WO2022268154A1 - New anti-hepatitis b compound - Google Patents

Abstract

Provided are a class of compounds for the treatment and prevention of hepatitis B virus infection, and an isomer or a pharmaceutically acceptable salt thereof. Further provided are a pharmaceutical composition containing the compound, a preparation method therefor and a method for the treatment and prevention of hepatitis B by means of using the compound. Specifically, provided are a compound as represented by formula (I), and an isomer or a pharmaceutically acceptable salt thereof.

Description

Novel Anti-Hepatitis B Compounds

This application requires submission to the China Patent Office on June 24, 2021, with the application number CN202110703116.1, and the Chinese patent application with the invention name "Novel Anti-Hepatitis B Compound", and submitted to the China Patent Office on September 17, 2021, with the application number CN202111089629 .4. The Chinese patent application with the title of invention "Novel Anti-Hepatitis B Compound", submitted to the China Patent Office on June 9, 2022, with the application number CN202210645720.8 and the priority of the Chinese patent application with the title of invention "New Anti-Hepatitis B Compound", The entire contents of which are incorporated by reference in this application.

technical field

The present invention relates to a class of compounds for treating and preventing hepatitis B virus infection. Specifically, it relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a preparation method and a method for treating and preventing hepatitis B by using the compound.

Background technique

Hepatitis B virus (HBV), belonging to the Hepatoviridae family, can cause acute persistent or progressive chronic disease, as well as many other clinical manifestations of pathomorphology, especially chronic inflammation of the liver, cirrhosis, and hepatocellular carcinoma. Its co-infection with hepatitis D can adversely affect the development of the disease. Hepatitis B virus is a spherical DNA virus with a diameter of about 42nm, forming a double structure, the outside is composed of HBs antigen (HBsAg), and the inside is composed of HBc antigen (HBcAg) and gene DNA (Tanaka et al., Modern Media Vol.54 , No.12, pp.347～352).

HBsAg is the glycosylated envelope protein on the surface of mature HBV, which is encoded and synthesized by the HBV outer membrane gene. These viral antigens (mainly surface antigen subviral particles) secreted into the blood circulation inhibit the immune system of the human body against HBV virus immunity. Plays an important role in "immune tolerance" to HBV and the development of chronic hepatitis B HBsAg quantification is a significant biomarker for prognosis and treatment response in chronic hepatitis B. Although HBsAg loss and achievement of seroconversion are rarely observed in chronically infected patients, they are still the ultimate goal of treatment.

Current therapies such as the use of nucleotide analogs to inhibit the DNA synthesis of HBV cannot reduce the level of HBsAg, so the use of nucleotide analogs to treat hepatitis B is not effective enough. In 2017-2018, a class of compounds that can inhibit HBsAg was reported, but these drugs can only make HBsAg negative in a very small number of patients to achieve the ideal end point, and HBsAg still persists in the body, causing systemic immunosuppression. For example, small molecule drugs reduce HbsAg levels by inducing the degradation of HBV-RNA. Oligonucleotide drugs prevent the release of HBsAg and reduce intracellular HBsAg levels by blocking the assembly of HBV subviral particles.

Therefore, clearing HBsAg and restoring the normal immune function of the human body is an important way to achieve chronic hepatitis B cure and functional cure. In addition, clinically it is also expected that HBsAg inhibitors can be combined with antiviral drugs (such as nucleotides or interferons) to achieve the effect of curing hepatitis B. At present, few domestic companies have developed this target, and only Fujian Guangshengtang has applied for the clinical trials of small molecule HBsAg inhibitors. The present invention aims to develop a novel compound that has inhibitory activity against HBsAg and has a lower risk of neurotoxicity.

Contents of the invention

The object of the present invention is to provide a compound with anti-HBV activity and HBsAg inhibitory activity, its isomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and a preparation method of the compound and its use for treating hepatitis B.

Specifically, the present invention provides a compound represented by formula (I), its isomer or a pharmaceutically acceptable salt thereof

in,

R ₂ is selected from 5-6 membered aryl, 5-6 membered heteroaryl; wherein the 5-6 membered aryl or 5-6 membered heteroaryl is optionally substituted by m R _x groups , wherein said R _{x is} selected from R _xa or R _xb , R _xa is selected from hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _{1 -4} alkoxy, C _1-4 haloalkyl, two (C _1-4 alkyl)-amino, 5-6 membered heteroaryl, C _1-4 alkanoyl, R _xb is selected from 4-7 membered heterocycle Alkyl, 5-6 membered heteroaryl, C _4-6 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 3-5 membered Cycloalkyl, wherein R _xb is optionally substituted by r R _xc groups, R _{xc is} selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, wherein m represents an integer of 0, 1, 2, 3, r represents an integer of 0, 1 or 2;

R ₃ is selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy;

R is selected from C _4-6 cycloalkyl, amino, _4-7 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered aryl and 5-6 membered heterocycloalkyl, 5-6 membered Heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 3-5 membered cycloalkyl, 7-10 membered spiroheterocyclyl, wherein the above-mentioned groups are optionally replaced by 1, 2 or 3 R _y substitutions;

Wherein R _y is selected from hydroxyl C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, two (C _1-4 alkyl)-amino, hydroxyl, 4 -7-membered heterocycloalkyl, 5-6-membered heteroaryl, C _4-6 cycloalkyl, halogen, cyano, wherein the C _1-4 alkyl, C _1-4 alkoxy, 4-7 The membered heterocycloalkyl group and the 5-6 membered heteroaryl group are optionally substituted by C _1-4 alkyl group or C _1-4 alkoxy group.

-C(O)CH ₃。 In some aspects of the present invention, the above-mentioned R _xa is selected from H, F, Cl, Br, CN, -CH ₃ , -CF ₃ , -OCH ₃ , -N(CH ₃ ) ₂ , CH ₃ OCH ₂ CH ₂ CH ₂ O-,

-C(O) _CH3 .

In some aspects of the present invention, the above-mentioned R _xa is selected from -CF ₃ , CN.

In some aspects of the present invention, the above-mentioned R _xc is selected from -OCH ₃ , F, -CH ₃ .

其中R _xc、r如上文所定义。 In some solutions of the present invention, the above-mentioned R _xb is selected from

wherein R _xc , r are as defined above.

其中R _xc、r如上文所定义。 In some solutions of the present invention, the above-mentioned R _xb is selected from

wherein R _xc , r are as defined above.

-CH ₂CH ₂OH、-CH ₂C(CH ₃) ₂OH。 In some aspects of the present invention, the above-mentioned R _y is selected from -CH ₃ , -OCH ₃ , -N(CH ₃ ) ₂ , CH ₃ OCH ₂ CH ₂ -, CH ₃ OCH ₂ -, -OH, -CH ₂ OH ,

_-CH2CH2OH , _{-CH2C ( CH3 )} 2OH.

其中T ₁选自CH或N；R _x、m如上文所定义。 In some schemes of the present invention, above-mentioned R ₂ is selected from

wherein T ₁ is selected from CH or N; R _x , m are as defined above.

其中R _x选自R _xb，且所述R _xb选自吡咯烷基，m如上文所定义。 In some schemes of the present invention, above-mentioned R ₂ is selected from

wherein R _{x is} selected from R _xb and said R _xb is selected from pyrrolidinyl, and m is as defined above.

其中R _xa、R _xb如上文所定义，p选自0、1或2的整数。 In some schemes of the present invention, above-mentioned R ₂ is selected from

wherein R _xa and R _xb are as defined above, and p is an integer selected from 0, 1 or 2.

其中R _xa、p、R _xc、r如上文所定义。 In some schemes of the present invention, above-mentioned R ₂ is selected from

wherein R _xa , p, R _xc , r are as defined above.

In some schemes of the present invention, above-mentioned R ₂ is selected from the following groups:

结构式中“*”代表手性碳原子。

"*" in the structural formula represents a chiral carbon atom.

In some schemes of the present invention, above-mentioned R ₄ is selected from the following groups:

结构式中“*”代表手性碳原子。

"*" in the structural formula represents a chiral carbon atom.

In some schemes of the present invention, above-mentioned R ₄ is selected from the following groups:

In some schemes of the present invention, the compound represented by the above formula (I), its isomer or pharmaceutically acceptable salt thereof, the compound has the structure of formula (II)

wherein, R _x , R ₃ , R ₄ , T ₁ and m are as defined above.

In some schemes of the present invention, the compound represented by the above formula (II), its isomer or a pharmaceutically acceptable salt thereof, the compound has the structure of formula (IIa) and formula (IIb)

wherein R ₃ , R ₄ , R _x , m, R _xa , R _xb , p are as defined above.

In some schemes of the present invention, the compound represented by the above formula (II), its isomer or a pharmaceutically acceptable salt thereof, the compound has the structure of formula (IIc)

wherein R _xa , R ₄ , p, R _xc and r are as defined above.

Some solutions of the present invention are formed by any combination of the above variables.

The present invention also provides the following compounds, their isomers or pharmaceutically acceptable salts thereof,

In some aspects of the present invention, the compounds of the present invention, their isomers or pharmaceutically acceptable salts thereof are used for treating or preventing hepatitis B virus infection.

In some aspects of the present invention, the compounds of the present invention, their isomers or pharmaceutically acceptable salts thereof, are used as DNA production inhibitors of hepatitis B virus.

In some aspects of the present invention, the compounds of the present invention, their isomers or pharmaceutically acceptable salts thereof, are used as HBsAg inhibitors.

The present invention also provides a pharmaceutical composition, which comprises the compound of the present invention, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

The present invention also provides an inhibitor of hepatitis B virus DNA production, which comprises the compound of the present invention, its isomer or a pharmaceutically acceptable salt thereof.

The present invention also provides an HBsAg inhibitor, which comprises the compound of the present invention, its isomer or a pharmaceutically acceptable salt thereof.

In some aspects of the present invention, the compounds of the present invention, their isomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present invention are used in the preparation of medicines for treating or preventing hepatitis B virus infection.

In some aspects of the present invention, the compounds of the present invention, their isomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present invention are used in the preparation of medicaments for inhibiting the production or secretion of HBsAg.

The present invention also provides a method for treating or preventing hepatitis B virus infection, which comprises administering to a patient a therapeutically effective amount of the compound of the present invention, its isomer or a pharmaceutically acceptable salt thereof, or comprising the compound of the present invention, its A pharmaceutical composition of an isomer or a pharmaceutically acceptable salt thereof.

technical effect

The compound of the present invention has good anti-HBV activity, good inhibitory effect on HBsAg, higher liver/plasma distribution ratio and lower brain tissue/cerebrospinal fluid exposure, further reducing the risk of neurotoxicity.

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to the salts of the compounds of the present invention, which are prepared from the compounds with specific substituents found in the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

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

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

Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.

Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.

Unless otherwise stated, "(D)" or "(+)" means dextrorotation, "(L)" or "(-)" means levorotation, and "(DL)" or "(±)" means racemization.

和楔形虚线键

表示一个立体中心的绝对构型，用直形实线键

和直形虚线键

表示立体中心的相对构型，用波浪线

表示楔形实线键

或楔形虚线键

或用波浪线

表示直形实线键

和直形虚线键

Unless otherwise noted, keys with wedge-shaped solid lines

and dotted wedge keys

Indicates the absolute configuration of a stereocenter, with a straight solid-line bond

and straight dashed keys

Indicates the relative configuration of the stereocenter, with a wavy line

Indicates wedge-shaped solid-line bond

or dotted wedge key

or with tilde

Indicates a straight solid line key

and straight dashed keys

Compounds of the invention may exist specific. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization. Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

Unless otherwise stated, the terms "isomer excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer 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. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( ³ H), iodine-125 ( ¹²⁵ I) or C-14 ( ¹⁴ C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

"Pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, especially mammals, including, for example, adjuvants, excipients or excipients according to the mode of administration and the nature of the dosage form. Diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants agents and dispersants. Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the purview of those of ordinary skill in the art. These include, but are not limited to: the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, such additional ingredients being included in formulations for a variety of reasons (e.g., stabilizing the active agent, binders, etc.) are well known to those of ordinary skill in the art .

The term "excipient" generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.

The term "prophylactically or therapeutically effective amount" means that a compound of the present invention or a pharmaceutically acceptable salt thereof means a sufficient amount of the compound to treat the disorder with a reasonable effect/risk ratio applicable to any medical treatment and/or prevention.

"Optionally substituted" or "optionally substituted" means that it can be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically realizable basis, for example, The term "optionally substituted by one or more R _a " means that it may be substituted by one or more R _a or may not be substituted by R _a .

When the number of a linking group is 0, such as -O(CH ₂ ) _n CH ₃ , n=0 means that the linking group is a single bond, ie -OCH ₃ .

表示取代基R ₁₂可以在苯环上的任意一个位置发生取代。 When a bond of a substituent can cross-link two atoms in a ring, the substituent can be bonded to any atom in the ring. For example, the structural unit

Indicates that the substituent R ₁₂ can be substituted at any position on the benzene ring.

或者-----时，表示该原子为键合原子，例如

与

均表示吗啉环上的N原子为键合原子。 When a substituent is listed without specifying the atom through which it is bonded to a compound included in a general chemical formula but not specifically mentioned, such a substituent may be bonded through any atom thereof. For example, pyrazole as a substituent means that any carbon atom on the pyrazole ring is connected to the substituted group;

Or -----, it means that the atom is a bonded atom, for example

and

Both indicate that the N atom on the morpholine ring is a bonding atom.

或者-----时，表示该原子为键合原子，例如

与

均表示吗啉环上的N原子为键合原子。 When a substituent is listed without specifying the atom through which it is bonded to a compound included in a general chemical formula but not specifically mentioned, such a substituent may be bonded through any atom thereof. For example, pyrazole as a substituent means that any carbon atom on the pyrazole ring is connected to the substituted group;

Or -----, it means that the atom is a bonded atom, for example

and

Both indicate that the N atom on the morpholine ring is a bonding atom.

The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

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

When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.

When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.

中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成

也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成

所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the linking group listed does not indicate its linking direction, its linking direction is arbitrary, for example,

The connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form

It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right

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

Unless otherwise specified, "ring" refers to saturated, partially saturated or unsaturated monocyclic rings and polycyclic rings, and "polycyclic rings" includes bicyclic rings, spiro rings, fused rings or bridged rings. Representative "ring" includes substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, said heteroatoms are generally selected from N, O, S, oxidized forms generally include NO, SO, S(O) ₂ , nitrogen atoms can be is substituted, that is, NR (R is H or other substituents defined in the text); the number of atoms on the ring is usually defined as the number of ring members, for example, "3-14 membered heterocycloalkyl" refers to 3-14 A single heterocyclic ring, a biheterocyclic ring, a spiro heterocyclic ring, a heterocyclic ring or a bridged heterocyclic ring arranged around 2 atoms, each ring optionally contains 1 to 3 heteroatoms, that is, N, O, S, NO, SO, S(O) ₂ or NR.

Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group. The polycyclic hydrocarbon group includes a spirocyclic group, a parallel ring group or a bridged ring group. When the bridging atom in the bridged ring group is zero, the A bridged ring group is equivalent to a parallel ring group. Preferably C _3-8 membered monocycloalkyl, more preferably C _4-6 membered monocycloalkyl, examples of these monocycloalkyl include but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl; "spirocyclyl" refers to a polycyclic hydrocarbon group that shares one carbon atom between the single rings. The spirocyclic group is preferably a 5-13-membered spirocyclic group, a 6-12-membered spirocyclic group, or a 7-11-membered spirocyclic group. The 6-12-membered spirocyclic group refers to a spirocyclic skeleton structure consisting of 6-12 atoms Consisting of hydrocarbon groups, examples of spirocyclyl include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[2.6]nonyl, spiro[ 3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, spiro [5.5] undecyl, spiro [5.6] dodecyl, spiro [6.6] tridecyl, spiro [6.7] tetradecyl; Atomic polycyclic hydrocarbon groups. The bridged ring group is preferably a 4-13-membered bridged ring group, a 5-12-membered bridged ring group, a 6-12-membered bridged ring group, a 6-11-membered bridged ring group, and a 7-11-membered bridged ring group. Examples of bridged ring groups include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.1.0]heptyl, bicyclo[4.1.0]heptyl, Cyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, bicyclo[3.2.1]octyl.

Unless otherwise specified, "C _4-6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 4 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, wherein the bicyclic ring system includes spiro ring, fused ring and Bridged ring, the C _4-6 cycloalkyl includes C _4-5 and C _5-6 cycloalkyl and the like; it can be monovalent, divalent or multivalent. Examples of C _4-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Unless otherwise specified, "heterocycloalkyl" refers to a monoheterocycloalkyl group and a polyheterocycloalkyl group containing a certain number of heteroatoms in the ring, and the heteroatoms are generally selected from N, O, S, NO, SO, S (O) ₂ and NR. The polyheterocycloalkyl group includes a spiroheterocyclyl, a heterocyclyl or a bridged heterocyclyl, and when the bridging atom in the bridged heterocyclyl is zero, the bridged heterocyclyl is equivalent to the heterocyclyl. It is preferably a 5-10 membered heterocycloalkyl group, more preferably a 5-8 membered heterocycloalkyl group, and more preferably a 4-7 membered heterocycloalkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, oxiranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 1 , 3-dioxolane, 1,4-dioxane, etc. "Spiroheterocyclic group" refers to a spirocyclic group in which one or more carbon atoms in the spirocyclic skeleton structure are replaced by heteroatoms, and the heteroatoms are selected from N, O, and S. Spiroheterocyclyl is preferably 5-13 membered spiroheterocyclyl, 6-12 membered spiroheterocyclyl, or 7-11 membered spiroheterocyclyl, more preferably 7-10 membered spiroheterocyclyl, more preferably 9 membered spiroheterocyclyl Ring base. Examples of spiroheterocyclyl include, but are not limited to, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2-oxa-7-azaspiro[5.3]nonan-7-yl , 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 2-oxa-8-aza Spiro[4.5]decane-8-yl, 1,4,9-triazaspiro[5.5]undecane-9-yl, 3-oxa-9-azaspiro[5.5]undecane-9 -yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2,7-diazaspiro[5.3]nonan-7-yl, 2,7-dioxaspiro[5.3] Nonyl, 3,9-diazaspiro[5.5]undec-3-yl, 1-oxa-4,9-diazaspiro[5.5]undec-9-yl, 1-oxa -4,8-diazaspiro[5.4]decane-8-yl, 3-azaspiro[5.5]undecane-3-yl, 7-azaspiro[3.5]decane-7-yl, 1-oxa-4,9-diazaspiro[5.5]undecane-4-yl, 6-oxa-2,9-diazaspiro[4.5]decane-9-yl, 9-oxo Hetero-2,6-diazaspiro[4.5]decane-6-yl, 3-azaspiro[5.5]undecane-3-yl, 4-oxa-1,9-diazaspiro[ 5.5] Undecane-9-yl; "bridged heterocyclic group" refers to a bridged ring group in which one or more carbon atoms constituting the bridged ring skeleton are replaced by heteroatoms, and the heteroatoms are selected from N, O, and S. Preferably, the bridging heterocyclic group is selected from the bridging ring skeleton carbon atoms are substituted by 1-3 heteroatoms selected from N, O, S following bridging ring groups: bicyclo[3.1.0]hexyl, bicyclo[3.2. 0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.1.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[4.4. 0]decyl, bicyclo[3.2.1]octyl. Examples of bridged heterocyclyl groups include, but are limited to, 1,4-diazabicyclo[4.4.0]decane-4-yl, 1,4-diazabicyclo[4.3.0]-nonane-4 -yl, 8-oxa-1,4-diazabicyclo[4.4.0]decane-4-yl, 1,4-diazabicyclo[4.4.0]decane-4-yl, 4,7-diazabicyclo[4.3.0]nonan-4-yl, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 3,7-diaza Heterobicyclo[4.3.0]nonan-3-yl, 3,7-diazabicyclo[3.3.0]octane-3-yl, 3,7-diazabicyclo[4.4.0] Decane-3-yl, 3,6-diazabicyclo[4.3.0]nonan-3-yl, 3,6-diazabicyclo[4.4.0]decane-3-yl, 3 ,6,9-Triazabicyclo[4.4.0]decane-3-yl, 3,7-diazabicyclo[4.2.0]octane-3-yl, 3,7-diazabicyclo [3.3.0] Octane-3-yl.

