物，其包括治疗有效剂量的本发明中任一项所述化合物或其 立体异构体，互变异构体或药学上可接受的盐及可药用的载体。
本发明中任意一项所述的化合物或其可药用的盐或根据本发明中述的药物组合物在制备用于治疗和改善糖尿病，心脑血管疾病，降低体重，脂肪肝，代谢相关疾病和在肿瘤治疗中应用。
本发明中任意一项所述的化合物或其可药用的盐或根据本发明中所述的药物组合物，作为SGLT1/SGLT2抑制剂，在制备治疗与SGLT1/SGLT2功能相关的疾病的药物或药物组合物中的应用。
本发明中的应用，其中所述患者已服用过或目前正服用其他治疗性药物，包括降血压药，降血脂药，抗糖尿病药，降血糖药，减肥药或食欲抑制剂。
附图说明
图1：大鼠连续给药14天后糖耐量(OGTT)试验结果
图2：小鼠连续给药5天后，第6天糖耐量(OGTT)试验结果
发明详述
如上文和本文其它地方所用，下列术语和缩写具有下面所定义的含义。如未定义，则本说明书所使用的所有技术和科学术语均具有本领域普通技术人员通常所理解的含义。
术语“氢”在本文中是指-H。
术语“卤素”在本文中是指-F，-Cl，-Br和-I。
术语“氟”在本文中是指-F；术语“氯”在本文中是指-Cl；术语“溴”在本文中是指-Br；术语“碘”在本文中是指-I。
术语“氰基”在本文中是指-CN。
术语“氨基”在本文中是指-NH 2。
术语“羟基”在本文中是指-OH。
术语“硝基”在本文中是指-NO 2。
术语“羧基”在本文中是指-COOH。
术语“连接臂”在本文中是指选自2～17个由碳，氧，氮原子组成的具有连接功能的化学结构。具体指直链或者支链结构的烷烃结构(包括饱和烷烃，烯烃和炔烃)或者一端带有羰基的类似烷烃结构；其中，任意碳原子在形成稳定化学结构的前提下，可以被氧原子，氮原子替换，也可以被取代基进一步取代，其中所述取代基包括：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，烯基，炔基和环烷氧基。本文所述“连接臂”包括但不限于以下化学结构：
Figure PCTCN2020131248-appb-000027
Figure PCTCN2020131248-appb-000028
术语“芳基”在本文中是指6至10元全碳单环或稠合多环(即共享相邻碳原子对的环)基团，具有共轭的π电子体系的多环(即带有相邻碳原子对的环)基团。芳基可以在产生稳定结构的任意碳原子上与所定义的化学结构共价连接。本文所述芳基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，烯基，炔基和环烷氧基。
术语“杂芳基”在本文中是指由5至10个原子所组成的并且含有至少一个选自N，O或S等杂原子的芳香族基团。该术语可以具有单个环(非限制性实例包括呋喃，噻吩，咪唑，吡唑，吡啶，吡嗪，恶唑，噻唑等)或多个稠环(非限制性实例包括苯并噻吩，苯并呋喃，吲哚，异吲哚等)，其中稠环可以是或者可以不是包含杂原子的芳香族基团，假定连接点是通过芳族杂芳基基团的原子。本文所述杂芳基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，氨基，烷基，烷氧基，酰基，酰氧基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，烯基，炔基和环烷氧基。
术语“环烷基”在本文中是指具有3至10个碳原子，具有单环或多环(包括稠环，桥环及螺环系统)的环状烷基。环烷基的非限制性实例包括环丙基，环丁基，环戊基，环己基等。本文所述环烷基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，氧代，烷氧基，酰基，酰氧基，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，环烷氧基，芳基或杂芳基。
术语“杂环基”是指取代的或未取代的饱和或者不饱和且至少含有1至5个选自N，O或S杂原子的芳香环，非芳香环，芳香环，非芳香环可以是3至10元的单环，4至20元的螺环，并环或桥环，杂环基环中选择性取代的N，S可被氧化成各种氧化态。优选3至12元杂环。非限制性实施例包括氧杂环丙烷基，氧杂环丁基，氧杂环戊基，氧杂环己基，氧杂环己基，氧杂环辛基，氮杂环丙烷基，氮杂环丁基，氮杂环戊基，氮杂环己基，氮杂环丙烯基，1,3-二氧环戊基，1,4-二氧环戊基，1,3-二氧环戊基，1,3-二氧环己基，1,3-二硫 环己基，氮杂环庚烯基，吗啉基，哌嗪基，吡啶基，呋喃基，噻吩基，吡咯基，吡喃基，N-烷基吡咯基，嘧啶基，吡嗪基，哒嗪基，咪唑基，哌啶基，硫代吗啉基，二氢吡喃，噻二唑基，噁唑基，噁二唑基，吡唑基，1,4-二氧杂环己二烯基等。
术语“杂环烷基”在本文中是指至少含有一个选自O，N和S等杂原子且任选含有一条或多条双键或三键的非芳族环烷基。杂环烷基作为整体可以具有3至10个环原子。杂环烷基可以在产生稳定结构的任意杂原子或碳原子上与所定义的化学结构共价连接。杂环烷基的非限制性实例包括：吡咯啉基，哌啶基，哌嗪基，四氢呋喃基，四氢吡喃基，吗啉基，吡喃基等。杂环烷基上的一个或多个N或S原子可以被氧化(例如吗啉N-氧化物，硫吗啉S-氧化物，硫吗啉S，S-二氧化物)。杂环烷基还可以含有一个或多个氧代基团，如邻苯二酰亚氨基，哌啶酮基，恶唑烷酮基，2,4(1H,3H)-二氧代-嘧啶基，吡啶-2(1H)-酮基等。本文所述杂环烷基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，氧代，酰基，酰氧基，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，环烷氧基，芳基或杂芳基。
术语“烯基”在本文中是指具有2至8个碳原子并且具有至少一个烯基不饱和位点的烯基基团。烯基的非限制性实例包括乙烯基，丙烯基，烯丙基，异丙烯基，丁烯基，异丁烯基等。本文所述烯基可以任选地被一个或多个下列取代基所取代：氘，氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，环烷氧基，巯基，烷基巯基，氘代烷基巯基，砜基，亚砜基，氨基，硅基，膦酰基，氘代烷基，杂环烷基，芳基，杂芳基，炔基，烯基，芳基烷基，酯基。
术语“炔基”在本文中是指涉及其中两个相邻碳原子通过三键连接的烷基，其中所述烷基如本文中所定义。炔基指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的不饱和烷基，例如乙炔基，1-丙炔基，2-丙炔基，1-，2-或3-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，其独立地选自氘，氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰胺基，酯基，胺基，磺酰基，亚磺酰基，环烷基，环烯基，杂环烷基，环烷氧基，巯基，烷基巯基，氘代烷基巯基，砜基，亚砜基，氨基，硅基，膦酰基，氘代烷基，杂环烷基，芳基，杂芳基，炔基，烯基，芳基烷基，酯基。
术语“烷基”在本文中是指具有1至10个碳原子的饱和脂肪族烃基基团，该术语包括直链和支链烃基。烷基的非限制性实例包括甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，新戊基，正己基等。本文所述烷基可以任选地被一个或多个下列取代基所取代：氟，氯，溴，碘，氰基，硝基，羟基，羧基，氨基，烷基，烷氧基，酰基，酰氧基，氧代，酰胺基，酯基，胺基，环烷基，环烯基，杂环烷基，烯基，烯氧基，炔基，环烷氧基，杂环烷基氧基，芳氧基，杂芳氧基，芳基或杂芳基。
术语“杂烷基”在本文中是指包括至少一个杂原子的烷基。
术语“烷氧基”在本文中是指烷基基团通过氧原子与分子其余部分相连(-O-烷基)，其中所述烷基如本文中所定义。烷氧基的非限制性实例包括甲氧基，乙氧基，三氟甲氧基，二氟甲氧基，正丙氧基，异丙氧基，正丁氧基，叔丁氧基，正戊氧基等。
术语“酰胺基”在本文中是指-NR 8-C(O)-烷基，-NR 8-C(O)-环烷基，-NR 8-C(O)-环烯基，-NR 8-C(O)-芳基，-NR 8-C(O)-杂芳基和-NR 8-C(O)-杂环烷基，其中R 8为氢，环烷基，环烯基，芳基，杂芳基，杂环烷基和烷基。其中所述氢，环烷基，环烯基，芳基，杂芳基，杂环烷基和烷基等基团如本文中所定义。
术语“酰基”在本文中是指H-C(O)-，R 9R 10N-C(O)-，烷基-C(O)-，环烷基-C(O)-，环烯基-C(O)-，杂环烷基-C(O)-，芳基-C(O)-和杂芳基-C(O)-，其中所述R 9和R 10分别独立地选自氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基或环烷基。其中所述氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基和环烷基等基团如本文中所定义。
术语“氧代基”是指氧原子对碳原子，氮原子，硫原子等的氧化态描述，当氧原子对碳原子，氮原子，硫原子等的氧化后，形成的代表性结构包括但不限于，羟基，烷氧基，羰基，氮氧化合物，亚砜，砜等官能团结构。
术语“磺酰基”在本文中是指R 11R 12N-S(O) 2-，环烷基-S(O) 2-，环烯基-S(O) 2-，芳基-S(O) 2-，杂芳基-S(O) 2-，杂环烷基-S(O) 2-和烷基-S(O) 2-，其中所述R 11和R 12分别独立地选自氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基或环烷基。其中所述氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基和环烷基等基团如本文中所定义。
术语“亚磺酰基”在本文中是指R 13R 14N-S(O)-，环烷基-S(O)-，环烯基-S(O)-，芳基-S(O)-，杂芳基-S(O)-，杂环烷基-S(O)-或烷基-S(O)-，其中所述R 13和R 14分别独立地选自氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基或环烷基。其中所述氢，羟基，烷基，杂环烷基，芳基，杂芳基，磺酰基，亚磺酰基，环烯基，酰基和环烷基等基团如本文中所定义。
术语“酰氧基”在本文中是指-O-C(O)-烷基，-O-C(O)-环烷基，-O-C(O)-环烯基，-O-C(O)-芳基，-O-C(O)-杂芳基和-O-C(O)-杂环烷基，其中所述烷基，环烷基，环烯基，芳基，杂芳基和杂环烷基等基团如本文中所定义。
术语“酯基”在本文中是指烷基-O-C(O)-，环烷基-O-C(O)-，环烯基-O-C(O)-，杂环烷基-O-C(O)-，芳基-O-C(O)-和杂芳基-O-C(O)-，其中所述烷基，环烷基，环烯基，杂环烷基，芳基和杂芳基等基团如本文中所定义。
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，并且该描述包括其中所述事件或情形出现的情况以及其中它不出现的情况。
术语“任选被……所取代”是指所述结构是未取代的或者被一个或多个本发明所述的取代基取代。术语“取代”在本文中是指任何基团由指定取代基单取代或多取代至这种单取代或多取代(包括在相同部分的多重取代)在化学上允许的程度，每个取代基可以位于该基团上任何可利用的位置，且可以通过所述取代基上任何可利用的原子连接。“任何可利用的位置”是指通过本领域已知的方法或本文教导的方法可化学得到，并且不产生过度不稳定的分子的所述基团上的任何位置。当在任何基团上有两个或多个取代基时，每个取代基独立于任何其它取代基而定义，因此可以是相同或不同的。
在本说明书的各个位置，本发明化合物的取代基以基团或范围的形式进行公开。这具体意味着本发明包括这样的基团和范围的每个成员或成员中的每个个体的亚组合。如术语“C 1-6烷基”具体意味着单独公开了甲基，乙基，C 3烷基，C 4烷基，C 5烷基和C 6烷基。
术语“本发明化合物”(除非另有具体指明)在本文中是指式(I)和式(II)化合物及其所有纯的和混合的立体异构体，几何异构体，互变异构体，溶剂合物，前药及同位素标记的化合物和任何药学上可接受的盐。本发明化合物的溶剂合物是指与化学计量和非化学计量的溶剂结合的化合物或其盐，如水合物，乙醇合物，甲醇合物，丙酮合物等。化合物也可以一种或多种结晶状态存在，即作为共晶体，多晶型物，或其可以无定形固体存在。所有此种形式均被权利要求所涵盖。
术语“药学上可接受”表示物质或组合物在化学上和/或毒理学上必须与构成制剂的其它成分和/或用其治疗的哺乳动物相容。
术语“立体异构体”在本文中是指具有一个或多个立体中心的手性不同的化合物，包括对应异构体和非对映异构体。
术语“互变异构体”在本文中是指具有不同能量的结构同分异构提可以越过低能垒，从而互相转化。诸如质子互变异构体包括通过质子迁移进行互变，如烯醇-酮互变异构体和亚胺-烯胺互变异构体，或者含有连接到环-NH-部分和环＝N-部分的环原子的杂芳基基团的互变异构形式，如吡唑，咪唑，苯并咪唑，三唑和四唑。化合价互变异构体包括一些成键电子重组而进行互变。
术语“前药”在本文中是指在对受试者给药时，能够直接或间接地提供本发明的化合物，其活性代谢物或残基的本发明化合物的任何衍生物。尤其优选的是那些能增加本发明化合物生物利用度，提高代谢稳定性及组织靶向性的衍生物或前药。
