PCSK9 and HMG-coa dual-target compound and use thereof

Abstract

The present invention belongs to the technical field of chemical drugs, and relates to a PCSK9 and HMG-CoA dual-target compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, a preparation method therefor, the use thereof as a PCSK9 inhibitor and / or HMG-CoA reductase inhibitor, and a method for using same to treat a plurality of specific diseases or disorders.

Description

PCSK9 and HMG-CoA dual-target compounds and their applications Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, and relates to a dual-target compound of PCSK9 and HMG-CoA, or its isomers, racemates, or pharmaceutically acceptable salts, as well as its preparation methods and applications. It is a PCSK9 inhibitor and / or an HMG-CoA reductase inhibitor, and a method for using it to treat various specific diseases or symptoms. Background Technology

[0002] Proprotein convertase subtilisin / kexin type 9 (PCSK9), also known as neuronal apoptosis-regulating convertase 1 (NARC-1), is a pro-proprotein convertase belonging to the subtilisin (S8) family of serine proteases. It is expressed in cells capable of proliferation and differentiation, including hepatocytes, renal interstitial cells, ileal and colonic epithelial cells, and embryonic telencephalon neurons. Studies have found that PCSK9 plays a role in the differentiation of hepatocytes and nerve cells. It not only specifically acts on cholesterol biosynthesis or uptake, but circulating PCSK9 can also directly bind to the low-density lipoprotein receptor (LDLR) on the surface of hepatocytes, being phagocytosed by hepatocytes along with LDLR. This promotes the degradation of LDLR in hepatocytes, hinders its recycling, and thus increases the level of LDL cholesterol (LDL-C) in plasma. Elevated LDL-C expression is closely related to dyslipidemia and cardiovascular diseases in humans.

[0003] HMG-CoA reductase inhibitors used for dyslipidemia include atorvastatin, rosuvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, and pitavastatin, with the following structural formulas:

[0004] No dual-target small molecule compounds of PCSK9 and HMG-CoA have been found so far. Summary of the Invention

[0005] In view of the problems existing in the prior art, this application provides a compound of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, as well as a method for its preparation and application. This is a novel PCSK9 and / or HMG-CoA inhibitor, and a method for using it to treat various specific diseases or symptoms.

[0006] In a first aspect, this application provides a compound of general formula (I), or its isomers, racemates, or pharmaceutically acceptable salts thereof:

[0007] A further preferred option is formula (Ia).

[0008] In a second aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0009] Thirdly, the present invention also provides the use of a therapeutically effective amount of the above-described compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition, said condition being a PCSK9 inhibitor-related disease, specifically, said condition being selected from conditions such as hypercholesterolemia.

[0010] Specifically, the present invention is achieved through the following technical solution:

[0011] A compound of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

[0012] A further preferred option is formula (Ia).

[0013] Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano.

[0014] Ring B is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R2, and the heterocycles are monocyclic, bicyclic or tricyclic, and R2 is independently selected from hydrogen, halogen, alkyl, cycloalkyl or cyano;

[0015] R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond;

[0016] T2 is selected from N or CH;

[0017] R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

[0018] As a preferred embodiment of the present invention, the compound is selected from a compound of general formula (IIa), (IIb), (IIc), or (IId), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

[0019] Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano.

[0020] R2 can be one or more, each independently selected from hydrogen, halogen, alkyl, cycloalkyl, or cyano;

[0021] R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond;

[0022] T2 is selected from N or CH;

[0023] R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

[0024] As a preferred embodiment of the present invention, the compound is selected from a compound of general formula (IIIa), (IIIb), (IIIc), or (IIId), or its isomers, racemates, or pharmaceutically acceptable salts, including:

[0025] Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano.

[0026] R2 can be one or more, each independently selected from hydrogen, halogen, alkyl, cycloalkyl, or cyano;

[0027] R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond;

[0028] T1 and T2 are each independently selected from N or CH;

[0029] R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

[0030] As a preferred embodiment of the present invention, the compound is selected from a compound of general formula (IV) or (IVa), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, including:

[0031] Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano.

[0032] R2 can be one or more, each independently selected from hydrogen, halogen, alkyl, cycloalkyl, or cyano;

[0033] R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond;

[0034] R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

[0035] As a preferred embodiment of the present invention, the compound is selected from a compound of general formula (Va), (Vb), (Vc), or (Vd), or its isomers, racemates, or pharmaceutically acceptable salts: R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond;

[0036] R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

[0037] As a preferred embodiment of the present invention, the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0038] As a preferred embodiment of the present invention, at least one of R3 is...

[0039] As a preferred embodiment of the present invention, the alkoxy group is selected from methoxy, ethoxy, propoxy, and isopropoxy.

[0040] As a preferred embodiment of the present invention, the cycloalkyl group is selected from C 3-6 The cycloalkyl group is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0041] In a preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0042] As a preferred embodiment of the present invention, the alkenyl group is selected from C 2-4 Alkenyl groups, including vinyl, propenyl, and butenyl.

[0043] As a preferred technical solution of the present invention, the Selected from Further including

[0044] As a preferred embodiment of the present invention, R1 is selected from H, F, Cl, Br, I, methyl, methoxy, methylthio, cyclopropyl, -OCHF2, and cyano.

[0045] As a preferred embodiment of the present invention, R2 is selected from H, F, Cl, Br, methyl, and cyclopropyl.

[0046] In a preferred embodiment of the present invention, R3 is one or more, each independently selected from hydrogen, methyl, ethyl, chlorine, ...

[0047] As a preferred embodiment of the present invention, R5 is selected from: Furthermore, Preferred from

[0048] As a preferred embodiment of the present invention, ring A is selected from...

[0049] As a preferred embodiment of the present invention, the replaced A ring is selected from...

[0050] As a preferred embodiment of the present invention, ring B is selected from... Links can be used through adjacent, intermediate, or opposite positions, with opposite positions being preferred, for example: The B ring that is further preferably substituted is selected from include

[0051] As a preferred technical solution of the present invention Selected from

[0052] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from compounds 1-89 shown in Table 1:

[0053] Table 1

[0054] As a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to the compound, or its isomer, its racemate, or its pharmaceutically acceptable salt, prepared with a pharmaceutically acceptable acid or base.

[0055] As a preferred embodiment of the present invention, one or more hydrogen atoms of the compound, or its isomer, racemate, or pharmaceutically usable salt thereof, are substituted with the isotope deuterium.

[0056] The present invention further provides a pharmaceutical composition characterized in that it comprises a therapeutically effective amount of the compound, or an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0057] The present invention further provides the pharmaceutical use of the said compound, or its isomers, racemates, or pharmaceutically usable salts thereof, and pharmaceutical compositions thereof, specifically, its use in the preparation of medicaments for treating diseases, said diseases being PCSK9 and / or HMG-CoA inhibitor-related diseases, specifically selected from conditions such as hypercholesterolemia.

[0058] The compounds of this invention exhibit PCSK9 and / or HMG-CoA inhibitory activity, with an IC50 value of [missing information]. 50 Each is <300nm, preferably <100nm, and more preferably <50nm.

[0059] For clarity, this article defines the general terminology used in the description of compounds.

[0060] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0061] The terms "monocyclic, bicyclic, or tricyclic" refer to a ring composed of carbon atoms, which can be saturated or unsaturated, with three or more carbon atoms, including rings composed of 3 to 20 carbon atoms. Unsaturation means containing one or more double bonds. Bicyclic and tricyclic rings are formed by one or more carbon atoms connected together. Furthermore, heterocyclic refers to a ring that can contain one or more heteroatoms, forming a monocyclic, bicyclic, or tricyclic heterocyclic ring, where the heteroatoms are selected from N, O, and S.

[0062] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0063] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0064] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0065] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, transisomers, racemic mixtures thereof, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0066] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, transisomers, etc., can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0067] The atoms in the compounds of this invention are isotopes. Isotope derivatization can typically prolong half-life, reduce clearance rate, stabilize metabolism, and enhance in vivo activity. Furthermore, one embodiment is included, wherein at least one atom is replaced by an atom having the same number of atoms (protons) but different mass numbers (protons and neutrons). Examples of isotopes included in the compounds of this invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising... 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomical examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with quantity and are not radioactive, therefore they can be used safely. When the atoms constituting the molecules of the compounds of this invention are isotopes, the isotopes can be converted according to common methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0068] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), Iodine-125 125 I) or C-14 14C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0069] Furthermore, one or more hydrogen atoms in the compound of the present invention are coated with the isotope deuterium ( 2 The compounds of this invention, after being substituted with H), have the effects of prolonged half-life, reduced clearance rate, metabolic stabilization, and increased in vivo activity.

[0070] The preparation methods of the isotope derivatives typically include phase-transfer catalysis. For example, a preferred deuteration method employs a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Using a phase-transfer catalyst to exchange the methylene protons of a diphenylmethane compound results in the introduction of higher levels of deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with Lewis acids such as aluminum trichloride using sodium deuterated borate.

[0071] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0072] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0073] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0074] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0075] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0076] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. Detailed Implementation

[0077] The present application will be described in further detail below with reference to the embodiments, but the implementation of the present application is not limited thereto.

[0078] Example 1

[0079] Synthesized 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one (1).

[0080] Step 1: Synthesis of 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0081] 3-Bromo-5-chloro-2-methoxypyridine (35.0 g, 157 mmol, 1.00 eq) was dissolved in tetrahydrofuran (350 mL) and cooled to -70 °C. Then, lithium diisopropylamine (2 M, 110 mL, 1.40 eq) was slowly added dropwise to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was stirred at -70 °C for 0.5 hours. Then, dry ice (69.2 g, 1.57 mol, 10.0 eq) was slowly added to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 12 hours. TLC monitoring showed that the reaction of the raw materials was complete. The reaction solution was quenched with a saturated ammonium chloride aqueous solution (400 mL). When the quenched mixture was concentrated to remove most of the tetrahydrofuran, a solid precipitated out. The mixture was then filtered, and the resulting filter cake was dried and concentrated to obtain 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (31.0 g, 116 mmol, 73.9% yield).

[0082] LCMS RT=0.349min,MS(ESI)m / z=267.9[M+1] +

[0083] Step 2: Synthesis of methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0084] 3-Bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (15.0 g, 56.3 mmol, 1.00 eq) was dissolved in methanol (150 mL) and tetrahydrofuran (150 mL). The reaction solution was cooled to 0 °C, and then trimethylsilyldiazomethane (2 M, 84.4 mL, 3.00 eq) was slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.577 min). The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (12.5 g, 44.6 mmol, 79.2% yield). LCMS RT = 0.577 min, MS (ESI) m / z = 281.9 [M+1] +

[0085] Step 3: Synthesis of methyl 5-chloro-3-isopropenyl-2-methoxy-pyridine-4-carboxylate

[0086] Methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (5.00 g, 17.8 mmol, 1.00 eq), phenazine isopropenylborate (3.29 g, 19.6 mmol, 1.10 eq), potassium carbonate (7.39 g, 53.5 mmol, 3.00 eq), and 1,1-bis(diphenylphosphine)ferrocene palladium(II) dichloromethane complex (1.46 g, 1.78 mmol, 0.10 eq) were dissolved in dioxane (50 mL) and water (10 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.609 min). The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (80 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-chloro-3-isopropenyl-2-methoxy-pyridine-4-carboxylate (4.20 g, 17.4 mmol, 97.5% yield).

[0087] LCMS RT=0.609min,MS(ESI)m / z=242.0[M+1] +

[0088] Step 4: Synthesis of methyl 5-(4-fluorophenyl)-3-isopropenyl-2-methoxy-pyridine-4-carboxylic acid

[0089] Methyl 5-chloro-3-isopropenyl-2-methoxypyridine-4-carboxylic acid (4.20 g, 17.4 mmol, 1.00 eq), 4-fluorophenylboronic acid (3.16 g, 22.6 mmol, 1.30 eq), 2-dicyclohexylphosphine-2,6-dimethoxyoxybiphenyl (713 mg, 1.74 mmol, 0.10 eq), potassium carbonate (7.21 g, 52.1 mmol, 3.00 eq), and palladium acetate (390 mg, 1.74 mmol, 0.10 eq) were dissolved in dioxane (40 mL) and water (8 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.572 min). The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-3-isopropenyl-2-methoxy-pyridine-4-carboxylic acid (4.50 g, 14.9 mmol, 85.9% yield). LCMS RT = 0.572 min, MS (ESI) m / z = 302.0 [M+1] +

[0090] Step 5: Synthesis of methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid

[0091] Methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid (4.50 g, 14.9 mmol, 1.00 eq) was dissolved in methanol (50 mL), and then wet palladium on carbon (450 mg, 423 μmol, 10% purity) was added in portions. After the addition was complete, the reaction solution was purged three times under a hydrogen atmosphere, and then stirred at 50 °C for 12 h under a hydrogen (50 Psi) atmosphere. The MS value of the product was monitored by LC-MS (RT = 0.668 min). The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid (4.00 g, 13.19 mmol, 88.3% yield). LCMS RT=0.668min,MS(ESI)m / z=304.1[M+1] +

[0092] Step 6: Synthesis of methyl 5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid

[0093] Methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid (4.00 g, 13.2 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL), and then trimethyliodosilane (5.54 g, 27.7 mmol, 2.10 eq) was added. After the addition was complete, the reaction mixture was stirred at 80 °C for 2 hours. TLC showed that the reaction proceeds were completely reacted. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid (2.50 g, 8.64 mmol, 65.5% yield).

[0094] LCMS RT=0.504min,MS(ESI)m / z=290.1[M+1] +

[0095] Step 7: Synthesis of 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-isopropyl-1H-pyridin-2-one

[0096] Methyl 5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid (2.50 g, 8.64 mmol, 1.00 eq) was dissolved in dichloromethane (30 mL) and cooled to -50 °C. Then, diisobutylaluminum hydride (1 M, 34.6 mL, 4.00 eq) was slowly added dropwise to the reaction solution, with the temperature maintained at approximately -50 °C throughout the addition. After the addition was complete, the reaction solution was stirred at 0 °C for 4 hours. TLC monitoring showed that the starting material had reacted completely. The reaction solution was quenched at approximately 0 °C with a saturated ammonium chloride aqueous solution (200 mL) and then extracted with dichloromethane (100 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-isopropyl-1H-pyridin-2-one (850 mg, 3.25 mmol, 37.6% yield). LCMS RT = 0.442 min, MS (ESI) m / z = 262.2 [M+1] +

[0097] Step 8: Synthesis of 4-(bromomethyl)-5-(4-fluorophenyl)-3-isopropyl-1H-pyridin-2-one

[0098] 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-isopropyl-1H-pyridin-2-one (370 mg, 1.42 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Phosphorus tribromide (575 mg, 2.12 mmol, 1.50 eq) was then slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 3 hours. The MS value of the product was monitored by LCMS (RT = 0.530 min). The reaction solution was quenched at approximately 0 °C with a saturated sodium bicarbonate aqueous solution (30 mL), and then extracted with dichloromethane (20 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(bromomethyl)-5-(4-fluorophenyl)-3-isopropyl-1H-pyridin-2-one (850 mg, 2.62 mmol, 92.6% yield). It was used directly in the next step without purification. LCMS RT = 0.530 min, MS (ESI) m / z = 324.0 [M+1] +

[0099] Step 9: Synthesis of 5-(4-fluorophenyl)-3-isopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one

[0100] 4-(bromomethyl)-5-(4-fluorophenyl)-3-isopropyl-1H-pyridin-2-one (850 mg, 2.62 mmol, 1.00 eq) and triphenylphosphine (825 mg, 3.15 mmol, 1.20 eq) were dissolved in toluene (10 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.464 min). The reaction mixture was concentrated to give 5-(4-fluorophenyl)-3-isopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one (1.30 g, 2.57 mmol, 98.1% yield). No purification was performed; it was used directly in the next step. LCMS RT = 0.464 min, MS (ESI) m / z = 506.3 [M+1] +

[0101] Step 10: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0102] 5-(4-fluorophenyl)-3-isopropyl-4-[(triphenylphosphine)methyl]-1H-pyridin-2-one (1.30 g, 2.57 mmol, 1.00 eq), 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (691 mg, 2.83 mmol, 1.10 eq), and potassium carbonate (712 mg, 5.14 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (20 mL), and the reaction mixture was stirred at 110 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.587 min). The reaction mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (50 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (870 mg, 1.79 mmol, 69.7% yield). LCMS RT = 0.587 min, MS (ESI) m / z = 486.2 [M+1]. +

[0103] Step 11: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0104] tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (840 mg, 1.73 mmol, 1.00 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3- Diamine (774 mg, 1.73 mmol, 1.00 eq), cuprous iodide (98.9 mg, 519 μmol, 0.30 eq), potassium carbonate (717 mg, 5.19 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (73.8 mg, 519 μmol, 0.30 eq) were dissolved in dimethyl sulfoxide (10 mL), and then stirred at 110 °C for 3 h. The MS value of the product was monitored by LCMS (RT = 0.571 min). The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl-2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.30 g, 1.62 mmol, 93.4% yield). It was used directly in the next step without purification. LCMS RT = 0.571 min, MS (ESI) m / z = 805.4 [M+1] +

[0105] Step 12: Synthesis of 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one

[0106] 100 mg, 124 μmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was dissolved in acetonitrile (3 mL), and then trifluoroacetic acid (42.5 mg, 373 μmol, 3.00 eq) was added. After the addition was complete, the reaction mixture was stirred at 20 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.459 min). The reaction solution was concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 18%-48% B over 15 min) to obtain 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4S)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one (29.44 mg).

[0107] LCMS RT=0.459min,MS(ESI)m / z=691.3[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ8.23(s,2H),7.99(d,J=2.6Hz,1H),7.51-7.42(m,2H),7.39(s,1H),7.34-7.28(m,2H),7.23-6.83(m,4H),6. 55-6.45(m,2H),5.45(dd,J=6.4,16.3Hz,1H),5.23(d,J=3.4Hz,1H),5.11-5.02(m,1H),4.38-4.24(m,2H),4.08-3.99(m,1H),3.25(br dd,J=7.0,13.9Hz,1H),2.62(dd,J=4.6,17.3Hz,1H),2.37(br dd,J=2.7,17.3Hz,1H),2.19-2.05(m,2H),1.95-1.81(m,2H),1.69-1.42(m,4H),1.28(d,J=6.8Hz,6H).

