Derivatives of six-membered heteroaromatic urea rings and their applications

Abstract

A derivative of a six-membered heteroaromatic urea ring represented by formula (I) and its use in preparing a drug for treating diabetic nephropathy or hypertensive nephropathy.

Description

[0001] This application claims priority to:

[0002] CN202110462009.4, April 27, 2021;

[0003] CN202210307799.3, March 25, 2022. Technical Field

[0004] The present invention discloses a class of six-membered heteroaromatic urea ring derivatives and applications thereof, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Background Art

[0005] Soluble guanylate cyclase (sGC) is widely present in the cytosol of mammals. It is a heterodimer composed of two subunits, α and β. The α and β subunits have two isoforms, α1 and α2, and β1 and β2, respectively. The α1β1 dimer is primarily distributed in cardiovascular tissues, and its expression level is positively correlated with the degree of tissue vascularization. The α2β1 dimer is primarily expressed in the brain and nervous system. Although the two have significant differences in tissue distribution and cellular localization, they play similar roles in maintaining sGC enzyme function.

[0006] Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. Upon activation in vivo, sGC catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is an important secondary messenger molecule that activates multiple downstream effector molecules, such as phosphodiesterases (PDEs), cyclic nucleotide-gated ion channels (CNGs), and protein kinase G (PKGs), triggering a series of downstream cascade reactions. cGMP plays important physiological roles in the gastrointestinal, circulatory, and nervous systems, including promoting vascular and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, apoptosis, and inflammation, and participating in neurotransmission. Under pathophysiological conditions, the NO / cGMP system can be inhibited, leading to conditions such as hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, and sexual dysfunction. In the past two years, studies have shown that abnormal sGC-mediated signaling pathways are closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.

[0007] Conventional stimulatory therapies targeting soluble guanylate cyclase use compounds whose effects are based on NO, such as organic nitrates. Nitric oxide is formed through biotransformation and activates soluble guanylate cyclase by attacking the central iron atom of heme. Besides side effects, the development of tolerance is a significant drawback of this treatment approach.

[0008] In October 2013, the FDA approved a new guanylate cyclase stimulator called Riociguat (WO2003095451A1), a pyrazolopyridine compound used to treat pulmonary arterial hypertension. However, it has a short half-life in the human body and a high clearance rate, and needs to be taken three times a day.

[0009]

[0010] In response to the current unmet market and clinical demand for such soluble guanylate cyclase stimulators, the present invention provides a new class of compounds that can be used as stimulators of soluble guanylate cyclase, have good in vitro stimulating activity on guanylate cyclase, and have excellent pharmacokinetic properties. Summary of the Invention

[0011] In one aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0012]

[0013] wherein R1 is H, F or Cl;

[0014] R2 is C 1-6 alkyl, -CH2-phenyl, -CH2-pyridyl or -CH2-pyrimidinyl, wherein the C 1-6 Alkyl, -CH2-phenyl, -CH2-pyridyl or -CH2-pyrimidinyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R a replaced by;

[0015] Each R a independently H, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -C(=O)OH, C 1-3 Alkoxy or C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 1-3 alkyl;

[0016] R3 and R4 are each independently H, F, Cl, Br, I, -OH, -CN or -NH2;

[0017] R5 is -LR b ;

[0018] L is a single bond, -NR c C(=O)O- or -NR c C(=O)-;

[0019] R b C1-6 alkyl, wherein the C 1-6 alkyl, R is independently optionally substituted by 1, 2 or 3 R c is H, -CH3 or -CH2CH3;

[0020] Each R is independently F, Cl, Br, I, -OH, -CN, -NH2, -NO2, C 1-3 Alkoxy or C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 1-3 alkyl;

[0021] Or R3 and R5 are connected to the carbon atoms to make the structural unit Selected from

[0022] R6, R7 and R8 are each independently F, Cl, Br, I, -OH, -CN, -NH2, -NO2 or C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 1-3 alkyl.

[0023] In some embodiments of the present invention, the above-mentioned L is a single bond, -NH-C(=O)O-, -NH-C(=O)-, -N(CH3)-C(=O)O- or -N(CH3)-C(=O)-, and other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (I-1) to (I-4):

[0025]

[0026] Among them, R1, R2, R4 and R b As defined in the present invention.

[0027] In some embodiments of the present invention, each R mentioned above is independently F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CF3, -CH2CF3, -CH2CH2CF3, -CH2OH or -CH2CH2OH, and other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, the above R b C 1-4 alkyl, wherein the C 1-4 alkyl, Each is independently optionally substituted with 1, 2 or 3 R, and R and other variables are as defined herein.

[0029] In some embodiments of the present invention, the above R b For -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, R and other variables are as defined herein.

[0030] In some embodiments of the present invention, the above R b For -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, Other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the above R5 is -NH-C(=O)OC 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -N(CH3)-C(=O)OC 1-4 Alkyl, -NH-C(=O)-(C 3-6 Cycloalkyl), -N(CH3)C(=O)-(C 3-6 cycloalkyl), -NH-C(=O)-phenyl, -N(CH3)-C(=O)-phenyl or 5-6 membered heterocycloalkyl, wherein said NH-C(=O)OC 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -N(CH3)-C(=O)OC 1-4 Alkyl, -NH-C(=O)-(C 3-6 Cycloalkyl), -N(CH3)C(=O)-(C 3-6 cycloalkyl), -NH-C(=O)-phenyl, -N(CH3)-C(=O)-phenyl and 5-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R, and R and other variables are as defined herein.

[0032] In some embodiments of the present invention, the above-mentioned R5 is -NH-C(=O)O-CH3, -NH-C(=O)O-CH2CH3, -NH-C(=O)O-CH2CH2CH3, -NH-C(=O)O-CH(CH3)2, -NH-C(=O)-CH3, -NH-C(=O)-CH2CH3, -NH-C(=O)-CH2CH2CH3, -NH-C(=O)-CH(CH3)2, -N(CH3)-C(=O)O-CH3, -N(CH3)-C(=O)O-CH2CH3, -N(CH3)-C(=O)O-CH2CH2CH3, -N(CH3)-C(=O)O-CH(CH3)2, R and other variables are as defined herein.

[0033] In some embodiments of the present invention, the above-mentioned R5-NH-C(=O)O-CH3, -NH-C(=O)O-CH2CH3, -NH-C(=O)O-CH2CH2CH3, -NH-C(=O)O-CH(CH3)2, -NH-C(=O)-CH3, -NH-C(=O)-CH2CH3, -NH-C(=O)-CH2CH2CH3, -NH-C(=O)- CH(CH3)2, -N(CH3)-C(=O)O-CH3, -N(CH3)-C(=O)O-CH2CH3, -N(CH3)-C(=O)O-CH2CH2CH3, -N(CH3)-C(=O)O-CH(CH3)2, Other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (I-5) to (I-13):

[0035]

[0036]

[0037] wherein p is 0, 1 or 2; R4 is H or -NH2; and R2 and R are as defined in the present invention.

[0038] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt has the structure shown in formula (I-14) to (I-15):

[0039]

[0040] wherein R1, R2, R4, R6, R7 and R8 are as defined in the present invention.

[0041] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (I-16) to (I-19):

[0042]

[0043] wherein R2, R6, R7 and R8 are as defined in the present invention.

[0044] In some embodiments of the present invention, the above structural unit for Other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above structural unit for Other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, R6, R7 and R8 are each independently F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -CH3, -CH2CH3, -CF3, -CH2CF3 or -CH2CH2OH, and other variables are as defined in the present invention.

[0047] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (I-20) to (I-25):

[0048]

[0049] Wherein, R2 is defined in the present invention.

[0050] In some embodiments of the present invention, the above R a are independently H, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -C(=O)OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2OH or -CH2CH2OH, and other variables are as defined herein.

[0051] In some embodiments of the present invention, the above R a is independently H, F, Cl, or -NH2, and other variables are as defined herein.

[0052] In some embodiments of the present invention, the above R2 is C 1-6alkyl, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrimidinyl or -CH2-pyrazinyl, wherein the C 1-6 Alkyl, phenyl, pyridyl, pyrimidyl and pyrazinyl are optionally substituted with 1, 2, 3, 4 or 5 R a Replaced by R a and other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the above R2 is R a and other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above R2 is Other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, R3 and R4 are each independently H or -NH2, and other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, the compound has a structure represented by formula (I-15-a), (I-15-b), (I-15-c) or (I-15-d):

[0057]

[0058] Among them, R1, R4, R7, R8 and R a As defined in the present invention.

[0059] Some other solutions of the present invention are obtained by any combination of the above variables.

[0060] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0061]

[0062]

[0063]

[0064] The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diabetic nephropathy or hypertensive nephropathy.

[0065] The present invention also provides a method for treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, comprising providing the subject with an effective dose of the compound defined in any of the above technical solutions or a pharmaceutically acceptable salt thereof.

[0066] Technical Effects

[0067] The present invention relates to a new class of soluble guanylate cyclase stimulators. The compounds involved have significant in vitro stimulating activity on guanylate cyclase, excellent pharmacokinetic properties, and relatively weak inhibition levels on five CYP isoenzymes.

[0068] Definition and Description

[0069] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0070] The term "pharmaceutically acceptable" as used herein 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 without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0071] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as 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, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0072] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0073] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0074] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0075] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0076] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0077] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0078] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0079] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomerism is possible (such as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valence tautomers) include interconversions carried out by the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one.

[0080] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0081] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0082] 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. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0083] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0084] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0085] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state 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. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0086] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0087] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0088] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0089] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the substituent is listed without specifying which atom it is connected to the substituted group, the substituent can be bonded through any atom of the substituent. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0090] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0091] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy lines in the phenyl group represent the connection to other groups through the carbon atoms at positions 1 and 2 in the phenyl group. Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0092] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0093] Unless otherwise specified, "3-12 membered ring" means a cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl group consisting of 3 to 12 ring atoms. The ring includes a monocyclic ring, and also includes bicyclic or polycyclic ring systems such as spirocyclic, fused ring and bridged ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N. The 3-12 membered ring includes 3-10 membered, 3-9 membered, 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 4-10 membered, 4-9 membered, 4-8 membered, 4-7 membered, 4-6 membered, 4-5 membered, 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 6-10 membered, 6-9 membered, 6-8 membered and 6-7 membered rings. The term "5-7 membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.

[0094] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-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 range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0095] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0096] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 、C 1-3 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). - Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0097] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0098] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0099] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affine substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chloro, bromo, iodo; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

[0100] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0101] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0102] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0103] The solvent used in the present invention is commercially available.

[0104] The present invention uses the following abbreviations: DMF represents N,N-dimethylformamide; K2CO3 represents potassium carbonate; MeI represents iodomethane; EtOAc represents ethyl acetate; EA represents ethyl acetate; THF represents tetrahydrofuran; NaHMDS represents sodium hexamethyldisilazide; MeOH represents methanol; DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; PE represents petroleum ether; EtOH represents ethanol; ACN represents acetonitrile; TFA represents trifluoroacetic acid; FA represents formic acid; NH3·H2O represents ammonia; TEA represents triethylamine; DIPEA represents N,N -diisopropylethylamine; Boc2O stands for di-tert-butyl dicarbonate; Boc stands for tert-butyloxycarbonyl, a protecting group for amino groups; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; CDI stands for N,N′-carbonyldiimidazole; DDQ stands for 2,3-dichloro-5,6-dicyanobenzoquinone; LCMS stands for liquid chromatography-mass spectrometry; HPLC stands for liquid chromatography; TLC stands for thin-layer chromatography; MEC stands for minimum effective concentration; LnCap stands for prostate cancer cell line; sGC stands for soluble guanylate cyclase; and cGMP stands for cyclic guanosine monophosphate.