本发明化合物可以以盐的形式被使用，如从无机酸或有机酸衍生得到的“医药上可接受的盐”。这些包括但并不限于下列所述：乙酸盐，己二酸盐，藻酸盐，柠檬酸盐，天冬氨酸盐，苯甲酸盐，苯磺酸盐，乙磺酸盐，硫酸氢盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，二葡萄糖酸盐，环戊烷丙酸盐，十二烷基硫酸盐，乙磺酸盐，葡糖庚酸盐，甘油磷酸盐，半硫酸盐，庚酸盐，己酸盐，延胡索酸盐，氢氯化物，氢溴酸盐，氢碘酸盐，2-羟基乙磺酸盐，乳酸盐，马来酸盐，甲磺酸盐，乙磺酸盐，盐酸盐，2-萘磺酸盐，草酸盐，果胶酯酸盐， 硫酸盐，3-苯基丙酸盐，苦味酸盐，三甲基乙酸盐，丙酸盐，琥珀酸盐，酒石酸盐，硫氰酸盐，对甲苯磺酸盐和癸酸盐。另外，碱性含氮基团可以与以下试剂发生季铵化反应生成季铵盐：如低碳烷基卤化物，包括甲基，乙基，丙基和丁基的氯化物，溴化物和碘化物；如二烷基硫酸盐，包括二甲基，二乙基，二丁基和二戊基的硫酸盐；如长链卤化物，包括癸基，月桂基，肉豆蔻基和硬脂基的氯化物，溴化物和碘化物；如芳烷基卤化物，如苯甲基和苯乙基的溴化物等。
本发明还包括同位素标记的本发明化合物，即与上述所公开的结构相同，但该结构中一个或多个原子被与其具有相同质子数但不同中子数的原子所替代。结合本发明化合物的同位素实施例包括氢，碳，氮，氧，硫，氟，氯，碘的同位素，分别如 2H， 3H， 13C， 14C， 15N， 18O， 17O， 35S， 18F， 36Cl和 131I等。
本发明的化合物，其立体异构体，互变异构体或医药上可接受的盐，以及含有上述同位素和/或其他原子同位素的所述以上形式的化合物，均在本发明范围内。某些同位素标记的本发明化合物，如被 3H或 14C所标记的那些化合物可以用于药物组织分布试验中，因此，这些 3H或 14C同位素由于其容易制备和检测是特别优选的。此外，被较重的同位素如 2H所替代的某些本发明化合物由于具有更好的代谢稳定性而具有某些治疗优势，如可以增加体内半衰期和较少剂量等，因此， 2H在某些情况下也是优选的。
具体实施方式
下面用实施例来进一步说明本发明，但本发明并不受其限制。贯穿本申请，本文提及本发明的化合物和方法的多个实施例。所述的多个实施例旨在提供多个说明性实例，不应将其解释为替代物的描述。同时应注意，本文中所论述的实施例(包括各种方法和参数)仅为了说明本发明，并不以任何方式限制本发明的保护范围。为描述本发明，以下列出了具体实施例。但需要理解，本发明不限于这些实施例，以下实施例只是提供实践本发明的方法，并不以任何方式限制本发明的范畴。
本发明中任一项所述式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐的制备方法，包括如下步骤，方案1：
Figure PCTCN2020131248-appb-000029
将SM1-1和SM2-1在一定的化学反应条件下，制备得到通式化合物(I)，其中各个取代基定义同前；
或者，一种如权利要求1至6中任一项所述式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐的制备方法，包括如下步骤，方案2：
Figure PCTCN2020131248-appb-000030
将SM1-2和SM2-2在一定的化学反应条件下，制备得到通式化合物(I)，其中各个取代基定义同前。
本发明提供的化合物可以通过本领域公知的标准合成方法来制备，本说明书提供了制备本发明化合物的一般方法。起始原料通常可通过商业化获得，例如通过Alfa
Figure PCTCN2020131248-appb-000031
Figure PCTCN2020131248-appb-000032
TCI，
Figure PCTCN2020131248-appb-000033
韶远化学，安耐吉化学等公司购买得到，或者通过本领域技术人员所熟知的方法进行制备。
下文通过实施例与制备进一步解释并列举本发明化合物及相应的制备方法。应了解，尽管具体实施例中给出了典型或优选的反应条件(如反应温度，时间，反应物的摩尔比， 反应溶剂以及压力等)，但是本领域技术人员也可以使用其它反应条件。最佳反应条件可随所用的特定反应底物或溶剂而发生改变，但所述条件可由所属领域的技术人员通过常规优化而确定。
下述实施例化合物的结构通过核磁共振(NMR)和/或质谱(MS)来表征。使用NMR波谱仪，将化合物溶于适当的氘代试剂中，环境温度下以TMS为内标进行 1H-NMR分析。NMR化学位移(δ)以ppm为单位，并使用以下简称：s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰；brs，宽单峰。MS通过质谱仪(ESI)测定。
反应起始原料，中间体以及实施例化合物可以通过沉淀，过滤，结晶，蒸发，蒸馏以及色谱法(如柱层析法，TLC分离纯化等)等常规技术进行分离与纯化。
TLC使用HSGF254薄层层析硅胶板(0.2±0.03mm)，TLC分离纯化使用HSGF254薄层层析厚制备板(0.9～1mm)，。柱层析以300～400目硅胶为载体。
试验中使用的商品化溶剂及试剂如无特殊说明，购买后均无需进一步纯化或处理直接使用。参考其它实施例或合成方法时，反应条件(反应温度，反应溶剂，反应物摩尔比或/和反应持续时间)可能不同。一般而言，可通过TLC监测反应进程，据此选择合适的时间终止反应并进行后处理。化合物的纯化条件也可能发生变化，一般而言，依据TLC的R f值选择合适柱层析洗脱剂，或通过制备TLC分离纯化相应化合物。
中间体制备
中间体：4-(4-(2-甲基-5-(2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基)丁酸
Figure PCTCN2020131248-appb-000034
5-溴-N-甲氧基-N,2-二甲基苯甲酰胺
于1升反应瓶中加入5-溴-2-甲基苯甲酸(24.0g)，二氯甲烷(600ml)，依次滴加二甲基亚砜(16.2ml)，N,N-二甲基甲酰胺(3.6ml)，滴毕后回至室温搅拌3h。将反应液浓缩至干，依次加入二氯甲烷(190ml)，N,O-二甲基羟胺盐酸盐(31.0g)，冰浴降温至0℃，滴加三乙胺(46.5ml)，加毕后回至室温搅拌15h。将反应液倒入1M的稀盐酸中，分液，水相用二氯甲烷萃取两次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱层析纯化，得23.1g无色液体。
(5-溴-2-甲基苯基)(4-氯苯基)甲酮
于500ml反应瓶中加入上一步产物(18.7g)，四氢呋喃(150ml)，降温至0℃，滴加4-氯苯基溴化镁(1M in Et 2O)，滴毕于室温搅拌2h。将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得18.0g白色固体。 1H NMR(400MHz,CDCl 3):δ7.76(m,2H),7.54(dd,J＝2.1,8.2Hz,1H),7.48(m,2H),7.43(d,J＝2.1Hz,1H),7.20(d,J＝8.2Hz,1H),2.27(s,3H)。
4-溴-2-(4-氯苄基)-1-甲苯
于500ml反应瓶加入(5-溴-2-甲基苯基)(4-氯苯基)甲酮(23.0g)，乙腈(230ml)和三乙基硅烷(52.9ml，331.2mmol)，降温至0℃，缓慢滴加三氟化硼乙醚(54.6ml)，加毕后继续保持0℃搅拌30min，然后加热至65℃搅拌2h。反应完毕，将反应液冷却至0℃，缓慢加入饱和碳酸氢钠水溶液至无气泡产生，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化(石油醚洗脱)，得18.5g白色固体。
(3-(4-氯苄基)-4-甲基苯基)((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)甲酮
于500ml反应瓶加入(3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)(吗啉基)甲酮(14.3g)和四氢呋喃(150ml)，降温至0℃，滴加叔丁基氯化镁(1M in THF，57.5ml，57.5mmol)，加毕，继续搅拌30min。
于1L反应瓶加入4-溴-2-(4-氯苄基)-1-甲苯(18.5g)和四氢呋喃(180ml)，氮气保护，降温至-78℃，缓慢滴加正丁基锂(1.6M in hexane)搅拌10min。然后加入上述新制备的格式反应液，加毕后回至室温继续搅拌1h。反应完毕，将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得14.2g白色固体。 1H NMR(400MHz,CDCl 3):δ7.90-7.88(dd,J＝1.8,7.9Hz,1H),7.77(d,J＝1.6Hz,1H),7.32-7.30(d,J＝8.0Hz,1H),7.28-7.26(m,2H),7.08-7.06(d,J＝8.4Hz,2H),6.10(d,J＝3.6Hz,1H),5.31(d,J＝2.7Hz,1H),4.61(d,J＝3.6Hz,1H),4.58(s,1H),4.02(s,2H),3.09(s,1H),2.31(s,3H),1.57(s,3H),1.38(s,3H)。
(3aS,5S,6R,6aS)-5-((s)-(3-(4-氯苄基)-4-甲基苯基)(羟基)甲基)-2,2-二甲基四氢呋喃并[2, 3-d][1,3]间二氧杂环戊烯-6-醇
于500ml反应瓶加入(3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)(吗啉基)甲酮(14.2g)，七水氯化铈(15.7g)和甲醇(280ml)，冰浴降温至0℃，缓慢滴入硼氢化钠(1.6g)的1M氢氧化钠水溶液(16ml)，滴毕后回至室温搅拌1h。将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得13.0g淡黄色固体，直接用于下一步反应。
(3S,4R,5S,6S)-6-(3-(4-氯苄基)-4-甲基苯基)四氢-2H-吡喃-2,3,4,5-四基四乙酸酯
于500ml反应瓶加入(3aS,5S,6R,6aS)-5-((s)-(3-(4-氯苄基)-4-甲基苯基)(羟基)甲基)-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-6-醇(13.0g)，冰醋酸(65ml)和水(65ml)，加热至110℃搅拌4h。反应液浓缩至干，用甲苯共沸蒸馏3次，残留物用130ml乙腈溶解，加入三乙胺(44.5ml)，氮气保护下，于35℃缓慢滴加醋酸酐(30.1ml)的乙腈溶液(65ml)，滴毕后自然冷却至室温搅拌15h。反应液用乙酸乙酯稀释，加水，分液，水相用乙酸乙酯萃取3次，合并有机相，依次用稀盐酸和饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩浓缩，柱层析纯化，得14.6g黄色固体。 1H NMR(400MHz,CDCl 3):δ7.26-7.23(m,2H),7.19-7.14(m,2H),7.09(s,1H),7.01(d,J＝8.5Hz,2H),5.88(d,J＝8.2Hz,1H),5.37(t,J＝9.5Hz,1H),5.28(t,J＝8.9Hz,1H),5.20(t,J＝9.6Hz,1H),4.50(d,J＝9.9Hz,1H),3.98-3.90(m,2H),2.18(s,3H),2.12(s,3H),2.08(s,3H),2.03(s,3H),1.78(s,3H)。
(2S,3S,4R,5S,6R)-2-(3-(4-氯苄基)-4-甲基苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯
于500ml反应瓶加入(3S,4R,5S,6S)-6-(3-(4-氯苄基)-4-甲基苯基)四氢-2H-吡喃-2,3,4,5-四基四乙酸酯(14.6g)，硫脲(4.2g)，1,4-二氧六环(150ml)，三氟甲磺酸三甲基硅酯(9.9ml)，加热至90℃搅拌2h。完全反应后，冷至室温，依次加入碘甲烷(5.1ml)，N,N-二异丙基乙胺(27.1ml)，室温搅拌15h。加入乙酸乙酯和水，搅拌，分液，水相用乙酸乙酯萃取3次，合并有机相，依次用稀盐酸、饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得11.4g淡黄色固体。 1H NMR(400MHz,CDCl 3):δ7.26-7.23(m,2H),7.18-7.14(m,2H),7.06(s,1H),7.03-7.00(m,2H),5.35(t,J＝9.4Hz,1H),5.23(t,J＝9.6Hz,1H),5.13(t,J＝9.7Hz,1H),4.53(d,J＝9.9Hz,1H),4.40(d,J＝9.8Hz,1H),3.99-3.88(m,2H),2.20(s,3H),2.19(s,3H),2.11(s,3H),2.03(s,3H),1.78(s,3H)。
