JP2024515985A - Derivatives of six-membered aromatic heterourea rings and uses thereof - Google Patents

Abstract

Disclosed are derivatives of 6-membered aromatic heterourea rings represented by formula (I) and their use in the manufacture of medicaments for treating diabetic or hypertensive nephropathy.

Description

Detailed Description of the Invention

This application claims priority to the following:
CN202110462009.4, filing date: April 27, 2021;
CN202210307799.3, filing date: March 25, 2022.

[Technical field]
The present invention discloses a class of 6-membered aromatic heterourea derivatives and uses thereof, specifically, the compounds represented by formula (I) and pharma- ceutically acceptable salts thereof.

[Background Art]
Soluble guanylate cyclase (sGC) is widely present in the cytosol of mammalian cells and is a heterodimer composed of α and β subunits, which each have two isoforms, α1, α2 and β1, β2. The α1β1 dimer is mainly distributed in cardiovascular tissues and its expression level is positively correlated with the degree of tissue angiogenesis, whereas the α2β1 dimer is mainly 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.

Soluble guanylate cyclase is an important signaling enzyme in the NO-sGC-cGMP signaling pathway, and after sGC is activated in the body, it catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is an important second messenger molecule that activates various downstream effector molecules, such as phosphodiesterase (PDE), cyclic nucleotide-gated ion channel (CNG), and protein kinase G (PKG), thereby triggering a series of downstream cascade reactions to play important physiological functions in the gastrointestinal system, blood circulation system, and nervous system, such as promoting relaxation of blood vessels and smooth muscles, platelet aggregation, vascular remodeling, suppressing cell apoptosis and inflammation, and participating in neurotransmission. Under pathophysiological conditions, the NO/cGMP system may be inhibited, which may lead to symptoms such as hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, and sexual dysfunction. Research over the past two years has demonstrated that abnormalities in the signaling pathway mediated by sGC are closely related to the development of fibrotic diseases such as chronic kidney disease and systemic sclerosis.

Conventional stimulation treatments of soluble guanylate cyclase only use compounds that exert their effect based on NO, such as organic nitrates, which are formed by biotransformation and activate soluble guanylate cyclase by attacking the central iron atom of heme. In addition to side effects, the development of resistance is also one of the crucial drawbacks of this type of treatment.

In October 2013, the FDA approved a new guanylate cyclase stimulator called riociguat (WO2003095451A1) for the treatment of pulmonary arterial hypertension, but it has a shorter half-life in the human body and high clearance, which requires three times daily dosing.

In view of the current unmet need for such soluble guanylate cyclase stimulators in the market and in clinical practice, the present invention provides a new class of compounds that can be used as stimulators of soluble guanylate cyclase, exhibit effective in vitro stimulatory activity against guanylate cyclase, and have excellent pharmacokinetic properties.

Summary of the Invention
In one aspect, the present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

where R ₁ is H, F or Cl;
R ₂ is C _1-6 alkyl, —CH ₂ -phenyl, —CH ₂ -pyridyl or —CH ₂ -pyrimidinyl, wherein said C _1-6 alkyl, —CH ₂ -phenyl, —CH ₂ -pyridyl or —CH ₂ -pyrimidinyl is each independently optionally substituted by 1, 2, 3, 4 or 5 R _a ;
each R _a is independently H, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -C(=O)OH, C _1-3 alkoxy or C 1-3 alkyl optionally substituted with 1 _, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH ₂ and -OCH ₃ ;
_R3 and _R4 are each independently H, F, Cl, Br, I, -OH, -CN, or _-NH2 ;
_R5 is -L- _Rb ;
L is a single bond, -NR _c C(=O)O- or -NR _c C(=O)-;
R _b is C _1-6 alkyl,

であり、ここで、前記Ｃ_１－６アルキル、

wherein said C _1-6 alkyl,

は、それぞれ独立して任意選択で１、２又は３つのＲにより置換され、Ｒ_ｃは、Ｈ、－ＣＨ_３又は－ＣＨ_２ＣＨ_３であり、

are each independently optionally substituted with 1, 2 or 3 R; R _c is H, —CH ₃ , or —CH ₂ CH ₃ ;

each R is independently F, Cl, Br, I, -OH, -CN, _-NH2 , _-NO2 , _C1-3alkoxy or _C1-3alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, _-NH2 and _-OCH3 ;
Alternatively, R ₃ and R ₅ are linked to the carbon atom to which they are linked to form a structural unit

が

but

から選択されるようにし、

Select from

R ₆ , R ₇ and R ₈ are each independently F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ or C _1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH ₂ and -OCH ₃ .

In some embodiments of the invention, L is a single bond, -NH-C(=O)O-, -NH-C(=O)-, -N(CH ₃ )-C(=O)O- or -N(CH ₃ )-C(=O)-, and all other variables are as defined herein.

In some embodiments of the present invention, the compound or a pharma- ceutically acceptable salt thereof has a structure represented by formulas (I-1) to (I-4).

wherein R ₁ , R ₂ , R ₄ and R _b are as defined in the present invention.
In some embodiments of the invention, each R is independently F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH 3 , -CF ₃ , -CH ₂ CF ₃ , -CH _{2 CH 2 CF 3} , -CH ₂ OH or -CH ₂ CH ₂ OH, with the other variables being as defined herein.

In some embodiments of the present invention, R _b is C _1-4 alkyl,

であり、ここで、前記Ｃ_１－４アルキル、

wherein said C _1-4 alkyl,

は、それぞれ独立して任意選択で１、２又は３つのＲにより置換され、Ｒ及び他の変量は本発明で定義された通りである。

is each independently optionally substituted with 1, 2 or 3 R, where R and the other variables are as defined herein.

In some embodiments of the invention, R _b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH 3 , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) CH ₂ CH _{3 ,} -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ ,

であり、Ｒ及び他の変量は本発明で定義された通りである。

where R and other variables are as defined herein.

In some embodiments of the invention, R _b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH 3 , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) CH ₂ CH _{3 ,} -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ ,

であり、他の変量は本発明で定義された通りである。

and other variables are as defined in the present invention.

In some embodiments of the present invention, R ₅ is -NH-C(=O)O-C _1-4 alkyl, -NHC(=O)-C _1-4 alkyl, -N(CH ₃ )-C(=O)O-C _1-4
and 5-6 membered heterocycloalkyl, wherein said NH-C(=O)O-C _1-4 alkyl, -NHC(=O)-C _1-4 alkyl, -N(CH ₃ )-C(=O)O-C _1-4 alkyl, -NH-C(=O)-(C _{3-6 cycloalkyl} ), -N(CH ₃ )-C(=O)-(C _3-6 cycloalkyl), -NH _- C(=O _{)-phenyl, -N(CH 3 )} -C(=O)-phenyl and _5-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R, and R and the other variables are as defined herein.

In some embodiments of the invention, R ₅ is -NH-C(=O)O-CH ₃ , -NH-C(=O)O-CH ₂ CH ₃ , -NH-C(=O)O-CH ₂ CH ₂ CH ₃ , -NH-C(=O)O-CH(CH ₃ ) ₂ , -NH-C(=O)-CH ₃ , -NH-C(=O)-CH ₂ CH ₃ , -NH-C(=O)-CH ₂ CH ₂ CH ₃ , -NH-C(=O)-CH(CH ₃ ) ₂ , -N(CH ₃ )-C(=O)O-CH ₃ , -N(CH ₃ )-C(=O)O-CH ₂ CH ₃ , -N(CH ₃ )-C(=O)O-CH ₂ CH ₂ CH ₃ , -N(CH ₃ )-C(=O)O-CH( _CH3 ) ₂ ,

であり、Ｒ及び他の変量は本発明で定義された通りである。

where R and other variables are as defined herein.

In some embodiments of the invention, R ₅ is -NH-C(=O)O-CH ₃ , -NH-C(=O)O-CH ₂ CH ₃ , -NH-C(=O)O-CH ₂ CH ₂ CH ₃ , -NH-C(=O)O-CH(CH ₃ ) ₂ , -NH-C(=O)-CH ₃ , -NH-C(=O)-CH ₂ CH ₃ , -NH-C(=O)-CH ₂ CH ₂ CH ₃ , -NH-C(=O)-CH(CH ₃ ) ₂ , -N(CH ₃ )-C(=O)O-CH ₃ , -N(CH ₃ )-C(=O)O-CH ₂ CH ₃ , -N(CH ₃ )-C(=O)O-CH ₂ CH ₂ CH ₃ , -N(CH ₃ )-C(=O)O-CH( _CH3 ) ₂ ,

であり、他の変量は本発明で定義された通りである。

and other variables are as defined in the present invention.

In some embodiments of the present invention, the compound or a pharma- ceutically acceptable salt thereof has a structure represented by formulas (I-5) to (I-13).

wherein p is 0, 1 or 2, R ₄ is H or —NH ₂ , and R ₂ and R are as defined herein.
In some embodiments of the present invention, in the above compound or a pharma- ceutically acceptable salt thereof, the compound has a structure represented by formula (I-14) to (I-15).

wherein R ₁ , R ₂ , R ₄ , R ₆ , R ₇ and R ₈ are as defined in the present invention.
In some embodiments of the present invention, in the above compound or a pharma- ceutically acceptable salt thereof, the compound has a structure represented by formulae (I-16) to (I-19).

wherein R ₂ , R ₆ , R ₇ and R ₈ are as defined in the present invention.
In some embodiments of the present invention, the structural unit

は、

teeth,

であり、他の変量は本発明で定義された通りである。

and other variables are as defined in the present invention.