Unless otherwise specified, the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings. In addition, as for the "5-10 membered heterocycloalkyl group", a heteroatom may occupy the attachment position of the heterocycloalkyl group to the rest of the molecule. The 5-10 membered heterocycloalkyl group includes 5-8 membered, 5-6 membered, 5-7 membered, 5-9 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like. Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

Unless otherwise specified, the term "5-8 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 8 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. In addition, with respect to the "5-8 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 5-8-membered heterocycloalkyl group includes 5-6-membered, 5-6-membered, 5-7-membered, 8-membered, 5-membered and 6-membered heterocycloalkyl groups and the like. Examples of 5-8 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

Unless otherwise specified, the term "4-7 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 7 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings. In addition, with respect to the "4-7 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 4-7-membered heterocycloalkyl group includes 4-5-membered, 4-6-membered, 5-6-membered, 5-7-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups. Examples of 4-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl Pyridyl or dioxepanyl, etc.

中，“R ₇与R ₈可以环化成C _4-6环烷基”即代表了该结构可以是

“R ₇与R ₈可以环化成4-6元杂环烷基”的实施例包括但不仅限于

“R ₇与R ₈可以环化成C _5-6芳基”即代表了该结构可以是

“R ₇与R ₈可以环化成5-7元杂芳基”的实施例包括但不仅限于

Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can all be fused with a benzene ring to form a corresponding polycyclic structure. example structure

In, "R ₇ and R ₈ can be cyclized to C _4-6 cycloalkyl" means that the structure can be

Examples of "R ₇ and R ₈ can be cyclized into 4-6 membered heterocycloalkyl" include but are not limited to

"R ₇ and R ₈ can be cyclized into C _5-6 aryl" means that the structure can be

Examples of "R ₇ and R ₈ can be cyclized into 5-7 membered heteroaryl" include but are not limited to

Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group which may be a single ring or multiple rings fused together. Examples of aryl include, but are not limited to, phenyl, naphthyl. It is preferably a 5-10 membered aryl group, more preferably a 5-6 membered aryl group.

Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom (N, O, S, NO, SO, S(O) ₂ or NR) . Preferably 5-10 membered heteroaryl, more preferably 5-6 membered heteroaryl, including 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heteroaryl; preferably comprising carbon atoms and 1 , 2, 3 or 4 ring heteroatoms independently selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, Pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl.

Unless otherwise specified, the term "5-6 membered heteroaryl" means a monocyclic group consisting of 5 to 6 ring atoms having a conjugated π-electron system, 1, 2, 3 or 4 of which are independently Heteroatoms selected from O, S and N, the remainder being carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) _p , where p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidyl (including 2-pyrimidyl and 4-pyrimidyl, etc.).

Unless otherwise specified, the term "alkyl" is used to denote a straight or branched chain saturated hydrocarbon group. Preferably it is a C _1-10 alkyl group, more preferably a C _1-6 alkyl group, more preferably a C _1-4 alkyl group. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, n-hexyl, and the like.

Unless otherwise specified, the term "C _1-10 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 10 carbon atoms. The C _1-10 alkyl group includes C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C ₈ , C ₇ , C ₆ and C ₅ alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C1-10 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.

Unless otherwise specified, the term "C _1-6 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl group includes C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C ₆ and C ₅ alkane group etc.; it may be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine). Examples of C _1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

Unless otherwise specified, the term "C _1-4 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C _1-4 alkyl group includes C _1-3 , C _1-2 , C _2-3 , C ₄ , C ₃ , C ₂ alkyl, etc.; it can be monovalent (such as methyl), divalent ( Such as methylene) or polyvalent (such as methine). Examples of C _1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C _1-6 haloalkyl is preferred, and examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl base, 2,2,2 trichloroethyl etc.

Unless otherwise specified, the term "alkoxy" refers to an alkyl group attached through an oxygen bridge, that is, a group obtained by replacing a hydrogen atom in a hydroxyl group with an alkyl group. Preferred are C _1-10 alkoxy and C _1-16 alkoxy, more preferably C _1-4 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentyloxy Oxygen, n-hexyloxy.

Unless otherwise specified, the term "C _1-10 alkoxy" denotes those alkyl groups containing 1 to 10 carbon atoms attached to the rest of the molecule through an oxygen atom. The C _1-10 alkoxy group includes C _1-9 , C _1-8 , C _1-7 , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. Examples of C _1-10 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy and the like.

Unless otherwise specified, the term "C _1-6 alkoxy" denotes those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom. The C _1-6 alkoxy group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. . Examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy and the like.

Unless otherwise specified, the term "C _1-4 alkoxy" denotes those alkyl groups containing 1 to 4 carbon atoms attached to the rest of the molecule through an oxygen atom. The C _1-4 alkoxy group includes C _1-2 , C _1-3 , C _2-3 , C _2-4 , C ₄ , C ₃ and C ₂ alkoxy groups and the like. Examples of C _1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, the terms "cycloalkyloxy" or "cycloalkoxy" refer to a cycloalkyl group attached through an oxygen bridge, ie, a group obtained by replacing a hydrogen atom in a hydroxyl group with a cycloalkyl group. Cycloalkyloxy is preferably 3-7-membered, 4-7-membered, or 5-7-membered cycloalkoxy. Examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

Unless otherwise specified, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy.

Unless otherwise specified, the term "cycloalkenyl" refers to a stable monocyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds in the ring. Examples of such cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and the like.

Unless otherwise specified, the term "heterocycloalkenyl" refers to a cycloalkenyl group containing 1-3 heteroatoms in the ring, preferably a 4-7 membered heterocycloalkenyl group.

Unless otherwise specified, the term "4-7 membered heterocycloalkenyl" by itself or in combination with other terms respectively means a partially unsaturated cyclic group consisting of 4 to 7 ring atoms containing at least one carbon-carbon double bond , whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be Oxidation (ie NO and S(O) _p , where p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro rings, parallel rings and bridged rings, and any ring in this system is non-aromatic. In addition, as for the "4-7 membered heterocycloalkenyl", a heteroatom may occupy the attachment position of the heterocycloalkenyl to the rest of the molecule. The 4-7 membered heterocycloalkenyl group includes 5-6 membered, 4-5 membered, 4-membered, 5-membered and 6-membered heterocycloalkenyl groups and the like. Examples of 4-7 membered heterocycloalkenyl include, but are not limited to

Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any specific instance of n to 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 , also including any range from n to 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 to n+m Member means that the number of atoms on the ring is from n to n+m. For example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, and a 10-membered ring. Rings, 11-membered rings, and 12-membered rings, also include any range from n to n+m, for example, 3-12-membered rings include 3-6-membered rings, 3-9-membered rings, 5-6-membered rings, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

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

Summary of Experimental Instruments

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS), or ultra-high performance liquid chromatography-mass chromatography (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is to use Bruker Neo400M or Bruker Ascend 400 nuclear magnetic instruments, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), heavy water (D ₂ O), and the internal standard was tetramethylsilane (TMS).

Agilent 1260-6125B single quadrupole mass spectrometer is used for liquid chromatography-mass chromatography LC-MS, the column is Welch Biomate column (C18, 2.7μm, 4.6*50mm), or waters H-Class SQD2, the column is Welch Ultimate column (XB -C18, 1.8μm, 2.1*50mm), the ion source of the mass spectrometer is electrospray ionization.

Waters UPLC H-class SQD mass spectrometer (ion source is electrospray ionization) was used for the determination of ultra-high performance liquid chromatography-mass chromatography UPLC-MS.

The determination of HPLC uses Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

Preparative HPLC uses Waters 2555-2489 (10 μm, ODS 250cm×5cm) or GILSON Trilution LC, and the column is Welch XB-C18 column (5 μm, 21.2*150mm).

Chiral HPLC uses waters acquity UPC2; the column is Daicel chiralpak AD-H (5μm, 4.6*250mm), Daicel chiralpak OD-H (5μm, 4.6*250mm), Daicel chiralpak IG-3 (3μm, 4.6*150mm), Chiral Technologies Europe AD-3 (3μm, 3.0*150mm) and Trefoil TM Technology Trefoil TM AMY1 (2.5μm, 3.0*150mm).

Supercritical fluid chromatography (SFC) uses waters SFC 80Q, and the column is Daicel Chiralcel OD/OJ/OZ (20 x 250mm, 10 μm) or Daicel Chiralpak IC/IG/IH/AD/AS (20 x 250mm, 10 μm).

Thin-layer chromatography silica gel plate uses Yantai Jiangyou Silica Gel Development Co., Ltd. GF254 silica gel plate or Rushan Shangbang New Material Co., Ltd. GF254 silica gel plate. The specification used by TLC is 0.15mm ~ 0.20mm, preparative type 20 x 20cm, column chromatography Generally used in Chenghua Chemical Industry 200-300 mesh silica gel as carrier.

detailed description

The present invention will be described in detail through examples below, but it does not imply any unfavorable limitation to the present invention. The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention. Unless otherwise specified, all reactions in the present invention are carried out under continuous magnetic stirring, under dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the unit of reaction temperature is Celsius. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.

Example 1

(R)-1-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin- 1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Step 1: Dissolve 2-amino-5-nitrophenol (10.0 g, 64.9 mmol) in absolute ethanol (150 ml), then add potassium hydroxide (4.4 g, 77.9 mmol) and carbon disulfide (100 ml) . The reaction system was heated to 50°C and stirred at reflux overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was acidified to pH 4-5 with 2N dilute hydrochloric acid (50 mL). Add water (50 ml) to dilute, extract with ethyl acetate (100 ml x 2 times), combine the organic phases, wash the organic phase with saturated brine (50 ml x 1 time), then dry over anhydrous sodium sulfate, Filtration and concentration under reduced pressure gave 11.8 g of 6-nitrobenzo[d]oxazole-2-thione (1-2, yield 92.7%).

MS(ESI)M/Z:194.9[MH] ^- .

Step 2: 6-Nitrobenzo[d]oxazole-2-thione (4.9 g, 25.0 mmol) was suspended in thionyl chloride (50 mL) at room temperature. Subsequently, a catalytic amount of N,N-dimethylformamide was added to the above solution at room temperature. The reaction solution was stirred at reflux for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was slurried with ethyl acetate (100 mL), filtered, and the solid was rinsed with ethyl acetate (20 mL) and dried to yield 3.1 g of 2-chloro-6-nitrobenzo[d]oxazole (1-3, Yield 62.6%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.45(d, J=2.1Hz, 1H), 8.36(dd, J=8.8, 2.1Hz, 1H), 7.82(d, J=8.8Hz, 1H).

Step 3: Mix 2-chloro-6-nitrobenzo[d]oxazole (500 mg, 2.5 mmol) and (R)-2-(methoxymethyl)pyrrolidine (290 mg, 2.5 mmol ) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (1.0 g, 7.6 mmol) was added. The reaction solution was heated to 125° C. for 40 minutes by microwave. The reaction solution was diluted with water, extracted with ethyl acetate (50 ml × 3 times), combined the organic phases, washed with saturated brine (50 ml × 1 time), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained crude product was directly Used in the next reaction (1-4).

MS(ESI)M/Z:278.0[M+H] ⁺ .

Step 4: After dissolving compound 1-4 with absolute ethanol (10 ml), iron powder (0.7 g, 12.7 mmol), ammonium chloride (1.3 g, 25.3 mmol) and water (10 ml) were added, and the reaction solution Heat to reflux for 2 hours. Filter, rinse the filter residue with hot ethanol (50 ml), concentrate the filtrate under reduced pressure to remove ethanol, extract the aqueous phase with ethyl acetate (50 ml × 3 times), combine the organic phases, and wash the organic phase with saturated brine (50 ml × 2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 330 mg of (R)-2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-amine (1-5 , two-step yield 52.8%).

MS(ESI)M/Z:247.8[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.14(d, J=8.2Hz, 1H), 6.68(s, 1H), 6.53(d, J=8.0Hz, 1H), 4.18(br.s., 1H ),3.73-3.51(m,3H),3.50-3.43(m,1H),3.37(s,3H),2.15-1.84(m,4H).

Step 5: Dissolve 4-(pyrrolidin-1-yl)benzoic acid (4 g, 20.94 mmol) in dry dichloromethane (30 mL), and add 2 drops of N,N-dimethylformaldehyde amides. The reaction solution was cooled to 0°C and stirred for 15 minutes, then oxalyl chloride (5.3 mL, 19.05 mmol) was slowly added dropwise. The reaction solution was raised to room temperature and stirred for 2 hours. Concentrate under reduced pressure and dry to obtain 4.22 g of 4-(pyrrolidin-1-yl)benzoyl chloride (1-7, yield 96%), which is directly used in the next reaction.

Step 6: Cool dry tetrahydrofuran (40 mL) to -70° C. and replace with nitrogen, and add lithium bistrimethylsilylamide (2M, 40 mL, 40 mmol). To this solution was added (E)-methyl 2-(dimethylamino)methylene)-3-oxobutanoate (4.48 g, 24.23 mmol) and 1-7 (4.22 g, 20.19 mmol ) in tetrahydrofuran (40 ml) and keep the internal temperature of the reaction system not exceeding -40°C. After the dropwise addition, the reaction solution was raised to room temperature and stirred for 20 minutes. The reaction solution was cooled to -40°C, and 3N aqueous hydrochloric acid (40 mL) was slowly added dropwise to quench the reaction. After filtration and drying, 2.7 g of ethyl 4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)-4H-pyran-3-carboxylate (1-8) was obtained.

MS(ESI)M/Z:314.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.52(s,1H),7.63(d,J=8.9Hz,2H),6.72(s,1H),6.63(d,J=8.9Hz,2H),4.37 (q,J=7.1Hz,2H),3.43-3.33(m,4H),2.12-2.02(m,4H),1.38(t,J=7.1Hz,3H).

Step 7: Mix ethyl 4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)-4H-pyran-3-carboxylate (400.0 mg, 1.2 mmol) and (R)-2-(2-(Methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-amine (330 mg, 1.3 mmol) dissolved in glacial acetic acid (10 mL) middle. Microwave heated to 120°C and react for 40 minutes. The reaction solution was concentrated under reduced pressure, the residue was diluted with dichloromethane (100 ml), and the organic phase was successively watered (20 ml × 2 times), saturated sodium bicarbonate solution (20 ml × 2 times) and saturated brine (10 ml) Washed, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 280 mg of (R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl) -Ethyl 4-oxo-6-(4-(pyridin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylate (1-9, yield 40.4%).

MS(ESI)M/Z:543.2[M+H] ⁺ .

Step 8: At room temperature, (R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo Ethyl 6-(4-(pyridin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylate (280 mg, 0.5 mmol) was dissolved in tetrahydrofuran (3 mL). Subsequently, an aqueous solution (3 mL) of sodium hydroxide (41 mg, 1.1 mmol) was added to the above solution under an ice-water bath. The reaction was continued to stir overnight at room temperature. Add 2N dilute hydrochloric acid (0.6 ml) to the reaction system to acidify to pH 3-4. Methanol (10 ml) was added to the reaction solution for dilution, and purified by preparative high-performance liquid chromatography to obtain 63.8 mg of product (R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl) Benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyridin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid (compound 1) .

MS(ESI)M/Z:514.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ16.00(s, 1H), 8.65(s, 1H), 7.26(d, J=8.4Hz, 1H), 7.05(d, J=1.9Hz, 1H), 6.95 (d,J=8.8Hz,3H),6.79(s,1H),6.34(d,J=8.8Hz,2H),4.22(s,1H),3.76-3.51(m,4H),3.38(s, 3H),3.27-3.19(m,4H),2.17-2.05(m,3H),2.04-1.94(m,5H).

Example 2

1-(2-(Dimethylamino)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)-1,4- Dihydropyridine-3-carboxylic acid

Using dimethylamine instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:445.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.50(s, 1H), 7.60(s, 1H), 7.25-7.15(m, 2H), 7.04(d, J=8.5Hz, 2H), 6.74( s,1H),6.36(d,J＝8.5Hz,2H),3.20-3.12(m,4H),3.11(s,6H),1.92-1.82(m,4H).

Example 3

(S)-1-(2-(3-methoxypyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1 -yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using (S)-3-methoxypyrrolidine instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:501.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.51(s, 1H), 7.64(d, J=1.8Hz, 1H), 7.25-7.17(m, 2H), 7.04(d, J=8.8Hz, 2H),6.75(s,1H),6.37(d,J＝8.9Hz,2H),4.12-4.05(m,1H),3.71-3.58(m,3H),3.58-3.47(m,1H),3.26 (s,3H),3.21-3.10(m,4H),2.15-2.00(m,2H),1.94-1.84(m,4H).