[0105] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0106] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0107] Example 1

[0108] Synthesis route:

[0109]

[0110] Step A: To a solution of 1-1 (2 g, 12.61 mmol, 1 eq) in toluene (20 mL) were added 2-fluorobenzylamine (1.89 g, 15.14 mmol, 1.72 mL, 1.2 eq) and cesium carbonate (6.17 g, 18.92 mmol, 1.5 eq). The atmosphere was replaced with nitrogen and the mixture was stirred at 80°C for 12 hours under nitrogen. Water (20 mL) was added to the reaction solution and the mixture was extracted with EtOAc (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 50:1-20:1). The crude product was stirred with petroleum ether (10 mL) and filtered to obtain compound 1-a.

[0111] Step B: Reduced iron powder (3.44 g, 61.56 mmol, 8 eq) and NH4Cl (4.94 g, 92.35 mmol, 3.23 mL, 12 eq) were added to a mixture of 1-a (2.5 g, 7.70 mmol, 1 eq) in EtOH (20 mL) and water (5 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 70°C for 3 hours. Water (20 mL) and EtOAc (50 mL) were added to the reaction solution, which was filtered and separated. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1-5: 1) to obtain compound 1-b.

[0112] Step C: To a solution of 1-b (1.1 g, 3.93 mmol, 1 eq) in THF (50.00 mL) was slowly added CDI (955.69 mg, 5.89 mmol, 1.5 eq). After the addition was complete, the mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE:EtOAc = 4:1-2:1) to provide compound 1-c.

[0113] Step D: To a solution of 1-2 (5.0 g, 28.89 mmol, 1 eq) in phosphorus oxychloride (49.50 g, 322.83 mmol, 30.00 mL, 11.18 eq) was slowly added dropwise 2,6-lutidine (13.80 g, 128.79 mmol, 15.00 mL, 4.46 eq) at 30°C. After the addition was complete, the atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to 30°C and concentrated under reduced pressure to remove excess solvent. Finally, the reaction mixture was slowly added to ice water (100 mL) at 0-5°C, and then extracted with PE / EA (100 mL, 1 / 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 20 / 1) to obtain compound 1-f.

[0114] Step E: To a solution of compound 1-f (3.3 g, 14.45 mmol, 1 eq) in ethanol (20 mL) was added an ethanol solution of NH3 (20 mL) at -20°C. The reaction solution was stirred at -20°C for 50 minutes. The reaction solution was filtered, the filter cake was collected, and then washed with water (10 mL) and ethanol (10 mL) to obtain compound 1-g.

[0115] Step F: To a solution of 1-c (200 mg, 800.87 μmol, 1 eq) in DMF (1.00 mL) were added 1-g (403.76 mg, 800.87 μmol, 1.0 eq), cesium carbonate (521.88 mg, 1.60 mmol, 2 eq), cuprous iodide (15.25 mg, 80.09 μmol, 0.10 eq), and 1,10-phenanthroline (28.86 mg, 160.17 μmol, 0.2 eq). The atmosphere was replaced with nitrogen, and the mixture was stirred at 90°C for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-d.

[0116] Step G: Reduced iron powder (845.42 mg, 15.14 mmol, 20 eq) and NH4Cl (809.79 mg, 15.14 mmol, 20 eq) were added to a mixture of 1-d (300 mg, 756.94 μmol, 1 eq) in MeOH (9 mL) and water (3 mL). The atmosphere was replaced with nitrogen, and the mixture was stirred at 70°C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (25 mL×2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to give compound 1-e.

[0117] Step H: To a solution of 1-e (120 mg, 293.82 μmol, 1 eq) in pyridine (1.5 mL) was added methyl chloroformate (41.65 mg, 440.72 μmol, 34.14 μL, 1.5 eq) at 0°C and stirred at 0°C for half an hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (50 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. EtOAc (10 mL) was added to the residue, stirred, and filtered to obtain compound 1. 1 H NMR (400MHz, DMSO-d6): δppm8.08-8.01(m, 2H), 7.95(br s, 1H), 7.35(m, 1H), 7.28-7.19(m, 2H), 7.18-7.08(m, 2H), 6.33(br s, 4H), 5.15 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m / z: 425.3[M+1] + .

[0118] Example 2

[0119] Synthesis route:

[0120]

[0121] To a solution of compound 1 (50 mg, 115.04 μmol, 1 eq) in DMF (1 mL) was added NaH (6.90 mg, 172.55 μmol, 60% purity, 1.5 eq) at 0°C, and the mixture was stirred at 0°C for 10 minutes. Then, iodomethane (24.49 mg, 172.55 μmol, 10.74 μL, 1.5 eq) was added, and the resulting mixture was stirred at 0°C for half an hour. Water (5 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL×2). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (EtOAc) to give compound 2. 1 H NMR (400MHz, DMSO-d6): δppm 8.09-8.02(m, 2H), 7.39-7.30(m, 1H), 7.27-7.19(m, 2H), 7.18-7.08(m, 2H), 6.55(br s, 4H), 5.15 (s, 2H), 3.66 (s, 1H), 3.55 (s, 2H), 3.00 (s, 3H); LCMS (ESI) m / z: 439.3[M+1] + .

[0122] Example 3

[0123] Synthesis route:

[0124]

[0125] Step A: Under nitrogen, to a solution of compound 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20.00 mL) were added cesium carbonate (5.54 g, 16.99 mmol, 1.5 eq) and 2-fluorobenzylamine (1.70 g, 13.60 mmol, 1.55 mL, 1.2 eq). The mixture was heated to 80°C and stirred for 12 hours. After cooling, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL). The organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE: EtOAc = 50: 1-5: 1) to obtain compound 3-a.

[0126] Step B: Reduced iron powder (1.26 g, 22.62 mmol, 4 eq) and NH4Cl (1.51 g, 53.49 mmol, 5 eq) were added to a mixture of 3-a (1.50 g, 5.66 mmol, 1 eq) in THF (20 mL) and water (10 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 60°C for 6 hours. The reaction solution was filtered and the filter cake was washed with EtOAc (40 mL). The filtrate was added with saturated brine (50 mL) and extracted with EtOAc (40 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 10: 1-4: 1) to obtain compound 3-b.

[0127] Step C: To a solution of 3-b (1.00 g, 4.25 mmol, 1 eq) in THF (20.00 mL) was slowly added CDI (1.03 g, 6.38 mmol, 1.5 eq). After the addition was complete, the mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc = 5:1-2:1) to afford compound 3-c. 1 H NMR (400MHz, CDCl3): δppm 9.99 (br s, 1H), 7.96 (t, J=2.1Hz, 1H), 7.33-7.29 (m, 1H), 7.28-7.24 (m, 1H), 7.16 (dd, J=2.5, 8.0Hz, 1H), 7.12-7.05 (m, 2H), 5.27 (s, 2H).

[0128] Step D: To a solution of 3-c (113 mg, 432.57 μmol, 1 eq) in DMF (4.00 mL) were added 1-g (261.70 mg, 519.09 μmol, 1.0 eq), cesium carbonate (281.88 mg, 865.15 μmol, 2 eq), cuprous iodide (8.24 mg, 43.26 μmol, 0.10 eq) and 1,10-phenanthroline (15.59 mg, 86.51 μmol, 0.2 eq). The atmosphere was replaced with nitrogen and the mixture was stirred at 100°C for 3 hours. After the reaction solution was cooled, saturated brine (20 mL) was added to the reaction solution and extracted with EtOAc (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (PE:EtOAc = 5:1-2:1) to obtain compound 3-d.

[0129] Step E: Reduced iron powder (64.70 mg, 1.16 mmol, 4 eq) and NH4Cl (77.46 mg, 1.45 mmol, 5 eq) were added to a mixture of 3-d (120 mg, 289.63 μmol, 1 eq) in MeOH (6 mL) and water (2 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 70°C for 3 hours. The reaction solution was filtered and the filter cake was washed with methanol (10 mL) and dichloromethane (10 mL). Saturated brine (10 mL) was added to the filtrate and the mixture was extracted with DCM (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to give compound 3-e.

[0130] Step F: To a solution of 3-e (42 mg, 91.06 μmol, 1 eq) in pyridine (1.5 mL) was added methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq) at 0°C and stirred at 0°C for 1 hour. The reaction solution was poured into ice water (20 mL), and saturated brine (10 mL) was added. The mixture was extracted with EtOAc (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 3. 1 H NMR (400MHz, DMSO-d6): δppm 8.18 (dd, J=2.5, 9.4Hz, 1H), 8.07 (s, 1H), 7.96 (br s, 1H), 7.41-7.31 (m, 1H), 7.30-7.11 (m, 3H), 6.37 (br s, 4H), 5.14 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m / z: 443.1[M+1]+ .

[0131] Example 4

[0132] Synthesis route:

[0133]

[0134] Step A: Under nitrogen, to a solution of 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20.00 mL) were added cesium carbonate (5.54 g, 16.99 mmol, 1.5 eq) and 2-trifluoromethylbenzylamine (2.38 g, 13.60 mmol, 1.55 mL, 1.2 eq). The mixture was heated to 80°C and stirred for 12 hours. After cooling, water (40 mL) was added and the mixture was extracted with EtOAc (40 mL). The organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE: EtOAc = 50: 1-5: 1) to give compound 4-a.

[0135] Step B: Reduced iron powder (1.20 g, 21.57 mmol, 4 eq) and NH4Cl (1.44 g, 26.97 mmol, 5 eq) were added to a mixture of 4-a (1.70 g, 5.39 mmol, 1 eq) in THF (20 mL) and water (10 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 60°C for 3 hours. The reaction solution was filtered and the filter cake was washed with EtOAc (40 mL). The filtrate was then added with saturated brine (60 mL) and extracted with EtOAc (50 mL). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE:EtOAc=10:1-4:1) to obtain compound 4-b.

[0136] Step C: To a solution of 4-b (1.21 g, 4.25 mmol, 1 eq) in THF (20.00 mL) was slowly added CDI (1.03 g, 6.38 mmol, 1.5 eq). After the addition was complete, the mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc = 4:1-2:1) to afford compound 4-c. 1 H NMR (400MHz, DMSO-d6): δppm 11.60(br s, 1H), 7.91 (t, J=2.0Hz, 1H), 7.80 (d, J=7.7Hz, 1H), 7.63-7.53 (m, 1H), 7.53-7.40 (m, 2H), 7.02 (d, J=7.7Hz, 1H), 5.19 (s, 2H).

