Substituted pyridine-2,4-dione derivatives

Abstract

The present invention relates to a series of substituted pyridine-2,4-dione derivatives and a method for preparing the same, specifically to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

Technology Field

[0001] This application claims the following priority.

[0002] CN202110214692.X, February 25, 2021;

[0003] CN202210103134.0, January 27, 2022;

[0004] CN202210153298.4, February 18, 2022.

[0005] The present invention relates to a series of substituted pyridine-2,4-dione derivatives and a method for preparing the same, specifically to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Background Technology

[0006] Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by hypertrophy of the heart muscle. It often affects the interventricular septum, narrowing the ventricular cavity, hindering blood filling in the left ventricle, and reducing compliance during left ventricular diastolic pressure. It is classified into obstructive and non-obstructive hypertrophic cardiomyopathy depending on the presence of obstruction of the left ventricular outflow tract, which may be associated with genetics. The global incidence of HCM is approximately 1 in 500. Clinical symptoms vary; the disease may be asymptomatic, or it may present with palpitations, exertional dyspnea, pre-chest pain, easy fatigue, syncope, or even sudden death. In the end-stage, symptoms of left heart failure appear.

[0007] Currently, there are limited drugs available for the treatment of HCM, and while β-receptor blockers or calcium channel blockers are mainly used to improve symptoms, their therapeutic effects are limited because they do not target the cause of the disease, thus failing to delay the progression of myocardial hypertrophy or improve the prognosis.

[0008] Myosin and actin are the material basis of myocardial contraction; myosin cross-links periodically bind to and detach from actin, allowing myofilaments to slide and inducing myocardial contraction. Myosin possesses ATPase activity, providing the driving force for myocardial contraction through the hydrolysis of ATP. Mutations in myosin prolong the binding time between myosin and actin, impairing the excessive contraction and relaxation of the left ventricular myocardium. This can lead to left ventricular hypertrophy and fibrosis, potentially causing HCM. MYK-461 is an allosteric modulator of myocardial myosin; by slowing the rate of phosphatization, reducing the binding time between myosin and actin, and generating a negative muscle force effect, it alleviates pathological changes, such as myocardial hypertrophy, caused by excessive left ventricular contraction. However, because elimination from the body is slow and the drug remains in the body for too long, it is inconvenient to rapidly adjust the dosage (Mark P. Grillo et al. Xenobiotica, 2019; 49(6):718-733). Therefore, developing myosin inhibitors with better activity and more ideal pharmacokinetic characteristics has significant clinical value and significance.

[0009] In addition, abnormalities in the myocardial sarcomere have been identified as a major cause of various heart diseases and conditions such as diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, and myosin ATPase inhibitors can also exert potential therapeutic effects to alleviate the pathological processes of the above diseases by inhibiting myocardial contraction. Effects of the invention

[0106] Effects of the invention

[0010] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and

[0011]

[0012] In the above formula,

[0013] R1 and R2 are independently H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 Selected from alkoxy, wherein the above C 1-4 Alkyl and C 1-4 Each alkoxy consists of 1, 2, or 3 R's independently a Arbitrarily substituted by;

[0014] Or R1 and R2 are C together with the carbon atoms connected to them. 3-6 Forming a cycloalkyl or a ternary to hexavalent heterocycloalkyl, wherein C 3-6 The cycloalkyl and ternary to hexavalent heterocycloalkyl groups each independently have 1, 2, 3, or 4 R b Arbitrarily substituted by;

[0015] R3 is selected from H and F;

[0016] R4 is H, C 1-4 Alkyl and C 3-4 Selected from cycloalkyl, wherein C 1-4 Alkyl and C 3-4 Each cycloalkyl group independently has 1, 2, or 3 R groups. c Arbitrarily substituted by;

[0017] R5 is H and C 1-4 Selected from alkyl;

[0018] R6 is H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 Selected from alkoxy, wherein the above C 1-4 Alkyl and C 1-4 Each alkoxy consists of 1, 2, or 3 R's independently d Arbitrarily substituted by;

[0019] R a Each independently F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, -CORa1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 and -CONR a1 R a2 Selected from, where the above C 1-4 Alkyl and C 1-4 Each alkoxy is independently and arbitrarily substituted by 1, 2, or 3 Rs;

[0020] R a1 and R a2 H and C, respectively, independently 1-4 Selected from alkyl;

[0021] or R a1 and R a2 ... forms a quaternary to hexavalent heterocycloalkyl with nitrogen atoms connected thereto, wherein each of the quaternary to hexavalent heterocycloalkyls independently has 1, 2, 3, or 4 R atoms e Arbitrarily substituted by;

[0022] R b Each independently F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, -COR b1 , -CO2R b1 , -SO2R b1 , -SO2NR b1 R b2 and -CONR b1 R b2 Selected from, where the above C 1-4 Alkyl and C 1-4 Each alkoxy is independently and arbitrarily substituted by 1, 2, or 3 Rs;

[0023] R b1 and R b2 H and C, respectively, independently 1-4 Selected from alkyl;

[0024] or R b1 and R b2... forms a quaternary to hexavalent heterocycloalkyl with nitrogen atoms connected thereto, wherein each of the quaternary to hexavalent heterocycloalkyls independently has 1, 2, 3, or 4 R atoms f It is arbitrarily substituted by;

[0025] R c Each independently F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 Selected from alkoxy;

[0026] R d Each independently F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 Selected from alkoxy;

[0027] R e Each independently F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 Selected from alkoxy;

[0028] R f Each independently F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 Selected from alkoxy;

[0029] R is each independently selected from F, Cl, Br, I, -OH, -NH2, and -CN;

[0030] n is selected from 1, 2, 3, or 4;

[0031] The above ternary to hexavalent heterocycloalkyl and quaternary to hexavalent heterocycloalkyl each independently include 1, 2, 3, or 4 atoms or atomic groups selected from N, O, S, and NH.

[0032] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and

[0033]

[0034] In the above formula,

[0035] R1 and R2 are independently H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Selected from alkyl;

[0036] Or, R1 and R2 are C together with the carbon atoms connected to them. 4-6 Forming a cycloalkyl or a 5- to 6-membered heterocycloalkyl, wherein C 4-6 The cycloalkyl and 5- to 6-membered heterocycloalkyl groups each independently have 1, 2, 3, or 4 R b Arbitrarily substituted by;

[0037] R3 is selected from H and F;

[0038] R4 is H and C 1-4 Selected from alkyl;

[0039] R5 is selected from H;

[0040] R6 is H, F, Cl, Br, I, and C 1-4 Selected from alkyl;

[0041] R b Each independently F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkoxy, -COR b1 and -CO2R b1 Selected from;

[0042] R b1 H and C 1-4 Selected from alkyl;

[0043] n is selected from 1 or 2;

[0044] The above 5- to 6-membered heterocycloalkyl comprises 1, 2, 3, or 4 atoms or atomic groups each independently selected from N, O, S, and NH.

[0045] In some aspects of the present invention, the R a1 and R a2Each is independently selected from H, and other variables are as defined in the present invention.

[0046] In some aspects of the present invention, the R a , R c , R d , R e and R f Each is independently selected from F and Cl, and other variables are as defined in the present invention.

[0047] In some aspects of the present invention, R1 and R2 are each independently selected from -CH3 and -CH2CH3, wherein -CH3 and -CH2CH3 are each independently 1, 2, or 3 Rs a Substituted by, and R a and other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, R1 and R2 are each independently selected from -CH3 and -CH2CH3, and other variables are as defined in the present invention.

[0049] In some aspects of the present invention, the R b1 and R b2 Each is independently selected from -CH3 and -CH2CH3, and other variables are as defined in the present invention.

[0050] In some aspects of the present invention, the R b Each is independently selected from F, Cl, Br, -OCH3, -COCH3, -CO2CH3 and -CO2CH2CH3, and other variables are as defined in the present invention.

[0051] In some aspects of the present invention, the R b Each is independently selected from F, Cl, Br, -OCH3, -COCH3 and -CO2CH2CH3, and other variables are as defined in the present invention.

[0052] In some aspects of the present invention, R1 and R2 are C together with carbon atoms connected thereto. 5-6 Forms a cycloalkyl or a 6-membered heterocycloalkyl, wherein C 5-6 Cycloalkyl and hexacyclic heterocycloalkyl groups each independently have 1, 2, 3, or 4 R groups. b It is arbitrarily substituted by, and R b and other variables are as defined in the present invention.

[0053] In some aspects of the present invention, R1 and R2 together with carbon atoms connected thereto , , , or Forming, and here the above , , , and Each is independently 1, 2, 3, or 4 R b It is arbitrarily substituted by, and R b and other variables are as defined in the present invention.

[0054] In some aspects of the present invention, R1 and R2 together with carbon atoms connected thereto , , or Forming, and here the above , , and Each is independently 1, 2, 3, or 4 R b It is arbitrarily substituted by, and R b and other variables are as defined in the present invention.

[0055] In some aspects of the present invention, R1 and R2 together with carbon atoms connected thereto , , , , , or Forming, R b and other variables are as defined in the present invention.

[0056] In some aspects of the present invention, R1 and R2 together with carbon atoms connected thereto , , , or Forming, R b and other variables are as defined in the present invention.

[0057] In some aspects of the present invention, R1 and R2 together with carbon atoms connected thereto , , , , , , , or It forms, and other variables are as defined in the present invention.

[0058] In some aspects of the present invention, R1 and R2 together with carbon atoms connected thereto , , , , , or It forms, and other variables are as defined in the present invention.

[0059] In some aspects of the present invention, the structural fragment Is , , , , , , , , , and Selected from, and other variables as defined in the present invention.

[0060] In some aspects of the present invention, the structural fragment Is , , , , , , , and Selected from, and other variables as defined in the present invention.

[0061] In some aspects of the present invention, the structural fragment Is , , , , , , and Selected from, and other variables as defined in the present invention.

[0062] In some embodiments of the present invention, R3 is selected from H, and other variables are as defined in the present invention.

[0063] In some aspects of the present invention, the R4 is C 1-4 Selected from alkyl, and other variables as defined in the present invention.

[0064] In some aspects of the present invention, R4 is selected from -CH3 and -CH2CH3, wherein -CH3 and -CH2CH3 are each independently 1, 2, or 3 Rs d Substituted by, and R d and other variables are as defined in the present invention.

[0065] In some aspects of the present invention, R4 is selected from -CH3 and -CH2CH3, and other variables are as defined in the present invention.

[0066] In some embodiments of the present invention, R4 is selected from -CH3, and other variables are as defined in the present invention.

[0067] In some embodiments of the present invention, R5 is selected from H, and other variables are as defined in the present invention.

[0068] In some aspects of the present invention, R6 is each independently selected from H, F, Cl, and -CH3, wherein -CH3 is 1, 2, or 3 R d Arbitrarily substituted by, and R d and other variables are as defined in the present invention.

[0069] In some embodiments of the present invention, R6 is each independently selected from H, F, Cl, and -CH3, and other variables are as defined in the present invention.

[0070] In some embodiments of the present invention, R6 is each independently selected from H, F, and -CH3, and other variables are as defined in the present invention.

[0071] In some aspects of the present invention, the compound has a structure represented by formula (I-1), and

[0072]

[0073] In the above formula, n, R1, R2, R3, R4, and R6 are as defined in the present invention.

[0074] In some aspects of the present invention, the compound has a structure represented by the formula (I-1-1), and

[0075]

[0076] In the above formula,

[0077] n is selected from 1 and 2;

[0078] m is selected from 0, 1, and 2;

[0079] q is selected from 0 and 1;

[0080] T is selected from CH2, O, and NH, and if T is selected from CH2 and NH, then T is R b It can be arbitrarily substituted by;

[0081] R b, R4 and R6 are as defined in the present invention.

[0082] In some aspects of the present invention, the compound has a structure represented by formula (I-1A) or formula (I-1B), and

[0083] or

[0084] In the above formula, n, R1, R2, R3, R4, and R6 are as defined in the present invention, and R4 is not H.

