Substituted pyridine-2,4-dione derivatives

Abstract

The present invention relates to a series of substituted pyridine-2,4-dione systems and processes for their preparation, in particular to compounds of formula (I) and pharma- ceutically acceptable salts thereof. JPEG2024508004000086.jpg4995

Description

[Technical field]

[0001] This application claims priority to: CN202110214692.X, February 25, 2021; CN202210103134.0, January 27, 2022; CN202210153298.4, February 18, 2022.

[0002] The present invention relates to a series of substituted pyridine-2,4-dione derivatives and a process for preparing the same, in particular to the compound represented by formula (I) and pharma- ceutically acceptable salts thereof. [Background technology]

[0003] Hypertrophic cardiomyopathy is a myocardial disease characterized by myocardial hypertrophy, often invading the interventricular septum, resulting in a smaller ventricular cavity, impeding blood filling of the left ventricle, and reducing the diastolic compliance of the left ventricle. It is divided into obstructive and nonobstructive hypertrophic cardiomyopathy based on the presence or absence of obstruction in the left ventricular outflow tract, and may be related to genetics, etc. The worldwide incidence of HCM is approximately 1 / 500, and its clinical symptoms range from asymptomatic to palpitations, exertional dyspnea, precordial pain, fatigue, syncope, and even sudden death and end-stage left heart failure.

[0004] Currently, there are only a limited number of treatments for HCM, and symptoms are mainly improved by beta-receptor blockers and calcium channel blockers, but they cannot target the cause, slow the progression of myocardial hypertrophy, or improve prognosis, so the therapeutic effect is limited.

[0005] Myosin and actin are the material basis of myocardial contraction, and myosin cross-bridges periodically bind and dissociate with actin, sliding myofilaments and causing myocardial contraction. Myosin has ATPase activity and provides power to myocardial contraction by hydrolyzing ATP. Mutations in myosin extend the binding time of myosin and actin, impairing the excessive contraction and relaxation of the left ventricular myocardium, causing hypertrophy and fibrosis of the left ventricular myocardium, leading to HCM. MYK-461 is an allosteric regulator of cardiac myosin, which slows down the rate of phosphate hydrolysis, shortens the binding time of myosin and actin, produces a negative inotropic effect, and alleviates pathological changes such as myocardial hypertrophy caused by excessive contraction of the left ventricular myocardium. However, it is excreted slowly in the body and the drug remains in the body for too long, making it inconvenient to adjust the dosage quickly (Mark P. Grillo et al. Xenobiotica, 2019; 49(6):718-733). Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, developing myosin inhibitors with better activity and more ideal pharmacokinetic properties is of great clinical value and significance.

[0007] Furthermore, abnormalities in myocardial sarcomeres have been identified as the cause of various cardiac diseases and conditions, such as diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathies, and myosin ATPase inhibitors could also play a potential therapeutic role in mitigating the pathological progression of the above diseases by inhibiting myocardial contraction. [Means for solving the problem]

[0008] The present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

[0009] [ka]

[0010] however, R1 and R2 are each independently H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 alkoxy, wherein said C 1-4 Alkyl and C 1-4 Alkoxy is independently one, two or three R a and optionally replaced by Alternatively, R1 and R2 together with the carbon atom connected thereto form a C 3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl, 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl each independently represent 1, 2, 3, or 4 R b and optionally replaced by R3 is selected from H and F; R4 is H, C 1-4 Alkyl and C 3-4 cycloalkyl, wherein said C 1-4 Alkyl and C 3-4 Cycloalkyl is each independently one, two or three R c and optionally replaced by R5 is H and C 1-4 alkyl, R6 is H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 Alkyl and C 1-4 alkoxy, wherein said C 1-4 Alkyl and C 1-4 Alkoxy is independently one, two or three R d and optionally replaced by R a are independently F, Cl, Br, I, -OH, -NH2, -CN, and C 1-4 Alkyl, C 1-4 Alkoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 and -CONRa1 R a2 wherein C is selected from 1-4 Alkyl and C 1-4 each alkoxy is optionally substituted by 1, 2 or 3 R; R a1 and R a2 are each independently H and C 1-4 alkyl, Or, R a1 and R a2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl each independently has 1, 2, 3, or 4 R e and optionally replaced by R b are independently 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 is selected from 1-4 Alkyl and C 1-4 each alkoxy is optionally substituted by 1, 2 or 3 R; R b1 and R b2 are each independently H and C 1-4 alkyl, Or, R b1 and R b2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl each independently has 1, 2, 3, or 4 R f and optionally replaced by R c are independently F, Cl, Br, I, -OH, -NH2, -CN, and C 1-4 Alkyl and C 1-4 alkoxy; Rd are independently F, Cl, Br, I, -OH, -NH2, -CN, and C 1-4 Alkyl and C 1-4 alkoxy; R e are independently F, Cl, Br, I, -OH, -NH2, -CN, and C 1-4 Alkyl and C 1-4 alkoxy; R f are independently F, Cl, Br, I, -OH, -NH2, -CN, and C 1-4 Alkyl and C 1-4 alkoxy; R is independently selected from F, Cl, Br, I, -OH, -NH2, and -CN; n is selected from 1, 2, 3 or 4; The 3- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl each independently contain 1, 2, 3, or 4 atoms or atomic groups selected from N, O, S, and NH.

[0011] The present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

[0012] [ka]

[0013] however, R1 and R2 are each independently H, F, Cl, Br, I, -OH, -NH2, -CN, C 1-4 alkyl, Alternatively, R1 and R2 together with the carbon atom connected thereto form a C 4-6 cycloalkyl or 5- to 6-membered heterocycloalkyl, 4-6 Cycloalkyl and 5- to 6-membered heterocycloalkyl each independently represent 1, 2, 3, or 4 R b and optionally replaced by R3 is selected from H and F; R4 is H and C 1-4 alkyl, R5 is selected from H; R6 is H, F, Cl, Br, I and C 1-4 alkyl, R b are independently F, Cl, Br, I, -OH, -NH2, -CN, and C 1-4 Alkoxy, -COR b1 and -CO2R b1 is selected from R b1 H and C 1-4 alkyl, n is selected from 1 or 2; The 5- to 6-membered heterocycloalkyl each contain 1, 2, 3, or 4 atoms or atomic groups independently selected from N, O, S, and NH.

[0014] In some embodiments of the present invention, the R a1 and R a2 are each independently selected from H, and the other variables are as defined herein.

[0015] In some embodiments of the present invention, the R a , R c , R d , R e and R f are each independently selected from F and Cl, and the other variables are as defined herein.

[0016] In some embodiments of the invention, R and R are each independently selected from -CH and -CHCH, where -CH and -CHCH are each independently selected from 1, 2 or 3 R a Optionally replaced by R a and other variables are as defined in the present invention.

[0017] In some embodiments of the present invention, R1 and R2 are each independently selected from -CH3 and -CH2CH3, and all other variables are as defined herein.

[0018] In some embodiments of the present invention, the R b1 and R b2 are each independently selected from -CH3 and -CH2CH3, and all other variables are as defined herein.

[0019] In some embodiments of the present invention, the R b are each independently selected from F, Cl, Br, -OCH3, -COCH3, -CO2CH3 and -CO2CH2CH3, and all other variables are as defined herein.

[0020] In some embodiments of the present invention, the R b are each independently selected from F, Cl, Br, -OCH3, -COCH3, and -CO2CH2CH3, and all other variables are as defined herein.

[0021] In some embodiments of the present invention, R and R together with the carbon atom connected thereto are C 5-6 cycloalkyl or 6-membered heterocycloalkyl, wherein said C 5-6 Cycloalkyl and 6-membered heterocycloalkyl each independently have 1, 2, 3 or 4 R b Optionally replaced by R b and other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, R1 and R2 together with the carbon atom connected thereto are

[0023] [ka]

[0024] wherein said

[0025] [ka]

[0026] each independently represents 1, 2, 3 or 4 R b Optionally replaced by R b and other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, R1 and R2 together with the carbon atom connected thereto are

[0028] [ka]

[0029] wherein said

[0030] [ka]

[0031] each independently represents 1, 2, 3 or 4 R b Optionally replaced by R b and other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, R1 and R2 together with the carbon atom connected thereto are

[0033] [ka]

[0034] Form R b and other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, R1 and R2 together with the carbon atom connected thereto are

[0036] [ka]

[0037] Form R b and other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, R1 and R2 together with the carbon atom connected thereto are

[0039] [ka]

[0040] and the other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, R1 and R2 together with the carbon atom connected thereto are

[0042] [ka]

[0043] and the other variables are as defined in the present invention.

[0044] In some embodiments of the invention, the structural fragment

[0045] [ka]

[0046] teeth,

[0047] [ka]

[0048] and the other variables are as defined herein.

[0049] In some embodiments of the invention, the structural fragment

[0050] [ka]

[0051] teeth,

[0052] [ka]

[0053] and the other variables are as defined herein.

[0054] In some embodiments of the invention, the structural fragment

[0055] [ka]

[0056] teeth,

[0057] [ka]

[0058] and the other variables are as defined herein.

[0059] In some embodiments of the present invention, R3 above is selected from H, and other variables are as defined herein.

[0060] In some embodiments of the present invention, R4 is C 1-4 alkyl, and the other variables are as defined herein.

[0061] In some embodiments of the invention, R4 is selected from -CH3 and -CH2CH3, wherein -CH3 and -CH2CH3 are each independently selected from 1, 2 or 3 R d Optionally replaced by R d and other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, R4 is selected from -CH3 and -CH2CH3, and other variables are as defined herein.

[0063] In some embodiments of the present invention, R4 is selected from -CH3, and other variables are as defined herein.

[0064] In some embodiments of the present invention, R5 above is selected from H, and other variables are as defined herein.

[0065] In some embodiments of the invention, each R6 is independently selected from H, F, Cl, and -CH3, where -CH3 is selected from 1, 2, or 3 R d Optionally replaced by R d and other variables are as defined in the present invention.

[0066] In some embodiments of the present invention, each R6 is independently selected from H, F, Cl, and -CH3, and all other variables are as defined herein.

[0067] In some embodiments of the present invention, each R6 is independently selected from H, F, and -CH3, and all other variables are as defined herein.

[0068] In some embodiments of the invention, the compound has a structure represented by formula (I-1).

[0069] [ka]

[0070] wherein n, R1, R2, R3, R4 and R6 are as defined in the present invention.

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

[0072] [ka]

[0073] however, n is selected from 1 and 2; m is selected from 0, 1 and 2; q is selected from 0 and 1; T is selected from CH2, O, and NH, and when T is selected from CH2 and NH, T is R b may be optionally replaced by R b , R4 and R6 are as defined in the present invention.