[0108] Example 2

[0109] Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(4-fluorophenyl)-5-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid (2)

[0110] Step 1: Synthesis of 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0111] 3-Bromo-5-chloro-2-methoxypyridine (35.0 g, 157 mmol, 1.00 eq) was dissolved in tetrahydrofuran (350 mL) and cooled to -70 °C. Then, lithium diisopropylamine (2 M, 110 mL, 1.40 eq) was slowly added dropwise to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was stirred at -70 °C for 0.5 hours. Then, dry ice (69.2 g, 1.57 mol, 10.0 eq) was slowly added to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 12 hours. TLC monitoring showed that the reaction proceeds were completely reacted. The reaction solution was quenched with a saturated ammonium chloride aqueous solution (400 mL). After quenching, the mixture was concentrated to remove most of the tetrahydrofuran, resulting in the precipitation of a solid. The solid was then filtered, and the resulting filter cake was dried and concentrated to obtain 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (31.0 g, 116 mmol, 73.9% yield). LC-MS RT = 0.349 min, MS (ESI) m / z = 267.9 [M+1] +

[0112] Step 2: Synthesis of methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0113] 3-Bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (15.0 g, 56.3 mmol, 1.00 eq) was dissolved in methanol (150 mL) and tetrahydrofuran (150 mL). The reaction solution was cooled to 0 °C, and then trimethylsilyldiazomethane (2 M, 84.4 mL, 3.00 eq) was slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.577 min). The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (12.5 g, 44.6 mmol, 79.2% yield). LCMS RT = 0.577 min, MS (ESI) m / z = 281.9 [M+1] +

[0114] Step 3: Synthesis of methyl 5-chloro-3-(4-fluorophenyl)-2-methoxy-pyridine-4-carboxylic acid

[0115] Methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (4.00 g, 14.3 mmol, 1.00 eq), 4-fluorophenylboronic acid (2.19 g, 15.69 mmol, 1.10 eq), potassium carbonate (5.91 g, 42.8 mmol, 3.00 eq), and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (1.16 g, 1.43 mmol, 0.10 eq) were dissolved in dioxane (40 mL) and water (8 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.566 min). The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (80 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-chloro-3-(4-fluorophenyl)-2-methoxy-pyridine-4-carboxylic acid (4.00 g, 13.5 mmol, 94.9% yield). LC-MS RT = 0.566 min, MS (ESI) m / z = 295.9 [M+1] +

[0116] Step 4: Synthesis of methyl 3-(4-fluorophenyl)-5-isopropenyl-2-methoxy-pyridine-4-carboxylic acid

[0117] Methyl 5-chloro-3-(4-fluorophenyl)-2-methoxypyridine-4-carboxylic acid (4.00 g, 13.5 mmol, 1.00 eq), phenazine isopropenylborate (2.96 g, 17.6 mmol, 1.30 eq), 2-dicyclohexylphosphine-2,6-dimethoxyoxybiphenyl (555 mg, 1.35 mmol, 0.10 eq), potassium carbonate (5.61 g, 40.6 mmol, 3.00 eq), and palladium acetate (303.70 mg, 1.35 mmol, 0.10 eq) were dissolved in dioxane (40 mL) and water (8 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.567 min). The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 3-(4-fluorophenyl)-5-isopropenyl-2-methoxy-pyridine-4-carboxylic acid (3.50 g, 11.6 mmol, 85.9% yield). LCMS RT = 0.567 min, MS (ESI) m / z = 302.2 [M+1] +

[0118] Step 5: Synthesis of methyl 3-(4-fluorophenyl)-5-isopropyl-2-methoxy-pyridine-4-carboxylic acid

[0119] Methyl 3-(4-fluorophenyl)-5-isopropyl-2-methoxy-pyridine-4-carboxylic acid (3.50 g, 11.6 mmol, 1.00 eq) was dissolved in methanol (40 mL), and then wet palladium on carbon (350 mg, 10% purity) was added in portions. After the addition was complete, the reaction solution was purged three times under a hydrogen atmosphere, and then stirred at 50 °C for 12 hours under a hydrogen (50 Psi) atmosphere. The MS value of the product was monitored by LCMS (RT = 0.576 min). The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 3-(4-fluorophenyl)-5-isopropyl-2-methoxy-pyridine-4-carboxylic acid (3.40 g, 11.2 mmol, 96.5% yield). LCMS RT = 0.576 min, MS (ESI) m / z = 304.0 [M+1] +

[0120] Step 6: Synthesis of methyl 3-(4-fluorophenyl)-5-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid

[0121] Methyl 3-(4-fluorophenyl)-5-isopropyl-2-methoxy-pyridine-4-carboxylic acid (3.40 g, 11.2 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL), and then trimethyliodosilane (4.71 g, 23.5 mmol, 2.10 eq) was added. After the addition was complete, the reaction mixture was stirred at 50 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.486 min). The reaction mixture was cooled to room temperature, then diluted with water (100 mL), and extracted with ethyl acetate (50 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 3-(4-fluorophenyl)-5-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid (2.65 g, 9.16 mmol, 81.7% yield). LCMS RT=0.486min,MS(ESI)m / z=290.1[M+1] +

[0122] Step 7: Synthesis of 3-(4-fluorophenyl)-4-(hydroxymethyl)-5-isopropyl-1H-pyridin-2-one

[0123] Methyl 3-(4-fluorophenyl)-5-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid (1.65 g, 5.70 mmol, 1.00 eq) was dissolved in dichloromethane (20 mL) and cooled to -50 °C. Then, diisobutylaluminum hydride (1 M, 22.8 mL, 4.00 eq) was slowly added dropwise to the reaction solution, with the temperature maintained at approximately -50 °C throughout the addition. After the addition was complete, the reaction solution was stirred at 0 °C for 4 hours. TLC monitoring showed that the starting material reacted completely. The reaction solution was quenched at approximately 0 °C with a saturated ammonium chloride aqueous solution (200 mL) and then extracted with dichloromethane (100 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 3-(4-fluorophenyl)-4-(hydroxymethyl)-5-isopropyl-1H-pyridin-2-one (1.05 g, 4.02 mmol, 70.5% yield). LCMS RT = 0.408 min, MS (ESI) m / z = 262.0 [M+1] +

[0124] Step 8: Synthesis of 4-(bromomethyl)-3-(4-fluorophenyl)-5-isopropyl-1H-pyridin-2-one

[0125] 3-(4-fluorophenyl)-4-(hydroxymethyl)-5-isopropyl-1H-pyridin-2-one (1.05 g, 4.02 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Phosphorus tribromide (1.63 g, 6.03 mmol, 1.50 eq) was then slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 3 hours. The MS value of the product was monitored by LCMS (RT = 0.510 min). The reaction solution was quenched at approximately 0 °C with a saturated sodium bicarbonate aqueous solution (30 mL), and then extracted with dichloromethane (20 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(bromomethyl)-3-(4-fluorophenyl)-5-isopropyl-1H-pyridin-2-one (1.20 g, 3.70 mmol, 92.1% yield). It was used directly in the next step without purification. LCMS RT = 0.5 × 10 min, MS (ESI) m / z = 324.0 [M+1] +

[0126] Step 9: Synthesis of 3-(4-fluorophenyl)-5-isopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one

[0127] 4-(bromomethyl)-3-(4-fluorophenyl)-5-isopropyl-1H-pyridin-2-one (1.20 g, 3.70 mmol, 1.00 eq) and triphenylphosphine (1.17 g, 4.44 mmol, 1.20 eq) were dissolved in toluene (15 mL), and the reaction mixture was stirred at 100 °C for 2 h. The MS value of the product was monitored by LCMS (RT = 0.429 min). The reaction mixture was concentrated to give 3-(4-fluorophenyl)-5-isopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one (1.80 g, 3.56 mmol, 96.2% yield). No purification was performed; it was used directly in the next step. LCMS RT = 0.429 min, MS(ESI) m / z = 506.3 [M+1] +

[0128] Step 10: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-(4-fluorophenyl)-5-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0129] 3-(4-fluorophenyl)-5-isopropyl-4-[(triphenylphosphine)methyl]-1H-pyridin-2-one (1.80 g, 3.56 mmol, 1.00 eq), 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (1.01 g, 3.92 mmol, 1.10 eq)] and potassium carbonate (984 mg, 7.12 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (20 mL), and the reaction mixture was stirred at 110 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.580 min). The reaction mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (50 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-(4-fluorophenyl)-5-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (800 mg, 1.65 mmol, 46.3% yield). LCMS RT = 0.580 min, MS (ESI) m / z = 486.3 [M+1] +

[0130] Step 11: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-5-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0131] 400 mg, 824 μmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-(4-fluorophenyl)-5-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate, (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-dioxane-4-yl]acetate. Amine (368 mg, 824 μmol, 1.00 eq), cuprous iodide (47.1 mg, 247 μmol, 0.30 eq), potassium carbonate (342 mg, 2.47 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (35.2 mg, 247 μmol, 0.30 eq) were dissolved in dimethyl sulfoxide (8 mL), and the mixture was stirred at 110 °C for 3 h. The MS value of the product was monitored by LCMS (RT = 0.584 min). The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by reverse-phase column chromatography (column: Phenomenex luna C18 150 * 40 mm * 15 μm; mobile phase: [water(FA)-ACN]; gradient: 50%-80% B over 15 min) to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-5-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (330 mg, 410 μmol, 49.8% yield). LCMS RT=0.584min,MS(ESI)m / z=805.3[M+1] +

[0132] Step 12: Synthesis of methyl(E,3R,5S)-7-[1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-5-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoate]

[0133] 300 mg, 373 μmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-5-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was dissolved in methanol (5 mL), and then HCl / MeOH (2 M, 5 mL, 26.8 eq) was added. After the addition was complete, the reaction mixture was stirred at 20 °C for 5 hours. The MS value of the product was monitored by LCMS (RT = 0.451 min). The reaction solution was concentrated to give methyl(E,3R,5S)-7-[1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-5-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoate (250 mg, 345.90 μmol, 92.8% yield). It was used directly in the next step without purification. LCMS RT = 0.451 min, MS (ESI) m / z = 723.3 [M+1] +

[0134] Step 13: Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(4-fluorophenyl)-5-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0135] 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4S)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one (250 mg, 346 μmol, 1.00 eq) was dissolved in MeOH (5 mL), and then NaOH (2 M, 700 μL, 4.00 eq) aqueous solution was added dropwise to the reaction solution. The reaction solution was stirred at 20 °C for 5 hours, and the MS value of the product was monitored by LCMS (RT = 0.428 min). The reaction solution was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (column: Waters Xbridge). 150*25mm*5um; Mobile phase: [water(NH4HCO3)-ACN]; Gradient: 10%-40% B over 15min) yielded (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-(4-fluorophenyl)-5-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid (145.12 mg). LCMS RT = 0.428 min, MS (ESI) m / z = 709.3 [M-1] +

[0136] 1 H NMR (400MHz, DMSO-d6): δ8.23(s,2H),7.98(d,J=2.6Hz,1H),7.51-7.40(m,2H),7.32(s,1H),7.19(dd,J=5 .9,8.8Hz,2H),7.14-6.83(m,4H),6.52(d,J=9.0Hz,1H),6.27(d,J=16.0Hz,1H),5.38(dd,J=5.4,16.1Hz, 1H),4.38-4.25(m,2H),4.04(q,J=6.4Hz,1H),3.71-3.64(m,1H),2.95(td,J=7.0,13.7Hz,2H),2.20-2.06 (m,4H),1.96-1.81(m,2H),1.60-1.42(m,2H),1.41-1.31(m,1H),1.15(d,J=6.9Hz,6H),1.12-1.07(m,1H).

[0137] Example 3

[0138] Synthesize (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid (3).

[0139] Step 1: Synthesis of 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0140] 3-Bromo-5-chloro-2-methoxypyridine (35.0 g, 157 mmol, 1.00 eq) was dissolved in tetrahydrofuran (350 mL) and cooled to -70 °C. Then, lithium diisopropylamine (2 M, 110 mL, 1.40 eq) was slowly added dropwise to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was stirred at -70 °C for 0.5 hours. Then, dry ice (69.2 g, 1.57 mol, 10.0 eq) was slowly added to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 12 hours. TLC monitoring showed that the reaction proceeds were completely reacted. The reaction solution was quenched with a saturated ammonium chloride aqueous solution (400 mL). After quenching, the mixture was concentrated to remove most of the tetrahydrofuran, resulting in the precipitation of a solid. The solid was then filtered, and the resulting filter cake was dried and concentrated to obtain 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (31.0 g, 116 mmol, 73.9% yield). LC-MS RT = 0.349 min, MS (ESI) m / z = 267.9 [M+1] +

[0141] Step 2: Synthesis of methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0142] 3-Bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (15.0 g, 56.3 mmol, 1.00 eq) was dissolved in methanol (150 mL) and tetrahydrofuran (150 mL). The reaction solution was cooled to 0 °C, and then trimethylsilyldiazomethane (2 M, 84.4 mL, 3.00 eq) was slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.577 min). The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (12.5 g, 44.6 mmol, 79.2% yield). LCMS RT = 0.577 min, MS (ESI) m / z = 281.9 [M+1] +

[0143] Step 3: Synthesis of methyl 5-chloro-3-isopropenyl-2-methoxy-pyridine-4-carboxylate

[0144] Methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (5.00 g, 17.8 mmol, 1.00 eq), phenazine isopropenylborate (3.29 g, 19.6 mmol, 1.10 eq), potassium carbonate (7.39 g, 53.5 mmol, 3.00 eq), and 1,1-bis(diphenylphosphine)ferrocene palladium(II) dichloromethane complex (1.46 g, 1.78 mmol, 0.10 eq) were dissolved in dioxane (50 mL) and water (10 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.609 min). The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (80 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-chloro-3-isopropenyl-2-methoxy-pyridine-4-carboxylate (4.20 g, 17.4 mmol, 97.5% yield). LCMS RT = 0.609 min, MS (ESI) m / z = 242.0 [M+1] +

[0145] Step 4: Synthesis of methyl 5-(4-fluorophenyl)-3-isopropenyl-2-methoxy-pyridine-4-carboxylic acid

[0146] Methyl 5-chloro-3-isopropenyl-2-methoxypyridine-4-carboxylic acid (4.20 g, 17.4 mmol, 1.00 eq), 4-fluorophenylboronic acid (3.16 g, 22.6 mmol, 1.30 eq), 2-dicyclohexylphosphine-2,6-dimethoxyoxybiphenyl (713 mg, 1.74 mmol, 0.10 eq), potassium carbonate (7.21 g, 52.1 mmol, 3.00 eq), and palladium acetate (390 mg, 1.74 mmol, 0.10 eq) were dissolved in dioxane (40 mL) and water (8 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.572 min). The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-3-isopropenyl-2-methoxy-pyridine-4-carboxylic acid (4.50 g, 14.9 mmol, 85.9% yield). LCMS RT = 0.572 min, MS (ESI) m / z = 302.0 [M+1] +

[0147] Step 5: Synthesis of methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid

[0148] Methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid (4.50 g, 14.9 mmol, 1.00 eq) was dissolved in methanol (50 mL), and then wet palladium on carbon (450 mg, 423 μmol, 10% purity) was added in portions. After the addition was complete, the reaction solution was purged three times under a hydrogen atmosphere, and then stirred at 50 °C for 12 h under a hydrogen (50 Psi) atmosphere. The MS value of the product was monitored by LC-MS (RT = 0.668 min). The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid (4.00 g, 13.19 mmol, 88.3% yield). LCMS RT=0.668min,MS(ESI)m / z=304.1[M+1] +

[0149] Step 6: Synthesis of methyl 5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid

[0150] Methyl 5-(4-fluorophenyl)-3-isopropyl-2-methoxy-pyridine-4-carboxylic acid (4.00 g, 13.2 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL), and then trimethyliodosilane (5.54 g, 27.7 mmol, 2.10 eq) was added. After the addition was complete, the reaction mixture was stirred at 80 °C for 2 hours. TLC showed that the reaction proceeds were completely reacted. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid (2.50 g, 8.64 mmol, 65.5% yield). LCMS RT=0.504min,MS(ESI)m / z=290.1[M+1] +

[0151] Step 7: Synthesis of 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-isopropyl-1H-pyridin-2-one

[0152] Methyl 5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridine-4-carboxylic acid (2.50 g, 8.64 mmol, 1.00 eq) was dissolved in dichloromethane (30 mL) and cooled to -50 °C. Then, diisobutylaluminum hydride (1 M, 34.6 mL, 4.00 eq) was slowly added dropwise to the reaction solution, with the temperature maintained at approximately -50 °C throughout the addition. After the addition was complete, the reaction solution was stirred at 0 °C for 4 hours. TLC monitoring showed that the starting material had reacted completely. The reaction solution was quenched at approximately 0 °C with a saturated ammonium chloride aqueous solution (200 mL) and then extracted with dichloromethane (100 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-isopropyl-1H-pyridin-2-one (850 mg, 3.25 mmol, 37.6% yield). LCMS RT = 0.442 min, MS (ESI) m / z = 262.2 [M+1] +

[0153] Step 8: Synthesis of 4-(bromomethyl)-5-(4-fluorophenyl)-3-isopropyl-1H-pyridin-2-one

[0154] 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-isopropyl-1H-pyridin-2-one (370 mg, 1.42 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Phosphorus tribromide (575 mg, 2.12 mmol, 1.50 eq) was then slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 3 hours. The MS value of the product was monitored by LCMS (RT = 0.530 min). The reaction solution was quenched at approximately 0 °C with a saturated sodium bicarbonate aqueous solution (30 mL), and then extracted with dichloromethane (20 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(bromomethyl)-5-(4-fluorophenyl)-3-isopropyl-1H-pyridin-2-one (850 mg, 2.62 mmol, 92.6% yield). It was used directly in the next step without purification. LCMS RT = 0.530 min, MS (ESI) m / z = 324.0 [M+1] +

[0155] Step 9: Synthesis of 5-(4-fluorophenyl)-3-isopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one

[0156] 4-(bromomethyl)-5-(4-fluorophenyl)-3-isopropyl-1H-pyridin-2-one (850 mg, 2.62 mmol, 1.00 eq) and triphenylphosphine (825 mg, 3.15 mmol, 1.20 eq) were dissolved in toluene (10 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.464 min). The reaction mixture was concentrated to give 5-(4-fluorophenyl)-3-isopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one (1.30 g, 2.57 mmol, 98.1% yield). No purification was performed; it was used directly in the next step. LCMS RT = 0.464 min, MS (ESI) m / z = 506.3 [M+1] +

[0157] Step 10: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0158] 5-(4-fluorophenyl)-3-isopropyl-4-[(triphenylphosphine)methyl]-1H-pyridin-2-one (1.30 g, 2.57 mmol, 1.00 eq), 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (691 mg, 2.83 mmol, 1.10 eq), and potassium carbonate (712 mg, 5.14 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (20 mL), and the reaction mixture was stirred at 110 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.587 min). The reaction mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (50 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (870 mg, 1.79 mmol, 69.7% yield). LCMS RT = 0.587 min, MS (ESI) m / z = 486.2 [M+1]. +

[0159] Step 11: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0160] tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (840 mg, 1.73 mmol, 1.00 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3- Diamine (774 mg, 1.73 mmol, 1.00 eq), cuprous iodide (98.9 mg, 519 μmol, 0.30 eq), potassium carbonate (717 mg, 5.19 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (73.8 mg, 519 μmol, 0.30 eq) were dissolved in dimethyl sulfoxide (10 mL), and then stirred at 110 °C for 3 h. The MS value of the product was monitored by LCMS (RT = 0.571 min). The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl-2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.30 g, 1.62 mmol, 93.4% yield). It was used directly in the next step without purification. LCMS RT = 0.571 min, MS (ESI) m / z = 805.4 [M+1] +

[0161] Step 12: Synthesis of 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one

[0162] 900 mg, 1.12 mmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was dissolved in 10 mL of dichloromethane, and then HCl / dioxane (4 M, 10 mL, 35.8 eq) was added. After the addition was complete, the reaction mixture was stirred at 20 °C for 5 hours. The reaction was confirmed to be complete, and the reaction solution was concentrated to obtain 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one (700 mg, crude). It was used directly in the next step without purification.