[0137] Step D: To a solution of 4-c (140 mg, 449.82 μmol, 1 eq) in DMF (1.00 mL) were added 1-g (226.78 mg, 449.82 μmol, 1.0 eq), cesium carbonate (293.12 mg, 899.64 μmol, 2 eq), cuprous iodide (8.57 mg, 44.98 μmol, 0.10 eq), and 1,10-phenanthroline (16.21 mg, 89.96 μmol, 0.2 eq). The atmosphere was replaced with nitrogen and the mixture was stirred at 100°C for 3 hours. The reaction mixture was cooled and filtered, and the filter cake was washed with MeOH (10 mL) and EtOAc (10 mL). The filtrate was then added with saturated brine (20 mL) and extracted with EtOAc (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-d.

[0138] Step E: Reduced iron powder (360.84 mg, 6.46 mmol, 20 eq) and NH4Cl (345.59 mg, 6.46 mmol, 20 eq) were added to a mixture of 4-d (150 mg, 323.04 μmol, 1 eq) in MeOH (9 mL) and water (3 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 70°C for 3 hours. The reaction mixture was filtered and the filter cake was washed with methanol (10 mL) and EtOAc (10 mL). The filtrate was concentrated and purified by thin layer chromatography (DCM:MeOH=10:1) to give compound 4-e.

[0139] Step F: To a solution of 4-e (39.55 mg, 91.06 μmol, 1 eq) in pyridine (1.0 mL) was added methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq) at 0°C and stirred at 0°C for 1 hour. The reaction solution was poured into ice water (10 mL) and saturated brine (10 mL) was added. The mixture was extracted with EtOAc (5 mL×3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 4. 1 H NMR (400MHz, DMSO-d6): δppm 8.18 (dd, J=2.5, 9.4Hz, 1H), 8.07 (s, 1H), 7.96 (br s, 1H), 7.41-7.31 (m, 1H), 7.30-7.11 (m, 3H), 6.37 (br s, 4H), 5.14 (s, 2H), 3.62 (br s, 3H); LCMS (ESI) m / z: 493.1[M+1] + .

[0140] Example 5

[0141] Synthesis route:

[0142]

[0143]

[0144] Step A: To a solution of 1-f (1.3 g, 5.69 mmol, 1 eq) in DCM (100.00 mL) was slowly added a solution of p-methoxybenzylamine (1.56 g, 11.38 mmol, 1.47 mL, 2 eq) in DCM (100.00 mL) at -20°C, and the mixture was stirred at -20°C for 1 hour. Water (50.00 mL) was added for washing, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was stirred with EtOAc (15 mL), filtered and dried to give compound 5-b.

[0145] Step B: To a solution of CoCl2·6H2O (1.71 g, 7.19 mmol, 0.1 eq) in THF (200.00 mL) and water (100.00 mL) was added 5-2 (10 g, 71.89 mmol, 8.00 mL, 1 eq), and then NaBH4 (13.60 g, 359.45 mmol, 5 eq) was added portionwise. The reaction solution was stirred at 30°C for 12 hours. NH3·H2O (25%, 20 mL) was slowly added to the reaction solution, followed by addition of water (100 mL), and the mixture was extracted with EtOAc (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EtOAc=10:1-3:1) to give compound 5-c.

[0146] Step C: To a solution of 5-c (3.65 g, 25.49 mmol, 2.99 mL, 1.5 eq) in toluene (30.00 mL) were added cesium carbonate (8.31 g, 25.49 mmol, 1.5 eq) and 3-1 (3.0 g, 16.99 mmol, 1 eq). The mixture was heated to 80° C. and stirred for 12 hours, filtered, and concentrated. The residue was separated by column chromatography (PE: EtOAc = 100: 1-10: 1) to give compound 5-d.

[0147] Step D: To a mixture of 5-d (2.0 g, 7.06 mmol, 1 eq) in EtOH (100 mL) and water (50 mL) were added reduced iron powder (1.97 g, 35.30 mmol, 5 eq) and NH4Cl (1.89 g, 35.30 mmol, 1.23 mL, 5 eq), stirred at 70°C for 1 hour, extracted with EtOAc (100 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (PE:EtOAc=10:1-3:1) to obtain compound 5-e.

[0148] Step E: To a solution of 5-e (1.0 g, 3.95 mmol, 1 eq) in THF (100.00 mL) was slowly added CDI (960.51 mg, 5.92 mmol, 1.5 eq). After the addition was complete, the mixture was stirred at 70°C for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc = 20:1-3:1) to afford compound 5-f.

[0149] Step F: To a solution of 5-f (450 mg, 1.61 mmol, 1 eq) in DMF (10.00 mL) were added 5-b (1.04 g, 2.42 mmol, 1.5 eq), cesium carbonate (630.13 mg, 1.93 mmol, 1.2 eq), cuprous iodide (30.69 mg, 161.16 μmol, 0.1 eq) and 8-hydroxyquinoline (23.39 mg, 161.16 μmol, 27.85 μL, 0.1 eq), the atmosphere was replaced with nitrogen, and the mixture was stirred at 100° C. for 3 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EtOAc = 10: 1-3: 1) to obtain compound 5-g.

[0150] Step G: To a solution of 5-g (900 mg, 1.34 mmol, 1 eq) in DCM (50.00 mL) and water (5.00 mL) was added DDQ (1.52 g, 6.69 mmol, 5 eq), and the mixture was stirred at 30°C for 12 hours. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (50 mL×2). The combined organic phases were washed with water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred with EtOAc (10 mL), filtered, and dried to obtain compound 5-h.

[0151] Step H: To a mixture of MeOH (3 mL) and water (1 mL) of 5-h (50 mg, 85.59 μmol, 1 eq) were added reduced iron powder (95.59 mg, 1.71 mmol, 20 eq) and NH4Cl (91.56 mg, 1.71 mmol, 20 eq), and the mixture was stirred at 70°C for 1 hour. After cooling, the reaction solution was filtered, and water (20 mL) was added to the filtrate, and the mixture was extracted with DCM (25 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5-i.

[0152] Step I: To a solution of 5-i (20 mg, 49.71 μmol, 1 eq) in pyridine (1.0 mL) was added methyl chloroformate (7.05 mg, 74.57 μmol, 5.78 μL, 1.5 eq) at 0°C, and the mixture was stirred at 0°C for 30 min. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL×2). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 5. 1 H NMR (400MHz, DMSO-d6): δppm 8.20 (dd, J=2.6, 9.4Hz, 1H), 8.07 (t, J=2.1Hz, 1H), 7.98 (br s, 1H), 7.44-7.30 (m, 1H), 7.22-7.08 (m, 2H), 6.37 (br s, 4H), 5.17 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m / z: 461.1[M+1] + .

[0153] Example 6

[0154] Synthesis route:

[0155]

[0156] To a solution of compound 5 (15 mg, 32.58 μmol, 1 eq) in DMF (1.00 mL) was added NaH (1.95 mg, 48.87 μmol, 60% purity, 1.5 eq) at 0°C. After stirring at 0°C for 30 minutes, iodomethane (6.94 mg, 48.87 μmol, 3.04 μL, 1.5 eq) was added and stirring was continued at 0°C for 30 minutes. The reaction solution was slowly poured into water (30 mL), and then extracted with EtOAc (30 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 6. 1H NMR (400MHz, DMSO-d6): δppm 8.47 (br s, 1H), 8.22 (br dd, J=2.6, 9.4Hz, 1H), 7.45-7.30 (m, 1H), 7.22-7.06 (m, 2H), 6.64-6.49 (m, 4H), 5.17 (s, 2H), 3.66-3.55 (s, 3H), 3.00 (s, 3H). LCMS(ESI)m / z: 475.1[M+1] + .

[0157] Example 7

[0158] Synthesis route:

[0159]

[0160] Step A: Under nitrogen protection, DIPEA (2.20 g, 16.99 mmol, 2.96 mL, 1.5 eq) and 2-chlorobenzylamine (1.60 g, 11.33 mmol, 1.37 mL, 1 eq) were added to a solution of 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20.00 mL). The mixture was heated to 80°C and stirred for 17 hours. After cooling, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE: EtOAc = 100: 1-50: 1) to give compound 7-a. 1 H NMR (400MHz, CDCl3) δppm 4.94 (d, J=6.02Hz, 2H) 7.17-7.34 (m, 2H) 7.37-7.47 (m, 2H) 8.22 (dd, J=7.91, 2.89Hz, 1H) 8.40 (d, J=2.89Hz, 1H) 8.47-8.67 (m, 1H).

[0161] Step B: Reduced iron powder (2.24 g, 40.03 mmol, 5 eq) and NH4Cl (1.71 g, 32.02 mmol, 1.12 mL, 4 eq) were added to a mixture of 7-a (3.13 g, 8.01 mmol, 1 eq) in THF (45 mL) and water (15 mL). The atmosphere was replaced with nitrogen and the mixture was stirred at 80°C for 17 hours. The reaction solution was filtered, and the filtrate was added with water (80 mL) and extracted with EtOAc (80 mL×3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 100: 1-5: 1) to obtain compound 7-b. 1H NMR (400MHz, DMSO-d6): δppm 7.44-7.38(m, 1H), 7.35-7.30(m, 1H), 7.28-7.24(m, 2H), 7.22(d, J=2.6Hz, 1H), 6.6 4 (dd, J=2.8, 10.4Hz, 1H), 6.09 (t, J=5.6Hz, 1H), 5.22 (s, 2H), 4.58 (d, J=5.6Hz, 2H).

[0162] Step C: To a solution of 7-b (1.16 g, 3.75 mmol, 1 eq) in THF (30.00 mL) was slowly added CDI (911.37 mg, 5.62 mmol, 1.5 eq). After the addition was complete, the mixture was stirred at 75°C for 4 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc = 20:1-4:1) to afford compound 7-c.

[0163] Step D: To a solution of 7-c (0.3 g, 1.08 mmol, 1 eq) in DMF (5.00 mL) were added 1-g (245.76 mg, 1.30 mmol, 1.2 eq), cesium carbonate (704.01 mg, 2.16 mmol, 2.0 eq), cuprous iodide (20.58 mg, 108.04 μmol, 0.1 eq) and 1,10-phenanthroline (38.94 mg, 216.08 μmol, 0.2 eq). The atmosphere was replaced with nitrogen and the mixture was stirred at 90°C for 3 hours. The reaction solution was cooled and filtered, and water (10 mL) was added to the filtrate. The mixture was extracted with DCM:MeOH = 5:1 (10 mL × 4). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7-d.

[0164] Step E: To a mixture of 7-d (276.00 mg, 640.70 μmol, 1 eq) in MeOH (8 mL) and water (2 mL) were added reduced iron powder (715.60 mg, 12.81 mmol, 20 eq) and NH4Cl (685.44 mg, 12.81 mmol, 448.00 μL, 20 eq), and the mixture was stirred at 75°C for 1.5 hours. After cooling, the reaction solution was filtered, the filtrate was concentrated, water (10 mL) was added, and the mixture was extracted with DCM:MeOH=10:1 (10 ml×3). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the concentrated residue was purified by thin layer chromatography (DCM:MeOH=10:1) to give compound 7-e.