(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-甲氧基-4-氧代丁-1-烯-1-基)苄基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡-3,4,5-三基三乙酸酯
于25ml微波反应管中加入(2S,3S,4R,5S,6R)-2-(3-(4-氯苄基)-4-甲基苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(1.0g)，3-丁烯酸甲酯(1.0ml)，Pd2(dba)3(366mg)，三叔丁基膦四氟化硼(232mg)，二环己基甲基胺(1.2ml)和N-甲基吡咯烷酮(10ml)，氮气置换后，微波加热至160℃反应1h。此操作过程重复10次共投10g原料。合并反应 液，用乙酸乙酯稀释，加水，分液，水相用乙酸乙酯萃取3次，合并有机相，依次用稀盐酸、饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得6.4g淡黄色固体。 1H NMR(400MHz,CDCl 3):δ7.30-7.28(m,2H),7.16-7.15(m,2H),7.04-7.02(m,3H),6.47(d,J＝15.9Hz,1H),6.30-6.22(m,1H),5.35(t,J＝9.4Hz,1H),5.23(t,J＝9.6Hz,1H),5.13(t,J＝9.7Hz,1H),4.53(d,J＝9.8Hz,1H),4.40(d,J＝9.9Hz,1H),4.01-3.90(m,2H),3.73(s,3H),3.26(dd,J＝1.2,7.1Hz,2H),2.21(s,3H),2.18(s,3H),2.11(s,3H),2.02(s,3H),1.77(s,3H)。
(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧代丁基)苄基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯
于250ml反应瓶加入(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-甲氧基-4-氧代丁-1-烯-1-基)苄基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡-3,4,5-三基三乙酸酯(6.8g)，甲醇(60ml)，四氢呋喃(60ml)，5％钯碳(1.4g)，氢气置换3次，室温搅拌4h。反应液垫硅藻土过滤，滤液减压浓缩，柱层析纯化，得5.6g淡黄色固体。
4-(4-(2-甲基-5-(2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基)丁酸
于250ml反应瓶加入(2S,3S,4R,5S,6R)-2-(3-(4-(4-甲氧基-4-氧代丁基)苄基)-4-甲基苯基)-6-(甲基硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(5.6g)，甲醇(30ml)，四氢呋喃(15ml)和水(30ml)，再缓慢加入氢氧化锂一水(4.0g)，加完后室温搅拌4h。反应液加水稀释，乙酸乙酯萃取3次，弃去有机相，水相用稀盐酸调pH至1，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩得2.8g白色固体。 1H NMR(400MHz,DMSO-d6):δ12.04(s,1H),7.11-7.04(m,7H),5.22(d,J＝5.5Hz,1H),5.13(br s,1H),4.88(d,J＝5.4Hz,1H),4.33(d,J＝9.4Hz,1H),4.05(d,J＝8.9Hz,1H),3.91(s,2H),3.29-3.15(m,3H),2.53(t,J＝7.4Hz,2H),2.20(t,J＝7.4Hz,2H),2.17(s,3H),2.03(s,3H),1.80-1.72(quin,J＝7.7Hz,2H).MS:m/z 445.2,[M-H] -。
中间体：3-((4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲硫基)四氢-2H-吡喃-2-基)苄基)苄基)氧基)丙酸
Figure PCTCN2020131248-appb-000035
Figure PCTCN2020131248-appb-000036
(3-氯-4-甲基苯基)((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)甲酮
于250ml反应瓶加入(3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)(吗啉基)甲酮(5.0g)，四氢呋喃(50ml)，氮气保护，冰浴降温至0℃，加入叔丁基氯化镁(1M in THF，20.1mL)，搅拌30min。
于500ml反应瓶加入2-氯-4-碘甲苯(5.5g)，四氢呋喃(50ml)，氮气保护，降温至-78℃，缓慢加入正丁基锂(1.6M in hexane，14.9ml)，加完后搅拌10分钟。加入上述新制备的格式反应液，加毕后回至室温搅拌1h。将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得4.0g白色固体。
(3aS,5S,6R,6aS)-5-((S)-(3-氯-4-甲基苯基)(羟基)甲基)-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-6-醇
于250ml反应瓶加入(3-氯-4-甲基苯基)((3aS,5R,6S,6aS)-6-羟基-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-5-基)甲酮(3.0g)，七水氯化铈(4.3g)，甲醇(60ml)，冰浴降温至0℃，缓慢滴入硼氢化钠(0.4g)的1M氢氧化钠水溶液(5ml)，滴毕后回至室温搅拌1h。将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤浓缩，得3.0g淡黄色固体。
(2R,3S,4R,5S,6S)-6-(3-氯-4-甲基苯基)四氢-2H-吡喃-2,3,4,5-四基四乙酸酯
于150ml反应瓶加入(3aS,5S,6R,6aS)-5-((S)-(3-氯-4-甲基苯基)(羟基)甲基)-2,2-二甲基四氢呋喃并[2,3-d][1,3]间二氧杂环戊烯-6-醇(3.0g)，冰醋酸(15ml)，水(15ml)，加热至110℃搅拌4h。反应液浓缩至干，用甲苯共沸蒸馏3次，残留物用30ml乙腈溶解， 加入三乙胺(13.3ml)，于35℃缓慢滴加醋酸酐(9.0ml)的乙腈溶液(18ml)，滴毕后冷却至室温搅拌15h。反应液用乙酸乙酯稀释，加水，分液，水相用乙酸乙酯萃取3次，合并有机相，稀盐酸洗一次，饱和食盐水洗一次，无水硫酸钠干燥，过滤浓缩得4.6g棕色油状物，直接投下一步反应。
(2S,3S,4R,5S,6R)-2-(3-氯-4-甲基苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三乙酸三酯
于150ml反应瓶加入(2R,3S,4R,5S,6S)-6-(3-氯-4-甲基苯基)四氢-2H-吡喃-2,3,4,5-四基四乙酸酯(4.6g(理论量))，硫脲(1.5g)，1,4-二氧六环(40ml)，三氟甲磺酸三甲基硅酯(3.5ml)，加热至90℃搅拌2h。将反应液冷至室温，加入碘甲烷(1.8ml)，N,N-二异丙基乙胺(9.5ml)，搅拌15h。向反应液中加入乙酸乙酯和水，分液，水相用乙酸乙酯萃取3次，合并有机相，用稀盐酸洗一次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得2.4g淡黄色固体。
1H NMR(CDCl 3,400MHz):δ7.33(d,J＝1.6Hz,1H),7.21(d,J＝7.9Hz,1H),7.17-7.14(dd,J＝1.6,7.8Hz,1H),5.36(t,J＝9.4Hz,1H),5.23(t,J＝9.7Hz,1H),5.10(t,J＝9.7Hz,1H),4.55(d,J＝9.9Hz,1H),4.41(d,J＝9.9Hz,1H),2.37(s,3H),2.22(s,3H),2.12(s,3H),2.04(s,3H),1.87(s,3H).MS:m/z 453.1,[M+Na] +。
(2S,3S,4R,5S,6R)-2-(4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯
于25ml微波管中加入(2S,3S,4R,5S,6R)-2-(3-氯-4-甲基苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三乙酸三酯(1.2g)，联硼酸频哪醇酯(1.4g)，醋酸钾(0.8g)，醋酸钯(0.05g)，2-二环己基膦-2’,6’-二甲氧基联苯(0.1g)，1,4-二氧六环(10ml)，氮气置换后，微波加热至60℃搅拌18h。反应液浓缩后，柱层析纯化，得1.1g淡黄色固体。 1H NMR(CDCl 3,400MHz):δ7.67(d,J＝2.0Hz,1H),7.37(dd,J＝2.1,8.0Hz,1H),7.17(d,J＝7.9Hz,1H),5.36(t,J＝9.4Hz,1H),5.24(t,J＝9.6Hz,1H),5.15(t,J＝9.7Hz,1H),4.54(d,J＝9.9Hz,1H),4.46(d,J＝9.9Hz,1H),2.52(s,3H),2.20(s,3H),2.12(s,3H),2.03(s,3H),1.85(s,3H),1.35(d,J＝3.3Hz,12H).MS:m/z 545.2,[M+Na] +。
3-(4-甲酰苄基)氧基)丙酸乙酯
于150ml反应瓶中，加入对羟甲基苯甲醛(3.0g)，四氢呋喃(30ml)，冰浴降温至0℃，缓慢滴入3-溴丙酸乙酯(14.1ml)的四氢呋喃溶液(15ml)，滴毕后回至室温搅拌15h。将反应液倒入饱和氯化铵水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得800mg无色液体。 1H NMR(CDCl 3,400MHz):δ10.03(s,1H),7.89(d,J＝8.2Hz,2H),7.52(d,J＝8.0Hz,2H),4.64(s,2H),4.19(q,J＝7.1Hz,2H),3.82(t,J＝6.3Hz,2H),2.66(t,J＝6.3Hz,2H),1.29(t,J＝7.1Hz,3H)。
3-(4-(羟甲基)苄氧基)-丙酸乙酯
于50ml反应瓶加入3-(4-甲酰苄基)氧基)丙酸乙酯(800mg)，甲醇(16ml)，冰浴 降温至0℃，分批加入硼氢化钠(193mg)，加毕后回至室温搅拌2h。将反应液倒入1N的HCl水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，减压浓缩，柱层析纯化，得600mg无色液体。 1H NMR(CDCl 3,400MHz):δ7.36-7.32(m,4H),4.68(s,2H),4.54(s,2H),4.17(q,J＝7.2Hz,2H),3.75(t,J＝6.4Hz,2H),2.62(t,J＝6.4Hz,2H),2.07(br s,1H),1.27(t,J＝7.1Hz,3H)。
3-((4-(((甲氧基羰基)氧基)甲基)苄基)氧基)丙酸乙酯
于50ml反应瓶中加入3-(4-(羟甲基)苄氧基)-丙酸乙酯(600mg)，吡啶(0.4ml)，二氯甲烷(6ml)，冰浴降温至0℃，缓慢滴入氯甲酸甲酯(0.5ml)的二氯甲烷溶液(2ml)，滴毕后回至室温搅拌3h。将反应液倒入1N的HCl水溶液中，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤浓缩，柱层析纯化，得620mg无色液体。 1H NMR(CDCl 3,400MHz):δ7.41-7.34(m,4H),5.17(s,2H),4.55(s,2H),4.18(q,J＝7.1Hz,2H),3.81(s,3H),3.76(t,J＝6.4Hz,2H),2.63(t,J＝6.4Hz,2H),1.28(t,J＝7.1Hz,3H)。
(2S,3S,4R,5S,6R)-2-(3-(4-(3-乙氧基-3-氧代丙基氧基)甲基)苄基)-4-甲基苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯
于25ml三口瓶中加入1,4-双(二苯基膦)丁烷(72mg)，氯化烯丙基钯(II)二聚物(32mg)，甲苯(4ml)，异丙醇(2ml)，氮气置换后，室温搅拌30min。