In some embodiments of the present invention, the structural unit

は、

teeth,

であり、他の変量は本発明で定義された通りである。

and other variables are as defined in the present invention.

In some embodiments of the invention, R ₆ , R ₇ and R ₈ are each independently F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CH ₂ CF ₃ or -CH ₂ CH ₂ OH, and other variables are as defined herein.

In some embodiments of the present invention, the compound or a pharma- ceutically acceptable salt thereof has a structure represented by formulas (I-20) to (I-25).

wherein _R2 is as defined herein.
In some embodiments of the invention, each R _a is independently H, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -C(═O)OH, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ OH or -CH ₂ CH ₂ OH, with the other variables being as defined herein.

In some embodiments of the invention, each R _a above is independently H, F, Cl, or _--NH2 , and all other variables are as defined herein.
In some embodiments of the invention, R ₂ is C _1-6 alkyl, -CH ₂ -phenyl, -CH ₂ -pyridyl, -CH ₂ -pyrimidinyl or -CH ₂ -pyrazinyl, wherein said C _1-6 alkyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl are optionally substituted by 1, 2, 3, 4 or 5 R _a , and R _a and other variables are as defined herein.

In some embodiments of the present invention, _R2 is

であり、Ｒ_ａ及び他の変量は本発明で定義された通りである。

where R _a and other variables are as defined herein.

In some embodiments of the present invention, _R2 is

であり、他の変量は本発明で定義された通りである。

and other variables are as defined in the present invention.

In some embodiments of the present invention, R ₃ and R ₄ are each independently H or -NH ₂ , and other variables are as defined herein.
In some embodiments of the invention, the compound has a structure represented by formula (I-15-a), (I-15-b), (I-15-c) or (I-15-d).

wherein R ₁ , R ₄ , R ₇ , R ₈ and R _a are as defined in the present invention.
Some embodiments of the present invention are further formed by any combination of the above variables.
In some embodiments of the invention, the compound, or a pharma- ceutically acceptable salt thereof, is selected from the following:

The present invention further provides the use of the above compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating diabetic or hypertensive nephropathy.
The present invention further provides a method for treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, comprising providing to the subject an effective amount of a compound defined in any of the above technical solutions or a pharma- ceutically acceptable salt thereof.

[Technical Effects]
The present invention relates to a class of soluble guanylate cyclase stimulators, the related compounds of which have significant in vitro stimulating activity against guanylate cyclase, excellent pharmacokinetic properties, and weak inhibitory effects against all five CYP isoenzymes.

[Definitions and Explanations]
Unless otherwise stated, the following terms and phrases used herein have the following meanings: A particular term or phrase, unless specifically defined, should be understood to be generally defined, not indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

As used herein, "pharmacologically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit/risk ratio.

The term "pharmaceutical acceptable salts" refers to salts of the compounds of the present invention, which are prepared with relatively non-toxic acids or bases with certain substituents found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a solution alone 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 these compounds with a sufficient amount of acid in a solution alone or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids. Some specific compounds of the present invention contain basic and acidic functional groups and can therefore be converted into any base or acid addition salt.

The pharma- ceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds that contain acidic or basic groups. Typically, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures, such as mixtures enriched in an enantiomer or diastereomer, and all such mixtures are included within the scope of the invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both included within the scope of the invention.

Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.
Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

Unless otherwise explained, the term "diastereomer" is a stereoisomer in which the molecules have two or more centers of chirality and the molecules are not mirror-images of each other.
Unless otherwise stated, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

Unless otherwise stated, solid wedge connections (

）及び楔形点線結合（

) and dotted wedge bonds (

）で１つの立体中心の絶対配置を、直線実線結合（

) to indicate the absolute configuration of one stereocenter, and a straight solid bond (

）及び直線点線結合（

) and straight dotted line bond (

）で立体中心の相対配置を、波線（

) to indicate the relative configuration of stereocenters, and wavy lines (

）で楔形実線結合（

) and solid wedge connection (

）又は楔形点線結合（

) or dotted wedge bond (

）を、或いは波線（

), or a wavy line (

）で直線実線結合（

) with a straight solid line connection (

）及び直線点線結合（

) and straight dotted line bond (

）を表す。

)

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

Unless otherwise stated, the terms "enriched in one isomer," "enriched in one enantiomer," or "enantiomer-enriched" refer to a mixture that contains less than 100% of one isomer or enantiomer and that contains 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

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

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. One enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the salt of the diastereomeric form with an appropriate optically active acid or base is formed, and then the separation of the diastereomers is carried out by conventional methods known in the art, followed by recovery to obtain the pure enantiomers. Separation of enantiomers and diastereomers is also typically carried out using chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization methods (e.g., forming carbamates from amines).

The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms that constitute the compounds. For example, the compounds may be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), C-14 ( ¹⁴ C), etc. Or, for example, deuterium may be substituted for hydrogen to form a deuterated drug, in which the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, enhanced efficacy, and extended biological half-life of the drug. Isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

The terms "optionally" and "optionally" mean that the following event or circumstance is possible but not necessarily occurring, and that the description includes instances where the described event or circumstance occurs and instances where the event or circumstance does not occur.

The term "substituted" means that any one or more hydrogen atoms at a particular atom have been replaced with a substituent, which may include variants of deuterium and hydrogen, provided that the particular valence state is correct and the compound is stable after substitution. When the substituent is a ketone group (i.e. =O), it means that two hydrogen atoms have been replaced. Ketone group substitution does not occur in aromatic groups. The term "optionally substituted" means that the group may or may not be substituted, and unless otherwise defined, the type and number of substituents are any that can be chemically expressed.

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

When the number of linking groups is 0, for example, --(CRR) ₀ -- means that the linking group is a single bond.
When one of the variables is a single bond, it indicates that the two groups connected by it are directly linked; for example, when L in ALZ represents a single bond, the structure actually becomes AZ.

If one substituent is empty, it means that the substituent is not present, for example, if X in A-X is empty, it means that the structure is actually A. If there is no indication of which atom a listed substituent is bonded to the substituted group through, such substituent may be bonded through any atom thereof, for example, pyridinyl as a substituent may be bonded to the substituted group through any carbon atom of the pyridine ring.

When the linking direction of the listed linking groups is not specified, the linking direction is arbitrary, for example,

における連結基Ｌは－Ｍ－Ｗ－である場合、－Ｍ－Ｗ－は左から右への読み取る順序と同じ方向に環Ａと環Ｂを連結して

When the linking group L in the formula (I) is -M-W-, -M-W- links ring A and ring B in the same direction as the order of reading from left to right.

を構成することができ、また、左から右への読み取る順序と逆方向に環Ａと環Ｂを連結して

It is also possible to construct the following by concatenating rings A and B in the reverse order of reading from left to right:

を構成することもできる。上記連結基、置換基及び／又はその変形体の組み合わせは、このような組み合わせが安定した化合物になる場合のみ許容される。

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

Unless otherwise specified, if a group has one or more bondable sites, any one or more of the sites of the group can be bonded to other groups by chemical bonds. If the bonding method of the chemical bond is delocalized and there is an H atom at the bondable site, when the chemical bond is bonded, the number of H atoms at the site is reduced to a group of the corresponding valence according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is represented by a straight solid bond (

）、直線破線結合（

), straight dashed bond (

）、又は波線（

), or wavy line (

）で表すことができる。例えば、－ＯＣＨ_３の直線実線結合は、基内の酸素原子を介して他の基に連結されていることを示し；

For example, the straight solid bond in _-OCH3 indicates that the group is connected to another group through the oxygen atom in the group;

の直線破線結合は、基内の窒素原子の両端を介した他の基に連結されていることを示し；

indicates that the nitrogen atom in the group is connected to another group through both ends;

の波線は、フェニルの１つ及び２つの炭素原子を介した他の基に連結されていることを示す。

The wavy lines indicate a link to another group via one and two carbon atoms of the phenyl.

は、当該ピペリジニルの任意の結合可能な部位が１つの化学結合によって他の基に結合できることを意味し、少なくとも

means that any available site on the piperidinyl can be bonded to another group by one chemical bond, and at least

の四つの結合形態を含み、Ｈ原子が－Ｎ－に描かれていても、

It includes the four bond forms, and even if the H atom is drawn as -N-,

には

for

の結合形態の基が含まれるが、１つの化学結合が接続されるとき、その部位のＨは１つ減少して対応する一価ピペリジンになる。

However, when one chemical bond is connected, the H at that site is reduced by one to the corresponding monovalent piperidine.

Unless otherwise stated, the number of atoms in a ring is generally defined as the number of ring members, e.g., a "5- to 7-membered ring" refers to a "ring" having from 5 to 7 atoms arranged around it.
Unless otherwise stated, a "3- to 12-membered ring" refers to a cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl consisting of 3 to 12 ring atoms. The ring includes monocyclic rings, as well as bicyclic or polycyclic ring systems such as spiro, fused, and bridged rings. Unless otherwise stated, the ring optionally includes 1, 2, or 3 heteroatoms independently selected from O, S, and N. The 3- to 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, and the like. The term "5- to 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, where each "ring" independently meets the above definition.