[0165] Step F: To a solution of 7-e (20 mg, 49.90 μmol, 1 eq) in pyridine (1.0 mL) was added methyl chloroformate (4.72 mg, 49.95 μmol, 3.87 μL, 1.00 eq) at 0°C and stirred at 0°C for 30 min. The reaction solution was poured into water (1 mL), extracted with EtOAc (2 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 7. 1 H NMR (400MHz, DMSO-d6) δppm 8.23 ​​(dd, J=9.47, 2.57Hz, 1H), 7.98-8.14 (m, 1H), 7.96 (br s, 1H), 7.51 (dd, J=7.84, 1.32Hz, 1H), 7.19-7.43 (m, 2H), 7.08 (d, J=6.40Hz, 1H), 6.37 (br s, 4H), 5.15 (s, 2H), 3.62 (br s, 3H); LCMS (ESI) m / z: 459.0[M+1] + .

[0166] Example 8

[0167] Synthesis route:

[0168]

[0169] Step A: To a solution of 3-e (40 mg, 104.06 μmol, 1 eq) in DMF (1 mL) were added trifluoroethyl trifluoromethanesulfonate (48.31 mg, 208.15 μmol, 2.0 eq) and DIPEA (40.35 mg, 312.22 μmol, 54.38 μL, 3.0 eq) in sequence. The mixture was stirred at 80°C for 12 hours. After cooling, water (20 mL) was added and the mixture was extracted with EA (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 15:1) to give compound 8-a.

[0170] Step B: To a solution of 8-a (15 mg, 32.16 μmol, 1 eq) in DMF (1 mL) was added CDI (10.43 mg, 64.33 μmol, 2.0 eq), and the mixture was stirred at 90°C for 6 hours. Saturated brine (10 mL) was added to the reaction solution, and the mixture was extracted with EA (8 mL x 2). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by preparative HPLC [mobile phase: water (10 mM NH4HCO3)-ACN] to obtain compound 8.1 H NMR (400MHz, DMSO-d6): δppm8.19 (dd, J=2.4, 9.3Hz, 1H), 8.10 (d, J=1.9Hz, 1H), 7.40-7.26 (m, 1H), 7. 26-7.19(m, 1H), 7.26-7.19(m, 1H), 7.18-7.12(m, 1H), 7.43-7.12(m, 1H), 7.12-7.04(m, 1H), 7.09(br s, 1H), 5.16 (s, 2H), 4.91 (q, J=9.0Hz, 2H); LCMS (ESI) m / z: 493.1[M+1] + .

[0171] Example 9

[0172] Synthesis route:

[0173]

[0174] Step A: Aqueous ammonia (3.64 g, 103.86 mmol, 4.00 mL, 4.03 eq) and diisopropylethylamine (5.00 g, 38.66 mmol, 6.73 mL, 1.5 eq) were dissolved in dichloromethane (80 mL) to obtain solution 1, and 9-1 (5 g, 25.78 mmol, 1 eq) was dissolved in dichloromethane (15 mL) to obtain solution 2. At 0°C, solution 1 was slowly added dropwise to solution 2, and stirred at 0°C for 1 hour. The reaction solution was filtered to obtain compound 9-a. 1 H NMR (400MHz, DMSO-d6): δppm 8.57 (br s, 1H) 9.01 (s, 1H) 9.19 (br s, 1H).

[0175] Step B: 9-a (0.2 g, 1.15 mmol, 1.2 eq), compound 3-c (249.44 mg, 954.86 μmol, 1 eq) and anhydrous potassium carbonate (263.94 mg, 1.91 mmol, 2 eq) were dissolved in DMF (5 mL), replaced with nitrogen three times, and stirred at 25° C. for 2 hours. The reaction solution was added dropwise to 40 mL of water, stirred for 15 minutes, and then filtered to obtain compound 9-b.

[0176] Step C: Compound 9-b (400 mg, 879.52 μmol, 1 eq) was dissolved in MeOH (9 mL) and H2O (3 mL). To the solution were added Fe (982.33 mg, 17.59 mmol, 20 eq) and NH4Cl (940.93 mg, 17.59 mmol, 614.99 μL, 20 eq), and the mixture was stirred at 75°C for 1 hour. The reaction solution was cooled to 25°C, filtered through celite, and the filtrate was concentrated and purified by thin layer chromatography (DCM:MeOH=10:1) to give compound 9-c.

[0177] Step D: Compound 9-c (45 mg, 121.84 μmol, 1 eq) was dissolved in pyridine (2 mL), and methyl chloroformate (17.27 mg, 182.76 μmol, 14.16 μL, 1.5 eq) was added dropwise at 0°C and stirred at this temperature for 30 minutes. The reaction solution was added dropwise to 2 mL of water and extracted with EA (3 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 9. 1 H NMR (400MHz, DMSO-d6) δppm 3.68 (s, 3H) 5.15 (s, 2H) 7.09-7.43 (m, 6H) 8.09 (d, J = 1.88Hz, 1H) 8.16 (dd, J = 9.35, 2.45Hz, 1H) 8.28 (br s, 1H) 8.85 (br s, 1H); LCMS (ESI) m / z: 428.0[M+1] + .

[0178] Example 10

[0179] Synthesis route:

[0180]

[0181] Step A: To a solution of compound 3-e (203 mg, 512.33 μmol, 1 eq) in pyridine (2.0 mL) at 0°C under nitrogen was added compound 10-1 (219.74 mg, 1.54 mmol, 158.09 μL, 3 eq) in a single portion. The mixture was stirred at 0°C for 1 hour. The resulting reaction solution was added dropwise to water (20 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (SiO2, DCM / MeOH = 15 / 1) to afford the crude product of compound 10-a, which was used in the next step without further purification. LCMS (ESI) m / z: 491.0 [M+1] + .

[0182] Step B: To a solution of compound 10-a (65 mg, 132.42 μmol, 1 eq) in THF (4.0 mL) was added NaHMDS (1 M, 264.85 μL, 2 eq) at 0°C under nitrogen, and the mixture was reacted at 0°C for 1 hour. The mixture was then added dropwise to an ice bath (10 mL), and then extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (0.04% NH3·H2O + 10 mM NH4HCO3)-ACN] to give compound 10. 1 H NMR (400MHz, DMSO-d6): δppm 11.77(br s, 1H), 8.17-8.05(m, 2H), 7.40-7.26(m, 2H), 7.26-7.12(m, 2H), 6.95(br s, 2H), 5.35 (t, J=4.9Hz, 1H), 5.15 (s, 2H), 3.97 (t, J=4.8Hz, 2H), 3.68-3.56 (m, 2H);

[0183] LCMS (ESI) m / z: 455.2 [M+1] + .

[0184] Example 11

[0185] Synthesis route:

[0186]

[0187] Compound 9-c (200 mg, 349.28 μmol, 1 eq) was dissolved in pyridine (2 mL), and 11-1 (55.82 mg, 523.92 μmol, 1.5 eq) was added dropwise at 0°C and stirred at this temperature for 30 minutes. After the reaction, the reaction solution was added dropwise to 2 mL of water and extracted with EA (4 mL × 3). The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to provide compound 11. 1 H NMR (400MHz, DMSO-d6) δppm 1.13 (d, J=6.78Hz, 6H) 2.67 (quin, J=6.78Hz, 1H) 5.15 (s, 2H) 7.10-7.18 (m, 1H) 7. 17-7.39 (m, 5H) 8.09 (s, 1H) 8.16 (dd, J=9.29, 2.38Hz, 1H) 8.37 (s, 1H) 9.33 (s, 1H). LCMS(ESI)m / z:440.1[M+1] + .

[0188] Example 12

[0189] Synthesis route:

[0190]

[0191] Compound 9-c (200 mg, 349.28 μmol, 1 eq) was dissolved in pyridine (2 mL), and 12-1 (76.81 mg, 523.92 μmol, 69.83 μL, 1.5 eq) was added dropwise at 0°C and stirred at this temperature for 30 minutes. The reaction solution was added dropwise to 2 mL of water and extracted with EA (4 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (10 mM NH4HCO3)-ACN] to obtain compound 12. 1 H NMR (400MHz, DMSO-d6): δppm1.15-1.56 (m, 3H) 1.40 (q, J=12.05Hz, 2H) 1.66 (br d, J=11.67Hz, 1H) 1.76 (br d, J=12.67Hz, 2H) 1.88 (br d, J=11.17Hz, 2H) 2.31-2.43 (m, 1H) 5.14 (s, 2H) 7.06-7.43 (m, 6H) 8.09 (t, J=2.07Hz, 1H) 8.15 (dd, J=9.22, 2.45Hz, 1H) 8.36 (s, 1H) 9.15 (br s, 1H). LCMS(ESI)m / z:480.0[M+1] + .

[0192] Example 13

[0193] Synthesis route:

[0194]

[0195] Compound 9-c (0.036 g, 94.06 μmol, 1 eq) was dissolved in DMF (1 mL), and DIEA (48.63 mg, 376.25 μmol, 65.54 μL, 4 eq) and 13-1 (24.00 mg, 103.47 μmol, 12.97 μL, 1.1 eq) were added. The resulting mixture was stirred at 130° C. for 2 hours. The reaction solution was purified by preparative HPLC [mobile phase: water (0.05% ammonia)-ACN] to give compound 13. 1 HNMR (400MHz, DMSO-d6): δppm 8.19-8.06(m, 2H), 7.99(s, 1H), 7.39-7.32(m, 1H), 7.31-7.19(m, 2H), 7.18-7.12(m , 1H), 5.15 (s, 2H), 3.83-3.71 (m, 4H), 2.95-2.80 (m, 4H); LCMS (ESI) m / z: 440.2[M+1] + .

[0196] Example 14

[0197] Synthesis route:

[0198]

[0199] At 25°C, 14-1 (0.159 g, 1.03 mmol, 1 eq) was dissolved in DCM (1 mL). Oxalyl chloride (117.88 mg, 928.70 μmol, 81.29 μL, 0.9 eq) and DMF (7.54 mg, 103.19 μmol, 7.94 μL, 0.1 eq) were added and stirred until gas evolution ceased. The reaction solution was then added dropwise to a solution of compound 9-c (119.09 mg, 206.38 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL). The mixture was stirred at 25°C for 2 hours. 2 mL of water was added to the reaction solution, and the mixture was extracted with DCM (4 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.04% NH3H2O)-ACN] to afford compound 14. 1H NMR (400MHz, DMSO-d6) δppm 1.31-1.38 (m, 2H) 1.68 (br s, 2H) 5.15 (s, 2H) 7.11-7.18 (m, 2H) 7.17-7.40 (m, 4H) 8.05-8.12 (m, 2H) 8.22 (dd, J=9.35, 2.57Hz, 1H) 9.10 (br s, 1H); LCMS (ESI) m / z: 506.0 [M+1] + .

[0200] Example 15

[0201] Synthesis route:

[0202]

[0203] Step A: Pyridinium tribromide (12.50 g, 7.81 mmol, 4 eq) was added to a solution of compound 15-1 (1.50 g, 9.77 mmol, 1 eq) in tert-butanol (54 mL) and stirred at 25°C for 6 hours. The reaction mixture was filtered, and the filter cake was washed with EA (20 mL). Water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was collected, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE:EA = 5:1-3:1) to obtain compound 15-a.