[0074] In some embodiments of the invention, the compound has a structure represented by formula (I-1A) or (I-1B).

[0075] [ka]

[0076] wherein n, R1, R2, R3, R4 and R6 are as defined herein, and R4 is not H.

[0077] In some embodiments of the invention, the compound has a structure represented by formula (I-1-1A) or (I-1-1B).

[0078] [ka]

[0079] however, n is selected from 1 and 2; m is selected from 0, 1 and 2; q is selected from 0 and 1; R4 is C 1-4 alkyl, T is selected from CH2, O, and NH, and when T is selected from CH2 and NH, T is R b may be optionally replaced by R b , R4 and R6 are as defined in the present invention.

[0080] Further embodiments of the present invention are formed by any combination of the above variables.

[0081] The present invention further provides a compound of the formula: or a pharma- ceutically acceptable salt thereof.

[0082] [ka]

[0083] The present invention further provides a compound of the formula: or a pharma- ceutically acceptable salt thereof.

[0084] [ka]

[0085] [ka]

[0086] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0087] The present invention further provides use of the above compound or a pharma- ceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a medicament for inhibiting cardiac myosin.

[0088] The present invention further provides the use of the above compound or a pharma- ceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a medicament for treating heart failure and hypertrophic cardiomyopathy.

[0089] The present invention further provides a method for treating a disease associated with a cardiac myosin inhibitor in a subject in need thereof, comprising administering to the subject an effective amount of a compound defined in any of the above embodiments or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition as defined above.

[0090] The present invention further provides a method for treating heart failure and hypertrophic cardiomyopathy in a subject in need thereof, comprising administering to the subject an effective amount of a compound defined in any of the above embodiments or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition as defined above. Effect of the Invention

[0091] The compounds of the present invention have good inhibitory effects on cardiac myosin ATPase and also have excellent pharmacokinetic properties. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0092] Definitions and Explanations

[0093] Unless otherwise stated, the following terms and phrases used herein shall have the following meanings: Certain terms or phrases, unless specifically defined, should not be considered indefinite or unclear, but should be understood according to their ordinary meaning. When trade names are mentioned herein, it is intended to refer to the corresponding trade name or its active ingredients.

[0094] As used herein, the term "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals and are commensurate with a reasonable benefit / risk ratio without undue toxicity, irritation, allergic response or other problem or complication.

[0095] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents found in the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of a base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or in a suitable inert solvent. Illustrative examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functionalities and thus can be converted into either base or acid addition salts.

[0096] The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound that contains an acid or base group by conventional methods. Generally, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0097] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. All such compounds contemplated by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and mixtures thereof are included within the scope of the present invention.

[0098] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

[0099] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of carbon atoms forming a ring.

[0100] Unless otherwise explained, the term "diastereomers" refers to stereoisomers whose molecules have two or more centers of chirality and which are not mirror images of each other.

[0101] Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0102] [ka]

[0103] The compounds of the present invention may exist specifically. Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can be rapidly interconverted. If tautomers are possible (e.g., in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of protons, such as keto-enol isomerization and imine-enol isomerization. Valence tautomers include interconversions via recombination of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0104] Unless otherwise specified, the terms "enriched in one isomer," "enriched in an isomer," "enriched in one enantiomer," or "enantiomer-enriched" refer to less than 100% isomer or enantiomer and having at least 60% of that isomer or enantiomer, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%.

[0105] Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present in 90% and the other isomer or enantiomer is present in 10%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0106] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. A single enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, followed by separation of the diastereomers by conventional methods known in the art, followed by recovery to provide the pure enantiomers. Separation of enantiomers and diastereomers is also typically accomplished using chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g., carbamate formation from amines).

[0107] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), C-14( 14 C). Or, for example, deuterium can be replaced with hydrogen to form a deuterated drug, where the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. Conversion of the isotopic composition of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.

[0108] The terms "optionally" and "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs as well as instances where the event or circumstance does not occur.

[0109] The term "substituted" means that any one or more hydrogen atoms at a particular atom are replaced with a substituent, which may include deuterium and hydrogen variants, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0110] The term "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise specified, the types and number of substituents are any that are chemically feasible.

[0111] When any variable (e.g., R) occurs more than one time in a composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group may be optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0112] When the number of linking groups is 0, for example, -(CRR)0- means that the linking group is a single bond.

[0113] When one of the variables is a single bond, it means that the two groups to which it is linked are directly bonded; for example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0114] When a substituent is empty, it means that the substituent is not present, for example, when X in AX is empty, it means that the structure is actually A. When there is no indication of which atom a recited substituent is bonded to the substituted group through, such substituent may be bonded through any atom thereof, for example, pyridinyl as a substituent may be bonded to the substituted group through any carbon atom of the pyridine ring.

[0115] When the listed linking group does not indicate the direction of the link, the direction of the link is arbitrary, for example:

[0116] [ka]

[0117] In the formula, the linking group L is -MW-, where -MW- links ring A and ring B in the same direction as the reading order from left to right.

[0118] [ka]

[0119] We can also construct the following by concatenating rings A and B in the reverse order of reading from left to right:

[0120] [ka]

[0121] Combinations of the above linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0122] Unless otherwise stated, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups via chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, the number of H atoms at the site is reduced to the corresponding valence of the group according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is:

[0123] [ka]

[0124] For example, the straight solid bond in -OCH3 represents a bond to another group through the oxygen atom in that group,

[0125] [ka]

[0126] The straight-dashed bond represents a bond between the nitrogen atom of the group and another group,

[0127] [ka]

[0128] The wavy lines indicate that the phenyl is bonded to another group via the 1st and 2nd carbon atoms of the phenyl.

[0129] [ka]

[0130] represents that any available bonding site of the piperidinyl can be bonded to another group via one chemical bond, and at least

[0131] [ka]

[0132] Even if the H atom is drawn as -N-,

[0133] [ka]

[0134] When one chemical bond is bonded, the H at that site decreases by one to the corresponding monovalent piperidinyl.

[0135] If a chemical bond of a substituent crosses the chemical bond between two atoms on a connecting ring, it means that the substituent can form a bond with any atom on the ring. If the atom bonded to a substituent is not specified, it means that the substituent may be bonded to any atom, and if the atom bonded to a substituent is a bicyclic or tricyclic ring system, it means that the substituent may be bonded to any atom of any ring in that system. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. For example, structural units

[0136] [ka]

[0137] means that substitution can occur at any position on the cyclohexyl or cyclopentyl.

[0138] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, e.g., a "5- to 7-membered ring" refers to a "ring" having 5 to 7 atoms arranged around it.

[0139] Unless otherwise stated, "C 1-3 The term "alkyl" is used to represent a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1-3 Alkyl has C 1-2 and C 2-3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). 1-3 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0140] Unless otherwise stated, "C 1-4 The term "alkyl" is used to represent a straight or branched chain saturated hydrocarbon group of 1 to 4 carbon atoms. 1-4 Alkyl has C 1-2 , C 1-3 and C 2-3alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). 1-4 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0141] Unless otherwise stated, "C 1-4 The term "alkoxy" refers to an alkyl group containing 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-4 Alkoxy is C 1-3 , C 1-2 , C 2-4 , C4 and C3 alkoxy, etc. 1-4 Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), and the like.

[0142] The term "heteroalkyl", by itself or in combination with other terms, refers to a stable linear or branched alkyl radical or combinations thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In some other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-6 heteroalkyl, and in some other embodiments, the heteroalkyl is C 1-3Heteroalkyl. The heteroatom or heteroatom group can be placed at any interior position of the heteroalkyl, including the position at which the alkyl is attached to the remainder of the molecule, although "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are conventional expressions and refer to alkyl attached to the remainder of the molecule via an oxygen, amino, or sulfur atom, respectively. Illustrative examples of heteroalkyl include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH, -S(=O)-CH, -CH-CH-S(=O)-CH. Up to two heteroatoms can be consecutive, for example, -CH-NH-OCH.

[0143] Unless otherwise stated, C n-n+m Or C n -C n+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 Including any one of the ranges of n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0144] Unless otherwise stated, "C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms, which includes monocyclic and bicyclic ring systems, and 3-6 Cycloalkyl has C 3-5 , C 4-5 Or C 5-6 Cycloalkyl and the like are included, which may be monovalent, divalent or polyvalent. C 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0145] Unless otherwise stated, "C 3-4 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 3 to 4 carbon atoms that is monocyclic and may be monovalent, divalent or polyvalent. 3-5 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0146] Unless otherwise stated, "C 4-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 4 to 6 carbon atoms, which includes monocyclic and bicyclic ring systems, and 4-6 Cycloalkyl has C 4-5 and C 5-6 Cycloalkyl and the like are included, which may be monovalent, divalent or polyvalent. C 4-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0147] Unless otherwise stated, "C5-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 5 to 6 carbon atoms, which includes monocyclic and bicyclic ring systems, and 3-6 Cycloalkyl includes 5-membered cycloalkyl and 6-membered cycloalkyl, and may be monovalent, divalent or polyvalent. 5-6 Illustrative examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, and the like.

[0148] Unless otherwise stated, the term "3- to 6-membered heterocycloalkyl", by itself or in combination with other terms, means a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p、 p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, for the "3- to 6-membered heterocycloalkyl", a heteroatom can occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. The 3- to 6-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl, etc. Illustrative examples of 3- to 6-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl, and the like.

[0149] Unless otherwise stated, the term "4- to 6-membered heterocycloalkyl", by itself or in combination with other terms, means a saturated cyclic group consisting of 4 to 6 ring atoms, each of which one, two, three, or four 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 be optionally oxidized (i.e., NO and S(O)). p、 p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, for the "4-6 membered heterocycloalkyl", a heteroatom can occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, etc. Illustrative examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl, and the like.

[0150] Unless otherwise stated, the term "5- to 6-membered heterocycloalkyl", by itself or in combination with other terms, means a saturated cyclic group consisting of 5 to 6 ring atoms, each of which 1, 2, 3, or 4 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 be optionally oxidized (i.e., C(=O), NO, and S(O)). p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, for the "5- to 6-membered heterocycloalkyl", a heteroatom can occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. The 5- to 6-membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl. Illustrative examples of 5-6 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, and the like.

[0151] Unless otherwise stated, the term "6-membered heterocycloalkyl", by itself or in combination with other terms, means a saturated cyclic group each consisting of 6 ring atoms, of which 1, 2, 3, or 4 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 be optionally oxidized (i.e., C(=O), NO, and S(=O)). p、p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, for the "6-membered heterocycloalkyl", a heteroatom can occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. Illustrative examples of 6-membered heterocycloalkyl include, but are not limited to, tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, and the like.