[0085] In some aspects of the present invention, the compound has a structure represented by formula (I-1-1A) or formula (I-1-1B), and

[0086] or

[0087] In the above formula,

[0088] n is selected from 1 and 2;

[0089] m is selected from 0, 1, and 2;

[0090] q is selected from 0 and 1;

[0091] R4 is C 1-4 Selected from alkyl;

[0092] T is selected from CH2, O, and NH, and if T is selected from CH2 and NH, then T is R b It can be arbitrarily substituted by;

[0093] R b , R4 and R6 are as defined in the present invention.

[0094] Some aspects of the present invention are formed by any combination of each of the above variables.

[0095] The present invention further provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof.

[0096] , , , , , , , , , , , , , , , , , , , , , , , .

[0097] The present invention further provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof.

[0098] , , , ,

[0099] , , , ,

[0100] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0101] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0102] The present invention further provides the use of said compound, said pharmaceutically acceptable salt thereof, or said pharmaceutical composition in the manufacture of a myocardial myosin inhibitor drug.

[0103] The present invention further provides the use of said compound, a pharmaceutically acceptable salt thereof, or said pharmaceutical composition in the manufacture of a drug for treating heart failure and hypertrophic cardiomyopathy.

[0104] The present invention further provides a method for treating a disease associated with a myocardial myosin inhibitor in a subject requiring treatment, wherein the method comprises providing the subject with a therapeutically effective amount of a compound limited to any of the above technical means, a pharmaceutically acceptable salt thereof, or said pharmaceutical composition.

[0105] The present invention further provides a method for treating heart failure and hypertrophic cardiomyopathy in a subject requiring treatment, wherein the method comprises providing the subject with a therapeutically effective amount of a compound limited to any of the above technical means, a pharmaceutically acceptable salt thereof, or said pharmaceutical composition.

[0107] The compound of the present invention has a relatively excellent inhibitory effect on myocardial myosin ATPase and also possesses excellent pharmacokinetic properties.

[0108] Definition and explanation

[0109] Unless otherwise specified, the following terms and short phrases used in this text shall have the following meanings. Unless otherwise specifically defined, any specific term or short phrase shall not be understood as indeterminate or unclear, but shall be understood according to its ordinary meaning. Where a product name appears in this text, it refers to the corresponding product or its active ingredient.

[0110] As used herein, the term “pharmaceutical acceptable” means that, within the scope of reasonable medical judgment, such compounds, materials, compositions and / or formulations are suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and correspond to a reasonable benefit / risk ratio.

[0111] The term “pharmaceutically acceptable salt” refers to a salt of a compound of the present invention prepared with a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt may be obtained by contacting a sufficient amount of base with a neutral form of such compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt may be obtained by contacting a sufficient amount of acid with a neutral form of such compound in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic salts, said inorganic acids including hydrochloric acid, hydrobromide, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphite, etc.; and includes organic acid salts, wherein the organic acid includes similar acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, souveric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; further include salts of amino acids (e.g., arginine, etc.) and salts of organic acids such as glucuronic acid, etc. Some specific compounds of the present invention contain basic and acidic functional groups and can be converted into any base or acid addition salt.

[0112] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid group or a base by conventional chemical methods. Generally, the method for preparing such salts involves reacting the free acid or base form of such compound with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both.

[0113] The compounds of the present invention may exist in specific geometric or stereoisomer forms. All such compounds considered by the present invention include cis and trans isomers, (-)- and (+)- enantiomers, ( R )- and ( S )-enhanced mirror image isomer, diastereomer, ( D )-isomer, ( L It includes racemic mixtures and other mixtures, such as mixtures rich in )-isomers, and enantiomers or diastereomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are included within the scope of the present invention.

[0114] Unless otherwise specified, the terms “enantiomer” or “optical isomer” refer to stereoisomers that are mirror images of each other.

[0115] Unless otherwise specified, the terms “cis-trans isomer” or “geometric isomer” refer to isomers that cannot rotate freely due to double bonds or single bonds of ring-forming carbon atoms.

[0116] Unless otherwise specified, the term “diastereomer” refers to stereoisomers in which molecules have two or more chiral centers and are asymmetric mirror images of each other.

[0117] Unless otherwise specified, “(+)” indicates priority, “(-)” indicates left-handedness, and “(±)” indicates racemic change.

[0118] Unless otherwise specified, wedge-shaped solid line joint ( ) and wedge-shaped dotted line connection ( Representing an absolute arrangement of a single three-dimensional center with ), and a linear solid line combination ( ) and linear dotted line combination( It represents the relative arrangement of the three-dimensional center with ), and the wavy line ( wedge-shaped solid line connection with ) ) or wedge-shaped dotted line connection ( Represents ) or a wavy line ( Straight solid line combination with ) ) and linear dotted line combination( It represents ).

[0119] The compounds of the present invention may specifically exist. Unless otherwise specified, the terms “tautomer” or “tautomeric form” refer to isomers having different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. Where tautomers are possible (e.g. in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) involve interconversion through the transfer of protons, such as keto-enol isomerization and imine-enamin isomerization. Valence tautomers involve interconversion by the recombination of some bonding electrons. A specific example of keto-enol tautomerization here is the interconversion between the two tautomers of pentan-2,4-dione and 4-hydroxypent-3-en-2-one.

[0120] Unless otherwise specified, the terms “rich in one isomer,” “rich in isomer,” “rich in one enantiomer,” or “rich in enantiomer” indicate that the content of one isomer or enantiomer is less than 100%, and the content of said isomer or enantiomer 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%.

[0121] Unless otherwise specified, the term “isomeric excess” or “enantiomer excess” refers to the difference value between the relative percentages of two isomers or 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 excess of isomers or enantiomers (ee value) is 80%.

[0122] Optically active ( R )- and ( S Not only )-isomers D and LIsomers may be produced by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of the compound of the present invention is desired, it may be produced by asymmetric synthesis or induction with a chiral aid, thereby separating the resulting mixture of diastereomers and cleaving the aid to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with an acid or base of appropriate optical activity, then the diastereomer is separated by conventional methods known in the art, and the pure enantiomer is recovered and obtained. Furthermore, the separation of enantiomers and diastereomers is typically performed using chromatography with a chiral stationary phase in combination with optional chemical derivatization methods (e.g., generating a carbamate with an amine).

[0123] The compound of the present invention may contain atomic isotopes in non-natural proportions in one or more atoms constituting the compound. For example, the compound is tritium ( 3 H), iodine-125( 125 I) or C-14( 14 It can be labeled with a radioactive isotope such as C). As another example, deuterium drugs can be formed by substituting hydrogen with deuterium; since the bond composed of deuterium and carbon is stronger than the bond composed of ordinary hydrogen and carbon, deuterium drugs have advantages over non-deuterium drugs, such as reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of the drug. All changes in the isotopic composition of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0124] The terms “arbitrarily” or “optional” refer to cases where the events or situations described below may occur but are not guaranteed to occur, and include cases where the said events or situations occur and cases where the said events or situations do not occur.

[0125] The term “substituted” refers to the substitution of any one or more hydrogen atoms of a specific atom by a substituent, and may include variants of deuterium and hydrogen, provided that the valence state of the specific atom is normal and the compound after substitution is stable. If the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur in aromatic groups.

[0126] The term “arbitrarily substituted” means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary in terms of chemical feasibility.

[0127] If any variant (e.g., R) appears one or more times in the composition or structure of a compound, the definition in each case is independent. Thus, for example, if a group is substituted by 0 to 2 Rs, the group may be arbitrarily substituted by up to 2 Rs as an independent option for each case of R. Furthermore, combinations of substituents and / or variants thereof are permitted only if such combinations produce a stable compound.

[0128] When the number of connectors is 0, as in -(CRR)0-, it indicates that the connector is a single connection.

[0129] When one of the variables is selected from a single bond, it indicates that the two connected groups are directly connected, and for example, when L in ALZ represents a single bond, the structure is actually AZ.

[0130] If one substituent is empty, it indicates that the substituent does not exist, for example, when X is empty in AX, it indicates that the structure is actually A. If it is not specified which atom a listed substituent is connected to the substituent, such substituent may be connected through any of its atoms, for example, pyridyl may be connected as a substituent to the substituted group through any carbon atom of the pyridine ring.

[0131] If the connection direction of a listed connector is not specified, its connection direction is arbitrary, for example, In this case, connector L is -MW-, where -MW- connects loop A and loop B in the same direction as the left-to-right reading order. You can construct it by connecting loop A and loop B in the opposite direction to the left-to-right reading order. It may also be composed of. The combination of the above linker substituents and / or variants thereof is permitted only if such combination produces a stable compound.

[0132] Unless otherwise specified, if a group has one or more connectable sites, any one or more sites of said group may be connected to another group through chemical bonding. The method of connecting said chemical bonds is not positioned, and if an H atom is present in the connectable site, when chemical bonding is connected, the number of H atoms in that site decreases according to the number of connected chemical bonds, and the corresponding valence group is converted. The chemical bond connecting said site and another group is a linear solid bond ( ), linear dotted line combination( ), or wavy line ( It can be represented as ). For example, the linear solid bond of -OCH3 indicates that the oxygen atom of the above group is connected to another group; The linear dotted bond indicates that the two ends of the nitrogen atom of the above group are connected to another group; The wavy line indicates that the phenyl group is connected to another group through the carbon atoms at positions 1 and 2. Indicates that any linkable site in piperidinyl can be connected to another group through one compound bond, and at least , , , It includes the four connection modes, and even if an H atom is drawn on -N- is still It includes a group of this type of linkage, and when only one chemical bond is linked, the H at that site is correspondingly reduced by one to become the corresponding monovalent piperidinyl.

[0133] If the chemical bond of a substituent intersects the chemical bond connecting two atoms of the ring, this indicates that the substituent may bond to any atom of the ring. If the atom connected to a substituent is not specified, the substituent may bond to any atom; and if the atom connected to the substituent is part of a double or triple ring system, it indicates that the substituent may bond to any atom of any ring in said ring system. Combinations of substituents and / or variants thereof are permitted only if such combinations produce a stable compound. For example, structural units or indicates that it can be substituted at any position of cyclohexyl or cyclopentyl.

[0134] Unless otherwise specified, the number of atoms in a ring is typically defined as the number of ring members, for example, “a 5- to 7-membered ring” refers to a “ring” surrounded and arranged by 5 to 7 atoms.

[0135] Unless otherwise specified, the term “C 1-3"Alkyl" represents a saturated hydrocarbon group composed of 1 to 3 carbon atoms in a straight or branched chain. The above C 1-3 Alkyl is C 1-2 and C 1-3 It includes alkyls, etc.; this may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include methyl (Me), ethyl (Et), and propyl ( n - Includes, but is not limited to, propyl and isopropyl) etc.

[0136] Unless otherwise specified, the term “C 1-4 "Alkyl" represents a saturated hydrocarbon group composed of 1 to 4 carbon atoms in a straight or branched chain. The above C 1-4 Alkyl is C 1-2 , C 1-3 and C 2-3 It includes alkyls, etc.; this may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include methyl (Me), ethyl (Et), and propyl ( n -Including propyl and isopropyl), butyl ( n -Butyl, isobutyl, s - Butyl and t - Includes butyl, etc., but is not limited thereto.

[0137] Unless otherwise specified, the term “C 1-4 “Alkoxy” represents an alkyl group comprising 1 to 4 carbon atoms connected to the rest of the molecule through one oxygen atom. The above C 1-4 Alkoxycea C 1-3 , C 1-2 , C 2-4 , C4 and C3 alkoxy, etc. are included. C 1-4 Examples of alkoxy include methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and butoxy ( n - Butoxy, isobutoxy, s - Butoxy and t- Includes but is not limited to butoxy(s), etc.

[0138] The term “heteroalkyl” refers to a stable straight-chain or branched-chain alkyl group or a composition thereof composed of at least one heteroatom or heterogroup, either by itself or in combination with other terms. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternarily ammonized. In other embodiments, the heterogroup is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-6 It is a heteroalkyl; and in some other embodiments, the heteroalkyl is C 1-3 It is a heteroalkyl. A heteroatom or heteroatom group may be located at any internal position of the heteroalkyl, including the connection site between the alkyl and the rest of the molecule, but the terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) each refer to such an alkyl group connected to the rest of the molecule through one oxygen atom, amino group, or sulfur atom. Examples of heteroalkyls include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, and -CH2-CH2-S(=O)2-CH3. Up to two heteroatoms may be consecutive, as in -CH2-NH-OCH3.