[0204] Step B: Compound 15-a (1.5 g, 4.58 mmol, 1 eq) and ammonium chloride (1.23 g, 22.91 mmol, 5 eq) were dissolved in tetrahydrofuran (16 mL) and water (8 mL). Zinc powder (1.50 g, 22.91 mmol, 5 eq) was then added to the mixture, and the reaction system was stirred at 25°C for 1 hour. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (20 mL × 2). The organic phase was collected, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (SiO2, PE:EA = 5:1-1:1) to obtain compound 15-b.

[0205] Step C: Compound 15-b (150 mg, 0.885 mmol, 1 eq) was dissolved in anhydrous DMF (15 mL). The atmosphere was replaced with nitrogen. NaH (35.38 mg, 0.885 mmol, 60% purity, 1 eq) was added to the reaction mixture at 0°C and stirred at 25°C for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (147.5 mg, 0.885 mmol, 156.6 μL, 1 eq) was then added dropwise and stirred at 25°C for 1 hour. The mixture was cooled to 0°C and NaH (70.76 mg, 1.77 mmol, 60% purity, 2 eq) was added to the reaction mixture under nitrogen. After stirring for 30 minutes, iodomethane (263.67 mg, 1.86 mmol, 115.65 μL, 2.1 eq) was added dropwise. The reaction mixture was stirred at 25°C for 1 hour. The reaction solution was poured into H2O (45 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-c.

[0206] Step D: To a solution of compound 15-c (70 mg, 213.49 μmol, 1 eq) and compound 3-c (66.92 mg, 256.19 μmol, 1.2 eq) in DMF (5.0 mL) was added cesium carbonate (139.12 mg, 426.98 μmol, 2.0 eq) and the nitrogen atmosphere was replaced. Under a nitrogen atmosphere, the reaction system was stirred at 100° C. for 15 hours. H 2 O (20 mL) was added to the reaction system and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-d; 1 H NMR (400MHz, CDCl3): δppm 8.43 (s, 1H), 8.15 (dd, J=8.85, 2.57Hz, 1H), 8.04 (dd, J=2.45, 1.57Hz, 1H), 7.38-7.42 (m, 1H), 7.23-7.25 (m, 1H), 7 .04-7.09 (m, 2H), 5.31 (s, 2H), 5.28 (s, 2H), 3.70 (t, J=8.4Hz, 2H), 1.52 (s, 6H), 0.99 (t, J=8.0Hz, 2H), 0.02 (s, 9H).

[0207] Step E: Trifluoroacetic acid (154 mg, 1.35 mmol, 18.66 eq) was added to a solution of compound 15-d (40 mg, 72.38 μmol, 1 eq) in anhydrous dichloromethane (5.0 mL) and stirred at 25°C for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (0.04% NH3·H2O)-ACN] to provide compound 15. 1 H NMR (400MHz, CDCl3): δppm 8.35 (s, 1H), 8.17 (d, J = 2.8Hz, 1H), 8.15 (d, J = 2.8Hz, 1H), 8.05-8.04 (m, 1H), 7.27-7 .24 (m, 1H), 7.07-7.03 (m, 2H), 5.29 (s, 2H), 1.51 (s, 6H); LCMS (ESI) m / z: 423.2[M+1] + .

[0208] Example 16

[0209] Synthesis route:

[0210]

[0211] At 25°C, p-fluorobenzoic acid (245.45 mg, 1.75 mmol, 1 eq) was dissolved in DCM (1 mL). DMF (7.54 mg, 103.19 μmol, 7.94 μL, 0.1 eq) and oxalyl chloride (200.12 mg, 1.58 mmol, 138.01 μL, 0.9 eq) were added and stirred until gas evolution ceased. The reaction solution was then added dropwise to a solution of compound 9-c (0.2 g, 350.37 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL) and stirred at 25°C for 2 hours. 2 mL of water was added to the reaction solution, and the mixture was extracted with DCM (4 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.04% NH3.H2O)-ACN] to provide compound 16. 1 H NMR (400MHz, DMSO-d6) δppm 5.16 (s, 2H) 7.12-7.18 (m, 1H) 7.19-7.26 (m, 1H) 7.27-7.43 (m, 6H) 8.04-8.18 (m, 3H) 8.18-8.34 (m, 2H) 9.82 (s, 1H). LCMS(ESI)m / z: 492.2[M+1] + .

[0212] Example 17

[0213] Synthesis route:

[0214]

[0215] Step A: At 0°C, to a solution of 17-1 (3 g, 25.84 mmol, 1 eq) in DMF (30 mL) was carefully and slowly added NaH (2.07 g, 51.67 mmol, 60% purity, 2 eq), stirred at 0°C for 0.5 hour, and then iodomethane (4.40 g, 31.00 mmol, 1.93 mL, 1.2 eq) was added to the solution, gradually restored to room temperature and stirred for 0.5 hour, stirred at 45°C for 3 hours, cooled to room temperature, added saturated ammonium chloride solution (60 mL) to quench the reaction, diluted with water (10 mL), extracted with DCM (30 mL×3), and the combined organic phases were washed with water (30 ml×3), dried over anhydrous sodium sulfate, filtered, and concentrated below 10°C to obtain compound 17-a. 1 HNMR (400MHz, DMSO-d6): δ3.65 (s, 3H), 3.30 (s, 3H), 1.31-1.27 (dd, J=4.8Hz, 8.4Hz, 2H), 1.17-1.14 (dd, J=4Hz, 7.2Hz, 2H).

[0216] Step B: To a solution of 17-a (0.56 g, 4.30 mmol, 1 eq) in MeOH (5 mL) was slowly added a solution of KOH (483.19 mg, 8.61 mmol, 2 eq) in water (2.5 mL). After the addition was complete, the mixture was stirred at 20°C for 15 hours. The reaction solution was concentrated below 40°C, washed with petroleum ether (15 mL), and the aqueous phase was poured into ice water (15 mL). The solution was adjusted to pH 5-6 with 3M aqueous hydrochloric acid and extracted with DCM (12 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 17-b. 1 H NMR (400MHz, DMSO-d6): δ 12.55 (s, 1H), 3.29 (s, 3H), 1.14-1.12 (dd, J=6Hz, 8.8Hz, 2H), 1.07-1.04 (dd, J=3.2Hz, 6.4Hz, 2H).

[0217] Step C: To a solution of 17-b (350 mg, 3.01 mmol, 1 eq) in DCM (2.00 mL) and DMF (22.03 mg, 301.43 μmol, 23.19 μL, 0.1 eq) was added oxalyl chloride (344.33 mg, 2.71 mmol, 237.47 μL, 0.9 eq) at 0°C, nitrogen was replaced, and the mixture was stirred at 0°C for 0.5 h. A solution of 9-c (261.94 mg, 602.85 μmol, 0.2 eq) in DCM (3 mL) was added dropwise, and then the mixture was added to the mixture. Pyridine (476.85 mg, 6.03 mmol, 486.59 μL, 2 eq) was added to the reaction mixture, and the mixture was stirred at 20°C for 5 hours. The reaction solution was quenched with water (20 mL), extracted with EtOAc (15 mL×3), and the organic phase was washed with saturated brine (15 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (PE: EtOAc=10:1-0.1:1) and the crude product was further purified by preparative HPLC [mobile phase: water (0.05% ammonia)-ACN] to obtain compound 17. 1 H NMR (400MHz, CD3OD): δppm 1.23-1.25 (dd, J=2.8Hz, 7.2Hz, 2H), 1.32-1.35 (dd, J=4Hz, 6.8Hz, 2H), 2.03 (s, 1H), 3.50 (s, 3H), 5.28 (s, 2H), 7.09-7.14 (t, J=6 Hz, 2H), 7.29-7.36 (dd, J=7.2Hz, 14.8Hz, 2H), 8.01 (s, 1H), 8.19 (s, 1H), 8.35-8.37 (d, J=2.4Hz, 1H); LCMS (ESI) m / z: 468.0[M+1] + .

[0218] Example 18

[0219] Synthesis route:

[0220]

[0221] To a solution of 3-e (100 mg, 260.18 μmol, 1 eq) in pyridine (4 mL) were added EDCI (399.02 mg, 2.08 mmol, 8 eq) and 14-1 (80.18 mg, 520.37 μmol, 2 eq), and the reaction mixture was stirred at 30°C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN]] to obtain compound 18.1 H NMR (400MHz, DMSO-d6): δppm 8.60(br s, 1H), 8.22 (dd, J=2.3, 9.4Hz, 1H), 8.08 (s, 1H), 7.39-7.31 (m, 1H), 7.31-7.19 (m, 2H), 7.18-7.12 (m, 1H), 6.26 (br s, 4H), 5.14 (s, 2H), 1.74 (br s, 2H), 1.32-1.15 (m, 2H); LCMS (ESI) m / z: 521.2[M+1] + .

[0222] Example 19

[0223] Synthesis route:

[0224]

[0225] To a solution of 1-e (100 mg, 272.96 μmol, 1 eq) in pyridine (3 mL) were added EDCI (418.62 mg, 2.18 mmol, 8 eq) and 14-1 (84.12 mg, 545.92 μmol, 2 eq), and the reaction mixture was stirred at 30°C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 19. 1 H NMR (400MHz, DMSO-d6): δppm 8.58 (br s, 1H), 8.14-8.01 (m, 2H), 7.38-7.32 (m, 1H), 7.29-7.20 (m, 2H), 7.18-7.11 (m, 2H), 6.22 (br s, 4H), 5.16 (s, 2H), 1.77-1.69 (m, 2H), 1.31-1.20 (m, 2H); LCMS (ESI) m / z: 503.2[M+1] + .

[0226] Example 20

[0227] Synthesis route:

[0228]

[0229] Compound 9 (169 mg, 395.45 μmol, 1 eq) was dissolved in THF (2 mL) at 0°C, and NaH (20.56 mg, 514.08 μmol, 60% purity, 1.3 eq) was added to the resulting solution. The mixture was stirred for 90 min, followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (110.14 mg, 474.54 μmol, 1.2 eq). The mixture was warmed to 20°C and stirred for 36 h. 2 mL of water was added to the reaction solution, and the pH was adjusted to 6-7 with 1 M aqueous hydrochloric acid. The mixture was then extracted with EA (4 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN] to afford compound 20. 1 H NMR (400MHz, DMSO-d6): δppm 4.85 (q, J=9.03Hz, 2H) 5.18 (s, 2H) 7.14-7.19 (m, 1H) 7.21-7.27 (m, 1H) 7.30-7.40 (m, 2H) 7. 99 (dd, J=9.10, 2.45Hz, 1H) 8.12 (t, J=2.13Hz, 1H) 8.52 (s, 1H); LCMS (ESI) m / z: 478.2[M+1] + .