[0152] The term "leaving group" refers to a functional group or atom that may be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like; and the like.

[0153] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino acid 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-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS). The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl. Representative hydroxyl protecting groups include, but are not limited to, alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-formyloxybenzyl (PMB), 9-fluorenylethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.

[0154] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternative methods known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0155] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art.For example, in single crystal X-ray diffraction (SXRD), the single crystal is grown and collected diffraction intensity data by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, and after collecting relevant data, the crystal structure can be further analyzed by direct method (Shelxs97) to confirm the absolute configuration.

[0156] The solvents used in the present invention can be obtained commercially.

[0157] The following abbreviations are used in the present invention: TEA stands for triethylamine; DIEA stands for N,N-diisopropylethylamine; PE stands for petroleum ether; EtOAc stands for ethyl acetate; EA stands for ethyl acetate; THF stands for tetrahydrofuran; MeOH stands for methanol; MTBE stands for methyl tert-butyl ether; DCM stands for dichloromethane; EtOH stands for ethanol; iPrOH stands for isopropanol; Boc2O stands for di-tert-butyl dicarbonate; L-selectride stands for lithium tri-sec-butylborohydride; TCFH stands for chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; FA stands for formic acid; TFA stands for trifluoroacetic acid; ACN stands for acetonitrile; TLC stands for thin layer chromatography; HPLC stands for high performance liquid chromatography; LCMS stands for liquid chromatography-mass spectrometry. DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; LDA stands for lithium diisopropylamide; DMAC stands for N,N-dimethylacetamide; PEG-400 stands for polyethylene glycol 400; EGTA stands for ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid; DMSO-d6 stands for deuterated dimethyl sulfoxide; and CDCl3 stands for deuterated chloroform.

[0158] Compounds are named according to conventional naming conventions in the art or using the ChemDraw (R) Compounds are named using the software, and commercially available compounds are named in the supplier's catalogue. EXAMPLES

[0159] The present invention will be described in detail below with reference to examples, but these are not intended to limit the present invention in any way. The compounds of the present invention can be produced by various synthesis methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthesis methods, and equivalent alternative methods known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention. Various changes and modifications to the specific embodiments of the present invention will be apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0160] Example 1

[0161] [ka]

[0162] Synthesis Route:

[0163] [ka]

[0164] Step A: At 20° C., DIEA (1.98 g, 15.33 mmol, 2.67 mL, 2 eq) was added to a 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) in EtOH (20 mL), and the reaction solution was stirred at 20° C. for 16 h. After concentration, compound 1-a was obtained.

[0165] Step B: Under nitrogen gas protection, 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 solution of compound 1-a (1.6 g, 6.83 mmol, 1 eq) in THF (30 mL) at 0 ° C., the reaction solution was stirred at 20 ° C. for 1 h, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain compound 1-b. LCMS (ESI) m / z: 377.3 (M + 1).

[0166] Step C: Under nitrogen gas protection, sodium tert-butoxide (1.53 g, 15.94 mmol, 4 eq) was added to a solution of compound 1-b (1.5 g, 3.98 mmol, 1 eq) in MeOH (30 mL), and the reaction solution was stirred at 20 °C for 4 h. Dilute hydrochloric acid (1 mol / L, 50 mL) was then added, and the mixture was extracted with EA (50 mL). 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 to 2: 1) to obtain compound 1-c.

[0167] Step D: Under nitrogen gas protection, lithium chloride (107.20 mg, 2.53 mmol, 51.79 μL, 2 eq) was added to a solution of compound 1-c (0.4 g, 1.26 mmol, 1 eq) in DMSO (4 mL), and the reaction solution was stirred at 125 °C for 20 h, filtered, and the filtrate was purified by preparative HPLC [mobile phase: water (0.1% TFA)-ACN; gradient: 21% to 51% ACN] to obtain compound 1. 1 H NMR (CDCl3, 400 MHz): 7.38 - 7.24 (m, 5H), 5.17 (br s, 1H), 4.63 (br d, J=6.4 Hz, 1H), 1.57 (d, J=6.7 Hz, 3H), 1.42 (s, 3H), 1.38 (s, 3H);LCMS(ESI) m / z: 259.4(M+1).

[0168] Example 2

[0169] [ka]

[0170] Synthesis Route:

[0171] [ka]

[0172] Step A: Under nitrogen gas protection, LDA (2M, 19.07mL, 1.1eq) was added dropwise to a solution of compound 2-1 (5g, 34.68mmol, 4.63mL, 1eq) in THF (80mL) at -78°C, the reaction solution was stirred at -78°C for 30 min, then methyl chloroformate (3.44g, 36.42mmol, 2.82mL, 1.05eq) was added, the reaction solution was slowly warmed to 20°C, and stirred for 16 h, after which water (200mL) was added to quench, and then extracted with EA (200mL), the organic phase was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain compound 2-a.

[0173] Step B: At 0° C., sodium hydroxide (494.51 mg, 12.36 mmol, 1 eq) was added to a solution of compound 2-a (2.5 g, 12.36 mmol, 1 eq) in MeOH (20 mL) and water (20 mL), and the reaction solution was stirred at 20° C. for 16 h, followed by addition of water (50 mL), followed by extraction with EA (50 mL), and after separation, the aqueous phase was adjusted to about pH 5 with 1M dilute hydrochloric acid, followed by extraction with EA (50 mL), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated to obtain compound 2-b.

[0174] Step C: Under nitrogen gas protection, 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 solution of compound 2-b (1.7 g, 9.03 mmol, 1 eq) in DCM (30 mL) at 0° C., and then oxalyl chloride (1.72 g, 13.55 mmol, 1.19 mL, 1.5 eq) was added. The reaction solution was stirred at 20° C. for 1 h and then concentrated to give compound 2-c.

[0175] Step D: Under nitrogen gas protection, 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) at 0 ° C., the reaction solution was stirred at 20 ° C. for 1 hour, concentrated, diluted with EA (30 mL), then washed with 1N dilute hydrochloric acid (30 mL), washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain compound 2-d.

[0176] Step E: Under nitrogen gas protection, sodium methoxide (2M, 7 mL, 16.18 eq) was added to a solution of compound 2-d (0.35 g, 865.36 μmol, 1 eq) in MeOH (5 mL), and the reaction solution was stirred at 50° C. for 2 hours, then concentrated. The residue was diluted with EA (20 mL), then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EtOAc=10:1 to 1:1) to obtain compound 2-e.

[0177] Step F: Compound 2-e (70 mg, 195.32 μmol, 1 eq) in 1,4-dioxane (7 mL) was added with hydrochloric acid (4 M, 7.00 mL, 143.35 eq), the reaction solution was stirred at 50° C. for 16 hours, concentrated, the residue was neutralized with 2N aqueous sodium hydroxide solution, and then extracted with EA (50 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [water (0.225% FA)-ACN]; gradient: 17% to 47% ACN) to obtain compound 2. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.62 (br s, 1H), 7.47 - 7.20 (m, 5H), 7.05 (br s, 1H), 4.60 (br t, J=6.7 Hz, 1H), 4.41 (s, 1H), 3.85 - 3.66 (m, 4H), 1.94 - 1.75 (m, 2H), 1.68 - 1.51 (m, 2H), 1.43 (d, J=6.8 Hz, 3H);LCMS(ESI) m / z: 301.4(M+1).

[0178] Example 3

[0179] [ka]

[0180] Synthesis Route:

[0181] [ka]

[0182] Step A: Under nitrogen gas protection, potassium carbonate (10.46 g, 75.69 mmol, 2 eq) was added to a 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) in DMF (50 mL), and the reaction solution was stirred at 50 °C for 16 h, after which EA (200 mL) was added, followed by washing with water (200 mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration. The residue was separated by column chromatography (PE: EtOAc = 20: 1 to 10: 1) to obtain compound 3-a.

[0183] Step B: To a solution of compound 3-a (4.5 g, 24.17 mmol, 1 eq) in MeOH (25 mL) and water (25 mL) was added sodium hydroxide (1.06 g, 26.58 mmol, 1.1 eq), the reaction solution was stirred at 20° C. for 16 h, water (30 mL) was added, and then extracted with EA (30 mL). After separation, the aqueous phase was adjusted to pH about 5 with 1 M dilute hydrochloric acid, then extracted with EA (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 3-b.

[0184] Step C: Under nitrogen gas protection, 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 solution of compound 3-b (2.1 g, 12.20 mmol, 1 eq) in DCM (30 mL) at -20°C, followed by addition of oxalyl chloride (2.01 g, 15.86 mmol, 1.39 mL, 1.3 eq). The reaction solution was stirred at 20°C for 1 hour and then concentrated to give compound 3-c.

[0185] Step D: Under nitrogen gas protection, 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) at -20 ° C., the reaction solution was stirred at 0 ° C. for 1 hour, concentrated, and the residue was diluted with EA (30 mL), then 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 to 5: 1) to obtain compound 3-d.

[0186] Step E: Under nitrogen gas protection, sodium methoxide (1M, 7.21mL, 4eq) was added to a solution of compound 3-d (0.7g, 1.80mmol, 1eq) in MeOH (4mL), and the reaction solution was stirred at 20°C for 16 hours. The reaction solution was adjusted to pH=5 by adding 1N dilute hydrochloric acid, and then extracted with EA (20mL). The organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3-e.

[0187] Step F: Compound 3-e (0.8 g, 2.34 mmol, 1 eq) in 1,4-dioxane (6 mL) was added with hydrochloric acid (4 M, 6 mL, 10.27 eq), and the reaction solution was stirred at 50° C. for 16 hours, then diluted with EA (50 mL), and then adjusted to pH=7 by adding 1N aqueous sodium hydroxide solution. After separation, the organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. MeOH (10 mL) was added to the residue and stirred for 20 minutes, filtered, and the cake was dried under high vacuum to obtain compound 3. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.49 (br s, 1H), 7.41 - 7.31 (m, 4H), 7.30 - 7.25 (m, 1H), 6.92 (br d, J=5.1 Hz, 1H), 4.60 (br t, J=6.7 Hz, LCMS(ESI) m / z: 285.4(M+1).

[0188] Example 4

[0189] [ka]

[0190] Synthesis Route:

[0191] [ka]

[0192] Step A: 4-1 (26 g, 113.07 mmol, 15.29 mL, 1 eq) and potassium carbonate (31.25 g, 226.15 mmol, 2 eq) were added to a solution of 3-1 (14.94 g, 113.07 mmol, 12.99 mL, 1 eq) in DMF (150 mL). After stirring the reaction solution at 50 °C for 16 h, EA (150 mL) was added, then washed with water (150 mL), the organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 50: 1 to 30: 1) to obtain compound 4-a.