Unless otherwise defined, C _n-n+m or C _n -C _n+m includes any one specific embodiment of n through n+m carbons, for example, C _1-12 includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , and C ₁₂ , and also includes any one range from n through n+m, for example, C _1-12 includes C _1-3 , C _1-6 , C _1-9 , C _3-6 , C _3-9 , C _{3-12, C 6-9 ,} C _6-12 , and C _9-12 , etc. Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

Unless otherwise defined, the term "C _1-6 alkyl" refers to a saturated hydrocarbon group composed of 1 to 6 carbon atoms in a straight or branched chain. The C _1-6 alkyl includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ and C ₅ alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Illustrative examples of C _1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, t-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), hexyl, and the like.

Unless otherwise defined, the term "C _1-4 alkyl" refers to a saturated hydrocarbon group composed of 1 to 4 carbon atoms in a straight or branched chain. Said C _1-4 alkyl includes C _1-2 , C _1-3 and C _2-3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Illustrative examples of C _1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

Unless otherwise defined, the term "C _1-3 alkyl" refers to a saturated hydrocarbon group composed of 1 to 3 carbon atoms in a straight or branched chain. Said C _1-3 alkyl includes C _1-2 and C _2-3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Illustrative examples of C _1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

Unless otherwise defined, the term "C _1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule via an oxygen atom. Said C _1-3 alkoxy includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy, etc. Illustrative examples of C _1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), etc.

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

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

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

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

All solvents used in this invention can be obtained commercially.
The present invention uses the following abbreviations: DMF stands for N,N-dimethylformamide; K ₂ CO ₃ stands for potassium carbonate; MeI stands for iodomethane; EtOAc stands for ethyl acetate; EA stands for ethyl acetate; THF stands for tetrahydrofuran; NaHMDS stands for sodium hexamethyldisilazane; MeOH stands for methanol; DCM stands for dichloromethane; DMSO stands for dimethylsulfoxide; PE stands for petroleum ether; EtOH stands for ethanol; ACN stands for acetonitrile; TFA stands for trifluoroacetic acid; FA stands for formic acid; NH _{3.H 2} O stands for aqueous ammonia; TEA stands for triethylamine; DIPEA stands for N,N-diisopropylethylamine; Boc ₂ O stands for di-tert-butyl dicarbonate; Boc stands for tert-butoxycarbonyl, an amino protecting group; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; CDI stands for N,N'-carbonyldiimidazole; DDQ stands for 2,3-dichloro-5,6-dicyano-p-benzoquinone; LCMS stands for liquid chromatography-mass chromatography; HPLC stands for high performance liquid chromatography; TLC stands for thin layer chromatography; MEC stands for minimum effective concentration; LnCap stands for prostate cancer cells; sGC stands for soluble guanylate cyclase; cGMP stands for cyclic guanosine monophosphate.

Compounds are named according to conventional naming principles in the art or using ChemDraw® software; commercially available compounds are named in the supplier's catalogue.

The present invention will be described in detail below with reference to examples, but this is not intended to impose any adverse restrictions on the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is clear to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

Example 1
Synthesis scheme:

Step A: 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) were added to a solution of 1-1 (2 g, 12.61 mmol, 1 eq) in toluene (20 mL). The mixture was replaced with nitrogen gas and stirred at 80°C for 12 hours under nitrogen gas protection. Water (20 mL) was added to the reaction solution, extracted with EtOAc (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EtOAc = 50: 1 to 20: 1), and the resulting crude product was stirred with petroleum ether (10 mL), filtered and dried to obtain compound 1-a.

Step B: Reduced iron powder (3.44 g, 61.56 mmol, 8 eq) and NH ₄ Cl (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 mixture was purged with nitrogen gas and stirred at 70° C. for 3 hours. Water (20 mL) and EtOAc (50 mL) were added to the reaction solution, which was then filtered and separated. The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to obtain compound 1-b.

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

Step D: 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) at 30 °C was added 2,6-lutidine (13.80 g, 128.79 mmol, 15.00 mL, 4.46
eq) was slowly added dropwise, and after completion of the addition, the atmosphere was replaced with nitrogen gas three times, and the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was cooled to 30° C., then concentrated under reduced pressure to remove excess solvent, and finally the reaction solution was slowly added to ice water (100 mL) at 0-5° C., then extracted with PE/EA (100 mL, 1/1), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE/EA=1/0-20/1) to obtain compound 1-f.

Step E: At −20° C., a solution of _NH3 in ethanol (20 mL) was added to a solution of compound 1-f (3.3 g, 14.45 mmol, 1 eq) in ethanol (20 mL), the reaction solution was stirred at −20° C. for 50 min, the reaction solution was filtered, the cake was collected, and then washed with water (10 mL) and ethanol (10 mL) to obtain compound 1-g.

Step F: 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) were added to a solution of 1-c (200 mg, 800.87 μmol, 1 eq) in DMF (1.00 mL). The mixture was replaced with nitrogen gas and stirred at 90°C for 3 hours. Water (20 mL) was added to the reaction solution, which was then extracted with EtOAc (50 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1-d.

Step G: Reduced iron powder (845.42 mg, 15.14 mmol, 20 eq) and NH ₄ Cl (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 mixture was purged with nitrogen gas and stirred at 70° C. for 2 hours. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (25 mL×2). The combined organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 1-e.

Step H: At 0° C., methyl chloroformate (41.65 mg, 440.72 μmol, 34.14 μL, 1.5 eq) was added to a pyridine (1.5 mL) solution of 1-e (120 mg, 293.82 μmol, 1 eq), and the mixture was stirred at 0° C. for 30 minutes. 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 saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. EtOAc (10 mL) was added to the residue, and the mixture was stirred. After filtering and drying, compound 1 was obtained. ¹ H NMR (400 MHz,
DMSO- _d6 ): δ ppm 8.08 - 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] ⁺ .

Example 2
Synthesis scheme:

At 0° C., NaH (6.90 mg, 172.55 μmol, 60% purity, 1.5 eq) was added to a solution of compound 1 (50 mg, 115.04 μmol, 1 eq) in DMF (1 mL), 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 30 minutes. Water (5 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (EtOAc) to obtain compound 2. ^1H NMR (400MHz, DMSO- _d6 ): δ ppm 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] ^<+ >.

Example 3
Synthesis scheme:

Step A: Under the protection of nitrogen gas, compound 3-1 (2 g, 11.33 mmol, 1 eq.) was added.
To a solution of 3-(2-fluorobenzylamine) 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 h. After cooling, water (40 mL) was added and 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.

Step B: Reduced iron powder (1.26 g, 22.62 mmol, 4 eq) and NH ₄ Cl (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 mixture was purged with nitrogen gas and stirred at 60° C. for 6 hours. The reaction solution was filtered, the cake was washed with EtOAc (40 mL), and saturated saline (50 mL) was added to the filtrate. The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 10: 1 to 4: 1) to obtain compound 3-b.

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 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE:EtOAc=5:1 to 2:1) to give compound 3-c. ^1H NMR (400 MHz, _CDCl3 ): δ ppm 9.99 (br s, 1H), 7.96 (t, J=2.1 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.28 - 7.24 (m, 1H), 7.16 (dd, J=2.5, 8.0 Hz, 1H), 7.12 - 7.05 (m, 2H), 5.27 (s, 2H).

Step D: To a solution of 3-c (113 mg, 432.57 μmol, 1 eq) in DMF (4.00 mL) was 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 gas, and the reaction solution was stirred at 100°C for 3 hours. After cooling, saturated saline (20 mL) was added to the reaction solution, which was then extracted with EtOAc (20 mL). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 3-d was obtained from the residue by column chromatography (PE: EtOAc = 5: 1 to 2: 1).

Step E: Reduced iron powder (64.70 mg, 1.16 mmol, 4 eq) and NH ₄ Cl (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 mixture was purged with nitrogen gas and stirred at 70° C. for 3 hours. The reaction solution was filtered, the cake was washed with methanol (10 mL) and dichloromethane (10 mL), saturated saline (10 mL) was added to the filtrate, and the mixture was extracted with DCM (10 mL). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 3-e.

Step F: At 0° C., methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq) was added to a solution of 3-e (42 mg, 91.06 μmol, 1 eq) in pyridine (1.5 mL), and the mixture was stirred at 0° C. for 1 hour. The reaction solution was poured into ice water (20 mL), saturated saline (10 mL) was added, and the mixture was extracted with EtOAc (20 mL). The organic phase was washed with saturated saline (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 obtain compound 3. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 8.18
(dd, J=2.5, 9.4 Hz, 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] ^<+> .

Example 4
Synthesis scheme:

Step A: Under the protection of nitrogen gas, 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) 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 12 hours. After cooling, water (40 mL) was added and extracted with EtOAc (40 mL). The organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 50: 1 to 5: 1) to obtain compound 4-a.

Step B: Reduced iron powder (1.20 g, 21.57 mmol, 4 eq) and NH ₄ Cl (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 mixture was purged with nitrogen gas and stirred at 60° C. for 3 hours. The reaction solution was filtered, the cake was washed with EtOAc (40 mL), and saturated saline (60 mL) was added to the filtrate. The mixture was extracted with EtOAc (50 mL). The organic phase was washed with saturated saline (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 10: 1 to 4: 1) to obtain compound 4-b.

Step C: To a solution of 4-b (1.21 g, 4.25 mmol, 1 eq) in THF (20.00 mL) was added CDI (1.03 g, 6.38 mmol, 1.5 eq) slowly. After the addition was complete, the mixture was stirred at 70° C. for 12 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE:EtOAc=4:1 to 2:1) to give compound 4-c. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 11.60 (br s, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.63 - 7.53 (m, 1H), 7.53 - 7.40 (m, 2H), 7.02 (d, J=7.7 Hz, 1H), 5.19 (s, 2H).

