Substituted pyridine-2,4-dione derivatives

Abstract

The present application relates to a series of substituted pyridine-2,4-diones and a preparation method thereof, and in particular to a compound shown in formula (I) and a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims the following priority:

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

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

[0004] CN 202210153298.4, February 18, 2022. Technical Field

[0005] This invention relates to a series of substituted pyridine-2,4-dione derivatives and methods for their preparation, specifically to compounds of formula (I) and their pharmaceutically acceptable salts. Background Technology

[0006] Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by thickening of the myocardium, often involving the interventricular septum, resulting in a smaller ventricular cavity, obstructed blood filling of the left ventricle, and decreased left ventricular diastolic compliance. Based on the presence or absence of left ventricular outflow tract obstruction, it is classified as obstructive or non-obstructive HCM, possibly related to genetics. The global incidence of HCM is approximately 1 in 500. Its clinical manifestations are diverse, ranging from asymptomatic to presenting with palpitations, exertional dyspnea, precordial pain, fatigue, syncope, and even sudden death. Late-stage manifestations include left heart failure.

[0007] Currently, there are limited drugs available for the treatment of HCM. These drugs mainly improve symptoms by using beta-blockers or calcium channel blockers, but they cannot target the cause, slow the progression of myocardial hypertrophy, or improve prognosis, resulting in limited therapeutic effects.

[0008] Myosin and actin are the material basis of myocardial contraction. Myosin cross-bridges periodically bind to and dissociate from actin, driving myofilaments to slide and thus causing myocardial contraction. Myosin has ATPase activity, providing power for myocardial contraction by hydrolyzing ATP. Myosin mutations lead to prolonged binding time between myosin and actin, excessive contraction and relaxation of the left ventricular myocardium, resulting in left ventricular myocardial hypertrophy and fibrosis, and triggering hemorrhage-induced myocardial infarction (HCM). MYK-461 is an allosteric regulator of myosin in cardiac muscle. It slows down the rate of phosphate hydrolysis and reduces the binding time between myosin and actin, producing a negative inotropic effect and alleviating pathological changes such as myocardial hypertrophy caused by excessive contraction of the left ventricular myocardium. However, it is eliminated slowly in vivo, and the drug stays in the body for too long, making it inconvenient to quickly adjust the dose (Mark P. Grillo et al. Xenobiotica, 2019; 49(6):718-733). Therefore, developing myosin inhibitors with better activity and more ideal pharmacokinetic properties has important clinical value and significance.

[0009] In addition, abnormalities of myocardial sarcomeres have been identified as the driving force of a variety of heart diseases and symptoms, such as diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. Myosin ATPase inhibitors, by inhibiting myocardial contraction, may also play a potential therapeutic role in alleviating the pathological processes of these diseases. Summary of the Invention

[0010] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0011]

[0012] in,

[0013] R1 and R2 are independently selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C, respectively. 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy groups are independently and optionally surrounded by 1, 2, or 3 R groups. a replace;

[0014] Or R1 and R2 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 Cycloalkyl and 3-6 membered heterocyclic alkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. b replace;

[0015] R3 is selected from H and F;

[0016] R4 is selected from H and C. 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl and C 3-4 Each cycloalkyl group is independently and optionally surrounded by 1, 2, or 3 R groups. c replace;

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

[0018] R6 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy groups are independently and optionally surrounded by 1, 2, or 3 R groups. d replace;

[0019] R a Each element is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, and C.1-4 Alkyl, C 1-4 Alkyl groups, -COR a1 -CO2R a1 -SO2R a1 -SO2NR a1 R a2 and -CONR a1 R a2 Wherein C 1-4 Alkyl and C 1-4 The alkoxy groups can be independently and optionally substituted by 1, 2 or 3 R groups;

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

[0021] Or R a1 and R a2 Together with the nitrogen atom to which it is attached, a 4-6 membered heterocyclic alkyl group is formed, wherein the 4-6 membered heterocyclic alkyl group is independently and optionally bound by 1, 2, 3 or 4 R atoms. e replace;

[0022] R b Each element is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, -COR b1 -CO2R b1 -SO2R b1 -SO2NR b1 R b2 and -CONR b1 R b2 Wherein C 1-4 Alkyl and C 1-4 The alkoxy groups can be independently and optionally substituted by 1, 2 or 3 R groups;

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

[0024] Or R b1 and R b2 Together with the nitrogen atom to which it is attached, a 4-6 membered heterocyclic alkyl group is formed, wherein the 4-6 membered heterocyclic alkyl group is independently and optionally bound by 1, 2, 3 or 4 R atoms. f replace;

[0025] R c Each element is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-4 Alkyl and C 1-4Alkoxy;

[0026] R d Each element is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-4 Alkyl and C 1-4 Alkoxy;

[0027] R e Each element is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-4 Alkyl and C 1-4 Alkoxy;

[0028] R f Each element is independently selected from F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-4 Alkyl and C 1-4 Alkoxy;

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

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

[0031] The 3-6 membered heterocyclic alkyl and 4-6 membered heterocyclic alkyl groups each independently comprise 1, 2, 3 or 4 atoms or groups of atoms independently selected from N, O, S and NH.

[0032] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0033]

[0034] in,

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

[0036] Alternatively, R1 and R2 together with the carbon atoms they are attached to form C. 4-6 Cycloalkyl or 5-6 membered heterocycloalkyl, wherein the C 4-6 Cycloalkyl and 5-6 membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. b replace;

[0037] R3 is selected from H and F;

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

[0039] R5 is selected from H;

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

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

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

[0043] n is selected from 1 or 2;

[0044] The 5-6 membered heterocyclic alkyl group comprises 1, 2, 3 or 4 atoms or groups of atoms independently selected from N, O, S and NH.

[0045] In some embodiments of the present invention, the above-mentioned R a1 and R a2 Each variable is independently selected from H, and other variables are as defined in this invention.

[0046] In some embodiments of the present invention, the above-mentioned R a R c R d R e and R f The variables are independently selected from F and Cl, respectively, and other variables are as defined in this invention.

[0047] In some embodiments of the present invention, R1 and R2 are independently selected from -CH3 and -CH2CH3, respectively, wherein CH3 and -CH2CH3 are independently and optionally selected by 1, 2 or 3 R... a Replaced by, R a Other variables are as defined in this invention.

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

[0049] In some embodiments of the present invention, the above-mentioned R b1 and R b2 The variables are independently selected from -CH3 and -CH2CH3, respectively, and other variables are as defined in this invention.

[0050] In some embodiments of the present invention, the above-mentioned R b The variables are independently selected from F, Cl, Br, -OCH3, -COCH3, -CO2CH3 and -CO2CH2CH3, and other variables are as defined in this invention.

[0051] In some embodiments of the present invention, the above-mentioned R bThe variables are independently selected from F, Cl, Br, -OCH3, -COCH3 and -CO2CH2CH3, and other variables are as defined in this invention.

[0052] In some embodiments of the present invention, R1 and R2 together with the carbon atoms they are attached to form C 5-6 cycloalkyl or 6-membered heterocycloalkyl, wherein the C 5-6 Cycloalkyl and 6-membered heterocycloalkyl groups are each independently and optionally bound by 1, 2, 3 or 4 R groups. b Replace, R b Other variables are as defined in this invention.

[0053] In some embodiments of the present invention, R1 and R2 are formed together with the carbon atoms to which they are attached. The above Each can be independently selected by 1, 2, 3 or 4 Rs. b Replace, R b Other variables are as defined in this invention.

[0054] In some embodiments of the present invention, R1 and R2 are formed together with the carbon atoms to which they are attached. The above Each of the 1, 2, 3, or 4 R's can be independently selected. b Replace, R b Other variables are as defined in this invention.

[0055] In some embodiments of the present invention, R1 and R2 are formed together with the carbon atoms to which they are attached. R b Other variables are as defined in this invention.