于25ml微波反应管中加入(2S,3S,4R,5S,6R)-2-(4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(911mg)，3-((4-(((甲氧基羰基)氧基)甲基)苄基)氧基)丙酸乙酯和异丙醇(8ml)，氮气置换后加入上述催化剂，微波80℃反应12h。将反应液减压浓缩，柱层析纯化，得540mg油状物。 1H NMR(CDCl 3,400MHz):δ7.23(d,J＝8.1Hz,2H),7.18-7.13(m,2H),7.07-7.05(m,3H),5.34(t,J＝9.4Hz,1H),5.22(t,J＝9.6Hz,1H),5.13(t,J＝9.7Hz,1H),4.53(d,J＝9.9Hz,1H),4.50(s,2H),4.40(d,J＝9.8Hz,1H),4.15(q,J＝7.2Hz,2H),4.00-3.92(m,2H),3.75(t,J＝6.4Hz,2H),2.61(t,J＝6.4Hz,2H),2.21(s,3H),2.18(s,3H),2.11(s,3H),2.02(s,3H),1.76(s,3H),1.27(t,J＝6.4Hz,3H)。
3-((4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲硫基)四氢-2H-吡喃-2-基)苄基)苄基)氧基)丙酸
于25ml反应瓶加入(2S,3S,4R,5S,6R)-2-(3-(4-(3-乙氧基-3-氧代丙基氧基)甲基)苄基)-4-甲基苯基)-6-(甲硫基)四氢-2H-吡喃-3,4,5-三基三乙酸酯(540mg)，甲醇(3ml)，四氢呋喃(1.5ml)，水(3ml)，一水氢氧化锂(368mg)，室温搅拌15h。反应液加水稀释，乙酸乙酯萃取3次，弃去有机相，水相用稀盐酸将pH调至1，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩至干，得300mg无色泡沫状物。 1H NMR(DMSO-d6,400MHz):δ12.19(br s,1H),7.22(d,J＝8.1Hz,2H),7.13-7.11(m,5H),5.22(br s,1H),4.89(br s,1H),4.42(s,2H),4.33(d,J＝9.4Hz,1H),4.05(d, J＝9.1Hz,1H),3.94(s,2H),3.61(t,J＝6.3Hz,2H),3.51-3.45(m,1H),3.30-3.17(m,3H),2.48(t,J＝6.3Hz,2H),2.18(s,3H),2.04(s,3H). 13C NMR(DMSO-d6,100MHz):δ173.2,140.0,138.7,137.9,136.3,135.8,130.1,129.7,128.9,128.1,126.0,85.8,81.8,78.6,74.8,72.7,72.2,66.0,38.9,35.2,19.5,11.5.MS:m/z 485.2,[M+Na] +。
中间体：N 1-甲基-N 1-(丙-2-炔-1-基)乙-1,2-二胺
Figure PCTCN2020131248-appb-000037
N-Boc-溴乙胺
于25ml反应瓶中依次加入四氢呋喃(4ml)，水(4ml)，溴乙胺氢溴酸(2.05g)，降温至10℃，加入碳酸氢钠(2.1g)，4-二甲氨基吡啶(61mg)，二碳酸二叔丁酯(2.05g)，加完后10℃搅拌8h。将反应液过滤，滤液分液，水相用二氯甲烷萃取两次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩得2.0g淡黄色液体。
N 1-甲基-N 1-(丙-2-炔-1-基)乙-1,2-二胺
于100ml反应瓶中依次加入N-甲基炔丙基胺(0.68g)，四氢呋喃(20ml)，水(20ml)，碳酸钾(2.46g，17.8mmol)，N-Boc-溴乙胺(2.0g)的四氢呋喃溶液(5ml)，加完后室温搅拌2h。反应液用乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，得1.72g淡黄色油状物。将所得粗品溶于乙腈(10ml)，缓慢滴入浓盐酸(5ml)，室温搅拌1h，将反应液减压浓缩，加入10ml乙腈溶解，加入碳酸钾(3.35g，24.3mmol)，35℃搅拌3h，冷却至室温，垫硅藻土过滤，乙腈洗涤，滤液浓缩至干，得0.67g淡黄色液体。MS：m/z 112.9,[M+H] +。
中间体：2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺
Figure PCTCN2020131248-appb-000038
于50ml反应瓶依次加入2-((叔丁氧基羰基)氨基)-2-甲基丙酸(894mg)，二氯甲烷(25ml)，冰浴降温至0℃，缓慢加入CDI(713mg)，加完后于0℃搅拌30分钟。加入N 1-甲基-N 1-(丙-2-炔-1-基)乙-1,2-二胺(450mg)，加毕后回至室温搅拌3h。反应液加入二氯甲烷稀释，加水分液，水相用二氯甲烷萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩至干，得1.04g淡黄色液体。将产物溶于乙腈(5ml)，缓慢滴入浓盐酸(2ml)，室温搅拌1h，将反应液浓缩至干，加入乙腈(10ml)溶解，加入碳酸钾(1.93g)，35℃搅拌3h，冷却至室温，垫硅藻土过滤，乙腈洗涤，滤液减压浓缩，得550mg淡黄色液体。MS:m/z 198.2,[M+H] +。
中间体：2-氨基-N-(2-(二甲基氨基)乙基)-2-甲基丙酰胺
Figure PCTCN2020131248-appb-000039
于50ml反应依次加入2-((叔丁氧基羰基)氨基)-2-甲基丙酸(2.03g)，二氯甲烷(25ml)，冰浴降温至0℃，缓慢加入CDI(1.62g)，加完后0℃搅拌30分钟。加入N,N-二甲基乙二胺(970mg)，加毕后回至室温搅拌3h。反应液加入二氯甲烷稀释，加水分液，水相用二氯甲烷萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，得1.96g淡黄色液体。将产物溶于乙腈(10ml)，缓慢滴入浓盐酸(4ml)，室温搅拌1h，将反应液浓缩至干，加入乙腈(10ml)溶解，加入碳酸钾(4.14g，30mmol)，35℃搅拌3h，冷却至室温，垫硅藻土过滤，乙腈洗涤，滤液减压浓缩，得930mg淡黄色液体。MS:m/z174.2,[M+H] +。
中间体：2-氨基-2-甲基-N-(2-(甲基(2-(甲基(丙-2-炔-1-基)氨基)-2-氧代乙基)氨基)乙基)丙酰胺
Figure PCTCN2020131248-appb-000040
N-(2-((叔丁氧基羰基)氨基)乙基)-N-甲基甘氨酸乙酯
于100ml反应瓶中依次加入2-(甲基氨基)乙基氨基甲酸叔丁酯(8.7g)，乙腈(100ml)，碳酸钾(10.4g)，溴乙酸乙酯(9.2g)，加热至35℃搅拌10h。反应液过滤，滤液减压浓缩，柱层析纯化，得9.89g淡黄色油状物。
2-((2-氨基乙基)(甲基)氨基)-N-甲基-N-(丙-2-炔-1-基)乙酰胺
于50ml反应瓶中依次加入N-(2-((叔丁氧基羰基)氨基)乙基)-N-甲基甘氨酸乙酯(5.5g)，四氢呋喃(25ml)，氢氧化锂一水合物(0.98g)，水(2ml)，室温搅拌5h。反应液减压浓缩，将浓缩残留物用二氯甲烷(25ml)溶解，依次加入HATU(9.62g)，DIPEA(5.57g)，N-甲基炔丙基胺(1.75g)，室温搅拌3h。反应液用二氯甲烷稀释，加入水，分液，有机相用饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，柱层析纯化，得3.2g淡黄色油状物。将产物溶于乙腈(15ml)，缓慢滴入浓盐酸(5ml)，室温搅拌1h。将反应液浓缩，加入乙腈(15ml)溶解，加入碳酸钾(6.24g)，35℃搅拌3h。反应液冷却至室温，垫硅藻土过滤，乙腈洗涤，滤液浓缩，得1.67g淡黄色液体。
2-氨基-2-甲基-N-(2-(甲基(2-(甲基(丙-2-炔-1-基)氨基)-2-氧代乙基)氨基)乙基)丙酰胺
于50ml反应瓶依次加入2-((叔丁氧基羰基)氨基)-2-甲基丙酸(2.03g)，二氯甲烷(25 ml)，冰浴降温至0℃，缓慢加入CDI(1.62g)，加完后于0℃搅拌30分钟。加入2-((2-氨基乙基)(甲基)氨基)-N-甲基-N-(丙-2-炔-1-基)乙酰胺(1.67g)，加毕后回至室温搅拌3h。向反应瓶中加入二氯甲烷稀释，加水分液，水相用二氯甲烷萃取3次，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩至干，柱层析纯化，得2.1g淡黄色油状物。将产物溶于乙腈(10ml)，缓慢滴入浓盐酸(4ml)，室温搅拌1h。将反应液浓缩至干，加入乙腈(10ml)溶解，加入碳酸钾(3.15g，22.8mmol)，35℃搅拌3h。反应液冷却至室温，垫硅藻土过滤，乙腈洗涤，滤液减压浓缩至干，得1.24g淡黄色油状物。MS:m/z269.2,[M+H] +。
中间体：N 1-苄基-N 1-甲基乙烷-1,2-二胺
Figure PCTCN2020131248-appb-000041
于250ml单口瓶中加入苄溴(10g)，乙腈(100ml)，2-(甲基氨基)乙基氨基甲酸叔丁酯(15.3g)和碳酸钾(16.1g)，加毕升温至75℃搅拌2小时。反应完毕，过滤除去不溶固体，滤液浓缩，硅胶柱层析纯化，得黄色液体11.2g。
向上步产品中加入二氯甲烷(100ml)，室温下加入三氟乙酸(30ml)，加毕室温搅拌4小时。反应完毕，加水稀释，静置分层，水相用二氯甲烷萃取3次，弃有机相。水相用碳酸钾水溶液调pH至10～11，再用二氯甲烷萃取4次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤浓缩，得黄色液体4.6g。 1H NMR(400MHz,DMSO-d 6):δ7.37-7.20(m,5H),3.48(s,2H),2.82(t,J＝6.4Hz,2H),2.49(t,J＝6.4Hz,2H),2.10(s,3H).MS:m/z 165.1,[M+H] +。
中间体：2-氨基-2-甲基-N-(2-(吡咯烷-1-基)乙基)丙酰胺
Figure PCTCN2020131248-appb-000042
于100ml单口瓶中加入N-叔丁氧羰基-2-甲基丙氨酸(5g)和二氯甲烷(35ml)，室温分批加入N,N'-羰基二咪唑(4.4g)，室温搅拌30分钟。降温至0℃，滴加N-(2-氨基乙基)吡咯烷(3.4g)的二氯甲烷溶液(10ml)，滴毕，回至室温搅拌1小时。反应完毕，加入水淬灭，静置分层，水相用二氯甲烷萃取3次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩至干，加入约10mL乙酸乙酯搅拌0.5小时，过滤，滤饼用冷却的乙酸乙酯冲洗两遍，真空干燥得白色固体5.7g。MS:m/z 300.2,[M+H] +。
向上一步产物(5.7g)中加入二氯甲烷(25ml)，0℃下加入三氟乙酸(18ml)，室温搅拌4小时。反应完毕，加水稀释，静置分层，弃有机相；水相用碳酸钾水溶液调pH至10～11，再用乙酸乙酯萃取4次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥， 过滤浓缩，得黄色液体3.2g。
中间体：2-氨基-2-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)丙酰胺
Figure PCTCN2020131248-appb-000043
于100ml单口瓶中加入N-叔丁氧羰基-2-甲基丙氨酸(5g)和二氯甲烷(35ml)，室温分批加入N,N'-羰基二咪唑(4.4g)，室温搅拌30分钟。降温至0℃，滴加4-甲基-1-哌嗪乙胺(4.2g)的二氯甲烷溶液(10mL)，滴毕，回至室温搅拌1小时。反应完毕，加入水淬灭，静置分层，水相用DCM萃取3次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤浓缩，硅胶柱层析，得淡黄色液体6.7g。MS:m/z 329.3,[M+H] +。
向上一步产品(6.7g)中加入二氯甲烷(33ml)，0℃条件下加入三氟乙酸(23ml)，室温搅拌3小时。反应完毕，加水稀释，静置分层，弃有机相；水相用碳酸钾水溶液调pH至10～11，再用乙酸乙酯萃取4次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤浓缩，有大量固体析出，加入二氯甲烷搅拌，将不溶物过滤，滤液旋干得黄色液体3.1g。MS:m/z 229.2,[M+H] +。
中间体：2-氨基-N-(2-(苄基(甲基)氨基)乙基)-2-甲基丙酰胺
Figure PCTCN2020131248-appb-000044
于50ml单口瓶中加入N-叔丁氧羰基-2-甲基丙氨酸(2g)和二氯甲烷(14ml)，室温分批加入N,N'-羰基二咪唑(1.75g)，室温搅拌30分钟。降温至0℃，滴加N 1-苄基-N 1-甲基乙烷-1,2-二胺(1.94g)的二氯甲烷溶液(5ml)，滴毕，回至室温搅拌1小时。反应完毕，加入水淬灭，静置分层，水相用二氯甲烷萃取3次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩至干，加入约10ml乙酸乙酯搅拌0.5小时，过滤，滤饼用冷却的乙酸乙酯冲洗两遍，真空干燥得白色固体1.0g。MS:m/z 350.2,[M+H] +。