Example 4

(R)-1-(2-(3-methoxypyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1 -yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using (R)-3-methoxypyrrolidine instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:501.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.51(s, 1H), 7.63(d, J=1.9Hz, 1H), 7.25-7.16(m, 2H), 7.04(d, J=8.8Hz, 2H),6.75(s,1H),6.36(d,J＝8.8Hz,2H),4.12-4.05(m,1H),3.72-3.58(m,3H),3.57-3.48(m,1H),3.26 (s,3H),3.20-3.10(t,J=6.2Hz,4H),2.15-1.99(m,2H),1.95-1.84(m,4H).

Example 5

1-(2-(4-(2-methoxyethyl)piperazin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidine -1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

1-(2-methoxyethyl)piperazine is used as raw material instead of (R)-2-(methoxymethyl)pyrrolidine, and the preparation method refers to Example 1.

MS(ESI)M/Z:544.0[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.68(s, 1H), 7.39(s, 1H), 7.31(d, J=8.0Hz, 1H), 7.23(d, J=8.0Hz, 1H), 7.03(d, J=7.8Hz, 2H), 6.80(s, 1H), 6.38(d, J=8.1Hz, 2H), 3.91(br.s., 4H), 3.70(br.s., 2H) ,3.41(s,3H),3.30-3.13(m,8H),2.04-1.92(m,4H).

Example 6

1-(2-(4-methoxypiperidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)benzene base)-1,4-dihydropyridine-3-carboxylic acid

Using 4-methoxypiperidine instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:515.1[M+H] ⁺ .

¹ HNMR (400MHz, CDCl ₃ ) δ8.67(s, 1H), 7.34(d, J=8.5Hz, 1H), 7.08(d, J=2.0Hz, 1H), 7.02-6.98(m, 1H), 6.95(d, J=8.7Hz, 2H), 6.86(s, 1H), 6.36(d, J=8.7Hz, 2H), 3.92-3.85(m, 2H), 3.70-3.60(m, 2H), 3.58 -3.51(m,1H),3.40(s,3H),3.29-3.20(m,4H),2.03-1.91(m,6H),1.86-1.76(m,2H).

Example 7

1-(2-(3-Methoxyazetidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1- yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 3-methoxyazetidine instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:487.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.32(d, J=8.4Hz, 1H), 7.06(d, J=1.9Hz, 1H), 7.02-6.97(m, 1H) ,6.93(d,J=8.8Hz,2H),6.81(s,1H),6.34(d,J=8.8Hz,2H),4.52-4.44(m,2H),4.44-4.38(m,1H), 4.21(dd,J=9.5,3.7Hz,2H),3.36(s,3H),3.28-3.18(m,4H),2.04-1.95(m,4H).

Example 8

(S)-1-(2-(3-(Dimethylamino)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidine -1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using (S)-N,N-dimethylpyrrolidin-3-amine instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:514.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.33(d, J=8.3Hz, 1H), 7.11(d, J=2.0Hz, 1H), 7.04-6.99(m, 1H) ,6.94(d,J=8.8Hz,2H),6.84(s,1H),6.35(d,J=8.9Hz,2H),4.16-4.01(m,3H),3.87-3.81(m,1H), 3.75(d,J=10.6Hz,1H),3.27-3.20(m,4H),2.92(s,6H),2.67-2.62(m,1H),2.57-2.53(m,1H),2.02-1.95( m,4H).

Example 9

(R)-1-(2-(3-(Dimethylamino)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidine -1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using (R)-N,N-dimethylpyrrolidin-3-amine instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:514.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.64(s, 1H), 7.31(d, J=8.3Hz, 1H), 7.09(s, 1H), 7.00(d, J=8.4Hz, 1H), 6.93 (d, J=8.6Hz, 2H), 6.82(s, 1H), 6.35(d, J=8.6Hz, 2H), 4.18-3.96(m, 3H), 3.90-3.79(m, 1H), 3.79- 3.69(m,1H),3.29-3.16(m,4H),2.91(s,6H),2.69-2.59(m,1H),2.56-2.49(m,1H),2.04-1.92(m,4H).

Example 10

(R)-6-(3-chloro-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[ d] oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 3-chloro-4-(pyrrolidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:550.6[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.73(s, 1H), 7.56(d, J=7.4Hz, 1H), 7.39(s, 1H), 7.25(s, 1H), 7.14(d, J= 7.4Hz,1H),7.00(s,1H),6.88(s,2H),4.48(br.s.,1H),3.94-3.76(m,2H),3.70-3.47(m,6H),3.36( s,3H),2.32-2.10(m,4H),2.04(br.s.,4H).

Example 11

(R)-6-(3-fluoro-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[ d] oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 3-fluoro-4-(pyrrolidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:532.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.68(s, 1H), 7.52(d, J=8.4Hz, 1H), 7.29(s, 1H), 7.05(d, J=8.2Hz, 1H), 6.91 (s,1H),6.74(d,J=12.1Hz,2H),6.50(t,J=8.6Hz,1H),4.43(br.s.,1H),3.90-3.81(m,1H),3.81 -3.71(m,1H),3.70-3.59(m,1H),3.56-3.48(m,1H),3.49-3.39(m,4H),3.36(s,3H),2.30-2.06(m,4H) ,2.00-1.89(m,4H).

Example 12

(R)-6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo [d]Oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Step 1: Methyl 3-cyano-4-fluorobenzoate (25 g, 140 mmol) and cesium carbonate (77.4 g, 237 mmol) were added to DMF (200 mL), followed by pyrrolidine (15 mL ), reacted at 95°C for 4 hours. After the reaction solution was cooled to room temperature, water (300 ml) was added, and a large amount of white solids were precipitated. After filtration and drying, 30 g of methyl 3-cyano-4-(pyrrolidin-1-yl)benzoate (12-2) was obtained.

MS(ESI)M/Z:230.9[M+H] ⁺ .

Step 2: Methyl 3-cyano-4-(pyrrolidin-1-yl)benzoate (30 g, 130.4 mmol) was dissolved in THF (100 mL) and water (50 mL), and sodium hydroxide was added (10.4 g, 260.9 mmol), stirred overnight at 50°C. Concentrate in vacuo to remove tetrahydrofuran, adjust the pH to 3 with 2M dilute hydrochloric acid in the aqueous phase, produce a large amount of white solid, vacuum filter and wash with water, and dry to obtain 27 grams of 3-cyano-4-(pyrrolidin-1-yl)benzoic acid ( 12-3).

MS(ESI)M/Z:216.8[M+H] ⁺ .

Step 3: Under ice bath, 3-cyano-4-(pyrrolidin-1-yl)benzoic acid (14 g, 64.8 mmol) was dissolved in dry dichloromethane (210 ml), and N , N-dimethylformamide (0.5 ml) was stirred for 15 minutes, then oxalyl chloride (16.5 ml) was added dropwise, and the temperature was controlled not to exceed 0°C. After the addition was complete, it was raised to room temperature and stirred for 2 hours. The reaction solution was concentrated and dried in vacuo to obtain 15 g of 3-cyano-4-(pyrrolidin-1-yl)benzoyl chloride (12-4), which was directly used in the next step.

Step 4: Under the protection of nitrogen, dissolve LiHMDS (1M, 128ml, 128mmol) in dry tetrahydrofuran (128ml), cool down to -60℃～-70℃ in a dry ice acetone bath, and slowly add 2-acetyl- 3-(Dimethylamino) ethyl acrylate (14.2 g, 76.8 mmol) and 3-cyano-4-(pyrrolidin-1-yl) benzoyl chloride (15 g, 64 mmol) in tetrahydrofuran (128 milliliter) solution, the temperature was controlled not to exceed -40°C, after the dropwise addition was completed, the dry ice bath was removed, and the solution was raised to room temperature and stirred for 20 minutes. 3M dilute hydrochloric acid (128 ml) was slowly added dropwise to the reaction solution and the temperature was controlled at about 10°C, and stirred for 10 minutes, a large amount of yellow solid precipitated, vacuum filtered and washed with water, dried to obtain 8.5 g of 6-(3-cyano- 4-(Pyrrolidin-1-yl)phenyl)-4-oxo-4H-pyran-3-carboxylic acid ethyl ester (12-5).

MS(ESI)M/Z:339.2[M+H] ⁺ .

Step 5: Ethyl 6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-4-oxo-4H-pyran-3-carboxylate (8.1 g, 23.96 mmol) and (R)-2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6amine (5.4 g, 21.86 mmol) was added to acetic acid solution (30 mL) , stirred at 5°C for 5 minutes, and the reaction system was heated to 95°C for 3 hours. Cool to room temperature, concentrate to remove most of the solvent, add saturated sodium carbonate solution (50 ml) to neutralize the reaction, dichloromethane (100 ml × 3 times) extract, combine the organic phase, the organic phase is first washed with saturated brine (100 ml × 3 times) washed, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5.9 g of (R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazole- 6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)-3-(cyano)phenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester (12 -6).

MS(ESI)M/Z:568.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.33(s, 1H), 7.28-7.22(m, 2H), 7.08(s, 1H), 6.99(d, J=7.9Hz, 1H), 6.91(d, J＝7.8Hz, 1H), 6.58(s, 1H), 6.41(d, J＝8.8Hz, 1H), 4.38(q, J＝7.2Hz, 2H), 4.24(br.s., 1H), 3.72 -3.62(m,2H),3.62-3.52(m,6H),3.38(s,3H),2.16-2.06(m,4H),2.04-1.93(m,4H),1.37(t,J＝7.2Hz ,3H).

Step 6: At room temperature, (R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo -Ethyl 6-(4-(pyrrolidin-1-yl)-3-(cyano)phenyl)-1,4-dihydropyridine-3-carboxylate (5.9 g, 10.39 mmol) dissolved in THF / aqueous solution (3:1, 60 ml), add lithium hydroxide monohydrate (872.53 mg, 20.77 mmol), and stir overnight at room temperature. Add an appropriate amount of water, concentrate to remove THF, filter, add citric acid aqueous solution (15 ml) to the filtrate to neutralize the reaction, and a yellow solid is precipitated as the product. Filter and dry to obtain 2.5 grams of (R)-6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidine -1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (compound 12)

MS(ESI)M/Z:540.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.59(s, 1H), 8.65(s, 1H), 7.32(d, J=8.3Hz, 1H), 7.25(s, 1H), 7.11(s, 1H) ,6.99-6.90(m,2H),6.76(s,1H),6.44(d,J＝9.0Hz,1H),4.29(s,1H),3.80-3.67(m,2H),3.64-3.55(m ,6H),3.39(s,3H),2.18-2.09(s,3H),2.05-1.98(m,5H).

Example 13

(R)-6-(3-methoxy-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzene [d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 3-methoxy-4-(pyrrolidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:544.9[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.71(s,1H),7.35(s,1H),7.30-7.17(m,2H),6.89-6.75(m,2H),6.64(s,1H) ,6.55(d,J=7.7Hz,1H),4.20(br.s.,1H),3.71-3.45(m,9H),3.33(s,3H),2.14-2.04(m,3H),2.03- 1.96(m,1H),1.92-1.81(m,4H).

Example 14

1-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(4-((R)-3 -Methoxypyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using (R)-4-(3-methoxypyrrolidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:545.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.51(s, 1H), 7.64(d, J=1.6Hz, 1H), 7.28-7.16(m, 2H), 7.05(d, J=8.7Hz, 2H), 6.75(s, 1H), 6.38(d, J=8.8Hz, 2H), 4.13(br.s., 1H), 4.03(s, 1H), 3.64-3.49(m, 3H), 3.49- 3.40(m,1H),3.35-3.30(m,2H),3.27(s,3H),3.24-3.16(m,5H),2.09-1.87(m,6H).

Example 15

1-(2-((S)-2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(4-((R)-3 -Methoxypyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using (S)-4-(3-methoxypyrrolidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:545.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.68(s, 1H), 7.50(d, J=8.5Hz, 1H), 7.15-7.05(m, 2H), 6.94(d, J=8.7Hz, 2H) ,6.90(s,1H),6.37(d,J=8.7Hz,2H),4.38(br.s.,1H),4.08(br.s.,1H),3.87-3.67(m,3H),3.64 -3.48(m,3H),3.46-3.28(m,8H),2.26-2.00(m,6H).

Example 16

1-(2-Morpholine benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)-1,4-dihydropyridine- 3-Carboxylic acid

Using morpholine instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, refer to Example 1 for the preparation method.

MS(ESI)M/Z:487.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.28(d, J=8.4Hz, 1H), 7.06(d, J=2.0Hz, 1H), 6.99(dd, J=8.3, 2.1Hz, 1H), 6.95(d, J=8.8Hz, 2H), 6.80(s, 1H), 6.34(d, J=8.9Hz, 2H), 3.87-3.79(m, 4H), 3.74-3.64( m,4H),3.28-3.17(m,4H),2.03-1.95(m,4H).

Example 17

6-(3-Chloro-4-(pyrrolidin-1-yl)phenyl)-1-(2-(4-(2-methoxyethyl)piperazin-1-yl)benzo[d] Oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Substitute 3-chloro-4-(pyrrolidin-1-yl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, 1-(2-methoxyethyl)piperazine for (R)-2 -(Methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:579.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.35(d, J=8.3Hz, 1H), 7.15-7.00(m, 3H), 6.84(s, 1H), 6.81-6.72( m,1H),6.56(d,J＝8.7Hz,1H),4.69-3.66(m,8H),3.52-3.08(m,11H),2.02-1.84(m,4H).

Example 18

(S)-1-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl )phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using (S)-pyrrolidin-3-ol instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:487.1[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.70(s,1H),7.34(s,1H),7.27-7.20(m,1H),7.18(br.s.,1H),7.02(br.s .,2H),6.80(br.s.,1H),6.39(d,J=6.7Hz,2H),4.53(br.s.,1H),3.79-3.67(m,3H),3.59(d, J＝10.5Hz,1H),3.21(br.s.,4H),2.21-2.12(m,1H),2.08-2.03(m,1H),2.01-1.90(m,4H).

Example 19

(S)-4-Oxo-6-(4-(pyrrolidin-1-yl)phenyl)-1-(2-((tetrahydrofuran-3-yl)amino)benzo[d]oxazole-6 -yl)-1,4-dihydropyridine-3-carboxylic acid

Using (S)-tetrahydrofuran-3-amine instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:487.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.70(s, 1H), 7.32(s, 1H), 7.24(d, J=8.3Hz, 1H), 7.19-7.12(m, 1H), 7.03(d ,J=8.7Hz,2H),6.81(s,1H),6.40(d,J=8.7Hz,2H),4.38(br.s.,1H),4.00-3.91(m,2H),3.89-3.75 (m,2H),3.25-3.16(m,4H),2.37-2.26(m,1H),2.10-1.92(m,5H).

Example 20

(R)-4-Oxo-6-(4-(pyrrolidin-1-yl)phenyl)-1-(2-((tetrahydrofuran-3-yl)amino)benzo[d]oxazole-6 -yl)-1,4-dihydropyridine-3-carboxylic acid

Using (R)-tetrahydrofuran-3-amine instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:487.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.70(s, 1H), 7.46-6.91(m, 5H), 6.87-6.53(m, 2H), 6.40(d, J=7.5Hz, 1H), 4.37 (s,1H),4.02-3.89(m,2H),3.89-3.72(m,2H),3.26-2.96(m,4H),2.38-2.24(m,1H),2.16-1.63(m,5H) .

Example 21

(R)-6-(3-methoxy-4-(3-methoxypropoxy)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl )Benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 3-methoxy-4-(3-methoxypropoxy)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:564.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.71(s, 1H), 7.57(d, J=8.2Hz, 1H), 7.19(d, J=7.8Hz, 1H), 7.07(s, 1H), 6.95 (s,1H),6.77(d,J=8.2Hz,1H),6.70(d,J=7.6Hz,1H),6.58(s,1H),4.42(s,1H),4.06(t,J= 6.4Hz, 2H), 3.88-3.72(m, 2H), 3.71-3.59(m, 4H), 3.58-3.49(m, 3H), 3.36(s, 3H), 3.34(s, 3H), 2.27-2.03 (m,6H).

Example 22

(R)-6-(3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrole Alk-1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:556.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.71(s, 1H), 7.97(s, 1H), 7.90(s, 1H), 7.52(d, J=8.3Hz, 1H), 7.38(d, J= 7.9Hz, 1H), 7.23-7.14(m, 2H), 7.00(s, 1H), 6.78(s, 1H), 6.74(d, J=7.9Hz, 1H), 4.36(s, 1H), 4.00( s,3H),3.85-3.77(m,4H),3.76-3.66(m,1H),3.64-3.54(m,1H),3.54-3.45(m,1H),3.33(s,3H),2.26- 2.02(m,4H).

Example 23

1-(2-(isoindoline-2-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)- 1,4-Dihydropyridine-3-carboxylic acid

Using isoindole instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:519.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.79(s, 1H), 7.59(d, J=8.4Hz, 1H), 7.41(s, 4H), 7.36(s, 1H), 7.11(d, J= 8.3Hz, 1H), 7.08(s, 1H), 7.04(d, J=8.5Hz, 2H), 6.63(d, J=8.5Hz, 2H), 5.14(s, 4H), 340-3.26(m, 4H),2.10-1.99(m,4H).

Example 24

4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)-1-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl )Benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid

Using hexahydrofuro[3,4-c]pyrrole instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:513.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.29(s, 1H), 7.05(d, J=2.1Hz, 1H), 6.99-6.94(m, 2H), 6.94-6.91( m,1H),6.79(s,1H),6.34(d,J=8.8Hz,2H),4.01-3.93(m,2H),3.93-3.86(m,2H),3.74(dd,J=9.2, 3.1Hz, 2H), 3.62(dd, J=11.1, 3.2Hz, 2H), 3.28-3.19(m, 4H), 3.18-3.08(m, 2H), 2.01-1.95(m, 4H).

Example 25

(R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(3-methyl-4-( Pyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 3-methyl-4-(pyrrolidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:529.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.70(s, 1H), 7.51(d, J=8.1Hz, 1H), 7.20(s, 2H), 7.16(d, J=8.6Hz, 1H), 7.10 -6.99(m,2H),6.90(s,1H),4.39(s,1H),3.86-3.66(m,6H),3.64-3.56(s,1H),3.55-3.48(m,1H),3.35 (s,3H),2.47(s,3H),2.31-2.05(m,8H).