Step D: To a solution of 4-c (140 mg, 449.82 μmol, 1 eq) in DMF (1.00 mL) was 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 gas, and the mixture was stirred at 100°C for 3 hours. The reaction solution was cooled and then filtered. The cake was washed with MeOH (10 mL) and EtOAc (10 mL). Saturated saline (20 mL) was added to the filtrate, which was then extracted with EtOAc (30 mL). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-d.

Step E: Reduced iron powder (360.84 mg, 6.46 mmol, 20 eq) and NH ₄ Cl (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 mixture was purged with nitrogen gas and stirred at 70° C. for 3 hours. The reaction solution was filtered, the cake was washed with methanol (10 mL) and EtOAc (10 mL), and the filtrate was concentrated and then purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 4-e.

Step F: At 0° C., methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq) was added to a solution of 4-e (39.55 mg, 91.06 μmol, 1 eq) in pyridine (1.0 mL), and the mixture was stirred at 0° C. for 1 hour. The reaction solution was poured into ice water (10 mL), saturated saline (10 mL) was added, and the mixture was extracted with EtOAc (5 mL×3). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 4. ^1H NMR (400MHz, DMSO- _d6 ): δ ppm 8.18 (dd, J=2.5, 9.4 Hz, 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] ⁺ .

Example 5
Synthesis scheme:

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

Step B: To a solution of CoCl ₂ ·6H ₂ O (1.71 g, 7.19 mmol, 0.1 eq) in THF (200.00 mL) and water (100.00 mL), 5-2 (10 g, 71.89 mmol, 8.00 mL, 1 eq) was added, and then NaBH ₄ (13.60 g, 359.45 mmol, 5 eq) was added in batches. The reaction solution was stirred at 30 ° C. for 12 hours, NH ₃ ·H ₂ O (25%, 20 mL) was slowly added to the reaction solution, and water (100 mL) was further added. Extraction was performed with EtOAc (100 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain compound 5-c.

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) was 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, and the residue was separated by column chromatography (PE: EtOAc = 100: 1 to 10: 1) to obtain compound 5-d.

Step D: To a mixture of 5-d (2.0 g, 7.06 mmol, 1 eq) in EtOH (100 mL) and water (50 mL), reduced iron powder (1.97 g, 35.30 mmol, 5 eq) and NH ₄ Cl (1.89 g, 35.30 mmol, 1.23 mL, 5 eq) were added, stirred at 70° C. for 1 h, extracted with EtOAc (100 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=10:1-3:1) to give compound 5-e.

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

Step F: 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) were added to a solution of 5-f (450 mg, 1.61 mmol, 1 eq) in DMF (10.00 mL), purged with nitrogen gas, stirred at 100°C for 3 hours, added water (50 mL) to the reaction solution, extracted with EtOAc (50 mL x 2), dried the combined organic phase over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain compound 5-g.

Step G: DDQ (1.52 g, 6.69 mmol, 5 eq) was added to a solution of 5-g (900 mg, 1.34 mmol, 1 eq) in DCM (50.00 mL) and water (5.00 mL), 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 x 2). The combined organic phase was washed with water (50 mL x 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.

Step H: Reduced iron powder (95.59 mg, 1.71 mmol, 20 eq) and NH ₄ Cl (91.56 mg, 1.71 mmol, 20 eq) were added to a mixture of 5-h (50 mg, 85.59 μmol, 1 eq) in MeOH (3 mL) and water (1 mL), and the mixture was stirred at 70° C. for 1 hour. After cooling, the reaction solution was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted with DCM (25 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-i.

Step I: At 0° C., methyl chloroformate (7.05 mg, 74.57 μmol, 5.78 μL, 1.5 eq) was added to a solution of 5-i (20 mg, 49.71 μmol, 1 eq) in pyridine (1.0 mL), and the mixture was stirred at 0° C. for 30 minutes. 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 saline (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 obtain compound 5. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 8.20 (dd, J=2.6, 9.4
Hz, 1H), 8.07 (t, J=2.1 Hz, 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] ⁺ .

Example 6
Synthesis scheme:

At 0° C., NaH (1.95 mg, 48.87 μmol, 60% purity, 1.5 eq) was added to a solution of compound 5 (15 mg, 32.58 μmol, 1 eq) in DMF (1.00 mL), and the mixture was stirred at 0° C. for 30 minutes, followed by the addition of iodomethane (6.94 mg, 48.87 μmol, 3.04 μL, 1.5 eq), 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 phase was dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 6. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 8.47 (br s, 1H), 8.22 (br dd, J=2.6, 9.4 Hz, 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] ^<+> .

Example 7
Synthesis scheme:

Step A: Under the protection of nitrogen gas, 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 extracted with EtOAc (20 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 100: 1 to 50: 1) to obtain compound 7-a. ^1H NMR (400 MHz, _CDCl3 ) δ ppm 4.94 (d, J=6.02 Hz, 2H) 7.17 - 7.34 (m, 2H) 7.37 - 7.47 (m, 2H) 8.22 (dd, J=7.91, 2.89
Hz, 1 H) 8.40 (d, J=2.89 Hz, 1 H) 8.47 - 8.67 (m, 1 H).

Step B: Reduced iron powder (2.24 g, 40.03 mmol, 5 eq) and NH ₄ Cl (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 mixture was purged with nitrogen gas and stirred at 80° C. for 17 hours. The reaction solution was filtered, and water (80 mL) was added to the filtrate. The mixture was extracted with EtOAc (80 mL×3). The combined organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 100: 1 to 5: 1) to obtain compound 7-b. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 7.44 - 7.38 (m, 1H), 7.35 - 7.30 (m, 1H),
7.28 - 7.24 (m, 2H), 7.22 (d, J=2.6 Hz,
1H), 6.64 (dd, J=2.8, 10.4 Hz, 1H), 6.09 (t, J=5.6 Hz, 1H), 5.22 (s, 2H), 4.58 (d, J=5.6 Hz, 2H).

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 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE:EtOAc=20:1 to 4:1) to give compound 7-c.

Step D: 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) were added to a solution of 7-c (0.3 g, 1.08 mmol, 1 eq) in DMF (5.00 mL). The mixture was replaced with nitrogen gas and stirred at 90°C for 3 hours. The reaction solution was cooled and then filtered. Water (10 mL) was added to the filtrate, and the mixture was extracted with DCM:MeOH = 5:1 (10 mL x 4). The combined organic phase was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7-d.

Step E: Reduced iron powder (715.60 mg, 12.81 mmol, 20 eq) and NH ₄ Cl (685.44 mg, 12.81 mmol, 448.00 μL, 20 eq) were added to a mixture of 7-d (276.00 mg, 640.70 μmol, 1 eq) in MeOH (8 mL) and water (2 mL), and the mixture was stirred at 75° C. for 1.5 hours. After cooling, the reaction solution was filtered, the filtrate was concentrated, and then water (10 mL) was added. The mixture was extracted with DCM:MeOH=10:1 (10 ml×3). The combined organic phase was washed with saturated saline (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 7-e.

Step F: At 0° C., methyl chloroformate (4.72 mg, 49.95 μmol, 3.87 μL, 1.00 eq) was added to a solution of 7-e (20 mg, 49.90 μmol, 1 eq) in pyridine (1.0 mL), stirred at 0° C. for 30 minutes, 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 obtain compound 7. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 8.23 (dd, J=9.47, 2.57 Hz, 1H), 7.98-8.14 (m, 1H), 7.96 (br s, 1H), 7.51 (dd, J=7.84, 1.32 Hz, 1H), 7.19-7.43 (m,
2H), 7.08 (d, J=6.40 Hz, 1H), 6.37 (br s, 4H), 5.15 (s, 2H), 3.62 (br s, 3H); LCMS (ESI) m/z: 459.0 [M+1] ^<+ >.

Example 8
Synthesis scheme:

Step A: To a solution of 3-e (40 mg, 104.06 μmol, 1 eq) in DMF (1 mL), 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) were added in sequence. The mixture was stirred at 80°C for 12 hours. After cooling, water (20 mL) was added, extracted with EA (10 mL x 2), the combined organic phase was washed with saturated saline (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 15:1) to obtain compound 8-a.

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 h. Saturated brine (10 mL) was added to the reaction solution, which was extracted with EA (8 mL×2), and the organic phase was washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the residue. The residue was purified by preparative HPLC [mobile phase: water (10 mM NH ₄ HCO ₃ )-ACN] to give compound 8. ^1H NMR (400MHz, DMSO- _d6 ): δ ppm 8.19 (dd, J=2.4, 9.3 Hz, 1H), 8.10 (d, J=1.9 Hz, 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=9.0 Hz, 2H); LCMS (ESI) m/z: 493.1 [M+1] ^<+> .

Example 9
Synthesis scheme:

Step A: Ammonia water (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, 9-1 (5 g, 25.78 mmol, 1 eq) was dissolved in dichloromethane (15 mL) to obtain solution 2, and solution 1 was slowly added dropwise to solution 2 under the condition of 0° C., and the mixture was stirred at 0° C. for 1 hour, and the reaction solution was filtered to obtain compound 9-a. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 8.57 (br s, 1 H) 9.01 (s, 1 H) 9.19 (br s, 1 H).

Step B: 9-a (0.2 g, 1.15 mmol, 1.2 eq), compound 3-c (2
Compound 9-b (49.44 mg, 954.86 μmol, 1 eq) and anhydrous potassium carbonate (263.94 mg, 1.91 mmol, 2 eq) were dissolved in DMF (5 mL), purged with nitrogen gas three times, and stirred for 2 hours at 25° C. The reaction solution was added dropwise to 40 mL of water, stirred for 15 minutes, and then filtered to obtain compound 9-b.