[0139] Unless otherwise specified, C n-n+m or C n -C n+m It includes any specific case containing n to n+m carbons, for example, C 1-12 C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 It includes, and also includes any range from n to n+m, e.g., C 1-12 is 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 Includes, etc.; likewise, n to n+m members indicate that the number of atoms on the ring is n to n+m, for example, 3 to 12 members include 3 members, 4 members, 5 members, 6 members, 7 members, 8 members, 9 members, 10 members, 11 members, and 12 members, and also include any range from n to n+m, for example, 3 to 12 members include 3 to 6 members, 3 to 9 members, 5 to 6 members, 5 to 7 members, 6 to 7 members, 6 to 8 members, and 6 to 10 members, etc.

[0140] Unless otherwise specified, “C 3-6 “Cycloalkyl” represents a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a single-ring and double-ring system, and the above C 3-6 Cycloalkyl is C 3-5 , C 4-5 and C 5-6 Includes cycloalkyl, etc.; this may be monovalent, divalent, or polyvalent. C 3-6Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0141] Unless otherwise specified, “C 3-4 “Cycloalkyl” represents a saturated cyclic hydrocarbon group composed of 3 to 4 carbon atoms, which is a monocyclic system; it can be monovalent, divalent, or polyvalent. C 3-5 Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0142] Unless otherwise specified, “C 4-6 “Cycloalkyl” represents a saturated cyclic hydrocarbon group composed of 4 to 6 carbon atoms, which is a single-ring and double-ring system, and the above C 4-6 Cycloalkyl is C 4-5 and C 5-6 Includes cycloalkyl, etc.; this may be monovalent, divalent, or polyvalent. C 4-6 Examples of cycloalkyls include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl.

[0143] Unless otherwise specified, “C 5-6 “Cycloalkyl” represents a saturated cyclic hydrocarbon group composed of 5 to 6 carbon atoms, which is a single-ring and double-ring system, and the above C 3-6 Cycloalkyls include pentagonal cycloalkyls and hexagonal cycloalkyls, etc.; these may be monovalent, divalent, or polyvalent. C 5-6 Examples of cycloalkyls include, but are not limited to, cyclopentyl, cyclohexyl, etc.

[0144] Unless otherwise specified, the term “ternary to hexavalent heterocycloalkyl” refers, either alone or in combination with other terms, to a saturated cyclic group composed of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternarily ammoninated, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p can be 1 or 2). This includes single ring and double ring systems, wherein the double ring system includes spiro rings, fused rings, and crosslinked rings. In addition, in the “ternary to hexavalent heterocycloalkyl”, the heteroatom may occupy a connecting position between the heterocycloalkyl and the rest of the molecule. The ternary to hexavalent heterocycloalkyl includes quaternary to hexavalent, quinary to hexavalent, quaternary, quinary, and hexavalent heterocycloalkyl, etc. Examples of ternary to hexavalent heterocycloalkyl groups include azetidinyl, oxetanyl, tietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or Includes, but is not limited to, hexahydropyridazinyl.

[0145] Unless otherwise specified, the term “tetracycloalkyl” refers, either alone or in combination with other terms, to a saturated ring group composed of 4 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternarily ammoninated, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p can be 1 or 2). This includes single ring and double ring systems, wherein the double ring system includes spiro rings, fused rings, and cross-linked rings. In addition, in the “tetracycloalkyl to hexacyclic heterocycloalkyl”, the heteroatom may occupy a connecting position between the heterocycloalkyl and the rest of the molecule. The tetracycloalkyl to hexacyclic heterocycloalkyl includes quint to hexacyclic, tetra, quint and hexacyclic heterocycloalkyls, etc. Examples of tetracycloalkyl groups consisting of quaternary to hexavalent groups include azetidinyl, oxetanyl, tietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or Includes, but is not limited to, hexahydropyridazinyl.

[0146] Unless otherwise specified, the term “penta-to-hexamolar heterocycloalkyl” refers to a saturated ring group consisting of 5 to 6 ring atoms, either alone or in combination with other terms, wherein 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternarily ammonized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO, and S(O) p , p can be 1 or 2). This includes single ring and double ring systems, wherein the double ring system includes spiro rings, fused rings, and crosslinked rings. In addition, in the “5- to 6-membered heterocycloalkyl,” the heteroatom may occupy a connecting position between the heterocycloalkyl and the rest of the molecule. The 5- to 6-membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyls. Examples of 5- to 6-membered heterocycloalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, etc.

[0147] Unless otherwise specified, the term “hexacycloalkyl” refers to a saturated ring group consisting of six ring atoms, either alone or in combination with other terms, wherein 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternarily ammonized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO, and S(O) p , p can be 1 or 2). This includes single ring and double ring systems, where the double ring system includes spiro rings, fused rings, and cross-linked rings. In addition, in the “6-membered heterocycloalkyl”, the heteroatom may occupy a connecting position between the heterocycloalkyl and the rest of the molecule. Examples of 6-membered heterocycloalkyls include, but are not limited to, tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, etc.

[0148] The term “leaving group” refers to a functional group or atom that can be substituted by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonates such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenebenzenesulfonate, etc.; and acyloxy, such as acetoxy, trifluoroacetoxy, etc.

[0149] The term “protecting group” includes, but is not limited to, “amino protecting group,” “hydroxy protecting group,” or “mercapto protecting group.” The term “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; acyls such as alkanoyls (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyls such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyls such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyls such as benzyl (Bn), triphenylmethyl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; and silyls such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS). The term “hydroxy protecting group” refers to a protecting group suitable for preventing side reactions of hydroxy. Representative hydroxy protecting groups include, but are not limited to, alkyls such as methyl, ethyl, and tert-butyl; acyls such as alkanoyls (e.g., acetyl); arylmethyls such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); and silyls such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).

[0150] The compounds of the present invention can be prepared by various synthesis methods known to those skilled in the art and include specific embodiments exemplified below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art; preferred embodiments include but are not limited to the embodiments of the present invention.

[0151] The structure of the compounds of the present invention can be determined by conventional methods known to those skilled in the art, and where the present invention relates to the absolute configuration of the compounds, said absolute configuration can be determined by conventional technical means in the art. For example, the absolute configuration can be determined by single-crystal X-ray diffraction (SXRD) by collecting diffraction intensity data of a cultured single crystal using a Bruker D8 venture diffractometer, with the light source being CuKα radiation and the scanning mode being φ / ω scan, and then further analyzing the crystal structure using the direct method (Shelxs97).

[0152] All solvents used in this invention are commercially available.

[0153] The present invention uses the following abbreviations. TEA represents triethylamine; and DIEA is N,N - Represents diisopropylethylamine; PE represents petroleum ether; EtOAc represents ethyl acetate; EA represents ethyl acetate; THF represents tetrahydrofuran; MeOH represents methanol; MTBE represents methyl tert-butyl ether; DCM represents dichloromethane; EtOH represents ethanol; iPrOH represents isopropanol; Boc2O represents di-tert-butyl dicarbonate; L-selectride represents lithium tri-sec-butylborohydride; TCFH represents N,N,N,N-tetramethylchloroformamidine hexafluorophosphate; FA represents formic acid; TFA represents trifluoroacetic acid; ACN represents acetonitrile; TLC represents thin-layer chromatography; HPLC represents high-performance liquid chromatography; LCMS stands for Liquid Chromatography Mass Spectrometry. DMSO represents dimethyl sulfoxide; DMF is N,N - represents dimethylformamide; LDA represents lithium diisopropylamide; DMAC is N,N- Represents dimethylacetamide; PEG-400 represents polyethylene glycol 400; EGTA represents ethylene glycol bis(2-aminoethyl ether)tetraacetic acid; DMSO- d 6 represents deuterium dimethyl sulfoxide; CDCl3 represents deuterium chloroform.

[0154] Compounds are named according to the conventional naming principles of the art or ChemDraw ® They are named using software, and commercially available compounds use the supplier's catalog. Specific details for implementing the invention

[0155] The present invention will be described in detail below through examples, but the present invention is not limited in any way. The compounds of the present invention can be prepared by various synthesis methods known to those skilled in the art and include specific embodiments exemplified below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention. Various changes and modifications to specific embodiments of the present invention will be obvious to those skilled in the art without departing from the gist and scope of the present invention.

[0156] Example 1

[0157]

[0158] Synthesis path:

[0159]

[0160] Step A: DIEA (1.98 g, 15.33 mmol, 2.67 mL, 2 eq) was added to an EtOH (20 mL) solution of compound 1-2 (929.08 mg, 7.67 mmol, 975.93 μL, 1 eq) and compound 1-1 (1.5 g, 7.67 mmol, 1 eq, HCl) at 20°C, the reaction mixture was stirred at 20°C for 16 hours, and after concentration, compound 1-a was obtained.

[0161] Step B: Under the protection of nitrogen gas at 0°C, DIEA (1.77 g, 13.66 mmol, 2.38 mL, 2 eq) and Compound 1-3 (1.34 g, 7.51 mmol, 1.1 eq) were added to a THF (30 mL) solution of Compound 1-a (1.6 g, 6.83 mmol, 1 eq), the reaction mixture was stirred at 20°C for 1 hour, the reaction mixture was concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain Compound 1-b. LCMS (ESI) m / z: 377.3 (M+1).

[0162] Step C: Under the protection of nitrogen gas, sodium tert-butoxide (1.53 g, 15.94 mmol, 4 eq) was added to a 30 mL MeOH solution of compound 1-b (1.5 g, 3.98 mmol, 1 eq), the reaction mixture was stirred at 20 °C for 4 hours, then dilute hydrochloric acid (1 mol / L, 50 mL) was added and extracted with EA (50 mL), then the organic phase was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 4:1 to 2:1) to obtain compound 1-c.

[0163] Step D: Under the protection of nitrogen gas, lithium chloride (107.20 mg, 2.53 mmol, 51.79 μL, 2 eq) was added to a DMSO (4 mL) solution of compound 1-c (0.4 g, 1.26 mmol, 1 eq), the reaction mixture was stirred at 125°C for 20 hours, filtered, and the filtrate was purified by preparative HPLC [mobile phase: water (0.1% TFA)-ACN; gradient: 21% to 51% ACN] to obtain compound 1. 1 H NMR (CDCl3, 400 MHz): 7.38 - 7.24 (m, 5H), 5.17 (br s, 1H), 4.63 (br d, J =6.4 Hz, 1H), 1.57 (d, J =6.7 Hz, 3H), 1.42 (s, 3H), 1.38 (s, 3H);LCMS(ESI) m / z: 259.4(M+1).

[0164] Example 2

[0165]

[0166] Synthesis path:

[0167]

[0168] Step A: Under the protection of nitrogen gas at -78°C, LDA (2M, 19.07 mL, 1.1 eq) is added to a THF (80 mL) solution of Compound 2-1 (5 g, 34.68 mmol, 4.63 mL, 1 eq), and the reaction mixture is stirred at -78°C for 30 minutes, then methyl chloroformate (3.44 g, 36.42 mmol, 2.82 mL, 1.05 eq) is added, the reaction mixture is slowly heated to 20°C and stirred for 16 hours, then water (200 mL) is added and quenched, then extracted with EA (200 mL), the organic phase is washed with saturated saline (200 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue is separated by silica gel column chromatography (PE:EtOAc = 10:1 to Compound 2-a was obtained by 3:1).

[0169] Step B: At 0°C, sodium hydroxide (494.51 mg, 12.36 mmol, 1 eq) was added to a solution of compound 2-a (2.5 g, 12.36 mmol, 1 eq) in MeOH (20 mL) and water (20 mL), and the reaction mixture was stirred at 20°C for 16 hours, then water (50 mL) was added, then extracted with EA (50 mL), separated, and the aqueous phase was adjusted to a pH of about 5 with 1 M dilute hydrochloric acid, then extracted with EA (50 mL), the organic phase was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-b.

[0170] Step C: At 0°C under the protection of nitrogen gas, TEA (4.57g, 45.17mmol, 6.29mL, 5eq) and DMF (33.02mg, 451.70μmol, 34.75μL, 0.05eq) were added to a DCM (30mL) solution of compound 2-b (1.7g, 9.03mmol, 1eq), then oxalyl chloride (1.72g, 13.55mmol, 1.19mL, 1.5eq) was added, and the reaction mixture was stirred at 20°C for 1 hour and then concentrated to obtain compound 2-c.