[0163] Step 13: Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0164] 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one (700 mg, crude) was dissolved in MeOH (10 mL). Then, NaOH (1 M) aqueous solution was added dropwise to the reaction solution until pH = 13. The reaction solution was stirred at 20 °C for 3 hours, and the reaction was checked for completeness. The reaction solution was concentrated to obtain the crude product, which was then purified by reverse-phase column chromatography (column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH3H2O)-ACN]; gradient: 0%-30% B over). (12 min) yielded (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid (125.15 mg).

[0165] LCMS RT=0.383min,MS(ESI)m / z=707.2[M-1] +

[0166] 1 H NMR (400MHz, DMSO-d6): δ8.23(s,2H),7.98(d,J=2.5Hz,1H),7.51-7.41(m,2H),7.35-7.26(m,3H ),7.23-6.82(m,4H),6.51(d,J=8.9Hz,1H),6.27(d,J=15.9Hz,1H),5.42(dd,J=4.9,16.2Hz,1H), 4.37-4.24(m,2H),4.12(q,J=6.1Hz,1H),3.57(dt,J=4.3,8.1Hz,1H),2.20-2.05(m,2H),2.03-1. 73(m,4H),1.60-1.45(m,2H),1.44-1.35(m,1H),1.32-1.21(m,6H),1.14(td,J=5.3,13.4Hz,1H).

[0167] Examples 4-8

[0168] Compounds 4-8 were prepared according to the aforementioned preparation examples:

[0169] Examples 9 and 10

[0170] Synthesized 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-methyl-2H-[1,3'-bipyridine]-2-one (9) and (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-methyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid (10).

[0171] Step 1: Synthesis of 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0172] 3-Bromo-5-chloro-2-methoxypyridine (35.0 g, 157 mmol, 1.00 eq) was dissolved in tetrahydrofuran (350 mL) and cooled to -70 °C. Then, lithium diisopropylamine (2 M, 110 mL, 1.40 eq) was slowly added dropwise to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was stirred at -70 °C for 0.5 hours. Then, dry ice (69.2 g, 1.57 mol, 10.0 eq) was slowly added to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 12 hours. TLC monitoring showed that the reaction proceeds were completely reacted. The reaction solution was quenched with a saturated ammonium chloride aqueous solution (400 mL). After quenching, the mixture was concentrated to remove most of the tetrahydrofuran, resulting in the precipitation of a solid. The solid was then filtered, and the resulting filter cake was dried and concentrated to obtain 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (31.0 g, 116 mmol, 73.9% yield). LC-MS RT = 0.349 min, MS (ESI) m / z = 267.9 [M+1] +

[0173] Step 2: Synthesis of methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0174] 3-Bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (15.0 g, 56.3 mmol, 1.00 eq) was dissolved in methanol (150 mL) and tetrahydrofuran (150 mL). The reaction solution was cooled to 0 °C, and then trimethylsilyldiazomethane (2 M, 84.4 mL, 3.00 eq) was slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.577 min). The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (12.5 g, 44.6 mmol, 79.2% yield). LCMS RT = 0.577 min, MS (ESI) m / z = 281.9 [M+1] +

[0175] Step 3: Synthesis of methyl 5-chloro-2-methoxy-3-methylisonicotinic acid

[0176] Methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (10.5 g, 37.4 mmol, 1.00 eq), methylboronic acid (2.46 g, 41.2 mmol, 1.10 eq), potassium carbonate (15.5 g, 112 mmol, 3.00 eq), and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (3.06 g, 3.74 mmol, 0.10 eq) were dissolved in dioxane (100 mL) and water (20 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 3 hours. The MS value of the product was monitored by LCMS (RT = 0.551 min). The reaction mixture was cooled to room temperature, then diluted with water (200 mL) and extracted with ethyl acetate (100 mL * 2). The concentrated organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-chloro-2-methoxy-3-methylisonicotinic acid (8.00 g, 37.1 mmol, 99.1% yield). LCMS RT = 0.551 min, MS (ESI) m / z = 216.1 [M+1] +

[0177] Step 4: Synthesis of methyl 5-(4-fluorophenyl)-2-methoxy-3-methylisonicotinic acid

[0178] Methyl 5-chloro-3-isopropenyl-2-methoxypyridine-4-carboxylic acid (4.00 g, 18.6 mmol, 1.00 eq), 4-fluorophenylboronic acid (3.37 g, 24.1 mmol, 1.30 eq), 2-dicyclohexylphosphine-2,6-dimethoxyoxybiphenyl (762 mg, 1.86 mmol, 0.10 eq), potassium carbonate (7.69 g, 55.7 mmol, 3.00 eq), and palladium acetate (416 mg, 1.86 mmol, 0.10 eq) were dissolved in dioxane (40 mL) and water (8 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.592 min). The reaction mixture was cooled to room temperature, then diluted with water (200 mL) and extracted with ethyl acetate (100 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-2-methoxy-3-methylisonicotinic acid (5.00 g, 18.16 mmol, 97.92% yield). LCMS RT = 0.592 min, MS (ESI) m / z = 276.0 [M+1] +

[0179] Step 5: Synthesis of methyl 5-(4-fluorophenyl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid

[0180] Methyl 5-(4-fluorophenyl)-2-methoxy-3-methylisonicotinic acid (5.00 g, 18.2 mmol, 1.00 eq) was dissolved in acetonitrile (50 mL), and then trimethyliodosilane (7.63 g, 38.2 mmol, 2.10 eq) was added. After the addition was complete, the reaction mixture was stirred at 80 °C for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.439 min). The reaction mixture was cooled to room temperature, alkalized to pH 7-8 with saturated NaHCO3 solution, and extracted with ethyl acetate (100 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2) and saturated sodium sulfite (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-(4-fluorophenyl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (4.00 g, 15.3 mmol, 84.3% yield). LCMS RT = 0.439 min, MS (ESI) m / z = 262.0 [M+1] +

[0181] Step 6: Synthesis of 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-methylpyridin-2(1H)-one

[0182] Methyl 5-(4-fluorophenyl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ester (4.00 g, 15.3 mmol, 1.00 eq) was dissolved in dichloromethane (40 mL) and cooled to -50 °C. Then, diisobutylaluminum hydride (1 M, 61.2 mL, 4.00 eq) was slowly added dropwise to the reaction solution while maintaining the temperature at approximately -50 °C. After the addition was complete, the reaction solution was stirred at 0 °C for 4 hours. The MS value of the product was monitored by LCMS (RT = 0.384 min). The reaction solution was quenched at approximately 0 °C with a saturated aqueous solution of potassium sodium tartrate (200 mL) and then extracted with dichloromethane (100 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-methylpyridin-2(1H)-one (3.00 g, 12.9 mmol, 84.0% yield). LCMS RT = 0.384 min, MS (ESI) m / z = 234.0 [M+1] +

[0183] Step 7: Synthesis of 4-(bromomethyl)-5-(4-fluorophenyl)-3-methylpyridin-2(1H)-one

[0184] 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-methylpyridin-2(1H)-one (3.00 g, 12.9 mmol, 1.00 eq) was dissolved in dichloromethane (30 mL) and cooled to 0 °C. Phosphorus tribromide (5.22 g, 19.3 mmol, 1.50 eq) was then slowly added dropwise to the reaction solution while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction solution was stirred at 20 °C for 3 hours. The MS value of the product was monitored by LCMS (RT = 0.489 min). The reaction solution was quenched at approximately 0 °C with a saturated sodium bicarbonate aqueous solution (200 mL), and then extracted with dichloromethane (100 mL * 2). The concentrated organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(bromomethyl)-5-(4-fluorophenyl)-3-methylpyridin-2(1H)-one (3.26 g, 11.0 mmol, 85.6% yield). It was used directly in the next step without purification. LCMS RT = 0.489 min, MS (ESI) m / z = 297.9 [M+1] +

[0185] Step 8: Synthesis of [5-(4-fluorophenyl)-3-methyl-2-oxo-1H-pyridin-4-yl]methyl-triphenylphosphine; bromide

[0186] 4-(bromomethyl)-5-(4-fluorophenyl)-3-methylpyridin-2(1H)-one (3.00 g, 10.1 mmol, 1.00 eq) and triphenylphosphine (3.19 g, 12.2 mmol, 1.20 eq) were dissolved in toluene (30 mL), and the reaction mixture was stirred at 100 °C for 2 h. The MS value of the product was monitored by LCMS (RT = 0.438 min). The reaction mixture was concentrated to give [5-(4-fluorophenyl)-3-methyl-2-oxo-1H-pyridin-4-yl]methyl-triphenylphosphine; bromide (5.60 g, 10.0 mmol, 99.0% yield). No purification was performed; it was used directly in the next step. LCMS RT = 0.438 min, MS(ESI) m / z = 478.2 [M+1] +

[0187] Step 9: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-methyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0188] [5-(4-fluorophenyl)-3-methyl-2-oxo-1H-pyridin-4-yl]methyl-triphenylphosphine; bromide (5.60 g, 10.0 mmol, 1.00 eq), 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (2.85 g, 11.0 mmol, 1.10 eq), and potassium carbonate (2.77 g, 20.0 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (60 mL), and the reaction mixture was stirred at 110 °C for 2 h. The MS value of the product was monitored by LCMS (RT = 0.558 min). The reaction mixture was cooled to room temperature, then diluted with water (150 mL), and extracted with ethyl acetate (100 mL * 2). The concentrated organic phase was washed with saturated brine (200 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-methyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.50 g, 3.28 mmol, 32.7% yield). LCMS RT = 0.558 min, MS (ESI) m / z = 458.2 [M+1] +

[0189] Step 10: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-methyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0190] 1.20 g, 2.62 mmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-methyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate, (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3 1,2-dimethylcyclohexane-1,2-diamine (1.17 g, 2.62 mmol, 1.00 eq), cuprous iodide (150 mg, 787 μmol, 0.30 eq), potassium carbonate (1.09 g, 7.87 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (112 mg, 787 μmol, 0.30 eq) were dissolved in dimethyl sulfoxide (20 mL) and stirred at 110 °C for 3 h. The MS value of the product was monitored by LCMS (RT = 0.567 min). The reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (100 mL * 2). The concentrated organic phase was washed with saturated brine (200 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-methyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.40 g, 1.80 mmol, 68.7% yield). LCMS RT = 0.567 min, MS (ESI) m / z = 777.3 [M+1]. +

[0191] Step 11: Synthesis of 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-methyl-2H-[1,3'-bipyridine]-2-one

[0192] 250 mg (322 μmol, 1.00 eq) of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-methyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was dissolved in dichloromethane (5 mL), followed by the addition of TFA (3.84 g, 33.7 mmol, 2.50 mL, 105 eq). The reaction mixture was stirred at 20 °C for 1 hour. The MS value of the product was monitored by LCMS (RT = 0.433 min). The reaction solution was concentrated to obtain a crude product, which was then purified by reverse-phase column chromatography (column: Phenomenex Luna C18 150*40mm*15um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 18%-48% B over 15.0 min) to obtain 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-methyl-2H-[1,3'-bipyridine]-2-one (118.96 mg). LCMS RT = 0.433 min, MS (ESI) m / z = 663.2 [M+1] +

[0193] 1 H NMR, (400MHz, DMSO-d6): δ8.23(s,2H),8.00(d,J=2.6Hz,1H),7.50-7.42(m,2H),7.39(s,1H),7.36-7.29(m ,2H),7.23-6.83(m,4H),6.52(d,J=9.0Hz,1H),6.39(d,J=16.4Hz,1H),5.61(dd,J=6.3,16.3Hz,1H),5.25( d,J=3.1Hz,1H),5.15-5.07(m,1H),4.31(sxt,J=6.8Hz,2H),4.10-4.04(m,1H),2.64(dd,J=4.6,17.5Hz,1H ),2.38(td,J=1.8,17.5Hz,1H),2.19-2.06(m,4H),1.95-1.82(m,2H),1.78-1.62(m,2H),1.58-1.43(m,2H).

[0194] Step 12: Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-methyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0195] 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-methyl-2H-[1,3'-bipyridine]-2-one (300 mg, 432 μmol, 1.00 eq) was dissolved in MeOH (5 mL), and then NaOH aqueous solution (1 M, 0.5 mL, 1.16 eq) was added dropwise to the reaction solution. The reaction solution was stirred at 20 °C for 1 hour. The MS value of the product was monitored by LCMS (RT = 0.423 min). The reaction solution was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (column: Phenomenex Luna C18). 150*25mm*10um; Mobile phase: [H2O(0.225% FA)-ACN]; Gradient: 10%-40% B over 15.0min) yielded (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-methyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid (203.66 mg). LCMS RT = 0.423 min, MS (ESI) m / z = 681.3 [M+1] +

[0196] 1H NMR, (400MHz, DMSO-d6): δ8.24(s,2H),8.01(d,J=2.8Hz,1H),7.53-7.42(m,2H),7.38-7.29 (m,3H),7.24-6.83(m,4H),6.53(d,J=9.0Hz,1H),6.24(d,J=16.1Hz,1H),5.60(dd,J=5.8,1 6.3Hz,1H),4.38-4.26(m,2H),4.22-4.12(m,1H),3.90-3.79(m,1H),2.36-2.28(m,1H),2.2 7-2.19(m,1H),2.18-2.08(m,5H),1.98-1.82(m,2H),1.61-1.45(m,3H),1.43-1.33(m,1H).

[0197] Example 11

[0198] Compound 11 was prepared according to the above-described compound preparation method:

[0199] Example 12

[0200] Synthesize (3R,5S,E)-7-(3-cyclopropyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid (12).

[0201] Step 1: Synthesis of 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0202] 3-Bromo-5-chloro-2-methoxypyridine (35.0 g, 157 mmol, 1.00 eq) was dissolved in tetrahydrofuran (350 mL) and cooled to -70 °C. Then, lithium diisopropylamine (2 M, 110 mL, 1.40 eq) was slowly added dropwise to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was stirred at -70 °C for 0.5 hours. Then, dry ice (69.2 g, 1.57 mol, 10.0 eq) was slowly added to the reaction solution, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 12 hours. TLC monitoring showed that the reaction proceeds were completely reacted. The reaction solution was quenched with a saturated ammonium chloride aqueous solution (400 mL). After quenching, the mixture was concentrated to remove most of the tetrahydrofuran, resulting in the precipitation of a solid. The solid was then filtered, and the resulting filter cake was dried and concentrated to obtain 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (31.0 g, 73.9% yield). MS (ESI) m / z = 267.9 [M+1] +

[0203] Step 2: Synthesis of methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0204] 15.0 g (56.3 mmol, 1.00 eq) of 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid was dissolved in 150 mL of methanol and 150 mL of tetrahydrofuran. The reaction mixture was cooled to 0 °C, and then trimethylsilyldiazomethane (2 M, 84.4 mL, 3.00 eq) was slowly added dropwise to the reaction mixture while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 2 hours. TLC monitoring showed complete reaction of the starting materials. The reaction mixture was concentrated to obtain a crude product, which was then purified by silica gel column chromatography to obtain methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (12.5 g, 79.2% yield). MS (ESI) m / z = 281.9 [M+1] +

[0205] Step 3: Synthesis of methyl 5-chloro-3-cyclopropyl-2-methoxyisonicotinic acid

[0206] Methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (5.00 g, 17.8 mmol, 1.00 eq), cyclopropylboronic acid (1.84 g, 21.4 mmol, 1.2 eq), potassium carbonate (7.39 g, 53.5 mmol, 3.00 eq), and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (1.46 g, 1.78 mmol, 0.10 eq) were dissolved in dioxane (50 mL x 2) and water (10 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LC-MS. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-chloro-3-cyclopropyl-2-methoxyisonicotinic acid (4.21 g, 97.5% yield). MS (ESI) m / z = 242.1 [M+1] +

[0207] Step 4: Synthesis of methyl 3-cyclopropyl-5-(4-fluorophenyl)-2-methoxyisonicotinic acid

[0208] Methyl 5-chloro-3-cyclopropyl-2-methoxyisonicotinic acid (4.20 g, 17.4 mmol, 1.00 eq), 4-fluorophenylboronic acid (3.17 g, 22.6 mmol, 1.30 eq), 2-dicyclohexylphosphine-2,6-dimethoxyoxybiphenyl (713 mg, 1.74 mmol, 0.10 eq), potassium carbonate (7.21 g, 52.1 mmol, 3.00 eq), and palladium acetate (390 mg, 1.74 mmol, 0.10 eq) were dissolved in dioxane (40 mL) and water (8 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LC-MS. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 3-cyclopropyl-5-(4-fluorophenyl)-2-methoxyisonicotinic acid (4.51 g, 85.9% yield). MS (ESI) m / z = 302.1 [M+1] +

[0209] Step 5: Synthesis of methyl 3-cyclopropyl-5-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid

[0210] Methyl 3-cyclopropyl-5-(4-fluorophenyl)-2-methoxyisonicotinic acid (4.00 g, 13.2 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL), and then trimethyliodosilane (5.54 g, 27.7 mmol, 2.10 eq) was added. After the addition was complete, the reaction mixture was stirred at 80 °C for 2 hours. TLC showed that the reaction proceeds were completely reacted. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain methyl 3-cyclopropyl-5-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.49 g, 65.5% yield). MS (ESI) m / z = 288.2 [M+1] +

[0211] Step 6: Synthesis of 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-cyclopropylpyridine-2(1H)-one

[0212] Methyl 3-cyclopropyl-5-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.49 g, 8.64 mmol, 1.00 eq) was dissolved in dichloromethane (30 mL) and cooled to -50 °C. Then, diisobutylaluminum hydride (1 M, 34.6 mL, 4.00 eq) was slowly added dropwise to the reaction solution, with the temperature maintained at approximately -50 °C throughout the addition. After the addition was complete, the reaction solution was stirred at 0 °C for 4 hours. TLC monitoring showed that the starting material had reacted completely. The reaction solution was quenched at approximately 0 °C with a saturated ammonium chloride aqueous solution (200 mL) and then extracted with dichloromethane (100 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-cyclopropylpyridine-2(1H)-one (850 mg, 37.6% yield). MS (ESI) m / z = 260.2 [M+1] +

[0213] Step 7: Synthesis of 4-(bromomethyl)-5-(4-fluorophenyl)-3-cyclopropyl-1H-pyridin-2-one

[0214] 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-cyclopropylpyridin-2(1H)-one (370 mg, 1.42 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Phosphorus tribromide (547 mg, 2.12 mmol, 1.50 eq) was then slowly added dropwise to the reaction mixture while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 3 hours. The MS value of the product was monitored by LC-MS. The reaction mixture was quenched at approximately 0 °C with a saturated sodium bicarbonate aqueous solution (30 mL), followed by extraction with dichloromethane (20 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(bromomethyl)-5-(4-fluorophenyl)-3-cyclopropyl-1H-pyridin-2-one (850 mg). This was used directly in the next step without purification. MS(ESI)m / z = 322.2[M+1] +

[0215] Step 8: Synthesis of 5-(4-fluorophenyl)-3-cyclopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one

[0216] 4-(bromomethyl)-5-(4-fluorophenyl)-3-cyclopropyl-1H-pyridin-2-one (850 mg, 2.62 mmol, 1.00 eq) and triphenylphosphine (832 mg, 3.15 mmol, 1.20 eq) were dissolved in toluene (10 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The MS value of the product was monitored by LCMS. The reaction mixture was concentrated to give 5-(4-fluorophenyl)-3-cyclopropyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one (1.30 g). It was used directly in the next step without purification. MS (ESI) m / z = 504.2 [M+1] +

[0217] Step 9: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-cyclopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0218] 5-(4-fluorophenyl)-3-cyclopropyl-4-[(triphenylphosphine)methyl]-1H-pyridin-2-one (1.30 g, 2.58 mmol, 1.00 eq), 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (733 mg, 2.83 mmol, 1.10 eq), and potassium carbonate (713 mg, 5.14 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (20 mL), and the reaction mixture was stirred at 110 °C for 2 hours. The MS value of the product was monitored by LC-MS. The reaction mixture was cooled to room temperature, then diluted with water (150 mL), and extracted with ethyl acetate (50 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-cyclopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (870 mg, 69.7% yield). MS (ESI) m / z = 484.2 [M+1] +

[0219] Step 10: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-cyclopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0220] tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-cyclopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (840 mg, 1.74 mmol, 1.00 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3- Diamine (777 mg, 1.74 mmol, 1.00 eq), cuprous iodide (98.9 mg, 519 μmol, 0.30 eq), potassium carbonate (717 mg, 5.19 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (73.8 mg, 519 μmol, 0.30 eq) were dissolved in dimethyl sulfoxide (10 mL), and then stirred at 110 °C for 3 hours. The MS values ​​of the products were monitored by LCMS. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl-2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-cyclopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.30 g). It was used directly in the next step without purification. MS (ESI) m / z = 803.4 [M+1] +

[0221] Step 11: Synthesis of 3R,5S,E)-7-(3-cyclopropyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0222] 100 mg, 124 μmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-cyclopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was dissolved in acetonitrile (3 mL). Then, 2 M hydrochloric acid aqueous solution was added to adjust the pH of the system to around 2. After the addition was complete, the reaction solution was stirred at 20 °C for 1 hour. Subsequently, 2 M sodium hydroxide aqueous solution was added to the system to adjust the pH to around 13, and the reaction was continued for 1 hour. The MS value of the product was monitored by LCMS. The reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography (column: Phenomenex luna C18150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 18%-48% B over 15min) to obtain 3R,5S,E)-7-(3-cyclopropyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid (29.6 mg).