向上一步产品(1g)加入二氯甲烷(5mL)，0℃条件下加入三氟乙酸(3ml)，室温搅拌2小时。反应完毕，加水稀释，静置分层，弃有机相；水相用碳酸钾水溶液调pH至10～11，再用乙酸乙酯萃取4次，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤浓缩，得黄色液体480mg。MS:m/z 250.2,[M+H] +。
化合物制备
实施例1
Figure PCTCN2020131248-appb-000045
于50ml单口瓶中加入4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基)丁酸(80mg)，2-氨基-2-甲基-N-(2-(吡咯烷-1-基)乙基)丙酰胺(38mg)，四氢呋喃(3ml)，N,N-二异丙基乙胺(70mg)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸盐(89mg)，加毕室温搅拌2小时。反应完毕，加入饱和氯化铵水溶液稀释，乙酸乙酯萃取，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析纯化，得白色固体55mg。 1H NMR(400MHz,CD 3OD):δ＝7.26-7.04(m,7H),4.42(d,J＝9.5Hz,1H),4.16(d,J＝9.3Hz,1H),3.97(s,2H),3.60(t,J＝5.5Hz,2H),3.55-3.36(m,8H),3.27-2.88(m,2H),2.61(t,J＝7.5Hz,2H),2.27(t,J＝7.6Hz,2H),2.22(s,3H),2.16(s,3H),2.04(m,4H),1.94-1.82(m,2H),1.43(s,6H).MS:m/z 628.3,[M+H] +。
实施例2
Figure PCTCN2020131248-appb-000046
于50ml单口瓶中加入4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基)丁酸(80mg)，2-氨基-2-甲基-N-(2-(4-甲基哌嗪-1-基)乙基)丙酰胺(42mg)，四氢呋喃(3ml)，N,N-二异丙基乙胺(70mg)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸盐(89mg)，加毕室温搅拌2小时。反应完毕，加入饱和氯化铵水溶液稀释，乙酸乙酯萃取，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析纯化，得白色固体16mg。 1H NMR(400MHz,CD 3OD):δ＝7.23-7.05(m,7H),4.41(d,J＝9.6Hz,1H),4.15(d,J＝9.3Hz,1H),3.98(s,2H),3.75(t,J＝6.5Hz,2H), 3.52-3.35(m,13H),2.62(t,J＝7.6Hz,4H),2.30-2.25(m,2H),2.24(s,3H),2.16(s,3H),1.95-1.84(m,4H),1.44(s,6H).MS:m/z 657.4,[M+H] +。
实施例3
Figure PCTCN2020131248-appb-000047
于50ml单口瓶中加入4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基)丁酸(80mg)，2-氨基-N-(2-(苄基(甲基)氨基)乙基)-2-甲基丙酰胺(45mg)，四氢呋喃(3ml)，N,N-二异丙基乙胺(70mg)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸盐(89mg)，加毕室温搅拌2小时。反应完毕，加入饱和氯化铵水溶液稀释，乙酸乙酯萃取，合并有机相，用饱和食盐水洗一次，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析纯化，得白色固体50mg。 1H NMR(400MHz,CD 3OD):δ＝7.37-7.23(m,5H),7.23-7.10(m,3H),7.10-7.00(m,4H),4.41(d,J＝9.4Hz,1H),4.15(d,J＝9.1Hz,1H),3.95(s,2H),3.59(s,2H),3.53-3.34(m,6H),2.65-2.53(m,4H),2.23(s,3H),2.22-2.18(m,5H),2.15(s,3H),1.93-1.80(m,2H),1.43(s,6H).MS:m/z 678.4,[M+H] +。
实施例4
Figure PCTCN2020131248-appb-000048
于25ml反应瓶中依次加入4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苯甲基)苯基)丁酸(参考文献方法Journal of Medicinal Chemistry 2017,60,710-721制备得到)(89mg)，N,N-二甲基甲酰胺(5ml)，N,N-二异丙基乙胺(52mg)，2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺(39mg)，2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸盐(84mg)，室温搅拌2小时。反应液用 二氯甲烷稀释，加入水洗，水相用二氯甲烷萃取三次，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩至干，柱层析纯化，得白色固体(42mg)。 1H NMR(400MHz,DMSO-d6):δppm 7.82(s,1H),7.27-7.23(t,J＝5.5Hz,1H),7.13-7.04(m,7H),5.23-5.21(d,J＝5.6Hz,1H),5.13-5.12(d,J＝4.6Hz,1H),4.88-4.86(d,J＝5.6Hz,1H),4.35-4.32(d,J＝9.4Hz,1H),4.07-4.04(d,J＝9.1Hz,1H),3.95-3.87(m,2H),3.31-3.16(m,4H),3.11-3.05(m,3H),2.37-2.34(t,J＝6.7Hz,2H),2.18(s,3H),2.16(s,3H),2.10-2.06(t,J＝7.5Hz,2H),2.04(s,3H),1.78-1.70(m,2H),1.29(s,6H). 13C NMR(100MHz,DMSO-d6):δppm 174.5,172.0,139.8,138.9,138.1,137.8,135.8,130.1,129.7,128.9,128.8,126.0,85.8,81.8,79.4,78.6,76.2,74.8,72.7,56.2,54.5,45.5,41.6,38.8,37.3,35.5,34.8,27.4,25.7,19.5,11.5；MS[M+H] +＝626.3。
实施例5
Figure PCTCN2020131248-appb-000049
参考实施例1类似的制备方案，得到化合物，ESI-MS：628.2[M+H] +。
具体制备方法如下：
Figure PCTCN2020131248-appb-000050
于25ml反应瓶中依次加入3-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基氧基)丙酸(63mg)，N,N-二甲基甲酰胺(5ml)，N,N-二异丙基乙胺(45mg)，2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺(36mg)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(70mg)，加毕室温搅拌4小时。反应液用二氯甲烷稀释，加入水洗，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩至干，柱层析纯化，得淡黄色固体30mg。
实施例6
Figure PCTCN2020131248-appb-000051
参考实施例1类似的制备方案，得到化合物，ESI-MS：642.2[M+H] +。
具体制备方法如下；
Figure PCTCN2020131248-appb-000052
于25ml反应瓶中依次加入3-((4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲硫基)四氢-2H-吡喃-2-基)苄基)苄基)氧基)丙酸(92mg)，N,N-二甲基甲酰胺(5ml)，N,N-二异丙基乙胺(52mg)，2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺(39mg)，2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸盐(84mg)，室温搅拌2h。反应液用二氯甲烷稀释，加入水洗，水相用二氯甲烷萃取3次，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩至干，柱层析纯化，得32mg白色固体。 1H NMR(400MHz,DMSO-d6):δ7.97(s,1H),7.24-7.10(m,7H),5.25(br s,1H),4.92(br s,1H),4.42(s,2H),4.33(d,J＝9.4Hz,1H),4.04(d,J＝9.0Hz,1H),3.94(s,2H),3.60(t,J＝6.4Hz,2H),3.29-3.21(m,4H),3.12(br s,1H),3.08-3.00(m,2H),2.38(t,J＝6.5Hz,2H),2.30(t,J＝6.7Hz,2H),2.17(s,3H),2.15(s,3H),2.03(s,3H),1.30(s,6H). 13C NMR(100MHz,DMSO-d6):δ174.4,170.2,140.0,138.7,137.9,136.4,135.8,130.1,129.8,128.9,128.0,126.0,85.8,81.8,79.5,78.6,76.2,74.8,72.7,72.1,70.2,66.7,56.3,45.6,41.6,38.9,37.4,36.8,25.7,19.5,11.5.MS:m/z 642.3,[M+H] +。
实施例7
Figure PCTCN2020131248-appb-000053
参考实施例1类似的制备方案，得到化合物，ESI-MS：624.4[M+H] +。
具体制备方法如下：
Figure PCTCN2020131248-appb-000054
于25ml反应瓶中依次加入(E)-4-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基)乙烯基乙酸(65mg)，N,N-二甲基甲酰胺(5ml)，N,N-二异丙基乙胺(45mg)，2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺(35mg)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(70mg)，加毕室温搅拌。反应液用二氯甲烷稀释，加入水洗，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩至干，柱层析纯化，得类白色固体32mg。
实施例8
Figure PCTCN2020131248-appb-000055
参考实施例1类似的制备方案，得到化合物，ESI-MS：638.3[M+H] +。
具体制备方法如下：
Figure PCTCN2020131248-appb-000056
于25ml反应瓶中依次加入3-(4-(2-乙炔基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基氧基)丙酸(55mg)，N,N-二甲基甲酰胺(5ml)，N,N-二异丙基乙胺(40mg)，2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺(30mg)， 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(60mg)，加毕室温搅拌。反应液用二氯甲烷稀释，加入水洗，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩至干，柱层析纯化，得浅黄色固体26mg。
实施例9
Figure PCTCN2020131248-appb-000057
参考实施例1类似的制备方案，得到化合物，ESI-MS：628.5[M+H] +。
具体制备方法如下：
Figure PCTCN2020131248-appb-000058
于25ml反应瓶中依次加入2-((4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苄基)氧基)乙酸(58mg)，N,N-二甲基甲酰胺(5ml)，N,N-二异丙基乙胺(34mg)，2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺(30mg)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(60mg)，加毕室温搅拌4小时。反应液用二氯甲烷稀释，加入水洗，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩至干，柱层析纯化，得浅黄色固体22mg。