[0171] Step D: Under the protection of nitrogen gas at 0°C, DIEA (2.50g, 19.36mmol, 3.37mL, 2eq) and compound 1-a (2.27g, 9.68mmol, 1eq) were added to a DCM (30mL) solution of compound 2-c (2.0g, 9.68mmol, 1eq), the reaction mixture was stirred at 20°C for 1 hour, then concentrated, diluted by adding EA (30mL), washed with 1N dilute hydrochloric acid (30mL), then washed with saturated saline (30mL), dried with anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain compound 2-d.

[0172] Step E: Under the protection of nitrogen gas, sodium methoxide (2M, 7mL, 16.18eq) was added to a 5mL solution of MeOH of compound 2-d (0.35g, 865.36μmol, 1eq), the reaction mixture was stirred at 50°C for 2 hours, then concentrated, the residue was diluted by adding EA (20mL), washed with saturated saline (20mL), dried with anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to obtain compound 2-e.

[0173] Step F: Hydrochloric acid (4M, 7.00mL, 143.35eq) was added to a 1,4-dioxane (7mL) solution of compound 2-e (70mg, 195.32μmol, 1eq), the reaction mixture was stirred at 50°C for 16 hours, then concentrated, and a 2N aqueous sodium hydroxide solution was added to the residue to neutralize it, then EA (50mL) was added for extraction, the organic phase was washed with saturated saline (30mL), dried with anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by preparative HPLC ([water (0.225% FA)-ACN], gradient: 17% to 47% ACN) to obtain compound 2. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 9.62 (br s, 1H), 7.47 - 7.20 (m, 5H), 7.05 (br s, 1H), 4.60 (br t, J =6.7 Hz, 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 =6.8 Hz, 3H);LCMS(ESI) m / z: 301.4(M+1).

[0174] Example 3

[0175]

[0176] Synthesis path:

[0177]

[0178] Step A: Under the protection of nitrogen gas, potassium carbonate (10.46 g, 75.69 mmol, 2 eq) was added to a DMF (50 mL) solution of compound 3-1 (5 g, 37.85 mmol, 4.35 mL, 1 eq) and 1,4-dibromobutane (8.17 g, 37.85 mmol, 4.57 mL, 1 eq), the reaction mixture was stirred at 50°C for 16 hours, then EA (200 mL) was added, washed with water (200 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 20:1 to 10:1) to obtain compound 3-a.

[0179] Step B: Sodium hydroxide (1.06 g, 26.58 mmol, 1.1 eq) was added to a solution of compound 3-a (4.5 g, 24.17 mmol, 1 eq) in MeOH (25 mL) and water (25 mL), and the reaction mixture was stirred at 20°C for 16 hours, then water (30 mL) was added, then extracted with EA (50 mL), separated, and the aqueous phase was adjusted to a pH of about 5 with 1 M dilute hydrochloric acid, then extracted with EA (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-b.

[0180] Step C: Under the protection of nitrogen gas at -20°C, TEA (4.94g, 48.79mmol, 6.79mL, 4eq) and DMF (44.57mg, 609.83μmol, 46.92μL, 0.05eq) were added to a DCM (30mL) solution of compound 3-b (2.1g, 12.20mmol, 1eq), then oxalyl chloride (2.01g, 15.86mmol, 1.39mL, 1.3eq) was added, and the reaction mixture was stirred at 20°C for 1 hour and then concentrated to obtain compound 3-c.

[0181] Step D: Under the protection of nitrogen gas at -20°C, TEA (2.44g, 24.13mmol, 3.36mL, 2eq) and Compound 1-a (2.83g, 12.07mmol, 1eq) were added to a DCM (30mL) solution of Compound 3-c (2.3g, 12.07mmol, 1eq), the reaction mixture was stirred at 0°C for 1 hour, then concentrated, the residue was diluted by adding EA (30mL), washed with saturated saline (30mL), dried with anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 20:1 to 5:1) to obtain Compound 3-d.

[0182] Step E: Under the protection of nitrogen gas, sodium methoxide (1M, 7.21mL, 4eq) was added to a MeOH (4mL) solution of compound 3-d (0.7g, 1.80mmol, 1eq), the reaction mixture was stirred at 20°C for 16 hours, the pH of the reaction mixture was adjusted to 5 with 1N dilute hydrochloric acid, then EA (20mL) was added for extraction, the organic phase was washed with saturated saline (20mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3-e.

[0183] Step F: Hydrochloric acid (4M, 6mL, 10.27eq) was added to a 1,4-dioxane (6mL) solution of compound 3-e (0.8g, 2.34mmol, 1eq), and the reaction mixture was stirred at 50°C for 16 hours. Then, EA (50mL) was added to dilute the mixture, and a 1N aqueous sodium hydroxide solution was added to adjust the pH to 7. After separation, the organic phase was washed with saturated saline solution (50mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated. MeOH (10mL) was added to the residue and stirred for 20 minutes. The mixture was filtered, and the cake was dried under high vacuum to obtain compound 3. 1 1 H NMR (DMSO- d 6, 400 MHz): δ ppm 9.49 (br s, 1H), 7.41 - 7.31 (m, 4H), 7.30 - 7.25 (m, 1H), 6.92 (br d, J =5.1 Hz, 1H), 4.60 (br t, J =6.7 Hz, 1H), 4.42 (s, 1H), 1.91 - 1.80 (m, 4H), 1.72 - 1.65 (m, 4H), 1.43 (d, J =6.8 Hz, 3H);LCMS(ESI) m / z: 285.4(M+1).

[0184] Example 4

[0185]

[0186] Synthesis path:

[0187]

[0188] Step A: 4-1 (26g, 113.07mmol, 15.29mL, 1eq) and potassium carbonate (31.25g, 226.15mmol, 2eq) were added to a 150mL DMF solution of 3-1 (14.94g, 113.07mmol, 12.99mL, 1eq). The reaction mixture was stirred at 50°C for 16 hours, then EA (150mL) was added, followed by washing with water (150mL), then washing the organic phase with saturated saline (100mL × 3), drying with anhydrous sodium sulfate, filtering, and concentrating. The residue was separated by column chromatography (PE:EtOAc = 50:1 to 30:1) to obtain compound 4-a.

[0189] Step B: Sodium hydroxide (1.38g, 34.46mmol, 1eq) was added to a solution of MeOH (40mL) and water (40mL) of 4-a (6.9g, 34.46mmol, 1eq), the reaction mixture was stirred at 15°C for 16 hours, then water (50mL) was added, followed by extraction with EA (100mL), and after separation, the aqueous phase was adjusted to a pH of about 5 with 1M dilute hydrochloric acid, followed by extraction with EA (100mL×2), then the combined organic phase was washed with saturated saline (100mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-b.

[0190] Step C: At 0°C, TEA (9.78g, 96.67mmol, 13.45mL, 4eq) and DMF (88.32mg, 1.21 mmol, 92.97μL, 0.05eq) were added to a 50mL solution of DCM of 4-b (4.5g, 24.17mmol, 1eq), then oxalyl chloride (3.99g, 31.42mmol, 2.75mL, 1.3eq) was added, and the reaction mixture was stirred at 10°C for 1 hour to obtain compound 4-c.

[0191] Step D: At 0°C, TEA (4.94g, 48.86mmol, 6.80mL, 2eq) was added to a DCM (50mL) solution of 4-c (5g, 24.43mmol, 1eq), then 1-a (5.72g, 24.43mmol, 1eq) was added, the reaction mixture was stirred at 0°C for 1 hour, then concentrated, and the residue was separated by column chromatography (PE:EtOAc = 30:1 to 10:1) to obtain compound 4-d.

[0192] Step E: Under the protection of nitrogen gas, sodium methoxide (1M, 28.57mL, 5eq) was added to a 15mL MeOH solution of 4-d (2.30g, 5.71mmol, 1eq), the reaction mixture was stirred at 10°C for 16 hours, then stirred at 50°C for 3 hours, 1N dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, then EA (50mL×2) was added for extraction, the combined organic phase was washed with saturated saline (50mL×2), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc=10:1 to 3:1) to obtain compound 4-e.

[0193] Step F: Hydrochloric acid (4M, 10.50mL, 21.38eq) was added to a solution of 1,4-dioxane (10mL) and THF (2mL) containing 4-e (0.7g, 1.96mmol, 1eq), and the reaction mixture was stirred at 50°C for 40 hours. Then, the pH was adjusted to about 7 with a 1N aqueous sodium hydroxide solution, extracted with DCM / MeOH = 10 / 1 (50mL × 2), the combined organic phase was washed with saturated saline (30mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated. MeOH (10mL) was added to the residue, stirred at 10°C for 30 minutes, filtered, and the cake was dried under high vacuum to obtain compound 4. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 9.38 (br s, 1H), 7.41 - 7.22 (m, 5H), 6.84 (br d, J = 5.4 Hz, 1H), 4.57 (br t, J = 6.8 Hz, 1H), 4.36 (s, 1H), 1.74 - 1.45 (m, 10H), 1.41 (d, J = 6.8 Hz, 3H);LCMS(ESI) m / z: 299.2(M+1).

[0194] Example 5

[0195]

[0196] Synthesis path:

[0197]

[0198] Step A: Under the protection of nitrogen gas at 20°C, DIEA (1.86g, 14.37mmol, 2.50mL, 2eq) was added to an EtOH (15mL) solution of compound 5-1 (1.00g, 7.19mmol, 1eq) and compound 1-1 (1.14g, 7.19mmol, 1eq), the reaction mixture was stirred at 20°C for 16 hours, and after concentration, compound 5-a was obtained.

[0199] Step B: Under the protection of nitrogen gas at 20°C, TEA (1.45g, 14.35mmol, 2.00mL, 2eq) was added to a DCM (30mL) solution of compound 5-a (1.81g, 7.17mmol, 1eq), then 3-c (1.37g, 7.17mmol, 1eq) was added, the reaction mixture was stirred at 20°C for 16 hours, then concentrated, the residue was diluted by adding EA (40mL), washed with water (40mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 20:1 to 10:1) to obtain compound 5-b.

[0200] Step C: Sodium methoxide (1M, 5.90mL, 4eq) was added to a 6mL MeOH solution of 5-b (600mg, 1.48mmol, 1eq) under the protection of nitrogen gas at 20°C, the reaction mixture was stirred at 40°C for 16 hours, the reaction mixture was added to water (40mL), extracted with EA (40mL×2), the combined organic phase was washed with saturated saline (40mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to obtain compound 5-c.

[0201] Step D: At 20°C, hydrochloric acid (4M, 3.82mL, 10eq) was added to a 1,4-dioxane (6mL) solution of 5-c (550mg, 1.53mmol, 1eq), the reaction mixture was stirred at 40°C for 16 hours, EA (40mL) was added to the reaction mixture, the pH was adjusted to about 7 with a 1N sodium hydroxide aqueous solution and the solution was separated, the aqueous phase was then extracted with EA (40mL), the combined organic phase was washed with saturated saline (50mL), dried with anhydrous sodium sulfate, filtered and concentrated, MeOH (5mL) was added to the residue and stirred, filtered, and the cake was dried under high vacuum to obtain compound 5. 1 1 H NMR (DMSO- d 6 , 400 MHz):δ ppm 9.48 (br s, 1H), 7.38 (dd, J =5.6, 8.6 Hz, 2H), 7.19 (t, J =8.8 Hz, 2H), 6.91 (br d, J =6.0 Hz, 1H), 4.62 (br t, J =6.7 Hz, 1H), 4.41 (s, 1H), 1.96 - 1.78 (m, 4H), 1.76 - 1.61 (m, 4H), 1.42 (d, J =6.8 Hz, 3H);LCMS(ESI) m / z: 302.8(M+1).

[0202] Example 6

[0203]

[0204] Synthesis path:

[0205]

[0206] Step A: Under the protection of nitrogen gas at 20°C, DIEA (1.86g, 14.37mmol, 2.50mL, 2eq) was added to an EtOH (15mL) solution of compound 6-1 (1.00g, 7.19mmol, 1eq) and compound 1-1 (1.14g, 7.19mmol, 1eq), the reaction mixture was stirred at 20°C for 16 hours, and after concentration, compound 6-a was obtained.

[0207] Step B: Under the protection of nitrogen gas at 20°C, TEA (1.45g, 14.35mmol, 2.00mL, 2eq) was added to a DCM (30mL) solution of 6-a (1.81g, 7.17mmol, 1eq), then 3-c (1.37g, 7.17mmol, 1eq) was added, the reaction mixture was stirred at 20°C for 16 hours, then concentrated, the residue was diluted by adding EA (40mL), washed with water (40mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 20:1 to 10:1) to obtain compound 6-b.

[0208] Step C: Sodium methoxide (1M, 8mL, 4.34eq) was added to a MeOH (8mL) solution of 6-b (750.00mg, 1.85mmol, 1eq) under the protection of nitrogen gas at 20°C, the reaction mixture was stirred at 40°C for 16 hours, cooled to room temperature, then EA (30mL) was added, the pH was adjusted to about 7 with 1N hydrochloric acid and separated, then the aqueous phase was extracted with EA (40mL×2), the combined organic phase was washed with saturated saline (40mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=5:1 to 1:1) to obtain compound 6-c.

[0209] Step D: At 20°C, hydrochloric acid (4M, 3.82mL, 10eq) was added to a 1,4-dioxane (4mL) solution of 6-c (550mg, 1.53mmol, 1eq), the reaction mixture was stirred at 40°C for 16 hours, water (40mL) was added to the reaction mixture, then a saturated sodium bicarbonate aqueous solution was added to adjust the pH to about 7, the mixture was extracted with EA (40mL×2), the combined organic phase was washed with saturated saline (40mL), dried with anhydrous sodium sulfate, filtered and concentrated, MeOH (6mL) was added to the residue, stirred for 15 minutes and filtered, and the cake was dried under high vacuum to obtain compound 6. 1 1 H NMR (DMSO- d 6 , 400 MHz):δ ppm 9.51 (br s, 1H), 7.49 - 7.35 (m, 1H), 7.19 (br d, J =7.7 Hz, 2H), 7.09 (dt, J =1.6, 8.2 Hz, 1H), 6.94 (br d, J =6.1 Hz, 1H), 4.63 (br t, J =6.7 Hz, 1H), 4.40 (s, 1H), 1.90 - 1.79 (m, 4H), 1.74 - 1.63 (m, 4H), 1.42 (d, J =6.7 Hz, 3H);LCMS(ESI) m / z: 302.8(M+1).

[0210] Example 7

[0211]

[0212] Synthesis path:

[0213]

[0214] Step A: Under the protection of nitrogen gas at 20°C, DIEA (1.26g, 9.77mmol, 1.70mL, 2eq) was added to an EtOH (15mL) solution of compound 7-1 (0.76g, 4.88mmol, 1eq) and compound 1-1 (777.38mg, 4.88mmol, 1eq), the reaction mixture was stirred at 20°C for 16 hours, and after concentration, compound 7-a was obtained.

[0215] Step B: Under the protection of nitrogen gas at 20°C, TEA (986.53 mg, 9.75 mmol, 1.36 mL, 2 eq) was added to a DCM (30 mL) solution of 7-a (1.31 g, 4.87 mmol, 1 eq), then 3-c (1.23 g, 6.45 mmol, 1.32 eq) was added, the reaction mixture was stirred at 20°C for 16 hours, then concentrated, the residue was diluted by adding EA (40 mL), washed with water (40 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 20:1 to 10:1) to obtain compound 7-b.

[0216] Step C: Under the protection of nitrogen gas at 20°C, sodium methoxide (1M, 8mL, 4.51eq) was added to a MeOH (8mL) solution of 7-b (750mg, 1.77mmol, 1eq), the reaction mixture was stirred at 40°C for 16 hours, cooled to room temperature, then EA (30mL) was added, the pH was adjusted to about 7 with 1N hydrochloric acid and separated, then the aqueous phase was extracted with EA (60mL×2), the combined organic phase was washed with saturated saline (60mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=4:1 to 1:1) to obtain compound 7-c.

[0217] Step D: At 20°C, hydrochloric acid (4M, 3.82mL, 10eq) was added to a 1,4-dioxane (4mL) solution of 7-c (575.11mg, 1.53mmol, 1eq), the reaction mixture was stirred at 40°C for 16 hours, water (40mL) was added to the reaction mixture, then a saturated sodium bicarbonate aqueous solution was added to adjust the pH to about 7, the mixture was extracted with EA (40mL×2), the combined organic phase was washed with saturated saline (40mL), dried with anhydrous sodium sulfate, filtered and concentrated, MeOH (4mL) was added to the residue, stirred for 15 minutes and filtered, and the cake was dried under high vacuum to obtain compound 7. 1 1 H NMR (DMSO- d 6 , 400 MHz) δ ppm 9.51 (br s, 1H), 7.48 - 7.37 (m, 2H), 7.36 - 7.27 (m, 2H), 6.95 (br d, J =5.1 Hz, 1H), 4.63 (br t, J =6.7 Hz, 1H), 4.41 (s, 1H), 1.90 - 1.80 (m, 4H), 1.72 - 1.64 (m, 4H), 1.42 (d, J =6.8 Hz, 3H);LCMS(ESI) m / z: 318.8(M+1).

[0218] Example 8

[0219]

[0220] Synthesis path:

[0221]

[0222] Step A: LDA (2M, 49.32 mL, 1.2 eq) was added to a THF (200 mL) solution of compound 8-1 (20 g, 82.20 mmol, 1 eq) at -78 °C under the protection of nitrogen gas, and the reaction mixture was stirred at -78 °C for 1 hour, then methyl chloroformate (8.54 g, 90.42 mmol, 7.00 mL, 1.1 eq) was added, the reaction mixture was slowly heated to 20 °C and stirred for 4 hours, then saturated ammonium chloride aqueous solution (600 mL) was added and quenched, then extracted with EA (600 mL), the organic phase was washed with saturated saline (200 mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 8-a.

[0223] Step B: Sodium hydroxide (3.58 g, 89.60 mmol, 1 eq) was added to a solution of compound 8-a (27 g, 89.60 mmol, 1 eq) in MeOH (200 mL) and water (200 mL), the reaction mixture was stirred at 15°C for 16 hours, water (200 mL) was added, then extracted with EA (200 mL), separated, and the aqueous phase was adjusted to a pH of about 5 with 1 M dilute hydrochloric acid, then extracted with EA (300 mL × 2), the combined organic phase was washed with saturated saline (200 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 8-b.

[0224] Step C: Under the protection of nitrogen gas at 0°C, TEA (32.40g, 320.21mmol, 44.57mL, 4eq) and DMF (292.56mg, 4.00mmol, 307.95μL, 0.05eq) were added to a DCM (200mL) solution of compound 8-b (23g, 80.05mmol, 1eq), then oxalyl chloride (13.21g, 104.07mmol, 9.11mL, 1.3eq) was added, and the reaction mixture was stirred at 10°C for 1 hour and then concentrated to obtain compound 8-c.

[0225] Step D: Under the protection of nitrogen gas at 0°C, TEA (23.83 g, 235.47 mmol, 32.78 mL, 3 eq) was added to a DCM (200 mL) solution of compound 1-a (23.38 g), then a DCM (200 mL) solution of compound 8-c (24 g, 78.49 mmol, 1 eq) was added, the reaction mixture was stirred at 10°C for 16 hours, then concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to obtain compound 8-d.

[0226] Step E: Under the protection of nitrogen gas, sodium methoxide (1M, 130mL, 4.89eq) was added to a 130mL solution of MeOH of compound 8-d (13.4g, 26.61mmol, 1eq), the reaction mixture was stirred at 50°C for 3 hours, then concentrated, the residue was adjusted to pH 5 to 6 with 1M dilute hydrochloric acid, extracted with EA (200mL×2), the combined organic phase was washed with saturated saline (200mL×2), dried with anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to obtain compound 8-e.

[0227] Step F: Hydrochloric acid (4M, 150mL, 36.60eq) was added to a 1,4-dioxane (150mL) solution of 8-e (7.5g, 16.39mmol, 1eq), the reaction mixture was stirred at 80°C for 16 hours, and after cooling, the pH of the reaction mixture was adjusted to 8 to 9 with a 2N aqueous sodium hydroxide solution, then extracted with EA / iPrOH=7:1 (200mL×4), the combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 8-f.

[0228] Step G: Under the protection of nitrogen gas at 0°C, DIEA (194.27 mg, 1.50 mmol, 261.83 μL, 3 eq) was added to a DCM (3 mL) solution of compound 8-f (0.15 g, 501.06 μmol, 1 eq), then a DCM (1 mL) solution of methyl chloroformate (49.72 mg, 526.11 μmol, 40.75 μL, 1.05 eq) was added, the reaction mixture was stirred at 0°C for 1 hour, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.05% ammonia solution)-ACN; gradient: 15% to 45% ACN] to obtain compound 8. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 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 = 6.8 Hz, 3H); LCMS (ESI) m / z: 358.2 (M+1).

[0229] Example 9

[0230]

[0231] Synthesis path:

[0232]

[0233] Step A: Under the protection of nitrogen gas, cesium carbonate (35.38 g, 108.59 mmol, 1.5 eq) was added to a 200 mL solution of DCM containing 9-1 (10 g, 72.39 mmol, 1 eq) and 9-2 (9.21 g, 76.01 mmol, 1.05 eq), the reaction mixture was stirred at 15°C for 16 hours, then filtered, and the filtrate was concentrated to obtain compound 9-a.

[0234] Step B: Under the protection of nitrogen gas at -78°C, methyl magnesium bromide (3M, 24.86 mL, 2 eq) was slowly added to a THF (100 mL) solution of 9-a (9 g, 37.29 mmol, 1 eq), and the reaction mixture was stirred at -78°C for 1 hour. Then, the reaction mixture was slowly added dropwise to a saturated aqueous ammonium chloride solution (800 mL), extracted with EA (200 mL × 2), the combined organic phase was washed with saturated saline (100 mL × 3), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain compound 9-b.

[0235] Step C: HCl / MeOH (4M, 100mL, 8.58eq) was added to a 100mL MeOH solution of 9-b (12g, 46.63mmol, 1eq), the reaction mixture was stirred at 20°C for 2 hours, and after concentration, the hydrochloride of compound 9-c was obtained.

[0236] Step D: 1-1 (9.58 g, 48.96 mmol, 1 eq, HCl) and DIEA (25.31 g, 195.83 mmol, 34.11 mL, 4 eq) were added to an EtOH (100 mL) solution of 9-c hydrochloride (7.5 g), the reaction mixture was stirred at 20°C for 16 hours, and after concentration, compound 9-d was obtained.

[0237] Step E: Boc2O (18.44g, 84.49mmol, 19.41mL, 1.5eq) and TEA (17.10g, 168.98mmol, 23.52mL, 3eq) were added to a DCM (150mL) solution of 9-d (15g, 56.33mmol, 1eq), the reaction mixture was stirred at 15°C for 16 hours, then concentrated under reduced pressure, and the residue was separated by column chromatography (PE:EtOAc=15:1) to obtain compound 9-e.

[0238] Step F: HCl / EtOAc (4M, 51.61 mL, 9.46 eq) was added to a 50 mL solution of EtOAc (8.00 g, 21.83 mmol, 1 eq) of 9-e, the reaction mixture was stirred at 20°C for 16 hours, and after concentrating the reaction mixture, the hydrochloride of compound 9-d was obtained.

[0239] Step G: TEA (10.03 g, 99.13 mmol, 13.80 mL, 3 eq) and 3-c (2.83 g, 12.07 mmol, 1 eq) were added to a DCM (60 mL) solution of 9-d hydrochloride (8.80 g) at -20 °C under the protection of nitrogen gas, the reaction mixture was stirred at -20 °C for 1 hour, then raised to 20 °C and stirred for 15 hours, after which the mixture was concentrated, and the residue was separated by column chromatography (PE:EtOAc = 30:1 to 10:1) to obtain compound 9-f.

[0240] Step H: Under the protection of nitrogen gas, sodium methoxide (1M, 41.62mL, 5eq) was added to a 40mL solution of MeOH (9-f, 3.5g, 8.32mmol, 1eq), the reaction mixture was stirred at 50°C for 16 hours, 1N dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, then EA (100mL×2) was added for extraction, the combined organic phase was washed with saturated saline (50mL×2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 9-g.

[0241] Step J: Hydrochloric acid (4M, 60mL, 29.95eq) was added to a 9-g (3g, 8.01mmol, 1eq) solution of 1,4-dioxane (60mL), and the reaction mixture was stirred at 70°C for 16 hours. Then, the pH was adjusted to 8 to 9 with a 2N aqueous sodium hydroxide solution and filtered. The cake was first separated by silica gel column chromatography (DCM:MeOH = 1:0 to 10:1), then MTBE (50mL) was added and stirred for 1 hour and filtered. The cake was dried under high vacuum to obtain compound 9. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 9.52 (br s, 1 H) 7.19 (br d, J =7.5 Hz, 1 H) 7.06 - 7.15 (m, 2 H) 6.91 (br d, J =6.8 Hz, 1 H) 4.66 - 4.76 (m, 1 H) 4.40 (s, 1 H) 2.28 (s, 3 H) 1.81 - 1.90 (m, 4 H) 1.64 - 1.72 (m, 4 H) 1.45 (d, J =6.8 Hz, 3 H);LCMS(ESI) m / z: 317.2(M+1).

[0242] Example 10

[0243]

[0244] Synthesis path:

[0245]

[0246] Step A: 10-2 (4.66 g, 38.43 mmol, 1.2 eq) and tetraethyl titanate (21.92 g, 96.07 mmol, 19.92 mL, 3 eq) were added to a 50 mL THF solution of 10-1 (5 g, 32.02 mmol, 4.07 mL, 1 eq) at 20 °C, the reaction mixture was stirred at 60 °C for 16 hours, ethyl acetate (100 mL) was added to the reaction mixture, the mixture was cooled to 0 °C, water (20 mL) was slowly added, the mixture was stirred for 0.5 hours and filtered, the filtrate was washed with saturated saline (50 mL × 3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10-a.

[0247] Step B: Under the protection of nitrogen gas at -78°C, L-selectride (1M, 41.65 mL, 1.2 eq) was slowly added dropwise to a THF (100 mL) solution of 10-a (9 g, 34.71 mmol, 1 eq), and the reaction mixture was stirred at -78°C for 2 hours. Then, the reaction mixture was slowly added to a saturated aqueous ammonium chloride solution (100 mL), extracted with EA (100 mL × 2), the combined organic phase was washed with saturated saline (100 mL × 3), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 5:1 to 3:1) to obtain compound 10-b.

[0248] Step C: HCl / MeOH (200 mmol, 50 mL, 7.92 eq) was added to a 50 mL MeOH solution of 10-b (6.6 g) at 20 °C, and the reaction mixture was stirred for 16 hours and then concentrated to obtain the hydrochloride of compound 10-c.

[0249] Step D: 1-1 (1.51 g, 7.74 mmol, 1.5 eq, HCl) and DIEA (4.00 g, 30.96 mmol, 5.40 mL, 6 eq) were added to an EtOH (100 mL) solution of 10-c hydrochloride (1 g) at 20°C, the reaction mixture was stirred at 20°C for 16 hours, and after concentration, compound 10-d was obtained.

[0250] Step E: Under the protection of nitrogen gas at -20°C, TEA (2.45g, 24.24mmol, 3.37mL, 3eq) was added to a DCM (15mL) solution of 10-d (1.54g, 8.08mmol, 1eq), then a DCM (15mL) solution of 3-c (1.39g, 5.14mmol, 6.37e-1eq) was added, the reaction mixture was stirred at 20°C for 16 hours, then concentrated, the residue was diluted by adding EA (30mL), washed with saturated saline (30mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 10:1 to 5:1) to obtain compound 10-e.

[0251] Step F: Under the protection of nitrogen gas, sodium methoxide (1M, 6.43mL, 1eq) was added to a 7.6mL MeOH solution of 10-e (0.648g, 1.53mmol, 1eq), the reaction mixture was stirred at 20°C for 16 hours, 1M dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, then EA (20mL) was added for extraction, the organic phase was washed with saturated saline (20mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10-f.

[0252] Step G: Hydrochloric acid (4M, 4mL, 17.40eq) was added to a solution of 1,4-dioxane (4mL) of 10-f (348mg, 919.74μmol, 1eq), the reaction mixture was stirred at 50°C for 16 hours, EA (30mL) was added to the reaction mixture, the pH was adjusted to about 8 with a 1M aqueous sodium hydroxide solution, the organic phase was washed with saturated saline (50mL×2), dried with anhydrous sodium sulfate, filtered and concentrated, MeOH (10mL) was added to the residue and stirred for 20 minutes and filtered, the cake was dried under high vacuum to obtain compound 10. 1 1 H NMR (DMSO- d 6, 400 MHz): δ ppm 9.60 - 9.47 (m, 1H), 7.34 - 7.26 (m, 2H), 7.25 - 7.16 (m, 1H), 6.96 (br d, J = 6.0 Hz, 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 = 6.4 Hz, 3H); LCMS (ESI) m / z: 321.2 (M+1).

[0253] Example 11

[0254]

[0255] Synthesis path:

[0256] Step A: 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) were added to a 15 mL EtOH solution of 11-1 (1 g, 7.40 mmol, 1.06 mL, 1 eq) at 20 °C, the reaction mixture was stirred at 20 °C for 12 hours, and after concentration, compound 11-a was obtained.

[0257] Step B: Under the protection of nitrogen gas at -20°C, TEA (4.32g, 42.65mmol, 5.94mL, 3eq) was added to a DCM (15mL) solution of 11-a (2.44g, 9.83mmol, 6.91e-1eq), then a DCM (15mL) solution of 3-c (2.71g, 14.22mmol, 6.37e-1eq) was added, the reaction mixture was stirred and concentrated at 20°C for 16 hours, the residue was diluted by adding EA (30mL), washed with saturated saline (30mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 10:1 to 8:1) to obtain compound 11-b.

[0258] Step C: Under the protection of nitrogen gas, sodium methoxide (1M, 7.37mL, 5eq) was added to a 9.2mL MeOH solution of 11-b (0.743g, 1.47mmol, 1eq), the reaction mixture was stirred at 20°C for 16 hours, 1M dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, then EA (20mL×3) was added for extraction, the combined organic phase was washed with saturated saline (20mL×3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11-c.

[0259] Step D: Hydrochloric acid (4M, 4mL, 17.40eq) was added to a 1,4-dioxane (4mL) solution of 11-c (399mg, 1.12mmol, 1eq), and the reaction mixture was stirred at 50°C for 16 hours, then diluted by adding EA (3mL), then adjusted the pH to about 8 with a 2M aqueous sodium hydroxide solution and filtered, then added MeOH (10mL) to the cake and stirred for 1 hour and filtered, and the cake was dried under high vacuum to obtain compound 11. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 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 = 7.2 Hz, 3H);LCMS(ESI) m / z: 299.1(M+1).

[0260] Example 12

[0261]

[0262] Synthesis path:

[0263]

[0264] Step A: 10-2 (17.08g, 140.91mmol, 2.2eq) and tetraethyl titanate (43.83g, 192.15mmol, 39.85mL, 3eq) were added to a 100mL THF solution of 12-1 (10g, 64.05mmol, 8.33mL, 1eq) at 20℃, the reaction mixture was stirred at 60℃ for 16 hours, cooled to 0℃, EA (100mL) was added to the reaction mixture, water (30mL) was slowly added, stirred for 0.5 hours, filtered, the filtrate was washed with saturated saline (30mL×3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 12-a.

[0265] Step B: L-selectride (1M, 25.21 mL, 1.2 eq) was slowly added dropwise to a THF (50 mL) solution of 12-a (5.45 g, 21.01 mmol, 1 eq) under the protection of nitrogen gas at -78 °C, the reaction mixture was stirred at 20 °C for 2 hours, the reaction mixture was slowly added to a saturated aqueous ammonium chloride solution (40 mL) at 0 °C, extracted with EA (30 mL × 2), the combined organic phase was washed with saturated saline (30 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 8:1 to 1:1) to obtain compound 12-b.

[0266] Step C: HCl / MeOH (4M, 30mL, 10.00eq) was added to a 30mL MeOH solution of 12-b (3.14g, 12.00mmol, 1eq) at 20℃, the reaction mixture was stirred for 16 hours and then concentrated, EA (20ml) was added to the residue and stirred for 0.5 hours, then filtered, and the cake was dried under high vacuum to obtain the hydrochloride of compound 12-c.

[0267] Step D: 1-1 (1.87 g, 11.72 mmol, 1 eq) and DIEA (4.54 g, 35.16 mmol, 6.12 mL, 3 eq) were added to an EtOH (20 mL) solution of 12-c hydrochloride (1.84 g) at 20°C under the protection of nitrogen gas, the reaction mixture was stirred at 20°C for 12 hours, and after concentration, compound 12-d was obtained.

[0268] Step E: Under the protection of nitrogen gas, 3-b (5.80 g, 33.71 mmol, 1 eq) and DIEA (6.53 g, 50.56 mmol, 8.81 mL, 1.5 eq) were added to a 50 mL THF solution of 12-d (9.11 g, 33.71 mmol, 1 eq), followed by the addition of 12-2 (12.92 g, 50.56 mmol, 1.5 eq). The reaction mixture was stirred at 20 °C for 1 hour, then concentrated. The residue was diluted with water (50 mL), extracted with EA (20 mL × 3), the combined organic phase was washed with saturated saline (20 mL × 3), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was then subjected to silica gel column chromatography. Compound 12-e was obtained by separation (PE:EtOAc=10:1).

[0269] Step F: Under the protection of nitrogen gas, sodium methoxide (1M, 44.56mL, 5eq) was added to a MeOH (44.56mL) solution of 12-e (3.78g, 8.91mmol, 1eq), the reaction mixture was stirred at 50°C for 16 hours, 1M dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, then EA (50mL×2) was added for extraction, the combined organic phase was washed with saturated saline (50mL×2), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc=5:1 to 2:1) to obtain compound 12-f.

[0270] Step G: Hydrochloric acid (4M, 3.91mL, 15.21eq) was added to a 1,4-dioxane (4mL) solution of 12-f (389mg, 1.03mmol, 1eq), the reaction mixture was stirred at 60°C for 16 hours, a 2M aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH to about 8 and filtered, MTBE (5mL) was added to the cake and stirred for 1 hour and filtered, and the cake was dried to obtain compound 12. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 9.52 (br s, 1H), 7.47 - 7.35 (m, 1H), 7.14 (br t, J = 8.8 Hz, 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 = 6.8 Hz, 3H); LCMS (ESI) m / z: 321.1 (M+1).

[0271] Example 13

[0272]

[0273] Synthesis path:

[0274]

[0275] Step A: 10-2 (4.66 g, 38.43 mmol, 2 eq) and tetraethyl titanate (13.15 g, 57.64 mmol, 11.95 mL, 3 eq) were added to a 30 mL THF solution of 13-1 (3 g, 19.21 mmol, 2.42 mL, 1 eq) at 20 °C, the reaction mixture was stirred at 60 °C for 16 hours, EA (60 mL) was added to the reaction mixture, cooled to 0 °C, water (10 mL) was slowly added, stirred for 0.5 hours, filtered, the filtrate was washed with saturated saline (30 mL × 3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13-a.

[0276] Step B: L-selectride (1M, 13.88 mL, 1.2 eq) was slowly added dropwise to a THF (20 mL) solution of 13-a (3 g, 11.57 mmol, 1 eq) under the protection of nitrogen gas at -78°C, the reaction mixture was stirred at -78°C for 2 hours, the reaction mixture was slowly added to a saturated aqueous ammonium chloride solution (20 mL) at 0°C, extracted with EA (20 mL × 2), the combined organic phase was washed with saturated saline (20 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 5:1 to 2:1) to obtain compound 13-b.

[0277] Step C: HCl / MeOH (4M, 15mL, 12.48eq) was added to a 15mL MeOH solution of 13-b (1.26g, 4.81mmol, 1eq), the reaction mixture was stirred at 20°C for 16 hours, then concentrated, EA (20mL) was added to the residue, stirred for 0.5 hours, filtered, and the cake was dried under high vacuum to obtain the hydrochloride of compound 13-c.