Step C: Compound 9-b (400 mg, 879.52 μmol, 1 eq) was dissolved in MeOH (9 mL) and H ₂ O (3 mL), and Fe (982.33 mg, 17.59 mmol, 20 eq) and NH ₄ Cl (940.93 mg, 17.59 mmol, 614.99 μL, 20 eq) were added to the solution and stirred at 75° C. for 1 hour. The reaction solution was cooled to 25° C. and filtered through diatomaceous earth. The filtrate was concentrated and then purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 9-c.

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 the temperature for 30 minutes. The reaction solution was added dropwise to 2 mL of water, extracted with EA (3 mL×3), the combined 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 (0.225% FA)-ACN] to obtain compound 9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.68 (s, 3 H) 5.15 (s,
2H) 7.09 - 7.43 (m, 6H) 8.09 (d, J = 1.88 Hz, 1H) 8.16 (dd, J = 9.35, 2.45 Hz, 1
1H) 8.28 (br s, 1H) 8.85 (br s, 1H); LCMS (ESI) m/z: 428.0 [M+1] ^<+> .
Example 10
Synthesis scheme:

Step A: At 0° C. and under the protection of nitrogen gas, compound 10-1 (219.74 mg, 1.54 mmol, 158.09 μL, 3 eq) was added in one portion to a solution of compound 3-e (203 mg, 512.33 μmol, 1 eq) in pyridine (2.0 mL), and the mixture was stirred and reacted 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×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (SiO ₂ , DCM/MeOH=15/1) to obtain the crude product of compound 10-a, which was directly used in the next step reaction without further purification. LCMS (ESI) m/z: 491.0 [M+1] ⁺ .

Step B: At 0° C. and under the protection of nitrogen gas, NaHMDS (1M, 264.85 μL, 2 eq) was added in one portion to a solution of compound 10-a (65 mg, 132.42 μmol, 1 eq) in THF (4.0 mL), and the mixture was reacted at 0° C. for 1 hour. Then, it was added dropwise to an ice bath (10 mL), and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated saline (20 mL), dried over anhydrous Na ₂ SO ₄ , and filtered under suction. The residue after the filtrate was concentrated under reduced pressure was purified by preparative HPLC [mobile phase: water (0.04% NH ₃ ·H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN] to obtain compound 10. ^1H NMR (400MHz, DMSO- _d6 ): δ ppm 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 = 4.9 Hz, 1H), 5.15 (s, 2H), 3.97
(t, J=4.8 Hz, 2H), 3.68-3.56 (m, 2H); LCMS (ESI) m/z: 455.2 [M+1] ⁺ .

Example 11
Synthesis scheme:

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 the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was added dropwise to 2 mL of water, extracted with EA (4 mL×3), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 11. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.13 (d, J=6.78 Hz, 6 H) 2.67 (quin, J=6.78 Hz, 1 H) 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, 2.38 Hz, 1H) 8.37 (s, 1H) 9.33 (s,
1H). LCMS (ESI) m/z: 440.1 [M+1] ^<+> .

Example 12
Synthesis scheme:

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., followed by stirring at the same temperature for 30 minutes. The reaction solution was added dropwise to 2 mL of water, extracted with EA (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (10 mM NH ₄ HCO ₃ )-ACN] to obtain compound 12. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 1.15 - 1.56 (m, 3H) 1.40 (q, J = 12.05 Hz, 2H) 1.66 (br d, J = 11.67 Hz,
1H) 1.76 (br d, J = 12.67 Hz, 2H) 1.88 (br d, J = 11.17 Hz, 2H) 2.31 - 2.43 (m, 1H) 5.14 (s, 2H) 7.06 - 7.43 (m, 6H) 8.09 (t, J = 2.07 Hz, 1H) 8.15 (dd, J = 9.22, 2.45 Hz, 1H) 8.36 (s, 1H) 9.15 (br s, 1H). LCMS (ESI) m/z: 480.0 [M+1] ^<+> .

Example 13
Synthesis scheme:

Compound 9-c (0.036 g, 94.06 μmol, 1 eq) was dissolved in DMF (1 mL) and mixed with 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).
was added, and the resulting mixture was stirred at 130° C. for 2 hours. The reaction solution was purified by preparative HPLC [mobile phase: water (0.05% aqueous ammonia)-ACN] to obtain compound 13. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ ppm 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] ⁺ .

Example 14
Synthesis scheme:

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 the mixture was stirred until gas was no longer released. The reaction solution was 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), and the mixture was stirred for 2 hours at 25° C. 2 mL of water was added to the reaction solution, which was then 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 [mobile phase: water (0.04% NH ₃ H ₂ O)-ACN] to give compound 14. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 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, 2.57 Hz, 1H) 9.10 (br s, 1H); LCMS (ESI) m/z: 506.0 [M+1] ⁺ .

Example 15
Synthesis scheme:

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 the mixture was stirred at 25° C. for 6 hours. The reaction solution was filtered, the 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 saline (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified and separated by column chromatography (SiO ₂ , PE:EA=5:1-3:1) to obtain compound 15-a.

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), then zinc powder (1.50 g, 22.91 mmol, 5 eq) was added to the above 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), and the organic phase was collected, washed with saturated saline (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by column chromatography (SiO ₂ , PE:EA=5:1-1:1) to obtain compound 15-b.

Step C: Compound 15-b (150 mg, 0.885 mmol, 1 eq) was dissolved in anhydrous DMF (15 mL), and the mixture was replaced with nitrogen gas. NaH (35.38 mg, 0.885 mmol, 60% purity, 1 eq) was added to the reaction solution at 0° C., and the mixture was stirred at 25° C. for 30 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (147.5 mg, 0.885 mmol, 156.6 μL, 1 eq) was added dropwise, and the mixture was 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 system under the protection of nitrogen gas, and the mixture was stirred for 30 minutes. After that, iodomethane (263.67 mg, 1.86 mmol, 115.65 μL, 2.1 eq) was added dropwise, and the reaction system was stirred at 25° C. for 1 hour. The reaction solution was poured into H ₂ O (45 mL) and extracted with ethyl acetate (40 mL×2). The combined organic phase was washed with saturated saline (40 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-c.

Step D: Cesium carbonate (139.12 mg, 426.98 μmol, 2.0 eq) was added 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), and the mixture was replaced with nitrogen gas. Under a nitrogen gas atmosphere, the reaction system was stirred at 100° C. for 15 hours. H ₂ O (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated saline (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-d. ¹ H NMR (400 MHz, CDCl ₃ ):
δ ppm 8.43 (s, 1H), 8.15 (dd, J=8.85, 2.57 Hz, 1H), 8.04 (dd, J=2.45, 1.57 Hz,
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=8.4 Hz, 2H), 1.52
(s, 6H), 0.99 (t, J=8.0 Hz, 2H), 0.02 (s, 9H).

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% NH ₃ ·H ₂ O)-ACN] to obtain compound 15. ¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 8.35
(s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.15 (d, J=2.8 Hz, 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] ⁺ .

Example 16
Synthesis scheme:

At 25° C., p-fluorobenzoic acid (245.45 mg, 1.75 mmol, 1 eq) was dissolved in DCM (1 mL) and mixed with DMF (7.54 mg, 103.19 μmol, 7.94 μL, 0.1 eq) and oxalyl chloride (200.12 mg, 1.58 mmol, 138
0.01 μL, 0.9 eq) was added and stirred until gas was no longer released, and the reaction solution was 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, 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 [mobile phase: water (0.04% NH ₃ H ₂ O)-ACN] to obtain compound 16. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 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] ⁺ .

Example 17
Synthesis scheme:

Step A: At 0° C., NaH (2.07 g, 51.67 mmol, 60% purity, 2 eq) was carefully and slowly added to a solution of 17-1 (3 g, 25.84 mmol, 1 eq) in DMF (30 mL), and the mixture was stirred at 0° C. for 0.5 hours. Further, iodomethane (4.40 g, 31.00 mmol, 1.93 mL, 1.2 eq) was added to the solution, and the mixture was slowly warmed to room temperature and stirred for 0.5 hours. The mixture was then stirred at 45° C. for 3 hours. After cooling to room temperature, the reaction was quenched by adding saturated ammonium chloride solution (60 mL), diluted with water (10 mL), and extracted with DCM (30 mL×3). The combined organic phase was washed with water (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated at 10° C. or less to obtain compound 17-a. ^1H NMR (400 MHz, DMSO- _d6 ): δ 3.65 (s, 3H), 3.30 (s, 3H), 1.31-1.27 (dd, J=4.8 Hz, 8.4 Hz, 2H), 1.17-1.14 (dd, J=4 Hz, 7.2 Hz, 2H).

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 h. The reaction solution was concentrated below 40° C., the concentrated solution was washed with petroleum ether (15 mL), and then the aqueous phase was poured into ice water (15 mL), the solution was adjusted to pH 5-6 with 3M aqueous hydrochloric acid, extracted with DCM (12 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 17-b.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.55 (s, 1H), 3.29 (s, 3H), 1.14-1.12 (dd, J=6 Hz, 8.8 Hz, 2H), 1.07-1.04 (dd, J=3.2 Hz, 6.4 Hz, 2H).