实施例10
Figure PCTCN2020131248-appb-000059
参考实施例1类似的制备方案，得到化合物，ESI-MS：640.0[M+H] +。
具体制备方法如下：
Figure PCTCN2020131248-appb-000060
于25ml反应瓶中依次加入5-(4-(2-甲基-5-((2S,3R,4R,5S,6R)-3,4,5-三羟基-6-(甲基硫基)四氢-2H-吡喃-2-基)苄基)苯基)戊酸(60mg)，N,N-二甲基甲酰胺(6ml)，N,N-二异丙基乙胺(34mg)，2-氨基-2-甲基-N-(2-(甲基(丙-2-炔-1-基)氨基)乙基)丙酰胺(31mg)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(60mg)，加毕室温搅拌。反应液用二氯甲烷稀释，加入水洗，水相用二氯甲烷萃取，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩至干，柱层析纯化，得浅黄色固体26mg。
本发明部分化合物引入了“炔”官能团有两方面的优势特点：
一方面，“炔”官能团可以利用“Click chemistry”连接生物荧光标记物，有利于准确判断化合物在体内的分布，例如，本发明化合物与具有荧光发色团的“叠氮类”化合物，在铜盐的催化作用下，发生的“Click chemistry”，生成具有“三氮唑结构”荧光化合物，本发明化合物还能与其他具有生物标记功能的化学物质进行连接，形成易于检测的新的化学物质，对充分研究该类化合物的有效性和安全性具有重要意义。
另一方面“炔”官能团，通过“Click chemistry”连接其他药效基团，有利于寻找综合性能更优的候选化合物。现举例说明如下：
利用“点击化学”进行探索性研究：
(1)制备具有发光特性的标记化合物
Figure PCTCN2020131248-appb-000061
将实施例4化合物，硫酸铜，和7-羟基-3-叠氮基香豆素(参考Journal of the American Chemical Society(2014),136(20),7205-7208；Chemistry-A European Journal(2011),17(12),3326-3331,S3326/1-S3326/21；Journal of Fluorescence(2013),23(1),181-186；Journal of Organic Chemistry(2011),76(12),4964-4972；Angewandte Chemie,International Edition(2019),58(21),6987-6992)于室温反应得到产物。Rf：0.14(二氯甲烷：甲醇＝10:1)。
(2)制备综合性能更优的候选化合物
Figure PCTCN2020131248-appb-000062
将实施例4化合物，硫酸铜，和环丙基叠氮化合物(参考Chemische Berichte(1985),118(4),1564-1574；Science of Synthesis(2010),41,543-612；Nature(London,United Kingdom)(2019),574(7776),86-89)于室温搅拌反应，待反应完成后，利用硅胶柱层析可以制备得到目标化合物。Rf：0.16(二氯甲烷：甲醇＝10:1)。该化合物与实施例4具有相同的生物活性，相比于实施例4化合物具有更优的脂溶性和水溶性特点。
生物测试
1.SGLT1抑制剂活性实验1
参考文献(Journal of Medicinal Chemistry 2017,60,710-721，Discovery of LX2761,a Sodium-Dependent Glucose Cotransporter 1(SGLT1)Inhibitor Restricted to the Intestinal Lumen,for theTreatment of Diabetes)记载的方法进行SGLT1的抑制活性测试。测试结果如下：
化合物编号 SGLT1活性
1(实施例4) A
2(实施例5) A
3(实施例6) A
4(实施例7) A
5(实施例8) A
其中A表示：活性IC50<50nM，B表示50nM<IC50<1000nM，C表示IC50>1000nM，
实验结果表明，本发明化合物具有显著的抑制SGLT1的活性。
在小鼠糖耐量试验中，本发明化合物具有改善试验动物血糖水平的作用。
本发明化合物助于体重降低，体内药效学研究中，本发明化合物降低实验动物的体重。
本发明化合物体内吸收很低或者不吸收，药代动力学研究表明，本发明化合物在实验动物体内几乎无检出，对体内其他器官几乎无副作用。
2.hSGLT1抑制剂活性实验2
参考文献[Acta Pharmaceutica Sinica 2017,52(6):897-903；Nature Protocols(2007),2(3),753-762；Journal of Biochemical and Biophysical Methods(2005),64(3),207-215；Diabetes Technology&Therapeutics(2011),13(7),743-775]记载的类似方法进行抑制活性测试。
本试验体外活性测定利用人胚胎肾上皮细胞(HEK293，稳定表达人SGLT1)对2-NBDG(2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose，CAS NO：186689-07-6)的摄入进行评价，通过测定其半数最大抑制浓度(IC 50)来确定目标化合物的SGLT1抑制活性。
将能够稳定表达人SGLT1基因的HEK293细胞接种于含有DMEM培养基的96孔透明底黑板中。在37℃，5％CO 2的细胞培养箱种孵育。吸取96孔板中培养基，用低糖无血清DMEM培养基处理，再用非特异性摄取缓冲液和Na +依赖性摄取缓冲液各洗一遍。向每孔细胞中加入含测试化合物的摄取缓冲液，再加入含有2-NBDG的摄取液进行葡萄糖摄取，将细胞板在37℃，5％CO 2下孵育。化合物梯度稀释。通过去除培养液，停止摄取反应，用冰冷的摄取缓冲液洗涤细胞后，移除洗涤液。加入NaOH裂解细胞，采用荧光酶标仪检测细胞内2-NBDG的含量。BCA法测裂解液蛋白浓度，通过荧光强度/蛋白含量对2-NBDG的摄入量进行量化，并使用GraphPad Prism对所得到的数据进行分析，确定待测化合物的半数抑制浓度(IC 50)。
对比化合物18即是文献(Journal of Medicinal Chemistry 2017,60,710-721，Discovery of LX2761,a Sodium-Dependent Glucose Cotransporter 1(SGLT1)Inhibitor Restricted to the Intestinal Lumen,for theTreatment of Diabetes)中编号为“18”的化合物。其制备按照文献记载的合成方法制备得到并鉴定之。
测试结果：
Figure PCTCN2020131248-appb-000063
实验结果表明，本发明实施例化合物，例如，实施例1，实施例2，实施例3，实施例4，具有显著的抑制SGLT1的活性。
3.大鼠连续给药14天后糖耐量(OGTT)试验
实验动物：SPF级雄性SD大鼠；
化合物准备：称取适量实施例1，实施例3，实施例4的化合物，用适量0.5％的CMC-Na溶液均匀混悬；
葡萄糖溶液准备：称取适量葡萄糖粉末，用适量纯水溶解；
给药剂量和方式：0.009mg/kg，口服灌胃；
实验过程：连续给药14天，动物正常饮食，第15天进行糖耐量试验，分别于给药前(-30min)，给予葡萄糖前(0min)，给予葡萄糖溶液后10，30，60，120min检测血糖，并观察动物排便情况。
实验结果：图1的结果表明，实施例1，实施例3，实施例4的化合物能够显著降低大鼠血糖水平，在实验的前后48h，实验动物均没有观察到稀便现象。
4.小鼠连续给药后糖耐量(OGTT)试验
实验动物：SPF级雄性小鼠；
化合物准备：称取适量实施例4化合物，用适量0.5％的CMC-Na溶液均匀混悬；
葡萄糖溶液准备：称取适量葡萄糖粉末，用适量纯水溶解；
给药方式和剂量：口服灌胃；空白溶媒组，高剂量组(1.5mg/kg)，低剂量组(0.1mg/kg)。
实验过程：
(1)将小鼠进行高糖饮食喂养6天，然后分组(每组10只)，进入给药阶段；
(2)第1至5天每天下午5点给予实施例化合物4，每天给药一次，然后动物高糖自由饮食，观察动物排便情况。
(3)第6天进行糖耐量试验，口服给予葡糖糖溶液(2g/kg)。分别于给予葡萄糖前(0min)，给予葡萄糖溶液后10，30，60min检测血糖。
实验结果：
(1)第1至5天，连续给药后动物排便情况观察总结如下：
Figure PCTCN2020131248-appb-000064
说明：表格中数据代表“稀便症状”动物总数与该组动物总数，例如“3/10”即是每组10只的动物中，有3只出现“稀便症状”。
(2)第6天糖耐量试验结果见图2。
实验总结：(1)第1至5天，连续给药实施例化合物4，高剂量组(1.5mg/kg)，第1天和第2天，仅有少数动物出现稀便现象，第3至5天，动物没有出现稀便现象；低剂 量组(0.1mg/kg)，连续给药5天，动物没有出现稀便现象。
(2)第6天，OGTT试验中，图2结果表明，实施例4化合物高低剂量组均能够显著降低小鼠血糖水平。
5.大鼠药代动力学研究
实验动物：SPF级雄性SD大鼠；
给药剂量和方式：10mg/kg，口服灌胃；
研究化合物：达格列净(Dapagliflozin)，实施例4化合物，实施例6化合物，对比化合物6；
试验方法：于给药前(0)，给药后1，4，8，24h眼眶静脉丛取血0.2ml，肝素抗凝，收集血浆。
说明：对比化合物6即是文献(Journal of Medicinal Chemistry 2017,60,710-721，Discovery of LX2761,a Sodium-Dependent Glucose Cotransporter 1(SGLT1)Inhibitor Restricted to the Intestinal Lumen,for theTreatment of Diabetes)中编号为“6”的化合物。其制备按照文献记载的合成方法制备得到并鉴定之。
大鼠药代动力学绝对生物利用度数据：
化合物 绝对生物利用度(F％)
实施例4 N/A
实施例6 N/A
达格列净 73％
对比化合物6 23％
N/A：由于血浆中药物浓度低于检测限，故未能检测到血浆中药物浓度，无法计算F％数值。
实验结果表明：实施例4，实施例6进行体内检测时，血浆药物浓度未达到检测限，无法定量检测实施例4和实施例6化合物进入体内的数量，表明实施例4，实施例6几乎无吸收，而对比化合物6其绝对生物利用度为23％，达格列净的绝对生物利用度为73％。因此，对比化合物6和达格列净，口服后，均吸收入血，其在体内器官(例如，大脑，心脏等器官)的暴露量高，具有潜在的，无法预知的毒性。
SGLT1除了在肾脏表达外，也存在于肠上皮细胞及心脏，大脑等器官内，本发明实施例4，实施例6化合物，与对比化合物6和达格列净相比，口服给药后，体内几乎未检出，因此，初步实验证据推断本发明实施例4，实施例6化合物，对心脏，大脑等各类脏器器官没有副作用。
6.联合西格列汀体内降糖药效实验
模型建立：本实验采用SPF级Balb/C雄性小鼠，采用腹腔注射链脲佐霉素(STZ)并辅以高脂高糖饲料喂养的方式诱导2型糖尿病小鼠模型的建立。
分组：每组10只
给药：正常组，模型组，低剂量联合给药组(实施例4化合物0.02mg/kg+西格列汀20mg/kg)，中剂量联合给药组(实施例4化合物0.05mg/kg+西格列汀20mg/kg)，高剂量联合给药组(实施例4化合物0.1mg/kg+西格列汀20mg/kg)，西格列汀组(20mg/kg)。正常组和模型组给予溶媒灌胃。
实验结果表明，实施例化合物4与西他列汀联用显著降低糖尿病模型动物的血糖水平，且具有量效关系。
7.化合物的肠道微生物代谢稳定性研究
方法：将采集的大鼠粪便进行处理，获取粪便悬浮液用于代谢稳定性测定。将大鼠粪便悬浮液与实施例5化合物组成的混合反应体系在37℃孵育3h，6h，12h，24h。对孵育体系中的实施例化合物4进行分析，测定剩余化合物的总量。其中“+”代表剩余量百分比为：<50％；“++”代表剩余量百分比为：50％～70％；“+++”代表剩余量百分比为：70％～90％；“++++”代表剩余量百分比为：>90％。
实验结果：
孵育时间 3h 6h 12h 24h
实施例4化合物剩余量百分比 ++++ ++++ +++ +++
试验结果表明，实施例4化合物在与大鼠粪便中的微生物孵育作用约24小时后，剩余的实施例4化合物仍然较多(>70％)。说明实施例4化合物，在肠道微生物代谢作用下，仍然可以保持较高的稳定性。