[0193] Step B: To a solution of 4-a (6.9 g, 34.46 mmol, 1 eq) in MeOH (40 mL) and water (40 mL) was added sodium hydroxide (1.38 g, 34.46 mmol, 1 eq), the reaction solution was stirred at 15° C. for 16 h, then water (50 mL) was added, followed by extraction with EA (100 mL), and after separation, the aqueous phase was adjusted to pH about 5 with 1 M dilute hydrochloric acid, followed by extraction with EA (100 mL×2), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4-b.

[0194] Step C: To a solution of 4-b (4.5 g, 24.17 mmol, 1 eq) in DCM (50 mL) 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, followed by oxalyl chloride (3.99 g, 31.42 mmol, 2.75 mL, 1.3 eq), and the reaction solution was stirred at 10 °C for 1 h and then concentrated to give compound 4-c.

[0195] Step D: At 0 °C, TEA (4.94 g, 48.86 mmol, 6.80 mL, 2 eq) was added to a solution of 4-c (5 g, 24.43 mmol, 1 eq) in DCM (50 mL), followed by addition of 1-a (5.72 g, 24.43 mmol, 1 eq). The reaction solution was stirred at 0 °C for 1 h, then concentrated, and the residue was separated by column chromatography (PE: EtOAc = 30: 1 to 10: 1) to give compound 4-d.

[0196] Step E: Under nitrogen gas protection, sodium methoxide (1M, 28.57mL, 5eq) was added to a solution of 4-d (2.30g, 5.71mmol, 1eq) in MeOH (15mL), the reaction solution was stirred at 10°C for 16 hours, then stirred at 50°C for 3 hours, 1N dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 5, and then EA (50mL x 2) was added for extraction, the combined organic phase was washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain compound 4-e.

[0197] Step F: To a solution of 4-e (0.7 g, 1.96 mmol, 1 eq) in 1,4-dioxane (10 mL) and THF (2 mL), hydrochloric acid (4 M, 10.50 mL, 21.38 eq) was added, and the reaction solution was stirred at 50° C. for 40 hours, and then 1N aqueous sodium hydroxide solution was added to adjust the pH to about 7, and then extracted with DCM / MeOH=10 / 1 (50 mL×2). The combined organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. MeOH (10 mL) was added to the residue and stirred at 10° C. for 30 minutes, filtered, and the cake was dried under high vacuum to obtain compound 4. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.38 (br s, 1H), 7.41 - 7.22 (m, 5H), 6.84 (br d, J = 5.4 Hz, 1H), 4.57 (br t, J = 6.8 Hz, 1H), 4.36 (s, 1H), 1.74 - 1.45 (m, 10H), 1.41 (d, J = 6.8 Hz, 3H); LCMS(ESI) m / z: 299.2(M+1).

[0198] Example 5

[0199] [ka]

[0200] Synthesis Route:

[0201] [ka]

[0202] Step A: Under nitrogen gas protection, DIEA (1.86 g, 14.37 mmol, 2.50 mL, 2 eq) was added to a solution of compound 5-1 (1.00 g, 7.19 mmol, 1 eq) and compound 1-1 (1.14 g, 7.19 mmol, 1 eq) in EtOH (15 mL) at 20° C., and the reaction solution was stirred at 20° C. for 16 hours. After concentration, compound 5-a was obtained.

[0203] Step B: Under nitrogen gas protection, TEA (1.45 g, 14.35 mmol, 2.00 mL, 2 eq) was added to a solution of 5-a (1.81 g, 7.17 mmol, 1 eq) in DCM (30 mL) at 20 °C, then 3-c (1.37 g, 7.17 mmol, 1 eq) was added, the reaction solution was stirred at 20 °C for 16 h, concentrated, the residue was diluted with EA (40 mL), then washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 20: 1 to 10: 1) to obtain compound 5-b.

[0204] Step C: Under nitrogen gas protection, sodium methoxide (1M, 5.90mL, 4eq) was added to a solution of 5-b (600mg, 1.48mmol, 1eq) in MeOH (6mL) at 20°C, the reaction solution was stirred at 40°C for 16 hours, the reaction solution was added to water (40mL), and then extracted with EA (40mL x 2), the combined organic phase was washed with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to obtain compound 5-c.

[0205] Step D: At 20° C., hydrochloric acid (4M, 3.82 mL, 10 eq) was added to a solution of 5-c (550 mg, 1.53 mmol, 1 eq) in 1,4-dioxane (4 mL), the reaction solution was stirred at 40° C. for 16 h, EA (40 mL) was added to the reaction solution, then 1N aqueous sodium hydroxide solution was added to adjust the pH to about 7, separated, the aqueous phase was extracted with EA (40 mL), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and then concentrated, MeOH (5 mL) was added to the residue, stirred, filtered, and the cake was dried under high vacuum to give compound 5. 1H NMR (DMSO-d6, 400 MHz):δ ppm 9.48 (br s, 1H), 7.38 (dd, J=5.6, 8.6 Hz, 2H), 7.19 (t, J=8.8 Hz, 2H), 6.91 (br d, J=6.0 Hz, 1H), 4.62 (br t, LCMS(ESI) m / z: 302.8(M+1).

[0206] Example 6

[0207] [ka]

[0208] Synthesis Route:

[0209] [ka]

[0210] Step A: Under nitrogen gas protection, DIEA (1.86 g, 14.37 mmol, 2.50 mL, 2 eq) was added to a solution of compound 6-1 (1.00 g, 7.19 mmol, 1 eq) and compound 1-1 (1.14 g, 7.19 mmol, 1 eq) in EtOH (15 mL) at 20° C., and the reaction solution was stirred at 20° C. for 16 hours. After concentration, compound 6-a was obtained.

[0211] Step B: Under nitrogen gas protection, TEA (1.45 g, 14.35 mmol, 2.00 mL, 2 eq) was added to a solution of 6-a (1.81 g, 7.17 mmol, 1 eq) in DCM (30 mL) at 20 °C, then 3-c (1.37 g, 7.17 mmol, 1 eq) was added, the reaction solution was stirred at 20 °C for 16 h, then concentrated, the residue was diluted with EA (40 mL), then washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 20: 1 to 10: 1) to obtain compound 6-b.

[0212] Step C: Under nitrogen gas protection, sodium methoxide (1M, 8mL, 4.34eq) was added to a solution of 6-b (750.00mg, 1.85mmol, 1eq) in MeOH (8mL) at 20℃, the reaction solution was stirred at 40℃ for 16 hours, cooled to room temperature, EA (30mL) was added, and then the pH was adjusted to about 7 with 1N hydrochloric acid, separated, the aqueous phase was extracted with EA (40mL×2), the combined organic phase was washed with saturated brine (40mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE:EtOAc=5:1-1:1) to obtain compound 6-c.

[0213] Step D: At 20° C., hydrochloric acid (4M, 3.82 mL, 10 eq) was added to a solution of 6-c (550 mg, 1.53 mmol, 1 eq) in 1,4-dioxane (4 mL), the reaction solution was stirred at 40° C. for 16 h, water (40 mL) was added to the reaction solution, and then saturated aqueous sodium bicarbonate was added to adjust the pH to about 7, extracted with EA (40 mL×2), the combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, MeOH (6 mL) was added to the residue, stirred for 15 min and then filtered, and the cake was dried under high vacuum to give compound 6. 1H NMR (DMSO-d6, 400 MHz):δ ppm 9.51 (br s, 1H), 7.49 - 7.35 (m, 1H), 7.19 (br d, J=7.7 Hz, 2H), 7.09 (dt, J=1.6, 8.2 Hz, 1H), 6.94 (br d, LCMS(ESI) m / z: 302.8(M+1).

[0214] Example 7

[0215] [ka]

[0216] Synthesis Route:

[0217] [ka]

[0218] Step A: Under nitrogen gas protection, DIEA (1.26 g, 9.77 mmol, 1.70 mL, 2 eq) was added to a solution of compound 7-1 (0.76 g, 4.88 mmol, 1 eq) and compound 1-1 (777.38 mg, 4.88 mmol, 1 eq) in EtOH (15 mL) at 20° C., and the reaction solution was stirred at 20° C. for 16 hours. After concentration, compound 7-a was obtained.

[0219] Step B: Under nitrogen gas protection, TEA (986.53 mg, 9.75 mmol, 1.36 mL, 2 eq) was added to a solution of 7-a (1.31 g, 4.87 mmol, 1 eq) in DCM (30 mL) at 20 °C, then 3-c (1.23 g, 6.45 mmol, 1.32 eq) was added, the reaction solution was stirred at 20 °C for 16 h, then concentrated, the residue was diluted with EA (40 mL), then washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 20: 1 to 10: 1) to obtain compound 7-b.

[0220] Step C: Under nitrogen gas protection, sodium methoxide (1M, 8mL, 4.51eq) was added to a solution of 7-b (750mg, 1.77mmol, 1eq) in MeOH (8mL) at 20℃, the reaction solution was stirred at 40℃ for 16 hours, cooled to room temperature, EA (30mL) was added, and then the pH was adjusted to about 7 with 1N hydrochloric acid, separated, the aqueous phase was extracted with EA (60mL×2), the combined organic phase was washed with saturated brine (60mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE:EtOAc=4:1-1:1) to obtain compound 7-c.

[0221] Step D: At 20° C., hydrochloric acid (4M, 3.82 mL, 10 eq) was added to a solution of 7-c (575.11 mg, 1.53 mmol, 1 eq) in 1,4-dioxane (4 mL), the reaction solution was stirred at 40° C. for 16 h, water (40 mL) was added to the reaction solution, and then saturated aqueous sodium bicarbonate was added to adjust the pH to about 7, extracted with EA (40 mL×2), the combined organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, MeOH (4 mL) was added to the residue, stirred for 15 min and then filtered, and the cake was dried under high vacuum to give compound 7. 1H NMR (DMSO-d6, 400 MHz) δ ppm 9.51 (br s, 1H), 7.48 - 7.37 (m, 2H), 7.36 - 7.27 (m, 2H), 6.95 (br d, J=5.1 Hz, 1H), 4.63 (br t, J=6.7 Hz, LCMS(ESI) m / z: 318.8(M+1).

[0222] Example 8

[0223] [ka]

[0224] Synthesis Route:

[0225] [ka]

[0226] Step A: Under nitrogen gas protection, LDA (2M, 49.32mL, 1.2eq) was added dropwise to a solution of compound 8-1 (20g, 82.20mmol, 1eq) in THF (200mL) at -78°C, 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 warmed to 20°C, and stirred for 4 hours, after which it was quenched by adding saturated aqueous ammonium chloride solution (600mL), and then extracted with EA (600mL), the organic phase was washed with saturated brine (200mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 8-a.