[0056] In some embodiments of the present invention, R1 and R2 are formed together with the carbon atoms to which they are attached. R b Other variables are as defined in this invention.

[0057] In some embodiments of the present invention, R1 and R2 are formed together with the carbon atoms to which they are attached. Other variables are as defined in this invention.

[0058] In some embodiments of the present invention, R1 and R2 are formed together with the carbon atoms to which they are attached. Other variables are as defined in this invention.

[0059] In some embodiments of the present invention, the above-mentioned structural segments Selected from Other variables are as defined in this invention.

[0060] In some embodiments of the present invention, the above-mentioned structural segments Selected from Other variables are as defined in this invention.

[0061] In some embodiments of the present invention, the above-mentioned structural segments Selected from Other variables are as defined in this 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 embodiments of the present invention, R4 is selected from C. 1-4 Alkyl groups, and other variables as defined in this invention.

[0064] In some embodiments of the present invention, the R4 is selected from -CH3 and -CH2CH3, wherein -CH3 and -CH2CH3 are each independently and optionally selected by 1, 2 or 3 R4 groups. d Replace, R d Other variables are as defined in this invention.

[0065] In some embodiments 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 embodiments of the present invention, the R6 is independently selected from H, F, Cl and -CH3, wherein the -CH3 is optionally divided by 1, 2 or 3 R6 groups. d Replace, R d Other variables are as defined in this invention.

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

[0071] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (I-1):

[0072]

[0073] Wherein, n, R1, R2, R3, R4 and R6 are as defined in this invention.

[0074] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (I-1-1):

[0075]

[0076] in,

[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. When T is selected from CH2 and NH, T can be arbitrarily selected by R. b replace;

[0081] R b R4 and R6 are as defined in this invention.

[0082] In some embodiments of the present invention, the above-mentioned compounds have the structure shown in formula (I-1A) or (I-1B):

[0083]

[0084] Wherein, n, R1, R2, R3, R4 and R6 are as defined in this invention, and R4 is not H.

[0085] In some embodiments of the present invention, the above-mentioned compounds have the structure shown in formula (I-1-1A) or (I-1-1B):

[0086]

[0087] in,

[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 selected from C 1-4 alkyl;

[0092] T is selected from CH2, O, and NH. When T is selected from CH2 and NH, T can be arbitrarily selected by R. b replace;

[0093] R bR4 and R6 are as defined in this invention.

[0094] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0095] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0096]

[0097]

[0098] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0099]

[0100]

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

[0102] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof or the above-described pharmaceutical compositions in the preparation of myosin inhibitor drugs.

[0103] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof or the above-described pharmaceutical compositions in the preparation of treatments for heart failure and hypertrophic cardiomyopathy.

[0104] The present invention also provides a method for treating a disease associated with cardiac myosin inhibitors in a subject in need, the method comprising providing the subject with an effective dose of the compound defined by any of the above-described technical solutions or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition.

[0105] The present invention also provides a method for treating heart failure and hypertrophic cardiomyopathy in subjects in need, the method comprising providing the subject with an effective dose of any of the above-described technical solutions of the compound or a pharmaceutically acceptable salt thereof or the above-described pharmaceutical composition.

[0106] Technical effect

[0107] The compounds of this invention have a good inhibitory effect on cardiac myosin ATPase and possess excellent pharmacokinetic properties.

[0108] Definitions and Explanations

[0109] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0110] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0111] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base 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. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0112] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0113] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

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

[0115] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0116] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0117] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0118] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0119] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0120] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the 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 stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0122] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0123] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0124] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0125] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent. Substituents can include deuterium and hydrogen variants, provided the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.

[0126] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0127] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0128] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0129] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0130] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, the structure is actually A. When the listed substituents do not specify which atom they are attached to the substituted group through, such substituents can be bonded to any of their atoms. For example, a pyridinium group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0131] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0132] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the diagram indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0133] When the chemical bond of a substituent intersects the chemical bonds of two atoms on the linking ring, it means that the substituent can bond with any atom on the ring. When the atom to which a substituent is attached is not specified, the substituent can bond with any atom. If the atom to which the substituent is attached is in a bicyclic or tricyclic system, it means that the substituent can bond with any atom in any ring of that system. Combinations of substituents and / or variables are only permitted if the combination produces a stable compound. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl or cyclopentyl group.

[0134] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a “5-7 elemental ring” refers to a “ring” with 5-7 atoms arranged around it.

[0135] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0136] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0137] Unless otherwise specified, the term "C" 1-4 "Alkoxy" refers to alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-4 Alkoxy groups include C 1-3 C 1-2 C 2-4 C4 and C3 alkoxy groups, etc. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), etc.

[0138] The term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heterogroup. 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 quaternized. 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 group is C 1-6 Heteroalkyl; in other embodiments, the heteroalkyl group is C10. 1-3 Heteroalkyl. Heteroatoms or heteroatomic groups can be located in any internal position of a heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkamino" and "alkthio" (or thioalkoxy) are conventional expressions referring to those alkyl groups that are attached to the rest of the molecule by an oxygen atom, an amino atom or a sulfur atom, respectively. Examples of heteroalkyl groups 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, -CH2-CH2-S(=O)2-CH3, and. At most two heteroatoms can be consecutive, for example, -CH2-NH-OCH3.

[0139] Unless otherwise specified, C n-n+m Or C n -Cn+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including 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 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0140] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0141] Unless otherwise specified, "C 3-4 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 4 carbon atoms, which is a monocyclic system; it can be monovalent, divalent, or polyvalent. 3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0142] Unless otherwise specified, "C 4-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which can be monocyclic or bicyclic. 4-6 Cycloalkyl groups include C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 4-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0143] Unless otherwise specified, "C 5-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 5 to 6 carbon atoms, which can be monocyclic or bicyclic systems. 3-6 Cycloalkyl groups include 5-membered and 6-membered cycloalkyl groups; they can be monovalent, divalent, or polyvalent. C 5-6 Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, etc.

[0144] Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "3-6 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 3-6 membered heterocyclic alkyl includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyls, etc. Examples of 3-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (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-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl or hexahydropyridazinyl, etc.

[0145] Unless otherwise specified, the term "4-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding the "4-6 membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl and the rest of the molecule. The 4-6 membered heterocyclic alkyl includes 5-6, 4, 5, and 6 membered heterocyclic alkyls, etc. Examples of 4-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (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-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl or hexahydropyridazinyl, etc.

[0146] Unless otherwise specified, the term "5-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)). p (where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "5-6 membered heterocyclic alkyl", the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 5-6 membered heterocyclic alkyl group includes 5-membered and 6-membered heterocyclic alkyl groups. Examples of 5-6 membered heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc.

[0147] Unless otherwise specified, the term "6-membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(O)). p(where p is 1 or 2). It includes monocyclic and bicyclic systems, with bicyclic systems including spirocyclic, fused, and bridged rings. Furthermore, regarding this "6-membered heterocyclic alkyl," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. Examples of 6-membered heterocyclic alkyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl), piperazine (including 1-piperazine and 2-piperazine), morpholinyl (including 3-morpholinyl and 4-morpholinyl), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc.

[0148] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0149] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenemethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0150] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0151] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0152] The volume used in this invention is commercially available.

[0153] The following abbreviations are used in this invention: TEA represents triethylamine; DIEA represents N,N-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 ditert-butyl dicarbonate; L-selectride represents lithium trisec-butylborohydride; TCFH represents N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate; FA represents formic acid; TFA represents trifluoroacetic acid; ACN represents acetonitrile; TLC represents thin-layer chromatography; HPLC represents high-performance liquid chromatography; LCMS represents liquid chromatography-mass spectrometry. DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; LDA stands for lithium diisopropylamino; DMAC stands for N,N-dimethylacetamide; PEG-400 stands for polyethylene glycol 400; EGTA stands for ethylene glycol bis(2-aminoethyl ether)tetraacetic acid; DMSO-d6 stands for deuterated dimethyl sulfoxide; CDCl3 stands for deuterated chloroform.