8.本发明化合物具有抗肿瘤效果，Hep3B异种移植瘤模型抗肿瘤实验中，发现本发明化合物能够抑制肿瘤的生长；在高脂饮食诱导的动物模型上的试验，提示本发明化合物有利于非酒精性脂肪肝病及非酒精性脂肪肝炎的缓解，以及与能量吸收代谢有关的肝脏和肾脏疾病的治疗。

Claims (18)

  1. 一种式(V)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100001
    其中，U，V，W和Q分别独立地选自氮原子或者CH；
    每个R 1a，R 1b，R 1c分别独立地选自卤素或者-OR 1A，-NHR 1A，其中每个R 1A独立的是氢，C1～C6烷基或者酰基；
    R 2选自-S(O) m-R 1A；
    每个R 3，R 4，R 5，R 6a，R 7a，R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6a和R 7a，R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
    R A，R B分别独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，卤代烷氧基，卤素，氨基，巯基，硝基，羟基，氰基，氧代基，C2～C8烯基，C2～C8炔基，环烷基，杂环基，芳基，杂芳基，-(CH 2) n1R aa，-(CH 2) n1OR aa，-SR aa，-(CH 2) n1C(O)R aa，-SR aa，-C(O)OR aa，-C(O)R aa，-S(O) m1R aa，-(CH 2) n1S(O) m1R aa，-NR aaR bb，-C(O)NR aaR bb，-NR aaC(O)R bb，-NR aaS(O) m1R bb；
    或者R A，R B连同与它们相连的氮原子一起形成3至8元杂环，该杂环可以包含一个或多个碳原子，氮原子，氧原子或硫原子，该杂环可以进一步被卤素，烷基，环烷基，芳基，烷氧基，烯基，炔基或氧代基取代；
    R aa，R bb各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，卤素，氰基，硝基，羟基，氨基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，其中所述的烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，任选进一步被选自氢，氘，硅基，烷基硅基，取代或未取代的烷基，卤素，羟基，取代或未取代的氨基，氧代基，硝基，氰基，取代或未取代烯基，取代或未取代炔基，取代或未取代烷氧基，取代或未取代羟烷基，取代或未取代的环烷基，取代或未取代的杂环基，取代或未取代的芳基和取代或未取代的杂芳基中一个或多个取代基所取代；
    Z选自氧原子，或者硫原子；
    n1＝0，1，2，3，4；
    m1＝0，1，2，3，4；
    m＝0，1，2；
    p＝0，1，2，3；
    q＝0，1，2，3；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y为连接基团，选自以下结构：
    Figure PCTCN2020131248-appb-100002
    其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
    E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
    s1＝0，1，2，3，4，5；
    s2＝0，1，2，3，4，5
    s3＝0，1，2，3，4，5。
  2. 一种式(VA)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100003
    其中，R 1a，R 1b，R 1c分别独立地选自卤素或者-OR 1A，-NHR 1A，其中R 1A独立的是氢，C1～C6烷基或者酰基；
    R 2选自-S(O) m-R 1A；
    每个R 3，R 4，R 5，R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被选自氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
    R A，R B分别独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，卤代烷氧基，卤素，氨基，巯基，硝基，羟基，氰基，氧代基，C2～C8烯基，C2～C8炔基，环烷基，杂环基，芳基，杂芳基，-(CH 2) n1R aa，-(CH 2) n1OR aa，-SR aa，-(CH 2) n1C(O)R aa，-SR aa，-C(O)OR aa，-C(O)R aa，-S(O) m1R aa，-(CH 2)n1S(O) m1R aa，-NR aaR bb，-C(O)NR aaR bb，-NR aaC(O)R bb，-NR aaS(O) m1R bb；
    或者R A，R B连同与它们相连的氮原子一起形成3至8元杂环，该杂环可以包含一个或多个碳原子，氮原子，氧原子或硫原子，该杂环可以进一步被卤素，烷基，环烷基，芳基，烷氧基，烯基，炔基或氧代基取代；
    R aa，R bb各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，卤素，氰基，硝基，羟基，氨基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，其中所述的烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，任选进一步被选自氢，氘，硅基，烷基硅基，取代或未取代的烷基，卤素，羟基，取代或未取代的氨基，氧代基，硝基，氰基，取代或未取代烯基，取代或未取代炔基，取代或未取代烷氧基，取代或未取代羟烷基，取代或未取代的环烷基，取代或未取代的杂环基，取代或未取代的芳基和取代或未取代的杂芳基中一个或多个取代基所取代；
    n1＝0，1，2，3，4；
    m1＝0，1，2，3，4；
    m＝0，1，2；
    p＝0，1，2，3；
    q＝0，1，2，3
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y为连接基团，选自以下结构：
    Figure PCTCN2020131248-appb-100004
    其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
    E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
    s1＝0，1，2，3，4，5；
    s2＝0，1，2，3，4，5
    s3＝0，1，2，3，4，5。
  3. 一种式(VA-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100005
    其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    每个R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被选自氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
    R A，R B分别独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，卤代烷氧基，卤素，氨基，巯基，硝基，羟基，氰基，氧代基，C2～C8烯基，C2～C8炔基，环烷基，杂环基，芳基，杂芳基，-(CH 2) n1R aa，-(CH 2) n1OR aa，-SR aa，-(CH 2) n1C(O)R aa，-SR aa，-C(O)OR aa，-C(O)R aa，-S(O) m1R aa，-(CH 2) n1S(O) m1R aa，-NR aaR bb，-C(O)NR aaR bb，-NR aaC(O)R bb，-NR aaS(O) m1R bb；
    R aa，R bb各自独立地选自氢，氘，烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，卤素，氰基，硝基，羟基，氨基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，其中所述的烷基，氘代烷基，卤代烷基，烷氧基，羟烷基，卤代烷氧基，烯基，炔基，氘代烯基，氘代炔基，环烷基，杂环基，芳基和杂芳基，任选进一步被选自氢，氘，硅基，烷基硅基，取代或未取代的烷基，卤素，羟基，取代或未取代的氨基，氧代基，硝基，氰基，取代或未取代烯基，取代或未取代炔基，取代或未取代烷氧基，取代或未取代羟烷基，取代或未取代的环烷基，取代或未取代的杂环基，取代或未取代的芳基和取代或未取代的杂芳基中一个或多个取代基所取代；
    n1＝0，1，2，3，4；
    m1＝0，1，2，3，4；
    p＝0，1，2，3；
    q＝0，1，2，3；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y为连接基团，选自以下结构：
    Figure PCTCN2020131248-appb-100006
  4. 下列化合物，其立体异构体，互变异构体，药学上可接受的盐，
    Figure PCTCN2020131248-appb-100007
    Figure PCTCN2020131248-appb-100008
  5. 一种式(VA-2)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100009
    其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    每个R 6b，R 7b，R 6c，R 7c分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；或者R 6b和R 7b，R 6c和R 7c可以分别连同与它们相连的碳原子一起形成3～8元碳环，其中，碳环可被选自氢，卤素，C1～6烷基，卤代C1～C6烷基取代；
    p＝0，1，2，3；
    q＝0，1，2，3；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    环B选自以下结构：
    Figure PCTCN2020131248-appb-100010
    其中，Z 1，Z 2选自氧原子，硫原子；
    T为化学键，氧原子，-NR 7h，取代或者未取代的碳原子，其中取代基包括氢，氘，卤素，C1～C6烷基或者酰基；
    每个R d1，R d2，R e1，R e2，R f1，R f2，R g1，R g2，R 7h分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
    r＝0，1，2，3；
    Y为连接基团，选自以下结构：
    Figure PCTCN2020131248-appb-100011
  6. 下列化合物，其立体异构体，互变异构体，药学上可接受的盐，
    Figure PCTCN2020131248-appb-100012
    Figure PCTCN2020131248-appb-100013
    Figure PCTCN2020131248-appb-100014
  7. 一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100015
    其中，R 1选自F或者-OR 1A，-NHR 1A，其中R 1A独立的是氢，C1～C6烷基或者酰基；
    R 2选自-S(O) m-R 1A，m＝0，1，2；
    R 3，R 4，R 5，R 6，R 7，R 8，R 9选自氢，氘，卤素，C1～C6烷基或者酰基；
    m2＝0，1，2，3；
    n2＝0，1，2，3；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y为连接基团，为2～17个由碳，氧，氮原子组成的连接臂；
    Z为O或者S。
  8. 一种式(I-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100016
    其中，R 1a，R 1b，R 1c分别独立地选自F或者-OR 1A，-NHR 1A，其中R 1A独立的是氢，C1～C6烷基或者酰基；
    R 2选自-S(O) m-R 1A，m＝0，1，2；
    每个R 3，R 4，R 5，R 6，R 7，R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基，环烷基，环烷基烷基或者酰基，炔基烷基；
    m2＝0，1，2，3；
    n2＝0，1，2，3；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y1为连接基团，选自以下结构：
    Figure PCTCN2020131248-appb-100017
    其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
    E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
    s1＝0，1，2，3，4，5；
    s2＝0，1，2，3，4，5
    s3＝0，1，2，3，4，5。
  9. 所述的式(I)化合物，包括以下通式结构(II)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100018
    其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
    m2＝0，1，2，3；
    n2＝1；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y为连接基团，为2～17个由碳，氧，氮原子组成的连接臂。
  10. 所述的式(I)化合物，包括以下通式结构(II-1)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100019
    其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基，环烷基，环烷基烷基或者酰基，炔基烷基；
    m2＝0，1，2，3；
    n2＝1；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y1为连接基团，选自以下结构：
    Figure PCTCN2020131248-appb-100020
    其中，R E，R F，R G，R H分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
    E，J分别独立地选自化学键，-CH 2-，氧，-NH-；
    s1＝0，1，2，3，4，5；
    s2＝0，1，2，3，4，5
    s3＝0，1，2，3，4，5。
  11. 所述的式(II)化合物，包括以下通式结构(III)化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100021
    其中，X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    R 8，R 9分别独立地选自氢，氘，卤素，C1～C6烷基或者酰基；
    m2＝0，1，2，3；
    n2＝1；
    X选自氢，氘，卤素，C1～C6烷基，C3～C6环烷基，C2～C6烯基，C2～C6炔基；
    Y 1为连接基团，为2～17个由碳，氧，氮原子组成的连接臂，选自以下结构：
    Figure PCTCN2020131248-appb-100022
    Figure PCTCN2020131248-appb-100023
  12. 所述的式(III)化合物，其中，X选自氢，氘，氟，溴，碘，甲基，乙基，乙烯基，乙炔基。
  13. 所述的式(III)化合物，其中，R 9选自氢，氘，氟，溴，碘，甲基，乙基，C3～C8环烷基，乙烯基，乙炔基。
  14. 下列化合物，包括以下结构化合物，其立体异构体，互变异构体或药学上可接受的盐，
    Figure PCTCN2020131248-appb-100024
    Figure PCTCN2020131248-appb-100025
    Figure PCTCN2020131248-appb-100026
    Figure PCTCN2020131248-appb-100027
  15. 一种药物组合物，其包括治疗有效剂量的权利要求1至14中任一项所述化合物或其立体异构体，互变异构体或药学上可接受的盐及可药用的载体。
  16. 根据权利要求1至14中任意一项所述的化合物或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗和改善糖尿病，心脑血管疾病，降低体重，脂肪肝，便秘，代谢相关疾病和在肿瘤治疗中应用。
  17. 根据权利要求1至14中任意一项所述的化合物或其可药用的盐或根据权利要求15所述的药物组合物，作为SGLT1/SGLT2抑制剂，在制备治疗与SGLT1/SGLT2功能相关的疾病的药物或药物组合物中的应用。
  18. 根据权利要求16中的应用，其中所述患者已服用过或目前正服用其他治疗性药物，包括降血压药，降血脂药，抗糖尿病药，降血糖药，减肥药或食欲抑制剂。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102414191A (zh) * 2009-02-23 2012-04-11 大正制药株式会社 4-异丙苯基山梨醇化合物作为sglt1抑制剂
CN104854096A (zh) * 2012-11-20 2015-08-19 莱西肯医药有限公司 钠葡萄糖协同转运蛋白1的抑制剂
CN108610385A (zh) * 2018-04-23 2018-10-02 中国科学院成都生物研究所 一种钠-葡萄糖协同转运蛋白1抑制剂的药物用途
CN110066302A (zh) * 2018-01-23 2019-07-30 广东东阳光药业有限公司 吡喃葡萄糖基衍生物及其用途
CN110092768A (zh) * 2018-04-23 2019-08-06 中国科学院成都生物研究所 包含钠-葡萄糖协同转运蛋白1抑制剂的组合物及使用方法
WO2020068661A1 (en) * 2018-09-26 2020-04-02 Lexicon Pharmaceuticals, Inc. Crystalline forms of n-(1 -((2-(dimethylamino)ethyl)amino)-2-m ethyl-1 -oopropan-2-yl)-4-(4-(2-methyl-5- (2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl) phenl)butanamide and methods of their synthesis

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102414191A (zh) * 2009-02-23 2012-04-11 大正制药株式会社 4-异丙苯基山梨醇化合物作为sglt1抑制剂
CN104854096A (zh) * 2012-11-20 2015-08-19 莱西肯医药有限公司 钠葡萄糖协同转运蛋白1的抑制剂
CN110066302A (zh) * 2018-01-23 2019-07-30 广东东阳光药业有限公司 吡喃葡萄糖基衍生物及其用途
CN108610385A (zh) * 2018-04-23 2018-10-02 中国科学院成都生物研究所 一种钠-葡萄糖协同转运蛋白1抑制剂的药物用途
CN110092768A (zh) * 2018-04-23 2019-08-06 中国科学院成都生物研究所 包含钠-葡萄糖协同转运蛋白1抑制剂的组合物及使用方法
WO2020068661A1 (en) * 2018-09-26 2020-04-02 Lexicon Pharmaceuticals, Inc. Crystalline forms of n-(1 -((2-(dimethylamino)ethyl)amino)-2-m ethyl-1 -oopropan-2-yl)-4-(4-(2-methyl-5- (2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2h-pyran-2-yl)benzyl) phenl)butanamide and methods of their synthesis

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
ACTA PHARMACEUTICA SINICA, vol. 52, no. 6, 2017, pages 897 - 903
ANGEWANDTE CHEMIE, INTERNATIONAL EDITION, vol. 58, no. 21, 2019, pages 6987 - 6992
CAS , no. 186689-07-6
CHEMISCHE BERICHTE, vol. 118, no. 4, 1985, pages 1564 - 1574
CHEMISTRY - A EUROPEAN JOURNAL, vol. 17, no. 12, 2011, pages 3326 - 3331
DATABASE REGISTRY 19 June 2014 (2014-06-19), ANONYMOUS : " Benzenebutanamide, N-[2-[[2-(dimethylamino)ethyl]amino]-1,1-dimethyl-2- oxoethyl]-4-[[2-methyl-5-[(5R)-5-C-(methylsulfonyl)-.beta.-Dxylopyranosyl]phenyl]methyl]- (CA INDEX NAME) ", XP055866032, retrieved from STN Database accession no. 1610955-64-0 *
DIABETES TECHNOLOGY & THERAPEUTICS, vol. 13, no. 7, 2011, pages 743 - 775
JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS, vol. 64, no. 3, 2005, pages 207 - 215
JOURNAL OF FLUORESCENCE, vol. 23, no. 1, 2013, pages 181 - 186
JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, 2017, pages 710 - 721
JOURNAL OF ORGANIC CHEMISTRY, vol. 76, no. 12, 2011, pages 4964 - 4972
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 136, no. 20, 2014, pages 7205 - 7208
LAUREN E. SIROIS, MATTHEW M. ZHAO, NGIAP-KIE LIM, MARK S. BEDNARZ, BRYCE A. HARRISON, WENXUE WU: "Process Development for a Locally Acting SGLT1 Inhibitor, LX2761, Utilizing sp 3 –sp 2 Suzuki Coupling of a Benzyl Carbonate", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 23, no. 1, 18 January 2019 (2019-01-18), US , pages 45 - 61, XP055636549, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.8b00325 *
NATURE PROTOCOLS, vol. 2, no. 3, 2007, pages 753 - 762
NATURE, vol. 574, no. 7776, 2019, pages 86 - 89
NICOLE C. GOODWIN, ZHI-MING DING, BRYCE A. HARRISON, ERIC D. STROBEL, ANGELA L. HARRIS, MELINDA SMITH, ANDREA Y. THOMPSON, WENDY X: "Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 60, no. 2, 26 January 2017 (2017-01-26), US , pages 710 - 721, XP055636395, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01541 *
REFERENCE JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, 2017, pages 710 - 721
SCIENCE OF SYNTHESIS, vol. 41, 2010, pages 543 - 612

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