[0227] Step B: To a solution of compound 8-a (27 g, 89.60 mmol, 1 eq) in MeOH (200 mL) and water (200 mL) was added sodium hydroxide (3.58 g, 89.60 mmol, 1 eq), the reaction solution was stirred at 15° C. for 16 h, water (200 mL) was added, and then extracted with EA (200 mL). After separation, the aqueous phase was adjusted to pH about 5 with 1M dilute hydrochloric acid, and then extracted with EA (300 mL×2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 8-b.

[0228] Step C: Under nitrogen gas protection, 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 solution of compound 8-b (23 g, 80.05 mmol, 1 eq) in DCM (200 mL) at 0° C., and then oxalyl chloride (13.21 g, 104.07 mmol, 9.11 mL, 1.3 eq) was added. The reaction solution was stirred at 10° C. for 1 hour, and then concentrated to give compound 8-c.

[0229] Step D: Under nitrogen gas protection, TEA (23.83 g, 235.47 mmol, 32.78 mL, 3 eq) was added to a solution of compound 1-a (23.38 g) in DCM (200 mL) at 0 °C, and then a solution of compound 8-c (24 g, 78.49 mmol, 1 eq) in DCM (200 mL) was added. The reaction solution was stirred at 10 °C for 16 hours, then concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to obtain compound 8-d.

[0230] Step E: Under nitrogen gas protection, sodium methoxide (1M, 130mL, 4.89eq) was added to a solution of compound 8-d (13.4g, 26.61mmol, 1eq) in MeOH (130mL), and the reaction solution was stirred at 50°C for 3 hours, then concentrated, the pH of the residue was adjusted to 5-6 with 1M dilute hydrochloric acid, extracted with EA (200mL x 2), and the combined organic phase was washed with saturated brine (200mL x 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 give compound 8-e.

[0231] Step F: Compound 8-e (7.5 g, 16.39 mmol, 1 eq) in 1,4-dioxane (150 mL) was added with hydrochloric acid (4 M, 150 mL, 36.60 eq), the reaction solution was stirred at 80 ° C for 16 hours, cooled, and then the reaction solution was added with 2N aqueous sodium hydroxide solution to adjust the pH to 8-9, and then extracted with EA / iPrOH = 7: 1 (200 mL × 4), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 8-f.

[0232] Step G: Under nitrogen gas protection, DIEA (194.27 mg, 1.50 mmol, 261.83 μL, 3 eq) was added to a solution of compound 8-f (0.15 g, 501.06 μmol, 1 eq) in DCM (3 mL) at 0 °C, then a solution of methyl chloroformate (49.72 mg, 526.11 μmol, 40.75 μL, 1.05 eq) in DCM (1 mL) was added, and the reaction solution was stirred at 0 °C for 1 h. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.05% aqueous ammonia)-ACN; gradient: 15% to 45% ACN] to obtain compound 8. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.80 - 9.51 (m, 1H), 7.40 - 7.31 (m, 4H), 7.30 - 7.23 (m, 1H), 7.11 - 6.97 (m, 1H), 4.60 (br s, 1H), 4.43 (s, 1H), 3.73 - 3.64 (m, 2H), 3.58 (s, 3H), 3.48 - 3.34 (m, 2H), 1.82 - 1.70 (m, 2H), 1.69 - 1.55 (m, 2H), 1.42 (d, J = 6.8 Hz, 3H);LCMS(ESI) m / z: 358.2(M+1).

[0233] Example 9

[0234] [ka]

[0235] Synthesis Route:

[0236] [ka]

[0237] Step A: Under nitrogen gas protection, cesium carbonate (35.38 g, 108.59 mmol, 1.5 eq) was added to a solution of 9-1 (10 g, 72.39 mmol, 1 eq) and 9-2 (9.21 g, 76.01 mmol, 1.05 eq) in DCM (200 mL), and the reaction solution was stirred at 15 °C for 16 h, then filtered, and the filtrate was concentrated to give compound 9-a.

[0238] Step B: Under nitrogen gas protection, methylmagnesium bromide (3M, 24.86mL, 2eq) was slowly added dropwise to a solution of 9-a (9g, 37.29mmol, 1eq) in THF (100mL) at -78°C. The reaction solution was stirred at -78°C for 1 hour, and then the reaction solution was slowly added dropwise to a saturated aqueous ammonium chloride solution (800mL), extracted with EA (200mL x 2), and the combined organic phase was washed with saturated brine (100mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 10:1 to 3:1) to obtain compound 9-b.

[0239] Step C: To a solution of 9-b (12 g, 46.63 mmol, 1 eq) in MeOH (100 mL) was added HCl / MeOH (4 M, 100 mL, 8.58 eq), and the reaction solution was stirred at 20 °C for 2 h. After concentration, the hydrochloride salt of compound 9-c was obtained.

[0240] Step D: To a solution of the hydrochloride salt of 9-c (7.5 g) in EtOH (100 mL) was added 1-1 (9.58 g, 48.96 mmol, 1 eq, HCl) and DIEA (25.31 g, 195.83 mmol, 34.11 mL, 4 eq), and the reaction solution was stirred at 20 °C for 16 h. After concentration, compound 9-d was obtained.

[0241] Step E: To a solution of 9-d (15 g, 56.33 mmol, 1 eq) in DCM (150 mL) was added BocO (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). The reaction solution was stirred at 15 °C for 16 h, then concentrated under reduced pressure. The residue was separated by column chromatography (PE: EtOAc = 15: 1) to give compound 9-e.

[0242] Step F: To a solution of 9-e (8.00 g, 21.83 mmol, 1 eq) in EtOAc (50 mL) was added HCl / EtOAc (4 M, 51.61 mL, 9.46 eq), and the reaction solution was stirred at 20° C. for 16 h. After the reaction solution was concentrated, the hydrochloride salt of compound 9-d was obtained.

[0243] Step G: Under nitrogen gas 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 solution of the hydrochloride salt of 9-d (8.80 g) in DCM (60 mL), and the reaction solution was stirred at -20°C for 1 h, warmed to 20°C and stirred for 15 h, then concentrated, and the residue was separated by column chromatography (PE: EtOAc = 30: 1 to 10: 1) to obtain compound 9-f.

[0244] Step H: Under nitrogen gas protection, sodium methoxide (1M, 41.62mL, 5eq) was added to a solution of 9-f (3.5g, 8.32mmol, 1eq) in MeOH (40mL), and the reaction solution was stirred at 50°C for 16 hours. The reaction solution was adjusted to pH about 5 by adding 1N dilute hydrochloric acid, and then extracted with EA (100mL x 2). The combined organic phase was washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 9-g.

[0245] Step J: To a solution of 9-g (3 g, 8.01 mmol, 1 eq) in 1,4-dioxane (60 mL), hydrochloric acid (4 M, 60 mL, 29.95 eq) was added, and the reaction solution was stirred at 70 °C for 16 h, and then 2N aqueous sodium hydroxide was added to adjust the pH to 8-9, and the mixture was filtered. The cake was first separated by silica gel column chromatography (DCM:MeOH = 1:0-10:1), and then MTBE (50 mL) was added and stirred for 1 h, and the mixture was filtered. The cake was dried under high vacuum to obtain compound 9. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.52 (br s, 1 H) 7.19 (br d, J=7.5 Hz, 1 H) 7.06 - 7.15 (m, 2 H) 6.91 (br d, J=6.8 Hz, 1 H) 4.66 - 4.76 (m, 1 H) 4.40 (s, 1 H) 2.28 (s, 3 H) 1.81 - 1.90 (m, 4 H) 1.64 - 1.72 (m, 4 H) 1.45 (d, J=6.8 Hz, 3 H);LCMS(ESI) m / z: 317.2(M+1).

[0246] Example 10

[0247] [ka]

[0248] Synthesis Route:

[0249] [ka]

[0250] Step A: At 20°C, 10-2 (4.66g, 38.43mmol, 1.2eq) and tetraethyl titanate (21.92g, 96.07mmol, 19.92mL, 3eq) were added to a solution of 10-1 (5g, 32.02mmol, 4.07mL, 1eq) in THF (50ml), and the reaction solution was stirred at 60°C for 16 hours. Ethyl acetate (100mL) was added to the reaction solution, and the solution was cooled to 0°C. Water (20mL) was then slowly added, and the mixture was stirred for 0.5 hours and filtered. The filtrate was washed with saturated saline (50mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10-a.

[0251] Step B: Under nitrogen gas protection, L-selectride (1M, 41.65mL, 1.2eq) was slowly added dropwise to a solution of 10-a (9g, 34.71mmol, 1eq) in THF (100mL) at -78℃. The reaction solution was stirred at -78℃ for 2 hours, then slowly added to a saturated aqueous ammonium chloride solution (100mL), extracted with EA (100mL×2), and the combined organic phase was 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.

[0252] Step C: To a solution of 10-b (6.6 g) in MeOH (50 mL) was added HCl / MeOH (200 mmol, .50 ml, 7.92 eq) at 20° C., the reaction solution was stirred for 16 h and then concentrated to give the hydrochloride salt of compound 10-c.

[0253] 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 the hydrochloride salt of 10-c (1 g) in EtOH (10 mL), and the reaction solution was stirred at 20 °C for 16 h. After concentration, compound 10-d was obtained.

[0254] Step E: Under nitrogen gas protection, TEA (2.45 g, 24.24 mmol, 3.37 mL, 3 eq) was added to a solution of 10-d (1.54 g, 8.08 mmol, 1 eq) in DCM (15 mL) at -20 °C, then a solution of 3-c (1.39 g, 5.14 mmol, 6.37 e-1 eq) in DCM (15 mL) was added, the reaction solution was stirred at 20 °C for 16 h, then concentrated, the residue was diluted with EA (30 mL), then washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 10: 1 to 5: 1) to obtain compound 10-e.

[0255] Step F: Under nitrogen gas protection, sodium methoxide (1M, 6.43ml, 1eq) was added to a solution of 10-e (0.648g, 1.53mmol, 1eq) in MeOH (7.6mL), and the reaction solution was stirred at 20°C for 16 hours. 1M diluted hydrochloric acid was added to the reaction solution to adjust the pH to about 5, and 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 give compound 10-f.

