WO2022179611A1 - 取代的吡啶-2,4-二酮类衍生物 - Google Patents

取代的吡啶-2,4-二酮类衍生物 Download PDF

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WO2022179611A1
WO2022179611A1 PCT/CN2022/077962 CN2022077962W WO2022179611A1 WO 2022179611 A1 WO2022179611 A1 WO 2022179611A1 CN 2022077962 W CN2022077962 W CN 2022077962W WO 2022179611 A1 WO2022179611 A1 WO 2022179611A1
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compound
added
pharmaceutically acceptable
acceptable salt
solution
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PCT/CN2022/077962
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English (en)
French (fr)
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颜小兵
来巍
丁照中
陈曙辉
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南京明德新药研发有限公司
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Priority to JP2023552332A priority Critical patent/JP2024508004A/ja
Priority to AU2022227712A priority patent/AU2022227712B2/en
Priority to KR1020237032728A priority patent/KR20230154889A/ko
Priority to CA3209693A priority patent/CA3209693A1/en
Priority to US18/278,715 priority patent/US20240189292A1/en
Priority to CN202280017417.1A priority patent/CN116940555A/zh
Priority to EP22758975.1A priority patent/EP4299561A1/en
Publication of WO2022179611A1 publication Critical patent/WO2022179611A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a series of substituted pyridine-2,4-dione derivatives and preparation methods thereof, in particular to compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
  • Hypertrophic cardiomyopathy is a myocardial disease characterized by myocardial hypertrophy, which often invades the ventricular septum, reduces the size of the ventricular chamber, obstructs left ventricular blood filling, and decreases left ventricular diastolic compliance. According to the presence or absence of left ventricular outflow tract obstruction, hypertrophic cardiomyopathy is divided into obstructive and non-obstructive hypertrophic cardiomyopathy, which may be related to genetics.
  • the global incidence of HCM is about 1/500, and its clinical manifestations vary from asymptomatic to palpitations, exertional dyspnea, precordial pain, fatigue, syncope and even sudden death.
  • HCM treatment drugs are limited, mainly through beta-blockers or calcium channel blockers to improve symptoms, can not target the cause, delay the progression of myocardial hypertrophy, do not improve the prognosis, the therapeutic effect is limited.
  • Myosin and actin are the material basis of myocardial contraction, and the myosin cross-bridge periodically binds and dissociates with actin to drive the sliding of myofilaments, resulting in myocardial contraction.
  • Myosin has ATPase activity and powers myocardial contraction by hydrolyzing ATP.
  • Myosin mutation can lead to prolonged binding time between myosin and actin, excessive contraction and impaired relaxation of left ventricular myocardium, resulting in hypertrophy and fibrosis of left ventricular myocardium, leading to HCM.
  • MYK-461 is an allosteric regulator of cardiac myosin, which slows down the rate of phosphate hydrolysis, reduces the binding time of myosin and actin, produces a negative inotropic effect, and relieves cardiac hypertrophy caused by excessive left ventricular myocardial contraction, etc. pathological changes.
  • the elimination in the body is slow, and the drug stays in the body for too long, making it inconvenient to adjust the dose quickly (Mark P.Grillo et al. Xenobiotica, 2019; 49(6):718-733). Therefore, the development of myosin inhibitors with better activity and more ideal pharmacokinetic properties has important clinical value and significance.
  • myocardial sarcomere abnormalities have been identified as drivers of various cardiac diseases and conditions, such as diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina, and restrictive cardiomyopathy.
  • Myosin ATPase Inhibitors can also play a potential therapeutic effect in alleviating the pathological process of the above diseases by inhibiting myocardial contraction.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy, wherein the C 1 -4 alkyl and C 1-4 alkoxy are each independently optionally substituted with 1, 2 or 3 R a ;
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, respectively independently optionally substituted with 1, 2 , 3 or 4 R;
  • R is selected from H and F
  • R 4 is selected from H, C 1-4 alkyl and C 3-4 cycloalkyl, wherein said C 1-4 alkyl and C 3-4 cycloalkyl are each independently optionally surrounded by 1, 2 or 3 R c substitution;
  • R 5 is selected from H and C 1-4 alkyl
  • R 6 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy, wherein the C 1-4 alkyl and C 1-4 alkoxy groups are each independently optionally substituted with 1, 2 or 3 R d ;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, -COR a1 , -CO 2 R a1 , -SO 2 R a1 , -SO 2 NR a1 R a2 , and -CONR a1 R a2 , wherein the C 1-4 alkyl and C 1-4 alkoxy groups are each independently optionally replaced by 1, 2 or 3 R replace;
  • R a1 and R a2 are independently selected from H and C 1-4 alkyl
  • R a1 and R a2 together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is each independently optionally substituted with 1, 2, 3 or 4 R e ;
  • R b is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, -COR b1 , -CO 2 R b1 , -SO 2 R b1 , -SO 2 NR b1 R b2 , and -CONR b1 R b2 , wherein the C 1-4 alkyl and C 1-4 alkoxy groups are each independently optionally replaced by 1, 2 or 3 R replace;
  • R b1 and R b2 are independently selected from H and C 1-4 alkyl
  • R b1 and R b2 together with the nitrogen atom to which they are attached form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is each independently optionally substituted with 1, 2, 3 or 4 R f ;
  • R c is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy;
  • R d is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy;
  • R e is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy;
  • R f is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy;
  • R is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • n is selected from 1, 2, 3 or 4;
  • the 3-6 membered heterocycloalkyl and 4-6 membered heterocycloalkyl each independently contain 1, 2, 3 or 4 atoms or atomic groups each independently selected from N, O, S and NH.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl;
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 4-6 cycloalkyl or 5-6 membered heterocycloalkyl, wherein the C 4-6 cycloalkyl and 5-6 membered heterocycloalkyl each independently optionally substituted with 1, 2 , 3 or 4 R;
  • R is selected from H and F
  • R 4 is selected from H and C 1-4 alkyl
  • R 5 is selected from H
  • R 6 is selected from H, F, Cl, Br, I, and C 1-4 alkyl
  • R b is each independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkoxy, -COR b1 and -CO 2 R b1 ;
  • R b1 is selected from H and C 1-4 alkyl
  • n is selected from 1 or 2;
  • the 5-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 atoms or groups of atoms each independently selected from N, O, S and NH.
  • R a1 and R a2 are independently selected from H, and other variables are as defined in the present invention.
  • Ra , Rc , Rd , Re and Rf are independently selected from F and Cl, respectively, and other variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from -CH 3 and -CH 2 CH 3 , wherein said CH 3 and -CH 2 CH 3 are independently optionally selected by 1, 2 or 3 R a is substituted, R a and other variables are as defined in the present invention.
  • R 1 and R 2 are independently selected from -CH 3 and -CH 2 CH 3 , and other variables are as defined in the present invention.
  • R b1 and R b2 are independently selected from -CH 3 and -CH 2 CH 3 , and other variables are as defined in the present invention.
  • R b are independently selected from F, Cl, Br, -OCH 3 , -COCH 3 , -CO 2 CH 3 and -CO 2 CH 2 CH 3 , and other variables are as defined in the present invention .
  • R b are independently selected from F, Cl, Br, -OCH 3 , -COCH 3 and -CO 2 CH 2 CH 3 , and other variables are as defined in the present invention.
  • the above R 1 and R 2 together with the carbon atom to which they are attached form a C 5-6 cycloalkyl or 6-membered heterocycloalkyl, wherein the C 5-6 cycloalkyl and 6-membered heterocycle
  • the alkyl groups are each independently optionally substituted with 1 , 2, 3 or 4 R b , R b and other variables as defined herein.
  • R 1 and R 2 together with the carbon atom to which they are attached form R 1 and R 2 together with the carbon atom to which they are attached wherein the Each independently is optionally substituted with 1, 2, 3 or 4 R b , R b and other variables as defined herein.
  • R 1 and R 2 are formed together with the carbon atom to which they are attached. wherein the Each independently is optionally substituted with 1, 2, 3 or 4 R b , R b and other variables as defined herein.
  • R 1 and R 2 are formed together with the carbon atom to which they are attached.
  • Rb and other variables are as defined in the present invention.
  • R 1 and R 2 are formed together with the carbon atom to which they are attached.
  • Rb and other variables are as defined in the present invention.
  • R 1 and R 2 are formed together with the carbon atom to which they are attached.
  • Other variables are as defined in the present invention.
  • R 1 and R 2 are formed together with the carbon atom to which they are attached.
  • Other variables are as defined in the present invention.
  • R 3 is selected from H, and other variables are as defined in the present invention.
  • R 4 is selected from C 1-4 alkyl, and other variables are as defined in the present invention.
  • R 4 is selected from -CH 3 and -CH 2 CH 3 , wherein the -CH 3 and -CH 2 CH 3 are each independently optionally substituted with 1, 2 or 3 R d , Rd and other variables are as defined herein.
  • R 4 is selected from -CH 3 and -CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 4 is selected from -CH 3 , and other variables are as defined in the present invention.
  • R 5 is selected from H, and other variables are as defined in the present invention.
  • R 6 are independently selected from H, F, Cl and -CH 3 , wherein the -CH 3 is optionally substituted by 1, 2 or 3 R d , R d and other variables such as as defined in the present invention.
  • R 6 are independently selected from H, F, Cl and -CH 3 , and other variables are as defined in the present invention.
  • R 6 are independently selected from H, F and -CH 3 , and other variables are as defined in the present invention.
  • n, R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the present invention.
  • n is selected from 1 and 2;
  • n 0, 1 and 2;
  • q is selected from 0 and 1;
  • T is selected from CH 2 , O and NH, and when T is selected from CH 2 and NH, T can be optionally substituted by R b ;
  • R b , R 4 and R 6 are as defined in the present invention.
  • the above-mentioned compound has the structure represented by formula (I-1A) or (I-1B):
  • n, R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the present invention, and R 4 is not H.
  • the above-mentioned compound has the structure represented by formula (I-1-1A) or (I-1-1B):
  • n is selected from 1 and 2;
  • n 0, 1 and 2;
  • q is selected from 0 and 1;
  • R 4 is selected from C 1-4 alkyl
  • T is selected from CH 2 , O and NH, and when T is selected from CH 2 and NH, T can be optionally substituted by R b ;
  • R b , R 4 and R 6 are as defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides the application of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a cardiac myosin inhibitor medicine.
  • the present invention also provides the application of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation and treatment of heart failure and hypertrophic myocardial disease.
  • the present invention also provides a method for treating a disease associated with a cardiac myosin inhibitor in a subject in need thereof, the method comprising providing the subject with an effective dose of the compound as defined in any of the above technical solutions or a pharmaceutically acceptable amount thereof.
  • the present invention also provides a method for treating heart failure and hypertrophic myocardial disease in a subject in need thereof, the method comprising providing the subject with an effective dose of a compound as defined in any of the above technical solutions or a pharmaceutically acceptable form thereof A salt or the above pharmaceutical composition.
  • the compound of the present invention has a good inhibitory effect on cardiac myosin ATPase, and has excellent pharmacokinetic properties.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
  • C1-4alkoxy refers to those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-4 alkoxy group includes C 1-3 , C 1-2 , C 2-4 , C 4 and C 3 alkoxy and the like.
  • Examples of C 1-4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) oxy, s-butoxy and t-butoxy) and the like.
  • heteroalkyl by itself or in combination with another term means a stable straight or branched chain alkyl radical or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C 1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C 1-3 heteroalkyl group.
  • a heteroatom or group of heteroatoms can be located at any internal position within a heteroalkyl group, including where the alkyl group is attached to the rest of the molecule, except that the terms "alkoxy,”"alkylamino,” and “alkylthio” (or thioalkyl) Oxygenyl) is a customary expression referring to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, eg -CH2
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • C3-4cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 4 carbon atoms, which is a monocyclic ring system; it may be monovalent, divalent or polyvalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • C 4-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 4-6 cycloalkyl group includes C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C4-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • C 5-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 5 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including 5-membered cycloalkyl and 6-membered cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C5-6 cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 5-6 membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl.
  • 5-6 membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hex
  • 6-membered heterocycloalkyl a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • 6-membered heterocycloalkyl include, but are not limited to, tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1- piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidine 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl and the like.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the volumes used in the present invention are commercially available.
  • TEA triethylamine
  • DIEA N,N-diisopropylethylamine
  • PE petroleum ether
  • EtOAc ethyl acetate
  • EA ethyl acetate
  • THF tetrahydrofuran
  • MeOH stands for methanol
  • MTBE stands for methyl tert-butyl ether
  • DCM stands for dichloromethane
  • EtOH stands for ethanol
  • iPrOH stands for isopropanol
  • Boc 2 O stands for di-tert-butyl dicarbonate
  • L-selectride stands for lithium tri-sec-butyl borohydride
  • TCFH stands for N,N,N,N-tetramethylchloroformamidine hexafluorophosphate
  • FA stands for formic acid
  • TFA stands for trifluoroacetic acid
  • ACN stands for acetonitrile
  • TLC stands for
  • DMSO dimethyl sulfoxide
  • DMF stands for N,N-dimethylformamide
  • LDA lithium diisopropylamide
  • DMAC stands for N,N-dimethylacetamide
  • PEG-400 stands for polyethylene glycol 400
  • EGTA stands for ethylene glycol bis(2-aminoethyl ether)tetraacetic acid
  • DMSO-d 6 stands for deuterated dimethyl sulfoxide
  • CDCl 3 stands for deuterated chloroform.
  • the present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
  • Step A To a solution of compound 1-2 (929.08 mg, 7.67 mmol, 975.93 ⁇ L, 1 eq) and compound 1-1 (1.5 g, 7.67 mmol, 1 eq, HCl) in EtOH (20 mL) at 20 °C was added DIEA (1.98 g, 15.33 mmol, 2.67 mL, 2 eq), the reaction solution was stirred at 20° C. for 16 hours, and concentrated to obtain compound 1-a.
  • Step D Under nitrogen protection, lithium chloride (107.20 mg, 2.53 mmol, 51.79 ⁇ L, 2 eq) was added to a solution of compound 1-c (0.4 g, 1.26 mmol, 1 eq) in DMSO (4 mL), and the reaction solution was at 125 After stirring at °C for 20 hours, filtering, the filtrate was purified by preparative HPLC [mobile phase: water (0.1% TFA)-ACN; gradient: 21%-51% ACN] to give compound 1 .
  • Step B Add sodium hydroxide (494.51 mg, 12.36 mmol, 1 eq) to a solution of compound 2-a (2.5 g, 12.36 mmol, 1 eq) in MeOH (20 mL) and water (20 mL) at 0 °C, and the reaction solution After stirring at 20°C for 16 hours, water (50 mL) was added, and then extracted with EA (50 mL). After separation, the pH of the aqueous phase was adjusted to about 5 with 1 M dilute hydrochloric acid, and then extracted with EA (50 mL). The organic phase was saturated with Washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 2-b.
  • Step C To a solution of compound 2-b (1.7g, 9.03mmol, 1eq) in DCM (30mL) was added TEA (4.57g, 45.17mmol, 6.29mL, 5eq) and DMF (33.02mg) under nitrogen protection at 0°C , 451.70 ⁇ mol, 34.75 ⁇ L, 0.05eq), then oxalyl chloride (1.72g, 13.55mmol, 1.19mL, 1.5eq) was added, and the reaction solution was stirred at 20 °C for 1 hour and concentrated to obtain compound 2-c.
  • Step F To a solution of compound 2-e (70mg, 195.32 ⁇ mol, 1eq) in 1,4-dioxane (7mL) was added hydrochloric acid (4M, 7.00mL, 143.35eq), the reaction solution was stirred at 50°C for 16 After 1 hour, it was concentrated, the residue was adjusted to neutrality by adding 2N aqueous sodium hydroxide solution, then EA (50 mL) was added for extraction, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was passed through Compound 2 was purified by preparative HPLC [water (0.225% FA)-ACN]; gradient: 17%-47% ACN).
  • Step B To a solution of compound 3-a (4.5g, 24.17mmol, 1eq) in MeOH (25mL) and water (25mL) was added sodium hydroxide (1.06g, 26.58mmol, 1.1eq), the reaction solution was heated at 20°C After stirring for 16 hours, add water (30 mL), then extract with EA (30 mL), adjust the pH of the aqueous phase to about 5 with 1 M dilute hydrochloric acid after separation, then extract with EA (30 mL), dry over anhydrous sodium sulfate, filter Concentration gave compound 3-b.
  • Step C To a solution of compound 3-b (2.1 g, 12.20 mmol, 1 eq) in DCM (30 mL) was added TEA (4.94 g, 48.79 mmol, 6.79 mL, 4 eq) and DMF (44.57 g) under nitrogen protection at -20 °C mg, 609.83 ⁇ mol, 46.92 ⁇ L, 0.05 eq), then oxalyl chloride (2.01 g, 15.86 mmol, 1.39 mL, 1.3 eq) was added, and the reaction solution was stirred at 20° C. for 1 hour and concentrated to obtain compound 3-c.
  • hydrochloric acid 4M, 6mL, 10.27eq
  • Step B To a solution of 4-a (6.9g, 34.46mmol, 1eq) in MeOH (40mL) and water (40mL) was added sodium hydroxide (1.38g, 34.46mmol, 1eq), the reaction solution was stirred at 15°C for 16 Water (50 mL) was added after 1 hour, and then extracted with EA (100 mL). After separation, the aqueous phase was adjusted to pH about 5 with 1M dilute hydrochloric acid, and then extracted with EA (100 mL ⁇ 2). The combined organic phase was then added with saturated table salt. Washed with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4-b.
  • Step C To a solution of 4-b (4.5g, 24.17mmol, 1eq) in DCM (50mL) at 0°C was added TEA (9.78g, 96.67mmol, 13.45mL, 4eq) and DMF (88.32mg, 1.21mmol) , 92.97 ⁇ L, 0.05eq), then oxalyl chloride (3.99g, 31.42 mmol, 2.75mL, 1.3eq) was added, and the reaction solution was stirred at 10°C for 1 hour and concentrated to obtain compound 4-c.
  • TEA 9.78g, 96.67mmol, 13.45mL, 4eq
  • DMF 88.32mg, 1.21mmol
  • oxalyl chloride 3.99g, 31.42 mmol, 2.75mL, 1.3eq
  • hydrochloric acid 4M, 10.50mL, 21.38eq
  • Step A To a solution of compound 5-1 (1.00 g, 7.19 mmol, 1 eq) and compound 1-1 (1.14 g, 7.19 mmol, 1 eq) in EtOH (15 mL) was added DIEA (1.86 g) under nitrogen protection at 20 °C , 14.37mmol, 2.50mL, 2eq), the reaction solution was stirred at 20° C. for 16 hours, and concentrated to obtain compound 5-a.
  • Step D Hydrochloric acid (4M, 3.82mL, 10eq) was added to a solution of 5-c (550mg, 1.53mmol, 1eq) in 1,4-dioxane (4mL) at 20°C, and the reaction solution was heated at 40°C Stir for 16 hours, add EA (40 mL) to the reaction solution, then add 1N aqueous sodium hydroxide solution to adjust the pH to about 7, separate the layers, extract the aqueous phase with EA (40 mL) again, and use the combined organic phase with saturated brine ( 50 mL) was washed, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was added with MeOH (5 mL) and stirred, filtered, and the filter cake was dried under high vacuum to obtain compound 5.
  • Step A To a solution of compound 6-1 (1.00 g, 7.19 mmol, 1 eq) and compound 1-1 (1.14 g, 7.19 mmol, 1 eq) in EtOH (15 mL) was added DIEA (1.86 g) under nitrogen protection at 20 °C , 14.37mmol, 2.50mL, 2eq), the reaction solution was stirred at 20° C. for 16 hours, and concentrated to obtain compound 6-a.
  • Step D Hydrochloric acid (4M, 3.82mL, 10eq) was added to a solution of 6-c (550mg, 1.53mmol, 1eq) in 1,4-dioxane (4mL) at 20°C, and the reaction solution was heated at 40°C After stirring for 16 hours, water (40 mL) was added to the reaction solution, then saturated aqueous sodium bicarbonate solution was added to adjust the pH to about 7, extracted with EA (40 mL ⁇ 2), and the combined organic phases were washed with saturated brine (40 mL). Dry over anhydrous sodium sulfate, filter and concentrate, add MeOH (6 mL) to the residue, stir for 15 minutes, filter, and dry the filter cake under high vacuum to obtain compound 6.
  • Step A To a solution of compound 7-1 (0.76 g, 4.88 mmol, 1 eq) and compound 1-1 (777.38 mg, 4.88 mmol, 1 eq) in EtOH (15 mL) was added DIEA (1.26 g) under nitrogen protection at 20 °C , 9.77mmol, 1.70mL, 2eq), the reaction solution was stirred at 20° C. for 16 hours, and concentrated to obtain compound 7-a.
  • Step D Add hydrochloric acid (4M, 3.82mL, 10eq) to a solution of 7-c (575.11mg, 1.53mmol, 1eq) in 1,4-dioxane (4mL) at 20°C, the reaction solution was heated at 40 Stir at °C for 16 hours, add water (40 mL) to the reaction solution, then add saturated aqueous sodium bicarbonate solution to adjust the pH to about 7, extract with EA (40 mL ⁇ 2), and wash the combined organic phases with saturated brine (40 mL) , dried over anhydrous sodium sulfate, filtered and concentrated, MeOH (4 mL) was added to the residue, stirred for 15 minutes, filtered, and the filter cake was dried under high vacuum to obtain compound 7.
  • Step A Under nitrogen protection at -78°C, to a solution of compound 8-1 (20g, 82.20mmol, 1eq) in THF (200mL) was added dropwise LDA (2M, 49.32mL, 1.2eq), the reaction solution was at -78°C After stirring for 1 hour, methyl chloroformate (8.54g, 90.42mmol, 7.00mL, 1.1eq) was added, the reaction solution was slowly warmed to 20°C, and after stirring for 4 hours, saturated aqueous ammonium chloride solution (600mL) was added to quench, and then Extracted with EA (600 mL), the organic phase was washed with saturated brine (200 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 8-a.
  • Step B To a solution of compound 8-a (27g, 89.60mmol, 1eq) in MeOH (200mL) and water (200mL) was added sodium hydroxide (3.58g, 89.60mmol, 1eq), the reaction solution was stirred at 15°C for 16 Water (200 mL) was added after 1 hour, and then extracted with EA (200 mL). After separation, the aqueous phase was adjusted to about pH 5 with 1M dilute hydrochloric acid, and then extracted with EA (300 mL ⁇ 2), and the combined organic phase was saturated brine. (200 mL) was washed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 8-b.
  • sodium hydroxide 3.58g, 89.60mmol, 1eq
  • Step C To a solution of compound 8-b (23 g, 80.05 mmol, 1 eq) in DCM (200 mL) under nitrogen protection at 0 °C, was added TEA (32.40 g, 320.21 mmol, 44.57 mL, 4 eq) and DMF (292.56 mg, 4.00mmol, 307.95 ⁇ L, 0.05eq), then oxalyl chloride (13.21g, 104.07mmol, 9.11mL, 1.3eq) was added, the reaction solution was stirred at 10°C for 1 hour and concentrated to obtain compound 8-c.
  • TEA 32.40 g, 320.21 mmol, 44.57 mL, 4 eq
  • DMF 292.56 mg, 4.00mmol, 307.95 ⁇ L, 0.05eq
  • oxalyl chloride 13.21g, 104.07mmol, 9.11mL, 1.3eq
  • hydrochloric acid 4M, 150mL, 36.60eq
  • Step G To a solution of compound 8-f (0.15 g, 501.06 ⁇ mol, 1 eq) in DCM (3 mL) was added DIEA (194.27 mg, 1.50 mmol, 261.83 ⁇ L, 3 eq) under nitrogen protection at 0°C, followed by chloroformic acid A solution of methyl ester (49.72 mg, 526.11 ⁇ mol, 40.75 ⁇ L, 1.05 eq) in DCM (1 mL), the reaction solution was stirred at 0 °C for 1 hour, the reaction solution was filtered, the filtrate was concentrated, and the residue was passed through preparative HPLC [mobile phase: water (0.05% ammonia water)-ACN; gradient: 15%-45% ACN] purification gave compound 8.
  • Step A To a solution of 9-1 (10 g, 72.39 mmol, 1 eq) and 9-2 (9.21 g, 76.01 mmol, 1.05 eq) in DCM (200 mL) under nitrogen protection was added cesium carbonate (35.38 g, 108.59 g) mmol, 1.5eq), the reaction solution was stirred at 15° C. for 16 hours, filtered, and the filtrate was concentrated to obtain compound 9-a.
  • cesium carbonate 35.38 g, 108.59 g
  • methylmagnesium bromide 3M, 24.86mL, 2eq
  • Step C To a solution of 9-b (12g, 46.63mmol, 1eq) in MeOH (100mL) was added HCl/MeOH (4M, 100mL, 8.58eq), the reaction solution was stirred at 20°C for 2 hours, and concentrated to obtain compound 9 -c hydrochloride.
  • Step D To a solution of 9-c hydrochloride (7.5g) in EtOH (100mL) was added 1-1 (9.58g, 48.96mmol, 1eq, HCl) and DIEA (25.31g, 195.83mmol, 34.11mL, 4eq ), the reaction solution was stirred at 20 °C for 16 hours, and concentrated to obtain compound 9-d.
  • Step F To a solution of 9-e (8.00g, 21.83mmol, 1eq) in EtOAc (50mL) was added HCl/EtOAc (4M, 51.61mL, 9.46eq), the reaction solution was stirred at 20°C for 16 hours, and the reaction solution was concentrated Then the hydrochloride salt of compound 9-d is obtained.
  • Step H Under nitrogen protection, sodium methoxide (1M, 41.62mL, 5eq) was added to a solution of 9-f (3.5g, 8.32mmol, 1eq) in MeOH (40mL), and the reaction solution was stirred at 50°C for 16 hours, 1N dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, then EA (100 mL ⁇ 2) was added for extraction, the combined organic phases were washed with saturated brine (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound 9-g.
  • hydrochloric acid 4M, 60mL, 29.95eq
  • Step A To a solution of 10-1 (5g, 32.02mmol, 4.07mL, 1eq) in THF (50ml) at 20°C was added 10-2 (4.66g, 38.43mmol, 1.2eq) and tetraethyl titanate Ester (21.92g, 96.07mmol, 19.92mL, 3eq), the reaction solution was stirred at 60°C for 16 hours, ethyl acetate (100mL) was added to the reaction solution, cooled to 0°C, water (20mL) was slowly added, and stirred for 0.5 h, filtered, and the filtrate was washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 10-a.
  • 10-1 5g, 32.02mmol, 4.07mL, 1eq
  • 10-2 4.66g, 38.43mmol, 1.2eq
  • tetraethyl titanate Ester 21
  • L-selectride (1M, 41.65mL, 1.2eq
  • Step C HCl/MeOH (200mmol.50ml, 7.92eq) was added to the MeOH (50mL) solution of 10-b (6.6g) at 20°C, the reaction solution was stirred for 16 hours and concentrated to obtain the salt of compound 10-c acid salt.
  • Step D To a solution of 10-c hydrochloride (1 g) in EtOH (10 mL) was added 1-1 (1.51 g, 7.74 mmol, 1.5 eq, HCl) and DIEA (4.00 g, 30.96 mmol) at 20 °C , 5.40mL, 6eq), the reaction solution was stirred at 20°C for 16 hours, and concentrated to obtain compound 10-d.
  • Step F Under nitrogen protection, to a solution of 10-e (0.648g, 1.53mmol, 1eq) in MeOH (7.6mL) was added sodium methoxide (1M, 6.43ml, 1eq), and the reaction solution was stirred at 20°C for 16 hours , 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, then EA (20 mL) was added for extraction, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 10-f.
  • Step G Hydrochloric acid (4M, 4mL, 17.40eq) was added to a solution of 10-f (348mg, 919.74 ⁇ mol, 1eq) in 1,4-dioxane (4mL), and the reaction solution was stirred at 50°C for 16 hours, EA (30 mL) was added to the reaction solution, and then 1M aqueous sodium hydroxide solution was added to adjust the pH to about 8. After separation, the organic phase was washed with saturated brine (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was added with MeOH (10 mL) and stirred for 20 minutes, filtered, and the filter cake was dried under high vacuum to obtain compound 10.
  • Step A To a solution of 11-1 (1 g, 7.40 mmol, 1.06 ml, 1 eq) in EtOH (15 mL) at 20 °C was added 1-1 (1.18 g, 7.40 mmol, 1.0 eq, HCl) and DIEA (2.87 g, 22.19 mmol, 3.86 mL, 3 eq), the reaction solution was stirred at 20° C. for 12 hours, and concentrated to obtain compound 11-a.
  • Step C Under nitrogen protection, to a solution of 11-b (0.743g, 1.47mmol, 1eq) in MeOH (9.2mL) was added sodium methoxide (1M, 7.37ml, 5eq), and the reaction solution was stirred at 20°C for 16 hours , 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, then EA (20mL ⁇ 3) was added for extraction, the combined organic phase was washed with saturated brine (20mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain Compound 11-c.
  • Step D To a solution of 11-c (399mg, 1.12mmol, 1eq) in 1,4-dioxane (4mL) was added hydrochloric acid (4M, 4mL, 17.40eq), the reaction solution was stirred at 50°C for 16 hours Add EA (30 mL) to dilute, then add 2M aqueous sodium hydroxide solution to adjust pH to about 8, filter, add MeOH (10 mL) to the filter cake, stir for 1 hour, filter, and dry the filter cake under high vacuum to obtain compound 11.
  • hydrochloric acid 4M, 4mL, 17.40eq
  • Step A To a solution of 12-1 (10 g, 64.05 mmol, 8.33 mL, 1 eq) in THF (100 mL) at 20 °C was added 10-2 (17.08 g, 140.91 mmol, 2.2 eq) and tetraethyl titanate Ester (43.83g, 192.15mmol, 39.85mL, 3eq), the reaction solution was stirred at 60°C for 16 hours, cooled to 0°C, EA (100mL) was added to the reaction solution, water (30mL) was slowly added, and stirred for 0.5 hours, After filtration, the filtrate was washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 12-a.
  • 10-2 17.08 g, 140.91 mmol, 2.2 eq
  • tetraethyl titanate Ester 43.83g, 192.15mmol, 39.85mL,
  • L-selectride (1M, 25.21mL, 1.2eq
  • Step C HCl/MeOH (4M, 30 mL, 10.00 eq) was added to a solution of 12-b (3.14 g, 12.00 mmol, 1 eq) in MeOH (30 mL) at 20 °C, the reaction solution was stirred for 16 hours and then concentrated, the residue EA (20 ml) was added to the mixture, stirred for 0.5 hours, filtered, and the filter cake was dried under high vacuum to obtain the hydrochloride salt of compound 12-c.
  • Step D To a solution of 12-c hydrochloride (1.84 g) in EtOH (20 mL) was added 1-1 (1.87 g, 11.72 mmol, 1 eq) and DIEA (4.54 g, 35.16 mmol) under nitrogen protection at 20 °C , 6.12mL, 3eq), the reaction solution was stirred at 20°C for 12 hours, and concentrated to obtain compound 12-d.
  • 3-b 5.80g, 33.71mmol, 1eq
  • DIEA 6.53g, 50.56mmol, 8.81mL, 1.5e
  • Step G To a solution of 12-f (389mg, 1.03mmol, 1eq) in 1,4-dioxane (4mL) was added hydrochloric acid (4M, 3.91mL, 15.21eq), the reaction solution was stirred at 60°C for 16 hours , adding 2M aqueous sodium hydroxide solution to the reaction solution to adjust pH to about 8, filtering, adding MTBE (5 mL) to the filter cake and stirring for 1 hour, filtering, and drying the filter cake to obtain compound 12.
  • hydrochloric acid 4M, 3.91mL, 15.21eq
  • Step A To a solution of 13-1 (3g, 19.21mmol, 2.42mL, 1eq) in THF (30mL) at 20°C was added 10-2 (4.66g, 38.43mmol, 2eq) and tetraethyl titanate (13.15g, 57.64mmol, 11.95mL, 3eq), the reaction solution was stirred at 60°C for 16 hours, EA (60mL) was added to the reaction solution, water (10mL) was slowly added after cooling to 0°C, stirred for 0.5 hours, filtered , the filtrate was washed with saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 13-a.
  • 10-2 4.66g, 38.43mmol, 2eq
  • tetraethyl titanate 13.15g, 57.64mmol, 11.95mL, 3eq
  • L-selectride (1M, 13.88mL, 1.2eq
  • Step C To a solution of 13-b (1.26g, 4.81mmol, 1eq) in MeOH (15mL) was added HCl/MeOH (4M, 15mL, 12.48eq), the reaction solution was stirred at 20°C for 16 hours and then concentrated, the residue was EA (20 mL) was added and stirred for 0.5 h, filtered, and the filter cake was vacuum dried to obtain the hydrochloride salt of compound 13-c.
  • Step D To a solution of 13-c hydrochloride (0.553 g) in EtOH (5 mL) was added 1-1 (560.12 mg, 3.52 mmol, 1 eq) and DIEA (1.36 g, 10.56 mmol) under nitrogen at 20 °C , 1.84mL, 3eq), the reaction solution was stirred at 20° C. for 12 hours, and concentrated to obtain compound 13-d.
  • Step F Under nitrogen protection, to a solution of 13-e (483 mg, 1.14 mmol, 1 eq) in MeOH (5 mL) was added sodium methoxide (1 M, 5.69 mL, 5 eq), the reaction solution was stirred at 50 °C for 16 hours, and then added to the solution. 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, then EA (30mL ⁇ 2) was added for extraction, the combined organic phase was washed with saturated brine (30mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 13 -f.
  • Step G To a solution of 13-f (117mg, 309.22 ⁇ mol, 1eq) in 1,4-dioxane (2mL) was added hydrochloric acid (4M, 2mL, 25.87eq), the reaction solution was stirred at 60°C for 16 hours, 2M aqueous sodium hydroxide solution was added to the reaction solution to adjust pH to about 8, filtered, MTBE (10 mL) was added to the filter cake and stirred for 1 hour, filtered, and the filter cake was dried to obtain compound 13.
  • hydrochloric acid 4M, 2mL, 25.87eq
  • Step A To a solution of 14-1 (0.8g, 5.75mmol, 1eq) in EtOH (10mL) at 20°C was added 1-1 (915.04mg, 5.75mmol, 1eq) and DIEA (1.49g, 11.50mmol, 2.00mL, 2eq), the reaction solution was stirred at 25°C for 16 hours, and concentrated to obtain compound 14-a.
  • DIEA 673.77 mg, 5.21 mmol, 908.04 ⁇ L, 1.5 eq
  • 12-2 (1.33 g , 5.21m
  • Step C Under nitrogen protection, to a solution of 14-b (231 mg, 568.34 ⁇ mol, 1 eq) in MeOH (5 mL) was added sodium methoxide (1 M, 2.84 mL, 5 eq), the reaction solution was stirred at 50° C. for 16 hours, and then added to the solution. 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, water (20mL) was added to dilute, then extracted with EA (10mL ⁇ 3), the combined organic phases were washed with saturated brine (10mL ⁇ 2), and dried over anhydrous sodium sulfate. , filtered and concentrated to obtain compound 14-c.
  • Step D To a solution of 14-c (170mg, 433.99 ⁇ mol, 92% purity, 1eq) in 1,4-dioxane (8.29mL) was added hydrochloric acid (4M, 8.29mL, 76.4eq), and the reaction solution was heated at 50 Stir at °C for 16 hours, add 1M aqueous sodium hydroxide solution to adjust pH to about 9, extract with EA (5mL ⁇ 4), wash the combined organic phase with saturated brine (10mL ⁇ 2), dry over anhydrous sodium sulfate, filter Concentrated, the residue was added to MTBE (5 mL) and stirred for 2 hours, filtered, and the filter cake was dried to give compound 14.
  • Step A To a solution of 15-1 (1 g, 6.37 mmol, 99.53% purity, 1 eq) in THF (10 mL) at 20 °C was added 10-2 (927.16 mg, 7.64 mmol, 1.2 eq) and tetratitanate Ethyl ester (4.36g, 19.11mmol, 3.97mL, 3eq), the reaction solution was stirred at 50°C for 16 hours, 10-2 (386.02mg, 3.19mmol, 0.5eq) was added to the reaction solution, and the stirring was continued at 50°C After 1.5 hours, cooled to 0 °C, ethyl acetate (30 mL) was added to the reaction solution to dilute, water (20 mL) was slowly added, stirred for 0.5 hours, filtered, and the filtrate was washed with saturated brine (10 mL ⁇ 2), anhydrous sodium sulfate. Dry, filter and concentrate to give compound 15-a.
  • L-selectride (1M, 4.40mL, 1.2eq
  • Step C HCl/MeOH (4M, 1.10 mL, 1 eq) was added to a solution of 15-b (1.15 g, 4.39 mmol, 1 eq) in MeOH (10 mL) at 20 °C, and the reaction solution was stirred at 20 °C for 16 hours , and concentrated to obtain the hydrochloride salt of compound 15-c.
  • Step D To a solution of 15-c hydrochloride (0.887 g) in EtOH (10 mL) was added 1-1 (898.41 mg, 4.59 mmol, 8.14e-1 eq, HCl) and DIEA ( 2.92 g, 22.58 mmol, 3.93 mL, 4 eq), the reaction solution was stirred at 20° C. for 16 hours, and concentrated to obtain compound 15-d.
  • Step G Hydrochloric acid (4M, 2mL, 50.45eq) was added to a solution of 15-f (60mg, 158.58 ⁇ mol, 1eq) in 1,4-dioxane (2mL), and the reaction solution was stirred at 60°C for 19 hours, 1M aqueous sodium hydroxide solution was added to the reaction solution to adjust pH to about 9, filtered, MTBE (2 mL) was added to the filter cake and stirred for 2 hours, filtered, and the filter cake was dried to obtain compound 15.
  • Step A To a solution of compound 3-1 (5g, 37.85mmol, 4.35mL, 1eq) and iodoethane (12.99g, 83.26mmol, 6.66mL, 2.2eq) in DMF (50mL) under nitrogen protection was added carbonic acid Cesium (27.13g, 83.26mmol, 2.2eq), the reaction solution was stirred at 20°C for 16 hours, water (200mL) was added, then EA (200mL) was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, Filtration and concentration gave compound 16-a.
  • Step B To a solution of compound 16-a (7g, 37.19mmol, 1eq) in MeOH (40mL) and water (40mL) was added sodium hydroxide (1.64g, 40.91mmol, 1.1eq), the reaction solution was stirred at 20°C Concentrate after 16 hours, add water (100mL) to the residue, then extract with MTBE (100mL), adjust the pH of the aqueous phase to about 5 with 1M dilute hydrochloric acid after separation, and then extract with EA (100mL), and use saturated salt for the organic phase. Washed with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 16-b.
  • sodium hydroxide 1.64g, 40.91mmol, 1.1eq
  • Step E To a solution of compound 16-d (0.15g, 394.34 ⁇ mol, 1eq) in 1,4-dioxane (5mL) was added hydrochloric acid (4M, 5mL, 50.72eq), and the reaction solution was stirred at 50°C for 16 After 1 hour, 1N sodium hydroxide was added to the reaction solution to adjust the pH to about 7, then the 1,4-dioxane was concentrated to remove the 1,4-dioxane, the residue was added with MTBE (20 mL), filtered, and the filter cake was dried under high vacuum to obtain compound 16.
  • hydrochloric acid (4M, 5mL, 50.72eq
  • Step C Under nitrogen protection, to a solution of compound 17-b (0.15g, 380.35 ⁇ mol, 1eq) in 1,4-dioxane (5mL) was added hydrochloric acid (4M, 5mL, 52.58eq), the reaction solution was Stir at 50°C for 20 hours, add saturated aqueous sodium bicarbonate solution to the reaction solution to adjust the pH to about 7, then concentrate the 1,4-dioxane, add water (10 mL) and MTBE (20 mL) to the residue, and stir for 30 10 minutes, filtered, and the filter cake was dried under high vacuum to give compound 17.
  • hydrochloric acid 4M, 5mL, 52.58eq
  • Step A To a solution of 18-1 (6.89 g, 39.92 mmol, 1 eq) in THF (70 mL) at 20 °C was added 10-2 (5.81 g, 47.91 mmol, 1.2 eq) and tetraethyl titanate ( 27.32g, 119.77mmol, 24.84mL, 3eq), the reaction solution was stirred at 60°C for 16 hours, ethyl acetate (100mL) was added to the reaction solution, cooled to 0°C, water (20mL) was slowly added, and stirred for 0.5 hours, After filtration, the filtrate was washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 18-a.
  • 10-2 5.81 g, 47.91 mmol, 1.2 eq
  • tetraethyl titanate 27.32g, 119.77mmol, 24.84mL
  • L-selectride 1M, 25.75mL, 1eq
  • Step C HCl/MeOH (4M, 25mL, 13.89eq) solution was added to 18-b (2g, 7.20mmol, 1eq), the reaction solution was stirred at 50°C for 1 hour and then concentrated to obtain the hydrochloride of compound 18-c .
  • Step D To a solution of 18-c hydrochloride (2 g) in EtOH (30 mL) was added 1-1 (2.05 g, 10.47 mmol, 1.1 eq, HCl) and DIEA (3.69 g, 28.56mmol, 4.97mL, 3eq), the reaction solution was stirred at 20°C for 16 hours and then concentrated, the residue was added with water (50mL), then adjusted to pH 5 with acetic acid, extracted with EA (50mL), and the aqueous phase was separated.
  • Step G Under nitrogen protection, to a solution of compound 18-f (0.69g, 1.68mmol, 1eq) in 1,4-dioxane (15mL) was added hydrochloric acid (4M, 15mL, 35.72eq), the reaction solution was Stir at 50°C for 16 hours, adjust the pH of the reaction solution to about 7 with 1N aqueous sodium hydroxide solution, then concentrate the 1,4-dioxane, add water (50 mL) and MTBE (50 mL) to the residue, and stir for 30 minutes , filtered, and the filter cake was dried under high vacuum to obtain compound 18.
  • hydrochloric acid 4M, 15mL, 35.72eq
  • Cardiac myosin S1 (Cytoskeleton, Cat. #MYS03)
  • Cardiac actin (Cytoskeleton, Cat. #AD99-A)
  • the compound of the present invention has a good inhibitory activity of cardiac myosin ATPase.
  • Animals in group 1 were given a single dose of 0.2 mg/kg at a concentration of 0.2 mg/mL via tail vein injection, and animals in group 2 were given compound at a dose of 1 mg/kg at a concentration of 0.2 mg/mL by gavage.
  • Plasma samples were collected from animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose.
  • the drug concentration in the plasma samples was determined by LC-MS/MS method, and the pharmacokinetic test results of the tested drugs are shown in Table 2.
  • the compounds of the present invention have good pharmacokinetic properties in rats.