Step C: At 0° C., oxalyl chloride (344.33 mg, 2.71 mmol, 237.47 μL, 0.9 eq) was added 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), purged with nitrogen gas, and stirred at 0° C. for 0.5 hours. To the solution was added a solution of 9-c (261.94 mg, 602.85 μmol, 0.2 eq) in DCM (3 mL) dropwise, and further pyridine (476.85 mg, 6.03 mmol) , 486.59 μL, 2 eq) was added, 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), the organic phase was washed with saturated saline (15 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by column chromatography (PE: EtOAc = 10: 1 to 0.1: 1), and the obtained crude product was further purified by preparative HPLC [mobile phase: water (0.05% aqueous ammonia) -ACN] to obtain compound 17. ^1H NMR (400MHz, _CD3OD ): δ ppm 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=6Hz, 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] ^<+> .

Example 18
Synthesis scheme:

EDCI (399.02 mg, 2.08 mmol, 8 eq) and 14-1 (80.18 mg, 520.37 μmol, 2 eq) were added to a pyridine (4 mL) solution of 3-e (100 mg, 260.18 μmol, 1 eq), and the reaction mixture was stirred at 30° C. for 2 hours. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and then 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 ): δ ppm 8.60 (br s, 1H
), 8.22 (dd, J=2.3, 9.4 Hz, 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] ⁺ .

Example 19
Synthesis scheme:

EDCI (418.62 mg, 2.18 mmol, 8 eq) and 14-1 (84.12 mg, 545.92 μmol, 2 eq) were added to a pyridine (3 mL) solution of 1-e (100 mg, 272.96 μmol, 1 eq), and the reaction mixture was stirred at 30° C. for 2 hours. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and then 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
(400 MHz, DMSO- _d6 ): δ ppm 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] ⁺ .

Example 20
Synthesis scheme:

Compound 9 (169 mg, 395.45 μmol, 1 eq) was dissolved in THF (2 mL) at 0° C., then NaH (20.56 mg, 514.08 μmol, 60% purity, 1.3 eq) was added to the resulting solution and stirred for 90 minutes, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (110.14 mg, 474.54 μmol, 1.2 eq) was added, the temperature was raised to 20° C., and the mixture was stirred for 36 hours. 2 mL of water was added to the reaction solution, and its pH was adjusted to 6-7 with 1 M aqueous hydrochloric acid, then extracted with EA (4 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN] to obtain compound 20. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 4.85 (q, J=9.03 Hz, 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, 2.45 Hz, 1H), 8.12 (t, J=2.13 Hz, 1H), 8.52 (s, 1H); LCMS (ESI) m/z: 478.2 [M+1] ⁺ .

Example 21
Synthesis scheme:

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 and stirred until gas was no longer 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, 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% to 62%, 10 min) to give compound 21. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm
0.53 - 0.75 (m, 2H) 1.14 (br d, J = 2.38
Hz, 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, 2.38 Hz, 1H) 8.85 (br s, 1H); LCMS (ESI) m/z: 452.2 [M+1] ⁺ .

Example 22
Synthesis scheme:

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., followed by stirring at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was added dropwise to 4 mL of water, extracted with ethyl acetate (5 mL×3), the organic phase was washed with saturated saline (5 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 22. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 1.02-1.33 (m, 3H) 4.06 (br d, J=6.78 Hz,
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 (br s, 1H) 8.06 (s, 1H) 8.18 (br d, J=9.03 Hz, 1H); LCMS (ESI) m/z: 457.0 [M+1] ⁺ .

Example 23
Synthesis scheme:

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), EDCI (399.02 mg, 2.08 mmol, 8 eq) was added thereto, and the reaction solution was reacted at 30° C. for 2 hours. The reaction solution was added dropwise to H ₂ O (4 mL), and then extracted with EA (5 mL×3), the organic phase was washed with saturated saline (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 23. ^1H NMR (400 MHz, DMSO- _d6 ): δ ppm 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=6.48 Hz, 1H) 8.07
(s, 1H) 8.22 (dd, J=9.35, 2.20 Hz, 1H) 8.60 (br s, 1H); LCMS (ESI) m/z: 478.0
[M+1] ⁺ .

Example 24
Synthesis scheme:

EDCI (399.02 mg, 2.08 mmol, 8 eq) and 17-b (90.63 mg, 780.55 μmol, 3 eq) were added to a solution of 3-e (100 mg, 260.18 μmol, 1 eq) in pyridine (5 mL). The reaction solution was stirred at 20° C. for 1 h. The reaction solution was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give the crude product compound, which was separated by preparative HPLC [mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile] and then further purified by thin layer chromatography (SiO 2 , DCM:MeOH=10:1) to give compound 24. ^1H NMR (400MHz, MeOH- _d4 ) δ=8.28-8.22 (m, 1H), 7.98-7.93 (m, 1H), 7.30 (t, J=7.5 Hz, 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] ^<+> .

Example 25
Synthesis scheme:

EDCI (598.53 mg, 3.12 mmol, 8 eq) and 1-methylcyclopropane-1-carboxylic acid (117.22 mg, 1.17 mmol, 3 eq) were added to a pyridine (5 mL) solution of 3-e (150 mg, 390.28 μmol, 1 eq), and the reaction mixture was stirred at 20° C. for 1 hour. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 25. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.29
(s, 1H), 8.20 (dd, J=2.4, 9.3 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 7.35 (q, J=7.3 Hz, 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=2.4 Hz, 2H), 0.63-0.46 (m, 2H). LCMS (ESI) m/z: 467.4 [M+1] ^<+> .

Example 26
Synthesis scheme:

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

Step B: Compound 26-a (20 g, 120.35 mmol, 1 eq), S-methylthiourea (27.04 g, 144.42 mmol, 1.2 eq, HSO ₄ ) and triethylamine (24.36 g, 240.71 mmol, 33.50 mL, 2 eq) were dissolved in DMF (60 mL), purged with nitrogen gas three times, and then 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 to 1/1) to obtain compound 26-b.

Step C: Compound 26-b (3.8 g, 16.94 mmol, 1 eq) was dissolved in DCM (50 mL) and then m-chloroperoxybenzoic acid (6.88 g, 33.89 mmol, 85% purity, 2 eq) was added. The reaction solution was stirred at 20° C. for 12 h. After completion of the reaction, it was filtered, the cake was collected, stirred with dichloromethane (100 mL), filtered and dried to give compound 26-c. LCMS (ESI) m/z: 257.2 [M+1] ⁺ .

Step D: At 20° C., potassium carbonate (8.28 g, 59.93 mmol, 3 eq) and 26-c (5.12 g, 19.98 mmol, 1.0 eq) were added to a solution of 3-c (5.74 g, 21.98 mmol, 1.1 eq) in DMF (30 mL), and the reaction solution was heated to 120° C. and reacted for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the cake was washed with methanol (20 mL) and DMF (20 mL). The filtrate was combined and concentrated under reduced pressure to remove methanol, and the remaining liquid was purified by preparative HPLC [mobile phase: water (0.1% FA)-ACN] to obtain compound 26. ¹ H NMR (400 MHz,
DMSO- _d6 ) δ = 11.15 (s, 1H), 8.27 (dd, J = 2.5, 9.4 Hz, 1H), 8.10 (t, J = 2.0 Hz, 1H),
7.39 - 7.32 (m, 1H), 7.29 (t, J=7.6 Hz,
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] ^<+> .

Example 27
Synthesis scheme:

To a solution of 5-f (200 mg, 670.45 μmol, 1 eq) in DMF (2 mL), 26-c (273 mg, 858.58 μmol, 1.28 eq) and potassium carbonate (200 mg, 1.45 mmol, 2.16 eq) were added. The mixture was purged with nitrogen gas and stirred at 120° C. for 12 hours. The reaction solution was filtered, the cake was washed with 2 mL of DMF, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 27. ¹ H
NMR (400 MHz, DMSO- _d6 ) δ ppm 1.34 (s, 6H) 5.18 (s, 2H) 6.94 - 7.22 (m, 4H) 7.37 (q, J = 8.23 Hz, 1H) 8.10 (t, J = 2.14
Hz, 1H) 8.27 (dd, J=9.48, 2.63 Hz, 1H); LCMS (ESI) m/z: 456.1 [M+1] ^<+> .

Example 28
Synthesis scheme:

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), 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) were added. The reaction solution was stirred at 20°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 5: 1 to 1: 1) to obtain compound 28-a.

Step B: Under the protection of nitrogen gas, 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), and the reaction solution was replaced with hydrogen gas three times, then stirred at 15 psi pressure and 20°C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was then concentrated to obtain compound 28-b.

Step C: 3-1 (2.5 g, 14.16 mmol, 1 eq) and 28-b (1.85 g, 16.99 mmol, 1.2 eq) were dissolved in toluene (100 mL), and the mixture was heated to 80°C and stirred 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 obtain compound 28-c.

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

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

Step F: 26-c (519 mg, 1.63 mmol, 2 eq) and potassium carbonate (338 mg, 2.45 mmol, 3 eq) were added to a solution of 28-e (200 mg, 815.62 μmol, 1 eq) in DMF (3 mL). The mixture was purged with nitrogen gas and stirred at 120° C. for 12 hours. The reaction solution was filtered, the cake was washed with 2 mL of DMF, and the filtrate was analyzed by preparative HPLC [
The residue was purified by elution with a ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 1.34 (s, 6
1H) 5.16 (s, 2H) 7.01 (br s, 2H) 8.06 - 8.17 (m, 1H) 8.29 (dd, J=9.48, 2.63 Hz, 1H) 8.84 (s, 2H) 9.12 (s, 1H); LCMS
(ESI) m/z: 422.1 [M+1] ^<+> .