[0256] Step G: Hydrochloric acid (4M, 4mL, 17.40eq) was added to a solution of 10-f (348mg, 919.74μmol, 1eq) in 1,4-dioxane (4mL), the reaction solution was stirred at 50℃ for 16 hours, EA (30mL) was added to the reaction solution, then 1M aqueous sodium hydroxide was added to adjust the pH to about 8, and after separation, the organic phase was washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, MeOH (10mL) was added to the residue and stirred for 20 minutes, filtered, and the cake was dried under high vacuum to obtain compound 10. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.60 - 9.47 (m, 1H), 7.34 - 7.26 (m, 2H), 7.25 - 7.16 (m, 1H), 6.96 (br d, J = 6.0 Hz, 1H), 4.82 - 4.71 (m, 1H), 4.44 - 4.34 (m, 1H), 1.93 - 1.81 (m, 4H), 1.70 (br s, 4H), 1.48 (br d, J = 6.4 Hz, 3H);LCMS(ESI) m / z: 321.2(M+1).

[0257] Example 11

[0258] [ka]

[0259] Synthesis Route:

[0260] [ka]

[0261] Step A: To a solution of 11-1 (1 g, 7.40 mmol, 1.06 ml, 1 eq) in EtOH (15 mL) at 20 °C, 1-1 (1.18 g, 7.40 mmol, 1.0 eq, HCl) and DIEA (2.87 g, 22.19 mmol, 3.86 mL, 3 eq) were added, and the reaction solution was stirred at 20 °C for 12 h. After concentration, compound 11-a was obtained.

[0262] Step B: Under nitrogen gas protection, TEA (4.32 g, 42.65 mmol, 5.94 mL, 3 eq) was added to a solution of 11-a (2.44 g, 9.83 mmol, 6.91 e-1 eq) in DCM (15 mL) at -20 °C, then a solution of 3-c (2.71 g, 14.22 mmol, 6.37 e-1 eq) in DCM (15 mL) was added, the reaction solution was stirred at 20 °C for 16 h, concentrated, the residue was diluted with EA (30 mL), then washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 10: 1 to 8: 1) to give compound 11-b.

[0263] Step C: Under nitrogen gas protection, sodium methoxide (1M, 7.37ml, 5eq) was added to a solution of 11-b (0.743g, 1.47mmol, 1eq) in MeOH (9.2mL), and the reaction solution was stirred at 20°C for 16 hours. 1M diluted hydrochloric acid was added to the reaction solution to adjust the pH to about 5, and then EA (20mL x 3) was added for extraction. The combined organic phase was washed with saturated brine (20mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 11-c.

[0264] Step D: To a solution of 11-c (399 mg, 1.12 mmol, 1 eq) in 1,4-dioxane (4 mL) was added hydrochloric acid (4 M, 4 mL, 17.40 eq), the reaction solution was stirred at 50° C. for 16 h, then diluted with EA (30 mL), and then 2 M aqueous sodium hydroxide was added to adjust the pH to about 8, filtered, MeOH (10 mL) was added to the cake, stirred for 1 h, filtered, and the cake was dried under high vacuum to give compound 11. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.52 (br s, 1H), 7.41 - 7.25 (m, 5H), 6.97 - 6.85 (m, 1H), 4.42 (s, 1H), 4.40 - 4.29 (m, 1H), 1.90 - 1.84 (m, 2H), 1.83 - 1.63 (m, 8H), 0.87 (t, J = 7.2 Hz, 3H); LCMS(ESI) m / z: 299.1(M+1).

[0265] Example 12

[0266] [ka]

[0267] Synthesis Route:

[0268] [ka]

[0269] Step A: At 20°C, 10-2 (17.08g, 140.91mmol, 2.2eq) and tetraethyl titanate (43.83g, 192.15mmol, 39.85mL, 3eq) were added to a solution of 12-1 (10g, 64.05mmol, 8.33mL, 1eq) in THF (100mL), the reaction solution was stirred at 60°C for 16 hours, cooled to 0°C, EA (100mL) was added to the reaction solution, water (30mL) was slowly added, the mixture was stirred for 0.5 hours, filtered, and the filtrate was washed with saturated brine (30mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 12-a.

[0270] Step B: Under nitrogen gas protection, L-selectride (1M, 25.21mL, 1.2eq) was slowly added dropwise to a solution of 12-a (5.45g, 21.01mmol, 1eq) in THF (50mL) at -78℃, the reaction solution was stirred at 20℃ for 2 hours, the reaction solution was slowly added to a saturated aqueous ammonium chloride solution (40mL) at 0℃, extracted with EA (30mL×2), the combined organic phase was washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=8:1 to 1:1) to obtain compound 12-b.

[0271] Step C: At 20° C., HCl / MeOH (4 M, 30 mL, 10.00 eq) was added to a solution of 12-b (3.14 g, 12.00 mmol, 1 eq) in MeOH (30 mL), and the reaction solution was stirred for 16 h, then concentrated, EA (20 mL) was added to the residue, stirred for 0.5 h, filtered, and the cake was dried under high vacuum to give the hydrochloride salt of compound 12-c.

[0272] Step D: At 20 °C, under nitrogen protection, 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 the hydrochloride salt of 12-c (1.84 g) in EtOH (20 mL), and the reaction solution was stirred at 20 °C for 12 h. After concentration, compound 12-d was obtained.

[0273] Step E: Under nitrogen gas protection, 3-b (5.80 g, 33.71 mmol, 1 eq), DIEA (6.53 g, 50.56 mmol, 8.81 mL, 1.5 eq) were added to a solution of 12-d (9.11 g, 33.71 mmol, 1 eq) in THF (50 mL), then 12-2 (12.92 g, 50.56 mmol, 1.5 eq) was added, the reaction solution was stirred at 20 ° C for 1 h, concentrated, the residue was diluted with water (50 mL), and then extracted with EA (20 mL × 3), the combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc = 10: 1) to obtain compound 12-e.

[0274] Step F: Under nitrogen gas protection, sodium methoxide (1M, 44.56mL, 5eq) was added to a solution of 12-e (3.78g, 8.91mmol, 1eq) in MeOH (44.56mL), and the reaction solution was stirred at 50°C for 16 hours. 1M diluted hydrochloric acid was added to the reaction solution to adjust the pH to about 5, and then EA (50mL x 2) was added for extraction. The combined organic phase was washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc = 5:1 to 2:1) to obtain compound 12-f.

[0275] Step G: To a solution of 12-f (389 mg, 1.03 mmol, 1 eq) in 1,4-dioxane (4 mL) was added hydrochloric acid (4 M, 3.91 mL, 15.21 eq), the reaction solution was stirred at 60° C. for 16 h, the reaction solution was adjusted to pH 8 by adding 2 M aqueous sodium hydroxide solution, filtered, the cake was added to MTBE (5 mL) and stirred for 1 h, filtered, and the cake was dried to give compound 12. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.52 (br s, 1H), 7.47 - 7.35 (m, 1H), 7.14 (br t, J = 8.8 Hz, 2H), 7.01 - 6.91 (m, 1H), 4.91 - 4.79 (m, LCMS(ESI) m / z: 321.1(M+1).

[0276] Example 13

[0277] [ka]

[0278] Synthesis Route:

[0279] [ka]

[0280] Step A: At 20°C, 10-2 (4.66g, 38.43mmol, 2eq) and tetraethyl titanate (13.15g, 57.64mmol, 11.95mL, 3eq) were added to a solution of 13-1 (3g, 19.21mmol, 2.42mL, 1eq) in THF (30mL), and the reaction solution was stirred at 60°C for 16 hours. EA (60mL) was added to the reaction solution, and the solution was cooled to 0°C. Then, water (10mL) was slowly added, and the mixture was stirred for 0.5 hours and filtered. The filtrate was washed with saturated brine (30mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 13-a.

[0281] Step B: Under nitrogen gas protection, L-selectride (1M, 13.88mL, 1.2eq) was slowly added dropwise to a solution of 13-a (3g, 11.57mmol, 1eq) in THF (20mL) at -78℃, the reaction solution was stirred at -78℃ for 2 hours, the reaction solution was slowly added to a saturated aqueous ammonium chloride solution (20mL) at 0℃, extracted with EA (20mL×2), the combined organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=5:1-2:1) to obtain compound 13-b.

[0282] Step C: To a solution of 13-b (1.26 g, 4.81 mmol, 1 eq) in MeOH (15 mL) was added HCl / MeOH (4 M, 15 mL, 12.48 eq), the reaction solution was stirred at 20 °C for 16 h, then concentrated, EA (20 mL) was added to the residue, stirred for 0.5 h, filtered, and the cake was dried in vacuum to give the hydrochloride salt of compound 13-c.

[0283] Step D: Under nitrogen protection, 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 the hydrochloride salt of 13-c (0.553 g) in EtOH (5 mL) at 20 °C, and the reaction solution was stirred at 20 °C for 12 h. After concentration, compound 13-d was obtained.

[0284] Step E: Under nitrogen gas protection, TEA (1.67 g, 16.52 mmol, 2.30 mL, 3 eq) was added to a solution of 3-c (1.05 g, 5.51 mmol, 1 eq) in DCM (15 mL) at -20 °C, then 13-d (950.02 mg, 3.52 mmol) was added, the reaction solution was stirred at 20 °C for 16 h, then concentrated, the residue was diluted with water (50 mL), and then extracted with EA (20 mL × 3), the combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 8: 1 to 1: 1) to give compound 13-e.

[0285] Step F: Under nitrogen gas protection, sodium methoxide (1M, 5.69mL, 5eq) was added to a solution of 13-e (483mg, 1.14mmol, 1eq) in MeOH (5mL), 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, and then EA (30mL x 2) was added for extraction, and the combined organic phase was washed with saturated brine (30mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 13-f.

[0286] Step G: To a solution of 13-f (117 mg, 309.22 μmol, 1 eq) in 1,4-dioxane (2 mL) was added hydrochloric acid (4 M, 2 mL, 25.87 eq), the reaction solution was stirred at 60° C. for 16 h, the reaction solution was adjusted to pH 8 by adding 2 M aqueous sodium hydroxide solution, filtered, the cake was added to MTBE (10 mL) and stirred for 1 h, filtered, and the cake was dried to give compound 13. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.54 (br s, 1H), 7.51 - 7.41 (m, 1H), 7.32 - 7.23 (m, 1H), 7.12 (br t, J = 8.0Hz, 1H), 6.95 (br d, J = 6.1 Hz, LCMS(ESI) m / z: 321.1(M+1).

[0287] Example 14

[0288] [ka]

[0289] Synthesis Route:

[0290] [ka]

[0291] Step A: To a solution of 14-1 (0.8 g, 5.75 mmol, 1 eq) in EtOH (10 mL) 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, and the reaction solution was stirred at 25 °C for 16 h. After concentration, compound 14-a was obtained.