[0223] [M+H] + =707, 1 H NMR (400MHz, DMSO-d6)δ 1H NMR(400MHz, DMSO-d6)δ8.24–8.22(s,2H),7.97–7.95(d,J=2.7Hz,1H),7.50–7.46(d ,J=7.2Hz,1H),7.44–7.40(dd,J=8.9,2.7Hz,1H),7.34–7.29(m,3H),7.22–7.12(m,2H ),7.06–6.82(m,2H),6.52–6.49(d,J=8.9Hz,1H),6.38–6.32(dd,J=16.2,1.4Hz,1H), 5.66–5.59(dd,J=16.2,5.6Hz,1H),4.35–4.24(m,2H),4.18–4.11(q,J=6.3Hz,1H),3. 86–3.78(tt,J=8.6,4.6Hz,1H),2.34–2.27(dd,J=14.9,4.6Hz,1H),2.24–2.17(m,1H ),2.16–2.06(tq,J=11.9,3.5,2.7Hz,2H),1.94–1.84(m,2H),1.84–1.75(tt,J=8.6,5 .8Hz,1H),1.59–1.44(dddd,J=16.2,14.1,11.2,6.7Hz,3H),1.39–1.30(dddd,J=13.5, 6.8, 4.6Hz, 1H), 1.00–0.95 (dq, J=5.7, 2.9Hz, 2H), 0.79–0.73 (dq, J=8.8, 3.1Hz, 2H).

[0224] Example 13

[0225] Synthesize (3R,5R)-7-[1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxy-heptanoic acid (13)

[0226] Step 1: Synthesis of 4-(bromomethyl)-1H-pyridin-2-one

[0227] 13-1 (4.00 g, 28.7 mmol, 1.00 eq) was added to HBr (29.8 g, 121 mmol, 20 mL, 33% purity, 4.23 eq). The mixture was stirred at 25 °C for 12 hours.

[0228] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness to obtain compound 13-2 (7.00 g, 22.3 mmol, 77.7% yield) as a brown oil.

[0229] Step 2: Synthesis of 4-[[bromo(triphenyl)-phosphino]methyl]-1H-pyridin-2-one

[0230] To a toluene solution (40 mL) of 13-2 (4.00 g, 21.2 mmol, 1.00 eq), PPh3 (6.70 g, 25.5 mmol, 1.20 eq) was added. The mixture was stirred at 110 °C for 2 hours. The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was slurryed with ethyl acetate to give compound 13-3 (8.00 g, crude) as a white solid.

[0231] Step 3: Synthesis of tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-[(E)-2-(2-oxo-1H-pyridin-4-yl)vinyl]-1,3-dioxane-4-yl]acetate

[0232] Add K₂CO₃ (1.23 g, 8.88 mmol, 2.00 eq) to 20 mL of DMSO solutions of 13-3 (2.00 g, 4.44 mmol, 1.00 eq) and 1a (1.15 g, 4.44 mmol, 1 eq). Stir the mixture at 110 °C for 1 hour.

[0233] The formation of the target product was detected by LCMS. The reaction solution was poured into water (150 mL), extracted with ethyl acetate (200 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by normal-phase preparative chromatography (column: YMC-Gel SiL-HG 250*50mm*10um; mobile phase: [Hexane-EtOH]; gradient: 5%-45% B over 15.0 min) to give compound 13-4 (900 mg, 2.58 mmol, 57.9% yield) as a brown oil.

[0234] Step 4: Synthesis of tert-butyl 2-[(4R,6R)-2,2-dimethyl-6-[2-(2-oxo-1H-pyridin-4-yl)ethyl]-1,3-dioxane-4-yl]acetate

[0235] Solution 1: A 13-4 (900 mg, 2.58 mmol, 1.00 eq) and NH3H2O ​​(271 mg, 1.93 mmol, 0.298 mL, 25% purity, 7.51 e-1 eq) THF solution (45 mL). A fixed bed (designated FLR1, 5 mL volume) was completely packed with particulate catalyst Ru / Al2O3 (3.00 g, 2.58 mmol, 5% purity, 1.00 eq). The H2 pressure regulator was adjusted to 0 MPa, and the H2 flow rate was 30 mL / min. Solution 1 was then pumped into the fixed bed {FLR1, SS, fixed bed, 6.350 (1 / 4”) mm, 1 mL, 31 °C} using pump {S1, P1, 0.4 mL / min}. The reaction mixture was then collected from the reactor effluent.

[0236] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness to obtain compound 13-5 (900 mg, crude) as a brown oil.

[0237] Step 5: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0238] To 10 mL of DMSO solutions of 13-5 (800 mg, 2.28 mmol, 1.00 eq) and 1b (1.02 g, 2.28 mmol, 1.00 eq), Ligand (97.1 mg, 682 μmol, 0.300 eq), CuI (130 mg, 682 μmol, 0.300 eq), and K₂CO₃ (943 mg, 6.83 mmol, 3.00 eq) were added. The mixture was stirred at 110 °C for 1 hour.

[0239] The formation of the target product was detected by LCMS. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (150 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1-0 / 1) to give compound 13-6 (1.30 g, 1.94 mmol, 85.1% yield) as a brown oil.

[0240] Step 6: Synthesis of (3R,5R)-7-[1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxy-heptanoic acid

[0241] To a methanol solution (3 mL) of 13-6 (300 mg, 447 μmol, 1.00 eq), add HCl (44.0 mg, 447 μmol, 1.00 eq). Stir the mixture at 25 °C for 1 hour, then add dropwise a NaOH solution (178 mg, 4.47 mmol, 10.0 eq) in H₂O (1 mL). Stir the mixture at 25 °C for 1 hour.

[0242] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase preparation (column: Waters xbridge 150*25mm 10um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 0%-30% B over 12.0 min) to obtain the target compound (179 mg).

[0243] LC-MS:[M+H] - =575.2. 1 H NMR (DMSO-d6, 400MHz): δ (ppm) = 8.23 ​​(s, 2H), 7.90 (d, J = 2.4Hz, 1H), 7.48 (dd, J = 2.0, 7.2Hz, 2H), 7. 37(dd,J=2.8,8.8Hz,1H),7.25-6.82(m,2H),6.51(d,J=9.0Hz,1H),6.23(s,1H),6.16(dd,J=2.0,7 .2Hz,1H),4.35-4.26(m,2H),3.80(m,1H),3.63(m,1H),2.59-2.52(m,1H),2.47-2.39(m,1H),2.20 -2.02(m,3H),1.94-1.81(m,3H),1.65(td,J=4.0,9.6Hz,1H),1.59-1.43(m,4H),1.42-1.33(m,1H).

[0244] Examples 14-15

[0245] Synthesized 5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[2-[(2R,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]ethyl]pyridin-2-one (14) and (3R,5R)-7-[5-chloro-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxy-heptanoic acid (15)

[0246] Step 1: Synthesis of 5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0247] 2,5-Dichloropyridine-4-carboxylic acid (10 g, 52.08 mmol, 1 eq) and sodium methoxide (8.44 g, 156.25 mmol, 3 eq) were added to dimethyl sulfoxide (40 mL), and the reaction mixture was stirred at 100 °C for 16 hours.

[0248] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 25°C, diluted with water (100 mL), acidified to pH 3 with 1 M HCl solution, and extracted with ethyl acetate (100 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product 5-chloro-2-methoxy-pyridine-4-carboxylic acid (9 g, crude product) as a yellow solid.

[0249] Step 2: Synthesis of methyl 5-chloro-2-methoxy-pyridine-4-carboxylic acid

[0250] Iodomethane (9.53 g, 67.17 mmol, 4.18 mL, 1.4 eq) was added dropwise to a DMF (100 mL) solution of 5-chloro-2-methoxy-pyridine-4-carboxylic acid (9 g, 47.98 mmol, 1 eq) and potassium carbonate (19.89 g, 143.94 mmol, 3 eq) under nitrogen atmosphere at 0–10 °C. After addition, the reaction mixture was stirred at 20–30 °C for 16 hours under nitrogen atmosphere.

[0251] LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product methyl 5-chloro-2-methoxy-pyridine-4-carboxylic acid (7.5 g, crude product), which is a yellow solid.

[0252] Step 3: Synthesis of (5-chloro-2-methoxy-4-pyridyl)methanol

[0253] Solution 1: Methyl 5-chloro-2-methoxy-pyridine-4-carboxylate, 1 eq, 4.5 g DCM solution, 45 mL, pump 1; Solution 2: DIBAL-H, 3.5 equivalents, 11.111 g (1 M, 78.122 mL), pump 2; start pump 1 and pump 2 simultaneously.

[0254] LC-MS showed complete consumption of the starting material and detection of 84% of the target product. Extraction was performed with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product (5-chloro-2-methoxy-4-pyridyl)methanol (3 g, 16.41 mmol) as a yellow solid.

[0255] Step 4: Synthesis of 3-bromo-5-chloro-4-(hydroxymethyl)-1H-pyridin-2-one

[0256] The mixture of (5-chloro-2-methoxy-4-pyridyl)methanol (2.1 g, 12.10 mmol, 1 eq) and hydrobromic acid / acetic acid (20 mL) was stirred at 100 °C under nitrogen for 16 hours.

[0257] LC-MS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure, the residue was diluted with water (30 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL * 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product 4-(bromomethyl)-5-chloro-1H-pyridin-2-one (3.3 g, crude), as a yellow solid.

[0258] Step 5: Synthesis of (5-chloro-2-oxo-1H-pyridin-4-yl)methyl-triphenyl-phosphine; bromide

[0259] 4-(bromomethyl)-5-chloro-1H-pyridin-2-one (3g, 13.49mmol, 1eq) and triphenylphosphine (3.71g, 14.16mmol, 1.05eq) were added to dimethyl sulfoxide (30mL), and the reaction mixture was stirred at 20-25°C under nitrogen for 2 hours.

[0260] TLC (petroleum ether / ethyl acetate = 1 / 1) indicated that the reaction was complete. The compound (5-chloro-2-oxo-1H-pyridin-4-yl)methyl-triphenyl-phosphine; bromide (6.54 g, 13.49 mmol, yield 100.00%) was a yellow liquid and could be used directly in the next step of the reaction.

[0261] Step 6: Synthesis of tert-butyl 2-[(4R,6S)-6-[(Z)-2-(5-chloro-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0262] (5-chloro-2-oxo-1H-pyridin-4-yl)methyl-triphenylphosphine bromide (6.54 g, 13.49 mmol, 1 eq), tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate (3.48 g, 13.49 mmol, 1 eq) and potassium carbonate (1.86 g, 13.49 mmol, 1 eq) were added to dimethyl sulfoxide (30 mL), and the reaction mixture was stirred at 70 °C under nitrogen for 30 minutes.

[0263] LC-MS showed detection of the desired product. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared by normal phase preparation (column: Welch Ultimate XB-CN 250 x 70 mm x 10 μm; mobile phase: [hexane-EtOH]; gradient: 1%-40% B over 15.0 min), normal phase preparation (column: YMC-Gel SiL-HG 250 x 50 mm x 10 μm; mobile phase: [hexane-EtOH]; gradient: 1%-35% B over 15.0 min), and normal phase preparation (column: YMC-Gel SiL-HG). The sample was purified by a process involving a 250*50mm*10μm filter; mobile phase: [hexane-EtOH]; gradient: 1%-35% B over 15.0 min to obtain the product tert-butyl 2-[(4R,6S)-6-[(Z)-2-(5-chloro-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (3 g, 7.82 mmol, yield 57.93%), which was a yellow oil.

[0264] Step 7: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-(5-chloro-2-oxo-1H-pyridin-4-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0265] Solution 1: {tert-butyl 2-[(4R,6S)-6-[(Z)-2-(5-chloro-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate, 1 eq, 3 g} dissolved in {MeOH, 45 mL} and {THF, 45 mL}. A fixed bed (named FLR1, volume 5 mL) was completely filled with 5% Ru / Al2O3 (3 g) particulate catalyst; the H2 back pressure regulator was adjusted to 0.5 mPa, and the H2 flow rate was 30 mL / min.

[0266] Solution S1 was then pumped into a fixed bed {FLR1,SS, fixed bed, 6.350 (1 / 4”) mm, 1 mL, 31 °C} using pump 1 {S1, P1, 0.303 mL / min}. The reaction mixture was then collected from the reactor output. The reaction mixture was evaporated under reduced pressure to give tert-butyl 2-[(4R,6R)-6-[2-(5-chloro-2-oxo-1H-pyridin-4-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.7 g, crude), as a yellow solid.

[0267] Step 8: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[5-chloro-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0268] tert-butyl 2-[(4R,6R)-6-[2-(5-chloro-2-oxo-1H-pyridin-4-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.7 g, 4.41 mmol, 1 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridinyl)cyclopentane-1,3-diamine (1.97 g, 4.41 mmol, 1 eq), 41 mmol (1 eq), cuprous iodide (251.71 mg, 1.32 mmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (187.99 mg, 1.32 mmol, 0.3 eq), and potassium carbonate (1.83 g, 13.22 mmol, 3 eq) were added to dimethyl sulfoxide (30 mL) and stirred at 110 °C under nitrogen for 2 hours.

[0269] LC-MS showed detection of the desired product. The reaction mixture was cooled to 20°C, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give tert-butyl 2-[(4R,6R)-6-[2-[5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.35 g, 1.48 mmol, yield 33.53%, purity 77.16%), as a brown solid. LC-MS(ESI) m / z = 705.4 [M+H]+

[0270] Step 9: Synthesis of 5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[2-[(2R,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]ethyl]pyridin-2-one

[0271] To a solution of tert-butyl 2-[(4R,6R)-6-[2-[5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxo-4-yl]acetate (0.3 g, 425.42 μmol, 1 eq) in 3 mL of dichloromethane, trifluoroacetic acid (4.61 g, 40.39 mmol, 3 mL, 94.94 eq) was added at 15–25 °C. The reaction mixture was stirred at 15–25 °C for 30 minutes.

[0272] LC-MS showed detection of the desired product. The reaction mixture was evaporated under reduced pressure. The crude product was purified by reverse-phase preparative chromatography (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 8%-38% B, 15.0 min) to give the product 5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[2-[(2R,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]ethyl]pyridin-2-one (120 mg).

[0273] LCMS RT=1.162min,MS(ESI)m / z=591.3[M+H] +

[0274] 1H NMR (400MHz, DMSO-d6): δ8.30-8.16(m,2H),7.95(d,J=2.6Hz,1H),7.90(s,1H),7.49(d,J=7.1Hz ,1H),7.40(dd,J=2.7,8.9Hz,1H),7.27-6.81(m,2H),6.52(d,J=8.9Hz,1H),6.45(s,1H),5.24(br s,1H),4.78-4.56(m,1H),4.40-4.24(m,2H),4.15(br s,1H),2.81-2.57(m,3H),2.45-2.38(m,1H),2.22-2.06(m,2H),1.99-1.67(m,6H),1.63-1.39(m,2H).

[0275] Step 10: Synthesis of methyl(3R,5R)-7-[5-chloro-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxyheptanoate

[0276] Dioxane hydrochloride (2M, 3mL, 14.10eq) was added to a methanol (3mL) solution of tert-butyl 2-[(4R,6R)-6-[2-[5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (0.3g, 425.42μmol, 1eq), and the reaction mixture was stirred at 15-25°C for 16 hours.

[0277] LC-MS indicated that the reaction was complete. Evaporation of the reaction mixture under reduced pressure yielded the crude compound methyl(3R,5R)-7-[5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxyheptanoate (265.05 mg, crude), as a yellow solid.

[0278] Step 11: Synthesis of (3R,5R)-7-[5-chloro-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxy-heptanoic acid

[0279] Sodium hydroxide (1M, 1mL, 2.35eq) was added to a mixture of methanol (1mL) and water (1mL) of methyl (3R,5R)-7-[5-chloro-1-[6-[[(1S,3S)-3-[[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxyheptanoate (265.05mg, 425.41μmol, 1eq), and the mixture was stirred at 15-25°C for 30 minutes.

[0280] LC-MS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure, and the crude product was purified by reverse-phase chromatography (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 5%-35% B, 15.0 min) to give the product (3R,5R)-7-[5-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]-3,5-dihydroxyheptanoic acid (95 mg).

[0281] LCMS RT=1.088min,MS(ESI)m / z=609.3[M+H] +

[0282] 1 H NMR (400MHz, DMSO-d6): δ8.32-8.12(m,2H),8.00-7.93(m,1H),7.86(s,1H),7.49(d,J=7.3 Hz,1H),7.40(dd,J=2.8,8.9Hz,1H),7.28-6.80(m,2H),6.57(s,1H),6.40(s,1H),4.42-4. 18(m,2H),4.08-3.94(m,1H),3.78-3.59(m,1H),2.78-2.61(m,1H),2.41-2.34(m,1H),2.3 0-2.20(m,1H),2.20-2.05(m,2H),1.98-1.83(m,2H),1.79-1.65(m,1H),1.64-1.41(m,5H).