[0154] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Detailed Implementation

[0155] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0156] Example 1

[0157]

[0158] Synthesis route:

[0159]

[0160] Step A: At 20°C, 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). The reaction solution was stirred at 20°C for 16 hours and concentrated to obtain compound 1-a.

[0161] Step B: Under nitrogen protection 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 solution was stirred at 20°C for 1 hour. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-3:1) to obtain compound 1-b. LCMS (ESI) m / z: 377.3 (M+1).

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

[0163] Step D: Under nitrogen protection, 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 solution was stirred at 125 °C for 20 hours and then filtered. The filtrate was purified by preparative HPLC [mobile phase: water (0.1% TFA)-ACN; gradient: 21%-51% ACN] to obtain compound 1. 1H NMR(CDCl3,400MHz):7.38-7.24(m,5H),5.17(br s,1H),4.63(br d, J=6.4Hz, 1H), 1.57 (d, J=6.7Hz, 3H), 1.42 (s, 3H), 1.38 (s, 3H); LCMS (ESI) m / z: 259.4 (M+1).

[0164] Example 2

[0165]

[0166] Synthesis route:

[0167]

[0168] Step A: Under nitrogen protection at -78°C, LDA (2M, 19.07mL, 1.1eq) was added dropwise to a THF (80mL) solution of compound 2-1 (5g, 34.68mmol, 4.63mL, 1eq). The reaction solution was stirred at -78°C for 30 minutes. Then, methyl chloroformate (3.44g, 36.42mmol, 2.82mL, 1.05eq) was added. The reaction solution was slowly heated to 20°C and stirred for 16 hours. Water (200mL) was added to quench the reaction, followed by extraction with EA (200mL). The organic phase was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-3:1) to obtain compound 2-a.

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

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

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

[0172] Step E: Under nitrogen protection, sodium methoxide (2M, 7mL, 16.18eq) was added to a MeOH (5mL) solution of compound 2-d (0.35g, 865.36μmol, 1eq). The reaction solution was stirred at 50°C for 2 hours and then concentrated. The residue was diluted with EA (20mL), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-1:1) 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 solution was stirred at 50°C for 16 hours and then concentrated. The residue was adjusted to neutral by adding 2N sodium hydroxide aqueous solution, and then extracted with EA (50mL). The organic phase was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [water (0.225% FA)-ACN]; gradient: 17%-47% ACN) to obtain compound 2. 1H NMR(DMSO-d6,400MHz): δppm 9.62(br s,1H),7.47-7.20(m,5H),7.05(brs,1H),4.60(br t, J=6.7Hz, 1H), 4.41 (s, 1H), 3.85-3.66 (m, 4H), 1.94-1.75 (m, 2H), 1.68-1.51 (m, 2H), 1.43 (d, J=6.8Hz, 3H); LCMS (ESI) m / z: 301.4 (M+1).

[0174] Example 3

[0175]

[0176] Synthesis route:

[0177]

[0178] Step A: Under nitrogen protection, 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 solution was stirred at 50 °C for 16 hours, and then EA (200 mL) was added. The solution was then washed with water (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 20:1-10:1) to obtain compound 3-a.

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

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

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

[0182] Step E: Under nitrogen protection, sodium methoxide (1M, 7.21mL, 4eq) was added to a MeOH (4mL) solution of compound 3-d (0.7g, 1.80mmol, 1eq). The reaction solution was stirred at 20°C for 16 hours. The pH was adjusted to 5 by adding 1N dilute hydrochloric acid. Then, EA (20mL) was added for extraction. The organic phase was washed with saturated brine (20mL), dried over 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). The reaction solution was stirred at 50°C for 16 hours and then diluted with EA (50mL). The pH was adjusted to 7 by adding 1N sodium hydroxide aqueous solution. After separation, the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was added with MeOH (10mL) and stirred for 20 minutes. After filtration, the filter cake was dried under high vacuum to obtain compound 3. 1 HNMR (DMSO-d6, 400MHz): δppm 9.49 (br s, 1H), 7.41-7.31 (m, 4H), 7.30-7.25 (m, 1H), 6.92 (br d, J=5.1Hz, 1H), 4.60 (br t, J=6.7Hz, 1H), 4.42 (s, 1H), 1.91-1.80 (m, 4H), 1.72-1.65 (m, 4H), 1.43 (d, J=6.8Hz, 3H); LCMS (ESI) m / z: 285.4 (M+1).

[0184] Example 4

[0185]

[0186] Synthesis route:

[0187]

[0188] Step A: Add 4-1 (26 g, 113.07 mmol, 12.99 mL, 1 eq) and potassium carbonate (31.25 g, 226.15 mmol, 2 eq) to a DMF (150 mL) solution of 3-1 (14.94 g, 113.07 mmol, 12.99 mL, 1 eq). After stirring the reaction solution at 50 °C for 16 hours, add EA (150 mL), then wash with water (150 mL). The organic phase is then washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue is separated by column chromatography (PE:EtOAc = 50:1-30:1) to obtain compound 4-a.

[0189] Step B: Add sodium hydroxide (1.38 g, 34.46 mmol, 1 eq) to a solution of 4-a (6.9 g, 34.46 mmol, 1 eq) in MeOH (40 mL) and water (40 mL). Stir the reaction solution at 15 °C for 16 hours, then add water (50 mL), and extract with EA (100 mL). After separation, adjust the pH of the aqueous phase to about 5 with 1 M dilute hydrochloric acid, and then extract with EA (100 mL × 2). Wash the combined organic phases with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain compound 4-b.

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

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

[0192] Step E: Under nitrogen protection, sodium methoxide (1M, 28.57mL, 5eq) was added to a MeOH (15mL) solution of 4-d (2.30g, 5.71mmol, 1eq). The reaction solution was stirred at 10°C for 16 hours, and then stirred at 50°C for 3 hours. 1N dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5. Then, EA (50mL × 2) was added for extraction. The combined organic phases were washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-3:1) 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). The reaction solution was stirred at 50°C for 40 hours. Then, 1N sodium hydroxide aqueous solution was added to adjust the pH to about 7. The mixture was then extracted with DCM / MeOH = 10 / 1 (50mL × 2). The combined organic phases were washed with saturated brine (30mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was added to MeOH (10mL) and stirred at 10°C for 30 minutes. The mixture was then filtered, and the filter cake was dried under high vacuum to obtain compound 4. 1 H NMR (DMSO-d6, 400MHz): δppm 9.38 (br s, 1H), 7.41-7.22 (m, 5H), 6.84 (br d, J=5.4Hz, 1H), 4.57 (br t, J=6.8Hz, 1H), 4.36 (s, 1H), 1.74-1.45 (m, 10H), 1.41 (d, J=6.8Hz, 3H); LCMS (ESI) m / z: 299.2 (M+1).

[0194] Example 5

[0195]

[0196] Synthesis route:

[0197]

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

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

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

[0201] Step D: At 20°C, hydrochloric acid (4M, 3.82mL, 10eq) was added to a 1,4-dioxane (4mL) solution of 5-c (550mg, 1.53mmol, 1eq). The reaction solution was stirred at 40°C for 16 hours. EA (40mL) was added to the reaction solution, and then 1N sodium hydroxide aqueous solution was added to adjust the pH to about 7. The mixture was separated, and the aqueous phase was extracted again with EA (40mL). The combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was added to MeOH (5mL) and stirred. After filtration, the filter cake was dried under high vacuum to obtain compound 5. 1 H NMR (DMSO-d6, 400MHz): δppm 9.48 (br s, 1H), 7.38 (dd, J=5.6, 8.6Hz, 2H), 7.19 (t, J=8.8Hz, 2H), 6.91 (br d, J=6.0Hz, 1H), 4.62 (br t, J=6.7Hz, 1H), 4.41 (s, 1H), 1.96-1.78 (m, 4H), 1.76-1.61 (m, 4H), 1.42 (d, J=6.8Hz, 3H); LCMS (ESI) m / z: 302.8 (M+1).

[0202] Example 6

[0203]

[0204] Synthesis route:

[0205]

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

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

[0208] Step C: Under nitrogen protection at 20°C, sodium methoxide (1M, 8mL, 4.34eq) was added to a MeOH (8mL) solution of 6-b (750.00mg, 1.85mmol, 1eq). The reaction solution was stirred at 40°C for 16 hours. After cooling to room temperature, EA (30mL) was added, and the pH was adjusted to about 7 with 1N hydrochloric acid. The mixture was separated, and the aqueous phase was extracted again with EA (40mL × 2). The combined organic phases were washed with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 5:1-1:1) 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 solution was stirred at 40°C for 16 hours. Water (40mL) was added to the reaction solution, and then a saturated sodium bicarbonate aqueous solution was added to adjust the pH to about 7. Extraction was performed with EA (40mL×2). The combined organic phases were washed with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was added to MeOH (6mL), stirred for 15 minutes, filtered, and the filter cake was dried under high vacuum to obtain compound 6. 1H NMR (DMSO-d6, 400MHz): δppm 9.51 (br s, 1H), 7.49-7.35 (m, 1H), 7.19 (br d, J = 7.7Hz, 2H), 7.09 (dt, J = 1.6, 8.2Hz, 1H), 6.94 (br d, J=6.1Hz, 1H), 4.63 (br t, J=6.7Hz, 1H), 4.40 (s, 1H), 1.90-1.79 (m, 4H), 1.74-1.63 (m, 4H), 1.42 (d, J=6.7Hz, 3H); LCMS (ESI) m / z: 302.8 (M+1).

[0210] Example 7

[0211]

[0212] Synthesis route:

[0213]

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

[0215] Step B: Under nitrogen protection 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), followed by 3-c (1.23 g, 6.45 mmol, 1.32 eq). The reaction solution was stirred at 20°C for 16 hours and then concentrated. The residue was diluted with EA (40 mL), washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 20:1-10:1) to obtain compound 7-b.

[0216] Step C: Under nitrogen protection 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 solution was stirred at 40°C for 16 hours. After cooling to room temperature, EA (30mL) was added, and the pH was adjusted to about 7 with 1N hydrochloric acid. The mixture was separated, and the aqueous phase was extracted again with EA (60mL × 2). The combined organic phases were washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 4:1-1:1) 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 solution was stirred at 40°C for 16 hours. Water (40mL) was added to the reaction solution, and then a saturated sodium bicarbonate aqueous solution was added to adjust the pH to about 7. Extraction was performed with EA (40mL×2). The combined organic phases were washed with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was added to MeOH (4mL), stirred for 15 minutes, filtered, and the filter cake was dried under high vacuum to obtain compound 7. 1 H NMR (DMSO-d6, 400MHz) δppm 9.51 (br s, 1H), 7.48-7.37 (m, 2H), 7.36-7.27 (m, 2H), 6.95 (br d, J=5.1Hz, 1H), 4.63 (br t, J=6.7Hz, 1H), 4.41 (s, 1H), 1.90-1.80 (m, 4H), 1.72-1.64 (m, 4H), 1.42 (d, J=6.8Hz, 3H); LCMS (ESI) m / z: 318.8 (M+1).

[0218] Example 8

[0219]

[0220] Synthesis route:

[0221]

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

[0223] Step B: Add sodium hydroxide (3.58 g, 89.60 mmol, 1 eq) to a MeOH (200 mL) and water (200 mL) solution of compound 8-a (27 g, 89.60 mmol, 1 eq). Stir the reaction solution at 15 °C for 16 hours, then add water (200 mL) and extract with EA (200 mL). After separation, adjust the pH of the aqueous phase to about 5 with 1 M dilute hydrochloric acid, and then extract with EA (300 mL × 2). Wash the combined organic phases with saturated brine (200 mL), dry with anhydrous sodium sulfate, filter and concentrate to obtain compound 8-b.

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

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

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

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

[0228] Step G: Under nitrogen protection 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), followed by a DCM (1 mL) solution of methyl chloroformate (49.72 mg, 526.11 μmol, 40.75 μL, 1.05 eq). 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)-ACN; gradient: 15%-45% ACN] to obtain compound 8. 1 H NMR (DMSO-d6, 400MHz): δppm 9.80-9.51(m,1H),7.40-7.31(m,4H),7.30-7.23(m,1H),7.11-6.97(m,1H),4.60(br s,1H),4.43(s,1H),3.73-3.64(m,2H),3.58(s,3H),3.48-3.34(m,2H),1.82-1. 70 (m, 2H), 1.69-1.55 (m, 2H), 1.42 (d, J = 6.8Hz, 3H); LCMS (ESI) m / z: 358.2 (M+1).

[0229] Example 9

[0230]

[0231] Synthesis route:

[0232]

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

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

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

[0236] Step D: Add 1-1 (9.58 g, 48.96 mmol, 1 eq, HCl) and DIEA (25.31 g, 195.83 mmol, 34.11 mL, 4 eq) to a solution of 7.5 g of 9-c hydrochloride in 100 mL of EtOH. Stir the reaction solution at 20 °C for 16 hours and concentrate to obtain compound 9-d.

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

[0238] Step F: Add HCl / EtOAc (4M, 51.61mL, 9.46eq) to a solution of 9-e (8.00g, 21.83mmol, 1eq) in EtOAc (50mL). Stir the reaction solution at 20°C for 16 hours. After concentration, the hydrochloride salt of compound 9-d is obtained.

[0239] Step G: Under nitrogen protection at -20°C, 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). The reaction solution was stirred at -20°C for 1 hour, then heated to 20°C and stirred for 15 hours. The mixture was then concentrated, and the residue was separated by column chromatography (PE:EtOAc = 30:1-10:1) to obtain compound 9-f.

[0240] Step H: Under nitrogen protection, sodium methoxide (1M, 41.62mL, 5eq) was added to a MeOH (40mL) solution of 9-f (3.5g, 8.32mmol, 1eq). The reaction solution was stirred at 50°C for 16 hours. 1N dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5. Then, EA (100mL×2) was added for extraction. The combined organic phases were washed with saturated brine (50mL×2), dried over 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). The reaction solution was stirred at 70℃ for 16 hours. Then, 2N sodium hydroxide aqueous solution was added to adjust the pH to 8-9. The mixture was filtered, and the filter cake was first separated by silica gel column chromatography (DCM:MeOH = 1:0-10:1). Then, MTBE (50mL) was added and stirred for 1 hour. The mixture was filtered, and the filter cake was dried under high vacuum to obtain compound 9. 1 H NMR (DMSO-d6, 400MHz): δppm 9.52 (br s, 1H) 7.19 (br d, J = 7.5Hz, 1H) 7.06-7.15 (m, 2H) 6.91 (br d,J=6.8Hz,1H)4.66-4.76(m,1H)4.40(s,1H)2.28(s,3H)1.81-1.90(m,4H)1.64-1.72(m,4H)1.45(d,J=6.8Hz,3H); LCMS (ESI) m / z: 317.2(M+1).

[0242] Example 10

[0243]

[0244] Synthesis route:

[0245]

[0246] Step A: At 20°C, 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 solution of 10-1 (5 g, 32.02 mmol, 4.07 mL, 1 eq) in 50 mL of THF. The reaction solution was stirred at 60°C for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution. After cooling to 0°C, water (20 mL) was slowly added and stirred for 0.5 hours. The mixture was filtered, and the filtrate was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10-a.

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

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

[0249] Step D: At 20°C, 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 a solution of 10-c hydrochloride (1 g) in EtOH (10 mL). The reaction solution was stirred at 20°C for 16 hours and concentrated to obtain compound 10-d.

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

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

[0252] Step G: Add hydrochloric acid (4M, 4mL, 17.40eq) to a solution of 1,4-dioxane (4mL) containing 10-f (348mg, 919.74μmol, 1eq). Stir the reaction solution at 50°C for 16 hours. Add EA (30mL) to the reaction solution, and then add 1M sodium hydroxide aqueous solution to adjust the pH to about 8. After separation, wash the organic phase with saturated brine (50mL×2), dry with anhydrous sodium sulfate, filter and concentrate. Add MeOH (10mL) to the residue and stir for 20 minutes. Filter and dry the filter cake under high vacuum to obtain compound 10. 1 H NMR (DMSO-d6, 400MHz): δppm 9.60-9.47(m,1H),7.34-7.26(m,2H),7.25-7.16(m,1H),6.96(br d,J=6.0Hz,1H),4.82-4.71(m,1H),4.44-4.34(m,1H),1.93-1.81(m,4H),1.70(br s,4H),1.48(br d,J=6.4Hz,3H); LCMS(ESI)m / z:321.2(M+1).

[0253] Example 11

[0254]

[0255] Synthesis route:

[0256]

[0257] Step A: At 20°C, 1-1 (1.18 g, 7.40 mmol, 1.06 mL, 1 eq) and DIEA (2.87 g, 22.19 mmol, 3.86 mL, 3 eq) were added to a solution of 11-1 (1 g, 7.40 mmol, 1.06 mL, 1 eq) of EtOH (15 mL). The reaction solution was stirred at 20°C for 12 hours and concentrated to obtain compound 11-a.

[0258] Step B: Under nitrogen protection at -20°C, TEA (4.32 g, 42.65 mmol, 5.94 mL, 3 eq) was added to a DCM (15 mL) solution of 11-a (2.44 g, 9.83 mmol, 6.91 e-1 eq), followed by a DCM (15 mL) solution of 3-c (2.71 g, 14.22 mmol, 6.37 e-1 eq). The reaction mixture was stirred at 20°C for 16 hours, concentrated, and the residue was diluted with EA (30 mL). The residue was then washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 10:1-8:1) to obtain compound 11-b.

[0259] Step C: Under nitrogen protection, sodium methoxide (1M, 7.37ml, 5eq) was added to a MeOH (9.2mL) solution of 11-b (0.743g, 1.47mmol, 1eq). The reaction solution was stirred at 20°C for 16 hours. 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 5. Then, EA (20mL×3) was added for extraction. The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 11-c.

[0260] Step D: Add hydrochloric acid (4M, 4mL, 17.40eq) to a 1,4-dioxane (4mL) solution of 11-c (399mg, 1.12mmol, 1eq). Stir the reaction solution at 50°C for 16 hours, then add EA (30mL) to dilute. Then add 2M sodium hydroxide aqueous solution to adjust the pH to about 8. Filter, add MeOH (10mL) to the filter cake and stir for 1 hour. Filter again, and dry the filter cake under high vacuum to obtain compound 11. 1H NMR(DMSO-d6,400MHz): δppm 9.52(br s,1H),7.41-7.25(m,5H),6.97-6.85(m,1H),4.42(s,1H),4.40-4.29(m,1H),1.90- 1.84 (m, 2H), 1.83-1.63 (m, 8H), 0.87 (t, J = 7.2Hz, 3H); LCMS (ESI) m / z: 299.1 (M+1).

[0261] Example 12

[0262]

[0263] Synthesis route:

[0264]

[0265] Step A: At 20°C, 10-2 (17.08 g, 140.91 mmol, 2.2 eq) and tetraethyl titanate (43.83 g, 192.15 mmol, 39.85 mL, 3 eq) were added to a solution of 12-1 (10 g, 64.05 mmol, 8.33 mL, 1 eq) in 100 mL of THF. The reaction solution was stirred at 60°C for 16 hours. After cooling to 0°C, EA (100 mL) was added to the reaction solution, followed by the slow addition of water (30 mL). The mixture was stirred for 0.5 hours, filtered, and the filtrate was washed with saturated brine (30 mL × 3). The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 12-a.

[0266] Step B: Under nitrogen protection at -78°C, L-selectride (1M, 25.21mL, 1.2eq) was slowly added dropwise to a solution of 12-a (5.45g, 21.01mmol, 1eq) in 50mL of THF. The reaction mixture was stirred at 20°C for 2 hours. At 0°C, the reaction mixture was slowly added to a saturated ammonium chloride aqueous solution (40mL). Extraction was performed with EA (30mL × 2). The combined organic phases were washed with saturated brine (30mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 8:1-1:1) to obtain compound 12-b.

[0267] Step C: At 20°C, HCl / MeOH (4M, 30mL, 10.00eq) was added to a MeOH (30mL) solution of 12-b (3.14g, 12.00mmol, 1eq). The reaction solution was stirred for 16 hours and then concentrated. The residue was added to EA (20mL), stirred for 0.5 hours, and then filtered. The filter cake was dried under high vacuum to obtain the hydrochloride of compound 12-c.

[0268] Step D: Under nitrogen protection at 20°C, 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 a solution of 12-c hydrochloride (1.84 g) in EtOH (20 mL). The reaction solution was stirred at 20°C for 12 hours and concentrated to obtain compound 12-d.

[0269] Step E: Under nitrogen protection, 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 THF (50 mL) solution of 12-d (9.11 g, 33.71 mmol, 1 eq), followed by 12-2 (12.92 g, 50.56 mmol, 1.5 eq). The reaction solution was stirred at 20 °C for 1 hour and then concentrated. The residue was diluted with water (50 mL) and extracted with EA (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE: EtOAc = 10:1) to give compound 12-e.

[0270] Step F: Under nitrogen protection, sodium methoxide (1M, 44.56mL, 5eq) was added to a MeOH (44.56mL) solution of 12-e (3.78g, 8.91mmol, 1eq). The reaction solution was stirred at 50°C for 16 hours. 1M dilute hydrochloric acid was added to adjust the pH to about 5. Then, EA (50mL×2) was added for extraction. The combined organic phases were washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 5:1-2:1) to obtain compound 12-f.

[0271] Step G: Add hydrochloric acid (4M, 3.91mL, 15.21eq) to a 1,4-dioxane (4mL) solution of 12-f (389mg, 1.03mmol, 1eq). Stir the reaction solution at 60°C for 16 hours. Add 2M sodium hydroxide aqueous solution to the reaction solution to adjust the pH to about 8. Filter, add MTBE (5mL) to the filter cake and stir for 1 hour. Filter again and dry the filter cake to obtain compound 12. 1H NMR(DMSO-d6,400MHz): δppm 9.52(br s,1H),7.47-7.35(m,1H),7.14(br t,J=8.8Hz,2H),7.01-6.91(m,1H),4.91-4.79(m,1H),4.44(s,1H),1.91-1.75 (m, 4H), 1.74-1.64 (m, 4H), 1.57 (d, J = 6.8Hz, 3H); LCMS (ESI) m / z: 321.1 (M+1).

[0272] Example 13

[0273]

[0274] Synthesis route:

[0275]

[0276] Step A: At 20°C, 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 solution of 13-1 (3 g, 19.21 mmol, 2.42 mL, 1 eq) in 30 mL of THF. The reaction solution was stirred at 60°C for 16 hours. EA (60 mL) was added to the reaction solution. After cooling to 0°C, water (10 mL) was slowly added and stirred for 0.5 hours. The mixture was filtered, and the filtrate was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13-a.

[0277] Step B: Under nitrogen protection at -78°C, L-selectride (1M, 13.88mL, 1.2eq) was slowly added dropwise to a solution of 13-a (3g, 11.57mmol, 1eq) in 20mL of THF. The reaction solution was stirred at -78°C for 2 hours. At 0°C, the reaction solution was slowly added to a saturated ammonium chloride aqueous solution (20mL). Extraction was performed with EA (20mL × 2). The combined organic phases were washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 5:1-2:1) to obtain compound 13-b.

[0278] Step C: Add HCl / MeOH (4M, 15mL, 12.48eq) to a MeOH (1.26g, 4.81mmol, 1eq) solution of 13-b. Stir the reaction solution at 20°C for 16 hours and concentrate. Add EA (20mL) to the residue and stir for 0.5 hours. Filter and vacuum dry the filter cake to obtain the hydrochloride of compound 13-c.

[0279] Step D: Under nitrogen protection at 20°C, 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 a solution of 13-c hydrochloride (0.553 g) in EtOH (5 mL). The reaction solution was stirred at 20°C for 12 hours and concentrated to obtain compound 13-d.

[0280] Step E: Under nitrogen protection 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), followed by 13-d (950.02 mg, 3.52 mmol). The reaction solution was stirred at 20°C for 16 hours and then concentrated. The residue was diluted with water (50 mL) and extracted with EA (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 8:1-1:1) to obtain compound 13-e.

[0281] Step F: Under nitrogen protection, sodium methoxide (1M, 5.69mL, 5eq) was added to a MeOH (5mL) solution of 13-e (483mg, 1.14mmol, 1eq). The reaction solution was stirred at 50°C for 16 hours. 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5. Then, EA (30mL×2) was added for extraction. The combined organic phases were washed with saturated brine (30mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13-f.

[0282] Step G: Add hydrochloric acid (4M, 2mL, 25.87eq) to a solution of 1,4-dioxane (2mL) containing 13-f (117mg, 309.22μmol, 1eq). Stir the reaction solution at 60°C for 16 hours. Add 2M sodium hydroxide aqueous solution to the reaction solution to adjust the pH to about 8. Filter the solution. Add 10mL of MTBE to the filter cake and stir for 1 hour. Filter the solution again and dry the filter cake to obtain compound 13. 1HNMR (DMSO-d6, 400MHz): δppm 9.54 (br s, 1H), 7.51-7.41 (m, 1H), 7.32-7.23 (m, 1H), 7.12 (br t, J=8.0Hz, 1H), 6.95 (br d, J=6.1Hz, 1H), 4.81-4.68 (m, 1H), 4.39 (s, 1H), 1.90-1.80 (m, 4H), 1.77-1.63 (m, 4H), 1.53-1.42 (d, J=6.7Hz, 3H); LCMS (ESI) m / z: 321.1 (M+1).

[0283] Example 14

[0284]

[0285] Synthesis route:

[0286]

[0287] Step A: At 20°C, 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). The reaction solution was stirred at 25°C for 16 hours and concentrated to obtain compound 14-a.

[0288] 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 solution at 25 °C for 0.5 h, concentrate, add water (50 mL) to the residue, and then extract with EA (20 mL × 3). Wash the combined organic phases with saturated brine (20 mL × 2), dry with anhydrous sodium sulfate, filter, concentrate, and separate the residue by column chromatography (PE:EtOAc = 10:1) to obtain compound 14-b.

[0289] Step C: Under nitrogen protection, sodium methoxide (1M, 2.84mL, 5eq) was added to a MeOH (5mL) solution of 14-b (231mg, 568.34μmol, 1eq). The reaction solution was stirred at 50°C for 16 hours. 1M dilute hydrochloric acid was added to adjust the pH to approximately 5. Water (20mL) was added for dilution, and then the solution was extracted with EA (10mL×3). The combined organic phases were washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 14-c.

[0290] Step D: Hydrochloric acid (4M, 8.29mL, 76.4eq) was added to a solution of 1,4-dioxane (8.29mL) containing 14-c (170mg, 433.99μmol, 92% purity, 1eq). The reaction mixture was stirred at 50°C for 16 hours. The pH was adjusted to approximately 9 by adding 1M sodium hydroxide aqueous solution. The mixture was extracted with EA (5mL × 4). The combined organic phases were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was added to MTBE (5mL) and stirred for 2 hours. The mixture was filtered, and the filter cake was dried to obtain compound 14. 1 HNMR(DMSO-d6,400MHz): δppm 9.70(br s,1H),7.45-7.39(m,1H),7.39-7.32(m,1H),7.25-7.20(m,2H),7.15(br s, 1H), 4.81-4.73 (m, 1H), 4.38 (s, 1H), 1.89-1.79 (m, 4H), 1.74-1.64 (m, 4H), 1.48 (d, J = 6.8Hz, 3H); LCMS (ESI) m / z: 303.2 (M+1).

[0291] Example 15

[0292]

[0293] Synthesis route:

[0294]

[0295] Step A: At 20°C, 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) were added to a solution of 15⁻¹ (1 g, 6.37 mmol, 99.53% purity, 1 eq) in 10 mL of THF. The reaction solution was stirred at 50°C for 16 hours. Then, 10⁻² (386.02 mg, 3.19 mmol, 0.5 eq) was added to the reaction solution, and the mixture was stirred at 50°C for another 1.5 hours. After cooling to 0°C, ethyl acetate (30 mL) was added to the reaction solution for dilution. Water (20 mL) was slowly added, and the mixture was stirred for 0.5 hours. The mixture was filtered, and the filtrate was washed with saturated brine (10 mL × 2). The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 15-a.

[0296] Step B: Under nitrogen protection at -78°C, L-selectride (1M, 4.40mL, 1.2eq) was slowly added dropwise to a solution of 15-a (950mg, 3.66mmol, 1eq) in 10mL of THF. The reaction solution was stirred at -78°C for 2 hours. The reaction solution was then slowly added to a saturated ammonium chloride aqueous solution (15mL) at 0°C. The solution was diluted with water (30mL) and extracted with ethyl acetate (10mL × 3). The combined organic phases were washed with saturated brine (15mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 5:1) to obtain compound 15-b.

[0297] Step C: At 20°C, HCl / MeOH (4M, 1.10mL, 1eq) was added to a MeOH (10mL) solution of 15-b (1.15g, 4.39mmol, 1eq). The reaction solution was stirred at 20°C for 16 hours and concentrated to obtain the hydrochloride salt of compound 15-c.

[0298] Step D: Under nitrogen protection at 20°C, 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 a solution of 15-c hydrochloride (0.887 g) in EtOH (10 mL). The reaction solution was stirred at 20°C for 16 hours and concentrated to obtain compound 15-d.

[0299] Step E: Under nitrogen protection, 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 THF (25 mL) solution of 15-d (2.3 g, 8.51 mmol, 1 eq), followed by 12-2 (3.26 g, 12.76 mmol, 1.5 eq). The reaction solution was stirred at 20 °C for 32 hours and then concentrated. The residue was diluted with water (50 mL) and then extracted with EA (10 mL × 4). The combined organic phases were washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 20:1) to give compound 15-e.

[0300] Step F: Under nitrogen protection, sodium methoxide (1M, 3mL, 4.90eq) was added to a MeOH (3mL) solution of 15-e (260mg, 612.58μmol, 1eq). The reaction solution was stirred at 50°C for 16 hours. 1M dilute hydrochloric acid was added to adjust the pH to about 5, and then water (10mL) was added. The mixture was extracted with EA (5mL×4). The combined organic phases were washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by thin-layer chromatography (PE:EtOAc = 20:1) to obtain compound 15-f.

[0301] Step G: Add hydrochloric acid (4M, 2mL, 50.45eq) to a solution of 1,4-dioxane (2mL) containing 15-f (60mg, 158.58μmol, 1eq). Stir the reaction solution at 60°C for 19 hours. Add 1M sodium hydroxide aqueous solution to the reaction solution to adjust the pH to about 9. Filter the solution. Add MTBE (2mL) to the filter cake and stir for 2 hours. Filter the solution again. After drying the filter cake, compound 15 is obtained. 1 HNMR (DMSO-d6, 400MHz): δppm9.55(m,1H),7.41-7.33(m,1H),7.28-7.20(m,2H),7.01(br d,J=4.6Hz,1H),4.83(br s, 1H), 4.40 (s, 1H), 1.91-1.79 (m, 4H), 1.75-1.65 (m, 4H), 1.50 (d, J = 6.8Hz, 3H); LCMS (ESI) m / z: 321.2 (M+1).

[0302] Example 16

[0303]

[0304] Synthesis route:

[0305]

[0306] Step A: Under nitrogen protection, 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 iodoethane (12.99 g, 83.26 mmol, 6.66 mL, 2.2 eq). The reaction solution was stirred at 20 °C for 16 hours, then water (200 mL) was added, followed by extraction with EA (200 mL). The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 16-a.

[0307] Step B: Sodium hydroxide (1.64 g, 40.91 mmol, 1.1 eq) was added to a MeOH (40 mL) and water (40 mL) solution of compound 16-a (7 g, 37.19 mmol, 1 eq). The reaction solution was stirred at 20 °C for 16 hours and then concentrated. The residue was added to water (100 mL) and then extracted with MTBE (100 mL). After separation, the pH of the aqueous phase was adjusted to about 5 with 1 M dilute hydrochloric acid and then extracted with EA (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 16-b.

[0308] Step C: Under nitrogen protection at 0°C, N-methylimidazole (1.82 g, 22.20 mmol, 1 eq) and TCFH (2.49 g, 8.88 mmol, 2 eq) were added to a 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) in ACN (20 mL). The reaction solution was stirred at 0°C for 1 hour and then concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 1:0-10:1) to obtain compound 16-c.

[0309] Step D: Under nitrogen protection, sodium tert-butoxide (1.75 g, 18.17 mmol, 5 eq) was added to a MeOH (20 mL) solution of compound 16-c (1.55 g, 3.63 mmol, 1 eq). The reaction solution was stirred at 20 °C for 16 hours. The reaction solution was poured into 1 N dilute hydrochloric acid (20 mL) and concentrated. The residue was added to water (30 mL) and extracted with EA (30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-3:1) to obtain compound 16-d.

[0310] Step E: Add hydrochloric acid (4M, 5mL, 50.72eq) to a 1,4-dioxane (5mL) solution of compound 16-d (0.15g, 394.34μmol, 1eq). Stir the reaction solution at 50°C for 16 hours. Add 1N sodium hydroxide to the reaction solution to adjust the pH to about 7. Then concentrate the 1,4-dioxane. Add MTBE (20mL) to the residue, filter, and dry the filter cake under high vacuum to obtain compound 16. 1 H NMR (DMSO-d6, 400MHz): δppm 9.69 (br s, 1H), 7.45-7.37 (m, 1H), 7.14 (t, J = 8.5Hz, 2H), 6.94 (br d, J = 7.6Hz, 1H), 4.88 (br t, J=6.8Hz, 1H), 4.58 (s, 1H), 1.76-1.50 (m, 7H), 0.65 (t, J=7.3Hz, 3H), 0.48 (t, J=7.3Hz, 3H); LCMS (ESI) m / z: 323.4 (M+1).

[0311] Example 17

[0312]

[0313] Synthesis route:

[0314]

[0315] Step A: Under nitrogen protection at 0°C, 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 a solution of compounds 2-b (325.84 mg, 1.73 mmol, 1.3 eq) and 10-d (0.36 g, 1.33 mmol, 1 eq) in ACN (10 mL). The reaction solution was stirred at 20°C for 2 hours and then concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-5:1) to obtain compound 17-a.

[0316] Step B: Under nitrogen protection, sodium tert-butoxide (370.94 mg, 3.86 mmol, 5 eq) was added to a MeOH (5 mL) solution of compound 17-a (0.34 g, 771.96 μmol, 1 eq). The reaction solution was stirred at 20 °C for 16 hours. The pH was adjusted to approximately 5 by adding 1 N dilute hydrochloric acid. The solution was concentrated, and the residue was extracted with water (10 mL) and EA (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-2:1) to obtain compound 17-b.

[0317] Step C: Under nitrogen protection, 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 solution was stirred at 50°C for 20 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to about 7. Then, 1,4-dioxane was concentrated. The residue was added to water (10mL) and MTBE (20mL), stirred for 30 minutes, filtered, and the filter cake was dried under high vacuum to obtain compound 17. 1 H NMR (DMSO-d6, 400MHz): δppm 9.67 (br s, 1H), 7.34-7.25 (m, 2H), 7.20 (dt, J=4.1, 8.1Hz, 1H), 7.07 (br d, J=5.9Hz, 1H), 4.76 (br s, 1H), 4.38 (s, 1H), 3.79-3.69 (m, 4H), 1.91-1.77 (m, 2H), 1.67-1.52 (m, 2H), 1.47 (d, J = 6.8Hz, 3H); LCMS (ESI) m / z: 337.3 (M+1).

[0318] Example 18

[0319]

[0320] Synthesis route:

[0321]

[0322] Step A: At 20°C, 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 solution of 18-1 (6.89 g, 39.92 mmol, 1 eq) in 70 mL of THF. The reaction solution was stirred at 60°C for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution. After cooling to 0°C, water (20 mL) was slowly added and stirred for 0.5 hours. The mixture was filtered, and the filtrate was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 18-a.

[0323] Step B: Under nitrogen protection at -78°C, L-selectride (1M, 25.75mL, 1eq) was slowly added dropwise to a solution of 18-a (7.1g, 25.75mmol, 1eq) in 100mL of THF. The reaction solution was slowly raised to 0°C and stirred for 1 hour. 0.5N dilute hydrochloric acid (100mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100mL). The organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 10:1-3:1) to obtain compound 18-b.

[0324] Step C: Add HCl / MeOH (4M, 25mL, 13.89eq) solution to 18-b (2g, 7.20mmol, 1eq), stir the reaction solution at 50°C for 1 hour, and concentrate to obtain the hydrochloride salt of compound 18-c.

[0325] Step D: Under nitrogen protection at 20°C, 1-1 (2.05 g, 10.47 mmol, 1.1 eq, HCl) and DIEA (3.69 g, 28.56 mmol, 4.97 mL, 3 eq) were added to a solution of 18-c hydrochloride (2 g) in EtOH (30 mL). The reaction solution was stirred at 20°C for 16 hours and then concentrated. The residue was added to water (50 mL), and the pH was adjusted to about 5 with acetic acid. The solution was extracted with EA (50 mL). After separation, the aqueous phase was adjusted to about 9 with saturated sodium bicarbonate solution and then extracted with EA (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 18-d.

[0326] Step E: Under nitrogen protection at 0°C, N-methylimidazole (1.72 g, 20.93 mmol, 1.67 mL, 5 eq) and TCFH (2.35 g, 8.37 mmol, 2 eq) were added to a solution of compounds 2-b (1.02 g, 5.44 mmol, 1.3 eq) and 18-d (1.2 g, 4.19 mmol, 1 eq) in ACN (10 mL). The reaction solution was stirred at 20°C for 1 hour and then concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-5:1) to obtain compound 18-e.

[0327] Step F: Under nitrogen protection, sodium tert-butoxide (1.01 g, 10.51 mmol, 4 eq) was added to a MeOH (10 mL) solution of compound 18-e (1.2 g, 2.63 mmol, 1 eq). The reaction solution was stirred at 50 °C for 1 hour. The pH was adjusted to approximately 5 by adding 1 N dilute hydrochloric acid. The solution was concentrated, and the residue was extracted with water (10 mL) and EA (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc = 10:1-2:1) to obtain compound 18-f.

[0328] Step G: Under nitrogen protection, 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 solution was stirred at 50°C for 16 hours. The pH was adjusted to approximately 7 by adding 1N sodium hydroxide aqueous solution to the reaction solution. Then, 1,4-dioxane was concentrated. The residue was added to water (50mL) and MTBE (50mL), stirred for 30 minutes, filtered, and the filter cake was dried under high vacuum to obtain compound 18. 1 H NMR(DMSO-d6,400MHz): δppm 9.63(br s,1H),7.54-7.49(m,1H),7.45-7.39(m,1H),7.34-7.27(m,1H),6.98(br s,1H),4.77(br s,1H),4.40(s,1H),3.79-3.69(m,4H),1.90-1.78(m,2H),1.59(br dd,J=14.3,19.1Hz,2H),1.47(d,J=6.7Hz,3H); LCMS(ESI)m / z:353.3(M+1).

[0329] Bioactivity testing:

[0330] Experiment Example 1: Inhibitory Effect of Cardiac Myosin ATPase Activity

[0331] Experimental reagents:

[0332] Cardiac tropomyosin / troponin complex (Cytoskeleton, Cat.#TT05)

[0333] Cardiac myosin S1 (Cytoskeleton, Cat.#MYS03)

[0334] Cardiac actin (Cytoskeleton, Cat. #AD99-A)

[0335] ATPase Assay Kit (Cytoskeleton, Cat.#BK051)

[0336] Experimental steps:

[0337] 1) Preparation of compounds

[0338] a) The compound was diluted 4-fold with DMSO in an Echo, resulting in 8 concentration gradients, and 200 nL of the compound was transferred into each well of a 96-well plate (Corning-3696).

[0339] b) Centrifuge at 1000 rpm for 15 seconds, then seal the plate for later use.

[0340] 2) Prepare F-actin

[0341] a) Prepare a buffer solution of 5mM Pipes-KOH pH 7.0, 500μM ATP, and 500μM dithiothreitol, and add 2.5mL of buffer to dissolve 1mg of F-actin, so that the protein concentration is 0.4mg / mL.

[0342] b) Let it sit at room temperature for 10 minutes to fully dissolve the protein.

[0343] c) Add 2.0 mM MgCl2 and 2.0 mM EGTA, and let stand at room temperature for 20 minutes to form protein polymers.

[0344] 3) Prepare fine skin filaments

[0345] a) Dissolve 1 mg of myocardial troponin / troponin complex in 200 μL of ice water to achieve a protein concentration of 5 mg / mL.

[0346] b) Add 1000 μL of the F-actin prepared in step 1 and mix well.

[0347] c) Let it sit at room temperature for 20 minutes.

[0348] d) Centrifuge at 87K xg at 4℃ for 1.5 hours.

[0349] e) Prepare PM12 buffer: 12mM Pipes-KOH, pH 7.0, 2mM MgCl2, and add 1200μL buffer to resuspend the protein.

[0350] 4) Prepare the reaction solution and begin the experiment.

[0351] a) Add 250 μL of ice-cold PM12 buffer to 250 μg of S1 myosin, resulting in a protein concentration of 1 mg / mL.

[0352] b) Add the reagents in the following order and mix to obtain the reaction mixture:

[0353] 400 μL of PM12,

[0354] 400 μL of 5x MSEG (from an ATPase assay kit),

[0355] 1200 μL of actin / cardiac troponin / troponin complex,

[0356] 40 μL of myosin S1,

[0357] 40 μL of 100x PNP (from the ATPase assay biochemical kit),

[0358] 10.4 μL of 100 mM ATP.

[0359] c) Add 10 μL of 440 μM CaCl2 solution to a 96-well plate and preheat it in an incubator at 37°C.

[0360] d) Add 100 μL of the reaction mixture to a 96-well plate and centrifuge at 1000 rpm for 10 seconds.

[0361] e) Take continuous readings on a SpectraMax 340PC for 10 minutes, with 30-second intervals, at an instrument temperature of 37°C and a wavelength of 360nm.

[0362] Data Analysis:

[0363] The data were analyzed using Prism, and the experimental results are shown in Table 1.

[0364] Table 1. Inhibitory effect of the compounds of this invention on cardiac myosin ATPase activity (IC50) 50 Value test results

[0365] Compounds IC 50 (μM) 1 14 2 3.97 3 0.73 4 2.2 5 2.08 6 1.71 7 0.3 9 0.04 10 0.22 11 0.51 12 0.06 13 1.08 14 1.19 15 0.21

[0366] Conclusion: The compounds of this invention have good inhibitory activity against cardiac myosin ATPase.

[0367] Experimental Example 2: Pharmacokinetic Evaluation in Rats

[0368] Experimental objective:

[0369] Detection of pharmacokinetic parameters of the compounds of this invention in rats

[0370] Experimental plan:

[0371] 1) Experimental reagents: the compounds of this invention;

[0372] 2) Experimental animals: Four male SD rats aged 7-9 weeks were randomly divided into two groups of two rats each;

[0373] 3) Drug preparation: Weigh an appropriate amount of drug and dissolve it in a mixed solvent of DMAC:PEG-400:30% 2-HP-β-CD = 5:25:70 to prepare a solution of 0.2 mg / mL;

[0374] Experimental procedure:

[0375] Group 1 animals were administered the drug via a single tail vein injection at a dose of 0.2 mg / kg and a concentration of 0.2 mg / mL, while Group 2 animals were administered the compound via gavage at a dose of 1 mg / kg and a concentration of 0.2 mg / mL. 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.

[0376] Data Analysis:

[0377] The drug concentration in plasma samples was determined using LC-MS / MS, and the pharmacokinetic results of the test drugs are shown in Table 2.

[0378] Table 2 Pharmacokinetic test results of the compounds of this invention

[0379]

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

[0381] Conclusion: The compounds of this invention exhibit good pharmacokinetic properties in rats.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, ， in, R1 and R2, together with the carbon atoms they are attached to, form C. 3-6 Cycloalkyl or 3-6-membered heterocycloalkyl, wherein the 3-6-membered heterocycloalkyl is optionally surrounded by 1, 2, 3 or 4 R... b replace; R3 is selected from H and F; R4 is selected from H and C. 1-4 alkyl; R5 is selected from H and C. 1-4 alkyl; R6 is independently selected from H, F, Cl, Br, I, and C, respectively. 1-4 alkyl; R b Selected independently from -CO2R b1 ; R b1 C 1-4 alkyl; n is selected from 1, 2, 3, or 4; The 3-6 membered heterocyclic alkyl groups each independently comprise 1, 2, 3 or 4 atoms or groups of atoms independently selected from N, O, S and NH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R b1 Selected from -CH3 and -CH2CH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 and R2 together with the carbon atoms they are attached to form , , , or , wherein , , , and Each of the 1, 2, 3, or 4 R's can be independently selected. b replace.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein, R1 and R2 together with the carbon atoms they are attached to form , , , , , or .

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, R1 and R2 together with the carbon atoms they are attached to form , , , , or .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from H.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from -CH3 and -CH2CH3.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R5 is selected from H.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R6 is independently selected from H, F, Cl and -CH3.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-1): ， in, n, R1, R2, R3, R4 and R6 are as defined in claim 1.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I-1A) or (I-1B): or , in, n, R1, R2, R3, R4 and R6 are as defined in claim 10, and R4 is not H.

12. A compound of the following formula or a pharmaceutically acceptable salt thereof, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 13. A compound of the following formula or a pharmaceutically acceptable salt thereof, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. The use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a medicament as a myosin inhibitor.

16. The use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating heart failure and hypertrophic cardiomyopathy.

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