Example 26

(R)-6-(4-cyclopentylphenyl)-1-(2-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazole-6 -yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-cyclopentylbenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:514.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.69(s, 1H), 7.39(d, J=8.3Hz, 1H), 7.13(t, J=7.6Hz, 3H), 7.04(d, J=7.8Hz ,2H),6.98(d,J=7.9Hz,1H),6.88(s,1H),4.31(s,1H),3.82-3.73(m,1H),3.73-3.63(m,1H),3.62- 3.49(m,2H),3.36(s,3H),2.99-2.87(m,1H),2.23-1.96(m,6H),1.81-1.59(m,4H),1.56-1.43(m,2H).

Example 27

1-(2-cyclopentylbenzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)-1,4-dihydropyridine- 3-Carboxylic acid

Step 1: At room temperature, add 2-amino-5-nitrophenol (500 mg, 3.25 mmol) into dichloromethane (15 ml) to dissolve, then add cyclopentanoyl chloride (430 mg, 3.25 mmol) and stir, After 10 minutes, triethylamine (1312 mg, 12.99 mmol) was added, and the reaction system was stirred overnight at room temperature. Add dichloromethane (50 ml) to the reaction solution for dilution, quench the reaction with 2N dilute hydrochloric acid (20 ml), adjust the pH to 1, extract the aqueous phase twice with dichloromethane, combine the organic phases, and wash the organic phases with saturated salt It was washed with water (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 650 mg of N-(2-hydroxy-4-nitrophenyl)cyclopentanecarboxamide (27-1).

MS(ESI)M/Z:251.0[M+H] ⁺ .

Step 2: Dissolve N-(2-hydroxy-4-nitrophenyl)cyclopentanecarboxamide (650 mg, 2.6 mmol), p-toluenesulfonic acid (753 mg, 3.17 mmol) in toluene (15 mL ), the reaction system was heated to reflux for 3 hours, cooled to room temperature, concentrated under reduced pressure to remove toluene, added water (20 ml), extracted with ethyl acetate (20 ml × 3 times), combined the organic phase, and the organic phase was first washed with saturated Wash with brine (20 ml×3 times), then dry with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure to obtain 500 mg of 2-cyclopentyl-6-nitrobenzo[d]oxazole (27-2) .

MS(ESI)M/Z:233.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.40(s, 1H), 8.28(dd, J=8.4, 2.0Hz, 1H), 7.75(d, J=8.8, 1H), 3.38-3.53(m, 1H ),2.24-2.18(m,2H),2.09-2.03(m,2H),1.92-1.84(m,2H),1.81-1.74(m,2H).

Step 3: Dissolve 2-cyclopentyl-6-nitrobenzo [d] oxazole (500 mg, 2.15 mmol) into the mixed system of ethanol (10 ml) and water (10 ml), add reduced iron powder (603.4 mg, 10.78 mmol) and ammonium chloride (1.15 g, 21.55 moles), react overnight at room temperature. After concentration under reduced pressure, water (20 ml) was added, extracted with dichloromethane (20 ml×3 times), the organic phases were combined, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 400 mg of 2-cyclopentylbenzo[d ] Oxazol-6-amine (27-3).

MS(ESI)M/Z:202.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.41 (d, J=8.4Hz, 1H), 6.78 (d, J=2.0Hz, 1H), 6.64 (dd, J=8.4, 2.0Hz, 1H), 3.37 -3.25(m,1H),2.15-2.09(m,2H),2.02-1.97(m,2H),1.85-1.81(m,2H),1.73-1.68(m,2H).

Step 4: Ethyl 6-(4-(pyrrolidin-1-yl)phenyl)-4-oxo-4H-pyran-3-carboxylate (400 mg, 1.28 mmol) and 2- Cyclopentylbenzo[d]oxazol-6-amine (283 mg, 1.41 mmol) was added to acetic acid solution (3 mL), the reaction was stirred at 5°C for 5 minutes, and heated to 95°C for 2 hours. Cool to room temperature, concentrate to remove most of the solvent, add saturated sodium bicarbonate solution (20 ml) to neutralize the reaction, dichloromethane (20 ml × 3 times) extract, combine the organic phase, the organic phase is first washed with saturated brine (20 ml ×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 103 mg of 1-(2-cyclopentylbenzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidinyl-1- yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester (27-4).

MS(ESI)M/Z:498.2[M+H] ⁺ .

Step 5: At room temperature, add 1-(2-cyclopentylbenzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidinyl-1-yl)phenyl) -Ethyl 1,4-dihydropyridine-3-carboxylate (103 mg, 0.21 mmol) was dissolved in tetrahydrofuran/water (3/1, 4 ml), and lithium hydroxide monohydrate (17.4 mg, 0.42 mol), the reaction was stirred overnight at room temperature. Add citric acid to the reaction system to neutralize the reaction, then add water (4 ml) and stir. The reaction solution was extracted with dichloromethane (3 mL×2 times), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solid residue was slurried with n-hexane, filtered, and dried to obtain 26 mg of 1-(2-cyclopentylbenzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1 -yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid (compound 27).

MS(ESI)M/Z:470.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.61(d, J=8.5Hz, 1H), 7.34(d, J=1.9Hz, 1H), 7.08(dd, J=8.4, 2.0Hz, 1H), 6.94(d, J=8.8Hz, 2H), 6.81(s, 1H), 6.34(d, J=8.8Hz, 2H), 3.43-3.33(m, 1H), 3.29-3.16( m,4H),2.24-2.13(m,2H),2.08-1.93(m,6H),1.89-1.81(m,2H),1.80-1.70(m,2H).

Example 28

6-(3-Bromo-4-(pyrrolidin-1-yl)phenyl)-1-(2-(4-(2-methoxyethyl)piperazin-1-yl)benzo[d] Oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Substitute 3-bromo-4-(pyrrolidin-1-yl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, 1-(2-methoxyethyl)piperazine for (R)-2 -(Methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:623.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.65(s,1H),7.39-7.30(m,2H),7.12-7.03(m,2H),6.85-6.78(m,2H),6.56(d,J ＝8.7Hz,1H),4.23-3.95(m,4H),3.81(s,2H),3.57-3.39(m,6H),3.37(s,3H),3.32(s,4H),1.98-1.86( m,4H).

Example 29

4-oxo-1-(2-phenylbenzo[d]oxazol-6-yl)-6-(4-(pyrrolidin-1-yl)phenyl)-1,4-dihydropyridine- 3-Carboxylic acid

Using benzoyl chloride instead of cyclopentanoyl chloride as the raw material, refer to Example 27 for the preparation method.

MS(ESI)M/Z:478.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.86(s,1H),8.70(s,1H),8.24(d,J=6.9Hz,2H),7.74(d,J=8.4Hz,1H),7.63 -7.51(m,3H),7.42(d,J=1.8Hz,1H),7.18(dd,J=8.4,1.9Hz,1H),6.95(d,J=8.7Hz,2H),6.83(s, 1H), 6.33(d, J=8.8Hz, 2H), 3.21(t, J=6.3Hz, 4H), 1.96(t, J=6.4Hz, 4H).

Example 30

(R)-6-(4-(Dimethylamino)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazole-6- base)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-(dimethylamino)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:489.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.73(s, 1H), 7.42(d, J=1.7Hz, 1H), 7.26(d, J=8.4Hz, 1H), 7.20(dd, J=8.3 ,1.8Hz,1H),7.09(d,J=8.9Hz,2H),6.84(s,1H),6.61(d,J=9.0Hz,2H),4.24(br.s.,1H),3.70- 3.61(m,2H),3.56(d,J=5.1Hz,2H),3.35(s,3H),2.92(s,6H),2.17-2.06(m,3H),2.04-1.98(m,1H) .

Example 31

(R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:583.1[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.74(s, 1H), 7.49-7.43(m, 2H), 7.30-7.19(m, 3H), 6.88-6.81(m, 2H), 4.24(br. s.,1H),3.73-3.60(m,2H),3.56(d,J＝4.9Hz,2H),3.38-3.32(m,7H),2.20-2.05(m,3H),2.04-1.98(m ,1H),1.97-1.85(m,4H).

Example 32

6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(3-methoxyazetidin-1-yl)benzo[d]oxazole -6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

With 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, 3-methoxyazetidine instead of (R)-2-( Methoxymethyl) pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:512.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.59(s, 1H), 8.64(s, 1H), 7.32-7.27(m, 2H), 7.07(d, J=1.7Hz, 1H), 6.93(dd, J=6.8,4.5Hz,2H),6.74(s,1H),6.41(d,J=9.1Hz,1H),4.51-4.44(m,2H),4.44-4.36(m,1H),4.25-4.15 (m,2H),3.64-3.52(m,4H),3.36(s,3H),2.04-1.95(m,4H).

Example 33

6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(4-(2-methoxyethyl)piperazin-1-yl)benzo[d ]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, 1-(2-methoxyethyl)piperazine instead of (R)- 2-(methoxymethyl)pyrrolidine is used as raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:569.0[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ11.97(s,1H),8.55(s,1H),7.61(d,J=1.9Hz,1H),7.48(d,J=2.3Hz,1H) ,7.27(dd,J=8.3,2.0Hz,1H),7.19-7.10(m,2H),6.87(s,1H),6.60(d,J=9.2Hz,1H),3.67(br.s., 8H),3.53-3.45(m,4H),2.60-2.51(m,7H),1.93-1.84(m,4H).

Example 34

(R)-1-(2-(2-(Methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6'-(pyrrolidine -1-yl)-1,4-dihydro-[2,3'-bipyridine]-5-carboxylic acid

Using 6-(pyrrolidin-1-yl)nicotinic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:516.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.72(s, 1H), 8.66(s, 1H), 8.03(s, 1H), 7.28(d, J=8.5Hz, 1H), 7.11-7.02(m, 2H), 6.95(d, J=7.9Hz, 1H), 6.78(s, 1H), 6.16(d, J=8.8Hz, 1H), 4.27-4.19(m, 1H), 3.75-3.62(m, 3H ),3.59(br.s.,2H),3.47-3.35(m,6H),2.17-2.06(m,3H),2.05-1.94(m,5H).

Example 35

(R)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( piperidin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 4-(piperidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:529.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.53(s,1H),7.64(s,1H),7.26-7.17(m,2H),7.08(d,J=8.8Hz,2H),6.84- 6.77(m,3H),4.13(s,1H),3.62-3.49(m,3H),3.48-3.41(m,1H),3.27(s,3H),3.22-3.11(m,4H),2.08- 1.97(m,2H),1.97-1.87(m,2H),1.52(s,6H).

Example 36

(R)-6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[ d] oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Step 1: Methyl 3-bromo-4-fluorobenzoate (5.0 g, 21.5 mmol), pyrrolidine (3.1 g, 101 mmol) and triethylamine (9.0 mL, 64.5 mmol) were dissolved in acetonitrile ( 100 ml), and the reaction solution was stirred overnight at room temperature. The reaction solution was quenched with water, diluted with ethyl acetate (400 ml), and the organic phase was washed successively with water (100 ml), 5% citric acid aqueous solution (100 ml×3 times), saturated brine (100 ml), and anhydrous It was dried over sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 6.0 g of methyl 3-bromo-4-(pyrrolidin-1-yl)benzoate (36-2).

MS(ESI)M/Z:285.4[M+H] ⁺ .

Step 2: Dissolve methyl 3-bromo-4-(pyrrolidin-1-yl)benzoate (6.0 g, 21.2 mmol) in THF (50 mL), add sodium hydroxide solution (1.7 g, 42.4 mmol , in 50 ml of water), the reaction solution was stirred overnight at room temperature. Add 2N dilute hydrochloric acid (25 ml) to adjust the pH to 3-4, extract the aqueous phase with ethyl acetate (100 ml x 3 times), combine the organic phases, and wash the organic phase with saturated brine (50 ml x 3 times). It was then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was slurried with petroleum ether/ethyl acetate, filtered, and dried to obtain 2.9 g of 3-bromo-4-(pyrrolidin-1-yl)benzoic acid (36-3).

MS(ESI)M/Z:225.8[M+H] ⁺ .

Step 3: After 3-bromo-4-(pyrrolidin-1-yl)benzoic acid (1.0 g, 3.7 mmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (1.3 g, 11.2 mmol) was added . After the reaction solution was reacted at 35°C for 1 hour, it was concentrated under reduced pressure to obtain crude 3-bromo-4-(pyrrolidin-1-yl)benzoyl chloride, which was directly used in the next reaction (36-4).

Step 4: After the crude 3-bromo-4-(pyrrolidin-1-yl)benzoyl chloride was dissolved in anhydrous tetrahydrofuran (20 mL), ethyl 2-acetyl-3-(dimethylamino)acrylate was added ( 0.8 g, 4.1 mmol), the resulting solution was added dropwise to lithium hexamethyldisilazide (1M, 9.3 ml, 9.3 mmol) pre-cooled to -78°C, and the reaction solution was reacted at -78°C for 1- 2 hours. Carefully quench the reaction with 2N dilute hydrochloric acid, then adjust the pH to 8-9 with sodium bicarbonate, extract with ethyl acetate (100 ml × 3 times), combine the organic phases, and first wash the organic phase with saturated brine (50 ml × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 480 mg of ethyl 6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-4-oxo-4H-pyran-3-carboxylate ( 36-5).

MS(ESI)M/Z:393.9[M+H] ⁺ .

Step 5: At room temperature, ethyl 6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-4-oxo-4H-pyran-3-carboxylate (300mg, 0.8mM mol) and (R)-2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-amine (208 mg, 0.9 mmol) dissolved in glacial acetic acid ( 10 ml). Microwave heating to 120°C for 40 minutes. After the reaction solution was concentrated under reduced pressure, the concentrated solution was diluted with dichloromethane (100 ml), and the organic phase was sequentially diluted with water (20 ml × 3 times), saturated sodium bicarbonate solution (20 ml × 3 times) and saturated brine (10 ml × 3 times). mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 170 mg of (R)-6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl) yl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (36-6).

MS(ESI)M/Z:621.5[M+H] ⁺ .

Step 6: At room temperature, (R)-6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidine- 1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (170 mg, 0.3 mmol) was dissolved in THF (2 mL )middle. To the above solution was added an aqueous solution (2 mL) of sodium hydroxide (22 mg, 0.6 mmol) under an ice-water bath. The reaction was continued to stir overnight at room temperature. 2N dilute hydrochloric acid (0.4 mL) was added to the reaction system to acidify the pH to 3-4. Ethyl acetate (50 ml) was added to the reaction solution for extraction, and the organic phase was washed with saturated brine (10 ml x 2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 37 mg of (R)-6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxy (methyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (compound 36).

MS(ESI)M/Z:594.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.68(s, 1H), 7.52(d, J=8.4Hz, 1H), 7.36(d, J=2.1Hz, 1H), 7.24-7.20(m, 1H) ,7.07(d,J=8.1Hz,1H),6.90(s,1H),6.82(dd,J=8.6,2.2Hz,1H),6.63(d,J=8.7Hz,1H),4.40(br. s.,1H),3.87-3.79(m,1H),3.79-3.69(m,1H),3.65-3.58(m,1H),3.57-3.42(m,5H),3.36(s,3H),2.28 -2.05(m,4H),2.00-1.89(m,4H).

Example 37

1-(2-(4-Methylpiperazin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)phenyl )-1,4-dihydropyridine-3-carboxylic acid

Using 1-methylpiperazine instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, refer to Example 1 for the preparation method.

MS(ESI)M/Z:500.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.50(s, 1H), 7.65(s, 1H), 7.32-7.21(m, 2H), 7.04(d, J=8.3Hz, 2H), 6.75( s,1H),6.37(d,J=8.4Hz,2H),3.69(br.s.,4H),3.16(br.s.,4H),2.68(br.s.,4H),2.42(s ,3H),1.89(br.s.,4H).

Example 38

4-oxo-1-(2-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(4-(pyrrolidin-1-yl)phenyl)-1, 4-Dihydropyridine-3-carboxylic acid

Using pyrrolidine instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, refer to Example 1 for the preparation method.

MS(ESI)M/Z:471.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.73(s,1H),7.52(s,1H),7.37(s,1H),7.12(s,1H),7.06-6.91(m,3H),6.48( d,J=7.7Hz,2H),3.83(br.s.,4H),3.30(br.s.,4H),2.17(br.s.,4H),2.03(br.s.,4H).

Example 39

6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-4-oxo-1-(2-(pyrrolidin-1-yl)benzo[d]oxazole-6- base)-1,4-dihydropyridine-3-carboxylic acid

Substitute 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid for 4-(pyrrolidin-1-yl)benzoic acid and pyrrolidine for (R)-2-(methoxymethyl)pyrrolidine As raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:496.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.61(s, 1H), 8.65(s, 1H), 7.29-7.23(m, 2H), 7.07(d, J=1.7Hz, 1H), 6.97(dd, J=9.1,2.1Hz,1H),6.89(dd,J=8.3,1.8Hz,1H),6.75(s,1H),6.41(d,J=9.1Hz,1H),3.73-3.63(m,4H ),3.61-3.51(m,4H),2.12-2.03(m,4H),2.02-1.94(m,4H).

Example 40

(R)-6-(4-(azetidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d ]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-(azetidin-1-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, refer to Example 1 for the preparation method.

MS(ESI)M/Z:501.2[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.72(s, 1H), 7.38(s, 1H), 7.24(d, J=8.3Hz, 1H), 7.17(d, J=8.4Hz, 1H), 7.05(d, J=8.7Hz, 2H), 6.82(s, 1H), 6.27(d, J=8.7Hz, 2H), 4.22(s, 1H), 3.84(t, J=7.3Hz, 4H), 3.72-3.60(m,2H),3.57(d,J=5.0Hz,2H),3.35(s,3H),2.39-2.31(m,2H),2.15-1.97(m,4H).

Example 41

1-(2-(7-oxo-2-azaspiro[3.5]non-2-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Pyrrolidin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 7-oxo-2-azaspiro[3.5]nonane instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:527.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.96(s, 1H), 8.64(s, 1H), 7.30-7.27(m, 1H), 7.05(d, J=2.0Hz, 1H), 6.98(dd, J=8.3,2.0Hz,1H),6.94(d,J=8.7Hz,2H),6.79(s,1H),6.33(d,J=8.8Hz,2H),4.03(s,4H),3.71- 3.62(m,4H),3.28-3.19(m,4H),2.03-1.94(m,4H),1.91-1.85(m,4H).