[0283] Example 16

[0284] Synthesis of 3-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[(E)-2-[(2S,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-5-methyl-pyridin-2-one (16)

[0285] Step 1: Synthesis of 5-bromo-3-chloro-2-methoxy-pyridine-4-carboxylic acid

[0286] Under nitrogen protection at -78°C, LDA (2M, 67.43 mL, 1.5 eq) was added dropwise to an anhydrous tetrahydrofuran (300 mL) solution of 5-bromo-3-chloro-2-methoxypyridine (20 g, 89.90 mmol, 1 eq), and the mixture was stirred at -78°C for 30 minutes. Then, dry ice (19.78 g, 449.51 mmol, 5 eq) was added in portions under nitrogen protection. After the addition, the reaction mixture was stirred at -78°C to 25°C for 16 hours.

[0287] LC-MS showed that the desired product was detected. The reaction mixture was quenched with saturated ammonium chloride solution (300 mL). The mixture was evaporated under reduced pressure to remove tetrahydrofuran, and the residue was diluted with water (200 mL). The solid was collected by vacuum filtration and dried under reduced pressure to give the product 5-bromo-3-chloro-2-methoxy-pyridine-4-carboxylic acid (25 g, crude product) as a white solid.

[0288] Step 2: Synthesis of methyl 5-bromo-3-chloro-2-methoxy-pyridine-4-carboxylic acid

[0289] Iodomethane (19.97 g, 140.73 mmol, 8.76 mL, 1.5 eq) was added dropwise to a DMF (250 mL) solution of 5-bromo-3-chloro-2-methoxy-pyridine-4-carboxylic acid (25 g, 93.82 mmol, 1 eq) and potassium carbonate (38.90 g, 281.45 mmol, 3 eq) at 0–10 °C under nitrogen protection. After addition, the reaction mixture was stirred at 20–30 °C for 16 hours under nitrogen protection.

[0290] LC-MS showed detection of the desired product. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product methyl 5-bromo-3-chloro-2-methoxy-pyridine-4-carboxylic acid (12 g, 42.78 mmol, yield 45.60%) as a yellow oil.

[0291] Step 3: Synthesis of methyl 3-chloro-2-methoxy-5-methyl-pyridine-4-carboxylic acid

[0292] Methyl 5-bromo-3-chloro-2-methoxy-pyridine-4-carboxylic acid (5.5 g, 19.61 mmol, 1 eq), methylboronic acid (2.93 g, 49.02 mmol, 2.5 eq), Pd(dppf)Cl2 (1.43 g, 1.96 mmol, 0.1 eq) and potassium carbonate (8.13 g, 58.82 mmol, 3 eq) were added to a mixed solution of dioxane (60 mL) and water (10 mL). The reaction solution was stirred at 110 °C under nitrogen protection for 2 hours.

[0293] LC-MS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give methyl 3-chloro-2-methoxy-5-methyl-pyridine-4-carboxylic acid (3.3 g, 15.30 mmol, yield 78.05%), which was a yellow oil.

[0294] Step 4: Synthesis of (3-chloro-2-methoxy-5-methyl-4-pyridyl)methanol

[0295] Solution 1: {methyl 3-chloro-2-methoxy-5-methyl-pyridine-4-carboxylic acid, 1 eq, 3.3 g, 100%, 3.3 g}, diluted to 33 mL with dichloromethane. Solution 2: {DIBAL-H, 3.5 eq, 7.618 g, 1 M, 53.563 mL, 14.2%, 53.645 g} (53.563 mL) was pumped into flow reactors 1 {FLR1, SS, static mixer, 0.93 mL, -30 °C} and {FLR1, PFA, coil reactor, 3.175 (1 / 8”) mm, 21.372 mL, -30 °C} using pump 1 {S1, P1, 4.247 mL / min}. Eluent 2 was pumped into flow reactors 1 {FLR1, SS, static mixer, 0.93 mL, -30 °C} and {FLR1, PFA, Coils reactor, 3.175 (1 / 8”) mm, 21.372 mL, -30 °C} using pump 2 {S2, P2, 6.904 mL / min}. The residence time in flow reactor 1 is {FLR1, 2 min}. Pumps 1 and 2 are started. The mixture is collected in a bottle (containing aqueous solution). (Quenching with potassium sodium tartrate solution).

[0296] TLC (petroleum ether: ethyl acetate = 3:1, UV 254nm (Rf = 0.20)) showed complete starting material and detected new spots. The reaction mixture was quenched with potassium sodium tartrate solution. The mixture was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the product (3-chloro-2-methoxy-5-methyl-4-pyridyl)methanol (2.6 g, crude), which is a yellow oil.

[0297] Step 5: Synthesis of 4-(bromomethyl)-3-chloro-5-methyl-1H-pyridin-2-one

[0298] (3-chloro-2-methoxy-5-methyl-4-pyridyl)methanol (2.5 g, 13.32 mmol, 1 eq) was added to HBr / AcOH solution (20 mL) and stirred for 3 hours under nitrogen protection at 100 °C.

[0299] LC-MS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure, the residue was diluted with water (50 mL), the pH was adjusted to 8 using saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product 4-(bromomethyl)-3-chloro-5-methyl-1H-pyridin-2-one (3.04 g, crude), as a yellow solid.

[0300] Step 6: Synthesis of (3-chloro-5-methyl-2-oxo-1H-pyridin-4-yl)methyl-triphenylphosphine; bromide

[0301] 4-(bromomethyl)-3-chloro-5-methyl-1H-pyridin-2-one (2.94 g, 12.43 mmol, 1 eq) and triphenylphosphine (3.42 g, 13.05 mmol, 1.05 eq) were added to dimethyl sulfoxide (30 mL), and the reaction mixture was stirred at 20-25 °C for 1 hour under nitrogen protection.

[0302] LC-MS indicated that the reaction was complete. The compound (3-chloro-5-methyl-2-oxo-1H-pyridin-4-yl)methyl-triphenylphosphine; bromide (6.20 g, 12.43 mmol, yield 100.00%) was a yellow liquid and could be used directly in the next step of the reaction.

[0303] Step 7: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-(3-chloro-5-methyl-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0304] (3-chloro-5-methyl-2-oxo-1H-pyridin-4-yl)methyl-triphenylphosphine bromide (6.20 g, 12.43 mmol, 1 eq), tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxanthracene-4-yl]acetate (3.85 g, 14.92 mmol, 1.2 eq), and potassium carbonate (3.44 g, 24.86 mmol, 2 eq) were added to dimethyl sulfoxide (30 mL), and the reaction mixture was stirred at 110 °C under nitrogen protection for 1 hour.

[0305] LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by normal-phase preparative chromatography (column: YMC-Gel SiL-HG 250 * 50 mm * 10 μm; mobile phase: [hexane-EtOH]; gradient: 5%-42% B over 45.0 min) to give tert-butyl 2-[(4R,6S)-6-[(E)-2-(3-chloro-5-methyl-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (2.4 g, 6.03 mmol, yield 48.52%) as a yellow solid.

[0306] Step 8: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-chloro-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-methyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0307] tert-butyl 2-[(4R,6S)-6-[(E)-2-(3-chloro-5-methyl-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (500 mg, 1.26 mmol, 1 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridinyl)cyclopentane-1,3-diamine (842.98 mg, 1 eq) 0.88 mmol (1.5 eq), cuprous iodide (71.80 mg, 376.99 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (53.62 mg, 376.99 μmol, 0.3 eq), and potassium carbonate (521.03 mg, 3.77 mmol, 3 eq) were added to dimethyl sulfoxide (10 mL). Under nitrogen protection, the reaction mixture was stirred at 120 °C for 6 hours.

[0308] LC-MS showed detection of the desired product. The reaction mixture was cooled to 20°C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-methyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (500 mg, crude product), as a yellow solid.

[0309] Step 9: Synthesis of 3-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[(E)-2-[(2S,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-5-methyl-pyridin-2-one

[0310] Add trifluoroacetic acid (5.12 g, 44.87 mmol, 3.33 mL, 64.37 eq) to a solution of tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-chloro-1-[6-[[(1S,3S)-3-[[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-methyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxo-4-yl]acetate (500 mg, 697.16 μmol, 1 eq) in dichloromethane (3 mL), and stir the mixture at 15-25 °C for 0.5 hours.

[0311] LC-MS showed that the desired product was detected. The crude product was concentrated under reduced pressure and then purified by reverse-phase chromatography (column: Phenomenex luna C18 150*40mm*15μm; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 10%-40% B, 15.0 min) to give the product 3-chloro-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[(E)-2-[(2S,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-5-methyl-pyridin-2-one (180 mg).

[0312] LCMS RT=0.407min,MS(ESI)m / z=603.2[M+H] +

[0313] 1 H NMR (400MHz, DMSO-d6): δ8.24(s,2H),7.96(d,J=2.8Hz,1H),7.56(d,J=0.9Hz,1H),7.50(d ,J=7.3Hz,1H),7.43(dd,J=2.8,8.9Hz,1H),7.26-6.77(m,2H),6.63-6.47(m,2H),6.27(dd, J=5.9,16.4Hz,1H),5.46-5.19(m,2H),4.44-4.25(m,2H),4.23-4.15(m,1H),2.76(dd,J=4. 6,17.4Hz,1H),2.48-2.42(m,1H),2.21-2.04(m,5H),2.03-1.84(m,4H),1.64-1.37(m,2H).

[0314] Example 17

[0315] Synthesis of 3-chloro-5-cyclopropyl-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[(E)-2-[(2S,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]pyridin-2-one (17)

[0316] Step 1: Synthesis of methyl 3-chloro-5-cyclopropyl-2-methoxy-pyridine-4-carboxylic acid

[0317] Methyl 5-bromo-3-chloro-2-methoxy-pyridine-4-carboxylic acid (5.5 g, 19.61 mmol, 1 eq), cyclopropylboronic acid (5.05 g, 58.82 mmol, 3 eq), Pd(dppf)Cl2 (1.43 g, 1.96 mmol, 0.1 eq), and potassium carbonate (5.42 g, 39.22 mmol, 2 eq) were added to a mixed solution of dioxane (60 mL) and water (10 mL). The reaction mixture was stirred at 110 °C under nitrogen protection for 2 hours.

[0318] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give methyl 3-chloro-5-cyclopropyl-2-methoxy-pyridine-4-carboxylic acid (4.1 g, 16.97 mmol, yield 86.52%), which is a yellow oil.

[0319] Step 2: Synthesis of (3-chloro-5-cyclopropyl-2-methoxy-4-pyridyl)methanol

[0320] Solution 1: {methyl 3-chloro-5-cyclopropyl-2-methoxy-pyridine-4-carboxylic acid, 1 eq, 5 g, 100%, 5 g}, diluted to 50 mL with dichloromethane. Solution 2: {DIBAL-H, 3.5 eq, 10.299 g, 1 M, 72.413 mL, 14.2%, 72.525 g} (72.525 mL) was pumped into flow reactors 1 {FLR1, SS, static mixer, 0.93 mL, -30 °C} and {FLR1, PFA, coil reactor, 3.175 (1 / 8”) mm, 21.372 mL, -30 °C} using pump 1 {S1, P1, 4.551 mL / min}. Eluent 2 was pumped into flow reactors 1 {FLR1, SS, static mixer, 0.93 mL, -30 °C} and {FLR1, PFA, Coils reactor, 3.175 (1 / 8”) mm, 21.372 mL, -30 °C} using pump 2 {S2, P2, 6.6 mL / min}.

[0321] The residence time of flow reactor 1 is {FLR1, 2 min}. Start pumps 1 and 2.

[0322] The mixture was collected in a bottle (containing aqueous solution). TLC (petroleum ether:ethyl acetate = 3:1, UV 254nm (Rf = 0.20)) showed complete initial composition and detected new spots. The reaction mixture was quenched with potassium sodium tartrate solution. The mixture was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product (3-chloro-5-cyclopropyl-2-methoxy-4-pyridyl)methanol (4.1 g, crude), which is a yellow oil.

[0323] Step 3: Synthesis of 4-(bromomethyl)-3-chloro-5-cyclopropyl-1H-pyridin-2-one

[0324] A solution of (3-chloro-5-cyclopropyl-2-methoxy-4-pyridyl)methanol (4.0 g, 18.72 mmol, 1 eq) in HBr / AcOH (30 mL) was stirred at 100 °C for 3 hours under nitrogen atmosphere.

[0325] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried in petroleum ether / ethyl acetate = 2 / 1 (30 mL) for 30 minutes, then the mixture was filtered and dried under reduced pressure to give the product 4-(bromomethyl)-3-chloro-5-cyclopropyl-1H-pyridin-2-one (2.87 g, crude product) as a yellow solid.

[0326] Step 4: Synthesis of (3-chloro-5-cyclopropyl-2-oxo-1H-pyridin-4-yl)methyl-triphenylphosphine bromide

[0327] 4-(bromomethyl)-3-chloro-5-cyclopropyl-1H-pyridin-2-one (2.77 g, 10.55 mmol, 1 eq) and triphenylphosphine (2.91 g, 11.08 mmol, 1.05 eq) were added to dimethyl sulfoxide (30 mL), and the reaction solution was stirred for 1 hour at 20-25 °C under nitrogen protection.

[0328] LC-MS indicated that the reaction was complete. The unseparated product (3-chloro-5-cyclopropyl-2-oxo-1H-pyridin-4-yl)methyl-triphenylphosphine was obtained; bromide (5.54 g, 10.56 mmol, yield 100.00%), a yellow liquid, which could be used directly in the next reaction.

[0329] Step 5: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-(3-chloro-5-cyclopropyl-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0330] (3-chloro-5-cyclopropyl-2-oxo-1H-pyridin-4-yl)methyl-triphenylphosphine bromide (5.54 g, 10.56 mmol, 1 eq), tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate (3.27 g, 12.67 mmol, 1.2 eq), and potassium carbonate (2.92 g, 21.11 mmol, 2 eq) were added to dimethyl sulfoxide (30 mL), and the reaction mixture was stirred at 110 °C under nitrogen protection for 1 hour.

[0331] LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by normal-phase chromatography (column: Welch Ultimate XB-SiOH 250 * 70 mm * 10 μm; mobile phase: [hexane-EtOH (0.1% NH3H2O)]; gradient: 1%-35% B, 15.0 min) to give tert-butyl 2-[(4R,6S)-6-[(E)-2-(3-chloro-5-cyclopropyl-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.9 g, 4.48 mmol, yield 42.46%) as a yellow solid.

[0332] Step 6: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-chloro-5-cyclopropyl-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0333] tert-butyl 2-[(4R,6S)-6-[(E)-2-(3-chloro-5-cyclopropyl-2-oxo-1H-pyridin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.1 g, 2.59 mmol, 1 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridinyl)cyclopentane-1,3-diamine (1.22 g, 2.72 mmol (1.05 eq), cuprous iodide (148.25 mg, 778.43 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (110.72 mg, 778.43 μmol, 0.3 eq), and potassium carbonate (1.08 g, 7.78 mmol, 3 eq) were added to dimethyl sulfoxide (15 mL), and the reaction mixture was stirred at 110 °C for 6 hours.

[0334] LC-MS showed detection of the desired product. The reaction mixture was cooled to 20°C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-chloro-5-cyclopropyl-1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.5 g, crude product), as a brown solid.

[0335] Step 7: Synthesis of 3-chloro-5-cyclopropyl-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[(E)-2-[(2S,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]pyridin-2-one

[0336] Trifluoroacetic acid (7.68 g, 67.31 mmol, 5 mL, 33.35 eq) was added to a solution of tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-chloro-5-cyclopropyl-1-[6-[[(1S,3S)-3-[[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.5 g, 2.02 mmol, 1 eq) in dichloromethane (5 mL), and the reaction mixture was stirred for 30 minutes at 20-25 °C under nitrogen protection.

[0337] LC-MS showed that the desired product was detected. The crude product was concentrated under reduced pressure and then purified by reverse-phase chromatography (column: Phenomenex luna C18 150*40mm*15μm; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 10%-40% B over 15.0 min) to give the product 3-chloro-5-cyclopropyl-1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-4-[(E)-2-[(2S,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]pyridin-2-one (300 mg).

[0338] LCMS RT=0.540min,MS(ESI)m / z=629.2[M+H] +

[0339] 1 H NMR (400MHz, DMSO-d6): δ8.24(s,2H),7.95(d,J=2.6Hz,1H),7.49(d,J=7.3Hz,1H),7.41(dd,J=2.6,8.9Hz,1H),7.3 1(d,J=0.8Hz,1H),7.24-6.83(m,2H),6.71(dd,J=1.3,16.4Hz,1H),6.53(d,J=8.9Hz,1H),6.43(dd,J=5.9,16.3Hz,1 H),5.42-5.24(m,2H),4.42-4.25(m,2H),4.19(qd,J=3.8,7.6Hz,1H),2.76(dd,J=4.6,17.3Hz,1H),2.49-2.43(m,1H ),2.20-2.06(m,2H),2.06-1.79(m,4H),1.76-1.66(m,1H),1.63-1.36(m,2H),0.85-0.74(m,2H),0.69-0.52(m,2H).

[0340] Examples 18-89

[0341] Following the aforementioned compound preparation method, compounds 18-89 were prepared, wherein:

[0342] Example 25

[0343] Step 1: Synthesis of 2-((4R,6S)-6-((E)-2-(6'-((1S,3S)-3-(6,7-dihydro-[1,4]dioxa[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0344] At room temperature, compound 25-1 (220 mg, 0.5 mmol), compound 25-2 (289 mg, 0.6 mmol, 1.2 eq), potassium carbonate (138 mg, 1 mmol, 2 eq), cuprous iodide (47 mg, 0.25 mmol, 0.5 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.25 mmol, 0.5 eq), and 1,4-dioxane (3 mL) were added sequentially to a 25 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere, and the temperature was raised to 100 °C for the reaction.

[0345] LC-MS detected the disappearance of the starting material and the formation of the target product. The reaction mixture was filtered, concentrated, and purified by C18 reverse column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% Bover 50 min) to obtain the target compound 25-3 (247 mg, 62% yield) as a gray oil.

[0346] Step 2: Synthesis of (3R,5S,E)-7-(6'-((1S,3S)-3-((6,7-dihydro-[1,4]dioxy[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0347] Compound 25-3 (247 mg, 0.31 mmol) was added to a 25 mL round-bottom flask at room temperature and dissolved in acetonitrile (2 mL). Then, 1 N aq. HCl (0.6 mL, 2 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the starting material. 2 N aq. NaOH (0.6 mL, 4 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the intermediate and the formation of the target product. The reaction mixture was concentrated and purified by C18 reverse-phase column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 25 (154 mg).

[0348] Example 26

[0349] Step 1: Synthesis of 2-((4R,6S)-6-((E)-2-(6'-((1S,3S)-3-((6,7-dihydro-[1,4]dioxa[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0350] At room temperature, compound 26-1 (205 mg, 0.5 mmol), compound 26-2 (289 mg, 0.6 mmol, 1.2 eq), potassium carbonate (138 mg, 1 mmol, 2 eq), cuprous iodide (47 mg, 0.25 mmol, 0.5 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.25 mmol, 0.5 eq), and 1,4-dioxane (3 mL) were added sequentially to a 25 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere, and the temperature was raised to 100 °C for the reaction.

[0351] LC-MS detected the disappearance of the starting material and the formation of the target product. The reaction mixture was filtered, concentrated, and purified by C18 reverse column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% Bover 50 min) to obtain the target compound 26-3 (236 mg, 58% yield) as a gray oil.