[0292] Step B: To a solution of 14-a (1 g, 3.48 mmol, purity: 87.68%, 1 eq) in THF (10 mL), DIEA (673.77 mg, 5.21 mmol, 908.04 μL, 1.5 eq) was added, then 12-2 (1.33 g, 5.21 mmol, 1.5 eq) and 3-b (598.40 mg, 3.48 mmol, 1 eq) were added, the reaction solution was stirred at 25 ° C for 0.5 h, concentrated, water (50 mL) was added to the residue, and then extracted with EA (20 mL × 3), the combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 10: 1) to obtain compound 14-b.

[0293] Step C: Under nitrogen gas protection, sodium methoxide (1M, 2.84mL, 5eq) was added to a solution of 14-b (231mg, 568.34μmol, 1eq) in MeOH (5mL), the reaction solution was stirred at 50℃ for 16 hours, 1M diluted hydrochloric acid was added to the reaction solution to adjust the pH to about 5, water (20mL) was added to dilute, and then extracted with EA (10mL×3), the combined organic phase was washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 14-c.

[0294] Step D: To a solution of 14-c (170 mg, 433.99 μmol, purity: 92%, 1 eq) in 1,4-dioxane (8.29 mL), hydrochloric acid (4 M, 8.29 mL, 76.4 eq) was added, and the reaction solution was stirred at 50° C. for 16 h. The pH was adjusted to about 9 by adding 1 M aqueous sodium hydroxide, and extracted with EA (5 mL×4). The combined organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. MTBE (5 mL) was added to the residue and stirred for 2 h. The mixture was filtered, and the cake was dried to give compound 14. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.70 (br s, 1H), 7.45-7.39 (m, 1H), 7.39-7.32 (m, 1H), 7.25 - 7.20 (m, 2H), 7.15 (br s, 1H), 4.81 - 4.73 (m, 1H), 4.38 (s, 1H), 1.89 - 1.79 (m, 4H), 1.74 - 1.64 (m, 4H), 1.48 (d, J = 6.8 Hz, 3H);LCMS(ESI) m / z: 303.2(M+1).

[0295] Example 15

[0296] [ka]

[0297] Synthesis Route:

[0298] [ka]

[0299] Step A: At 20°C, 10-2 (927.16mg, 7.64mmol, 1.2eq) and tetraethyl titanate (4.36g, 19.11mmol, 3.97mL, 3eq) were added to a solution of 15-1 (1g, 6.37mmol, purity: 99.53%, 1eq) in THF (10mL), and the reaction solution was stirred at 50°C for 16 hours. 10-2 (386.02mg, 3.19mmol, 0.5eq) was added to the reaction solution, and the mixture was stirred at 50°C for 1.5 hours. After cooling to 0°C, the reaction solution was diluted with ethyl acetate (30mL), water (20mL) was slowly added, and the mixture was stirred for 0.5 hours and filtered. The filtrate was washed with saturated saline (10mL x 2), dried over anhydrous sodium sulfate, and concentrated after filtration to obtain compound 15-a.

[0300] Step B: Under nitrogen gas protection, L-selectride (1M, 4.40mL, 1.2eq) was slowly added dropwise to a solution of 15-a (950mg, 3.66mmol, 1eq) in THF (10mL) at -78℃, the reaction solution was stirred at -78℃ for 2 hours, the reaction solution was slowly added to a saturated aqueous ammonium chloride solution (15mL) at 0℃, diluted with water (30mL), extracted with ethyl acetate (10mL×3), the combined organic phase was washed with saturated brine (15mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=5:1) to obtain compound 15-b.

[0301] Step C: To a solution of 15-b (1.15 g, 4.39 mmol, 1 eq) in MeOH (10 mL) at 20 °C, HCl / MeOH (4 M, 1.10 mL, 1 eq) was added, and the reaction solution was stirred at 20 °C for 16 h. After concentration, the hydrochloride salt of compound 15-c was obtained.

[0302] Step D: At 20 °C, under nitrogen protection, 1-1 (898.41 mg, 4.59 mmol, 8.14e-1 eq, HCl) and DIEA (2.92 g, 22.58 mmol, 3.93 mL, 4 eq) were added to a solution of the hydrochloride salt of 15-c (0.887 g) in EtOH (10 mL), and the reaction solution was stirred at 20 °C for 16 h. After concentration, compound 15-d was obtained.

[0303] Step E: Under nitrogen gas protection, 3-b (1.47 g, 8.51 mmol, 1 eq), DIEA (1.65 g, 12.76 mmol, 2.22 mL, 1.5 eq) were added to a solution of 15-d (2.3 g, 8.51 mmol, 1 eq) in THF (25 mL), then 12-2 (3.26 g, 12.76 mmol, 1.5 eq) was added, the reaction solution was stirred at 20 ° C for 32 h, concentrated, the residue was diluted with water (50 mL), and then extracted with EA (10 mL × 4), the combined organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 20: 1) to obtain compound 15-e.

[0304] Step F: Under nitrogen gas protection, sodium methoxide (1M, 3mL, 4.90eq) was added to a solution of 15-e (260mg, 612.58μmol, 1eq) in MeOH (3mL), the reaction solution was stirred at 50℃ for 16 hours, 1M diluted hydrochloric acid was added to the reaction solution to adjust the pH to about 5, then water (10mL) was added, extracted with EA (5mL×4), the combined organic phase was washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by thin layer chromatography (PE:EtOAc=20:1) to obtain compound 15-f.

[0305] Step G: To a solution of 15-f (60 mg, 158.58 μmol, 1 eq) in 1,4-dioxane (2 mL) was added hydrochloric acid (4 M, 2 mL, 50.45 eq), the reaction solution was stirred at 60° C. for 19 h, the reaction solution was adjusted to pH approx. 9 by adding 1 M aqueous sodium hydroxide solution, filtered, MTBE (2 mL) was added to the cake, stirred for 2 h, filtered, and the cake was dried to give compound 15. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.55 (m, 1H), 7.41 - 7.33 (m, 1H), 7.28 - 7.20 (m, 2H), 7.01 (br d, J = 4.6 Hz, 1H), 4.83 (br s, 1H), 4.40 (s, 1H), 1.91 - 1.79 (m, 4H), 1.75 - 1.65 (m, 4H), 1.50 (d, J = 6.8 Hz, 3H); LCMS(ESI) m / z: 321.2(M+1).

[0306] Example 16

[0307] [ka]

[0308] Synthesis Route:

[0309] [ka]

[0310] Step A: Under nitrogen gas protection, cesium carbonate (27.13 g, 83.26 mmol, 2.2 eq) was added to a solution of compound 3-1 (5 g, 37.85 mmol, 4.35 mL, 1 eq) and ethyl iodide (12.99 g, 83.26 mmol, 6.66 mL, 2.2 eq) in DMF (50 mL), and the reaction solution was stirred at 20° C. for 16 h. Then, water (200 mL) was added, followed by extraction with EA (200 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 16-a.

[0311] Step B: To a solution of compound 16-a (7 g, 37.19 mmol, 1 eq) in MeOH (40 mL) and water (40 mL) was added sodium hydroxide (1.64 g, 40.91 mmol, 1.1 eq). The reaction solution was stirred at 20° C. for 16 h, then concentrated, water (100 mL) was added to the residue, and then extracted with MTBE (100 mL). After separation, the aqueous phase was adjusted to pH about 5 with 1 M dilute hydrochloric acid, then extracted with EA (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 16-b.

[0312] Step C: Under nitrogen gas protection, N-methylimidazole (1.82 g, 22.20 mmol, 1.77 mL, 5 eq) and TCFH (2.49 g, 8.88 mmol, 2 eq) were added to a solution of compound 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) at 0 °C. The reaction solution was stirred at 0 °C for 1 h, then concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc = 1: 0 to 10: 1) to obtain compound 16-c.

[0313] Step D: Under nitrogen gas protection, sodium tert-butoxide (1.75 g, 18.17 mmol, 5 eq) was added to a solution of compound 16-c (1.55 g, 3.63 mmol, 1 eq) in MeOH (20 mL), and the reaction solution was stirred at 20 ° C for 16 h. The reaction solution was poured into 1N dilute hydrochloric acid (20 mL), concentrated, water (30 mL) was added to the residue, 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 to 3: 1) to obtain compound 16-d.

[0314] Step E: To a solution of compound 16-d (0.15 g, 394.34 μmol, 1 eq) in 1,4-dioxane (5 mL), hydrochloric acid (4 M, 5 mL, 50.72 eq) was added, and the reaction solution was stirred at 50° C. for 16 h. The reaction solution was adjusted to pH about 7 by adding 1N sodium hydroxide, and then the 1,4-dioxane was concentrated to remove it, and MTBE (20 mL) was added to the residue, filtered, and the cake was dried under high vacuum to obtain compound 16. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.69 (br s, 1H), 7.45 - 7.37 (m, 1H), 7.14 (t, J = 8.5 Hz, 2H), 6.94 (br d, J = 7.6 Hz, 1H), 4.88 (br t, J = LCMS(ESI) m / z: 323.4(M+1).

[0315] Example 17

[0316] [ka]

[0317] Synthesis Route:

[0318] [ka]

[0319] Step A: Under nitrogen gas protection, 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 compound 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) at 0 °C, and the reaction solution was stirred at 20 °C for 2 hours, then concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to obtain compound 17-a.

[0320] Step B: Under nitrogen gas protection, sodium tert-butoxide (370.94 mg, 3.86 mmol, 5 eq) was added to a solution of compound 17-a (0.34 g, 771.96 μmol, 1 eq) in MeOH (5 mL), and the reaction solution was stirred at 20 ° C for 16 h. The reaction solution was adjusted to pH about 5 by adding 1N dilute hydrochloric acid, concentrated, water (10 mL) was added to the residue, and extracted with 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 to 2: 1) to obtain compound 17-b.

[0321] Step C: Under nitrogen gas protection, hydrochloric acid (4M, 5mL, 52.58eq) was added to a solution of compound 17-b (0.15g, 380.35μmol, 1eq) in 1,4-dioxane (5mL), the reaction solution was stirred at 50°C for 20 hours, a saturated aqueous solution of sodium bicarbonate was added to the reaction solution to adjust the pH to about 7, then 1,4-dioxane was concentrated to remove, water (10mL) and MTBE (20mL) were added to the residue, stirred for 30 minutes, filtered, and the cake was dried under high vacuum to obtain compound 17. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.67 (br s, 1H), 7.34 - 7.25 (m, 2H), 7.20 (dt, J = 4.1, 8.1 Hz, 1H), 7.07 (br d, J = 5.9 Hz, 1H), 4.76 (br LCMS(ESI) m / z: 337.3(M+1).