Example 42

(R)-1-(2-(2-(Hydroxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidine -1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using (R)-pyrrolidin-2-ylmethanol instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:501.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.66(s,1H),7.36(s,1H),7.19(s,1H),7.04(s,1H),6.93(d,J＝8.3Hz,2H) ,6.88(s,1H),6.37(d,J=8.4Hz,2H),4.32(br.s.,1H),3.96-3.63(m,4H),3.25(br.s.,4H),2.34 -2.05(m,3H),2.00(br.s.,4H),1.90(br.s.,1H).

Example 43

4-oxo-6-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1-(2-(tetrahydro-1H-furano[3,4-c] Pyrrol-5(3H)-yl)benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid

Substituting 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, hexahydro-1H-furo[3,4-c]pyrrole Instead of (R)-2-(methoxymethyl)pyrrolidine as the raw material, refer to Example 1 for the preparation method.

MS(ESI)M/Z:581.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.70(s, 1H), 8.66(s, 1H), 7.41(d, J=2.0Hz, 1H), 7.29(d, J=8.3Hz, 1H), 7.05 (d, J=1.8Hz, 1H), 6.96(dd, J=8.6, 1.9Hz, 2H), 6.79(s, 1H), 6.62(d, J=9.0Hz, 1H), 4.02-3.85(m, 4H), 3.75(dd, J=9.1, 2.8Hz, 2H), 3.62(dd, J=11.0, 3.0Hz, 2H), 3.42-3.29(m, 4H), 3.14(s, 2H), 2.00-1.87 (m,4H).

Example 44

1-(2-(4-(2-methoxyethyl)piperazin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidine -1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substitute 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, 1-(2-methoxyethyl)piperazine for (R)-2-(methoxymethyl)pyrrolidine is used as raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:612.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.70(s, 1H), 8.65(s, 1H), 7.41(d, J=2.2Hz, 1H), 7.29-7.24(m, 1H), 7.04(d, J=1.8Hz,1H),6.99-6.94(m,2H),6.79(s,1H),6.62(d,J=9.0Hz,1H),3.76(s,4H),3.55(s,2H), 3.43-3.30(m,7H),2.65(br.s.,6H),1.99-1.89(m,4H).

Example 45

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin- 1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 3-azabicyclo[3.1.0]hexane instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:483.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.99(s,1H),8.64(s,1H),7.23(s,1H),7.03(s,1H),6.94(d,J＝8.8Hz,3H) ,6.79(s,1H),6.33(d,J＝8.3Hz,2H),3.90-3.81(m,2H),3.74-3.65(m,2H),3.28-3.19(m,4H),2.03-1.93 (m,4H),1.76-1.66(m,2H),0.89-0.80(m,1H),0.34-0.25(m,1H).

Example 46

1-(2-(Hexahydro-1H-furo[3,4-c]pyrrolyl)benzo[d]oxazol-6-yl)-4-oxo-6-(3-cyano-4- (Pyrrolidin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substitute 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid for 4-(pyrrolidin-1-yl)benzoic acid and hexahydro-1H-furo[3,4-c]pyrrole for (R) -2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:538.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.66(s,1H),7.39(d,J=7.6Hz,1H),7.25(s,1H),7.15(s,1H),6.96(s,2H) ,6.80(s,1H),6.44(d,J=7.8Hz,1H),3.96(br.s.,4H),3.79(d,J=8.8Hz,2H),3.74-3.63(m,2H) ,3.59(br.s.,4H),3.18(br.s.,2H),2.09-1.94(m,4H).

Example 47

6-(3-Bromo-4-(pyrrolidin-1-yl)phenyl)-4-oxo-1-(2-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl )-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl) benzoic acid with 4-(pyrrolidin-1-yl)-3-bromobenzoic acid, and pyrrolidine replaces (R)-2-(methoxymethyl)pyrrolidine as Raw materials, preparation method refer to Example 1.

MS(ESI)M/Z:550.7[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.68(s,1H),8.66(s,1H),7.35(s,1H),7.30(d,J＝8.1Hz,1H),7.03(s,1H) ,6.97(d,J=9.1Hz,1H),6.81(d,J=8.3Hz,1H),6.78(s,1H),6.59(d,J=8.7Hz,1H),3.73-3.64(m, 4H),3.47-3.38(m,4H),2.12-2.03(m,4H),1.97-1.87(m,4H).

Example 48

1-(2-(3-Azabicyclo[3.1.0]hexyl)benzo[d]oxazol-6-yl)-4-oxo-6-(3-bromo-4-(pyrrolidin-1 -yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

4-(pyrrolidin-1-yl)-3-bromobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, 3-azabicyclo[3.1.0]hexane instead of (R)-2- (Methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:562.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.63(s,1H),8.65(s,1H),7.37(s,1H),7.31(d,J＝8.2Hz,1H),7.03(s,1H) ,6.98(d,J=9.7Hz,1H),6.81(d,J=8.7Hz,1H),6.78(s,1H),6.71(s,1H),3.89(d,J=10.1Hz,2H) ,3.74(d,J=9.1Hz,2H),3.46(br.s.,4H),1.96(br.s.,4H),1.76-1.69(m,2H),0.91-0.83(m,1H) ,0.35-0.29(m,1H).

Example 49

1-(2-(3-methoxyazetidine)benzo[d]oxazol-6-yl)-4-oxo-6-(3-bromo-4-(pyrrolidine-1- yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-bromobenzoic acid, 3-methoxyazetidine instead of (R)-2-(methyl Oxymethyl) pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:566.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.36-7.30(m, 2H), 7.04(s, 1H), 6.99(d, J=8.2Hz, 1H), 6.84-6.76( m,2H),6.67(s,1H),4.52-4.45(m,2H),4.44-4.38(m,1H),4.22(dd,J＝9.3,3.7Hz,2H),3.49-3.40(m, 4H),3.36(s,3H),2.00-1.91(m,4H).

Example 50

1-(2-(7-oxa-2-azaspiro[3.5]nonyl-2-yl)benzo[d]oxazol-6-yl)-6-(3-bromo-4-( Pyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

With 4-(pyrrolidin-1-yl)-3-bromobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, 7-oxo-2-azaspiro[3.5]nonane instead of (R )-2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:607.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.35-7.29(m, 2H), 7.02(s, 1H), 7.00(d, J=8.6Hz, 1H), 6.81(d, J=8.7Hz,1H),6.78(s,1H),6.58(d,J=8.8Hz,1H),4.05(s,4H),3.71-3.62(m,4H),3.65-3.47(m,4H ),1.96-1.85(m,8H).

Example 51

(R)-6-(3-Azabicyclo[3.1.0]hexan-3-yl)phenyl)-1-(2-((R)-(2-(methoxymethyl)pyrrolidine- 1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-(3-azabicyclo[3.1.0]hexane-3-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:527.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.66(s, 1H), 7.44(d, J=8.4Hz, 1H), 7.15(d, J=1.7Hz, 1H), 7.04-6.98(m, 1H) ,6.92(d,J=8.7Hz,2H),6.87(s,1H),6.34(d,J=8.7Hz,2H),4.34(s,1H),3.82-3.76(m,1H),3.74- 3.66(m,1H),3.63-3.57(m,1H),3.56-3.51(m,1H),3.44(d,J=9.3Hz,2H),3.37(s,3H),3.27(d,J= 8.3Hz,2H),2.26-2.03(m,4H),1.70-1.59(m,2H),0.81-0.72(m,1H),0.27-0.23(m,1H).

Example 52

1-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Hexahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 4-(hexahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as raw material, the preparation method refers to the example 1.

MS(ESI)M/Z:557.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.67(s, 1H), 7.44(d, J=8.1Hz, 1H), 7.12(s, 1H), 7.03(d, J=7.8Hz, 1H), 6.96 (d,J=8.2Hz,2H),6.88(s,1H),6.41(d,J=8.3Hz,2H),4.34(s,1H),4.02-3.91(m,2H),3.83-3.75( m,1H),3.74-3.65(m,3H),3.63-3.42(m,4H),3.36(s,3H),3.21(d,J＝9.4Hz,2H),3.06(s,2H),2.27 -1.99(m,4H).

Example 53

1-(2-(indol-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)phenyl)-1, 4-Dihydropyridine-3-carboxylic acid

Using indoline instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:519.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.96(s, 1H), 8.68(s, 1H), 7.97(d, J=8.0Hz, 1H), 7.42(d, J=8.3Hz, 1H), 7.33 -7.27(m,2H),7.18(s,1H),7.09-7.01(m,2H),6.96(d,J=8.3Hz,2H),6.81(s,1H),6.33(d,J=8.5 Hz, 2H), 4.33(t, J=8.6Hz, 2H), 3.32(t, J=8.5Hz, 2H), 3.26-3.16(m, 4H), 2.02-1.91(m, 4H).

Example 54

6-(3-Bromo-4-(pyrrolidin-1-yl)phenyl)-4-oxo-1-(2-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H )-yl)benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 3-bromo-4-(pyrrolidin-1-yl)benzoic acid, replace (R)- 2-(methoxymethyl)pyrrolidine is used as raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:592.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.69(s, 1H), 8.67-8.63(m, 1H), 7.35(s, 1H), 7.29(d, J=8.2Hz, 1H), 7.03(s, 1H), 6.98(d, J=8.4Hz, 1H), 6.83-6.76(m, 2H), 6.55(d, J=8.7Hz, 1H), 4.00-3.94(m, 2H), 3.94-3.86(m ,2H),3.78-3.71(m,2H),3.63(dd,J＝11.1,2.5Hz,2H),3.47-3.38(m,4H),3.13(s,2H),1.97-1.87(m,4H ).

Example 55

1-(2-(2-Oxa-7-azaspiro[3.5]nonan-7-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4- (Pyrrolidin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 2-oxo-7-azaspiro[3.5]nonane instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:527.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.96(s,1H),8.64(s,1H),7.24(s,1H),7.04(s,1H),6.99-6.91(m,3H),6.79( s,1H),6.34(d,J＝8.3Hz,2H),4.50(s,4H),3.68-3.58(m,4H),3.28-3.17(m,4H),2.04-1.93(m,8H) .

Example 56

4-oxo-6-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1-(2-(pyrrolidin-1-yl)benzo[d]oxa Azol-6-yl)-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid, pyrrolidine instead of (R)-2-(methoxymethyl) Base) pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:539.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.73(s,1H),8.67(s,1H),7.41(s,1H),7.27(s,1H),7.04(s,1H),7.01-6.91( m,2H),6.79(s,1H),6.62(d,J＝8.9Hz,1H),3.71-3.61(m,4H),3.39-3.29(m,4H),2.11-2.03(m,4H) ,1.97-1.88(m,4H).

Example 57

1-(2-(isoindol-2-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)-3-(tri Fluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, isoindoline instead of (R)-2-(methoxy Base methyl) pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:587.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.70(s, 1H), 8.69(s, 1H), 7.42(d, J=1.9Hz, 1H), 7.39-7.32(m, 5H), 7.12(d, J＝1.7Hz, 1H), 7.02-6.96(m, 2H), 6.81(s, 1H), 6.63(d, J＝9.1Hz, 1H), 5.02(s, 4H), 3.39-3.31(m, 4H ),1.96-1.89(m,4H).

Example 58

1-(2-(3-Methoxyazetidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1- Base)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substitute 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid and 3-methoxyazetidine for (R) -2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:555.2[M+H] ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ8.54(s,1H),7.68(s,1H),7.42(s,1H),7.31-7.22(m,3H),6.86(s,1H), 6.82(d, J=9.0Hz, 1H), 4.43-4.32(m, 3H), 4.02(d, J=6.9Hz, 2H), 3.29-3.19(m, 7H), 1.89-1.79(m, 4H) .

Example 59

6-(3-cyano-4-(R)-3-methoxypyrrolidin-1-yl)phenyl)-4-oxo-1-(2-(tetrahydro-1H-furan[3, 4-c]pyrrol-5(3H)-yl)benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid

Step 1-3: replace 4-(pyrrolidin-1-yl)benzoic acid with 4-bromo-3-cyanobenzoic acid, the preparation method refers to Example 1, step 5-7 obtains 6-(4-bromo-3 -cyanophenyl)-4-oxo-1-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzo[d]oxazole-6- base)-1,4-dihydropyridine-3-carboxylic acid ethyl ester (59-4).

MS(ESI)M/Z:576.3[M+H] ⁺ .

Step 4: Add 6-(4-bromo-3-cyanophenyl)-4-oxo-1-(2-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)- Base) benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester (220 mg, 0.38 mmol), (R)-3-methoxypyrrolidine ( 105.4 mg, 0.77 mmol), cesium carbonate (375 mg, 1.15 mmol) was dissolved in 1,4-dioxane (15 ml), added X-Phos-PdG ₂ (catalytic amount), the reaction solution was heated to 120 React for 2 hours. Cool to room temperature and filter. The filtrate was extracted with dichloromethane, washed with saturated brine, the organic phases were combined, dried, and concentrated to obtain 170 mg of 6-(3-cyano-4-((R)-3-methoxypyrrolidin-1-yl) Phenyl)-4-oxo-1-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzo[d]oxazol-6-yl)- Ethyl 1,4-dihydropyridine-3-carboxylate (59-5).

MS(ESI)M/Z:595.4[M+H] ⁺ .

Step 5: Add 6-(3-cyano-4-((R)-3-methoxypyrrolidin-1-yl)phenyl)-4-oxo-1-(2-( Tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester ( 170 mg, 0.29 mmol) was dissolved in tetrahydrofuran (9 mL). Subsequently, an aqueous solution (8 mL) of sodium hydroxide (23 mg, 0.57 mmol) was added to the above solution under an ice-water bath. The reaction was continued to stir overnight at room temperature. Add saturated citric acid (1 ml) to the reaction system to acidify to pH 5-6. After adding dichloromethane (20 ml) to the reaction solution for extraction, the organic phase was washed with saturated brine (10 ml x 2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was separated by preparative high performance liquid chromatography to obtain 24 mg of 6-(3-cyano-4-(R)-3-methoxypyrrolidin-1-yl)phenyl)-4-oxo-1-( 2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid (Compound 59).

MS(ESI)M/Z:568.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.58(s,1H),8.65(s,1H),7.34-7.27(m,2H),7.07-6.91(m,3H),6.75(s,1H), 6.42(d,J=9.0Hz,1H),4.06(br.s.,1H),4.01-3.87(m,4H),3.84-3.72(m,3H),3.72-3.54(m,5H),3.34 (s,3H),3.14(br.s.,2H),2.26-2.15(m,1H),2.03-1.93(m,1H).

Example 60

6-(4-((R)-3-methoxypyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-4-oxo-1-(2-(tetrahydro-1H -Furo[3,4-c]pyrrol-5(3H)-yl)benzo[d]oxazol-6-yl)-1,4-dihydropyridine-3-carboxylic acid

Substitute 4-bromo-3-(trifluoromethyl)benzoic acid for 4-bromo-3-cyanobenzoic acid, and refer to Example 59 for the preparation method.

MS(ESI)M/Z:611.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.68(s, 1H), 8.66(s, 1H), 7.41(s, 1H), 7.31(d, J=8.3Hz, 1H), 7.04-6.95(m, 3H),6.79(s,1H),6.63(d,J＝8.8Hz,1H),4.02(br.s.,1H),4.00-3.87(m,4H),3.78-3.71(m,2H), 3.67-3.58(m,3H),3.57-3.47(m,1H),3.38-3.27(m,5H),3.14(br.s.,2H),2.17-2.09(m,1H),2.04-1.92( m,1H).

Example 61

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-6-(3-cyano-4-(pyrrolidin- 1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, replace (R)-2 with 3-azabicyclo[3.1.0]hexane -(Methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:508.1[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.71(s, 1H), 7.45-7.38(m, 2H), 7.29-7.18(m, 2H), 7.15(dd, J=9.1, 2.2Hz, 1H) ,6.83(s,1H),6.57(d,J＝9.1Hz,1H),3.84-3.78(m,2H),3.74-3.65(m,2H),3.59-3.51(m,4H),2.04-1.93 (m,4H),1.79-1.71(m,2H),0.88-0.81(m,1H),0.27(q,J=4.2Hz,1H).

Example 62

1-(2-(7-Oxa-2-azaspiro[3.5]non-2-yl)benzo[d]oxazol-6-yl)-6-(3-cyano-4-( Pyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, 7-oxo-2-azaspiro[3.5]nonane instead of ( R)-2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:551.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.58(s,1H),8.64(s,1H),7.30-7.22(m,2H),7.09(s,1H),6.98(d,J=9.1Hz, 1H), 6.92(d, J=8.4Hz, 1H), 6.74(s, 1H), 6.42(d, J=9.1Hz, 1H), 4.05(s, 4H), 3.71-3.63(m, 4H), 3.60-3.53(m,4H),2.02-1.95(m,4H),1.93-1.86(m,4H).

Example 63

1-(2-(2-Azabicyclo[3.1.0]hex-2-yl)benzoxazol-6-yl)-4-oxazol-6-(4-(pyrrolidin-1-yl )phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 2-azabicyclo[3.1.0]hexane instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, refer to Example 1 for the preparation method.

MS(ESI)M/Z:483.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ16.01(s, 1H), 8.66(s, 1H), 7.28(s, 1H), 7.05(s, 1H), 7.00-6.91(m, 3H), 6.80( s,1H),6.34(d,J＝8.4Hz,2H),4.00-3.90(m,1H),3.72-3.64(m,1H),3.33-3.16(m,5H),2.38-2.24(m, 1H), 2.15(t, J=10.4Hz, 1H), 1.99(br.s., 4H), 1.84-1.72(m, 1H), 0.96-0.84(m, 1H), 0.75-0.65(m, 1H ).

Example 64

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin- 1-yl)phenyl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid, 3-azabicyclo[3.1.0]hexane instead of ( R)-2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:551.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.72(s,1H),8.65(s,1H),7.41(s,1H),7.04(s,1H),6.95(d,J＝6.2Hz,2H) ,6.79(s,1H),6.62(d,J=8.9Hz,1H),3.86(d,J=10.3Hz,2H),3.70(d,J=10.1Hz,2H),3.35(br.s. ,4H),1.94(br.s.,4H),1.71(br.s.,3H),0.85(q,J=7.6Hz,1H),0.31(q,J=4.8Hz,1H).