[0352] Step 2: Synthesis of (3R,5S,E)-7-(6'-((1S,3S)-3-((6,7-dihydro-[1,4]dioxy[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0353] Compound 26-3 (236 mg, 0.29 mmol) was added to a 25 mL round-bottom flask at room temperature and dissolved in acetonitrile (2 mL). Then, 1 N aq. HCl (0.6 mL, 2 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the starting material. 2 N aq. NaOH (0.6 mL, 4 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the intermediate and the formation of the target product. The reaction mixture was concentrated and purified by C18 reverse-phase column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound (114 mg).

[0354] Example 30

[0355] Step 1: Synthesis of 2-((4R,6S)-6-((E)-2-(5-(4-fluorophenyl)-3-isopropyl-6'-((1S,3S)-3-((5-methylpyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0356] At room temperature, compound 30-1 (198 mg, 0.5 mmol), compound 30-2 (289 mg, 0.6 mmol, 1.2 eq), potassium carbonate (138 mg, 1 mmol, 2 eq), cuprous iodide (47 mg, 0.25 mmol, 0.5 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.25 mmol, 0.5 eq), and 1,4-dioxane (3 mL) were added sequentially to a 25 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere, and the temperature was raised to 100 °C for the reaction.

[0357] LC-MS detected the disappearance of the starting material and the formation of the target product. The reaction mixture was filtered, concentrated, and purified by C18 reverse column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 30-3 (241 mg, 64% yield) as a gray oil.

[0358] Step 2: Synthesis of (3R,5S,E)-7-(5-(4-fluorophenyl)-3-isopropyl-6'-((1S,3S)-3-((5-methylpyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0359] Compound 30-3 (241 mg, 0.32 mmol) was added to a 25 mL round-bottom flask at room temperature and dissolved in acetonitrile (2 mL). Then, 1 N aq. HCl (0.6 mL, 2 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the starting material. 2 N aq. NaOH (0.6 mL, 4 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the intermediate and the formation of the target product. The reaction mixture was concentrated and purified by C18 reverse-phase column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 30 (130 mg).

[0360] Example 31

[0361] Step 1: Synthesis of 2-((4R,6S)-6-((E)-2-(5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-6'-((1S,3S)-3-((5-methylpyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0362] At room temperature, compound 31-1 (182 mg, 0.5 mmol), compound 31-2 (289 mg, 0.6 mmol, 1.2 eq), potassium carbonate (138 mg, 1 mmol, 2 eq), cuprous iodide (47 mg, 0.25 mmol, 0.5 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.25 mmol, 0.5 eq), and 1,4-dioxane (3 mL) were added sequentially to a 25 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere, and the temperature was raised to 100 °C for the reaction.

[0363] LC-MS detected the disappearance of the starting material and the formation of the target product. The reaction mixture was filtered, concentrated, and purified by C18 reverse column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 31-3 (250 mg, 65% yield) as a gray oil.

[0364] Step 2: Synthesis of (3R,5S,E)-7-(5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-6'-((1S,3S)-3-((5-methylpyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0365] Compound 31-3 (250 mg, 0.32 mmol) was added to a 25 mL round-bottom flask at room temperature and dissolved in acetonitrile (2 mL). Then, 1 N aq. HCl (0.6 mL, 2 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the starting material. 2 N aq. NaOH (0.6 mL, 4 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the intermediate and the formation of the target product. The reaction mixture was concentrated and purified by C18 reverse-phase column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 31 (149 mg).

[0366] Example 34

[0367] Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0368] Step 1: Synthesis of tert-butyl((1S,3S)-3-((5-bromo-3-fluoropyridin-2-yl)amino)cyclopentyl)carbamate

[0369] Dissolve 34-2 (10.0 g, 49.9 mmol, 1.00 eq) and 34-1 (10.6 g, 54.9 mmol, 1.10 eq) in DMSO (50 mL) solution, add DIEA (12.9 g, 99.8 mmol, 17.3 mL, 2.00 eq), and stir the mixture at 80 °C for 2 hours.

[0370] The formation of the target product was detected by LC-MS. The reaction solution was poured into water (200 mL), extracted with ethyl acetate (250 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-4 / 1) to give compound 34-3 (17.0 g, 45.4 mmol, 90.9% yield) as a white solid.

[0371] Step 2: Synthesis of (1S,3S)-N1-(5-bromo-3-fluoropyridin-2-yl)cyclopentane-1,3-diamine

[0372] 34-3 (17.0 g, 45.4 mmol, 1.00 eq) was added to a dioxane hydrochloride solution (2 M, 200 mL). The mixture was stirred at 25 °C for 1 hour. The formation of the target product was detected by LC-MS. The reaction solution was concentrated and evaporated to dryness to give compound 34-4 (20 g, crude) as a white solid.

[0373] Step 3: Synthesis of (1S,3S)-N1-(5-bromo-3-fluoropyridin-2-yl)-N3-(5-(difluoromethoxy)pyrimidin-2-yl)cyclopentane-1,3-diamine

[0374] K₂CO₃ (1.91 g, 13.8 mmol, 5.00 eq) was added to DMSO (10 mL) solutions of 34-5 (500 mg, 2.77 mmol, 1.00 eq) and 34-4 (759 mg, 2.77 mmol, 1.00 eq). The mixture was stirred at 120 °C for 12 hours.

[0375] The formation of the target product was detected by LC-MS. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (120 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-3 / 1) to give compound 34-6 (700 mg, 1.67 mmol, 60.4% yield) as a brown oil.

[0376] Step 4: Synthesis of tert-butyl 2-(((4R,6S)-6-((E)-2-(6'-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate

[0377] To DMSO (10 mL) solutions of 34-6 (600 mg, 1.43 mmol, 1.00 eq) and 34-7 (557 mg, 1.15 mmol, 0.80 eq), K₂CO₃ (594 mg, 4.30 mmol, 3.00 eq), quinoline-8-ol (41.6 mg, 286 μmol, 0.20 eq), and CuI (54.65 mg, 286 μmol, 0.20 eq) were added. The mixture was stirred at 110 °C for 12 hours.

[0378] The formation of the target product was detected by LCMS. The reaction solution was poured into water (60 mL), extracted with ethyl acetate (80 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1-1 / 1) to give compound 34-8 (700 mg, 535 μmol, 37.3% yield, 63.0% purity) as a yellow oil.

[0379] Step 5: Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0380] Add HCl (45.2 mg, 459 μmol, 1.00 eq) dropwise to a MeOH solution (6 mL) of 34-8 (600 mg, 459 μmol, 1.00 eq). Stir the mixture at 25 °C for 30 minutes. Then add a NaOH solution (183 mg, 4.59 mmol, 10.0 eq) in H₂O (2 mL) dropwise. Stir the mixture at 25 °C for 30 minutes.

[0381] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 8%-38% B over 9.0 min) to obtain compound 34 (205.79 mg) as a white solid, which was identified as the target product by NMR.

[0382] Example 35

[0383] Synthesis of ((3R,5S,E)-7-(6'-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0384] Step 1: Synthesis of (1S,3S)-N1-(5-cyclopropylpyrimidin-2-yl)-N3-(5-iodopyridin-2-yl)cyclopentane-1,3-diamine

[0385] Dissolve 35-1 (1.00 g, 3.30 mmol, 1.00 eq) and 35-2 (509 mg, 3.30 mmol, 1.00 eq) in DMSO (8 mL) solution, add DIEA (1.28 g, 9.90 mmol, 1.72 mL, 3.00 eq), and stir the mixture at 120 °C for 12 hours.

[0386] The formation of the target product was detected by LC-MS. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (120 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-2 / 1) to give compound 35-3 (270 mg, 640 μmol, 19.4% yield) as a brown oil.

[0387] Step 2: Synthesis of tert-butyl 2-((4R,6S)-6-((E)-2-(6'-((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate

[0388] To 4 mL of DMSO solutions of 35-3 (240 mg, 569 μmol, 1.00 eq), K₂CO₃ (236 mg, 1.71 mmol, 3.00 eq), (1S,2S)-N₁,N₂-dimethylcyclohexane-1,2-diamine (16.2 mg, 113 μmol, 0.20 eq), and CuI (21.7 mg, 113 μmol, 0.20 eq) were added. The mixture was stirred at 110 °C for 2 hours.

[0389] The formation of the target product was detected by LCMS. The reaction solution was poured into water (40 mL), extracted with ethyl acetate (80 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1-0 / 1) to give compound 35-5 (400 mg, 410 μmol, 72.1% yield, 80% purity) as a yellow solid.

[0390] Step 3: Synthesis of ((3R,5S,E)-7-(6'-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0391] Add HCl (37.9 mg, 385 μmol, 1.00 eq) dropwise to a 6 mL solution of MeOH (300 mg, 385 μmol, 1.00 eq) at 35°C. Stir the mixture at 25°C for 1 hour. Then add 2 mL solution of H₂O (154 mg, 3.85 mmol, 10.0 eq) dropwise. Stir the mixture at 25°C for 1 hour.

[0392] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 6%-36% B over 12.0 min) to obtain compound 35 (228 mg), which was identified as the target product by NMR.

[0393] Example 36

[0394] Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0395] Step 1: Synthesis of 2-chloro-5-cyclopropylpyrimidine

[0396] Pd(dppf)Cl2 (1.13 g, 1.55 mmol, 0.10 eq) and K2CO3 (10.7 g, 77.5 mmol, 5.00 eq) were added to a solution of 36-1 (3.00 g, 15.5 mmol, 1.00 eq) and cyclopropylboronic acid (4.00 g, 46.5 mmol, 3.00 eq) in THF (20 mL) and H2O (4 mL). The mixture was stirred at 65 °C for 12 hours under nitrogen protection.

[0397] The formation of the target product was detected by LC-MS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 36-2 (2.20 g, 14.2 mmol, 91.7% yield) as a yellow solid.

[0398] Step 2: Synthesis of (1S,3S)-N1-(5-bromo-3-fluoropyridin-2-yl)-N3-(5-cyclopropylpyrimidin-2-yl)cyclopentane-1,3-diamine

[0399] K₂CO₃ (3.02 g, 21.8 mmol, 6.00 eq) was added to 10 mL of DMSO solution containing 36-2 (563 mg, 3.65 mmol, 1.00 eq) and 36-3 (1.00 g, 3.65 mmol, 1.00 eq). The mixture was stirred at 120 °C for 12 hours.

[0400] The formation of the target product was detected by LC-MS. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (120 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1-2 / 1) to give compound 36-4 (600 mg, 1.53 mmol, 41.9% yield) as a brown oil.

[0401] Step 3: Synthesis of tert-butyl 2-((4R,6S)-6-((E)-2-(6'-((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxa-4-yl)acetate

[0402] To DMSO (10 mL) solutions of 36-4 (500 mg, 1.27 mmol, 1.00 eq) and 36-5 (495 mg, 1.02 mmol, 0.80 eq), K₂CO₃ (528 mg, 3.82 mmol, 3.00 eq), (1S,2S)-N₁,N₂-dimethylcyclohexane-1,2-diamine (36.2 mg, 254 μmol, 0.2 eq), and CuI (48.5 mg, 254 μmol, 0.20 eq) were added. The mixture was stirred at 110 °C for 12 hours.

[0403] The formation of the target product was detected by LCMS. The reaction solution was poured into water (80 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1-0 / 1) to give compound 36-6 (700 mg, 878 μmol, 68.9% yield) as a yellow solid.

[0404] Step 4: Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0405] Add HCl (37.0 mg, 376 μmol, 1.00 eq) dropwise to a 3 mL solution of MeOH (300 mg, 376 μmol, 1.00 eq). Stir the mixture at 25 °C for 30 minutes. Then add a 1 mL solution of NaOH (150 mg, 3.76 mmol, 10.0 eq) in H₂O dropwise. Stir the mixture at 25 °C for 30 minutes.

[0406] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 8%-38% B over 9.0 min) to obtain compound 36 (182.87 mg) as a white solid, which was identified as the target product by NMR.

[0407] Example 37

[0408] Synthesis of (3R,5S,E)-7-(5-(4-fluorophenyl)-3-isopropyl-6'-(((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0409] Step 1: Synthesis of (1S,3S)-N1-(5-iodopyridin-2-yl)-N3-(5-methoxypyrimidin-2-yl)cyclopentane-1,3-diamine

[0410] K₂CO₃ (2.39 g, 17.2 mmol, 5.00 eq) was added to a DMSO (10 mL) solution of 2-chloro-5-methoxypyrimidine (500 mg, 3.46 mmol, 1.00 eq) and 37-1 (1.05 g, 3.46 mmol, 1.00 eq). The mixture was stirred at 120 °C for 12 hours.

[0411] The formation of the target product was detected by LC-MS. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (120 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1-1 / 1) to give compound 37-2 (360 mg, 875 μmol, 25.3% yield) as a brown oil.

[0412] Step 2: Synthesis of tert-butyl 2-((4R,6S)-6-((E)-2-(5-(4-fluorophenyl)-3-isopropyl-6'-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate

[0413] To 5 mL of DMSO solutions of 37-2 (330 mg, 802 μmol, 1.00 eq) and 37-3 (311 mg, 641 μmol, 0.80 eq), K₂CO₃ (332 mg, 2.41 mmol, 3.00 eq), (1S,2S)-N₁,N₂-dimethylcyclohexane-1,2-diamine (22.8 mg, 160 μmol, 0.20 eq) and CuI (30.5 mg, 160 μmol, 0.20 eq) were added. The mixture was stirred at 110 °C for 2 hours.

[0414] The formation of the target product was detected by LCMS. The reaction solution was poured into water (60 mL), extracted with ethyl acetate (80 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1-0 / 1) to give compound 37-4 (550 mg, 715 μmol, 89.1% yield) as a brown oil.

[0415] Step 3: Synthesis of (3R,5S,E)-7-(5-(4-fluorophenyl)-3-isopropyl-6'-(((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0416] Add HCl (64.0 mg, 650 μmol, 1.00 eq) dropwise to a MeOH solution (6 mL) at 37-4°C. Stir the mixture at 25°C for 30 minutes. Then add a NaOH solution (260 mg, 6.50 mmol, 10.0 eq) in H₂O (2 mL) dropwise. Stir the mixture at 25°C for 30 minutes.

[0417] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 5%-35% B over 9.0 min) to obtain compound 37 (234.15 mg), which was identified as the target product by NMR.

[0418] Example 38

[0419] Synthesize (3R,5R)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptanoic acid.

[0420] Step 1: Synthesis of tert-butyl 2-((4R,6R)-6-(2-(5-(4-fluorophenyl)-3-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate

[0421] Solution S1: {tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate, 1.00 eq, 300 mg} and {ammonia, 20.0 eq, 0.433 g, 0.476 mL} in {tetrahydrofuran, 60 mL}. Fixed bed: (named FLR1, volume 5 mL) packed with 3.00 g granular 5% Pd / Al2O3 catalyst. H2 back pressure was adjusted to 0.7 MPa, and the flow rate was {H2, 30 mL / min}. Solution S1 was then pumped from pump 1 {S1, P1, 0.4 mL / min} to a fixed bed {FLR1, SS, fixed bed, 6.350 (1 / 4) mm, 1 mL, 37 °C}. The reaction mixture was then collected from the reactor output. The reaction solution was concentrated to give tert-butyl 2-((4R,6R)-6-(2-(5-(4-fluorophenyl)-3-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate (300 mg, 615 μmol). It was used directly for the next step without purification.

[0422] Step 2: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0423] tert-butyl 2-((4R,6R)-6-(2-(5-(4-fluorophenyl)-3-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate (300 mg, 615 μmol, 1.00 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-di Amine (275 mg, 615 μmol, 1.00 eq), cuprous iodide (35.2 mg, 185 μmol, 0.30 eq), potassium carbonate (255 mg, 1.85 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (26.3 mg, 185 μmol, 0.30 eq) were dissolved in dimethyl sulfoxide (8 mL), and the mixture was stirred at 110 °C for 3 h. The MS value of the product was monitored by LCMS (RT = 0.599 min). The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl-2-[(4R,6R)-6-[2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (420 mg, 521 μmol, 84.6% yield). It was used directly in the next step without purification.

[0424] Step 3: Synthesis of 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-(2-(((2R,4S)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one

[0425] 420 mg (521 μmol, 1.00 eq) of tert-butyl 2-[(4R,6R)-6-[2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (3.07 g, 26.9 mmol, 2 mL, 51.7 eq). The reaction mixture was stirred at 20 °C for 0.5 h. The MS value of the product was monitored by LCMS (RT = 0.462 min). The reaction solution was concentrated to give 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-(2-(((2R,4S)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one (320 mg, 462 μmol, 88.8% yield). It was used directly in the next step without purification.

[0426] Step 4: Synthesis of (3R,5R)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyheptanoic acid

[0427] 6'-((((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-4-(2-(((2R,4S)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3-isopropyl-2H-[1,3'-bipyridine]-2-one (320 mg, 462 μmol, 1.00 eq) was dissolved in MeOH (5 mL), and then NaOH (1 M) aqueous solution was added dropwise to the reaction solution until pH = 13. The reaction solution was stirred at 20 °C for 0.5 h. The MS value of the product was monitored by LCMS (RT = 0.452 min), indicating that the reaction was complete. The reaction solution was concentrated to obtain the crude product, which was purified by reverse-phase column chromatography (column: Phenomenex Luna C18). 150*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 15%-45% B over 10.0min) yielded (3R,5R)-7-(6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptanoic acid (107.97mg).

[0428] Example 42

[0429] Synthesis of (3R,5S,E)-7-(5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-6'-(((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0430] Step 1: Synthesis of (1S,3S)-N1-(5-bromo-3-fluoropyridin-2-yl)-N3-(5-methoxypyrimidin-2-yl)cyclopentane-1,3-diamine

[0431] K₂CO₃ (2.39 g, 17.2 mmol, 5.00 eq) was added to a DMSO (10 mL) solution of 2-chloro-5-methoxypyrimidine (500 mg, 3.46 mmol, 1.00 eq) and 42-1 (948 mg, 3.46 mmol, 1.00 eq). The mixture was stirred at 120 °C for 12 hours.

[0432] The formation of the target product was detected by LC-MS. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (120 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1-2 / 1) to give compound 42-2 (460 mg, 1.20 mmol, 34.7% yield) as a brown oil.

[0433] Step 2: Synthesis of tert-butyl 2-((4R,6S)-6-((E)-2-(5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-6'-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate

[0434] To 8 mL of DMSO solutions of 42-2 (400 mg, 1.05 mmol, 1.00 eq) and 42-3 (406 mg, 837 μmol, 0.80 eq), K₂CO₃ (433 mg, 3.14 mmol, 3.00 eq), (1S,2S)-N₁,N₂-dimethylcyclohexane-1,2-diamine (29.7 mg, 209 μmol, 0.20 eq) and CuI (39.8 mg, 209 μmol, 0.20 eq) were added. The mixture was stirred at 110 °C for 12 hours.

[0435] The formation of the target product was detected by LCMS. The reaction solution was poured into water (60 mL), extracted with ethyl acetate (80 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 42-4 (700 mg, 707 μmol, 67.5% yield, 79.5% purity) as a yellow oil.

[0436] Step 3: Synthesis of (3R,5S,E)-7-(5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-6'-(((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0437] Add HCl (59.7 mg, 606 μmol, 1.00 eq) dropwise to a 6 mL solution of MeOH (600 mg, 606 μmol, 1.00 eq). Stir the mixture at 25 °C for 30 minutes. Then add a 2 mL solution of H₂O (242 mg, 6.06 mmol, 10.0 eq) dropwise. Stir the mixture at 25 °C for 30 minutes.

[0438] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 7%-37% B over 9.0 min) to obtain compound 42 (303 mg, 436 μmol, 72.0% yield), which was identified as the target product by NMR.

[0439] Example 44

[0440] Synthesis of (E,3R,5S)-7-[1-[6-[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoic acid

[0441] Step 1: Synthesis of (1S,3S)-N3-(5-chloropyrimidin-2-yl)-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine

[0442] (1S,3S)-N3-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine (1 g, 2.94 mmol, 1 eq, hydrochloride), 2,5-dichloropyrimidine (526.42 mg, 3.53 mmol, 1.2 eq), and diisopropylethylamine (1.14 g, 8.83 mmol, 1.54 mL, 3 eq) were added to dimethyl sulfoxide (10 mL), and the reaction mixture was stirred at 100 °C under nitrogen protection for 2 hours.

[0443] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 25°C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give (1S,3S)-N3-(5-chloropyrimidin-2-yl)-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine (0.83 g, 1.94 mmol, yield 65.98%, purity 97.29%) as a yellow solid. LC-MS (ESI) m / z = 416.1 [M + H] +

[0444] Step 2: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate

[0445] (1S,3S)-N3-(5-chloropyrimidin-2-yl)-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine (0.3 g, 721.75 μmol, 1 eq) and tert-butyl-2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (350.47 mg, 721.75 μmol, 1 eq) were added. 75 μmol, 1 eq), cuprous iodide (41.24 mg, 216.52 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (30.80 mg, 216.52 μmol, 0.3 eq), and potassium carbonate (299.25 mg, 2.17 mmol, 3 eq) were added to dimethyl sulfoxide (10 mL), the mixture was purged with nitrogen, and the reaction mixture was stirred at 110 °C under nitrogen protection for 2 hours.

[0446] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude tert-butyl-2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (600 mg, crude), which was a brown solid.

[0447] Step 3: Synthesis of 1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-4-[(E)-2-[(2S,4S)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-3-isopropyl-pyridin-2-one

[0448] Add trifluoroacetic acid (176.93 mg, 1.55 mmol, 115.27 μL, 2 eq) to a solution of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate (600 mg, 775.86 μmol, 1 eq) in dichloromethane (2 mL), and stir the mixture at 15-25 °C for 10 minutes.

[0449] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-4-[(E)-2-[(2S,4S)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-3-isopropyl-pyridin-2-one (500 mg, crude), which is a brown solid.

[0450] Step 4: Synthesis of (E,3R,5S)-7-[1-[6-[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoic acid

[0451] Add sodium hydroxide solution (1M, 1.14 mL, 1.5 eq) to a methanol (2 mL) solution of 1-[6-[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-4-[(E)-2-[(2S,4S)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-3-isopropyl-pyridin-2-one (500 mg, 758.55 μmol, 1 eq), and stir the reaction mixture at 15-25 °C for 30 minutes.

[0452] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mm NH4HCO3)-ACN]; gradient: 15%-45% B, 15.0 min) to give the product (E,3R,5S)-7-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoic acid (280 mg).

[0453] Example 45

[0454] Synthesis of (E,3R,5S)-7-[1-[6-[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoic acid

[0455] Step 1: Synthesis of (1S,3S)-N1-(5-bromo-3-fluoro-2-pyridyl)-N3-(5-chloropyrimidin-2-yl)cyclopentane-1,3-diamine

[0456] (1S,3S)-N3-(5-bromo-3-fluoro-2-pyridyl)cyclopentane-1,3-diamine (1 g, 3.22 mmol, 1 eq, hydrochloride), 2,5-dichloropyrimidine (575.59 mg, 3.86 mmol, 1.2 eq), and diisopropylethylamine (1.25 g, 9.66 mmol, 1.68 mL, 3 eq) were added to dimethyl sulfoxide (10 mL), and the reaction mixture was stirred at 100 °C under nitrogen for 2 hours.

[0457] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 25°C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give (1S,3S)-N1-(5-bromo-3-fluoro-2-pyridyl)-N3-(5-chloropyrimidin-2-yl)cyclopentane-1,3-diamine (890 mg, 2.30 mmol, yield 71.49%) as a yellow solid.

[0458] Step 2: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate

[0459] (1S,3S)-N1-(5-bromo-3-fluoro-2-pyridyl)-N3-(5-chloropyrimidin-2-yl)cyclopentane-1,3-diamine (0.3 g, 775.90 μmol, 1 eq), tert-butyl-2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (376.76 mg, 77 5.90 μmol, 1 eq), cuprous iodide (44.33 mg, 232.77 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (33.11 mg, 232.77 μmol, 0.3 eq), and potassium carbonate (321.70 mg, 2.33 mmol, 3 eq) were added to dimethyl sulfoxide (10 mL), the mixture was purged with nitrogen, and the reaction mixture was stirred at 110 °C under nitrogen protection for 12 hours.

[0460] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product tert-butyl-2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate (600 mg, crude product), which is a brown solid.

[0461] Step 3: Synthesis of 1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-4-[(E)-2-[(2S,4S)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-3-isopropyl-pyridin-2-one

[0462] Add trifluoroacetic acid (172.91 mg, 1.52 mmol, 112.64 μL, 2 eq) to a solution of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (600 mg, 758.22 μmol, 1 eq) in dichloromethane (2 mL), and stir the mixture at 15-25 °C for 30 minutes.

[0463] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. Water (10 mL) was added, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-4-[(E)-2-[(2S,4S)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-3-isopropyl-pyridin-2-one (513.65 mg, crude), as a brown solid.

[0464] Step 4: Synthesis of (E,3R,5S)-7-[1-[6-[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoic acid

[0465] Add sodium hydroxide solution (1M, 1.14mL, 1.5eq) to a methanol (2mL) solution of 1-[6-[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-4-[(E)-2-[(2S,4S)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]vinyl]-3-isopropyl-pyridin-2-one (513.65mg, 758.55μmol, 1eq), and stir the reaction mixture at 15-25℃ for 30 minutes.

[0466] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mm NH4HCO3)-ACN]; gradient: 18%-48% B over 15.0 min) to give the product (E,3R,5S)-7-[1-[6-[[[(1S,3S)-3-[(5-chloropyrimidin-2-yl)amino]cyclopentyl]amino]-5-fluoro-3-pyridyl]-5-(4-fluorophenyl)-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoic acid (330 mg).

[0467] Example 47

[0468] Synthesis of (E,3R,5S)-7-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptane-6-enoic acid

[0469] Step 1: Synthesis of (1S,3S)-N1-(5-bromo-3-fluoro-2-pyridyl)-N3-thiazo[5,4-b]pyridin-2-yl-cyclopentane-1,3-diamine

[0470] (1S,3S)-N3-(5-bromo-3-fluoro-2-pyridyl)cyclopentane-1,3-diamine (1 g, 3.22 mmol, 1 eq, hydrochloride), 2-chlorothiazo[5,4-b]pyridine (659.20 mg, 3.86 mmol, 1.2 eq) and diisopropylethylamine (1.25 g, 9.66 mmol, 1.68 mL, 3 eq) were added to dimethyl sulfoxide (10 mL), and the reaction mixture was stirred at 100 °C under nitrogen protection for 2 hours.

[0471] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 25°C, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give the product (1S,3S)-N1-(5-bromo-3-fluoro-2-pyridyl)-N3-thiazo[5,4-b]pyridin-2-yl-cyclopentane-1,3-diamine (1.04 g, 2.55 mmol, yield 79.11%) as a yellow solid.

[0472] Step 2: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0473] (1S,3S)-N1-(5-bromo-3-fluoro-2-pyridinyl)-N3-thiazo[5,4-b]pyridin-2-yl-cyclopentane-1,3-diamine (300 mg, 734.77 μmol, 1 eq) and tert-butyl-2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-isopropyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (374.63 mg) 771.51 μmol, 1.05 eq), cuprous iodide (41.98 mg, 220.43 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (31.35 mg, 220.43 μmol, 0.3 eq), and potassium carbonate (304.65 mg, 2.20 mmol, 3 eq) were added to dimethyl sulfoxide (9 mL), the mixture was purged with nitrogen, and the reaction mixture was stirred at 110 °C under nitrogen protection for 12 hours.

[0474] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate (480 mg, crude product), which is a brown solid.

[0475] Step 3: Synthesis of tert-butyl(E,3R,5S)-7-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoate

[0476] Add dioxane hydrochloride solution (2M, 1.92mL, 6.50eq) to a methanol (2mL) solution of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (480mg, 590.43μmol, 1eq) and stir the mixture at 15-25℃ for 30min.

[0477] LC-MS indicated that the reaction was complete. Concentration of the reaction mixture under reduced pressure yielded the crude product tert-butyl(E,3R,5S)-7-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoate (475.3 mg, crude), a brown solid. LC-MS (ESI) m / z = 773.3 [M+H] +

[0478] Step 4: Synthesis of (E,3R,5S)-7-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptane-6-enoic acid

[0479] Add sodium hydroxide solution (1M, 2mL, 3.25eq) to a methanol (2mL) solution of tert-butyl(E,3R,5S)-7-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoate (475.3mg, 614.96μmol, 1eq) and stir at 15-25℃ for 10min.

[0480] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mm NH4HCO3)-ACN]; gradient: 15%-45% B, 15.0 min) to give the product (E,3R,5S)-7-[5-(4-fluorophenyl)-1-[5-fluoro-6-[[(1S,3S)-3-(thiazo[5,4-b]pyridin-2-ylamino)cyclopentyl]amino]-3-pyridyl]-3-isopropyl-2-oxo-4-pyridyl]-3,5-dihydroxy-heptyl-6-enoic acid (180 mg, 248.41 μmol, yield 40.39%, purity 98.92%), as a white solid.

[0481] Example 57

[0482] Synthesize (3R,5S,E)-7-(3-ethyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid.

[0483] Step 1: Synthesis of methyl 5-chloro-3-ethyl-2-methoxyisonicotinic acid

[0484] Methyl 3-bromo-5-chloro-2-methoxy-pyridine-4-carboxylic acid (5.00 g, 17.8 mmol, 1.00 eq), ethylboronic acid (1.59 g, 21.4 mmol, 1.2 eq), potassium carbonate (7.39 g, 53.5 mmol, 3.00 eq), and 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex (1.46 g, 1.78 mmol, 0.10 eq) were dissolved in dioxane (50 mL x 2) and water (10 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LC-MS. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 5-chloro-3-ethyl-2-methoxyisonicotinic acid (4.00 g, 97.5% yield). MS (ESI) m / z = 230.1 [M+1] +

[0485] Step 2: Synthesis of methyl 3-ethyl-5-(4-fluorophenyl)-2-methoxyisonicotinic acid

[0486] Methyl 5-chloro-3-ethyl-2-methoxyisonicotinic acid (4.00 g, 17.4 mmol, 1.00 eq), 4-fluorophenylboronic acid (3.17 g, 22.6 mmol, 1.30 eq), 2-bicyclohexylphosphine-2,6-dimethoxyoxybiphenyl (715 mg, 1.74 mmol, 0.10 eq), potassium carbonate (7.23 g, 52.1 mmol, 3.00 eq), and palladium acetate (391 mg, 1.74 mmol, 0.10 eq) were dissolved in dioxane (40 mL) and water (8 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 12 hours. The MS value of the product was monitored by LCMS. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 3-ethyl-5-(4-fluorophenyl)-2-methoxyisonicotinic acid (4.33 g, 85.9% yield). MS (ESI) m / z = 290.1 ​​[M+1] +

[0487] Step 3: Synthesis of methyl 3-ethyl-5-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid

[0488] Methyl 3-ethyl-5-(4-fluorophenyl)-2-methoxyisonicotinic acid (4.00 g, 13.8 mmol, 1.00 eq) was dissolved in acetonitrile (40 mL), and then trimethyliodosilane (5.8 g, 28.9 mmol, 2.10 eq) was added. After the addition was complete, the reaction mixture was stirred at 80 °C for 2 hours. TLC showed that the reaction proceeds were completely reacted. The reaction mixture was cooled to room temperature, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain methyl 3-ethyl-5-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.49 g, 65.5% yield). MS (ESI) m / z = 276.1 [M+1] +

[0489] Step 4: Synthesis of 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-ethylpyridin-2(1H)-one

[0490] Methyl 3-ethyl-5-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid ester (2.49 g, 9.05 mmol, 1.00 eq) was dissolved in dichloromethane (30 mL) and cooled to -50 °C. Then, diisobutylaluminum hydride (1 M, 36.2 mL, 4.00 eq) was slowly added dropwise to the reaction solution, with the temperature maintained at approximately -50 °C throughout the addition. After the addition was complete, the reaction solution was stirred at 0 °C for 4 hours. TLC monitoring showed that the starting material reacted completely. The reaction solution was quenched at approximately 0 °C with a saturated ammonium chloride aqueous solution (200 mL) and then extracted with dichloromethane (100 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-ethylpyridin-2(1H)-one (844 mg, 37.6% yield). MS (ESI) m / z = 248.2 [M+1] +

[0491] Step 5: Synthesis of 4-(bromomethyl)-5-(4-fluorophenyl)-3-ethyl-1H-pyridin-2-one

[0492] 5-(4-fluorophenyl)-4-(hydroxymethyl)-3-ethylpyridin-2(1H)-one (370 mg, 1.42 mmol, 1.00 eq) was dissolved in dichloromethane (10 mL) and cooled to 0 °C. Phosphorus tribromide (606 mg, 2.12 mmol, 1.50 eq) was then slowly added dropwise to the reaction mixture while maintaining the temperature at approximately 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 3 hours. The MS value of the product was monitored by LC-MS. The reaction mixture was quenched at approximately 0 °C with a saturated sodium bicarbonate aqueous solution (30 mL), followed by extraction with dichloromethane (20 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(bromomethyl)-5-(4-fluorophenyl)-3-ethyl-1H-pyridin-2-one (850 mg). This was not purified and was used directly in the next step. MS(ESI)m / z = 310.2[M+1] +

[0493] Step 6: Synthesis of 5-(4-fluorophenyl)-3-ethyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one

[0494] 4-(bromomethyl)-5-(4-fluorophenyl)-3-ethyl-1H-pyridin-2-one (850 mg, 2.75 mmol, 1.00 eq) and triphenylphosphine (864 mg, 3.15 mmol, 1.20 eq) were dissolved in toluene (10 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The MS value of the product was monitored by LCMS. The reaction mixture was concentrated to give 5-(4-fluorophenyl)-3-ethyl-4-[(triphenyl-phosphine)methyl]-1H-pyridin-2-one (1.30 g). It was used directly in the next step without purification. MS (ESI) m / z = 492.2 [M+1] +

[0495] Step 7: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-ethyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0496] 5-(4-fluorophenyl)-3-ethyl-4-[(triphenylphosphine)methyl]-1H-pyridin-2-one (1.30 g, 2.64 mmol, 1.00 eq), 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (751 mg, 2.83 mmol, 1.10 eq), and potassium carbonate (730 mg, 5.14 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (20 mL), and the reaction mixture was stirred at 110 °C for 2 hours. The MS value of the product was monitored by LC-MS. The reaction mixture was cooled to room temperature, then diluted with water (150 mL), and extracted with ethyl acetate (50 mL x 2). The concentrated organic phase was washed with saturated brine (100 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-ethyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (869 mg, 69.7% yield). MS (ESI) m / z = 472.2 [M+1] +

[0497] Step 8: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-ethyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0498] tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-(4-fluorophenyl)-3-ethyl-2-oxo-1H-pyridin-4-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (840 mg, 1.78 mmol, 1.00 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3- Diamine (797 mg, 1.74 mmol, 1.00 eq), cuprous iodide (102 mg, 519 μmol, 0.30 eq), potassium carbonate (738 mg, 5.19 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (75.9 mg, 519 μmol, 0.30 eq) were dissolved in dimethyl sulfoxide (10 mL), and then stirred at 110 °C for 3 hours. The MS values ​​of the products were monitored by LCMS. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (30 mL * 2). The concentrated organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl-2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-ethyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.2 g). It was used directly in the next step without purification. MS (ESI) m / z = 791.3 [M+1] +

[0499] Step 9: Synthesis of 3R,5S,E)-7-(3-ethyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0500] 100 mg, 124 μmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-5-(4-fluorophenyl)-3-ethyl-2-oxo-4-pyridyl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was dissolved in acetonitrile (3 mL), and then 2 M hydrochloric acid aqueous solution was added to adjust the pH of the system to about 2. After the addition was complete, the reaction solution was stirred at 20 °C for 1 hour. Subsequently, 2 M sodium hydroxide aqueous solution was added to the system to adjust the pH of the system to about 13, and the reaction was continued for 1 hour. The MS value of the product was monitored by LCMS. The reaction solution was concentrated to obtain the crude product. The crude product was purified by reverse-phase column chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 18%-48% B over 15min) to obtain 3R,5S,E)-7-(3-ethyl-6'-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-5-(4-fluorophenyl)-2-oxo-2H-[1,3'-bipyridine]-4-yl)-3,5-dihydroxyhept-6-enoic acid (29.0 mg).

[0501] Example 58

[0502] Synthesis of (3R,5S,E)-7-(1-(5-fluoro-6-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-5-isopropyl-6-oxo-1,6-dihydropyridazine-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0503] Step 1: Methyl 3-chloro-6-oxo-1,6-dihydropyridazine-4-carboxylate

[0504] 10 g of 3-chloro-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (57.29 mmol) and 3.68 g of concentrated sulfuric acid (37.52 mmol) were added sequentially to MT (60 mL). After the addition was complete, the reaction was carried out at 100 °C.

[0505] MS monitoring showed product formation. The reaction solution was concentrated, water (40 mL) was added, and the pH was adjusted to neutral. Extraction was performed with EA (40 mL x 3). The organic phases were combined to give a brown solid methyl 3-chloro-6-oxo-1,6-dihydropyridazine-4-carboxylic acid methyl ester (9 g, yield 83.30%). LC-MS: [M+H]+ = 188.9

[0506] Step 2: Synthesis of methyl 3-chloro-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazine-4-carboxylate

[0507] Methyl 3-chloro-6-oxo-1,6-dihydropyridazine-4-carboxylate (7.6 g, 40.30 mmol) was added to pure water, followed by 2-methylpropionic acid (4.26 g, 48.36 mmol), TFA (4.60 g, 40.3 mmol), silver nitrate (1.37 g, 8.06 mmol), and sodium persulfate (11.51 g, 48.36 mmol). After addition, the reaction was carried out at 60 °C. MS monitoring showed product formation. The pH was adjusted to neutral with saturated sodium bicarbonate solution, and the reaction was quenched with saturated sodium thiosulfate solution. Extraction was performed with EA (40 mL x 3). The organic phases were combined and column chromatography (EA / Hex = 1:3, 30%) to give a white solid methyl 3-chloro-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazine-4-carboxylate (5 g, yield 53.79%, purity 100%). LC-MS: [M+H]+=230.9

[0508] Step 3: Synthesis of methyl 3-(4-fluorophenyl)-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazine-4-carboxylate

[0509] Methyl 3-chloro-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazine-4-carboxylate (4.2 g, 18.21 mmol), 4-fluorophenylboronic acid (5.10 g, 36.42 mmol), potassium acetate (3.57 g, 36.42 mmol), and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (R3, 6.66 g, 9.11 mmol, Purity 100%) were added to a mixed solvent of 1,4-dioxane (60 mL) and water (5 mL), and the reaction was carried out at 120 °C.