[0322] Example 18

[0323] [ka]

[0324] Synthesis Route:

[0325] [ka]

[0326] Step A: At 20°C, 10-2 (5.81g, 47.91mmol, 1.2eq) and tetraethyl titanate (27.32g, 119.77mmol, 24.84mL, 3eq) were added to a solution of 18-1 (6.89g, 39.92mmol, 1eq) in THF (70ml), and the reaction solution was stirred at 60°C for 16 hours. Ethyl acetate (100mL) was added to the reaction solution, and the solution was cooled to 0°C. Water (20mL) was then slowly added, and the mixture was stirred for 0.5 hours and filtered. The filtrate was washed with saturated saline (50mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 18-a.

[0327] Step B: Under nitrogen gas protection, L-selectride (1M, 25.75mL, 1eq) was slowly added dropwise to a solution of 18-a (7.1g, 25.75mmol, 1eq) in THF (100mL) at -78℃, the reaction solution was slowly warmed to 0℃, stirred for 1 hour, 0.5N dilute hydrochloric acid (100mL) was added to the reaction solution, extracted with ethyl acetate (100mL), the organic phase was washed with saturated saline (100mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=10:1-3:1) to obtain compound 18-b.

[0328] Step C: To 18-b (2 g, 7.20 mmol, 1 eq) was added a solution of HCl / MeOH (4 M, 25 mL, 13.89 eq), and the reaction solution was stirred at 50° C. for 1 h and then concentrated to give the hydrochloride salt of compound 18-c.

[0329] Step D: Under nitrogen gas protection, 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 hydrochloride salt of 18-c (2 g) in EtOH (30 mL) at 20 ° C., the reaction solution was stirred at 20 ° C. for 16 h, then concentrated, water (50 mL) was added to the residue, and the pH was adjusted to about 5 with acetic acid, extracted with EA (50 mL), and after separation, the aqueous phase was adjusted to about 9 with saturated sodium bicarbonate solution, then extracted with EA (50 mL × 2), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 18-d.

[0330] Step E: Under nitrogen gas protection, 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 compound 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) at 0 °C, and the reaction solution was stirred at 20 °C for 1 h, then concentrated, and the residue was separated by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to obtain compound 18-e.

[0331] Step F: Under nitrogen gas protection, sodium tert-butoxide (1.01 g, 10.51 mmol, 4 eq) was added to a solution of compound 18-e (1.2 g, 2.63 mmol, 1 eq) in MeOH (10 mL), and the reaction solution was stirred at 50 ° C. for 1 h. The reaction solution was adjusted to pH about 5 by adding 1N dilute hydrochloric acid, concentrated, water (10 mL) was added to the residue, and extracted with 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 to 2: 1) to obtain compound 18-f.

[0332] Step G: Under nitrogen gas protection, hydrochloric acid (4M, 15mL, 35.72eq) was added to a solution of compound 18-f (0.69g, 1.68mmol, 1eq) in 1,4-dioxane (15mL), the reaction solution was stirred at 50°C for 16 hours, 1N aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to about 7, then 1,4-dioxane was concentrated to remove, water (50mL) and MTBE (50mL) were added to the residue, stirred for 30 minutes, filtered, and the cake was dried under high vacuum to obtain compound 18. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.63 (br s, 1H), 7.54 - 7.49 (m, 1H), 7.45 - 7.39 (m, 1H), 7.34 - 7.27 (m, 1H), 6.98 (br s, 1H), 4.77 (br s, 1H), 4.40 (s, 1H), 3.79 - 3.69 (m, 4H), 1.90 - 1.78 (m, 2H), 1.59 (br dd, J = 14.3, 19.1 Hz, 2H), 1.47 (d, J = 6.7 Hz, 3H);LCMS(ESI) m / z: 353.3(M+1).

[0333] Biological activity tests:

[0334] Experimental Example 1: Experiment on the inhibitory effect of cardiac myosin ATPase activity Experimental Reagents: Tropomyosin-Troponin Complex (Cytoskeleton, Catalog Number: TT05) Cardiac myosin S1 (Cytoskeleton, Catalog number: MYS03) Cardiac actin (Cytoskeleton, Catalog number: AD99-A) ATPase measurement biochemistry kit (Cytoskeleton, Catalog number: BK051)

[0335] Experimental steps: 1) Preparation of compounds: a) Compounds were diluted 4-fold in 8 concentration gradients with DMSO in the Echo and 200 nL of each compound was transferred to a 96-well plate (Corning-3696). b) Centrifuge at 1000 rpm for 15 seconds and seal the plate for later use. 2) Preparation of F-actin: a) A buffer solution of 5 mM Pipes-KOH, pH: 7.0, 500 μM ATP, and 500 μM dithiothreitol was prepared, and 2.5 mL of the buffer solution was added to dissolve 1 mg of F-actin, and the protein concentration was 0.4 mg / mL. b) The mixture was left at room temperature for 10 minutes to completely dissolve the protein. c) 2.0 mM MgCl2 and 2.0 mM EGTA were added and left at room temperature for 20 minutes to allow protein polymer formation. 3) Preparation of actin filaments: a) 200 μL of ice water was added to dissolve 1 mg of tropomyosin-troponin complex, resulting in a protein concentration of 5 mg / mL. b) 1000 μL of F-actin prepared in step 1 was added and mixed well. c) Allow to stand at room temperature for 20 minutes. d) Centrifugation was performed at 87K x g and 4°C for 1.5 hours. e) PM12 buffer was prepared: 12 mM Pipes-KOH, pH: 7.0, 2 mM MgCl2, and 1200 μL of buffer was added to resuspend the protein. 4) The reaction solution was prepared and the experiment was started. a) 250 μL of ice-cold PM12 buffer was added to 250 μg of S1 myosin, resulting in a protein concentration of 1 mg / mL. b) The reagents were added and mixed in the following order to obtain a reaction mixture. 400 μL PM12, 400 μL of 5x MSEG (from the ATPase measurement biochemical kit), 1200 μL actin / tropomyosin-troponin complex, 40 μL of myosin S1, 40 μL of 100x PNP (from the ATPase measurement biochemistry kit) 10.4 μL 100 mM ATP. c) 10 μL of 440 μM CaCl2 solution was added to a 96-well plate and placed in a 37° C. incubator to pre-warm. d) 100 μL of the reaction mixture was added to a 96-well plate and centrifuged at 1000 rpm for 10 seconds. e) SpectraMax 340PC was read continuously at 30 second intervals for 10 minutes, the instrument temperature was 37°C and the wavelength was 360 nm.

[0336] Data Analysis: The data was analyzed using Prism, and the experimental results are shown in Table 1.

[0337] [Table 1]

[0338] Conclusion: The compounds of the present invention have good cardiac myosin ATPase inhibitory activity.

[0339] Experimental Example 2: Pharmacokinetic evaluation in rats Purpose of the experiment: The object is to detect the pharmacokinetic parameters of the compound of the present invention in rats. Testing Protocol: 1) Experimental drug: was a compound of the present invention. 2) Experimental animals: Four male SD rats aged 7-9 weeks were randomly divided into two groups, each with two animals. 3) Drug preparation: An appropriate amount of drug was weighed and dissolved in a mixed solvent of DMAC:PEG-400:30% 2-HP-β-CD=5:25:70 to prepare a 0.2 mg / mL solution. Experimental Procedure: Animals in group 1 were administered the drug via a single tail vein injection at a concentration of 0.2 mg / mL and a dose of 0.2 mg / kg, while animals in group 2 were administered the compound via intragastric administration at a concentration of 0.2 mg / mL and a dose of 1 mg / kg. Plasma samples were taken from animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. Data Analysis: The drug concentrations in plasma samples were measured by LC-MS / MS, and the pharmacokinetic test results of the test drugs are shown in Table 2.

[0340] [Table 2]

[0341] Conclusion: The compounds of the present invention have good in vivo pharmacokinetic properties in rats.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (however, R １ and R ２ are each independently C １－４ is alkyl, Or, R １ and R ２ are C together with the carbon atoms connected to them. ３－６ cycloalkyl or 3- to 6-membered heterocycloalkyl, ３－６ Cycloalkyl and 3- to 6-membered heterocycloalkyl each independently have 1, 2, 3, or 4 R ｂ and optionally replaced by R ３ is H, R ４ is H and C １－４ alkyl, R ５ is H and C １－４ alkyl, R ６ are each independently H, F, Cl, Br, I, or C. １－４ alkyl, R ｂ Each independently represents -CO ２ R ｂ１ and Each Rb1 is independently C １－４ is alkyl, n is selected from 1, 2, 3 or 4; The 3- to 6-membered heterocycloalkyl each contain 1, 2, 3, or 4 atoms or groups of atoms independently selected from N, O, S, and NH.

2. R １ and R ２ Each independently represents -CH ３ and -CH ２ CH ３ 2. The compound of claim 1, selected from:

3. Each R b1 is independently -CH ３ and -CH ２ CH ３ 2. The compound of claim 1, selected from:

4. R ｂ Each independently represents -CO ２ CH ３ and -CO ２ CH ２ CH ３ 4. The compound according to claim 1 or 3, or a pharma- ceutically acceptable salt thereof, selected from:

5. R １ and R ２ together with the carbon atoms connected to them 【Chemistry 2】 wherein said 【Chemistry 3】 each independently represents 1, 2, 3 or 4 R ｂ 2. The compound of claim 1, optionally substituted by: or a pharma- ceutically acceptable salt thereof.

6. R １ and R ２ together with the carbon atoms connected to them 【Chemistry 4】 6. The compound of claim 5, which forms:

7. R １ and R ２ together with the carbon atoms connected to them 【Chemistry 5】 7. The compound of claim 6, which forms:

8. Structural Fragment 【Chemistry 6】 teeth, 【Chemistry 7】 2. The compound of claim 1, selected from:

9. R ３ is H; or a pharma- ceutically acceptable salt thereof.

10. R ４ is -CH ３ and -CH ２ CH ３ 2. The compound of claim 1, selected from:

11. R ６ are each independently H, F, Cl, or -CH ３ 2. The compound of claim 1, selected from:

12. The compound of claim 1, having a structure represented by formula (I-1): or a pharma- ceutically acceptable salt thereof. 【Chemistry 8】 (where n, R １ , R ２ , R ３ , R ４ and R ６ is as defined in claim 1.

13. 13. The compound of claim 12, wherein the compound has a structure represented by formula (I-1A) or (I-1B), or a pharma- ceutically acceptable salt thereof. 【Chemistry 9】 (where n, R １ , R ２ , R ３ , R ４ and R ６ is as defined in claim 12, and R ４ is not H.)

14. A compound of the formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 10】

15. A compound of the formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 11】 【Chemistry 12】

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

17. Use of a compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for inhibiting cardiac myosin.

18. Use of a compound according to any one of claims 1 to 15 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for treating heart failure and hypertrophic cardiomyopathy.

19. A compound of the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 13】

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