Example 65

1-(2-(7-oxo-2-azaspiro[3.5]non-2-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Pyrrolidin-1-yl)phenyl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substituting 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, 7-oxo-2-azaspiro[3.5] Nonane (R)-2-(methoxymethyl)pyrrolidine is used as raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:595.1[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.75(s, 1H), 7.45(s, 2H), 7.34-7.20(m, 3H), 6.92-6.79(m, 2H), 4.07(br.s. ,4H),3.69-3.61(m,4H),3.40-3.32(m,4H),1.98-1.91(m,4H),1.91-1.82(m,4H).

Example 66

6-(3-cyano-4-(R)-3-methoxypyrrolidin-1-yl)phenyl)-1-(2-((2(R)-2-(methoxymethyl) Pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-3-cyanobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:570.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.59(s,1H),8.65(s,1H),7.33-7.27(m,2H),7.10-6.87(m,3H),6.75(s,1H), 6.43(d,J=9.1Hz,1H),4.26(s,1H),4.06(s,1H),3.84-3.51(m,8H),3.38(s,3H),3.34(s,3H),2.26 -1.93(m,6H).

Example 67

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-6-(4-((R)-3-methoxy ylpyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-bromo-3-(trifluoromethyl)benzoic acid, and refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:581.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.69(s, 1H), 8.65(s, 1H), 7.41(d, J=1.8Hz, 1H), 7.28(s, 1H), 7.02-6.93(m, 3H),6.78(s,1H),6.63(d,J=8.9Hz,1H),4.02(s,1H),3.85(d,J=10.4Hz,2H),3.70(d,J=10.1Hz, 2H),3.66-3.57(m,1H),3.56-3.47(m,1H),3.38-3.26(m,5H),2.17-2.08(m,1H),2.03-1.91(m,1H),1.76- 1.67(m,2H),0.84(q,J=7.6Hz,1H),0.32(q,J=4.3Hz,1H).

Example 68

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-6-(3-cyano-4-((R) -3-fluoropyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-3-cyanobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:526.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ15.55(s,1H),8.65(s,1H),7.32-7.27(m,2H),7.08-6.85(m,3H),6.75(s,1H), 6.45(d, J=9.1Hz, 1H), 5.35(d, J=52.5Hz, 1H), 4.03-3.62(m, 8H), 2.47-2.32(m, 1H), 2.21-1.98(m, 1H) ,1.77-1.66(m,2H),0.86(q,J=7.6Hz,1H),0.32(d,J=4.6Hz,1H).

Example 69

(R)-6-(3-fluoro-4-(3-methoxypyrrolidin-1-yl)phenyl)-1-(2-(3-methoxyazetidin-1-yl) )Benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-bromo-3-fluorobenzoic acid, and refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:535.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.75(s, 1H), 8.64(s, 1H), 7.30(d, J=8.8Hz, 1H), 7.00(d, J=6.8Hz, 2H), 6.76 (s,1H),6.71(d,J=12.5Hz,2H),6.40(t,J=8.7Hz,1H),4.51-4.44(m,2H),4.44-4.36(m,1H),4.24- 4.16(m,2H),4.01(br.s.,1H),3.63-3.55(m,1H),3.55-3.38(m,3H),3.34(d,J＝4.3Hz,6H),2.16-2.07 (m,1H),2.02-1.90(m,1H).

Example 70

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-6-(3-cyano-4-((R) -3-methoxypyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-3-cyanobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:538.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.59(s, 1H), 8.64(s, 1H), 7.28(s, 1H), 7.05-6.89(m, 3H), 6.74(s, 1H), 6.41( d,J=9.1Hz,1H),4.06(s,1H),3.86(d,J=10.3Hz,2H),3.82-3.53(m,7H),3.34(s,3H),2.26-2.16(m ,1H),2.04-1.92(m,1H),1.76-1.67(m,2H),0.85(q,J=7.6Hz,1H),0.38-0.29(m,1H).

Example 71

(R)-6-(3-cyano-4-(3-methoxypyrrolidin-1-yl)phenyl)-1-(2-(3-methoxyazetidine-1- Base) benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-3-cyanobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:542.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.56(s, 1H), 8.65(s, 1H), 7.32(d, J=8.3Hz, 1H), 7.28(d, J=2.0Hz, 1H), 7.07 -6.91(m,3H),6.75(s,1H),6.42(d,J＝9.1Hz,1H),4.54-4.45(m,2H),4.45-4.37(m,1H),4.23(dd,J =9.1,3.6Hz,2H),4.07(s,1H),3.85-3.74(m,1H),3.72-3.56(m,3H),3.36(d,J=3.1Hz,6H),2.25-2.18( m,1H),2.05-1.93(m,1H).

Example 72

1-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(4-((R)-3 -Methoxypyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-bromo-3-(trifluoromethyl)benzoic acid, and refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:613.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.70(s, 1H), 8.66(s, 1H), 7.42(s, 1H), 7.29(d, J=8.3Hz, 1H), 7.05-6.94(m, 3H),6.79(s,1H),6.64(d,J＝8.9Hz,1H),4.24(s,1H),4.02(s,1H),3.75-3.49(m,6H),3.37(br.s .,4H),3.32(br.s.,4H),2.18-2.06(m,4H),2.05-1.92(m,2H).

Example 73

(R)-1-(2-(3-methoxyazetidin-1-yl)benzo[d]oxazol-6-yl)-6-(4-(3-methoxypyrrole Alk-1-yl)-3-(trifluoromethyl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-bromo-3-(trifluoromethyl)benzoic acid, and refer to Example 1 and Example 59 for the preparation method.

MS(ESI)M/Z:585.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.66(s, 1H), 8.66(s, 1H), 7.40(d, J=2.2Hz, 1H), 7.31(d, J=8.5Hz, 1H), 7.04 -6.94(m,3H),6.79(s,1H),6.64(d,J＝8.9Hz,1H),4.51-4.44(m,2H),4.44-4.37(m,1H),4.21(dd,J ＝9.3,3.7Hz,2H),4.05-4.00(m,1H),3.66-3.58(m,1H),3.57-3.47(m,1H),3.39-3.28(m,8H),2.17-2.09(m ,1H),2.03-1.93(m,1H).

Example 74

(R)-6-(3-bromo-4-(3-methoxypyrrolidin-1-yl)phenyl)-1-(2-(4-(2-methoxyethyl)piperazine- 1-yl)benzo[d]oxazol-6-yl)-4-oxyl-1,4-dihydropyridine-3-carboxylic acid

MS(ESI)M/Z:653.6[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.69(s, 1H), 8.65(s, 1H), 7.34(d, J=2.1Hz, 1H), 7.28(d, J=8.3Hz, 1H), 7.03 -6.93(m,2H),6.82(dd,J=8.6,2.2Hz,1H),6.77(s,1H),6.55(d,J=8.7Hz,1H),4.03-3.98(m,1H), 3.83-3.70(m,5H),3.58-3.50(m,3H),3.41-3.29(m,8H),2.64(br.s.,6H),2.12-2.05(m,1H),2.04-1.93( m,1H).

Example 75

1-(2-(2-Azaspiro[4.4]non-2-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1- yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 2-azaspiro[4.4]nonane instead of (R)-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:525.6[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ16.02(s, 1H), 8.65(s, 1H), 7.24(s, 1H), 7.03(d, J=2.0Hz, 1H), 6.97-6.92(m, 3H), 6.79(s, 1H), 6.34(d, J=8.8Hz, 2H), 3.71(t, J=6.9Hz, 2H), 3.48(s, 2H), 3.27-3.19(m, 4H), 2.01-1.96(m,4H),1.94(t,J=7.0Hz,2H),1.73-1.68(m,4H),1.67-1.58(m,4H).

Example 76

1-(2-(5-Methylhexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)benzo[d]oxazol-6-yl)-4-oxo-6-( 4-(Pyrrolidin-1-yl-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substituting 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, 2-methyloctahydropyrrole[3,4-c] Pyrrole replaces (R)-2-(methoxymethyl)pyrrolidine as a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:594.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.72(s, 1H), 8.66(s, 1H), 7.41(d, J=2.3Hz, 1H), 7.28(d, J=8.3Hz, 1H), 7.03 (d,J=2.1Hz,1H),6.99-6.92(m,2H),6.79(s,1H),6.62(d,J=9.0Hz,1H),3.91-3.80(m,2H),3.63( d,J=11.5Hz,2H),3.41-3.30(m,4H),3.13(br.s.,2H),2.81(br.s.,2H),2.67(br.s.,2H),2.45 (br.s.,3H),1.94(t,J=6.5Hz,4H).

Example 77

1-(2-(5-(2-methoxyethyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)benzo[d]oxazol-6-yl)-4 -Oxo-6-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substituting 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, 2-(2-methoxyethyl)octahydropyrrole [3,4-c]pyrrole replaces (R)-2-(methoxymethyl)pyrrolidine as a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:638.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.72(s, 1H), 8.66(s, 1H), 7.40(d, J=2.2Hz, 1H), 7.29(d, J=8.3Hz, 1H), 7.06 (d,J=2.1Hz,1H),6.99-6.94(m,2H),6.79(s,1H),6.63(d,J=9.0Hz,1H),3.86-3.77(m,2H),3.73- 3.57(m,4H),3.42-3.28(m,8H),3.18(brs,3H),2.88(br.s.,2H),2.68(br.s.,2H),1.99-1.90(m,4H ).

Example 78

6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(5-methylhexahydropyrrole[3,4-c]pyrrol-2(1H)-yl )Benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, 2-methyloctahydropyrrole[3,4-c]pyrrole instead of (R )-2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:551.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.62(s, 1H), 8.65(s, 1H), 7.29-7.27(m, 2H), 7.04(d, J=2.1Hz, 1H), 6.93(dd, J=8.3,2.1Hz,2H),6.75(s,1H),6.41(d,J=9.1Hz,1H),3.91-3.82(m,2H),3.63(d,J=10.9Hz,2H), 3.58(t,J=6.5Hz,4H),3.12(br.s.,2H),2.80(br.s.,2H),2.70(br.s.,2H),2.44(s,3H),2.04 -1.95(m,4H).

Example 79

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-6-(3-cyano-4-(3,3 -Difluoropyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-3-cyanobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1 and Example 59.

MS(ESI)M/Z:544.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.65(s,1H),7.37(d,J=8.3Hz,1H),7.31(d,J=2.0Hz,1H),7.13(s,1H),7.07 (dd,J=9.0,1.9Hz,1H),6.92(d,J=7.2Hz,1H),6.79(s,1H),6.45(d,J=9.0Hz,1H),3.98(t,J= 12.5Hz, 2H), 3.88(d, J=10.5Hz, 2H), 3.84-3.71(m, 4H), 2.54-2.41(m, 2H), 1.79-1.72(m, 2H), 0.91(q, J =7.8Hz,1H),0.33(q,J=4.3Hz,1H).

Example 80

1-(2-(3-Azabicyclo[3.1.0]hexane-3-yl)benzo[d]oxazol-6-yl)-6-(3-cyano-4-((S) -3-fluoropyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-3-cyanobenzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid as the raw material, the preparation method refers to Example 1 and Example 59.

MS(ESI)M/Z:526.6[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.40(d, J=8.3Hz, 1H), 7.29(s, 1H), 7.12(s, 1H), 7.02(d, J= 8.8Hz,1H),6.96(s,1H),6.80(s,1H),6.47(d,J＝9.1Hz,1H),4.01-3.94(m,1H),3.93-3.82(m,3H), 3.81-3.75(m,2H),3.74-3.66(m,2H),2.46-2.34(m,1H),2.21-1.97(m,2H),1.80-1.71(m,2H),0.94-0.84(m ,1H),0.37-0.30(m,1H).

Example 81

(R)-6-(3-(4-pyrazole)-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1- Base) benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester

At room temperature, (R)-6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl ) ethyl benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (200 mg, 0.32 mmol) was added to DME (7 mL) and water (3.5 ml), add potassium carbonate (133.5 mg, 0.97 mmol) and pyrazole-4-boronic acid (72 mg, 0.64 mmol), and finally add Pd(PPh ₃ ) ₄ (catalytic amount), react at 90°C for 2 hours . The reaction solution was cooled to room temperature, water (20 ml) was added, dichloromethane (20 ml × 3 times) was extracted, the organic phases were combined, and the organic phase was first washed with saturated brine (20 ml × 3 times), and then washed with anhydrous sulfuric acid Dry over sodium, filter and finally concentrate under reduced pressure. The crude product was purified by preparative high performance liquid chromatography and lyophilized to give 21.22 mg of (R)-6-(3-(4-pyrazole)-4-(pyrrolidin-1-yl)phenyl)-1-(2-( 2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (compound 81).

MS(ESI)M/Z:581.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.67(s, 1H), 7.54(br.s., 2H), 7.33(d, J=8.3Hz, 1H), 7.10(d, J=2.1Hz, 1H ),7.00-6.90(m,3H),6.84(s,1H),6.67(d,J＝8.5Hz,1H),3.78-3.65(m,1H),3.64-3.55(m,2H),3.40- 3.34(m,4H),2.95(br.s.,4H),2.15-2.09(m,4H),2.09-2.01(d,J=13.5Hz,1H),1.80(s,4H).

Example 82

6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-((2R,5S)-2,5-dimethylpyrrolidin-1-ylbenzo[ d] oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Step 1: 2-Chloro-6-nitrobenzo[d]oxazole (500 mg, 2.52 mmol) was dissolved in DCM/DMF (2/1, 15 mL), and (2R,5S)-2,5 - Dimethylpyrrolidine (411 mg, 3.03 mmol) and triethylamine (770 mg, 7.6 mmol), the reaction system was kept at room temperature overnight. Cool to room temperature, add water (20 ml), extract with dichloromethane (20 ml × 3 times), combine the organic phases, wash the organic phase with saturated brine (20 ml × 3 times), dry over anhydrous sodium sulfate, filter, and finally Concentration under reduced pressure gave 630 mg of 2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-nitrobenzo[d]oxazole (82-1).

MS(ESI)M/Z:261.7[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.15(d, J=8.4Hz, 1H), 6.71(s, 1H), 6.55(dd, J=8.0, 2.0Hz, 1H), 4.15-4.11(m, 2H), 3.15(s, 2H), 2.21-2.02(m, 2H), 1.78-1.74(m, 2H), 1.41(s, 3H), 1.40(s, 3H).

Step 2: Dissolve 2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-nitrobenzo[d]oxazole (630 mg, 2.42 mmol) in ethanol (10 ml) and water (10 ml) mixed system, added reduced iron powder (678.5 mg, 12.11 mmol) and ammonium chloride (1295 mg, 24.2 mmol), and the reaction system reacted overnight at room temperature. Cooled to room temperature, concentrated under reduced pressure, added water (20 ml), extracted with dichloromethane (20 ml × 3 times), combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 500 mg of 2-( (2R,5S)-2,5-Dimethylpyrrolidin-1-yl)-6-aminobenzo[d]oxazole (82-2).

MS(ESI)M/Z:230.7[M+H] ⁺ .

Step 3: Ethyl 6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-4-oxo-4H-pyran-3-carboxylate (404 mg, 1.20 mmol) and 2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)-6-aminobenzo[d]oxazole (250 mg, 1.09 mmol) were added to acetic acid solution (6 mL ), stirred at 5°C for 5 minutes, and the reaction system was heated to 95°C for 2 hours. Cool to room temperature, concentrate most of the solvent, add saturated sodium bicarbonate solution (20 ml) to neutralize the reaction, dichloromethane (20 ml × 3 times) extract, combine the organic phase, the organic phase is first washed with saturated brine (20 ml × 3) Wash, then dry with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 250 mg of 6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-((2R,5S)-2,5- Dimethylpyrrolidin-1-ylbenzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (82-3).

MS(ESI)M/Z:552.4[M+H] ⁺ .

Step 4: At room temperature, add 6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-((2R,5S)-2,5-dimethylpyrrolidine -1-ylbenzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (250 mg, 0.45 mmol) dissolved in THF/water ( 3/1, 10 ml), add lithium hydroxide monohydrate (38.1 mg, 0.91 mmol), and stir overnight at room temperature. Add citric acid (2 ml) to the reaction system to neutralize the reaction, then add water (4 ml) Stirring, dichloromethane (3 milliliters * 2 times) extraction, combined organic phase, then dried with anhydrous sodium sulfate, concentrated under reduced pressure.The resulting residue was purified by preparative high performance liquid chromatography to obtain 28.1 mg of 6-(3-cyanogen Base-4-(pyrrolidin-1-yl)phenyl)-1-(2-((2R,5S)-2,5-dimethylpyrrolidin-1-ylbenzo[d]oxazole-6 -yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (compound 82).

MS(ESI)M/Z:524.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.64(s,1H),7.41(d,J=8.3Hz,1H),7.25(d,J=2.1Hz,1H),7.22(s,1H),6.99 (d,J=6.6Hz,1H),6.92(d,J=8.2Hz,1H),6.78(s,1H),6.47(d,J=8.9Hz,1H),4.29(s,2H),3.66 -3.54(m,4H),2.27-2.17(m,2H),2.05-1.96(m,4H),1.92-1.81(m,2H),1.47(d,J＝6.1Hz,6H).

Example 83

6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2R,5R)-2,5-dimethylpyrrolidin-1-ylbenzo[d ]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, (2R,5R)-2,5-dimethylpyrrolidine instead of (R )-2-(methoxymethyl)pyrrolidine as raw material, the preparation method refers to Example 1 and Example 82.

MS(ESI)M/Z:524.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.46(d, J=8.4Hz, 1H), 7.26-7.22(m, 2H), 7.00(s, 1H), 6.92(d, J＝8.4Hz,1H),6.80(s,1H),6.52-6.44(m,1H),4.48-4.36(m,2H),3.63-3.56(m,4H),2.39-2.29(m,2H) ,2.05-1.95(m,4H),1.85-1.75(m,2H),1.35(d,J＝4.0Hz,6H).

Example 84

(R)-6-(3-acetyl-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo [d]Oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Step 1: At room temperature, (R)-6-(3-bromo-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidine- 1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (400 mg, 0.65 mmol), tributyl (1 -Ethoxyvinyl)tin (232 mg, 0.65 mmol), Pd(PPh ₃ )Cl ₂ (catalytic amount) was suspended in DMF, replaced with nitrogen, and reacted overnight at 100°C. The reaction solution was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate (20 mL x 3 times), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative high-performance liquid chromatography to obtain 78 mg of (R)-6-(3-(4-pyrazole)-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2 -(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (84- 1).