Example 29
Synthesis scheme:

Step A: Under the protection of nitrogen gas, 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 extracted with EtOAc (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to obtain compound 29-a.

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 29-a (650 mg, 2.44 mmol, 1 eq) in tetrahydrofuran (15 mL) and water (5 mL). The reaction solution 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 to 2:1) to obtain compound 29-b.

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

Step D: Potassium carbonate (316 mg, 2.29 mmol, 3 eq) and 26-c (485 mg, 1.53 mmol, 2 eq) were added to a solution of 29-c (200 mg, 762.73 μmol, 1 eq) in DMF (3 mL), and then reacted at 120° C. for 12 h. The reaction solution was filtered, the cake was washed with DMF (2 mL), and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to obtain compound 29. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 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, 1.10 Hz, 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] ^<+> .

Example 30
Synthesis scheme:

Step A: 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) were added to a solution of 3-c (250 mg, 957.02 μmol, 1 eq) in DMF (2.00 mL). The reaction was stirred at 120° C. for 12 hours, cooled, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer chromatography (SiO ₂ , PE:EtOAc=2:1) to give compound 30-a.

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(II) dichloride (162.02 mg, 230.84 μmol, 0.5 eq) were dissolved in 1,4-dioxane (5 mL), purged with nitrogen gas three times, and then 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 phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.1% TFA)-ACN] to obtain compound 30. ^1H NMR (400MHz, DMSO- _d6 ) δ=8.55 (br d, J=9.3 Hz, 1H), 8.22 (d, J=1.7 Hz, 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, 8.3 Hz, 2H),
0.63 (dd, J=1.7, 5.3 Hz, 2H). LCMS (ESI)
m/z: 395.3 [M+1] ⁺ .

Example 31
Synthesis scheme:

Step A: To a solution of 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20 mL) was 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 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE: EtOAc = 100: 1 to 30: 1) to obtain compound 31-a.

Step B: Under nitrogen gas protection, 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 mixture was evacuated and replaced with hydrogen gas three times, and the reaction solution was stirred under an atmosphere of hydrogen gas (15 psi) at 45°C for 12 hours. The reaction solution was filtered through diatomaceous earth, the cake was washed with methanol (10 mL x 3), and the filtrate was concentrated to obtain compound 31-b.

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), and the reaction solution was heated to 70° C. and stirred for 2 hours. The reaction solution was concentrated to obtain a residue, which was purified by column chromatography (PE/EA=5/1-1/1) to obtain compound 31-c. LCMS (ESI) m/z: 262.5 [M+1] ⁺ .

Step F: Under the protection of nitrogen gas, 26-c (510 mg, 1.99 mmol, 2 eq) and potassium carbonate (413 mg, 2.99 mmol, 3 eq) were added to a solution of 31-c (260 mg, 995.30 μmol, 1 eq) in DMF (3 mL). The reaction solution was stirred at 120° C. for 12 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to obtain compound 31. ¹ H NMR (4
00 MHz, DMSO- _d6 ) δ ppm 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, 6.24 Hz, 1H) 8.10 (t, J=2.08 Hz, 1H) 8.26 (dd, J=9.35, 2.51 Hz, 1H) 11.12 (br s, 1H); LCMS (ESI) m/z: 438.1 [M+1] ⁺ .

Example 32
Synthesis scheme:

Step A: Under the protection of nitrogen gas, 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), and the reaction solution was stirred at 100°C for 4 hours. After cooling the reaction solution, it was washed with water (40 mL) and separated. The organic phase was concentrated under reduced pressure, and then methanol was added and stirred for 1 hour. It was filtered, and the cake was dried in vacuum to obtain compound 32-a.

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

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

Step D: Under nitrogen gas 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), and the reaction solution was stirred at 120°C for 4 hours. The reaction solution was diluted with water (40 mL), filtered, and the cake was dried in vacuum to obtain compound 32-d.

Step E: To a solution of 32-d (1.6 g, 3.34 mmol, 1 eq) in DMF (4 mL), 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) were added, and the mixture was stirred at 50°C for 2 hours under nitrogen gas protection. The reaction solution was diluted with water (25 mL), filtered, and the cake was dried in vacuum to obtain compound 32-e.

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 obtain compound 32-f.

Step G: 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) were added to a solution of 32-f (0.6 g, 1.34 mmol, 1 eq) in DMF (5 mL). The reaction solution was reacted at 50°C for 1 hour under nitrogen gas protection. The reaction solution 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.

Step H: Under the protection of nitrogen gas, 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 solution was stirred at 50° C. for 16 hours. The reaction solution was poured into an aqueous solution of sodium hydroxide (80 mL, 1 mol/L) to neutralize it, extracted with ethyl acetate (60 mL), and the organic phase was concentrated under reduced pressure, and then purified by preparative HPLC [water (0.075% TFA)-acetonitrile] to obtain compound 32. ^1H NMR (400MHz, DMSO- _d6 ) δ=11.14 (s, 1H), 8.26 (dd, J=2.6, 9.4 Hz, 1H), 8.15 (t, J=2.1 Hz, 1H), 7.01 (br s, 2H), 4.22 (t, J=6.9 Hz, 2H), 2.90-2.72 (m, 2H), 1.35 (s, 6H). LCMS (ESI) m/z: 476.2 [M+1] ^<+> .

Biological Test Experimental Example 1: In Vitro Activity Test cGMP Expression Test Based on lnCap Cells 1. Experimental Steps 1) Preparation of Solution 10% BSA (bovine serum albumin)
10 g of BSA was dissolved in 100 mL of double distilled water (ddH ₂ O) to obtain 10% BSA.
5 mM DETA (diethylenetriamine)-NO
10 mg of DETA-NO was weighed out and dissolved in 12.2 mL of double distilled water (ddH ₂ O) to obtain 5 mM DETA-NO, which was then aliquoted and stored frozen in a -20°C refrigerator.

Washing Buffer (50mL)

・Assay Buffer (50mL)

Detection Buffer
a) 50 μL of cGMP-D2 (D2-labeled cyclic guanosine monophosphate) was added to 1 mL of lysis buffer and mixed uniformly.

b) 50 μL of anti-cGMP cryptate (Eu ³⁺ cryptate-labeled anti-cyclic guanosine monophosphate antibody) was added to 1 mL of lysis buffer and mixed uniformly.

2) Compound dilution (1) Compounds were diluted to 5 mM in DMSO. 10 μL of compound was transferred to an Echo shallow well plate.

(2) A gradient dilution of the compounds was performed using Echo, where each compound was diluted into a concentration gradient of 10 and 50 nL of each was added to a 384 microwell plate.
3) Preparation of LNCap cells (1) LNCap medium: RPMI1640 + 10% fetal bovine serum + 1% double antibody (2) Phosphate buffer, trypsin, and medium used for cell passage were preheated in a 37°C water bath.

(3) Cells (passage 14) were removed from the 37° C., 5% CO ₂ incubator, and the old medium in the culture flask was removed using a pipette.
(4) 5 mL of phosphate buffer was aspirated and added to the culture flask to wash the cells, and the liquid was removed.

(5) 3 mL of trypsin was aspirated and added to the culture flask, shaken, the liquid was removed, and the culture flask was placed in the incubator.
(6) After about 2 minutes, the culture flask was removed, and after confirming that the cells had been separated, 9 mL of medium was added to the culture flask, and the cell suspension was transferred to a 50 mL centrifuge tube after repeated pipetting several times.

(7) 0.7 mL of the cell suspension was pipetted into a counting cup and counted using a ViCell XR. The remaining cells were centrifuged at 1000 rpm for 5 minutes and the supernatant was removed.

(8) The cells were washed by adding 10 mL of washing buffer, centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed.
(9) An assay buffer was added to adjust the cell concentration to 1.25×10 ⁶ /mL, and 8 μL/well of the solution was added to the microplate.

4) Preparation and Addition of DETA-NO (1) 10 μL 5 mM DETA-NO was added to 1240 μL and 1657 μL of assay buffer, respectively, to obtain 40 μM and 30 μM DETA-NO.

(2) Using a Bravo, 2 μL/well of DETA-NO was transferred to a 384 microwell plate.
(3) Centrifuge at 1500 rpm for 5 minutes. The microplate was incubated at 37° C. for 30 minutes.

5) Preparation of cGMP standard curve (1) 1 mM cGMP stock solution was diluted to 10 μM with assay buffer, then diluted 4-fold with 11 concentration gradients.

(2) The diluted cGMP was added to the microwell plate at 10 μL/well.
6) Detection reagent was added and the plate was read (1) Using the Bravo, 5 μL/well of cGMP-D2 was transferred to a 384 microwell plate. Centrifuge at 1500 rpm for 1 minute.

(2) Using a Bravo, 5 μL/well of the anti-cGMP cryptate was transferred to a 384-microwell plate, followed by centrifugation at 1500 rpm for 1 minute.
(3) The mixture was incubated at room temperature for 1 hour.

(4) 65/615 was read on envisage.
7) Data Analysis (1) cGMP standard curve: A standard curve was prepared based on cGMP concentration and the 665/615 ratio using Graphpad prism.

(2) The HTRF (homogeneous time-resolved fluorescence technique) ratio (665/615) was converted to cGMP concentration: In Graphpad Prism, the HTRF ratio (665/615) was copied to the ratio column of the cGMP standard curve, analyzed by running "Log inhibitor vs response-variable slope," and selected "interpolate" to convert the HTRF ratio (665/615) to cGMP concentration.