[0510] MS monitoring showed product formation. Water (40 mL) was added, and the mixture was extracted with EA (40 mL x 3). The organic phases were combined and subjected to column chromatography (EA / Hex = 50%) to give a brown solid, methyl 3-(4-fluorophenyl)-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazine-4-carboxylate (4 g, yield 75.67%). LC-MS: [M+H]+ = 291.0

[0511] Step 4: Synthesis of 6-(4-fluorophenyl)-5-(hydroxymethyl)-4-(propyl-2-yl)-2,3-dihydropyridazin-3-one

[0512] Methyl 3-(4-fluorophenyl)-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazine-4-carboxylate (1 g, 3.44 mmol) was added to DCM (10 mL), and diisobutylaluminum hydride (1.96 g, 13.76 mmol) was added dropwise at -50 °C. After the addition was complete, the reaction was carried out at 0 °C.

[0513] MS monitoring showed product formation. The reaction was quenched with saturated ammonium chloride aqueous solution, and extracted with EA (40 mL x 3). The organic phases were combined to give a white solid 6-(4-fluorophenyl)-5-(hydroxymethyl)-4-(propyl-2-yl)-2,3-dihydropyridazin-3-one (0.7 g, yield 77.48%). LC-MS: [M+H]+=263.0

[0514] Step 5: Synthesis of 5-(bromomethyl)-6-(4-fluorophenyl)-4-(propyl-2-yl)-2,3-dihydropyridazin-3-one

[0515] Under ice bath conditions, 6-(4-fluorophenyl)-5-(hydroxymethyl)-4-(propyl-2-yl)-2,3-dihydropyridazin-3-one (0.6 g, 2.29 mmol) was dissolved in DCM (5 mL), and phosphorus tribromide (0.68 g, 2.52 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature.

[0516] MS monitoring showed product formation. The pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with EA (40 mL x 3). The organic phases were combined to give a white solid, 5-(bromomethyl)-6-(4-fluorophenyl)-4-(propyl-2-yl)-2,3-dihydropyridazin-3-one (0.5 g, yield 67.21%). LC-MS: [M+H]+ = 325.1, 327.1

[0517] Step 6: Synthesis of 6-(4-fluorophenyl)-4-(propyl-2-yl)-5-[(triphenyl-λ^5-phosphine)methyl]-2,3-dihydropyridazin-3-one

[0518] 5-(bromomethyl)-6-(4-fluorophenyl)-4-(propyl-2-yl)-2,3-dihydropyridazin-3-one (0.5 g, 1.54 mmol) and triphenylphosphine (0.48 g, 1.85 mmol) were added sequentially to toluene (5 mL) and reacted at 100 °C.

[0519] MS monitoring showed product formation. Concentrating the reaction solution yielded a white solid, 6-(4-fluorophenyl)-4-(propyl-2-yl)-5-[(triphenyl-λ^5-phosphine)methyl]-2,3-dihydropyridazin-3-one (0.76 g, yield 98%), which required no further purification and was used directly in the next step. LC-MS: [M+H]+=507.0

[0520] Step 7: Synthesis of tert-2-[(4R,6S)-6-[(E)-2-(3-(4-fluorophenyl)-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid

[0521] 6-(4-fluorophenyl)-4-(prop-2-yl)-5-[(triphenyl-λ^5-phosphine)methyl]-2,3-dihydropyridazin-3-one (0.5 g, 0.99 mmol), 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (0.33 g, 1.29 mmol), and potassium carbonate (0.27 g, 1.98 mmol) were added sequentially to DMSO (5 mL). After the addition was complete, the reaction was carried out at 110 °C. MS monitoring showed that a product was formed. The reaction solution was purified by reverse-phase column chromatography (acetonitrile:water = 42%). Concentrate and lyophilize to give a white solid 2-[(4R,6S)-6-[(E)-2-(3-(4-fluorophenyl)-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]tert-butyl acetate (0.3 g, Yield 62.46%). LC-MS: [M+H]+=487.1

[0522] Step 8: Synthesis of 2-((4R,6S)-6-((E)-2-(1-(5-fluoro-6-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-5-isopropyl-6-oxo-1,6-dihydropyridazin-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0523] 0.15 g (0.31 mmol) of tert-butyl 2-[(4R,6S)-6-[(E)-2-(3-(4-fluorophenyl)-6-oxo-5-(propyl-2-yl)-1,6-dihydropyridazin-4-yl)vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate, (1S,3S)-N1-(5-bromo-3-fluoropyridin-2-yl)-N3-(5-methoxypyrimidine) -2-yl)cyclopentane-1,3-diamine (0.15 g, 0.33 mmol), potassium carbonate (0.13 g, 0.93 mmol), cuprous iodide (0.018 g, 0.093 mmol), and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.013 g, 0.093 mmol) were added sequentially to DMSO (5 mL), and the reaction was carried out in a microwave environment at 110 °C under nitrogen protection.

[0524] MS monitoring showed product formation, so the reaction was stopped. Water (40 mL) was added, and the mixture was extracted with EA (40 mL × 3). The organic phases were combined and subjected to column chromatography (MeOH:DCM = 1:30). The mixture was concentrated to give a brown solid 2-((4R,6S)-6-((E)-2-(1-(5-fluoro-6-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-5-isopropyl-6-oxo-1,6-dihydropyridazin-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate (0.15 g).

[0525] Step 9: (3R,5S,E)-7-(1-(5-fluoro-6-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-5-isopropyl-6-oxo-1,6-dihydropyridazine-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0526] Dissolve 2-((4R,6S)-6-((E)-2-(1-(5-fluoro-6-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-5-isopropyl-6-oxo-1,6-dihydropyridazin-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate in MT (5 mL), add HCl (0.0069 g, 0.19 mmol) in methanol, stir for 2 h, add lithium hydroxide (0.046 g, 1.9 mmol) in aqueous solution, and stir for 2 h.

[0527] MS monitoring showed product formation. After adjusting the pH to 3 and purifying by preparative liquid chromatography, (3R,5S,E)-7-(1-(5-fluoro-6-((1S,3S)-3-((5-methoxypyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-5-isopropyl-6-oxo-1,6-dihydropyridazin-4-yl)-3,5-dihydroxyhept-6-enoic acid (0.056 g) was obtained.

[0528] Example 60

[0529] Step 1: Synthesis of 2-((4R,6S)-6-((E)-2-(1-(5-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyrazin-2-yl)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0530] At room temperature, compound 60-1 (200 mg, 0.5 mmol), compound 60-2 (289 mg, 0.6 mmol, 1.2 eq), potassium carbonate (138 mg, 1 mmol, 2 eq), cuprous iodide (47 mg, 0.25 mmol, 0.5 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.25 mmol, 0.5 eq), and 1,4-dioxane (3 mL) were added sequentially to a 25 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere, and the temperature was raised to 100 °C for the reaction.

[0531] LC-MS detected the disappearance of the starting material and the formation of the target product. The reaction mixture was filtered, concentrated, and purified by C18 reverse column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 60-3 (286 mg, 71% yield) as a gray oil.

[0532] Step 2: Synthesis of (3R,5S,E)-7-(1-(5-((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyrazin-2-yl)-5-(4-fluorophenyl)-3-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-3,5-dihydroxyhept-6-enoic acid

[0533] Compound 60-3 (286 mg, 0.36 mmol) was added to a 25 mL round-bottom flask at room temperature and dissolved in acetonitrile (2 mL). Then, 1 N aq. HCl (0.7 mL, 2 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the starting material. 2 N aq. NaOH (0.7 mL, 4 eq) was added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the intermediate and the formation of the target product. The reaction mixture was concentrated and purified by C18 reverse-phase column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 60 (149 mg).

[0534] Example 61

[0535] Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0536] Step 1: Synthesis of (1S,3S)-N1-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-N3-(5-bromo-3-fluoropyridin-2-yl)cyclopentane-1,3-diamine

[0537] t-BuONa (588 mg, 6.12 mmol, 3.00 eq) and BrettPhos Pd G3 (184 mg, 204 μmol, 0.10 eq) were added to 10 mL solutions of dioxane (10 mL) of 61-1 (500 mg, 2.04 mmol, 1.00 eq) and 61-2 (1.12 g, 4.08 mmol, 2.00 eq). The mixture was stirred at 120 °C for 3 hours.

[0538] The formation of the target product was detected by LC-MS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1-0 / 1) to give compound 61-3 (500 mg, crude) as a brown oil.

[0539] Step 2: Synthesis of tert-butyl 2-((4R,6S)-6-((E)-2-(6'-((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)vinyl)-2,2-dimethyl-1,3-dioxa-4-yl)acetate

[0540] To a DMSO (6 mL) solution of 61-3 (440 mg, 731 μmol, 1.00 eq) and 415-11 (283 mg, 584 μmol, 0.80 eq), K₂CO₃ (303 mg, 2.19 mmol, 3.00 eq), (1S,2S)-N₁,N₂-dimethylcyclohexane-1,2-diamine (20.8 mg, 146 μmol, 0.20 eq) and CuI (27.8 mg, 146 μmol, 0.20 eq) were added. The mixture was stirred at 110 °C for 12 hours.

[0541] The formation of the target product was detected by LCMS. The reaction solution was poured into water (60 mL), extracted with ethyl acetate (80 mL), and the organic phase was washed with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1-0 / 1) to give compound 61-4 (500 mg, crude) as a brown oil.

[0542] Step 3: Synthesis of (3R,5S,E)-7-(6'-(((1S,3S)-3-([1,2,4]triazolo[1,5-a]pyridin-2-ylamino)cyclopentyl)amino)-5'-fluoro-5-(4-fluorophenyl)-3-isopropyl-2-oxo-2H-[1,3'-bipyridin]-4-yl)-3,5-dihydroxyheptane-6-enoic acid

[0543] Add HCl (16.7 mg, 169 μmol, 1.00 eq) dropwise to a MeOH solution (6 mL) of 61-4 (450 mg, 169.62 μmol, 1.00 eq). Stir the mixture at 25 °C for 30 minutes. Then add a NaOH solution (67.8 mg, 1.70 mmol, 10.0 eq) of H₂O (2 mL) dropwise. Stir the mixture at 25 °C for 30 minutes.

[0544] The formation of the target product was detected by LCMS. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by reverse-phase preparation (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 5%-35% B over 10.0 min) to obtain compound 61 (29.26 mg), which was identified as the target product by NMR.

[0545] Example 73

[0546] Synthesis of 1-(5-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyrazin-2-yl)-5-(4-fluorophenyl)-4-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-3-isopropylpyridine-2(1H)-one

[0547] Compound 60 (71 mg, 0.1 mmol) was added to a 10 mL round-bottom flask at room temperature and dissolved in 1 mL of DCM. Then, EDCI (38 mg, 0.2 mmol, 2 eq) and DMAP (1.2 mg, 0.01 mmol, 0.1 eq) were added, and the mixture was stirred at room temperature. LC-MS detected the disappearance of the starting material and the formation of the target product. The reaction mixture was concentrated and purified by C18 reverse-phase column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min) to obtain the target compound 73 (56 mg).

[0548] The structures and identification data of compounds 18-89 are as follows:

[0549] Example 90: Affinity test of the compound with PCSK9 protein

[0550] The binding affinity of the compounds of this invention to PCSK9 protein was determined by fluorescence polarization method.

[0551] All compounds were dissolved in DMSO to prepare 10 mM stock solutions. Positive and test compounds were serially diluted 5-fold with DMSO, starting at 10 mM, for a total of 8 concentration gradients. First, a certain volume of fluorescent probe solution was prepared to a concentration of 5 nM using test buffer (20 mM HEPES, 150 mM NaCl, 1 mM CaCl2, and 0.01% Tween-20). Then, the serial DMSO solutions of the test compounds were diluted 50-fold with the fluorescent probe solution. Finally, a solution of 9 μg / mL human recombinant PCSK9 protein (provided by Chengdu Xinlitai) was prepared using test buffer. After the test solution was prepared, 5 μL of PCSK9 protein was added to a black 384-well plate (PerkinElmer, Cat#6008260), along with 5 μL of a mixture of different concentrations of the compound and fluorescent probe (DMSO final concentration 1%). A positive control group (test buffer + equal volume of target protein + equal proportion of fluorescent probe molecules) and a negative control group (test buffer + equal proportion of fluorescent probe molecules) were also set up. The final concentration of probe molecules in the system was 2.5 nM, and the median concentration of PCSK9 protein was 4.5 μg / mL. After shaking and mixing at room temperature, the mixture was incubated for 18 hours. Fluorescence polarization values ​​were read using a microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 520 nm. The inhibition rate of the drug was calculated as [1 - (mP(drug screening group) - mP(negative control group)] ÷ [mP(positive control group) - mP(negative control group))] × 100. A 4-parameter nonlinear regression curve was fitted with the logarithm of the compound concentration on the x-axis and the inhibition rate on the y-axis to calculate the IC50. 50 Value(Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)), where: Hillslope represents the slope of this curve, IC 50 This indicates the half-maximal inhibitory concentration (MCI).

[0552] Table 2. FP-IC 50 data

[0553] A<300nm.

[0554] The results are shown in Table 1. As can be seen from Table 1, the compounds of the present invention have a strong affinity for PCSK9.

[0555] Example 91: Test for inhibition of human HMG-CoA reductase activity

[0556] The human HMG-CoA reductase (Cat#9264-HM) used was purchased from R&D Systems, USA. The NADPH (Cat#N7505) and HMG-CoA (CAT#H6132) detection reagents were purchased from Sigma-Aldrich, USA. The positive control drug, atorvastatin calcium (Cat#BD18107), was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0557] The specific experiments were conducted according to the reagent instructions.

[0558] Reagent preparation:

[0559] HMG-CoA reductase: original concentration 0.214 mg / ml, total 20 μg. 10 μl / tube, store frozen at -80℃.

[0560] HMG-CoA: Add 0.5 mL of ddH2O to HMG-CoA and dissolve completely to form a 10 mM stock solution. 80 μl / tube, store frozen at -80°C.

[0561] NAAPH: Add 1500 μl of ddH2O to NADPH and dissolve completely to form a 20 mM stock solution. Store 50 μl / tube at -80°C.

[0562] Assay buffer: 50mM Tris, 500mM KCl, 1mg / ml BSA, pH 7.0. Used for dilution of enzymes and substrates.

[0563] Experimental steps:

[0564] All compounds were dissolved in DMSO to prepare 10 mM stock solutions. Positive reference and test compounds were serially diluted 4-fold with DMSO starting at 300 μM, for a total of 8 concentration gradients. The serially diluted DMSO drugs were then diluted 100-fold with assay buffer to prepare working solutions.

[0565] Add 50 μl of the compound of the present invention (1.5 μg / ml HMG-CoA) and 50 μl of a series of working solutions diluted to a specific concentration to a 96-well plate and incubate at room temperature for 30 min. After incubation, add 50 μl of 1.5 mM NADPH and 0.6 mM HMG-CoA. The NADPH oxidation absorbance was immediately measured at 340 nM using a microplate reader (model: Pherastar) in enzyme kinetic mode (37°C, 1 min / test, 20 min). The enzyme activity was determined based on the rate of decrease in absorbance, and the sample concentration required to inhibit HMG-CoA reductase activity by 50% was calculated. Each unit of enzyme activity is defined as the amount of enzyme required to catalyze the oxidation of 1 mmol of NADPH per minute.

[0566] Table 3. HMG-CoA reductase activity data

[0567] B < 300nm.

[0568] The results are shown in Table 2. As can be seen from Table 2, the compounds of the present invention have a strong inhibitory effect on HMG-CoA reductase activity.

[0569] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A compound of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano. Ring B is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R2, and the heterocycles are monocyclic, bicyclic or tricyclic, and R2 is independently selected from hydrogen, halogen, alkyl, cycloalkyl or cyano; R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond; T2 is selected from N or CH; R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

2. A compound of general formula (IIa) or (IIb), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano. Ring B is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R2, and the heterocycles are monocyclic, bicyclic or tricyclic, and R2 is independently selected from hydrogen, halogen, alkyl, cycloalkyl or cyano; R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond; T2 is selected from N or CH; R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

3. A compound of general formula (IIIa) or (IIIb), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano. R2 can be one or more, each independently selected from hydrogen, halogen, alkyl, cycloalkyl, or cyano; R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond; T1 and T2 are each independently selected from N or CH; R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

4. A compound of general formula (IV), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from one or more saturated or unsaturated heterocycles that are substituted or unsubstituted with R1. The heterocycles are monocyclic, bicyclic, or tricyclic. R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano. R2 can be one or more, each independently selected from hydrogen, halogen, alkyl, cycloalkyl, or cyano; R3 can be one or more, each independently selected from hydrogen, alkyl, cycloalkyl, phenyl, halophenyl, -C(O)-NH-benzene, Wherein, R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond; R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

5. The compound according to any one of claims 1-3, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Compounds selected from those represented by general formula (Va), or (Vb), or (Vc), or (Vd), or their isomers, racemates, or pharmaceutically acceptable salts thereof: R5 is selected from substituted or unsubstituted alkyl carboxylic acids, substituted or unsubstituted cycloalkyl carboxylic acid esters, and the substituent is selected from hydroxyl groups. It can be represented as a single bond or a double bond; R6 is selected from hydrogen, substituted or unsubstituted alkyl or alkenyl groups, and the substituent is selected from hydroxyl or halogen.

6. The compound according to any one of claims 1-5, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl. The alkoxy group is selected from methoxy, ethoxy, propoxy, and isopropoxy. The cycloalkyl group is selected from C 3-6 The cycloalkyl group is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane; T1 and T2 are each independently selected from N or CH.

7. The compound according to any one of claims 1-5, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The halogen is selected from fluorine, chlorine, bromine, and iodine; the alkenyl group is selected from C. 2-4 Alkenyl groups, including vinyl, propenyl, and butenyl.

8. The compound according to any one of claims 1-5, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from H, F, Cl, Br, I, methyl, methoxy, methylthio, cyclopropyl, -OCHF2, cyano; and / or R2 is selected from H, F, Cl, Br, methyl, cyclopropyl.

9. The compound according to any one of claims 1-5, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R3 is one or more, each independently selected from hydrogen, methyl, ethyl, chlorine, ...

10. The compound according to any one of claims 1-5, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R5 is selected from: Furthermore, Preferred from 11. The compound according to any one of claims 1-5, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: Ring A is selected from Preferably, the substituted A ring is selected from... And / or ring B is selected from: The B ring that is further preferably substituted is selected from Further including 12. The compound according to any one of claims 1-5, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from compounds 1-89 shown in Table 1.

13. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective amount of any one of claims 1-12, or an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

14. The pharmaceutical use of the compound of any one of claims 1-12, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically usable salt thereof, or the pharmaceutical use of the pharmaceutical composition of claim 13, specifically, in the preparation of a medicament for treating a disease, said disease being a disease associated with PCSK9 and / or HMG-CoA reductase inhibitors, preferably from conditions such as hypercholesterolemia.

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