[0278] Step D: 1-1 (560.12 mg, 3.52 mmol, 1 eq) and DIEA (1.36 g, 10.56 mmol, 1.84 mL, 3 eq) were added to an EtOH (5 mL) solution of 13-c hydrochloride (0.553 g) at 20°C under the protection of nitrogen gas, the reaction mixture was stirred at 20°C for 12 hours, and after concentration, compound 13-d was obtained.

[0279] Step E: Under the protection of nitrogen gas at -20°C, TEA (1.67 g, 16.52 mmol, 2.30 mL, 3 eq) was added to a DCM (15 mL) solution of 3-c (1.05 g, 5.51 mmol, 1 eq), then 13-d (950.02 mg, 3.52 mmol) was added, the reaction mixture was stirred at 20°C for 16 hours, then concentrated, the residue was diluted by adding water (50 mL), then extracted with EA (20 mL × 3), the combined organic phase was washed with saturated saline (20 mL × 3), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 8:1 to 1:1) to obtain compound 13-e.

[0280] Step F: Under the protection of nitrogen gas, sodium methoxide (1M, 5.69mL, 5eq) was added to a 5mL solution of 13-e (483mg, 1.14mmol, 1eq) in MeOH, the reaction mixture was stirred at 50°C for 16 hours, 1M dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, then EA (30mL×2) was added for extraction, the combined organic phase was washed with saturated saline (30mL×2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13-f.

[0281] Step G: Hydrochloric acid (4M, 2mL, 25.87eq) was added to a solution of 1,4-dioxane (2mL) of 13-f (117mg, 309.22μmol, 1eq), the reaction mixture was stirred at 60°C for 16 hours, a 2M aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH to about 8 and filtered, MTBE (10mL) was added to the cake and stirred for 1 hour and filtered, and the cake was dried to obtain compound 13. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 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 = 6.1 Hz, 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 = 6.7 Hz, 3H); LCMS (ESI) m / z: 321.1 (M+1).

[0282] Example 14

[0283]

[0284] Synthesis path:

[0285]

[0286] Step A: 1-1 (915.04 mg, 5.75 mmol, 1 eq) and DIEA (1.49 g, 11.50 mmol, 2.00 mL, 2 eq) were added to a 10 mL EtOH solution of 14-1 (0.8 g, 5.75 mmol, 1 eq) at 20 °C, the reaction mixture was stirred at 25 °C for 16 hours, and after concentration, compound 14-a was obtained.

[0287] Step B: Add DIEA (673.77 mg, 5.21 mmol, 908.04 μL, 1.5 eq) to a THF (10 mL) solution of 14-a (1 g, 3.48 mmol, 87.68% purity, 1 eq), then add 12-2 (1.33 g, 5.21 mmol, 1.5 eq) and 3-b (598.40 mg, 3.48 mmol, 1 eq), stir the reaction mixture at 25°C for 0.5 hours and concentrate, add water (50 mL) to the residue, extract with EA (20 mL × 3), wash the combined organic phase with saturated saline (20 mL × 2), dry with anhydrous sodium sulfate, filter and concentrate, and the residue is subjected to column chromatography Compound 14-b was obtained by separation (PE:EtOAc=10:1).

[0288] Step C: Under the protection of nitrogen gas, sodium methoxide (1M, 2.84mL, 5eq) was added to a 5mL MeOH solution of 14-b (231mg, 568.34μmol, 1eq), the reaction mixture was stirred at 50°C for 16 hours, 1M dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, then water (20mL) was added to dilute, then extracted with EA (10mL×3), the combined organic phase was washed with saturated saline (10mL×2), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 14-c.

[0289] Step D: Hydrochloric acid (4M, 8.29mL, 76.4eq) was added to a solution of 1,4-dioxane (8.29mL) of 14-c (170mg, 433.99μmol, 92% purity, 1eq), the reaction mixture was stirred at 50°C for 16 hours, a 1M aqueous sodium hydroxide solution was added to adjust the pH to about 9, the mixture was extracted with EA (5mL×4), the combined organic phase was washed with saturated saline (10mL×2), dried with anhydrous sodium sulfate, filtered and concentrated, MTBE (5mL) was added to the residue and stirred for 2 hours and filtered, and the cake was dried to obtain compound 14. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 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 = 6.8 Hz, 3H); LCMS (ESI) m / z: 303.2 (M+1).

[0290] Example 15

[0291]

[0292] Synthesis path:

[0293]

[0294] Step A: Add 10-2 (927.16 mg, 7.64 mmol, 1.2 eq) and tetraethyl titanate (4.36 g, 19.11 mmol, 3.97 mL, 3 eq) to a 10 mL THF solution (15-1) (1 g, 6.37 mmol, 99.53% purity, 1 eq) at 20 °C, stir the reaction mixture at 50 °C for 16 hours, add 10-2 (386.02 mg, 3.19 mmol, 0.5 eq) to the reaction mixture and continue stirring at 50 °C for 1.5 hours, cool to 0 °C, dilute the reaction mixture by adding ethyl acetate (30 mL), slowly add water (20 mL), stir for 0.5 hours, filter, and the filtrate to saturated saline solution (10 mL × 2) Compound 15-a was obtained by washing, drying with anhydrous sodium sulfate, filtering, and concentrating.

[0295] Step B: Under the protection of nitrogen gas at -78°C, L-selectride (1M, 4.40 mL, 1.2 eq) was slowly added dropwise to a THF (10 mL) solution of 15-a (950 mg, 3.66 mmol, 1 eq), the reaction mixture was stirred at -78°C for 2 hours, the reaction mixture was slowly added to a saturated ammonium chloride aqueous solution (15 mL) at 0°C, diluted with water (30 mL), extracted with ethyl acetate (10 mL × 3), the combined organic phase was washed with saturated saline (15 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=5:1) to obtain compound 15-b.

[0296] Step C: HCl / MeOH (4M, 1.10mL, 1eq) was added to a 10mL MeOH solution of 15-b (1.15g, 4.39mmol, 1eq) at 20℃, the reaction mixture was stirred at 20℃ for 16 hours, and after concentration, the hydrochloride of compound 15-c was obtained.

[0297] Step D: 1-1 (898.41 mg, 4.59 mmol, 8.14 e-1 eq, HCl) and DIEA (2.92 g, 22.58 mmol, 3.93 mL, 4 eq) were added to an EtOH (10 mL) solution of 15-c hydrochloride (0.887 g) at 20°C under the protection of nitrogen gas, the reaction mixture was stirred at 20°C for 16 hours, and after concentration, compound 15-d was obtained.

[0298] Step E: Under the protection of nitrogen gas, 3-b (1.47 g, 8.51 mmol, 1 eq) and DIEA (1.65 g, 12.76 mmol, 2.22 mL, 1.5 eq) were added to a 15-d (2.3 g, 8.51 mmol, 1 eq) solution of THF (25 mL), followed by the addition of 12-2 (3.26 g, 12.76 mmol, 1.5 eq). The reaction mixture was stirred at 20°C for 32 hours, then concentrated. The residue was diluted with water (50 mL), extracted with EA (10 mL × 4), the combined organic phase was washed with saturated saline (15 mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 20:1) to obtain the compound 15-e was obtained.

[0299] Step F: Under the protection of nitrogen gas, sodium methoxide (1M, 3mL, 4.90eq) was added to a 3mL solution of 15-e (260mg, 612.58μmol, 1eq) in MeOH, the reaction mixture was stirred at 50°C for 16 hours, 1M dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5, water (10mL) was added, and the mixture was extracted with EA (5mL×4), the combined organic phase was washed with saturated saline (10mL×2), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by thin-layer chromatography (PE:EtOAc=20:1) to obtain compound 15-f.

[0300] Step G: Hydrochloric acid (4M, 2mL, 50.45eq) was added to a 1,4-dioxane (2mL) solution of 15-f (60mg, 158.58μmol, 1eq), the reaction mixture was stirred at 60°C for 19 hours, a 1M aqueous sodium hydroxide solution was added to the reaction mixture to adjust the pH to about 9 and filtered, MTBE (2mL) was added to the cake and stirred for 2 hours and filtered, and the cake was dried to obtain compound 15. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 9.55 (m, 1H), 7.41 - 7.33 (m, 1H), 7.28 - 7.20 (m, 2H), 7.01 (br d, J = 4.6 Hz, 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 = 6.8 Hz, 3H); LCMS (ESI) m / z: 321.2 (M+1).

[0301] Example 16

[0302]

[0303] Synthesis path:

[0304]

[0305] Step A: Under the protection of nitrogen gas, cesium carbonate (27.13 g, 83.26 mmol, 2.2 eq) was added to a DMF (50 mL) solution of compound 3-1 (5 g, 37.85 mmol, 4.35 mL, 1 eq) and ethyl iodide (12.99 g, 83.26 mmol, 6.66 mL, 2.2 eq), the reaction mixture was stirred at 20°C for 16 hours, water (200 mL) was added, then extracted with EA (200 mL), then the organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 16-a.

[0306] Step B: Sodium hydroxide (1.64 g, 40.91 mmol, 1.1 eq) was added to a solution of compound 16-a (7 g, 37.19 mmol, 1 eq) in MeOH (40 mL) and water (40 mL), the reaction mixture was stirred at 20°C for 16 hours, then concentrated, water (100 mL) was added to the residue, then extracted with MTBE (100 mL), separated, the aqueous phase was adjusted to a pH of about 5 with 1 M dilute hydrochloric acid, then extracted with EA (100 mL), the organic phase was washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 16-b.

[0307] Step C: N-methylimidazole (1.82 g, 22.20 mmol, 1.77 mL, 5 eq) and TCFH (2.49 g, 8.88 mmol, 2 eq) were added to an ACN (20 mL) solution of compounds 12-d (1.2 g, 4.44 mmol, 1 eq) and 16-b (928.09 mg, 5.33 mmol, 1.2 eq) under the protection of nitrogen gas at 0°C, the reaction mixture was stirred at 0°C for 1 hour, then concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 1:0 to 10:1) to obtain compound 16-c.

[0308] Step D: Under the protection of nitrogen gas, sodium tert-butoxide (1.75 g, 18.17 mmol, 5 eq) was added to a 20 mL MeOH solution of compound 16-c (1.55 g, 3.63 mmol, 1 eq), the reaction mixture was stirred at 20 °C for 16 hours, the reaction mixture was poured into 1 N dilute hydrochloric acid (20 mL) and concentrated, water (30 mL) was added to the residue and extracted with EA (30 mL), the organic phase was washed with saturated saline (30 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain compound 16-d.

[0309] Step E: Hydrochloric acid (4M, 5mL, 50.72eq) was added to a 1,4-dioxane (5mL) solution of compound 16-d (0.15g, 394.34μmol, 1eq), the reaction mixture was stirred at 50°C for 16 hours, a 1N sodium hydroxide aqueous solution was added to the reaction mixture to adjust the pH to about 7, then concentrated to remove 1,4-dioxane, MTBE (20mL) was added to the residue and filtered, and the cake was dried under high vacuum to obtain compound 16. 1 1 H NMR (DMSO- d 6 , 400 MHz): δ ppm 9.69 (br s, 1H), 7.45 - 7.37 (m, 1H), 7.14 (t, J = 8.5 Hz, 2H), 6.94 (br d, J = 7.6 Hz, 1H), 4.88 (br t, J = 6.8 Hz, 1H), 4.58 (s, 1H), 1.76 - 1.50 (m, 7H), 0.65 (t, J = 7.3 Hz, 3H), 0.48 (t, J = 7.3 Hz, 3H);LCMS(ESI) m / z: 323.4(M+1).

[0310] Example 17

[0311]

[0312] Synthesis path:

[0313]

[0314] Step A: N-methylimidazole (546.80 mg, 6.66 mmol, 530.88 μL, 5 eq) and TCFH (747.45 mg, 2.66 mmol, 2 eq) were added to an ACN (10 mL) solution of compounds 2-b (325.84 mg, 1.73 mmol, 1 eq) and 10-d (0.36 g, 1.33 mmol, 1 eq) under the protection of nitrogen gas at 0°C, the reaction mixture was stirred at 20°C for 2 hours, then concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to obtain compound 17-a.