[0230] Example 21

[0231] Synthesis route:

[0232]

[0233] At 25°C, 21-1 (203 mg, 2.03 mmol, 1 eq) was dissolved in DCM (1 mL), and oxalyl chloride (231.63 mg, 1.82 mmol, 159.74 μL, 0.9 eq) and DMF (14.82 mg, 202.77 μmol, 15.60 μL, 0.1 eq) were added. The mixture was stirred until no gas was released, and the reaction solution was added dropwise to a solution of compound 9-c (176.20 mg, 405.53 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL), and stirred at 25°C for 2 hours. 2 mL of water was added to the reaction solution, and the mixture was extracted with DCM (4 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [water (0.04% NH 3 · H 2 O + 10 mM NH 4 HCO 3 )-ACN]; acetonitrile: 35%-62%, 10 min) to give compound 21. 1H NMR (400MHz, DMSO-d6): δppm 0.53-0.75(m, 2H)1.14(br d, J=2.38Hz, 2H) 1.44 (s, 3H) 5.16 (s, 2H) 7.12-7.28 (m, 4H) 7.27-7.40 (m, 2H) 8.07 (s, 1H) 8.11 (s, 1H) 8.21 (dd, J=9.29, 2.38Hz, 1H) 8.85 (br s, 1H); LCMS (ESI) m / z: 452.2[M+1] + .

[0234] Example 22

[0235] Synthesis route:

[0236]

[0237] Compound 3-e (0.1 g, 260.18 μmol, 1 eq) was dissolved in pyridine (2 mL), and ethyl chloroformate (42.35 mg, 390.28 μmol, 37.15 μL, 1.5 eq) was added dropwise at 0°C, and stirred at this temperature for 30 minutes. After the reaction, the reaction solution was added dropwise to 4 mL of water and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [[mobile phase: water (0.225% FA)-ACN] to obtain compound 22. 1 H NMR (400MHz, DMSO-d6): δppm 1.02-1.33 (m, 3H) 4.06 (br d, J=6.78Hz, 2H) 5.13 (s, 2H) 6.33 (br s, 4H) 7.10-7.17 (m, 1H) 7.18-7.29 (m, 2H) 7.30-7.39 (m, 1H) 7.92 (brs, 1H) 8.06 (s, 1H) 8.18 (br d, J=9.03Hz, 1H); LCMS (ESI) m / z: 457.0[M+1] + .

[0238] Example 23

[0239] Synthesis route:

[0240]

[0241] Compound 3-e (100 mg, 260.18 μmol, 1 eq) and 23-1 (57.81 mg, 520.37 μmol, 2 eq) were dissolved in pyridine (4 mL), and EDCI (399.02 mg, 2.08 mmol, 8 eq) was added. The reaction mixture was allowed to react at 30°C for 2 hours. The reaction mixture was added dropwise to H2O (4 mL), then extracted with EA (5 mL x 3). The organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to provide compound 23. 1 H NMR (400MHz, DMSO-d6): δppm 1.50-1.64 (m, 2H) 1.64-1.87 (m, 2H) 5.14 (s, 2H) 6.47 (br s, 4H) 7.10-7.19 (m, 1H) 7.18-7.30 (m, 2H) 7.35 (q, J=6.48Hz, 1H) 8.07 (s, 1H) 8.22 (dd, J=9.35, 2.20Hz, 1H) 8.60 (br s, 1H); LCMS (ESI) m / z: 478.0[M+1] + .

[0242] Example 24

[0243] Synthesis route:

[0244]

[0245] To a solution of 3-e (100 mg, 260.18 μmol, 1 eq) in pyridine (5 mL) were added EDCI (399.02 mg, 2.08 mmol, 8 eq) and 17-b (90.63 mg, 780.55 μmol, 3 eq). The reaction solution was stirred at 20°C for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude compound, which was separated by preparative HPLC [mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile] and then purified by thin layer chromatography (SiO2, DCM:MeOH=10:1) to obtain compound 24. 1H NMR (400MHz, MeOH-d4) δ = 8.28-8.22 (m, 1H), 7.98-7.93 (m, 1H), 7.30 (t, J = 7.5Hz, 1H), 7.27-7. 20 (m, 1H), 7.07-7.00 (m, 2H), 5.24 (s, 2H), 3.46 (s, 3H), 1.41-1.31 (m, 2H), 1.26-1.16 (m, 2H). LCMS(ESI)m / z:483.4[M+1] + .

[0246] Example 25

[0247] Synthesis route:

[0248]

[0249] To a solution of 3-e (150 mg, 390.28 μmol, 1 eq) in pyridine (5 mL) were added EDCI (598.53 mg, 3.12 mmol, 8 eq) and 1-methylcyclopropyl-1-carboxylic acid (117.22 mg, 1.17 mmol, 3 eq), and the reaction mixture was stirred at 20° C. for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 25. 1 HNMR (400MHz, DMSO-d6) δ = 8.29 (s, 1H), 8.20 (dd, J = 2.4, 9.3Hz, 1H), 8.08 (d, J = 1 .7Hz, 1H), 7.35(q, J=7.3Hz, 1H), 7.31-7.19(m, 2H), 7.18-7.12(m, 1H), 6.21(br s, 4H), 5.14 (s, 2H), 1.43 (s, 3H), 1.11 (br d, J=2.4Hz, 2H), 0.63-0.46 (m, 2H). LCMS(ESI)m / z:467.4[M+1] + .

[0250] Example 26

[0251] Synthesis route:

[0252]

[0253] Step A: Malononitrile (14.93 g, 225.98 mmol, 14.22 mL, 1 eq) was dissolved in THF (100 mL), and then potassium tert-butoxide (27.89 g, 248.58 mmol, 1.1 eq) was added. The reaction solution was stirred at 50°C for 0.5 hours, and then compound 26-1 (45 g, 248.58 mmol, 32.14 mL, 1.1 eq) was added. The reaction solution was stirred at 50°C for 11.5 hours. After the reaction was completed, 100 mL of water was added to quench the reaction, and then the mixture was extracted with EtOAc (100 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE / EtOAc=10 / 1-5 / 1) to obtain compound 26-a.

[0254] Step B: Compound 26-a (20 g, 120.35 mmol, 1 eq), S-methylthiourea (27.04 g, 144.42 mmol, 1.2 eq, HSO4) and triethylamine (24.36 g, 240.71 mmol, 33.50 mL, 2 eq) were dissolved in DMF (60 mL). The mixture was replaced with nitrogen three times and stirred at 100°C for 12 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (PE / EtOAc = 10 / 1-1 / 1) to obtain compound 26-b.

[0255] Step C: Dissolve compound 26-b (3.8 g, 16.94 mmol, 1 eq) in DCM (50 mL) and add m-chloroperbenzoic acid (6.88 g, 33.89 mmol, 85% purity, 2 eq). The reaction mixture was stirred at 20°C for 12 hours. After the reaction was complete, the filter cake was collected and stirred with dichloromethane (100 mL). Filter and dry to obtain compound 26-c. LCMS (ESI) m / z: 257.2 [M+1] + .

[0256] Step D: To a solution of 3-c (5.74 g, 21.98 mmol, 1.1 eq) in DMF (30 mL) were added potassium carbonate (8.28 g, 59.93 mmol, 3 eq) and 26-c (5.12 g, 19.98 mmol, 1.0 eq) at 20°C. The reaction mixture was heated to 120°C and kept for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (20 mL) and DMF (20 mL). The filtrates were combined and concentrated under reduced pressure to remove methanol. The residue was purified by preparative HPLC [mobile phase: water (0.1% FA)-ACN] to obtain compound 26. 1HNMR (400MHz, DMSO-d6) δ = 11.15 (s, 1H), 8.27 (dd, J = 2.5, 9.4Hz, 1H), 8.10 (t, J = 2.0Hz, 1H ), 7.39-7.32(m, 1H), 7.29(t, J=7.6Hz, 1H), 7.25-7.20(m, 1H), 7.18-7.12(m, 1H), 7.03(br s, 2H), 5.15 (s, 2H), 1.35 (s, 6H). LCMS(ESI)m / z:428.4[M+1] + .

[0257] Example 27

[0258] Synthesis route:

[0259]

[0260] To a solution of 5-f (200 mg, 670.45 μmol, 1 eq) in DMF (2 mL) were added 26-c (273 mg, 858.58 μmol, 1.28 eq) and potassium carbonate (200 mg, 1.45 mmol, 2.16 eq). The atmosphere was replaced with nitrogen and the mixture was stirred at 120°C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with 2 mL of DMF. The filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to afford compound 27. 1 H NMR (400MHz, DMSO-d6) δppm 1.34 (s, 6H) 5.18 (s, 2H) 6.94-7.22 (m, 4H) 7.37 (q, J = 8.23Hz, 1H) 8.10 (t, J = 2.14Hz, 1H) 8.27 (dd, J = 9.48, 2.63Hz, 1H); LCMS (ESI) m / z: 456.1 [M+1] + .

[0261] Example 28

[0262] Synthesis route:

[0263]

[0264] Step A: To a mixture of 28-1 (3.5 g, 31.79 mmol, 1 eq) in dichloromethane (100.00 mL) and toluene (10 mL) were added diphenylphosphoryl azide (17.49 g, 63.57 mmol, 13.78 mL, 2 eq) and 1.8-diazabicyclo[5.4.0]undec-7-ene (9.68 g, 63.57 mmol, 9.58 mL, 2 eq). The reaction mixture was stirred at 20° C. for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 5: 1-1: 1) to give compound 28-a.

[0265] Step B: Under nitrogen protection, wet Pd / C (1.0 g, 10% purity) was added to a solution of 28-a (3.0 g, 22.20 mmol, 1 eq) in methanol (10 mL). The reaction solution was replaced with hydrogen three times and stirred at 20°C under a pressure of 15 psi for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain compound 28-b.

[0266] Step C: Dissolve 3-1 (2.5 g, 14.16 mmol, 1 eq) and 28-b (1.85 g, 16.99 mmol, 1.2 eq) in toluene (100 mL), and heat the mixture to 80°C and stir for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EtOAc=1:1) to give compound 28-c.

[0267] Step D: Under nitrogen, to a solution of 28-c (2.4 g, 9.63 mmol, 1 eq) in methanol (10 mL) was added Pd / C (1.0 g, 9.63 mmol, 10% purity). The reaction solution was replaced with hydrogen three times and then stirred at 30°C under 15 psi for 2 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated to obtain compound 28-d.

[0268] Step E: To a solution of 28-d (2.1 g, 9.58 mmol, 1 eq) in THF (100 mL) was added CDI (3.11 g, 19.16 mmol, 2 eq). The mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc = 1:1 to 0:1) to afford compound 28-e.

[0269] Step F: To a solution of 28-e (200 mg, 815.62 μmol, 1 eq) in DMF (3 mL) were added 26-c (519 mg, 1.63 mmol, 2 eq) and potassium carbonate (338 mg, 2.45 mmol, 3 eq). The atmosphere was replaced with nitrogen and the mixture was stirred at 120°C for 12 hours. The reaction mixture was filtered, the filter cake was washed with 2 mL of DMF, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to afford compound 28. 1 H NMR (400MHz, DMSO-d6) δppm 1.34 (s, 6H) 5.16 (s, 2H) 7.01 (br s, 2H) 8.06-8.17 (m, 1H) 8.29 (dd, J=9.48, 2.63Hz, 1H) 8.84 (s, 2H) 9.12 (s, 1H); LCMS (ESI) m / z: 422.1 [M+1] + .