MS(ESI)M/Z:585.3[M+H] ⁺ .

Step 2: At room temperature, (R)-6-(3-acetyl-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidine -1-yl)benzo[d]oxazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester (78 mg, 0.13 mmol) dissolved in tetrahydrofuran (6 ml). Subsequently, an aqueous solution (2 mL) of sodium hydroxide (10.6 mg, 0.27 mmol) was added to the above solution under an ice-water bath. The reaction was continued to stir overnight at room temperature. After adding water (10 ml), concentrated under reduced pressure to remove tetrahydrofuran, added citric acid to the reaction system to adjust the pH to 5-6, a yellow solid precipitated, and filtered to obtain 13.53 mg of (R)-6-(3-acetyl-4-( Pyrrolidin-1-yl)phenyl)-1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo -1,4-Dihydropyridine-3-carboxylic acid (Compound 84).

MS(ESI)M/Z:557.0[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.74(s, 1H), 7.50-7.37(m, 2H), 7.31-7.17(m, 3H), 6.88(s, 1H), 6.73(d, J= 8.9Hz, 1H), 4.21(br.s., 1H), 3.71-3.58(m, 2H), 3.55(d, J=4.8Hz, 2H), 3.34(s, 3H), 3.07-3.00(m, 4H),2.37(s,3H),2.15-2.06(m,3H),2.03-1.97(m,1H),1.94-1.88(m,4H).

Example 85

1-(2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidone-1- Base)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

With 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, 1-(2-hydroxyethyl)piperazine instead of (R )-2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:597.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.66(s, 1H), 7.37-7.33(m, 2H), 7.13(d, J=2.1Hz, 1H), 7.04(dd, J=8.4, 2.2Hz, 1H), 7.01-6.97(m, 1H), 6.82(s, 1H), 6.65(d, J=9.0Hz, 1H), 4.17(br.s., 4H), 4.11-4.06(m, 2H), 3.52(br.s.,4H),3.39-3.30(m,4H),3.28-3.25(m,2H),1.98-1.89(m,4H).

Example 86

1-(2-(2-(2-hydroxy-2-methylpropyl)piperazin-1-yl)benzo[d]oxazol-6-yl)-6-(4-(pyrrolidinyl- 1-yl)pyridine-3-(trifluoromethyl)phenyl)-1,4-dihydro-4-oxo-3-carboxylic acid

With 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid instead of 4-(pyrrolidin-1-yl)benzoic acid, 2-methyl-1-(piperazin-1-yl ) acetone-2-ol instead of (R)-2-(methoxymethyl)pyrrolidine as a raw material, the preparation method refers to Example 1.

MS(ESI)M/Z:626.6[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.72(s, 1H), 7.39-7.33(m, 2H), 7.24(d, J=2.0Hz, 1H), 7.03-6.96(m, 3H), 6.65( d,J＝9.1Hz,1H),4.44-3.80(m,6H),3.38(br.s.,5H),3.21(br.s.,3H),1.98-1.92(m,4H),1.44( s,6H).

Example 87

(S)-6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-methylpyrrolidin-1-yl)benzo[d]oxazole -6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, (S)-2-dimethylpyrrolidine instead of (R)-2- (Methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:510.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.48(d, J=8.4Hz, 1H), 7.26-7.21(m, 2H), 7.02-6.97(m, 1H), 6.96- 6.91(m,1H),6.80(s,1H),6.49-6.44(m,1H),4.40(s,1H),3.91-3.84(m,1H),3.79-3.72(m,1H),3.62- 3.57(m,4H),2.25-2.11(m,3H),2.03-1.99(m,4H),1.90-1.83(m,1H),1.41(d,J=6.4Hz,3H).

Example 88

(R)-6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2-(2-methylpyrrolidin-1-yl)benzo[d]oxazole -6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, (R)-2-dimethylpyrrolidine instead of (R)-2- (Methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:510.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.58(br.s., 1H), 8.65(s, 1H), 7.34(d, J=8.4Hz, 1H), 7.25(s, 1H), 7.14(s ,1H),6.98(d,J=9.0Hz,1H),6.91(dd,J=8.4,1.9Hz,1H),6.76(s,1H),6.44(d,J=8.0Hz,1H),4.30 (br.s.,1H),3.84-3.76(m,1H),3.74-3.65(m,1H),3.63-3.54(m,4H),2.24-2.12(m,2H),2.02-1.98(m ,4H),1.83-1.78(m,2H),1.39(d,J＝6.4Hz,3H).

Example 89

1-(2-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Pyrrolidin-1-yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 4-(pyrrolidin-1-yl)benzoic acid, (2R,5S)-2,5-dimethylpyrrolidine instead of (R)-2-(methoxymethyl)pyrrolidine as raw materials, preparation method Refer to Example 1 and Example 82.

MS(ESI)M/Z:499.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.64(s, 1H), 7.35(d, J=8.4Hz, 1H), 7.13(d, J=2.0Hz, 1H), 7.00-6.95(m, 3H) ,6.81(s,1H),6.37(d,J=8.6Hz,2H),4.23(br.s.,2H),3.30-3.20(m,4H),2.20-2.16(m,2H),2.02- 1.97(m,4H),1.87-1.81(m,2H),1.44(d,J＝4.0Hz,6H).

Example 90

(R)-1-(2-(2-Methylpyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1- yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Using 4-(pyrrolidin-1-yl)benzoic acid, (R)-2-dimethylpyrrolidine instead of (R)-2-(methoxymethyl)pyrrolidine as raw materials, the preparation method refers to Example 1 and Example 82.

MS(ESI)M/Z:485.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.42(d, J=8.4Hz, 1H), 7.17(s, 1H), 7.01-6.97(m, 1H), 6.95-6.91( m,2H),6.82(s,1H),6.39-6.34(m,2H),4.36(br.s.,1H),3.89-3.80(m,1H),3.77-3.69(m,1H),3.29 -3.22(m,4H),2.22-2.07(m,2H),2.02-1.98(m,4H),1.86-1.81(m,2H),1.39(d,J＝6.4Hz,3H).

Example 91

1-(2-(R)-2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(4-(R)-2-methyl ylpyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-benzoyl chloride instead of 4-bromo-3-cyanobenzoic acid, (R)-2-methylpyrrole instead of (R)-3-methoxypyrrolidine as raw materials, the preparation method refers to Example 1 and Example 59.

MS(ESI)M/Z:529.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.67(s, 1H), 7.43(d, J=8.4Hz, 1H), 7.18(s, 1H), 7.02(d, J=9.7Hz, 1H), 6.97 -6.92(m,2H),6.88(s,1H),6.44-6.38(m,2H),4.34(br.s.,1H),3.87-3.82(m,1H),3.80-3.76(m,1H ),3.73-3.67(m,1H),3.62-3.57(m,1H),3.56-3.52(m,1H),3.42-3.38(m,1H),3.37(s,3H),3.17-3.10(m ,1H),2.19-1.98(m,8H),1.13(d,J＝6.4Hz,3H).

Example 92

1-(2-(S)-2-(methoxymethyl)pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(4-(S)-2-methyl ylpyrrolidin-1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Using 4-bromo-benzoyl chloride instead of 4-bromo-3-cyanobenzoic acid, (S)-2-methylpyrrole instead of (R)-3-methoxypyrrolidine as raw materials, the preparation method refers to Example 1 and Example 59.

MS(ESI)M/Z:529.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.70(s, 1H), 7.51(d, J=8.6Hz, 1H), 7.06(d, J=8.2Hz, 1H), 7.01-6.94(m, 3H) ,6.60-6.53(m,2H),4.43(s,1H),3.88-3.81(m,2H),3.80-3.72(m,1H),3.67-3.59(m,1H),3.55-3.44(m, 2H), 3.37(s, 3H), 3.22-3.12(m, 1H), 2.27-2.00(m, 8H), 1.16(d, J=6.4Hz, 3H).

Example 93

1-(2-((2R,5S)-2,6-dimethylpyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid, (2R,5S)-2,5-dimethylpyrrole Alkanes are used as raw materials instead of (R)-2-(methoxymethyl)pyrrolidine, and the preparation method refers to Example 1 and Example 82.

MS(ESI)M/Z:567.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.75(s, 1H), 8.66(s, 1H), 7.45(d, J=2.4Hz, 1H), 7.28(s, 1H), 7.07(d, J= 2.2Hz, 1H), 6.97(dd, J=9.0, 2.4Hz, 1H), 6.93(dd, J=8.4, 2.2Hz, 1H), 6.80(s, 1H), 6.63(d, J=9.0Hz, 1H),4.20-4.12(m,2H),3.39-3.33(m,4H),2.18-2.13(m,2H),1.97-1.90(m,4H),1.85-1.77(m,2H),1.43( d,J=6.4Hz,6H).

Example 94

1-(2-((2R,5R)-2,6-dimethylpyrrolidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substituting 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, (2R,5R)-2,5-dimethylpyrrole Alkanes are used as raw materials instead of (R)-2-(methoxymethyl)pyrrolidine, and the preparation method refers to Example 1 and Example 82.

MS(ESI)M/Z:567.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.68(s, 1H), 7.50(d, J=8.4Hz, 1H), 7.40(d, J=2.3Hz, 1H), 7.25(s, 1H), 7.01 -6.94(m,2H),6.89(s,1H),6.66(d,J＝9.0Hz,1H),4.46-4.39(m,2H),3.38(br.s,4H),2.41-2.28(m ,2H),1.99-1.91(m,4H),1.86-1.75(m,2H),1.33(d,J＝6.3Hz,6H).

Example 95

1-(2-((2R,6S)-2,6-dimethylpiperidin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-( Pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Substituting 4-(pyrrolidin-1-yl)-3-(trifluoromethyl)benzoic acid for 4-(pyrrolidin-1-yl)benzoic acid, (2R,6S)-2,6-dimethylpiper Pyridine is used as raw material instead of (R)-2-(methoxymethyl)pyrrolidine, and the preparation method refers to Example 1.

MS(ESI)M/Z:581.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.73(br.s., 1H), 8.66(s, 1H), 7.42(d, J=2.4Hz, 1H), 7.28(s, 1H), 7.06(d ,J=2.0Hz,1H),6.98(dd,J=9.0,2.4Hz,1H),6.93(dd,J=8.4,2.2Hz,1H),6.80(s,1H),6.64(d,J= 8.8Hz,1H),4.57-4.46(m,2H),3.40-3.32(m,4H),1.97-1.92(m,4H),1.86-1.76(m,3H),1.73-1.68(m,3H) ,1.37(d,J=7.0Hz,6H).

Example 96

6-(3-cyano-4-(pyrrolidin-1-yl)phenyl)-1-(2R,6S)-2,6-dimethylpiperidin-1-yl)benzo[d]oxa Azol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Replace 4-(pyrrolidin-1-yl)benzoic acid with 4-(pyrrolidin-1-yl)-3-cyanobenzoic acid, (2R,6S)-2,6-dimethylpiperidine instead of (R )-2-(methoxymethyl)pyrrolidine is a raw material, and the preparation method refers to Example 1.

MS(ESI)M/Z:538.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ8.65(s, 1H), 7.34(d, J=8.4Hz, 1H), 7.29(s, 1H), 7.14(s, 1H), 7.00-6.95(m, 1H),6.92-6.88(m,1H),6.77(s,1H),6.48-6.43(m,1H),4.60-4.51(m,2H),3.61-3.56(m,4H),2.02-1.98( m,4H),1.95-1.83(m,6H),1.41(d,J＝6.9Hz,6H).

Example 97

1-(2-((2R,6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazin-1-yl)benzo[d]oxazol-6-yl) -4-Oxo-6-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid

Step 1: Dissolve tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (5.0 g, 23.35 mmol) in DMF (50 mL) at room temperature and add 2 - bromoethyl methyl ether (6.49 g, 46.7 mmol) and potassium carbonate (3.55 g, 25.69 mmol), and the reaction solution was heated to reflux overnight. Cool to room temperature, add water (50 ml) to quench the reaction, extract with dichloromethane (50 ml x 3 times), combine the organic phases, wash with saturated brine (50 ml x 3 times), dry over anhydrous sodium sulfate, filter, Finally, after concentration under reduced pressure, 4.2 g of (2R,6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (97-2) was obtained.

MS(ESI)M/Z:272.8[M+H] ⁺ .

Step 2: Dissolve tert-butyl (2R,6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazine-1-carboxylate (4.2 g, 15.44 mmol) in acetic acid Ethyl ester (30 ml), hydrogen chloride/ethyl acetate (6N, 30 ml) solution was added under ice bath, reacted at room temperature for 2 hours and then concentrated under reduced pressure to obtain 3.4 g of (3R, 5S)-1-(2-methoxy (ethylethyl)-3,5-dimethylpiperazine hydrochloride (97-3).

MS(ESI)M/Z:173.1[M+H] ⁺ .

Step 3: 2-Chloro-6-nitrobenzo[d]oxazole (2.68 g, 13.58 mmol) was dissolved in DCM/DMF (2/1, 30 mL), and (3R, 5S)-1- (2-Methoxyethyl)-3,5-dimethylpiperazine hydrochloride (3.4 g, 16.3 mmol) and triethylamine (8.2 g, 81.5 mmol) were stirred overnight at room temperature. Add water (50 ml) to quench the reaction, extract with dichloromethane (50 ml × 3 times), combine the organic phases, wash with saturated brine (50 ml × 2 times), dry over anhydrous sodium sulfate, filter, and finally reduce Concentrate under reduced pressure to obtain 3.0 grams of 2-((2R, 6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazin-1-yl)-6-nitrobenzo[d] Oxazole (97-4).

MS(ESI)M/Z:335.0[M+H] ⁺ .

Step 4: Adding 2-((2R,6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazin-1-yl)-6-nitrobenzo[d]oxane Azole (3.0 g, 8.99 mmol) was dissolved in a mixed system of ethanol (40 ml) and water (40 ml), and reduced iron powder (2.52 g, 44.95 mmol) and ammonium chloride (4.8 g, 89.9 mmol) were added , stirred overnight at room temperature. Cool to room temperature, concentrate under reduced pressure, add water (50 ml), and extract with dichloromethane (50 ml × 3 times), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure and then concentrate on a silica gel column Analysis and purification gave 500 mg of 2-((2R, 6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazin-1-yl)benzo[d]oxazole-6- Amine (97-5).

MS(ESI)M/Z:327.3[M+Na] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ7.18-7.13 (m, 1H), 6.69 (d, J=2.2Hz, 1H), 6.56-6.52 (m, 1H), 4.32-4.24 (m, 2H), 3.62-3.56(m,2H),3.38(s,3H),2.85-2.78(m,2H),2.65(br.s.,2H),2.42(br.s.,2H),1.44(d,J =7.0Hz,6H).

Step 5: Ethyl 6-(3-trifluoromethyl-4-(pyrrolidin-1-yl)phenyl)-4-oxo-4H-pyran-3-carboxylate (704 mg, 1.8 mmol) and 2-((2R,6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazin-1-yl)benzo[d]oxazole- 6-Amine (500 mg, 1.64 mmol) was added into acetic acid solution (8 mL), and after stirring for 5 minutes, the reaction solution was heated to 95° C. for 2 hours. Cool to room temperature, remove most of the solvent under reduced pressure, neutralize by adding saturated sodium bicarbonate solution (40 ml), extract with dichloromethane (40 ml × 3 times), combine the organic phases and wash with saturated brine (40 ml × 3 times) Washed, then dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by silica gel column chromatography to obtain 200 mg of 1-(2-((2R, 6S)-4-(2-methoxyethyl)-2, 6-Dimethylpiperazin-1-yl)benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)-3-(trifluoromethane yl)phenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester (97-6).

Step 6: At room temperature, 1-(2-((2R,6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazin-1-yl)benzo[d]oxa Azol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester (200 mg, 0.29 mmol) was dissolved in THF/water (3/1, 15 mL), sodium hydroxide (35 mg, 0.87 mmol) was added, and stirred overnight at room temperature. Add saturated citric acid (5 ml) to the reaction system to acidify to pH 3-4. The reaction solution was extracted with dichloromethane (5 mL×3), and the organic phase was washed with saturated brine (10 mL×2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain 28.4 mg of 1-(2-((2R,6S)-4-(2-methoxyethyl)-2,6-dimethylpiperazine-1- Base) benzo[d]oxazol-6-yl)-4-oxo-6-(4-(pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1,4- Dihydropyridine-3-carboxylic acid (Compound 97).

MS(ESI)M/Z:640.6[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ15.72(s, 1H), 8.66(s, 1H), 7.41(d, J=2.4Hz, 1H), 7.30-7.23(m, 1H), 7.07(s, 1H),6.99(dd,J=8.9,2.4Hz,1H),6.93(dd,J=8.3,1.9Hz,1H),6.80(s,1H),6.64(d,J=8.9Hz,1H), 4.33(br.s.,2H),3.59(s,2H),3.39-3.33(m,7H),2.86(s,2H),2.66(s,2H),2.45(s,2H),1.97-1.92 (m,4H),1.48(d,J=6.6Hz,6H).

The following is the structure of the reference compound 1-3, which was synthesized according to the methods disclosed in the prior art such as patent US2020/0017459 or according to methods known in the art.

Control 1

6-(3-Chloro-4-(pyrrolidin-1-yl)phenyl)-1-(2-(4-(2-methoxyethyl)piperazin-1-yl)benzothiazole-6 -yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Control 2

(R)-6-(3-fluoro-4-(3-methoxypyrrolidin-1-yl)phenyl)-1-(2-(3-methoxyazetidin-1-yl) )Benzothiazol-6-yl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

Control 3

1-(2-(R)-2-(methoxymethyl)pyrrolidin-1-yl)benzothiazol-6-yl)-6-(4-(R)-3-methoxypyrrolidine -1-yl)phenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid

HBV in vitro test

The content of HBV surface antigen and E antigen was detected by enzyme-linked immunosorbent assay (ELISA), and the inhibitory effect of the compound on HBV was evaluated by using the IC ₅₀ value of the compound as an index.