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Abstract

本发明涉及一系列取代的吡啶-2,4-二酮类及其制备方法，具体涉及式(I)所示化合物及其药学上可接受的盐。

Description

取代的吡啶-2,4-二酮类衍生物
本申请主张如下优先权：
CN202110214692.X，2021年02月25日；
CN202210103134.0，2022年01月27日；
CN 202210153298.4，2022年02月18日。
技术领域
本发明涉及一系列取代的吡啶-2,4-二酮类衍生物及其制备方法，具体涉及式(I)所示化合物及其药学上可接受的盐。
背景技术
肥厚型心肌病是一种以心肌肥厚为特征的心肌疾病，常侵及室间隔，心室内腔变小，左心室血液充盈受阻，左心室舒张期顺应性下降。根据左心室流出道有无梗阻分为梗阻性及非梗阻性肥厚型心肌病，可能与遗传等有关。HCM全球发病率约1/500，其临床表现多样，可以无症状，也可以有心悸、劳力性呼吸困难、心前区闷痛、易疲劳、晕厥甚至猝死，晚期出现左心衰的表现。
目前HCM治疗药物有限，主要通过β受体阻滞剂或钙通道阻滞剂来改善症状，无法针对病因，延缓心肌肥厚进展，也不改善预后，治疗效果有限。
肌球蛋白和肌动蛋白是心肌收缩的物质基础，肌球蛋白横桥周期性地与肌动蛋白结合、解离，驱动肌丝滑动，导致心肌收缩。肌球蛋白具有ATP酶活性，通过水解ATP为心肌收缩提供动力。肌球蛋白变异会导致肌球蛋白与肌动蛋白结合时间延长，左心室心肌过度收缩和舒张受损，导致左心室心肌肥大、纤维化，引发HCM。MYK-461是心肌肌球蛋白别构调控剂，其减慢磷酸水解速度、降低肌球蛋白与肌动蛋白结合时间，产生负性肌力效应，缓解因左心室心肌过度收缩所致心肌肥大等病理改变。但体内消除缓慢，药物在体内停留时间过长，不便于快速调节剂量(Mark P.Grillo et al.Xenobiotica,2019；49(6):718-733)。因此，开发具有更好活性、更理想药代动力学特性的肌球蛋白抑制剂具有重要临床价值和意义。
此外，心肌肌节的异常已鉴别为多种心脏疾病及病状的驱动原因，如射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛和限制性心肌病等，肌球蛋白ATP酶抑制剂通过抑制心肌收缩，也可以在缓解上述疾病病理过程中发挥潜在治疗效应。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022077962-appb-000001
其中，
R 1和R 2分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基，其中所述C 1-4烷 基和C 1-4烷氧基分别独立地任选被1、2或3个R a取代；
或R 1和R 2与其连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基，其中所述C 3-6环烷基和3-6元杂环烷基分别独立地任选被1、2、3或4个R b取代；
R 3选自H和F；
R 4选自H、C 1-4烷基和C 3-4环烷基，其中所述C 1-4烷基和C 3-4环烷基分别独立地任选被1、2或3个R c取代；
R 5选自H和C 1-4烷基；
R 6选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2或3个R d取代；
R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、-COR a1、-CO 2R a1、-SO 2R a1、-SO 2NR a1R a2和-CONR a1R a2，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2或3个R取代；
R a1和R a2分别独立选自H和C 1-4烷基；
或R a1和R a2与其连接的氮原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基分别独立地任选被1、2、3或4个R e取代；
R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、-COR b1、-CO 2R b1、-SO 2R b1、-SO 2NR b1R b2和-CONR b1R b2，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2或3个R取代；
R b1和R b2分别独立选自H和C 1-4烷基；
或R b1和R b2与其连接的氮原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基分别独立地任选被1、2、3或4个R f取代；
R c分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
R d分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
R e分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
R f分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
R分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN；
n选自1、2、3或4；
所述3-6元杂环烷基和4-6元杂环烷基分别独立地包含1、2、3或4个分别独立地选自N、O、S和NH的原子或原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022077962-appb-000002
其中，
R 1和R 2分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基；
或，R 1和R 2与其连接的碳原子一起形成C 4-6环烷基或5-6元杂环烷基，其中所述C 4-6环烷基和5-6元杂环 烷基分别独立地任选被1、2、3或4个R b取代；
R 3选自H和F；
R 4选自H和C 1-4烷基；
R 5选自H；
R 6选自H、F、Cl、Br、I、和C 1-4烷基；
R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷氧基、-COR b1和-CO 2R b1；
R b1选自H和C 1-4烷基；
n选自1或2；
所述5-6元杂环烷基包含1、2、3或4个分别独立地选自N、O、S和NH的原子或原子团。
本发明的一些方案中，上述R a1和R a2分别独立地选自H，其他变量如本发明所定义。
本发明的一些方案中，上述R a、R c、R d、R e和R f分别独立地选自F和Cl，其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2分别独立地选自-CH 3和-CH 2CH 3，其中所述CH 3和-CH 2CH 3分别独立地任选被1、2或3个R a所取代，R a及其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2分别独立地选自-CH 3和-CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R b1和R b2分别独立地选自-CH 3和-CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、-OCH 3、-COCH 3、-CO 2CH 3和-CO 2CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、-OCH 3、-COCH 3和-CO 2CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与其连接的碳原子一起形成C 5-6环烷基或6元杂环烷基，其中所述C 5-6环烷基和6元杂环烷基分别独立地任选被1、2、3或4个R b取代，R b及其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与其连接的碳原子一起形成R 1和R 2与其连接的碳原子一起形成
Figure PCTCN2022077962-appb-000003
其中所述
Figure PCTCN2022077962-appb-000004
Figure PCTCN2022077962-appb-000005
分别独立地任选被1、2、3或4个R b取代，R b及其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与其连接的碳原子一起形成
Figure PCTCN2022077962-appb-000006
Figure PCTCN2022077962-appb-000007
其中所述
Figure PCTCN2022077962-appb-000008
分别独立地任选被1、2、3或4个R b取代，R b及其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与其连接的碳原子一起形成
Figure PCTCN2022077962-appb-000009
Figure PCTCN2022077962-appb-000010
R b及其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与其连接的碳原子一起形成
Figure PCTCN2022077962-appb-000011
Figure PCTCN2022077962-appb-000012
R b及其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与其连接的碳原子一起形成
Figure PCTCN2022077962-appb-000013
Figure PCTCN2022077962-appb-000014
其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与其连接的碳原子一起形成
Figure PCTCN2022077962-appb-000015
Figure PCTCN2022077962-appb-000016
其他变量如本发明所定义。
本发明的一些方案中，上述结构片段
Figure PCTCN2022077962-appb-000017
选自
Figure PCTCN2022077962-appb-000018
Figure PCTCN2022077962-appb-000019
其他变量如本发明所定义。
本发明的一些方案中，上述结构片段
Figure PCTCN2022077962-appb-000020
选自
Figure PCTCN2022077962-appb-000021
Figure PCTCN2022077962-appb-000022
其他变量如本发明所定义。
本发明的一些方案中，上述结构片段
Figure PCTCN2022077962-appb-000023
选自
Figure PCTCN2022077962-appb-000024
Figure PCTCN2022077962-appb-000025
其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自C 1-4烷基，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自-CH 3和-CH 2CH 3，其中所述-CH 3和-CH 2CH 3分别独立地任选被1、2或3个R d取代，R d及其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自-CH 3和-CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 5选自H，其他变量如本发明所定义。
本发明的一些方案中，上述R 6分别独立地选自H、F、Cl和-CH 3，其中所述-CH 3任选被1、2或3个R d取代，R d及其他变量如本发明所定义。
本发明的一些方案中，上述R 6分别独立地选自H、F、Cl和-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 6分别独立地选自H、F和-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-1)所示结构：
Figure PCTCN2022077962-appb-000026
其中，n、R 1、R 2、R 3、R 4和R 6如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-1-1)所示结构：
Figure PCTCN2022077962-appb-000027
其中，
n选自1和2；
m选自0、1和2；
q选自0和1；
T选自CH 2、O和NH，当T选自CH 2和NH时，T可以任选被R b取代；
R b、R 4和R 6如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-1A)或(I-1B)所示结构：
Figure PCTCN2022077962-appb-000028
其中，n、R 1、R 2、R 3、R 4和R 6如本发明所定义，且R 4不为H。
本发明的一些方案中，上述化合物具有式(I-1-1A)或(I-1-1B)所示结构：
Figure PCTCN2022077962-appb-000029
其中，
n选自1和2；
m选自0、1和2；
q选自0和1；
R 4选自C 1-4烷基；
T选自CH 2、O和NH，当T选自CH 2和NH时，T可以任选被R b取代；
R b、R 4和R 6如本发明所定。
本发明还有一些方案是由上述各变量任意组合而来。
本发明还提供了下式化合物或其药学上可接受的盐，
Figure PCTCN2022077962-appb-000030
Figure PCTCN2022077962-appb-000031
本发明还提供了下式化合物或其药学上可接受的盐，
Figure PCTCN2022077962-appb-000032
Figure PCTCN2022077962-appb-000033
本发明还提供了一种药物组合物，其含有治疗有效量的上述化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述药物组合物在制备心肌肌球蛋白抑制剂药物中的应用。
本发明还提供了上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗心衰和肥厚型心肌疾病中的应用。
本发明还提供了一种在需要的受试者中治疗与心肌肌球蛋白抑制剂相关的疾病的方法，方法包括向受试者提供有效剂量的上述任意技术方案所限定的化合物或其药学上可接受的盐或上述药物组合物。
本发明还提供了一种在需要的受试者中治疗心衰和肥厚型心肌疾病的方法，方法包括向受试者提供有效剂量的上述任意技术方案所限定的化合物或其药学上可接受的盐或上述药物组合物。
技术效果
本发明化合物对心肌肌球蛋白ATP酶有较好的抑制作用，且其具有优良的药代动力学性质。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022077962-appb-000034
和楔形虚线键
Figure PCTCN2022077962-appb-000035
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022077962-appb-000036
和直形虚线键
Figure PCTCN2022077962-appb-000037
表示立体中心的相对构型，用波浪线
Figure PCTCN2022077962-appb-000038
表示楔形实线键
Figure PCTCN2022077962-appb-000039
或楔形虚线键
Figure PCTCN2022077962-appb-000040
或用波浪线
Figure PCTCN2022077962-appb-000041
表示直形实线键
Figure PCTCN2022077962-appb-000042
和直形虚线键
Figure PCTCN2022077962-appb-000043
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学 上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022077962-appb-000044
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022077962-appb-000045
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022077962-appb-000046
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022077962-appb-000047
直形虚线键
Figure PCTCN2022077962-appb-000048
或波浪线
Figure PCTCN2022077962-appb-000049
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022077962-appb-000050
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2022077962-appb-000051
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连。
Figure PCTCN2022077962-appb-000052
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022077962-appb-000053
Figure PCTCN2022077962-appb-000054
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022077962-appb-000055
仍包括
Figure PCTCN2022077962-appb-000056
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价 哌啶基。
当某取代基的化学键与连接环上两原子的化学键相交时，说明该取代基可与环上任意原子成键。当某取代基连接的原子并没有指明的时候，该取代基可以与任意原子成键，如果取代基连接的原子在双环或者三环体系中，则说明该取代基可与该体系中任意环的任意原子成键。取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。例如，结构单元
Figure PCTCN2022077962-appb-000057
表示其可在环己基或者环戊基上的任意一个位置发生取代。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C 1-4烷基包括C 1-2、C 1-3和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。
除非另有规定，术语“C 1-4烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C 1-4烷氧基包括C 1-3、C 1-2、C 2-4、C 4和C 3烷氧基等。C 1-4烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)等。
术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C 1-6杂烷基；在另一些实施方案中，所述杂烷基为C 1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3、和。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元 环、6-7元环、6-8元环、和6-10元环等。
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，“C 3-4环烷基”表示由3至4个碳原子组成的饱和环状碳氢基团，其为单环体系；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
除非另有规定，“C 4-6环烷基”表示由4至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 4-6环烷基包括C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 4-6环烷基的实例包括，但不限于，环丁基、环戊基、环己基等。
除非另有规定，“C 5-6环烷基”表示由5至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括5元环烷基和6元环烷基等；其可以是一价、二价或者多价。C 5-6环烷基的实例包括，但不限于，环戊基、环己基等。
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基或六氢哒嗪基等。
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基或六氢哒嗪基等。
除非另有规定，术语“5-6元杂环烷基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-6元杂环烷基包括5元和6元杂环烷基。5-6元杂环烷基的实例包括 但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基等。
除非另有规定，术语“6元杂环烷基”本身或者与其他术语联合分别表示由6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。6元杂环烷基的实例包括但不限于四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022077962-appb-000058
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的容积可经市售获得。
本发明采用下述缩略词：TEA代表三乙胺；DIEA代表N,N-二异丙基乙胺；PE代表石油醚；EtOAc代表乙酸乙酯；EA代表乙酸乙酯；THF代表四氢呋喃；MeOH代表甲醇；MTBE代表甲基叔丁基醚；DCM代表二氯甲烷；EtOH代表乙醇；iPrOH代表异丙醇；Boc 2O代表二碳酸二叔丁酯；L-selectride代表三仲丁基硼氢化锂；TCFH代表N,N,N,N-四甲基氯甲脒六氟磷酸盐；FA代表甲酸；TFA代表三氟乙酸；ACN代 表乙腈；TLC代表薄层色谱；HPLC代表高效液相色谱；LCMS代表液质联用色谱。DMSO代表二甲亚砜；DMF代表N,N-二甲基甲酰胺；LDA代表二异丙基氨基锂；DMAC代表N,N-二甲基乙酰胺；PEG-400代表聚乙二醇400；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸；DMSO-d 6代表氘代二甲亚砜；CDCl 3代表氘代氯仿。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022077962-appb-000059
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2022077962-appb-000060
合成路线：
Figure PCTCN2022077962-appb-000061
步骤A:在20℃下，向化合物1-2(929.08mg,7.67mmol,975.93μL,1eq)和化合物1-1(1.5g,7.67mmol,1eq,HCl)的EtOH(20mL)溶液中加入DIEA(1.98g,15.33mmol,2.67mL,2eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物1-a。
步骤B:在氮气保护0℃下，向化合物1-a(1.6g,6.83mmol,1eq)的THF(30mL)溶液中加入DIEA(1.77g,13.66mmol,2.38mL,2eq)和化合物1-3(1.34g,7.51mmol,1.1eq)，反应液在20℃下搅拌1小时，反应液浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-3:1)得到化合物1-b。LCMS(ESI)m/z:377.3(M+1)。
步骤C:在氮气保护下，向化合物1-b(1.5g,3.98mmol,1eq)的MeOH(30mL)溶液中加入叔丁醇钠(1.53g,15.94mmol,4eq)，反应液在20℃下搅拌4小时后加入稀盐酸(1mol/L,50mL)，用EA(50mL)萃取，有机相再用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离 (PE：EtOAc＝4:1-2:1)得到化合物1-c。
步骤D:在氮气保护下，向化合物1-c(0.4g,1.26mmol,1eq)的DMSO(4mL)溶液中加入氯化锂(107.20mg,2.53mmol,51.79μL,2eq)，反应液在125℃下搅拌20小时后过滤，滤液通过制备HPLC[流动相：水(0.1％TFA)-ACN；梯度：21％-51％ACN]纯化得到化合物1。 1H NMR(CDCl 3,400MHz):7.38-7.24(m,5H),5.17(br s,1H),4.63(br d,J＝6.4Hz,1H),1.57(d,J＝6.7Hz,3H),1.42(s,3H),1.38(s,3H)；LCMS(ESI)m/z:259.4(M+1)。
实施例2
Figure PCTCN2022077962-appb-000062
合成路线：
Figure PCTCN2022077962-appb-000063
步骤A:在氮气保护-78℃下，向化合物2-1(5g,34.68mmol,4.63mL,1eq)的THF(80mL)溶液中滴加LDA(2M,19.07mL,1.1eq)，反应液在-78℃下搅拌30分钟，然后加入氯甲酸甲酯(3.44g,36.42mmol，2.82mL,1.05eq)，反应液缓慢升温到20℃，搅拌16小时后加入水(200mL)淬灭，然后用EA(200mL)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-3:1)得到化合物2-a。
步骤B:在0℃下，向化合物2-a(2.5g,12.36mmol,1eq)的MeOH(20mL)和水(20mL)溶液中加入氢氧化钠(494.51mg,12.36mmol,1eq)，反应液在20℃下搅拌16小时后加入水(50mL)，然后用EA(50mL)萃取，分液后水相用1M稀盐酸调节pH到5左右,然后再用EA(50mL)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物2-b。
步骤C:在氮气保护0℃下，向化合物2-b(1.7g,9.03mmol,1eq)的DCM(30mL)溶液中加入TEA(4.57g,45.17mmol,6.29mL,5eq)和DMF(33.02mg,451.70μmol,34.75μL,0.05eq)，然后加入草酰氯(1.72g,13.55mmol,1.19mL,1.5eq)，反应液在20℃搅拌1小时后浓缩得到化合物2-c。
步骤D:在氮气保护0℃下，向化合物2-c(2.0g,9.68mmol,1eq)的DCM(30mL)溶液中加入DIEA(2.50g,19.36mmol,3.37mL,2eq)和化合物1-a(2.27g,9.68mmol,1eq)，反应液在20℃下搅拌1小时后 浓缩，加入EA(30mL)稀释，然后加入1N稀盐酸(30mL)洗涤，再用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-3:1)得到化合物2-d。
步骤E:在氮气保护下，向化合物2-d(0.35g,865.36μmol,1eq)的MeOH(5mL)溶液中加入甲醇钠(2M,7mL,16.18eq)，反应液在50℃下搅拌2小时后浓缩，残留物加入EA(20mL)稀释，然后用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-1:1)得到化合物2-e。
步骤F:向化合物2-e(70mg,195.32μmol,1eq)的1,4-二氧六环(7mL)溶液中加入盐酸(4M,7.00mL,143.35eq)，反应液在50℃下搅拌16小时后浓缩，残留物加入2N的氢氧化钠水溶液调节到中性，然后加入EA(50mL)萃取，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过制备HPLC[水(0.225％FA)-ACN]；梯度：17％-47％ACN)纯化得到化合物2。 1H NMR(DMSO-d 6,400MHz):δppm 9.62(br s,1H),7.47-7.20(m,5H),7.05(br s,1H),4.60(br t,J＝6.7Hz,1H),4.41(s,1H),3.85-3.66(m,4H),1.94-1.75(m,2H),1.68-1.51(m,2H),1.43(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:301.4(M+1)。
实施例3
Figure PCTCN2022077962-appb-000064
合成路线：
Figure PCTCN2022077962-appb-000065
步骤A:在氮气保护下，向化合物3-1(5g,37.85mmol,4.35mL,1eq)和1,4-二溴丁烷(8.17g,37.85mmol,4.57mL,1eq)的DMF(50mL)溶液中加入碳酸钾(10.46g,75.69mmol,2eq)，反应液在50℃下搅拌16小时后加入EA(200mL),然后用水(200mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝20:1-10:1)得到化合物3-a。
步骤B:向化合物3-a(4.5g,24.17mmol,1eq)的MeOH(25mL)和水(25mL)溶液中加入氢氧化钠(1.06g,26.58mmol,1.1eq)，反应液在20℃下搅拌16小时后加入水(30mL)，然后用EA(30mL)萃取，分液后水相用1M稀盐酸调节pH到5左右,然后再用EA(30mL)萃取，无水硫酸钠干燥，过滤后浓缩得到化合物3-b。
步骤C:在氮气保护-20℃下，向化合物3-b(2.1g,12.20mmol,1eq)的DCM(30mL)溶液中加入TEA(4.94g,48.79mmol,6.79mL,4eq)和DMF(44.57mg,609.83μmol,46.92μL,0.05eq)，然后加入草酰氯(2.01g,15.86mmol,1.39mL,1.3eq)，反应液在20℃搅拌1小时后浓缩得到化合物3-c。
步骤D:在氮气保护-20℃下，向化合物3-c(2.3g,12.07mmol,1eq)的DCM(30mL)溶液中加入TEA(2.44g,24.13mmol,3.36mL,2eq)和化合物1-a(2.83g,12.07mmol,1eq)，反应液在0℃下搅拌1小时后浓缩，残留物加入EA(30mL)稀释，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝20:1-5:1)得到化合物3-d。
步骤E:在氮气保护下，向化合物3-d(0.7g,1.80mmol,1eq)的MeOH(4mL)溶液中加入甲醇钠(1M,7.21mL,4eq)，反应液在20℃下搅拌16小时，向反应液中加入1N的稀盐酸调节pH＝5，然后加入EA(20mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物3-e。
步骤F:向化合物3-e(0.8g,2.34mmol,1eq)的1,4-二氧六环(6mL)溶液中加入盐酸(4M,6mL,10.27eq)，反应液在50℃下搅拌16小时后加入EA(50mL)稀释，然后加入1N的氢氧化钠水溶液调节pH＝7，分液后有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入MeOH(10mL)并搅拌20分钟，过滤，滤饼高真空干燥后得到化合物3。 1H NMR(DMSO-d 6,400MHz):δppm 9.49(br s,1H),7.41-7.31(m,4H),7.30-7.25(m,1H),6.92(br d,J＝5.1Hz,1H),4.60(br t,J＝6.7Hz,1H),4.42(s,1H),1.91-1.80(m,4H),1.72-1.65(m,4H),1.43(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:285.4(M+1)。
实施例4
Figure PCTCN2022077962-appb-000066
合成路线：
Figure PCTCN2022077962-appb-000067
步骤A:向3-1(14.94g,113.07mmol,12.99mL,1eq)的DMF(150mL)溶液中加入4-1(26g,113.07mmol,15.29mL,1eq)和碳酸钾(31.25g,226.15mmol,2eq)。反应液在50℃下搅拌16小时后加入EA(150mL)，然后用水(150mL)洗涤，有机相再用饱和食盐水洗涤(100mL×3)，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝50:1-30:1)得到化合物4-a。
步骤B:向4-a(6.9g,34.46mmol,1eq)的MeOH(40mL)和水(40mL)溶液中加入氢氧化钠(1.38g,34.46mmol,1eq)，反应液在15℃下搅拌16小时后加入水(50mL)，然后用EA(100mL)萃取，分液后水相用1M稀盐酸调节pH到5左右,然后再用EA(100mL×2)萃取，合并的有机相再用饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤后浓缩得到化合物4-b。
步骤C:在0℃下，向4-b(4.5g,24.17mmol,1eq)的DCM(50mL)溶液中加入TEA(9.78g,96.67mmol,13.45mL,4eq)和DMF(88.32mg,1.21mmol,92.97μL,0.05eq)，然后加入草酰氯(3.99g,31.42 mmol,2.75mL,1.3eq)，反应液在10℃搅拌1小时后浓缩得到化合物4-c。
步骤D:在0℃下，向4-c(5g,24.43mmol,1eq)的DCM(50mL)溶液中加入TEA(4.94g,48.86mmol,6.80mL,2eq)，然后加入1-a(5.72g,24.43mmol,1eq)，反应液在0℃下搅拌1小时后浓缩，残留物通过柱层析分离(PE：EtOAc＝30:1-10:1)得到化合物4-d。
步骤E:在氮气保护下，向4-d(2.30g,5.71mmol,1eq)的MeOH(15mL)溶液中加入甲醇钠(1M,28.57mL,5eq)，反应液在10℃下搅拌16小时，然后在50℃下搅拌3小时，向反应液中加入1N稀盐酸调节pH到大约5，然后加入EA(50mL×2)萃取，合并的有机相用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-3:1)得到化合物4-e。
步骤F:向4-e(0.7g,1.96mmol,1eq)的1,4-二氧六环(10mL)和THF(2mL)溶液中加入盐酸(4M,10.50mL,21.38eq)，反应液在50℃下搅拌40小时后加入1N氢氧化钠水溶液调节pH到7左右，然后用DCM/MeOH＝10/1(50mL×2)萃取，合并的有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入MeOH(10mL)并在10℃下搅拌30分钟，过滤，滤饼高真空干燥后得到化合物4。 1H NMR(DMSO-d 6,400MHz):δppm 9.38(br s,1H),7.41-7.22(m,5H),6.84(br d,J＝5.4Hz,1H),4.57(br t,J＝6.8Hz,1H),4.36(s,1H),1.74-1.45(m,10H),1.41(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:299.2(M+1)。
实施例5
Figure PCTCN2022077962-appb-000068
合成路线：
Figure PCTCN2022077962-appb-000069
步骤A:在氮气保护20℃下，向化合物5-1(1.00g,7.19mmol,1eq)和化合物1-1(1.14g,7.19mmol,1eq)的EtOH(15mL)溶液中加入DIEA(1.86g,14.37mmol,2.50mL,2eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物5-a。
步骤B:在氮气保护20℃下，向5-a(1.81g,7.17mmol,1eq)的DCM(30mL)溶液中加入TEA(1.45g,14.35mmol,2.00mL,2eq)，然后加入3-c(1.37g,7.17mmol,1eq)，反应液在20℃下搅拌16小时后浓缩，残留物加入EA(40mL)稀释,然后用水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝20:1-10:1)得到化合物5-b。
步骤C:在氮气保护20℃下，向5-b(600mg,1.48mmol,1eq)的MeOH(6mL)溶液中加入甲醇钠(1M,5.90mL,4eq)，反应液在40℃下搅拌16小时，反应液加入到水(40mL)中，然后用EA(40mL×2)萃取，合并的有机相用饱和食盐水洗涤(40mL)，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝5:1-1:1)得到化合物5-c。
步骤D:在20℃下，向5-c(550mg,1.53mmol,1eq)的1,4-二氧六环(4mL)溶液中加入盐酸(4M,3.82mL,10eq)，反应液在40℃下搅拌16小时，向反应液中加入EA(40mL)，然后加入1N氢氧化钠水溶液调节pH到7左右，分液，水相再用EA(40mL)萃取，合并的有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入MeOH(5mL)并搅拌，过滤，滤饼高真空干燥后得到化合物5。 1H NMR(DMSO-d 6,400MHz):δppm 9.48(br s,1H),7.38(dd,J＝5.6,8.6Hz,2H),7.19(t,J＝8.8Hz,2H),6.91(br d,J＝6.0Hz,1H),4.62(br t,J＝6.7Hz,1H),4.41(s,1H),1.96-1.78(m,4H),1.76-1.61(m,4H),1.42(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:302.8(M+1)。
实施例6
Figure PCTCN2022077962-appb-000070
合成路线：
Figure PCTCN2022077962-appb-000071
步骤A:在氮气保护20℃下，向化合物6-1(1.00g,7.19mmol,1eq)和化合物1-1(1.14g,7.19mmol,1eq)的EtOH(15mL)溶液中加入DIEA(1.86g,14.37mmol,2.50mL,2eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物6-a。
步骤B:在氮气保护20℃下，向6-a(1.81g,7.17mmol,1eq)的DCM(30mL)溶液中加入TEA(1.45g,14.35mmol,2.00mL,2eq)，然后加入3-c(1.37g,7.17mmol,1eq)，反应液在20℃下搅拌16小时后浓缩，残留物加入EA(40mL)稀释,然后用水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝20:1-10:1)得到化合物6-b。