[0315] Step B: Under the protection of nitrogen gas, sodium tert-butoxide (370.94 mg, 3.86 mmol, 5 eq) was added to a 5 mL MeOH solution of compound 17-a (0.34 g, 771.96 μmol, 1 eq), the reaction mixture was stirred at 20°C for 16 hours, 1 N dilute hydrochloric acid (20 mL) was added to the reaction mixture to adjust the pH to about 5 and concentrated, water (10 mL) was added to the residue and extracted with EA (10 mL), the organic phase was washed with saturated saline (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 2:1) to obtain compound 17-b.

[0316] Step C: Under the protection of nitrogen gas, hydrochloric acid (4M, 5mL, 52.58eq) was added to a 1,4-dioxane (5mL) solution of compound 17-b (0.15g, 380.35μmol, 1eq), the reaction mixture was stirred at 50°C for 20 hours, an aqueous solution of saturated sodium bicarbonate was added to the reaction mixture to adjust the pH to about 7, then concentrated to remove 1,4-dioxane, water (10mL) and MTBE (20mL) were added to the residue, stirred for 30 minutes, filtered, and the cake was dried under high vacuum to obtain compound 17. 1 1 H NMR (DMSO- d 6, 400 MHz): δ ppm 9.67 (br s, 1H), 7.34 - 7.25 (m, 2H), 7.20 (dt, J = 4.1, 8.1 Hz, 1H), 7.07 (br d, J = 5.9 Hz, 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 = 6.8 Hz, 3H);LCMS(ESI) m / z: 337.3(M+1).

[0317] Example 18

[0318]

[0319] Synthesis path:

[0320]

[0321] Step A: 10-2 (5.81 g, 47.91 mmol, 1.2 eq) and tetraethyl titanate (27.32 g, 119.77 mmol, 24.84 mL, 3 eq) were added to a 70 mL THF solution of 18-1 (6.89 g, 39.92 mmol, 1 eq) at 20 °C, the reaction mixture was stirred at 60 °C for 16 hours, ethyl acetate (100 mL) was added to the reaction mixture, cooled to 0 °C, water (20 mL) was slowly added, stirred for 0.5 hours, and filtered, the filtrate was washed with saturated saline (50 mL × 3), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 18-a.

[0322] Step B: L-selectride (1M, 25.75 mL, 1 eq) was slowly added dropwise to a THF (100 mL) solution of 18-a (7.1 g, 25.75 mmol, 1 eq) at -78 °C under the protection of nitrogen gas, the reaction mixture was slowly heated to 0 °C and stirred for 1 hour, 0.5 N dilute hydrochloric acid (100 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL), the organic phase was washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain compound 18-b.

[0323] Step C: An HCl / MeOH (4M, 25mL, 13.89eq) solution was added to 18-b (2g, 7.20mmol, 1eq), the reaction mixture was stirred at 50°C for 1 hour, and then concentrated to obtain the hydrochloride of compound 18-c.

[0324] Step D: Under the protection of nitrogen gas at 20°C, 1-1 (2.05g, 10.47 mmol, 1.1 eq, HCl) and DIEA (3.69g, 28.56 mmol, 4.97 mL, 3 eq) were added to an EtOH (30 mL) solution of 18-c hydrochloride (2g), and the reaction mixture was stirred at 20°C for 16 hours, then concentrated, water (50 mL) was added to the residue, the pH was adjusted to about 5 with acetic acid, extracted with EA (50 mL), separated, the aqueous phase was adjusted to about 9 with a saturated sodium bicarbonate solution, extracted with EA (50 mL × 2), the combined organic phase was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 18-d.

[0325] Step E: Under the protection of nitrogen gas at 0°C, N-methylimidazole (1.72g, 20.93mmol, 1.67mL, 5eq) and TCFH (2.35g, 8.37mmol, 2eq) were added to an ACN (10mL) solution of compounds 2-b (1.02g, 5.44mmol, 1.3eq) and 18-d (1.2g, 4.19mmol, 1eq), the reaction mixture was stirred at 20°C for 1 hour, then concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 5:1) to obtain compound 18-e.

[0326] Step F: Under the protection of nitrogen gas, sodium tert-butoxide (1.01 g, 10.51 mmol, 4 eq) was added to a 10 mL MeOH solution of compound 18-e (1.2 g, 2.63 mmol, 1 eq), the reaction mixture was stirred at 50°C for 1 hour, 1 N dilute hydrochloric acid was added to the reaction mixture to adjust the pH to about 5 and concentrated, water (10 mL) was added to the residue and extracted with EA (10 mL), the organic phase was washed with saturated saline solution (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 2:1) to obtain compound 18-f.

[0327] Step G: Under the protection of nitrogen gas, hydrochloric acid (4M, 15mL, 35.72eq) was added to a 1,4-dioxane (15mL) solution of compound 18-f (0.69g, 1.68mmol, 1eq), the reaction mixture was stirred at 50°C for 16 hours, a 1N sodium hydroxide aqueous solution was added to the reaction mixture to adjust the pH to about 7, then concentrated to remove 1,4-dioxane, water (50mL) and MTBE (50mL) were added to the residue, stirred for 30 minutes, filtered, and the cake was dried under high vacuum to obtain compound 18. 1 1 H NMR (DMSO- d 6, 400 MHz): δ ppm 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, 19.1 Hz, 2H), 1.47 (d, J = 6.7 Hz, 3H);LCMS(ESI) m / z: 353.3(M+1).

[0328] Biological activity test:

[0329] Experimental Example 1: Experiment on the inhibitory effect of cardiac myosin ATPase activity

[0330] Experimental Reagents:

[0331] Cardiac tropomyosin / troponin complex (Cytoskeleton, Cat. # TT05)

[0332] Cardiac myosin S1 (Cytoskeleton, Cat. # MYS03)

[0333] Cardiac actin (Cytoskeleton, Cat. # AD99-A)

[0334] ATPase Analysis Biochemistry Kit (Cytoskeleton, Cat. # BK051)

[0335] Experimental phase:

[0336] 1) Preparation of compounds

[0337] a) The compound was diluted fourfold with eight concentration gradients using DMSO in an echo, and 200 nL of each compound was transferred to a 96-well plate (Corning-3696).

[0338] b) Centrifuge at 1000 rpm for 15 seconds and seal the plate for later use.

[0339] 2) Preparation of F-actin

[0340] a) A buffer solution of 5 mM Pipes-KOH pH 7.0, 500 μM ATP, and 500 μM dithiothreitol was prepared, and 2.5 mL of the buffer solution was added to dissolve 1 mg of F-actin, and the protein concentration was 0.4 mg / mL.

[0341] b) The protein was left at room temperature for 10 minutes to be completely dissolved.

[0342] c) 2.0 mM MgCl2 and 2.0 mM EGTA were added, and the mixture was left at room temperature for 20 minutes to form a protein polymer.

[0343] 3) Preparation of thin filament

[0344] a) 200 μL of ice water was added to dissolve 1 mg of tropomyosin / troponin complex, and the protein concentration was 5 mg / mL.

[0345] b) 1000 μL of F-actin prepared in Step 1 was added and mixed uniformly.

[0346] c) Left at room temperature for 20 minutes.

[0347] d) Centrifuged at 87K xg at 4℃ for 1.5 hours.

[0348] e) A PM12 buffer solution was prepared with 12 mM Pipes-KOH, pH 7.0, and 2 mM MgCl2, and 1200 μL of buffer was added to resuspend the protein.

[0349] 4) Preparation of reaction solution and start of experiment

[0350] a) 250 μL of cold PM12 buffer was added to 250 μg of S1 myosin, and the protein concentration was 1 mg / mL.

[0351] b) To obtain the reaction mixture, the reagents were added sequentially in the following order.

[0352] 400μL of PM12,

[0353] 400μL of 5× MSEG (from the ATPase assay biochemistry kit),

[0354] 1200μL of actin / myocardial tropomyosin / troponin complex,

[0355] 40μL of myosin S1,

[0356] 40μL of 100× PNP (from the ATPase assay biochemistry kit),

[0357] 10.4 μL of 100 mM ATP

[0358] c) 10 μL of 440 μM CaCl2 solution was added to a 96-well plate and preheated in a 37°C incubator.

[0359] d) 100 μL of the reaction mixture was added to a 96-well plate and centrifuged at 1000 rpm for 10 seconds.

[0360] e) Continuous readings were taken at 30-second intervals for 10 minutes on a SpectraMax 340PC, with the device temperature at 37℃ and the wavelength at 360nm.

[0361] Data Analysis:

[0362] Data was analyzed using Prism, and the experimental results are shown in Table 1.

[0363] Table 1 Inhibitory effect of the compound of the present invention on myocardial myosin ATPase activity IC 50 Value test results

[0364]

[0365] conclusion: The compound of the present invention has relatively excellent myocardial myosin ATPase inhibitory activity.

[0366] Experimental Example 2: Evaluation of In vivo Pharmacokinetics in Rats

[0367] Experimental Objective:

[0368] We intend to detect the pharmacokinetic parameters of the compound of the present invention in rats.

[0369] Experimental Plan:

[0370] 1) Experimental drug: Compound of the present invention;

[0371] 2) Experimental animals: Four male SD rats aged 7 to 9 weeks were randomly divided into two groups of two;

[0372] 3) Drug preparation: An appropriate amount of drug was weighed and dissolved in a mixed solvent of DMAC:PEG-400:30% 2-HP-β-CD=5:25:70 to prepare 0.2 mg / mL;

[0373] Experimental manipulation:

[0374] A single injection of a drug with a dose of 0.2 mg / kg and a concentration of 0.2 mg / mL was administered to animals in Group 1 via tail vein, and a compound with a dose of 1 mg / kg and a concentration of 0.2 mg / mL was administered to animals in Group 2 via gastric administration. Plasma samples were collected from the animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.

[0375] Data Analysis:

[0376] Drug concentrations in plasma samples were measured using the LC-MS / MS method, and the results of the pharmacokinetic tests of the obtained test drugs are shown in Table 2.

[0377] Table 2 Results of pharmacokinetic tests of the compounds of the present invention

[0378]

[0379]

[0380] -- indicates that it does not exist.

[0381] Conclusion: The compound of the present invention has good pharmacokinetic properties in rats.

Claims

Claim 1 Compound represented by formula (I) or a pharmaceutically acceptable salt thereof: In the above formula, R1 and R2 are C along with the carbon atoms connected to them. 3-6 Forming a cycloalkyl group; R3 is selected from H and F; R4 is selected from H and C 1-4 Selected from alkyl; R5 is H and C 1-4 Selected from alkyls; R6 are each independently H, F, Cl, Br, I, and C 1-4 Selected from alkyl; n is selected from 1, 2, 3 or 4. Claim 2 In paragraph 1, R1 and R2 together with carbon atoms connected thereto or A compound forming or a pharmaceutically acceptable salt thereof. Claim 3 In paragraph 1, R3 is a compound selected from H or a pharmaceutically acceptable salt thereof. Claim 4 In claim 1, R4 is a compound selected from -CH3 and -CH2CH3 or a pharmaceutically acceptable salt thereof. Claim 5 In paragraph 1, R5 is a compound selected from H or a pharmaceutically acceptable salt thereof. Claim 6 In claim 1, R6 is a compound independently selected from H, F, Cl, and -CH3 or a pharmaceutically acceptable salt thereof. Claim 7 In claim 1, the compound has a structure represented by formula (I-1), In the above formula, n, R1, R2, R3, R4, and R6 are compounds as defined in claim 1 or pharmaceutically acceptable salts thereof. Claim 8 In paragraph 7, the compound has a structure represented by formula (I-1A) or formula (I-1B), or In the above formula, n, R1, R2, R3, R4, and R6 are as defined in Clause 7, and R4 is a compound other than H or a pharmaceutically acceptable salt thereof. Claim 9 Compounds represented by the following formulas or pharmaceutically acceptable salts thereof: , , , , , , , , , , or . Claim 10 Compounds represented by the following formulas or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , or . Claim 11 A pharmaceutical composition for use in the manufacture of a drug for treating heart failure and hypertrophic cardiomyopathy, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete

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