[0270] Example 29

[0271] Synthesis route:

[0272]

[0273] Step A: Under nitrogen, diisopropylethylamine (2.11 g, 16.31 mmol, 2.84 mL, 4 eq) and 3-fluoro-2-pyridylmethylamine hydrochloride (893 mg, 4.49 mmol, 1.1 eq) were added to a solution of 3-1 (720 mg, 4.08 mmol, 1 eq) in toluene (20.00 mL). The mixture was heated to 70°C and stirred for 12 hours. After cooling, water (100 mL) was added and the mixture was extracted with EtOAc (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1-5:1) to obtain compound 29-a.

[0274] Step B: Reduced zinc powder (638 mg, 9.77 mmol, 4 eq) and ammonium chloride (653 mg, 12.21 mmol, 5 eq) were added to a solution of 29-a (650 mg, 2.44 mmol, 1 eq) in tetrahydrofuran (15 mL) and water (5 mL). The reaction mixture was stirred at 70°C for 12 hours, filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1-2:1) to obtain compound 29-b.

[0275] Step C: To a solution of 29-b (430 mg, 1.82 mmol, 1 eq) in THF (20.00 mL) was added CDI (442 mg, 2.73 mmol, 1.5 eq). The atmosphere was purged with nitrogen three times, and the mixture was stirred at 70°C for 12.5 hours. The reaction solution was concentrated, and the residue was directly purified by column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to obtain compound 29-c.

[0276] Step D: To a solution of 29-c (200 mg, 762.73 μmol, 1 eq) in DMF (3 mL) were added potassium carbonate (316 mg, 2.29 mmol, 3 eq) and 26-c (485 mg, 1.53 mmol, 2 eq), followed by reaction at 120°C for 12 hours. The reaction mixture was filtered, the filter cake was washed with DMF (2 mL), and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to afford compound 29. 1 HNMR (400MHz, DMSO-d6) δppm 1.22-1.48 (m, 6H) 5.30 (s, 2H) 7.02 (br s, 2H) 7.26-7.52 (m, 1H) 7.76 (ddd, J=10.06, 8.53, 1.10Hz, 1H) 7.94-8.13 (m, 1H) 8.15-8.36 (m, 2H) 11.12 (br s, 1H). LCMS(ESI)m / z: 439.1[M+1] + .

[0277] Example 30

[0278] Synthesis route:

[0279]

[0280] Step A: To a solution of 3-c (250 mg, 957.02 μmol, 1 eq) in DMF (2.00 mL) were added 2-chloro-4-amino-5-bromopyrimidine (199.49 mg, 957.02 μmol, 1 eq) and potassium carbonate (264.53 mg, 1.91 mmol, 2 eq). The reaction was stirred at 120°C for 12 hours. After cooling, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (SiO2, PE:EtOAc=2:1) ​​to give compound 30-a.

[0281] Step B: 30-a (200 mg, 461.67 μmol, 1 eq), cyclopropylboronic acid (118.97 mg, 1.39 mmol, 3 eq), potassium carbonate (191.42 mg, 1.39 mmol, 3 eq) and bis(triphenylphosphine)palladium dichloride (162.02 mg, 230.84 μmol, 0.5 eq) were dissolved in 1,4-dioxane (5 mL), purged with nitrogen three times, and stirred at 100° C. for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.1% TFA)-ACN]] to obtain compound 30. 1 H NMR (400MHz, DMSO-d6) δ = 8.55 (br d, J=9.3Hz, 1H), 8.22 (d, J=1.7Hz, 1H), 7.85 (s, 1H), 7.41-7.33 (m, 2H), 7.24 (m, 1H), 7.20-7. 11 (m, 1H), 5.19 (s, 2H), 1.67 (m, 1H), 0.96 (dd, J=1.9, 8.3Hz, 2H), 0.63 (dd, J=1.7, 5.3Hz, 2H). LCMS(ESI)m / z: 395.3[M+1] + .

[0282] Example 31

[0283] Synthesis route:

[0284]

[0285] Step A: To a solution of 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20 mL) were added m-fluorobenzylamine (1.56 g, 12.46 mmol, 1.42 mL, 1.1 eq) and N,N-diisopropylethylamine (4.39 g, 33.99 mmol, 5.92 mL, 3 eq). After the addition was complete, the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=100:1-30:1) to give compound 31-a.

[0286] Step B: Under nitrogen, wet palladium on carbon (300 mg) was added to a solution of 31-a (1.62 g, 6.52 mmol, 1 eq) in methanol (30 mL). After the addition was complete, the hydrogen atmosphere was replaced by vacuum three times. The reaction solution was stirred at 45°C under a hydrogen atmosphere (15 psi) for 12 hours. The reaction solution was filtered through celite, the filter cake was washed with methanol (10 mL x 3), and the filtrate was concentrated to obtain compound 31-b.

[0287] Step C: To a solution of compound 31-b (2 g, 8.50 mmol, 1 eq) in tetrahydrofuran (20 mL) was added CDI (2.76 g, 17.00 mmol, 2 eq). The reaction mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was concentrated to obtain a residue, which was purified by column chromatography (PE / EA = 5 / 1 to 1 / 1) to obtain compound 31-c. LCMS (ESI) m / z: 262.5 [M+1] + .

[0288] Step F: To a solution of 31-c (260 mg, 995.30 μmol, 1 eq) in DMF (3 mL) was added 26-c (510 mg, 1.99 mmol, 2 eq) and potassium carbonate (413 mg, 2.99 mmol, 3 eq) under nitrogen. The reaction mixture was stirred at 120°C for 12 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to afford compound 31. 1 HNMR (400MHz, DMSO-d6) δppm 1.35 (s, 6H) 5.10 (s, 2H) 7.00 (br s, 2H) 7.07-7.14 (m, 1H) 7.15-7.23 (m, 2H) 7.38 (td, J = 8.01, 6.24Hz, 1H) 8.10 (t, J = 2.08Hz, 1H) 8.26 (dd, J = 9.35, 2.51Hz, 1H) 11.12 (br s, 1H); LCMS (ESI) m / z: 438.1[M+1] + .

[0289] Example 32

[0290] Synthesis route:

[0291]

[0292] Step A: Under nitrogen, 2,4-dimethoxybenzylamine (1.33 g, 7.93 mmol, 1.19 mL, 1 eq) and triethylamine (1.60 g, 15.86 mmol, 2.21 mL, 2 eq) were added to a solution of 3-1 (1.4 g, 7.93 mmol, 1 eq) in toluene (40 mL). The reaction mixture was stirred at 100° C. for 4 hours. After cooling, the reaction mixture was washed with water (40 mL), separated, and the organic phase was concentrated under reduced pressure. Methanol was added and stirred for 1 hour, filtered, and the filter cake was dried under vacuum to obtain compound 32-a.

[0293] Step B: To a solution of 32-a (2 g, 6.51 mmol, 1 eq) in tetrahydrofuran (60 mL) and water (20 mL) were added zinc powder (2.13 g, 32.54 mmol, 5 eq) and ammonium chloride (1.74 g, 32.54 mmol, 5 eq), and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give compound 32-b.

[0294] Step C: Under nitrogen, to a solution of 32-b (1.6 g, 5.77 mmol, 1 eq) in tetrahydrofuran (30 mL) was added CDI (1.87 g, 11.54 mmol, 2 eq). The reaction mixture was stirred at 60°C for 16 hours and then quenched with water (2 mL). The reaction mixture was concentrated under reduced pressure, and the residue was added with methanol (20 mL) and stirred for 2 hours. The mixture was filtered, and the filter cake was dried under vacuum to obtain compound 32-c.

[0295] Step D: Under nitrogen protection, 26-c (1.73 g, 5.44 mmol, 1.5 eq) and potassium carbonate (1.50 g, 10.88 mmol, 3 eq) were added to a solution of 32-c (1.1 g, 3.63 mmol, 1 eq) in DMF (10 mL). The reaction solution was stirred at 120°C for 4 hours. Water (40 mL) was added to the reaction solution to dilute it, and the mixture was filtered. The filter cake was dried in vacuo to obtain compound 32-d.

[0296] Step E: To a solution of 32-d (1.6 g, 3.34 mmol, 1 eq) in DMF (4 mL) were added potassium carbonate (922.41 mg, 6.67 mmol, 2 eq) and p-methoxybenzyl chloride (731.66 mg, 4.67 mmol, 636.23 μL, 1.4 eq). The mixture was stirred at 50° C. under nitrogen for 2 hours. The reaction solution was diluted with water (25 mL), filtered, and the filter cake was dried in vacuo to obtain compound 32-e.

[0297] Step F: A solution of 32-e (1.8 g, 3.00 mmol, 1 eq) in TFA (27.72 g, 243.11 mmol, 18.00 mL, 80.98 eq) was stirred at 30°C for 3 hours. The reaction solution was concentrated and the residue was separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give compound 32-f.

[0298] Step G: To a solution of 32-f (0.6 g, 1.34 mmol, 1 eq) in DMF (5 mL) were added 1,1,1,2,2-pentafluoro-4-iodobutane (1.46 g, 5.34 mmol, 4 eq) and potassium carbonate (922.55 mg, 6.68 mmol, 5 eq). The reaction mixture was reacted at 50° C. under nitrogen for 1 hour. The reaction mixture was neutralized by adding dilute hydrochloric acid (30 mL, 1 mol / L), then extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The residue was separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 32-g.

[0299] Step H: Under nitrogen, trifluoromethanesulfonic acid (3.40 g, 22.66 mmol, 2 mL, 67.45 eq) was added to a solution of 32-g (0.2 g, 335.85 μmol, 1 eq) in TFA (2 mL). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into an aqueous solution of sodium hydroxide (80 mL, 1 mol / L) and neutralized. The mixture was extracted with ethyl acetate (60 mL). The organic phase was concentrated under reduced pressure and purified by preparative HPLC [water (0.075% TFA)-acetonitrile] to give compound 32. 1 H NMR (400MHz, DMSO-d6) δ = 11.14 (s, 1H), 8.26 (dd, J = 2.6, 9.4Hz, 1H), 8.15 (t, J = 2.1Hz, 1H), 7.01 (br s, 2H), 4.22 (t, J=6.9Hz, 2H), 2.90-2.72 (m, 2H), 1.35 (s, 6H). LCMS (ESI) m / z: 476.2[M+1] + .

[0300] Biological testing

[0301] Experimental Example 1: In vitro activity test

[0302] cGMP expression test based on lnCap cells

[0303] 1. Experimental Procedure

[0304] 1) Solution preparation

[0305] ● 10% BSA (bovine serum albumin)

[0306] 10 g of BSA was dissolved in 100 mL of double distilled water (ddH2O) to obtain 10% BSA.

[0307] ● 5mM DETA (diethylenetriamine)-NO

[0308] Weigh 10 mg of DETA-NO and dissolve it in 12.2 mL of double-distilled water (ddH2O) to obtain 5 mM DETA-NO, which was then aliquoted and stored in a -20°C refrigerator.

[0309] ● Washing Buffer (50 mL)

[0310]

[0311] ● Assay Buffer (50 mL)

[0312]

[0313] ● Detection Buffer

[0314] a) Add 50 μL of cGMP-D2 (D2-labeled cyclic GMP) to 1 mL of lysis buffer and mix well.

[0315] b) Add 50 μL of anti-cGMP cryptate (Eu 3+ The cryptate-labeled anti-cyclic GMP antibody was added to 1 mL of lysis buffer and mixed evenly.