步骤C:在氮气保护20℃下，向6-b(750.00mg,1.85mmol,1eq)的MeOH(8mL)溶液中加入甲醇钠(1M,8mL,4.34eq)，反应液在40℃下搅拌16小时，冷却到室温后加入EA(30mL)，然后用1N盐酸调节pH到7左右，分液，水相再用EA(40mL×2)萃取，合并的有机相用饱和食盐水洗涤(40mL)，无水硫酸 钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝5:1-1:1)得到化合物6-c。
步骤D:在20℃下，向6-c(550mg,1.53mmol,1eq)的1,4-二氧六环(4mL)溶液中加入盐酸(4M,3.82mL,10eq)，反应液在40℃下搅拌16小时，向反应液中加入水(40mL)，然后加入饱和碳酸氢钠水溶液调节pH到7左右，用EA(40mL×2)萃取，合并的有机相用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入MeOH(6mL)，搅拌15分钟后过滤，滤饼高真空干燥后得到化合物6。 1H NMR(DMSO-d 6,400MHz):δppm 9.51(br s,1H),7.49-7.35(m,1H),7.19(br d,J＝7.7Hz,2H),7.09(dt,J＝1.6,8.2Hz,1H),6.94(br d,J＝6.1Hz,1H),4.63(br t,J＝6.7Hz,1H),4.40(s,1H),1.90-1.79(m,4H),1.74-1.63(m,4H),1.42(d,J＝6.7Hz,3H)；LCMS(ESI)m/z:302.8(M+1)。
实施例7
Figure PCTCN2022077962-appb-000072
合成路线：
Figure PCTCN2022077962-appb-000073
步骤A:在氮气保护20℃下，向化合物7-1(0.76g,4.88mmol,1eq)和化合物1-1(777.38mg,4.88mmol,1eq)的EtOH(15mL)溶液中加入DIEA(1.26g,9.77mmol,1.70mL,2eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物7-a。
步骤B:在氮气保护20℃下，向7-a(1.31g,4.87mmol,1eq)的DCM(30mL)溶液中加入TEA(986.53mg,9.75mmol,1.36mL,2eq)，然后加入3-c(1.23g,6.45mmol,1.32eq)，反应液在20℃下搅拌16小时后浓缩，残留物加入EA(40mL)稀释,然后用水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝20:1-10:1)得到化合物7-b。
步骤C:在氮气保护20℃下，向7-b(750mg,1.77mmol,1eq)的MeOH(8mL)溶液中加入甲醇钠(1M,8mL,4.51eq)，反应液在40℃下搅拌16小时，冷却到室温后加入EA(30mL)，然后用1N盐酸调节pH到7左右，分液，水相再用EA(60mL×2)萃取，合并的有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝4:1-1:1)得到化合物7-c。
步骤D:在20℃下，向7-c(575.11mg,1.53mmol,1eq)的1,4-二氧六环(4mL)溶液中加入盐酸(4M,3.82mL,10eq)，反应液在40℃下搅拌16小时，向反应液中加入水(40mL)，然后加入饱和碳酸氢钠水 溶液调节pH到7左右，用EA(40mL×2)萃取，合并的有机相用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入MeOH(4mL)，搅拌15分钟后过滤，滤饼高真空干燥后得到化合物7。 1H NMR(DMSO-d 6,400MHz)δppm 9.51(br s,1H),7.48-7.37(m,2H),7.36-7.27(m,2H),6.95(br d,J＝5.1Hz,1H),4.63(br t,J＝6.7Hz,1H),4.41(s,1H),1.90-1.80(m,4H),1.72-1.64(m,4H),1.42(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:318.8(M+1)。
实施例8
Figure PCTCN2022077962-appb-000074
合成路线：
Figure PCTCN2022077962-appb-000075
步骤A:在氮气保护-78℃下，向化合物8-1(20g,82.20mmol,1eq)的THF(200mL)溶液中滴加LDA(2M,49.32mL,1.2eq)，反应液在-78℃下搅拌1小时，然后加入氯甲酸甲酯(8.54g,90.42mmol,7.00mL,1.1eq)，反应液缓慢升温到20℃，搅拌4小时后加入饱和氯化铵水溶液(600mL)淬灭，然后用EA(600mL)萃取，有机相用饱和食盐水(200mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物8-a。
步骤B:向化合物8-a(27g,89.60mmol,1eq)的MeOH(200mL)和水(200mL)溶液中加入氢氧化钠(3.58g,89.60mmol,1eq)，反应液在15℃下搅拌16小时后加入水(200mL)，然后用EA(200mL)萃取，分液后水相用1M稀盐酸调节pH到5左右,然后再用EA(300mL×2)萃取，合并的有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物8-b。
步骤C:在氮气保护0℃下，向化合物8-b(23g,80.05mmol,1eq)的DCM(200mL)溶液中加入TEA(32.40g,320.21mmol,44.57mL,4eq)和DMF(292.56mg,4.00mmol,307.95μL,0.05eq)，然后加入草酰氯(13.21g,104.07mmol,9.11mL,1.3eq)，反应液在10℃搅拌1小时后浓缩得到化合物8-c。
步骤D:在氮气保护0℃下，向化合物1-a(23.38g)的DCM(200mL)溶液中加入TEA(23.83g,235.47mmol,32.78mL,3eq)，然后加入化合物8-c(24g,78.49mmol,1eq)的DCM(200mL)溶液，反应液在10℃ 下搅拌16小时后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-5:1)得到化合物8-d。
步骤E:在氮气保护下，向化合物8-d(13.4g,26.61mmol,1eq)的MeOH(130mL)溶液中加入甲醇钠(1M,130mL,4.89eq)，反应液在50℃下搅拌3小时后浓缩，残留物用1M稀盐酸调节pH到5～6，用EA(200mL×2)萃取，合并的有机相用饱和食盐水(200mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝3:1-1:1)得到化合物8-e。
步骤F:向化合物8-e(7.5g,16.39mmol,1eq)的1,4-二氧六环(150mL)溶液中加入盐酸(4M,150mL,36.60eq)，反应液在80℃下搅拌16小时，冷却后向反应液中加入2N的氢氧化钠水溶液调节pH到8～9，然后用EA/iPrOH＝7:1(200mL×4)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩得到化合物8-f。
步骤G:在氮气保护0℃下，向化合物8-f(0.15g,501.06μmol,1eq)的DCM(3mL)溶液中加入DIEA(194.27mg,1.50mmol,261.83μL,3eq)，然后加入氯甲酸甲酯(49.72mg,526.11μmol,40.75μL,1.05eq)的DCM(1mL)溶液，反应液在0℃下搅拌1小时，将反应液过滤，滤液浓缩，残留物通过制备HPLC[流动相：水(0.05％氨水)-ACN；梯度：15％-45％ACN]纯化得到化合物8。 1H NMR(DMSO-d 6,400MHz):δppm 9.80-9.51(m,1H),7.40-7.31(m,4H),7.30-7.23(m,1H),7.11-6.97(m,1H),4.60(br s,1H),4.43(s,1H),3.73-3.64(m,2H),3.58(s,3H),3.48-3.34(m,2H),1.82-1.70(m,2H),1.69-1.55(m,2H),1.42(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:358.2(M+1)。
实施例9
Figure PCTCN2022077962-appb-000076
合成路线：
Figure PCTCN2022077962-appb-000077
步骤A:在氮气保护下，向9-1(10g,72.39mmol,1eq)和9-2(9.21g,76.01mmol,1.05eq)的DCM(200 mL)溶液中加入碳酸铯(35.38g,108.59mmol,1.5eq)，反应液在15℃下搅拌16小时后过滤,滤液浓缩得到化合物9-a。
步骤B:在氮气保护-78℃下，向9-a(9g,37.29mmol,1eq)的THF(100mL)溶液中缓慢滴加甲基溴化镁(3M,24.86mL,2eq)，反应液在-78℃下搅拌1小时后，将反应液缓慢滴加到饱和氯化铵水溶液(800mL)中，用EA(200mL×2)萃取，合并的有机相用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝10:1-3:1)得到化合物9-b。
步骤C:向9-b(12g,46.63mmol,1eq)的MeOH(100mL)溶液中加入HCl/MeOH(4M,100mL,8.58eq)，反应液在20℃下搅拌2小时，浓缩后得到化合物9-c的盐酸盐。
步骤D:向9-c的盐酸盐(7.5g)的EtOH(100mL)溶液中加入1-1(9.58g,48.96mmol,1eq,HCl)和DIEA(25.31g,195.83mmol,34.11mL,4eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物9-d。
步骤E:向9-d(15g,56.33mmol,1eq)的DCM(150mL)溶液中加入Boc 2O(18.44g,84.49mmol,19.41mL,1.5eq)和TEA(17.10g,168.98mmol,23.52mL,3eq)，反应液在15℃下搅拌16小时后,减压浓缩，残留物通过柱层析分离(PE：EtOAc＝15:1)得到化合物9-e。
步骤F:向9-e(8.00g,21.83mmol,1eq)的EtOAc(50mL)溶液中加入HCl/EtOAc(4M,51.61mL,9.46eq)，反应液在20℃下搅拌16小时，反应液浓缩后得到化合物9-d的盐酸盐。
步骤G:在氮气保护-20℃下，向9-d的盐酸盐(8.80g)的DCM(60mL)溶液中加入TEA(10.03g,99.13mmol,13.80mL,3eq)和3-c(2.83g,12.07mmol,1eq)，反应液在-20℃下搅拌1小时，升温到20℃下搅拌15小时后浓缩，残留物通过柱层析分离(PE：EtOAc＝30:1-10:1)得到化合物9-f。
步骤H:在氮气保护下，向9-f(3.5g,8.32mmol,1eq)的MeOH(40mL)溶液中加入甲醇钠(1M,41.62mL,5eq)，反应液在50℃下搅拌16小时，向反应液中加入1N稀盐酸调节pH到大约5，然后加入EA(100mL×2)萃取，合并的有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物9-g。
步骤J:向9-g(3g,8.01mmol,1eq)的1,4-二氧六环(60mL)溶液中加入盐酸(4M,60mL,29.95eq)，反应液在70℃下搅拌16小时后，加入2N氢氧化钠水溶液调节pH到8～9，过滤，滤饼先通过硅胶柱层析分离(DCM：MeOH＝1:0-10:1)，然后加入MTBE(50mL)搅拌1小时，过滤，滤饼高真空干燥后得到化合物9。 1H NMR(DMSO-d 6,400MHz):δppm 9.52(br s,1H)7.19(br d,J＝7.5Hz,1H)7.06-7.15(m,2H)6.91(br d,J＝6.8Hz,1H)4.66-4.76(m,1H)4.40(s,1H)2.28(s,3H)1.81-1.90(m,4H)1.64-1.72(m,4H)1.45(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:317.2(M+1)。
实施例10
Figure PCTCN2022077962-appb-000078
合成路线：
Figure PCTCN2022077962-appb-000079
步骤A:在20℃下，向10-1(5g,32.02mmol,4.07mL,1eq)的THF(50ml)的溶液中加入10-2(4.66g,38.43mmol,1.2eq)和钛酸四乙酯(21.92g,96.07mmol,19.92mL,3eq)，反应液在60℃下搅拌16小时，向反应液中加入乙酸乙酯(100mL)，冷却到0℃后缓慢加入水(20mL)，搅拌0.5小时，过滤，滤液用饱和食盐水洗涤(50mL×3)，无水硫酸钠干燥，过滤后浓缩得到化合物10-a。
步骤B:在氮气保护-78℃下，向10-a(9g,34.71mmol,1eq)的THF(100ml)的溶液缓慢滴加L-selectride(1M,41.65mL,1.2eq)，反应液在-78℃下搅拌2小时后缓慢加入到饱和氯化铵水溶液(100mL)中，用EA萃取(100mL×2)，合并的有机相用饱和食盐水洗涤(100mL×3)，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝5:1-3:1)得到化合物10-b。
步骤C:在20℃下，向10-b(6.6g)的MeOH(50mL)溶液中加入HCl/MeOH(200mmol.50ml,7.92eq)，反应液搅拌16小时后浓缩得到化合物10-c的盐酸盐。
步骤D:在20℃下，向10-c的盐酸盐(1g)的EtOH(10mL)溶液中加入1-1(1.51g,7.74mmol,1.5eq,HCl)和DIEA(4.00g,30.96mmol,5.40mL,6eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物10-d.
步骤E:在氮气保护-20℃下，向10-d(1.54g,8.08mmol,1eq)的DCM(15mL)溶液中加入TEA(2.45g,24.24mmol,3.37mL,3eq)，然后加入3-c(1.39g,5.14mmol,6.37e-1eq)的DCM(15mL)溶液，反应液在20℃下搅拌16小时后浓缩，残留物加入EA(30mL)稀释，然后用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝10:1-5:1)得到化合物10-e.
步骤F:在氮气保护下，向10-e(0.648g,1.53mmol,1eq)的MeOH(7.6mL)溶液中加入甲醇钠(1M,6.43ml,1eq)，反应液在20℃下搅拌16小时，向反应液中加入1M稀盐酸调节pH到5左右，然后加入EA(20mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物10-f。
步骤G:向10-f(348mg,919.74μmol,1eq)的1,4-二氧六环(4mL)溶液中加入盐酸(4M,4mL,17.40eq)，反应液在50℃下搅拌16小时，向反应液中加入EA(30mL)，然后加入1M氢氧化钠水溶液调节pH到8左右，分液后有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入MeOH (10mL)并搅拌20分钟，过滤，滤饼高真空干燥后得到化合物10。 1H NMR(DMSO-d 6,400MHz):δppm 9.60-9.47(m,1H),7.34-7.26(m,2H),7.25-7.16(m,1H),6.96(br d,J＝6.0Hz,1H),4.82-4.71(m,1H),4.44-4.34(m,1H),1.93-1.81(m,4H),1.70(br s,4H),1.48(br d,J＝6.4Hz,3H)；LCMS(ESI)m/z:321.2(M+1)。
实施例11
Figure PCTCN2022077962-appb-000080
合成路线：
Figure PCTCN2022077962-appb-000081
步骤A：在20℃下，向11-1(1g,7.40mmol,1.06ml,1eq)的EtOH(15mL)溶液中加入1-1(1.18g,7.40mmol,1.0eq,HCl)和DIEA(2.87g,22.19mmol,3.86mL,3eq)，反应液在20℃下搅拌12小时，浓缩后得到化合物11-a。
步骤B:在氮气保护-20℃下，向11-a(2.44g,9.83mmol.6.91e-1eq)的DCM(15mL)溶液中加入TEA(4.32g,42.65mmol,5.94mL,3eq)，然后加入3-c(2.71g,14.22mmol,6.37e-1eq)的DCM(15mL)溶液，反应液在20℃搅拌16小时，浓缩，残留物加入EA(30mL)稀释，然后用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝10:1-8:1)得到化合物11-b。
步骤C:在氮气保护下,向11-b(0.743g,1.47mmol,1eq)的MeOH(9.2mL)溶液中加入甲醇钠(1M,7.37ml,5eq)，反应液在20℃下搅拌16小时，向反应液中加入1M稀盐酸调节pH约等于5，然后加入EA(20mL×3)萃取，合并的有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物11-c。
步骤D:向11-c(399mg,1.12mmol,1eq)的1,4-二氧六环(4mL)溶液中加入盐酸(4M,4mL,17.40eq)，反应液在50℃下搅拌16小时后加入EA(30mL)稀释，然后加入2M氢氧化钠水溶液调节pH到8左右，过滤，滤饼加入MeOH(10mL)搅拌1小时，过滤，滤饼高真空干燥后得到化合物11。 1H NMR(DMSO-d 6,400MHz):δppm 9.52(br s,1H),7.41-7.25(m,5H),6.97-6.85(m,1H),4.42(s,1H),4.40-4.29(m,1H),1.90-1.84(m,2H),1.83-1.63(m,8H),0.87(t,J＝7.2Hz,3H)；LCMS(ESI)m/z:299.1(M+1)。
实施例12
Figure PCTCN2022077962-appb-000082
合成路线：
Figure PCTCN2022077962-appb-000083
步骤A:在20℃下，向12-1(10g,64.05mmol,8.33mL,1eq)的THF(100mL)的溶液中加入10-2(17.08g,140.91mmol,2.2eq)和钛酸四乙酯(43.83g,192.15mmol,39.85mL,3eq)，反应液在60℃下搅拌16小时，冷却到0℃后向反应液中加入EA(100mL)，缓慢加入水(30mL)，搅拌0.5小时，过滤，滤液用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，过滤后浓缩得到化合物12-a。
步骤B:在氮气保护-78℃下，向12-a(5.45g,21.01mmol,1eq)的THF(50mL)的溶液缓慢滴加L-selectride(1M,25.21mL,1.2eq)，反应液在20℃下搅拌2小时，在0℃下将反应液缓慢加入到饱和氯化铵水溶液(40mL)中，用EA萃取(30mL×2)，合并的有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝8:1-1:1)得到化合物12-b。
步骤C:在20℃下，向12-b(3.14g,12.00mmol,1eq)的MeOH(30mL)溶液中加入HCl/MeOH(4M,30mL,10.00eq)，反应液搅拌16小时后浓缩，残留物加入EA(20ml)，搅拌0.5小时后过滤，滤饼高真空干燥后得到化合物12-c的盐酸盐。
步骤D:在20℃氮气保护下，向12-c的盐酸盐(1.84g)的EtOH(20mL)溶液中加入1-1(1.87g,11.72mmol,1eq)和DIEA(4.54g,35.16mmol,6.12mL,3eq)，反应液在20℃下搅拌12小时，浓缩后得到化合物12-d.
步骤E:在氮气保护下，向12-d(9.11g,33.71mmol,1eq)的THF(50mL)溶液中加入3-b(5.80g,33.71mmol,1eq)，DIEA(6.53g,50.56mmol,8.81mL,1.5eq)，然后加入12-2(12.92g,50.56mmol,1.5eq)，反应 液在20℃下搅拌1小时后浓缩，残留物加入水(50mL)稀释，然后用EA(20mL×3)萃取，合并的有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1)得到化合物12-e。
步骤F:在氮气保护下,向12-e(3.78g,8.91mmol,1eq)的MeOH(44.56mL)溶液中加入甲醇钠(1M,44.56mL,5eq)，反应液在50℃下搅拌16小时，向反应液中加入1M稀盐酸调节pH到5左右，然后加入EA(50mL×2)萃取，合并的有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝5:1-2:1)得到化合物12-f。
步骤G:向12-f(389mg,1.03mmol,1eq)的1,4-二氧六环(4mL)溶液中加入盐酸(4M,3.91mL,15.21eq)，反应液在60℃下搅拌16小时，向反应液中加入2M氢氧化钠水溶液调节pH到8左右，过滤，滤饼加入MTBE(5mL)并搅拌1小时，过滤，滤饼干燥后得到化合物12。 1H NMR(DMSO-d 6,400MHz):δppm 9.52(br s,1H),7.47-7.35(m,1H),7.14(br t,J＝8.8Hz,2H),7.01-6.91(m,1H),4.91-4.79(m,1H),4.44(s,1H),1.91-1.75(m,4H),1.74-1.64(m,4H),1.57(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:321.1(M+1)。
实施例13
Figure PCTCN2022077962-appb-000084
合成路线：
Figure PCTCN2022077962-appb-000085
步骤A:在20℃下，向13-1(3g,19.21mmol,2.42mL,1eq)的THF(30mL)的溶液中加入10-2(4.66g,38.43mmol,2eq)和钛酸四乙酯(13.15g,57.64mmol,11.95mL,3eq),反应液在60℃下搅拌16小时，向反应液中加入EA(60mL)，冷却到0℃后缓慢加入水(10mL)，搅拌0.5小时，过滤，滤液用饱和食盐水 洗涤(30mL×3)，无水硫酸钠干燥，过滤后浓缩得到化合物13-a。
步骤B:在氮气保护-78℃下，向13-a(3g,11.57mmol,1eq)的THF(20mL)的溶液缓慢滴加L-selectride(1M,13.88mL,1.2eq)，反应液在-78℃下搅拌2小时，在0℃下将反应液缓慢的加入到饱和氯化铵水溶液(20mL)中，用EA(20mL×2)萃取，合并的有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝5:1-2:1)得到化合物13-b。
步骤C:向13-b(1.26g,4.81mmol,1eq)的MeOH(15mL)溶液中加入HCl/MeOH(4M,15mL,12.48eq)，反应液在20℃下搅拌16小时后浓缩，残留物加入EA(20mL)并搅拌0.5小时，过滤，滤饼真空干燥得到化合物13-c的盐酸盐。
步骤D:在氮气保护20℃下，向13-c的盐酸盐(0.553g)的EtOH(5mL)溶液中加入1-1(560.12mg,3.52mmol,1eq)和DIEA(1.36g,10.56mmol,1.84mL,3eq)，反应液在20℃下搅拌12小时，浓缩后得到化合物13-d。
步骤E:在氮气保护-20℃下，向3-c(1.05g,5.51mmol,1eq)的DCM(15mL)溶液中加入TEA(1.67g,16.52mmol,2.30mL,3eq)，然后加入13-d(950.02mg,3.52mmol)，反应液在20℃下搅拌16小时后浓缩，残留物加入水(50mL)稀释，然后用EA(20mL×3)萃取，合并的有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝8:1-1:1)得到化合物13-e。
步骤F:在氮气保护下，向13-e(483mg,1.14mmol,1eq)的MeOH(5mL)溶液中加入甲醇钠(1M,5.69mL,5eq)，反应液在50℃下搅拌16小时，向反应液中加入1M稀盐酸调节pH到5左右，然后加入EA(30mL×2)萃取，合并的有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物13-f。
步骤G:向13-f(117mg,309.22μmol,1eq)的1,4-二氧六环(2mL)溶液中加入盐酸(4M,2mL,25.87eq)，反应液在60℃下搅拌16小时，向反应液中加入2M氢氧化钠水溶液调节pH到8左右，过滤，滤饼加入MTBE(10mL)并搅拌1小时，过滤，滤饼干燥后得到化合物13。 1H NMR(DMSO-d 6,400MHz):δppm 9.54(br s,1H),7.51-7.41(m,1H),7.32-7.23(m,1H),7.12(br t,J＝8.0Hz,1H),6.95(br d,J＝6.1Hz,1H),4.81-4.68(m,1H),4.39(s,1H),1.90-1.80(m,4H),1.77-1.63(m,4H),1.53-1.42(d,J＝6.7Hz,3H)；LCMS(ESI)m/z:321.1(M+1)。
实施例14
Figure PCTCN2022077962-appb-000086
合成路线：
Figure PCTCN2022077962-appb-000087
步骤A：在20℃下，向14-1(0.8g,5.75mmol,1eq)的EtOH(10mL)溶液中加入1-1(915.04mg,5.75mmol,1eq)和DIEA(1.49g,11.50mmol,2.00mL,2eq)，反应液在25℃下搅拌16小时，浓缩后得到化合物14-a。
步骤B:向14-a(1g,3.48mmol,87.68％纯度,1eq)的THF(10mL)溶液中加入DIEA(673.77mg,5.21mmol,908.04μL,1.5eq),然后加入12-2(1.33g,5.21mmol,1.5eq)和3-b(598.40mg,3.48mmol,1eq)，反应液在25℃搅拌0.5小时，浓缩，残留物加入水(50mL)，然后用EA(20mL×3)萃取，合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝10:1)得到化合物14-b。
步骤C:在氮气保护下，向14-b(231mg,568.34μmol,1eq)的MeOH(5mL)溶液中加入甲醇钠(1M,2.84mL,5eq)，反应液在50℃下搅拌16小时，向反应液中加入1M稀盐酸调节pH约等于5，加入水(20mL)稀释，然后用EA(10mL×3)萃取，合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物14-c。
步骤D:向14-c(170mg,433.99μmol,92％纯度,1eq)的1,4-二氧六环(8.29mL)溶液中加入盐酸(4M,8.29mL,76.4eq)，反应液在50℃下搅拌16小时，加入1M氢氧化钠水溶液调节pH到9左右，用EA(5mL×4)萃取，合并的有机相用饱和食盐水洗涤(10mL×2)，无水硫酸钠干燥，过滤后浓缩，残留物加入MTBE(5mL)并搅拌2小时，过滤，滤饼干燥后得到化合物14。 1H NMR(DMSO-d 6,400MHz):δppm 9.70(br s,1H),7.45-7.39(m,1H),7.39-7.32(m,1H),7.25-7.20(m,2H),7.15(br s,1H),4.81-4.73(m,1H),4.38(s,1H),1.89-1.79(m,4H),1.74-1.64(m,4H),1.48(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:303.2(M+1)。
实施例15
Figure PCTCN2022077962-appb-000088
合成路线：
Figure PCTCN2022077962-appb-000089
步骤A:在20℃下，向15-1(1g,6.37mmol,99.53％纯度,1eq)的THF(10mL)的溶液中加入10-2(927.16mg,7.64mmol,1.2eq)和钛酸四乙酯(4.36g,19.11mmol,3.97mL,3eq)，反应液在50℃下搅拌16小时，向反应液中加入10-2(386.02mg,3.19mmol,0.5eq)，在50℃下继续搅拌1.5小时，冷却到0℃后向反应液中加入乙酸乙酯(30mL)稀释，缓慢加入水(20mL)，搅拌0.5小时，过滤，滤液用饱和食盐水洗涤(10mL×2)，无水硫酸钠干燥，过滤后浓缩得到化合物15-a。
步骤B:在氮气保护-78℃下，向15-a(950mg,3.66mmol,1eq)的THF(10mL)的溶液缓慢滴加L-selectride(1M,4.40mL,1.2eq)，反应液在-78℃下搅拌2小时，在0℃下将反应液缓慢加入到饱和氯化铵水溶液(15mL)中，加入水(30mL)稀释，用乙酸乙酯萃取(10mL×3)，合并的有机相用饱和食盐水洗涤(15mL×2)，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝5:1)得到化合物15-b。
步骤C:在20℃下，向15-b(1.15g,4.39mmol,1eq)的MeOH(10mL)溶液中加入HCl/MeOH(4M,1.10mL,1eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物15-c的盐酸盐。
步骤D:在20℃氮气保护下，向15-c的盐酸盐(0.887g)的EtOH(10mL)溶液中加入1-1(898.41mg,4.59mmol,8.14e-1eq,HCl)和DIEA(2.92g,22.58mmol,3.93mL,4eq)，反应液在20℃下搅拌16小时，浓缩后得到化合物15-d。
步骤E:在氮气保护下，向15-d(2.3g,8.51mmol,1eq)的THF(25mL)溶液中加入3-b(1.47g,8.51mmol,1eq)，DIEA(1.65g,12.76mmol,2.22mL,1.5eq)，然后加入12-2(3.26g,12.76mmol,1.5eq)，反应液在20℃下搅拌32小时后浓缩，残留物加入水(50mL)稀释，然后用EA(10mL×4)萃取，合并的有机相用饱和食盐水(15mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝20:1)得到化合物15-e。
步骤F:在氮气保护下,向15-e(260mg,612.58μmol,1eq)的MeOH(3mL)溶液中加入甲醇钠(1M,3mL,4.90eq)，反应液在50℃下搅拌16小时，向反应液中加入1M稀盐酸调节pH到5左右，然后加入 水(10mL)，用EA(5mL×4)萃取，合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过薄层色谱法分离(PE：EtOAc＝20:1)得到化合物15-f。
步骤G:向15-f(60mg,158.58μmol,1eq)的1,4-二氧六环(2mL)溶液中加入盐酸(4M,2mL,50.45eq)，反应液在60℃下搅拌19小时，向反应液中加入1M氢氧化钠水溶液调节pH到9左右，过滤，滤饼加入MTBE(2mL)并搅拌2小时，过滤，滤饼干燥后得到化合物15。 1H NMR(DMSO-d 6,400MHz):δppm9.55(m,1H),7.41-7.33(m,1H),7.28-7.20(m,2H),7.01(br d,J＝4.6Hz,1H),4.83(br s,1H),4.40(s,1H),1.91-1.79(m,4H),1.75-1.65(m,4H),1.50(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:321.2(M+1)。
实施例16
Figure PCTCN2022077962-appb-000090
合成路线：
Figure PCTCN2022077962-appb-000091
步骤A:在氮气保护下，向化合物3-1(5g,37.85mmol,4.35mL,1eq)和碘乙烷(12.99g,83.26mmol,6.66mL,2.2eq)的DMF(50mL)溶液中加入碳酸铯(27.13g,83.26mmol,2.2eq)，反应液在20℃下搅拌16小时后加入水(200mL)，然后EA(200mL)萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物16-a。
步骤B:向化合物16-a(7g,37.19mmol,1eq)的MeOH(40mL)和水(40mL)溶液中加入氢氧化钠(1.64g,40.91mmol,1.1eq)，反应液在20℃下搅拌16小时后浓缩，残留物加入水(100mL)，然后用MTBE(100mL)萃取，分液后水相用1M稀盐酸调节pH到5左右,然后再用EA(100mL)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物16-b。
步骤C:在氮气保护0℃下，向化合物12-d(1.2g,4.44mmol,1eq)和16-b(928.09mg,5.33mmol,1.2eq)的ACN(20mL)溶液中加入N-甲基咪唑(1.82g,22.20mmol,1.77mL,5eq)和TCFH(2.49g,8.88mmol,2eq)，反应液在0℃下搅拌1小时后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝1:0-10:1)得到化合物16-c。
步骤D:在氮气保护下，向化合物16-c(1.55g,3.63mmol,1eq)的MeOH(20mL)溶液中加入叔丁醇钠(1.75g,18.17mmol,5eq)，反应液在20℃下搅拌16小时，反应液倒入到1N的稀盐酸(20mL)中，浓缩，残留物加入水(30mL)，用EA(30mL)萃取，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-3:1)得到化合物16-d。
步骤E:向化合物16-d(0.15g,394.34μmol,1eq)的1,4-二氧六环(5mL)溶液中加入盐酸(4M,5mL,50.72eq)，反应液在50℃下搅拌16小时，向反应液中加入1N氢氧化钠调节pH到大约7，然后浓缩掉1,4-二氧六环，残留物加入MTBE(20mL)，过滤，滤饼高真空干燥后得到化合物16。 1H NMR(DMSO-d 6,400MHz):δppm 9.69(br s,1H),7.45-7.37(m,1H),7.14(t,J＝8.5Hz,2H),6.94(br d,J＝7.6Hz,1H),4.88(br t,J＝6.8Hz,1H),4.58(s,1H),1.76-1.50(m,7H),0.65(t,J＝7.3Hz,3H),0.48(t,J＝7.3Hz,3H)；LCMS(ESI)m/z:323.4(M+1)。
实施例17
Figure PCTCN2022077962-appb-000092
合成路线：
Figure PCTCN2022077962-appb-000093
步骤A:在氮气保护0℃下，向化合物2-b(325.84mg,1.73mmol,1.3eq)和10-d(0.36g,1.33mmol,1eq)的ACN(10mL)溶液中加入N-甲基咪唑(546.80mg,6.66mmol,530.88μL,5eq)和TCFH(747.45mg,2.66mmol,2eq)，反应液在20℃下搅拌2小时后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-5:1)得到化合物17-a。
步骤B:在氮气保护下，向化合物17-a(0.34g,771.96μmol,1eq)的MeOH(5mL)溶液中加入叔丁醇钠(370.94mg,3.86mmol,5eq)，反应液在20℃下搅拌16小时，向反应液中加入1N的稀盐酸调节到pH到大约5，浓缩，残留物加入水(10mL)，用EA(10mL)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-2:1)得到化合物17-b。
步骤C:在氮气保护下，向化合物17-b(0.15g,380.35μmol,1eq)的1,4-二氧六环(5mL)溶液中加入 盐酸(4M,5mL,52.58eq)，反应液在50℃下搅拌20小时，向反应液中加入饱和碳酸氢钠水溶液调节pH到大约7，然后浓缩掉1,4-二氧六环，残留物加入水(10mL)和MTBE(20mL)，搅拌30分钟，过滤，滤饼高真空干燥后得到化合物17。 1H NMR(DMSO-d 6,400MHz):δppm 9.67(br s,1H),7.34-7.25(m,2H),7.20(dt,J＝4.1,8.1Hz,1H),7.07(br d,J＝5.9Hz,1H),4.76(br s,1H),4.38(s,1H),3.79-3.69(m,4H),1.91-1.77(m,2H),1.67-1.52(m,2H),1.47(d,J＝6.8Hz,3H)；LCMS(ESI)m/z:337.3(M+1)。
实施例18
Figure PCTCN2022077962-appb-000094
合成路线：
Figure PCTCN2022077962-appb-000095
步骤A:在20℃下，向18-1(6.89g,39.92mmol,1eq)的THF(70mL)的溶液中加入10-2(5.81g,47.91mmol,1.2eq)和钛酸四乙酯(27.32g,119.77mmol,24.84mL,3eq)，反应液在60℃下搅拌16小时，向反应液中加入乙酸乙酯(100mL)，冷却到0℃后缓慢加入水(20mL)，搅拌0.5小时，过滤，滤液用饱和食盐水洗涤(50mL×3)，无水硫酸钠干燥，过滤后浓缩得到化合物18-a。
步骤B:在氮气保护-78℃下，向18-a(7.1g,25.75mmol,1eq)的THF(100mL)的溶液缓慢滴加L-selectride(1M,25.75mL,1eq)，反应液缓慢升到0℃并搅拌1小时，向反应液中加入0.5N稀盐酸(100mL)，用乙酸乙酯萃取(100mL)，有机相用饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE：EtOAc＝10:1-3:1)得到化合物18-b。
步骤C:向18-b(2g,7.20mmol,1eq)中加入HCl/MeOH(4M,25mL,13.89eq)溶液，反应液在50℃下搅拌1小时后浓缩得到化合物18-c的盐酸盐。
步骤D:在氮气保护20℃下，向18-c的盐酸盐(2g)的EtOH(30mL)溶液中加入1-1(2.05g,10.47mmol,1.1eq,HCl)和DIEA(3.69g,28.56mmol,4.97mL,3eq)，反应液在20℃下搅拌16小时后浓缩，残留物加入水(50mL)，然后用醋酸调节pH到大约5，用EA萃取(50mL)，分液后水相再用饱和碳酸氢钠溶液调节pH到大约9，然后用EA萃取(50mL×2)，合并的有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤后浓缩得到化合物18-d。
步骤E:在氮气保护0℃下，向化合物2-b(1.02g,5.44mmol,1.3eq)和18-d(1.2g,4.19mmol,1eq)的ACN(10mL)溶液中加入N-甲基咪唑(1.72g,20.93mmol,1.67mL,5eq)和TCFH(2.35g,8.37mmol,2eq)，反应液在20℃下搅拌1小时后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-5:1)得到化合物18-e。
步骤F:在氮气保护下，向化合物18-e(1.2g,2.63mmol,1eq)的MeOH(10mL)溶液中加入叔丁醇钠(1.01g,10.51mmol,4eq)，反应液在50℃下搅拌1小时，向反应液中加入1N的稀盐酸调节到pH到大约5，浓缩，残留物加入水(10mL)，用EA(10mL)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析分离(PE：EtOAc＝10:1-2:1)得到化合物18-f。
步骤G:在氮气保护下，向化合物18-f(0.69g,1.68mmol,1eq)的1,4-二氧六环(15mL)溶液中加入盐酸(4M,15mL,35.72eq)，反应液在50℃下搅拌16小时，向反应液中1N氢氧化钠水溶液调节pH到大约7，然后浓缩掉1,4-二氧六环，残留物加入水(50mL)和MTBE(50mL)，搅拌30分钟，过滤，滤饼高真空干燥后得到化合物18。 1H NMR(DMSO-d 6,400MHz):δppm 9.63(br s,1H),7.54-7.49(m,1H),7.45-7.39(m,1H),7.34-7.27(m,1H),6.98(br s,1H),4.77(br s,1H),4.40(s,1H),3.79-3.69(m,4H),1.90-1.78(m,2H),1.59(br dd,J＝14.3,19.1Hz,2H),1.47(d,J＝6.7Hz,3H)；LCMS(ESI)m/z:353.3(M+1)。
生物活性测试：
实验例1：心肌肌球蛋白ATP酶活性的抑制效应实验
实验试剂：
心肌原肌球蛋白/肌钙蛋白复合物(Cytoskeleton,Cat.#TT05)
心肌肌球蛋白S1(Cytoskeleton,Cat.#MYS03)
心肌肌动蛋白(Cytoskeleton,Cat.#AD99-A)
ATP酶测定生化试剂盒(Cytoskeleton,Cat.#BK051)
实验步骤：
1)准备化合物
a)在Echo中用DMSO对化合物进行4倍稀释，8个浓度梯度，并分别转移200nL化合物到96孔板(Corning-3696)中。
b)1000rpm离心15秒，封板待用。
2)准备F-肌动蛋白
a)配置缓冲液5mM Pipes-KOH pH 7.0,500μM ATP,500μM二硫苏糖醇，并加入2.5mL缓冲液溶解1mg F-肌动蛋白，蛋白浓度为0.4mg/mL。
b)室温放置10分钟以充分溶解蛋白。
c)加入2.0mM MgCl 2和2.0mM EGTA，室温放置20分钟以形成蛋白聚合物。
3)准备细肌丝
a)加入200μL冰水溶解1mg心肌原肌球蛋白/肌钙蛋白复合物，蛋白浓度为5mg/mL。
b)加入1000μL步骤1中准备的F-肌动蛋白，混匀。
c)室温放置20分钟。
d)87K xg 4℃离心1.5小时。
e)配置PM12缓冲液12mM Pipes-KOH,pH 7.0,2mM MgCl 2，并加入1200μL缓冲液重悬蛋白。
4)准备反应溶液，并开始实验
a)加入250μL冰的PM12缓冲液到250μg S1肌球蛋白中，蛋白浓度为1mg/mL。
b)按照下面的顺序，依次加入试剂混合，以得到反应混合液：
400μL的PM12，
400μL的5x MSEG(来自ATP酶测定生化试剂盒)，
1200μL的肌动蛋白/心肌原肌球蛋白/肌钙蛋白复合物，
40μL的肌球蛋白S1，
40μL的100x PNP(来自ATP酶测定生化试剂盒)，
10.4μL的100mM ATP。
c)加入10μL 440μM CaCl 2溶液到96孔板中，放置到37℃培养箱预热。
d)加入100μL反应混合液到96孔板中，1000rpm离心10秒。
e)在SpectraMax 340PC上连续读数10分钟，间隔30秒，仪器温度37℃，波长360nm。
数据分析：
用Prism分析数据，实验结果见表1。
表1 本发明化合物对心肌肌球蛋白ATP酶活性的抑制效应IC 50值测试结果
化合物 IC 50(μM)
1 14
2 3.97
3 0.73
4 2.2
5 2.08
6 1.71
7 0.3
9 0.04
10 0.22
11 0.51
12 0.06
13 1.08
14 1.19
15 0.21
结论：本发明化合物具有较好的心肌肌球蛋白ATP酶抑制活性。
实验例2：大鼠体内药代动力学评价
实验目的：
检测本发明化合物在大鼠体内的药代动力学参数
实验方案：
1)实验药品：本发明化合物；
2)实验动物：4只7-9周龄的雄性SD大鼠，随机分为2组，每组2只；
3)药物配制：称取适量药物，溶于DMAC：PEG-400：30％2-HP-β-CD＝5:25:70的混合溶剂中，配置成0.2mg/mL；
实验操作：
第1组动物通过尾静脉单次注射给予剂量为0.2mg/kg、浓度为0.2mg/mL的药物，第2组动物通过灌胃给予剂量为1mg/kg、浓度为0.2mg/mL的化合物。动物于给药后0.0833(仅尾静脉注射组)、0.25、0.5、1、2、4、6、8和24小时采集血浆样品。
数据分析：
使用LC-MS/MS方法测定血浆样品中的药物浓度，得出测试药物的药代动力学测试结果见表2。
表2 本发明化合物的药代动力学测试结果
Figure PCTCN2022077962-appb-000096
--表示不存在
结论：本发明化合物具有良好的大鼠体内药代动力学性质。

Claims (22)

  1. 式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2022077962-appb-100001
    其中，
    R 1和R 2分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2或3个R a取代；
    或R 1和R 2与其连接的碳原子一起形成C 3-6环烷基或3-6元杂环烷基，其中所述C 3-6环烷基和3-6元杂环烷基分别独立地任选被1、2、3或4个R b取代；
    R 3选自H和F；
    R 4选自H、C 1-4烷基和C 3-4环烷基，其中所述C 1-4烷基和C 3-4环烷基分别独立地任选被1、2或3个R c取代；
    R 5选自H和C 1-4烷基；
    R 6分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基，其中所述C 1-4烷基和C 1- 4烷氧基分别独立地任选被1、2或3个R d取代；
    R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、-COR a1、-CO 2R a1、-SO 2R a1、-SO 2NR a1R a2和-CONR a1R a2，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2或3个R取代；
    R a1和R a2分别独立选自H和C 1-4烷基；
    或R a1和R a2与其连接的氮原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基分别独立地任选被1、2、3或4个R e取代；
    R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、-COR b1、-CO 2R b1、-SO 2R b1、-SO 2NR b1R b2和-CONR b1R b2，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2或3个R取代；
    R b1和R b2分别独立选自H和C 1-4烷基；
    或R b1和R b2与其连接的氮原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基分别独立地任选被1、2、3或4个R f取代；
    R c分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
    R d分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
    R e分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
    R f分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基；
    R分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN；
    n选自1、2、3或4；
    所述3-6元杂环烷基和4-6元杂环烷基分别独立地包含1、2、3或4个分别独立地选自N、O、S和NH的原子或原子团。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R a、R c、R d、R e和R f分别独立地选自F和Cl。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 1和R 2分别独立地选自-CH 3和-CH 2CH 3，其中所述CH 3和-CH 2CH 3分别独立地任选被1、2或3个R a所取代。
  4. 根据权利要求2所述的化合物或其药学上可接受的盐，其中，R 1和R 2分别独立地选自-CH 3和-CH 2CH 3。
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R b1和R b2分别独立地选自-CH 3和-CH 2CH 3。
  6. 根据权利要求1或5所述的化合物或其药学上可接受的盐，其中，R b分别独立地选自F、Cl、Br、-OCH 3、-COCH 3、-CO 2CH 3和-CO 2CH 2CH 3。
  7. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 1和R 2与其连接的碳原子一起形成
    Figure PCTCN2022077962-appb-100002
    其中所述
    Figure PCTCN2022077962-appb-100003
    Figure PCTCN2022077962-appb-100004
    分别独立地任选被1、2、3或4个R b取代。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，其中，R 1和R 2与其连接的碳原子一起形成
    Figure PCTCN2022077962-appb-100005
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中，R 1和R 2与其连接的碳原子一起形成
    Figure PCTCN2022077962-appb-100006
  10. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构片段
    Figure PCTCN2022077962-appb-100007
    选自
    Figure PCTCN2022077962-appb-100008
    Figure PCTCN2022077962-appb-100009
  11. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 3选自H。
  12. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 4选自-CH 3和-CH 2CH 3。
  13. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 5选自H。
  14. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 6分别独立地选自H、F、Cl和-CH 3，其中所述-CH 3任选被1、2或3个R d取代。
  15. 根据权利要求14所述的化合物或其药学上可接受的盐，其中，R 6分别独立地选自H、F、Cl和-CH 3。
  16. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物具有式(I-1)所示结构：
    Figure PCTCN2022077962-appb-100010
    其中，n、R 1、R 2、R 3、R 4和R 6如权利要求1所定义。
  17. 根据权利要求16述的化合物或其药学上可接受的盐，其中所述化合物具有式(I-1A)或(I-1B)所示结构：
    Figure PCTCN2022077962-appb-100011
    其中，n、R 1、R 2、R 3、R 4和R 6如权利要求16所定义，且R 4不为H。
  18. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022077962-appb-100012
    Figure PCTCN2022077962-appb-100013
  19. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022077962-appb-100014
    Figure PCTCN2022077962-appb-100015
  20. 一种药物组合物，其含有治疗有效量的根据权利要求1～19任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  21. 根据权利要求1～19任意一项所述的化合物或其药学上可接受的盐或根据权利要求20所述的药物组合物在制备心肌肌球蛋白抑制剂药物中的应用。
  22. 根据权利要求1～19任意一项所述的化合物或其药学上可接受的盐或根据权利要求20所述的药物组合物在制备治疗心衰和肥厚型心肌疾病中的应用。
PCT/CN2022/077962 2021-02-25 2022-02-25 取代的吡啶-2,4-二酮类衍生物 WO2022179611A1 (zh)

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