1 Experimental materials

Cell line: HepG2.2.15 cells

HepG2.2.15 cell culture medium (MEM, Gibco-12561056; 10v/v% serum, Gibco-10099-141; 100units/mL penicillin and 100μg/mL streptomycin, Gibco-15140122; 1% non-essential amino acid solution, Gibco- 11140050; 1v/v% GlutaMAX, Gibco-35050061)

2 reagents:

Pancreatin (Gibco-25200-072)

DPBS (Dulbureau's phosphate buffered saline, Gibco-14200075)

Hepatitis B surface antigen detection kit (KHB Kehua Bio)

Cell-Tilter Glo Reagent (Promega-G7572)

3 consumables and instruments:

96-well cell culture plate (Corning-CLS3690)

EnVision multi-function microplate reader (PerkinElmer)

_CO2 incubator (Thermofisher, Steri-i160)

4 Experimental steps and methods:

4.1 HepG2.2.15 cells (1.5×10 ⁴ cells/well) were seeded into 96-well plates and placed in a 5v/v% CO ₂ incubator at 37°C for overnight culture.

4.2 The compound was diluted with a 3-fold gradient according to the highest concentration of 1 μM, with a total of 9 concentrations. 24 hours after the cells were seeded, the serially diluted compounds were added to duplicate wells. Make sure that the concentration of DMSO (dimethyl sulfoxide) in the final medium is 0.5v/v%, 1μM RG7834 is used as 100% inhibition control, and 0.5v/v% DMSO is used as 0% inhibition control.

4.3 On the third day after adding the drug, the culture medium in the 96-well plate was collected, and the ELISA experiment was performed according to a 1:5 dilution to detect the expression of the hepatitis B virus S antigen and E antigen; 50 μL of CTG reagent was added to the cells to detect the cytotoxicity of the drug.

4.4 ELISA detection of hepatitis B virus S antigen content

Add 60 μL of DPBS to the ELISA plate as a diluent, then add 15 μL of supernatant, mix well and incubate in a 37°C incubator for 30 minutes; then add 50 μL of enzyme conjugates to each well, shake and mix, and incubate in a 37°C incubator 30 minutes; wash the plate 5 times with plate washing solution, add 50 μL of chromogenic solution A and 50 μL of chromogenic solution B to each well, incubate in a 37°C incubator for 10 minutes, add 50 μL of luminescent substrate, and finally use a microplate reader to detect the intensity of chemiluminescence .

4.5 ELISA detection of hepatitis B virus E antigen content

Add 40 μL DPBS to the ELISA plate as a diluent, then add 10 μL supernatant, mix thoroughly, add 50 μL enzyme conjugate to each well, shake and mix, incubate at 37°C for 30 minutes; wash the plate 5 times with the washing solution , add 50 μL of chromogenic solution A and 50 μL of chromogenic solution B to each well, incubate in a 37°C incubator for 10 minutes, add 50 μL of luminescent substrate, and finally use a microplate reader to detect the intensity of chemiluminescence.

4.6 Cell Viability Detection

Cell-Tilter Glo reagent was used for detection, 50 μL CTG reagent was added to the 96-well plate, shaken for 10 minutes, and the fluorescence intensity was detected with a microplate reader.

5Data analysis:

Calculate percent inhibition: %Inh. = (100% inhibition - value in sample/100% inhibition - 0% inhibition) x 100.

Calculation of IC ₅₀ : GraphPad Prism software was used to calculate the 50% inhibitory concentration (IC ₅₀ ) value of the compound against HBV.

Experimental results

The test results are shown in Table 1.

Table 1 The inhibitory effect of compound of the present invention on hepatitis B virus surface antigen (HBsAg) and hepatitis B virus E antigen (HBeAg)

Example HBsAg _IC50 (nM) HBeAg _IC50 (nM) Control 1 2.25 3.83 Control 2 3.62 5.92 Control 3 7.41 14.50 1 4.07 4.86 2 5.02 4.86 5 5.71 6.67 7 6.68 5.02 9 5 13

10 5.64 8.54 11 5.61 5.81 12 2.1 3.09 14 5.54 9.6 17 4.76 7.88 twenty three 6.7 3.8 twenty four 4.8 3.9 28 1.1 1.8 31 2.1 2.3 32 3.9 1.9 36 3.3 4.4 39 1.8 2.8 43 1.1 1.7 44 1.3 1.6 45 4.1 4.8 46 6.4 9.7 47 6.1 13.2 48 5.6 11.3 49 7.2 11.2 50 5.1 6.9 54 6 9.95 56 3.4 6.8 57 2.4 3.3 58 1.1 1.8 60 2.32 3.05 61 0.88 1.28 62 2.4 3.6 64 2.04 2.94 65 1.2 2.32 67 1.56 1.37 72 1.44 1.53 73 4.03 6.44 76 6.85 16.42 77 3.18 5.95 82 0.57 0.72 83 1.34 1.53 86 1.97 2.8 87 1.14 1.73 88 1.02 1.58 89 2.95 4.49 90 4.81 4.11 91 0.95 1.11 93 0.82 0.99

94 3.37 4.05 95 2.75 4.06 96 0.96 1.22 97 0.7 1.50

Conclusion: The representative compound of the present invention can effectively inhibit hepatitis B virus surface antigen (HBsAg) and hepatitis B virus E antigen (HBeAg).

HBV-DNA in vitro test

1. Purpose of the experiment:

The HBV DNA content in HepG2.2.15 cells was detected by real-time quantitative qPCR (real time-qPCR), and the _IC50 was used to evaluate the inhibitory effect of the compound on HBV.

2. Experimental materials:

2.1 Cell line: HepG2.2.15 cells

HepG2.2.15 cell culture medium (MEM, Gibco-12561056; 10v/v% serum, Gibco-10099-141; 100units/mL penicillin and 100μg/mL streptomycin, Gibco-15140122; 1v/v% non-essential amino acid solution, Gibco-11140050; 1v/v% GlutaMAX, Gibco-35050061)

2.2 Reagents:

Pancreatin (Gibco-25200-072)

DPBS (Gibco-14200075)

qPCR reagent (PowerUp ^™ SYBR ^™ Green Master Mix, Applied Biosystems-A25742)

3. Consumables and instruments:

96-well cell culture plate (Corning-CLS3690)

qPCR plate (Applied Biosystem-4483354)

qPCR instrument (Applied Biosystems)

_CO2 incubator (Thermofisher, Steri-i160)

4. Experimental steps and methods:

4.1 HepGG2.2.15 cells (1.0×104 cells/well) were seeded into a 96-well plate, placed in a 5v/v% CO ₂ incubator at 37°C and cultured overnight.

4.2 Dilute the compound according to the highest concentration of 1000nM, 3-fold gradient dilution, a total of 9 concentrations. 24 hours after the cells were seeded, the serially diluted compounds were added to the wells in triplicate. Make sure that the DMSO concentration in the final medium is 0.5v/v%, 100nM RG7834 CT value is used as 100% inhibition control, and 0.5v/v% DMSO CT value is used as 0% inhibition control.

4.3 Discard the supernatant in the 96-well plate on the fifth day after adding the drug. After washing with PBS, use 20 μL of 0.2wt% CA630 to lyse the cells for 15 minutes.

4.4 Add 80 μL of ultrapure water.

4.5 Take 8 μL for qPCR.

4.6 Preparation of qPCR reaction solution:

Reagent Volume (microliter) Power Up Mix 10 Front primer (10 micromolar) 1 Back primer (10 micromolar) 1 template 8 total capacity 20

Front primer sequence: CTGTGCCTTGGGTGGCTTT (SEQ NO ID.1);

Back primer sequence: AAGGAAAGAAGTCAGAAGGCAAAA (SEQ NO ID.2).

4.7 Add 20 μL of reaction mixture to each well of a 96-well PCR plate. The qPCR conditions are: 55°C for 2 minutes, heating at 95°C for 10 minutes, denaturation at 95°C for 15 seconds, and extension at 60°C for 1 minute, a total of 40 cycles.

5. Data analysis:

Calculate percent inhibition:

%Inh.=[1/2 ^{(CT value in 0% inhibition sample-CT value in sample to be tested)} ]×100%.

Calculation of IC ₅₀ : GraphPad Prism software was used to calculate the 50% inhibitory concentration (IC ₅₀ ) value of the compound on HBV-DNA.

Experimental results

The test results are shown in Table 2.

Table 2 The inhibitory effect of compound of the present invention on HBV-DNA

Example HBV-DNA _IC50 (nM) 11 2.74 12 0.62 43 0.69 47 0.98 77 1.39 82 0.20 83 0.40 86 0.33 87 0.19 88 0.28 89 0.16 91 0.68 93 0.23 94 0.74 95 0.60 96 0.11

Conclusion: The representative compounds of this invention can effectively inhibit HBV-DNA.

Rat tissue distribution test

1. Purpose of the experiment

Each compound was administered orally to SD rats, and the drug concentration in rat plasma, liver, brain tissue and cerebrospinal fluid at different time points after administration of each compound was detected, and the distribution and brain penetration of each compound in the rat were investigated. sex.

2. Experimental materials

2.1 Test animals

Healthy adult SD rats, male, SPF grade, 180-200 g, 15 for each compound.

2.2 Reagents

Polyoxyethylene hydrogenated castor oil RH40 (RH40), absolute ethanol or 95v/v% ethanol, ultrapure water;

Methanol, acetonitrile, DMSO, isopropanol, formic acid.

3. Main instruments

High performance liquid chromatography (Shimadzu HPLC 20-AD)

Mass Spectrometer (AB Sciex API 4000 Triple Quadrupole)

Electronic balance (Mettler Toledo XSE205)

Pure water meter (Millipore Milli-Q Integral 3)

High-speed refrigerated centrifuge (Sigma 2-16K/Thermo Scientific Sorvall ST8R)

Vortex shaker (Scientific Industries VORTEX-2)

Multi-tube vortex oscillator (Beijing Tajin Technology Co., Ltd. VX-II)

-20℃/2-8℃ refrigerator (Qingdao Haier Co., Ltd. BCD-290W)

-80℃ ultra-low temperature refrigerator (Qingdao Haier Co., Ltd. DW-86L628)

Pipettes (Eppendorf/Thermo/BIO-DL/RAININ)

C18 3.5μm(3.0×50mm) Column: Waters

C18 3.5μm (3.0×50mm)

4. Experimental steps and methods

4.1 Preparation of the test product

Weigh an appropriate amount of compound, add solvent: 5v/v% RH40 + 5v/v% ethanol + 90v/v% pure water (NaOH solution to adjust pH to 8-9), mix well, if not completely dissolved, use 1mmol/L NaOH solution to fine-tune the pH to obtain a clear solution, but the pH should not exceed 9.

4.2 Sample Collection

SD rats were fasted overnight, administered by intragastric administration, and given different compounds according to body weight, and the administration volume was 10 mL/kg. At 5 time points of 0.25h±2min, 1h±5min, 2h±5min, 4h±10min and 8h±10min, 3 animals were used for each time point of each compound, and about 1 mL of blood was collected from the large abdominal vein of the animal after anesthesia , Cerebrospinal fluid 0.1 ~ 0.2mL, collect brain tissue and liver. Whole blood was anticoagulated with heparin, centrifuged at 12,000 rpm for 1 min, and plasma was obtained. Plasma and tissue were frozen at -70°C until testing.

4.3 Biological sample detection

Tissue samples (brain tissue and liver) were weighed, and ultrapure water was added according to the ratio of tissue sample: ultrapure water (1 g: 5 mL) for tissue homogenization to obtain tissue homogenate.

Biological samples (plasma, cerebrospinal fluid, liver homogenate, and brain tissue homogenate) were pretreated with methanol or acetonitrile solution containing internal standards for protein precipitation, and samples were taken for LC-MS/MS analysis after centrifugation.

Eight calibration concentration levels were used, excluding blank samples and zero concentration samples. The blank and zero-concentration sample results are not involved in the calculation of the standard curve parameters, and the standard curve range is 2 to 2000 ng/mL.

5. Data analysis

The chromatograms of the analyte and internal standard were collected by AB Sciex mass spectrometer, and the peak area was calculated by Analyst 1.7.2 software, and the concentration was calculated by establishing a linear regression equation with ¹ /C2 weighting. Concentration unit: ng/mL or ng/g.

Experimental results

The test results are shown in Table 3.

Table 3 The drug concentration of compound of the present invention and reference substance in tissue

Conclusion: Compared with the control, the representative compounds of the present invention have higher liver/plasma distribution ratio and lower brain tissue/cerebrospinal fluid exposure, further reducing the risk of neurotoxicity.

Claims (28)

Compound represented by formula (I), its isomer or pharmaceutically acceptable salt thereof

in, R ₂ is selected from 5-6 membered aryl, 5-6 membered heteroaryl; wherein the 5-6 membered aryl or 5-6 membered heteroaryl is optionally substituted by m R _x groups , wherein said R _{x is} selected from R _xa or R _xb , R _xa is selected from hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _{1 -4} alkoxy, C _1-4 haloalkyl, two (C _1-4 alkyl)-amino, 5-6 membered heteroaryl, C _1-4 alkanoyl, R _xb is selected from 4-7 membered heterocycle Alkyl, 5-6 membered heteroaryl, C _4-6 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 3-5 membered Cycloalkyl, wherein R _xb is optionally substituted by r R _xc groups, R _{xc is} selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, wherein m represents an integer of 0, 1, 2, 3, r represents an integer of 0, 1 or 2; R ₃ is selected from H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy; R is selected from C _4-6 cycloalkyl, amino, _4-7 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered aryl and 5-6 membered heterocycloalkyl, 5-6 membered Heterocycloalkyl and 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 3-5 membered cycloalkyl, 7-10 membered spiroheterocyclyl, wherein the above-mentioned groups are optionally replaced by 1, 2 or 3 R _y substitutions; Wherein R _y is selected from hydroxyl C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, two (C _1-4 alkyl)-amino, hydroxyl, 4 -7-membered heterocycloalkyl, 5-6-membered heteroaryl, C _4-6 cycloalkyl, halogen, cyano, wherein the C _1-4 alkyl, C _1-4 alkoxy, 4-7 The membered heterocycloalkyl group and the 5-6 membered heteroaryl group are optionally substituted by C _1-4 alkyl group or C _1-4 alkoxy group. The compound according to claim 1, its isomer or its pharmaceutically acceptable salt, wherein _Rxa is selected from H, F, Cl, Br, CN, -CH ₃ , -CF ₃ , -OCH ₃ , -N (CH ₃ ) ₂ , CH ₃ OCH ₂ CH ₂ CH ₂ O-,

-C(O) _CH3 . The compound, its isomer or a pharmaceutically acceptable salt thereof according to claim 2, wherein R _xa is selected from -CF ₃ , CN. The compound, its isomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R _{xc is} selected from -OCH ₃ , F, -CH ₃ . According to the compound described in any one of claims 1-4, its isomer or pharmaceutically acceptable salt thereof, wherein R _xb is selected from

wherein R _xc is as defined in any one of claims 1-4, and r is as defined in claim 1. The compound according to claim 5, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R _xb is selected from

wherein R _xc and r are as defined in claim 5 . According to any one of claims 1-6, the compound, its isomer or a pharmaceutically acceptable salt thereof, wherein R _y is selected from -CH ₃ , -OCH ₃ , -N(CH ₃ ) ₂ , CH ₃ OCH ₂ CH ₂ -, CH ₃ OCH ₂ -, -OH, -CH ₂ OH,

_-CH2CH2OH , _{-CH2C ( CH3 )} 2OH. According to the _compound described in any one of claims 1-7, its isomer or pharmaceutically acceptable salt thereof, wherein R is selected from

Wherein T ₁ is selected from CH or N; R _x , m are as defined in any one of claims 1-7. The compound according to claim ₈ , its isomer or pharmaceutically acceptable salt thereof, wherein R is selected from

R _{x is} selected from R _xb , and said R _xb is selected from pyrrolidinyl; m is as defined in claim 8 . The compound according to claim ₈ , its isomer or pharmaceutically acceptable salt thereof, wherein R is selected from

Wherein R _xa and R _xb are as defined in any one of claims 1-7, and p is an integer selected from 0, 1 or 2. The compound according to claim ₁₀ , an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R is selected from

Wherein R _xa and p are as defined in claim 10, R _xc is as defined in claim 1 or 4, and r is as defined in claim 1. According to the _compound described in any one of claims 1-11, its isomer or pharmaceutically acceptable salt thereof, wherein R is selected from

"*" in its structural formula represents a chiral carbon atom. _The compound according to any one of claims 1-12, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from the following groups:

"*" in the above structural formula represents a chiral carbon atom. The compound according to claim ₁₃ , an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R is selected from the following groups:

According to the compound described in any one of claims 1-14, its isomer or pharmaceutically acceptable salt thereof, the compound has the structure of formula (II)

Wherein, R _x , R ₃ , R ₄ , T ₁ and m are as defined in any one of claims 1-14. According to the compound, its isomer or pharmaceutically acceptable salt thereof according to claim 15, said compound has the structure of formula (IIa) and formula (IIb)

Wherein R ₃ , R ₄ , R _x and m are as defined in claim 15, R _xa and R _xb are as defined in any one of claims 1-14, and p is as defined in claim 10. According to the compound according to claim 16, its isomer or pharmaceutically acceptable salt thereof, the compound has the structure of formula (IIc)

Wherein, R _xa , R ₄ , p are as defined in claim 16, and R _xc and r are as defined in any one of claims 1-14. Compounds shown below, their isomers or pharmaceutically acceptable salts thereof,

The compound according to any one of claims 1-18, its isomer or pharmaceutically acceptable salt thereof, for treating or preventing hepatitis B virus infection. The compound according to any one of claims 1-18, its isomer or a pharmaceutically acceptable salt thereof, for use as a DNA production inhibitor of hepatitis B virus. The compound according to any one of claims 1-18, its isomer or a pharmaceutically acceptable salt thereof, for use as an HBsAg inhibitor. A pharmaceutical composition comprising the compound according to any one of claims 1-18, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. A DNA production inhibitor of hepatitis B virus, which comprises the compound according to any one of claims 1-18, its isomer or a pharmaceutically acceptable salt thereof. An HBsAg inhibitor comprising the compound of any one of claims 1-18, its isomer or a pharmaceutically acceptable salt thereof. Use of the compound, its isomer or pharmaceutically acceptable salt thereof according to any one of claims 1-18 in the preparation of a medicament for treating or preventing HBV infection. Use of the compound according to any one of claims 1-18, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 22 in the preparation of medicines, which are used for treatment and prevention HBV infection. Use of the compound according to any one of claims 1-18, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 22 in the preparation of medicines for inhibiting HBsAg production or secretion. A method for treating or preventing HBV infection, comprising administering to a patient a therapeutically effective amount of the compound of any one of claims 1-18, its isomer or a pharmaceutically acceptable salt thereof.