[0316] 2) Compound dilution

[0317] (1) Dilute the compound to 5 mM with DMSO. Transfer 10 μL of the compound to a shallow well plate for Echo.

[0318] (2) Perform gradient dilution of the compound using Echo, dilute each compound into 10 concentration gradients and add 50 nL to a 384-well microplate.

[0319] 3) Preparation of LNCap cells

[0320] (1) LNCap culture medium: RPMI1640 + 10% fetal bovine serum + 1% double antibody

[0321] (2) Preheat the phosphate buffer, trypsin, and culture medium used in the cell passaging process in a 37°C water bath.

[0322] (3) Remove the cells (passage 14) from the 37°C 5% CO2 incubator and remove the old culture medium in the culture flask with a pipette.

[0323] (4) Pipette 5 mL of phosphate buffer into the culture flask to rinse the cells, and then discard the liquid.

[0324] (5) Pipette 3 mL of pancreatic enzyme into the culture flask, shake it, discard the liquid, and place the culture flask in the incubator.

[0325] (6) After about 2 minutes, remove the culture flask and observe that all cells have separated. Then, pipette 9 mL of culture medium into the culture flask and pipette it several times to transfer the cell suspension to a 50 mL centrifuge tube.

[0326] (7) Pipette 0.7 mL of cell suspension into a counting cup and count on a ViCell XR. Centrifuge the remaining cells at 1000 rpm for 5 min and discard the supernatant.

[0327] (8) Add 10 mL of washing buffer to wash the cells, centrifuge at 1000 rpm for 5 min, and remove the supernatant.

[0328] (9) Add assay buffer and adjust the cell concentration to 1.25×10 6 / mL. 8μL / well was added to the microplate.

[0329] 4) DETA-NO preparation and addition

[0330] (1) Take 10 μL of 5 mM DETA-NO and add it to 1240 μL and 1657 μL of assay buffer, respectively, to obtain 40 μM and 30 μM DETA-NO.

[0331] (2) Use Bravo to transfer 2 μL / well of DETA-NO to a 384-well microplate.

[0332] (3) Centrifuge at 1500 rpm for 5 min. Incubate the microplate at 37°C for 30 min.

[0333] 5) Prepare cGMP standard curve

[0334] (1) Dilute the 1 mM cGMP stock solution to 10 μM with assay buffer. Then perform a 4-fold serial dilution to 11 concentration gradients.

[0335] (2) Add 10 μL / well of the diluted cGMP to the microplate.

[0336] 6) Add detection reagent and read the plate

[0337] (1) Transfer 5 μL / well of cGMP-D2 to a 384-well microplate using Bravo. Centrifuge at 1500 rpm for 1 min.

[0338] (2) Use Bravo to transfer 5 μL / well of anti-cGMP cryptate to a 384-well microplate. Centrifuge at 1500 rpm for 1 min.

[0339] (3) Incubate at room temperature for 1 hour.

[0340] (4) Use Envision to read 665 / 615.

[0341] 7) Data Analysis

[0342] (1) cGMP standard curve: A standard curve was prepared using Graphpad Prism based on the cGMP concentration and the 665 / 615 ratio.

[0343] (2) Conversion of HTRF (homogeneous time-resolved fluorescence) ratio (665 / 615) to cGMP concentration: In Graphpadprism, copy the HTRF ratio (665 / 615) to the ratio column of the cGMP standard curve, run the analysis "Loginhibitor vs response-variable slope", select "interpolate", and convert the HTRF ratio (665 / 615) to cGMP concentration.

[0344] (3) Compound activation curve: The curve was drawn based on the converted cGMP concentration and the compound concentration using the “Log agonist vs response-variable slope” analysis method in Graphpad Prism.

[0345] Table 1 MEC values ​​of the stimulating activity of the compounds of the present invention on sGC

[0346] Compound number MEC (nM) Compound 2 320.6 Compound 8 12 Compound 9 66 Compound 10 293 Compound 11 234 Compound 12 94 Compound 14 39 Compound 15 61 Compound 16 150 Compound 17 95 Compound 18 48 Compound 19 101 Compound 21 151 Compound 22 346 Compound 23 299 Compound 26 5 Compound 27 3.8 Compound 28 37 Compound 29 73 Compound 31 27.6 Compound 32 12.9

[0347] It can be seen from the experimental results that the compound of the present invention has a good stimulating activity on sGC.

[0348] Experimental Example 2: Pharmacokinetic evaluation in rats

[0349] Purpose of the experiment:

[0350] Detection of pharmacokinetic parameters of the compound of the present invention in rats

[0351] Experimental plan:

[0352] 1) Experimental animals: Six male SD rats aged 7-9 weeks were randomly divided into two groups, with 3 rats in each group;

[0353] 2) Drug preparation: Weigh an appropriate amount of drug and dissolve it in a mixed solvent of 10% DMSO, 50% PEG400, and 40% H2O to a concentration of 0.2 mg / mL. Weigh an appropriate amount of drug and dissolve it in a mixed solvent of 10% EtOH, 40% PEG400, and 50% H2O to a concentration of 0.3 mg / mL.

[0354] Experimental operation:

[0355] Group 1 animals received a single injection of the drug at a dose of 1.0 mg / kg at a concentration of 0.2 mg / mL via the tail vein, while Group 2 animals received the compound at a dose of 3 mg / kg at a concentration of 0.3 mg / mL via oral gavage. Plasma samples were collected from the animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration.

[0356] Data Analysis:

[0357] The drug concentrations in plasma samples were determined using LC-MS / MS, and the kinetic parameters of the tested drugs are shown in Table 2.

[0358] Table 2 Pharmacokinetic test results of the compounds of the present invention

[0359]

[0360] --Indicates that it does not exist

[0361] Conclusion: The compounds of the present invention have good pharmacokinetic properties in rats.

[0362] Experimental Example 3: Human Liver Microsome CYP Inhibition Experiment

[0363] The aim of the research project was to evaluate the inhibitory activity of the test articles against human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) using a 5-in-1 probe substrate for CYP isoenzymes.

[0364] Pooled human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA) or other suppliers and stored below -70°C before use.

[0365] A series of diluted test sample working solutions were added to an incubation system containing human liver microsomes, probe substrates, and cofactors of the circulating system. A control containing no test sample but solvent was used as an enzyme activity control (100%). The concentration of metabolites generated by the probe substrate in the sample was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Nonlinear regression analysis of the average percentage activity of the test sample versus the concentration was performed using SigmaPlot (V.11). IC was calculated using a three-parameter or four-parameter sigmoidal logarithmic equation. 50 The test results are shown in Table 3:

[0366] Table 3 Inhibition of CYP isoenzymes by the compounds of the present invention in vitro

[0367]

[0368] Conclusion: The compounds of the present invention have weak inhibition on the five CYP isozymes.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R1 is H, F or Cl; R2 is C 1-6 alkyl, -CH2-phenyl, -CH2-pyridyl or -CH2-pyrimidinyl, wherein the C 1-6 Alkyl, -CH2-phenyl, -CH2-pyridyl or -CH2-pyrimidinyl are each independently optionally substituted by 1, 2, 3, 4 or 5 R a replaced by; Each R a independently H, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -C(=O)OH, C 1-3 Alkoxy or C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 1-3 alkyl; R3 and R4 are each independently H, F, Cl, Br, I, -OH, -CN or -NH2; R5 is -LR b ; L is a single bond, -NR c C(=O)O- or -NR c C(=O)-; R b C 1-6 alkyl, wherein the C 1-6 alkyl, are each independently optionally substituted with 1, 2 or 3 R; R c is H, -CH3 or -CH2CH3; Each R is independently F, Cl, Br, I, -OH, -CN, -NH2, -NO2, C 1-3 Alkoxy or C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 1-3 alkyl; Or R3 and R5 are connected to the carbon atoms to make the structural unit Selected from R6, R7 and R8 are each independently F, Cl, Br, I, -OH, -CN, -NH2, -NO2 or C optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 1-3 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is a single bond, -NH-C(=O)O-, -NH-C(=O)-, -N(CH3)-C(=O)O- or -N(CH3)-C(=O)-.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-1) to (I-4): in, R1, R2, R4 and R b As defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R is independently F, Cl, Br, -OH, -CN, -NH2, -NO2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CF3, -CH2CF3, -CH2CH2CF3, -CH2OH or -CH2CH2OH.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R b C 1-4 alkyl, wherein the C 1-4 alkyl, are each independently optionally substituted with 1, 2 or 3 R.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein said R b For -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, 7. The compound according to claim 4 or 6 or a pharmaceutically acceptable salt thereof, wherein R b For -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is -NH-C(=O)O-CH3, -NH-C(=O)O-CH2CH3, -NH-C(=O)O-CH2CH2CH3, -NH-C(=O)O-CH(CH3)2, -NH-C(=O)-CH3, -NH-C(=O)-CH2CH3, -NH-C(=O)-CH2CH2CH3, -NH-C(=O)-CH(CH3)2, -N(CH3)-C(=O)O-CH3, -N(CH3)-C(=O)O-CH2CH3, -N(CH3)-C(=O)O-CH2CH2CH3, -N(CH3)-C(=O)O-CH(CH3)2, 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R5 is -NH-C(=O)O-CH3, -NH-C(=O)O-CH2CH3, -NH-C(=O)O-CH2CH2CH3, -NH-C(=O)O-CH(CH3)2, -NH-C(=O)-CH3, -NH-C(=O)-CH2CH3, -NH-C(=O)-CH2CH2CH3, -NH-C(=O)-CH(CH3)2, -N(CH3)-C(=O)O-CH3, -N(CH3)-C(=O)O-CH2CH3, -N(CH3)-C(=O)O-CH2CH2CH3, -N(CH3)-C(=O)O-CH(CH3)2, 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-5) to (I-13): in, p is 0, 1 or 2; R4 is H or -NH2; R2 is as defined in claim 1; R is as defined in claim 1.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-5) to (I-13): in, p is 0, 1 or 2; R4 is H or -NH2; R2 is as defined in claim 1; R is as defined in claim 4.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-14) to (I-15): in, R1, R2, R4, R6, R7 and R8 are as defined in claim 1.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-16) to (I-19): in, R2, R6, R7 and R8 are as defined in claim 12.

14. The compound according to claim 1 or 12 or a pharmaceutically acceptable salt thereof, wherein the structural unit for 15. The compound according to claim 1 or 12 or a pharmaceutically acceptable salt thereof, wherein the structural unit for 16. The compound according to any one of claims 1, 12 or 13, or a pharmaceutically acceptable salt thereof, wherein R6, R7 and R8 are each independently F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -CH3, -CH2CH3, -CF3, -CH2CF3 or -CH2CH2OH.

17. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-20) to (I-25): in, R2 is as defined in claim 13.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R a are independently H, F, Cl, Br, I, -OH, -CN, -NH2, -NO2, -C(=O)OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3, -CH2OH or -CH2CH2OH.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein each R a are independently H, F, Cl or -CF3.

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is 21. The compound according to claim 18 or 20, or a pharmaceutically acceptable salt thereof, wherein R2 is 22. A compound of the following formula or a pharmaceutically acceptable salt thereof:

23. Use of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diabetic nephropathy or hypertensive nephropathy.

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