(3) Compound activation curve: A curve was created using the "Log agonist vs response-variable slope" analysis method in Graphpad Prism for the converted cGMP concentration and compound concentration.

The experimental results show that the compounds of the present invention have good stimulating activity on sGC.
Experimental Example 2: Evaluation of pharmacokinetics in rats Experimental objective:
The purpose is to detect the pharmacokinetic parameters of the compound of the present invention in the rat body.

Experimental scheme:
1) Experimental animals: Six male SD rats aged 7-9 weeks were selected and randomly divided into two groups, with three rats in each group.

2) Preparation of drugs: An appropriate amount of drug was weighed and dissolved in a mixed solvent of 10% DMSO + 50% PEG400 + 40% _H2O to prepare a concentration of 0.2 mg/mL; an appropriate amount of drug was weighed and dissolved in a mixed solvent of 10% EtOH + 40% PEG400 + 50% _H2O to prepare a concentration of 0.3 mg/mL.

Experimental procedure:
Animals in group 1 were administered the drug at a dose of 1.0 mg/kg and a concentration of 0.2 mg/mL by a single tail vein injection, and animals in group 2 were administered the compound at a dose of 3 mg/kg and a concentration of 0.3 mg/mL by intragastric administration. Plasma samples were taken from the animals at 0.0833 hours (tail vein injection group only), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration.
Data Analysis:
Drug concentrations in plasma samples were measured using an LC-MS/MS method, and the pharmacokinetic parameters of the test drugs were obtained and shown in Table 2.

Conclusion: The compounds of the present invention exhibited good pharmacokinetic properties in rats.
Experimental Example 3: Human liver microsomal CYP inhibition experiment The purpose of the research project is to evaluate the inhibitory effect of test substances on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) using 5-in-1 probe substrates for CYP isoenzymes.

Mixed human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA) or other suppliers and were stored at <-70°C until use.

A working solution of the test substance diluted to a series of concentrations was added to an incubation system containing human liver microsomes, probe substrates and circulatory cofactors, and a control containing solvent but no test substance served as an enzyme activity control (100%). The concentrations of metabolites generated by the probe substrate in the samples were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Nonlinear regression analysis of the mean percentage of activity versus the concentration of the test substance was performed using SigmaPlot (V.11). _IC50 values were calculated using a three-parameter or four-parameter antilogarithmic equation. The test results are shown in Table 3.

Conclusion: The compounds of the present invention showed weak inhibitory effects against all five CYP isoenzymes.

Claims (24)

A compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

(wherein R ₁ is H, F or Cl;
R ₂ is C _1-6 alkyl, —CH ₂ -phenyl, —CH ₂ -pyridyl or —CH ₂ -pyrimidinyl, wherein said C _1-6 alkyl, —CH ₂ -phenyl, —CH ₂ -pyridyl or —CH ₂ -pyrimidinyl is each independently optionally substituted by 1, 2, 3, 4 or 5 R _a ;
each R _a is independently H, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -C(═O)OH, C _1-3 alkoxy or C 1-3 alkyl optionally substituted with 1 _, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH ₂ and -OCH ₃ ;
_R3 and _R4 are each independently H, F, Cl, Br, I, -OH, -CN, or _-NH2 ;
_R5 is -L- _Rb ;
L is a single bond, -NR _c C(=O)O- or -NR _c C(=O)-;
R _b is C _1-6 alkyl,

wherein said C _1-6 alkyl,

are each independently optionally substituted by 1, 2 or 3 R;
R _c is H, _{-CH3 or -CH2CH3} ;
each R is independently F, Cl, Br, I, -OH, -CN, _-NH2 , _-NO2 , _C1-3alkoxy or _C1-3alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, _-NH2 and _-OCH3 ;
Alternatively, R ₃ and R ₅ may be joined with the carbon atom to which they are attached to form a structural unit

but

to be selected from
R ₆ , R ₇ and R ₈ are each independently F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ or C _1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH ₂ and -OCH ₃ . The compound according to claim 1, or a pharma- ceutically 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)-. The compound of claim 1, having a structure represented by any one of formulas (I-1) to (I-4), or a pharma- ceutically acceptable salt thereof.

(wherein R ₁ , R ₂ , R ₄ and R _b are as defined in claim 1 ). The compound of claim 1, _or a _{pharma- ceutically} 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 . The R _b is C _1-4 alkyl,

wherein said C _1-4 alkyl,

is each independently optionally substituted by 1, 2 or 3 R, or a pharma- ceutically acceptable salt thereof. The R _b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ ,

6. The compound of claim 5, which is: or a pharma- ceutically acceptable salt thereof. The R _b is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ ,

7. The compound according to claim 4 or 6, which is: or a pharma- ceutically acceptable salt thereof. said R ₅ is -NH-C(=O)O-C _1-4 alkyl, -NHC(=O)-C _1-4 alkyl, -N(CH ₃ )-C(=O)O-C _1-4 alkyl, -NH-C(=O)-(C _3-6 cycloalkyl), -N(CH ₃ )C(=O)-(C _3-6 cycloalkyl), -NH-C(=O)-phenyl, -N(CH ₃ )-C(=O)-phenyl or 5-6 membered heterocycloalkyl, wherein said NH-C(=O)O-C _1-4 alkyl, -NHC(=O)-C _1-4 alkyl, -N(CH ₃ )-C(=O)O-C _1-4 alkyl, -NH-C(=O)-(C _3-6 cycloalkyl), -N(CH ₃ )C(=O)-(C _3-6 membered cycloalkyl), -NH-C(=O)-phenyl, -N(CH ₃ )-C(=O)-phenyl and 5-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R, or a pharma- ceutically acceptable salt thereof. Said R ₅ is -NH-C(=O)O-CH ₃ , -NH-C(=O)O-CH ₂ CH ₃ , -NH-C(=O)O-CH ₂ CH ₂ CH ₃ , -NH-C(=O)O-CH(CH ₃ ) ₂ , -NH-C(=O)-CH ₃ , -NH-C(=O)-CH ₂ CH ₃ , -NH-C(=O)-CH ₂ CH ₂ CH ₃ , -NH-C(=O)-CH(CH ₃ ) ₂ , -N(CH ₃ )-C(=O)O-CH ₃ , -N(CH ₃ )-C(=O)O-CH ₂ CH ₃ , -N(CH ₃ )-
C(=O)O _{- CH2CH2CH3} , -N( _CH3 )-C( ₌ O)O-CH( _CH3 ) ₂ ,

9. The compound of claim 8, which is: or a pharma- ceutically acceptable salt thereof. Said R ₅ is -NH-C(=O)O-CH ₃ , -NH-C(=O)O-CH ₂ CH ₃ , -NH-C(=O)O-CH ₂ CH ₂ CH ₃ , -NH-C(=O)O-CH(CH ₃ ) ₂ , -NH-C(=O)-CH ₃ , -NH-C(=O)-CH ₂ CH ₃ , -NH-C(=O)-CH ₂ CH ₂ CH ₃ , -NH-C(=O)-CH(CH ₃ ) ₂ , -N(CH ₃ )-C(=O)O-CH ₃ , -N(CH ₃ )-C(=O)O-CH ₂ CH ₃ , -N(CH ₃ )-C(=O)O-CH ₂ CH ₂ CH ₃ , -N(CH ₃ )-C(=O)O-CH( _CH3 ) ₂ ,

10. The compound of claim 9, which is: or a pharma- ceutically acceptable salt thereof. The compound of claim 1, having a structure represented by any one of formulas (I-5) to (I-13), or a pharma- ceutically acceptable salt thereof.

wherein p is 0, 1 or 2, _R4 is H or _-NH2 , _R2 is as defined in claim 1, and R is as defined in claim 1 or 4. The compound according to claim 1, having a structure represented by formula (I-14) to (I-15), or a pharma- ceutically acceptable salt thereof.

(wherein R ₁ , R ₂ , R ₄ , R ₆ , R ₇ and R ₈ are as defined in claim 1 ). The compound according to claim 12, having a structure represented by any one of formulas (I-16) to (I-19), or a pharma- ceutically acceptable salt thereof.

(wherein R ₂ , R ₆ , R ₇ and R ₈ are as defined in claim 12). The structural unit

teeth,

13. The compound of claim 1 or 12, which is: or a pharma- ceutically acceptable salt thereof. The structural unit

teeth,

13. The compound of claim 1 or 12, which is: or a pharma- ceutically acceptable salt thereof. The compound or a pharma- ceutically acceptable salt thereof according to any one of claims ₁ , 12 or 13, wherein _R6 , _R7 and _R8 are each independently F, Cl, Br, _I , -OH, -CN, _-NH2 , _-NO2 , _-CH3 , _-CH2CH3 , _{-CF3 , -CH2CF3} or _-CH2CH2OH . The compound of claim 13, having a structure represented by any one of formulas (I-20) to (I-25), or a pharma- ceutically acceptable salt thereof.

(wherein _R2 is as defined in claim 13). The compound of claim 1, or a pharma- _ceutically acceptable salt thereof, wherein each R _a is 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 of claim 18, or a pharma- ceutically acceptable salt thereof, wherein each R _a is independently H, F, Cl, or _-CF3 . The _R2 is

2. The compound of claim 1, wherein: The _R2 is

21. The compound of claim 18 or 20, which is: or a pharma- ceutically acceptable salt thereof. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof:

Use of a compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating diabetic nephropathy or hypertensive nephropathy. A method for treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, comprising providing to the subject an effective amount of a compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof.