PCSK9 and HMG-coa bicyclic compound, and preparation and use thereof

Abstract

The present invention relates to the technical field of chemical drugs, and in particular to a PCSK9 and HMG-CoA bicyclic compound, or an isomer, racemate or pharmaceutically acceptable salt thereof, a preparation method therefor, and a use thereof. The present invention further relates to a use of the PCSK9 and HMG-CoA bicyclic compound as a PCSK9 inhibitor and / or an HMG-CoA reductase inhibitor, and a method for the treatment of multiple specific diseases or conditions using the PCSK9 and HMG-CoA bicyclic compound.

Description

[Amended according to Rule 26, 2014.11.2025] PCSK9 and HMG-CoA bicyclic compounds, their preparation and application Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, and relates to a bicyclic 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 represented by 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 intended as a 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] 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.

[0008] 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 condition, specifically selected from conditions such as hypercholesterolemia.

[0009] Specifically, the present invention is achieved through the following technical solution:

[0010] A compound of general formula (I), or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

[0011] Ring A is selected from one or more saturated or unsaturated heterocycles with or without R1 substitution. The heterocycle can be monocyclic, bicyclic, or tricyclic, and R1 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, and cyano.

[0012] Ring B is selected from one or more saturated or unsaturated heterobicycles with or without R3 substitution;

[0013] R2 can be one or more, each independently selected from hydrogen, halogen, alkyl, cycloalkyl, or cyano;

[0014] R3 is one or more, each independently selected from hydrogen, alkyl, oxo, halogen, cycloalkyl, cycloalkylalkyl, 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;

[0015] T is selected from CH or N.

[0016] 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.

[0017] As a preferred embodiment of the present invention, the alkoxy group is selected from methoxy, ethoxy, propoxy, and isopropoxy.

[0018] 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. In a preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0019] As a preferred embodiment of the present invention, R1 is selected from H, F, Cl, Br, methyl, cyclopropyl, -OCHF2, and cyano.

[0020] As a preferred embodiment of the present invention, R2 is selected from H, F, Cl, Br, methyl, and cyclopropyl.

[0021] In a preferred embodiment of the present invention, R3 is one or more, each independently selected from hydrogen, methyl, ethyl, chlorine, ...

[0022] As a preferred embodiment of the present invention, R5 is selected from: Furthermore, Preferred from

[0023] As a preferred embodiment of the present invention, ring A is selected from...

[0024] As a preferred embodiment of the present invention, the compound is selected from the compound represented by general formula (II) or formula (III), or its isomer, racemate, or pharmaceutically acceptable salt thereof.

[0025] As a preferred embodiment of the present invention, the replaced A ring is selected from...

[0026] As a preferred embodiment of the present invention, ring B is selected from:

[0027] Indicates a connection key.

[0028] In a preferred embodiment of the present invention, ring B is independently substituted by one or more R3s; more preferably, at least one carbon atom adjacent to N is oxidized, for example...

[0029] It can then be replaced independently by one or more R3s.

[0030] Furthermore, the substituted B ring is selected from:

[0031] As a preferred embodiment of the present invention, the compound, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is selected from:

[0032] 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.

[0033] 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.

[0034] 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.

[0035] The present invention further provides the pharmaceutical use of the said compound, or its isomers, racemates, or pharmaceutically usable salts 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.

[0036] 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.

[0037] For clarity, this article defines the general terminology used in the description of compounds.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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).

[0045] 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 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0051] 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.

[0052] 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.

[0053] "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.

[0054] 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

[0055] 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.

[0056] Example 1

[0057] Synthesis of (3R,5S,E)-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-1-isopropyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-3,5-dihydroxyhept-6-enoic acid

[0058] Synthesis route:

[0059] Step 1: Synthesis of methyl 4-bromo-1-isopropyl-1H-pyrrole-2-carboxylate

[0060] At room temperature, compound 1-1 (20 g, 98 mmol), DMSO (200 mL), and potassium hydroxide (27.4 g, 490 mmol, 5 eq) were added sequentially to a 500 mL round-bottom flask. The mixture was stirred at room temperature for 30 min, and then 2-iodopropane (50 g, 294 mmol, 3 eq) was added all at once. The mixture was stirred at room temperature for about 3 h and the reaction was monitored.

[0061] LC-MS detected the disappearance of the starting material and the formation of the target product. 300 mL of EA and 300 mL of water were added to the reaction system to separate the organic and aqueous phases. The aqueous phase was extracted twice more with 200 mL of EA. The organic phases were combined, washed three times with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compounds 1-2 (24 g, 99.5% yield) as a pale yellow oily liquid.

[0062] Step 2: Synthesis of methyl 4-(4-fluorophenyl)-1-isopropyl-1H-pyrrole-2-carboxylate

[0063] At room temperature, compounds 1-2 (23 g, 88 mmol), 4-fluorophenylboronic acid (14.8 g, 106 mmol, 1.2 eq), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (3.2 g, 4.4 mmol, 0.05 eq), sodium carbonate (18.7 g, 176 mmol, 2 eq), 1,4-dioxane (250 mL), and water (50 mL) were added sequentially to a 1000 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere and stirred overnight at 95 °C.

[0064] The formation of the target product was detected by LCMS. 300 mL of EA and 200 mL of water were added to the reaction system to separate the organic and aqueous phases. The aqueous phase was extracted twice more with 200 mL of EA. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compounds 1-3 (18 g, 74% yield) as a pale yellow oily liquid.

[0065] Step 3: Synthesis of methyl 5-bromo-4-(4-fluorophenyl)-1-isopropyl-1H-pyrrole-2-carboxylate

[0066] Compound 1-3 (17 g, 65 mmol, 1.00 eq), THF (200 mL), and NBS (12 g, 68.3 mmol, 1.05 eq) were added to a 500 mL round-bottom flask at room temperature and stirred overnight at room temperature.

[0067] The formation of the target product was detected by LCMS. The reaction liquid was directly evaporated to dryness. Purification was performed by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compounds 1-4 (18 g, 82% yield) as a pale yellow oily liquid.

[0068] Step 4: Synthesis of 5-bromo-4-(4-fluorophenyl)-1-isopropyl-1H-pyrrole-2-carboxylic acid

[0069] At room temperature, compounds 1-4 (17.8 g, 52.4 mmol, 1.0 eq), THF (150 mL), methanol (100 mL), and sodium hydroxide (52 mL, 2.0 M in water, 104 mmol, 2 eq) were added sequentially to a 500 mL round-bottom flask, and the mixture was stirred overnight at room temperature.

[0070] The formation of the target product was detected by LCMS. The pH of the reaction system was adjusted to approximately 2 by adding 100 mL of 1N HCl aqueous solution. 200 mL of DCM was added, and the organic and aqueous phases were separated. The aqueous phase was extracted twice more with DCM. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compounds 1-5 (16 g, 93% yield) as a white solid.

[0071] Step 5: Synthesis of 5-bromo-N-(2,2-dimethoxyethyl)-4-(4-fluorophenyl)-1-isopropyl-1H-pyrrole-2-carboxamide

[0072] At room temperature, compound 1-5 (16 g, 49.2 mmol, 1.0 eq) and thionyl chloride (11.7 g, 98.4 mmol, 2 eq) were added to a 100 mL round-bottom flask. The reaction system was then purged under a nitrogen atmosphere and heated to 60 °C. The mixture was stirred for about 2 h until all the solids were dissolved and no gas was produced. The reaction system was then cooled to room temperature, and excess thionyl chloride was removed under reduced pressure. The intermediate was then transferred to a 500 mL round-bottom flask, purged under a nitrogen atmosphere, and dichloromethane (200 mL) was added. The mixture was cooled to 0 °C, and triethylamine (15 g, 148 mmol, 3.0 eq) and 2,2-dimethoxyethylamine (7.7 g, 73.8 mmol, 1.5 eq) were added. The reaction mixture was then heated to room temperature and reacted for 3 h. The reaction was then monitored.

[0073] The formation of the target product was detected by LCMS. The reaction system was quenched with 100 mL of water, and 100 mL of DCM was added to separate the organic and aqueous phases. The aqueous phase was extracted twice more with DCM. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compounds 1-6 (15 g, 74% yield) as a reddish-brown solid.

[0074] Step 6: Synthesis of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0075] Compound 1-6 (14.8 g, 36 mmol, 1.0 eq) and trifluoroacetic acid (36 mL) were added to a 100 mL round-bottom flask at room temperature, and the reaction was monitored after 3 h at room temperature.

[0076] The formation of the target product was detected by LCMS. Purification was performed by silica gel column chromatography under reduced pressure to remove excess trifluoroacetic acid (petroleum ether: ethyl acetate = 3:1), yielding compounds 1-7 (11 g, 88% yield) as a brown solid.

[0077] Step 7: Synthesis of 2-((4R,6S)-6-((E)-2-(3-(4-fluorophenyl)-1-isopropyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0078] At room temperature, compounds 1-7 (2 g, 5.7 mmol, 1.0 eq), 2-((4R,6S)-2,2-dimethyl-6-vinyl-1,3-dioxane-4-yl)tert-butyl acetate (1.47 g, 5.7 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium (0.66 g, 0.57 mmol, 0.1 eq), sodium carbonate (1.2 g, 11.4 mmol, 2 eq), and DMF (11 mL) were added sequentially to a 100 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere and stirred overnight at 120 °C.

[0079] The formation of the target product was detected by LCMS. 100 mL of EA and 50 mL of water were added to the reaction system to separate the organic and aqueous phases. The aqueous phase was extracted twice more with 1200 mL of EA. The organic phases were combined, washed three times with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compounds 1-8 (0.7 g, 23% yield) as a gray solid.

[0080] Step 8: 2-((4R,6S)-6-((E)-2-(6-(((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-1-isopropyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)tert-butyl acetate

[0081] At room temperature, compounds 1-8 (350 mg, 0.66 mmol, 1.0 eq), compounds 1-9 (328 mg, 0.73 mmol, 1.1 eq), cuprous iodide (38 mg, 0.2 mmol, 0.3 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (29 mg, 0.2 mmol, 0.3 eq), potassium carbonate (183 mg, 1.3 mmol, 2 eq), and DMSO (5 mL) were added sequentially to a 50 mL round-bottom flask. The reaction system was then replaced with a nitrogen atmosphere and heated to 140 °C with stirring overnight.

[0082] The formation of the target product was detected by LCMS. The reaction mixture was diluted with 50 mL of EA, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Purification was performed using a C18 reverse-phase column (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min). Compounds 1-10 (120 mg, 22% yield) were obtained as a gray solid.

[0083] Step 9: Synthesis of (3R,5S,E)-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-1-isopropyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-3,5-dihydroxyhept-6-enoic acid

[0084] At room temperature, compound 1-10 (60 mg, 0.071 mmol, 1.0 eq), acetonitrile (2 mL), and 1 N HCl aqueous solution (1 mL) were added sequentially to a 25 mL round-bottom flask. The mixture was stirred at room temperature for about 2 hours until the starting material disappeared. Then, 2 N NaOH aqueous solution (1 mL) was added and the mixture was stirred at room temperature overnight.

[0085] The formation of the target product was detected by LCMS. The pH was adjusted to approximately 7 by adding about 1 mL of 1N HCl aqueous solution. The reaction mixture was then purified directly by a C18 reverse-phase column (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min). (3R,5S,E)-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-1-isopropyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-2-yl)-3,5-dihydroxyhept-6-enoic acid (34 mg).

[0086] MRI 1H NMR (400MHz, DMSO-d6) δ8.26(s,2H),7.94(d,J=2.6Hz,1H),7.51(d,J=7.2Hz,1H),7.42(dd,J=8.8,2.7Hz,1H),7.38(ddd,J=8.4,5.6,2 .5Hz,2H),7.26(dd,J=9.3,7.4Hz,3H),7.15(d,J=7.1Hz,1H),7.07–6.84(m,2H),6.63(d,J=16.1Hz,1H),6.56(d,J=8.9Hz,1H),6.32(d ,J=7.1Hz,1H),5.68(d,J=15.4Hz,1H),4.34(q,J=7.0Hz,2H),4.24(d,J=6.9Hz,1H),3.69–3.50(m,1H),2.14(ddt,J=16.9,7.3,5.3Hz, 2H), 2.00 (dq, J=9.8, 3.2Hz, 1H), 1.97–1.86 (m, 3H), 1.80 (ddd, J=14.5, 8.5, 5.6Hz, 1H), 1.57 (q, J=10.2, 8.4Hz, 9H), 1.53–1.43 (m, 2H).

[0087] Example 2

[0088] Synthesis of 6-(6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-2-((E)-2-(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1-isopropyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0089] Synthesis route:

[0090] Step 1: Synthesis of 6-(6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-2-((E)-2-(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1-isopropyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0091] At room temperature, compound 1 (160 mg, 0.19 mmol, 1.0 eq), acetonitrile (3 mL), and trifluoroacetic acid (216 mg, 1.9 mmol, 10 eq) were added sequentially to a 25 mL round-bottom flask, and the mixture was stirred at room temperature for 24 h.

[0092] The formation of the target product was detected by LCMS. The reaction mixture was purified directly by C18 reverse-phase column chromatography (mobile phase: water(FA)-ACN; gradient: 0%-80% B over 50 min). 6-(6-((1S,3S)-3-(5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-3-(4-fluorophenyl)-2-((E)-2-(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1-isopropyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (34 mg).

[0093] MRI: 1 H NMR (400MHz, DMSO-d6) δ8.17(s,2H),7.84(d,J=2.7Hz,1H),7.41(d,J=7.2Hz,1H),7.32(dq,J=10.3,3. 7Hz,3H),7.23(dd,J=11.0,6.6Hz,2H),7.17–6.76(m,4H),6.48(d,J=8.9Hz,1H),6.28(d,J=7.1Hz,1H) ,5.89(d,J=23.7Hz,1H),5.33(s,1H),5.03(s,1H),4.36–4.19(m,2H),3.93(s,1H),3.44(d,J=2.2Hz,1 H),2.35–2.27(m,1H),2.07(ddd,J=12.5,7.1,4.8Hz,4H),1.83(q,J=6.8Hz,2H),1.48(t,J=7.1Hz,9H).

[0094] Example 3-25

[0095] Compounds 3-15 were prepared according to Examples 1-2 and the following preparation methods, specifically:

[0096] Example 5

[0097] Synthesis of (3R,5R)-7-[6-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-1-isopropyl-7-oxo-pyrrolo[2,3-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0098] Synthesis route:

[0099] Step 1: Synthesis of 7-chloro-3-iodo-1H-pyrrolo[2,3-c]pyridine

[0100] NIS (28.47 g, 126.52 mmol, 1.35 eq) was added in portions to a methanol solution (500 mL) of 7-chloro-1H-pyrrolo[2,3-c]pyridine (14.3 g, 93.72 mmol, 1 eq) at 15-25 °C. After the addition was complete, the mixture was stirred at 15-25 °C for 16 hours under nitrogen protection.

[0101] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (500 mL), then washed successively with saturated sodium sulfite solution (300 mL) and brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 7-chloro-3-iodo-1H-pyrrolo[2,3-c]pyridine (24 g, crude), as a yellow solid. LC-MS (ESI) m / z = 279.0 [M+H] +

[0102] Step 2: Synthesis of 7-chloro-3-iodo-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine

[0103] 7-Chloro-3-iodo-1H-pyrrolo[2,3-c]pyridine (24 g, 86.18 mmol, 1 eq), DMAP (1.05 g, 8.62 mmol, 0.1 eq), and diisopropylethylamine (33.42 g, 258.55 mmol, 45.03 mL, 3 eq) were added to dichloromethane (250 mL). TosCl (24.65 g, 129.27 mmol, 1.5 eq) was added in batches with stirring. After the addition was complete, the mixture was stirred at 15-25 °C for 2 hours.

[0104] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to give the product 7-chloro-3-iodo-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine (30.2 g, 69.80 mmol, yield 80.99%) as a yellow solid.

[0105] Step 3: Synthesis of 7-chloro-3-(4-fluorophenyl)-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine

[0106] 7-Chloro-3-iodo-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine (30 g, 69.34 mmol, 1 eq), (4-fluorophenyl)boronic acid (10.67 g, 76.27 mmol, 1.1 eq), Pd(dppf)Cl2 (5.07 g, 6.93 mmol, 0.1 eq), and potassium carbonate (28.75 g, 208.01 mmol, 3 eq) were added to dioxane (300 mL) and water (50 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred at 110 °C under nitrogen protection for 2 hours.

[0107] 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 = 20 / 1 to 2 / 1) to give the product 7-chloro-3-(4-fluorophenyl)-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine (24 g, 59.87 mmol, yield 86.35%) as a yellow solid. LC-MS (ESI) m / z = 401.1 [M+H] +

[0108] Step 4: Synthesis of 7-chloro-3-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine

[0109] 24 g (59.87 mmol, 1 eq) of 7-chloro-3-(4-fluorophenyl)-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine and 12.56 g (299.36 mmol, 5 eq) of LiOH·H2O were added to a mixed solvent of tetrahydrofuran (400 mL) and water (200 mL), and the reaction mixture was stirred at 70 °C for 17 hours.

[0110] LC-MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Water (300 mL) was added to the residue, and the mixture was stirred at 15–25 °C for 10 minutes. The mixture was filtered and the solid was collected. The solid was concentrated under reduced pressure to give the product 7-chloro-3-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine (13 g, crude), as a yellow solid. LC-MS (ESI) m / z = 247.1 [M+H] +

[0111] Step 5: Synthesis of 2-bromo-7-chloro-3-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine

[0112] Bromosuccinimide (13.03 g, 73.22 mmol, 1.4 eq) was added to a solution of 7-chloro-3-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine (12.9 g, 52.30 mmol, 1 eq) in N,N-dimethylformamide (300 mL). The reaction mixture was stirred at 50 °C under nitrogen protection for 16 hours.

[0113] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 20–30 °C, diluted with water (600 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The remaining crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1–2 / 1) to give 4.6 g of 2-bromo-7-chloro-3-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine as a yellow solid.

[0114] Step 6: Synthesis of 2-bromo-7-chloro-3-(4-fluorophenyl)-1-isopropyl-pyrrolo[2,3-c]pyridine

[0115] 2-Bromo-7-chloro-3-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine (4.6 g, 14.13 mmol, 1 eq), 2-iodopropane (4.4 g, 25.88 mmol, 2.58 mL, 1.83 eq), and potassium carbonate (5.86 g, 42.39 mmol, 3 eq) were added to N,N-dimethylformamide (50 mL), and the reaction mixture was stirred at 80 °C under nitrogen protection for 16 hours.

[0116] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 20–30 °C, diluted with water (200 mL), and extracted with ethyl acetate (50 mL x 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 silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1–3 / 1) to give 2-bromo-7-chloro-3-(4-fluorophenyl)-1-isopropyl-pyrrolo[2,3-c]pyridine (4.4 g, 10.69 mmol, yield 75.66%, purity 89.32%) as a yellow solid. LC-MS (ESI) m / z = 369.0 [M+H] +

[0117] Step 7: Synthesis of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-6H-pyrrolo[2,3-c]pyridin-7-one

[0118] 2-Bromo-7-chloro-3-(4-fluorophenyl)-1-isopropyl-pyrrolo[2,3-c]pyridine (4.4 g, 11.97 mmol, 1 eq) and ammonium acetate (21.22 g, 275.27 mmol, 23 eq) were added to glacial acetic acid (60 mL), and the reaction mixture was stirred at 120 °C for 18 hours under nitrogen protection.

[0119] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove most of the acetic acid. The residue was adjusted to pH 7–8 with saturated sodium bicarbonate solution (200 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 = 20 / 1–2 / 1) to give the product 2-bromo-3-(4-fluorophenyl)-1-isopropyl-6H-pyrrolo[2,3-c]pyridin-7-one (4.0 g, 11.45 mmol, yield 95.71%) as a yellow solid. LC-MS (ESI) m / z = 351.1 [M+H] +

[0120] Step 8: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-(4-fluorophenyl)-1-isopropyl-7-oxo-6H-pyrrolo[2,3-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0121] 2-Bromo-3-(4-fluorophenyl)-1-isopropyl-6H-pyrrolo[2,3-c]pyridin-7-one (3.5 g, 10.02 mmol, 1 eq), tert-butyl-2-[(4R,6S)-2,2-dimethyl-6-vinyl-1,3-dioxane-4-yl]acetate (7.71 g, 30.07 mmol, 3 eq), tetrakis(triphenylphosphine)palladium (1.16 g, 1.00 mmol, 0.1 eq), and sodium carbonate (3.19 g, 30.07 mmol, 3 eq) were added to N,N-dimethylformamide (100 mL), the mixture was purged with nitrogen, and the reaction mixture was stirred at 130 °C under nitrogen protection for 16 hours.

[0122] LC-MS showed that 33% of the desired product was detected. The reaction mixture was cooled to 15–25 °C, diluted with water (300 mL), extracted with ethyl acetate (300 mL x 3), the combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase preparation (column: Kromasil Eternity XT 250*70mm*10μm; mobile phase: [H2O(10mm NH4HCO3)-ACN]; gradient: 54%-84% B over 20.0 min) to give tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-(4-fluorophenyl)-1-isopropyl-7-oxo-6H-pyrrolo[2,3-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (2.1 g, 3.69 mmol, yield 36.80%, purity 92.15%), as a yellow solid. LC-MS (ESI) m / z = 525.4 [M+H] +

[0123] Step 9: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[3-(4-fluorophenyl)-1-isopropyl-7-oxo-6H-pyrrolo[2,3-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0124] Solution S1: {tert-butyl 2-[(4R,6S)-6-[(E)-2-[3-(4-fluorophenyl)-1-isopropyl-7-oxo-6H-pyrrolo[2,3-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate, 1 eq, 2.1 g, 100%, 2.1 g} and {NH3H2O, 20 eq, 2.806 g, 3.083 mL, 100%, 2.806 g} dissolved in {THF, 84 mL}, a fixed bed (named FLR1, volume 20 mL) completely filled with 5% Pd / Al2O3 granular catalyst (15 g).

[0125] Adjust the H2 back pressure regulator to 1.5 mPa and the H2 flow rate to 80 mL / min.

[0126] Then, solution S1 is pumped into the fixed bed {FLR1,SS, fixed bed, 12.700(1 / 2") mm, 4 mL, 50 ℃} using pump 1 {S1,P1,1.201 mL / min}.

[0127] LC-MS indicated that the reaction was complete. Concentration under reduced pressure yielded crude product tert-butyl 2-[(4R,6R)-6-[2-[3-[3-(4-fluorophenyl)-1-isopropyl-7-oxo-6H-pyrrolo[2,3-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.5 g, crude product), which was a yellow oil.

[0128] Step 10: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[6-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-1-isopropyl-7-oxo-pyrrolo[2,3-c]pyrrolo-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0129] tert-butyl 2-[(4R,6R)-6-[2-[3-(4-fluorophenyl)-1-isopropyl-7-oxo-6H-pyrrolo[2,3-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate (1.38 g, 2.62 mmol, 1 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine (1.17 g, 2.62 mmol, 1 eq) 1 ol (1 eq), cuprous iodide (149.72 mg, 786.12 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,(1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (111.82 mg, 786.12 μmol, 0.3 eq) and potassium carbonate (1.09 g, 7.86 mmol, 3 eq) were added to dimethyl sulfoxide (10 mL), and the reaction solution was stirred at 110 °C for 3 hours under nitrogen protection.

[0130] LC-MS showed detection of the desired product. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 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,6R)-6-[2-[6-[6-[[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-1-isopropyl-7-oxo-pyrrolo[2,3-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (1.5 g, 1.77 mmol, yield 67.67%), as a yellow solid. LC-MS (ESI) m / z = 846.5 [M+H] +

[0131] Step 11: Synthesis of (3R,5R)-7-[6-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-1-isopropyl-7-oxo-pyrrolo[2,3-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0132] Hydrochloric acid (102.00 mg, 923.18 μmol, 0.1 mL, purity 33%, 2.60 eq) was added to a mixed solution of tert-butyl 2-[(4R,6R)-6-[2-[6-[6-[[[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-3-(4-fluorophenyl)-1-isopropyl-7-oxo-pyrrolo[2,3-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (300 mg, 354.63 μmol, 1 eq) in methanol (3 mL) and water (1 mL). The mixture was stirred at 0-25 °C for 2 hours.

[0133] LC-MS showed that the starting material was completely consumed. Then, sodium hydroxide solution (1M, 1.77 mL, 5 eq) was added to the reaction mixture, and the mixture was stirred at 25°C for 10 minutes.

[0134] LC-MS showed detection of the desired product. The reaction mixture was concentrated under reduced pressure. The crude product was prepared by reversed-phase chromatography (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 5%-35% B, 15.0 min) and reversed-phase chromatography (column: Phenomenex Luna C18). Purification was performed using a membrane with a diameter of 150*25mm*10μm; mobile phase: [H2O(0.225%FA)-ACN]; gradient: 15%-45%B, 15.0min) to obtain the product (3R,5R)-7-[6-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-3-(4-fluorophenyl)-1-isopropyl-7-oxo-pyrrolo[2,3-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid (40mg).

[0135] Examples 6 & 8

[0136] Synthesis of (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0137] Synthesis route:

[0138] Step 1: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0139] 2.0 g (3.78 mmol, 1 eq) of tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydro-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate and DDQ (1.72 g, 7.57 mmol, 2 eq) were added to anhydrous dioxane (30 mL), and the reaction mixture was stirred at 100 °C under nitrogen for 17 hours.

[0140] LC-MS analysis showed the desired product was detected. The reaction mixture was concentrated under reduced pressure, DCM (20 mL) was added to the residue, and the mixture was stirred at 20–30 °C for 30 minutes. The mixture was filtered, and the filtrate was 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 a mixture of tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate and tert-butyl 2-[(4R,6R)-6-[2-[7-chloro-1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate, totaling 460 mg. The product was a yellow gel. LC-MS (ESI) m / z = 527.3 [M+H] + LC-MS(ESI) m / z = 561.3 [M+H] +

[0141] Step 2: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[5-[6-[[[(1S,3S)-3-[[5-(dioxomethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0142] A mixture (460 mg) of 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate and 2-[(4R,6R)-6-[2-[7-chloro-1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate, and (1S,3S)-N3-[5-(difluoromethoxy)pyrimidine]pyrimidine [Pyridin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine (390.63 mg, 873.46 μmol, 2.13 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (17.52 mg, 123.16 μmol, 0.3 eq), cuprous iodide (23.46 mg, 123.16 μmol, 0.3 eq), and potassium carbonate (170.22 mg, 1.23 mmol, 3 eq) were added to dimethyl sulfoxide (10 mL), the mixture was purged with nitrogen three times, and the reaction mixture was stirred at 110 °C under nitrogen for 6 hours.

[0143] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 15-25°C, diluted with water (30 mL), and extracted with ethyl acetate (30 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 0 / 1) to give the product tert-butyl2-[(4R,6R)-6-[2-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl] A mixture (680 mg) of acetate and tert-butyl 2-[(4R,6R)-6-[2-[7-chloro-5-[6-[[(1S,3S)-3-[[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was present as a yellow gel. LC-MS (ESI) m / z = 846.4 [M+H] + LC-MS(ESI) m / z = 880.3 [M+H] +

[0144] Step 3: Synthesis of (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrido[3,4-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0145] tert-butyl 2-[(4R,6R)-6-[2-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate was reacted with tert-butyl 2-[(4R,6R)-6-[2-[7-chloro-5-[6-[[(1S,3S)-3-[[ A mixture of [5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (680 mg) was added to methanol (10 mL), followed by the addition of hydrochloric acid (204.00 mg, 1.85 mmol, 0.2 mL, 33% purity, 8.83 eq). The mixture was stirred at 15-25 °C for 20 minutes.

[0146] LC-MS showed that both starting materials were completely consumed. Sodium hydroxide (2M, 1.04 mL, 10 eq) was then added to the reaction mixture, adjusting the pH to approximately 12-14, and the reaction mixture was stirred at 15-25°C for 16 hours.

[0147] LC-MS showed that the intermediate reaction was complete and the target product was detected. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase chromatography (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mm NH4HCO3)-ACN]; gradient: 20%-50% B over 15.0 min) to obtain the product (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid (106.86 mg);

[0148] LCMS RT=0.457min,MS(ESI)m / z=750.4[M+H] +

[0149] 1 H NMR (400MHz, DMSO-d6): δ8.23(s,2H),7.88(d,J=2.5Hz,1H),7.57-7.40(m,3H),7.39-7.27(m,3H),7 .25-6.82(m,1H),6.80-6.71(m,2H),6.52(d,J=8.8Hz,1H),6.03(d,J=7.4Hz,1H),4.39-4.26(m,2H) ,4.25-4.15(m,1H),4.12-3.98(m,1H),3.91-3.74(m,1H),3.65-3.56(m,1H),3.54-3.43(m,1H),2.3 0-2.22(m,1H),2.20-2.08(m,3H),1.95-1.84(m,2H),1.77-1.67(m,1H),1.66-1.48(m,4H),1.45(br d,J=6.8Hz,6H),1.40-1.31(m,1H).

[0150] And the product (3R,5R)-7-[7-chloro-5-[6-[[[(1S,3S)-3-[[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,4-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid (108.22 mg).

[0151] LCMS RT=0.475min,MS(ESI)m / z=784.4[M+H] +

[0152] 1H NMR (400MHz, DMSO-d6): δ8.23 (s, 2H), 7.90 (d, J = 2.3Hz, 1H), 7.53-7.39 (m, 3H), 7.39-7.32 (m, 1H), 7.27(t,J=8.7Hz,2H),7.22-6.83(m,2H),6.81(d,J=6.6Hz,1H),6.52(d,J=8.9Hz,1H),4.39-4.19( m,2H),4.10-3.95(m,1H),3.91-3.70(m,2H),3.61-3.45(m,2H),2.27-2.19(m,1H),2.18-2.05(m,3 H),1.97-1.81(m,2H),1.72-1.60(m,1H),1.59-1.47(m,3H),1.46-1.34(m,7H),1.32-1.18(m,1H).

[0153] Example 7

[0154] Synthesis of (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydropyrrolo[3,4-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0155] Synthetic route

[0156] Step 1: Synthesis of ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-vinylpyrrole-3-carboxylic acid

[0157] Ethyl 4-bromo-1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-pyrrole-3-carboxylic acid (62.00 g, 101.55 mmol, 1 eq), potassium vinyltrifluoroborate (27.20 g, 203.10 mmol, 2 eq), Pd(dppf)Cl2 (7.43 g, 10.15 mmol, 0.1 eq), and sodium carbonate (21.53 g, 203.10 mmol, 2 eq) were added to a mixed solvent of ethylene glycol dimethyl ether (300 mL) and water (60 mL). The reaction mixture was stirred at 120 °C for 3 hours under nitrogen atmosphere.

[0158] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 25°C, diluted with water (300 mL), and extracted with ethyl acetate (300 mL x 3). The combined organic phases were washed with brine (300 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 = 50 / 1 to 5 / 1) to give ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-vinyl-pyrrole-3-carboxylic acid (51.00 g, 91.45 mmol, yield 90.05%) as a yellow oil. LC-MS (ESI) m / z = 558.5 [M + H] +

[0159] Step 2: Synthesis of ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-[(E)-2-nitrovinyl]pyrrole-3-carboxylic acid

[0160] Ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-vinylpyrrole-3-carboxylate (17.00 g, 30.48 mmol, 1 eq), tert-butyl nitrite (6.29 g, 60.97 mmol, 7.25 mL, 2 eq), and TEMPO (1.92 g, 12.19 mmol, 0.4 eq) were added to 1,4-dioxane (300 mL), and the mixture was purged three times with oxygen. The reaction mixture was stirred at 90 °C (oxygen bulb, 15 psi) for 16 hours.

[0161] LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give the product ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-[(E)-2-nitrovinyl]pyrrole-3-carboxylic acid ester (13.00 g, 21.57 mmol, yield 23.59%), as a yellow oil.

[0162] Step 3: Synthesis of ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-(2-nitroethyl)pyrrole-3-carboxylic acid

[0163] Sodium borohydride (2.99 g, 79.03 mmol, 3.66 eq) was added to a mixture of anhydrous tetrahydrofuran (200 mL) and water (5 mL) of ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-[(E)-2-nitrovinyl]pyrrole-3-carboxylic acid (13.00 g, 21.57 mmol, 1 eq) at 0 °C under nitrogen protection. The reaction mixture was stirred at 15-25 °C for 1 hour under nitrogen.

[0164] LC-MS indicated that the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL * 2). 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 silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-(2-nitroethyl)pyrrole-3-carboxylic acid ester (10.0 g, 16.54 mmol, yield 76.67%), as a yellow oil. LC-MS (ESI) m / z = 605.4 [M + H] +

[0165] Step 4: Synthesis of ethyl 4-(2-aminoethyl)-1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-pyrrole-3-carboxylic acid

[0166] Under nitrogen protection (hydrogenation flask), Raney-Ni (20.00 g, 233.44 mmol, 4.71 eq) was added to a solution of ethyl 1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-(2-nitroethyl)pyrrole-3-carboxylate (30.00 g, 49.61 mmol, 1 eq) in N,N-dimethylformamide (300 mL). The mixture was purged with hydrogen three times, and the reaction mixture was stirred at 45 °C (hydrogen, 45 PSI) for 16 hours.

[0167] LC-MS indicated that the reaction was complete. The reaction mixture was filtered through diatomaceous earth under nitrogen protection. The filtrate was concentrated under reduced pressure (oil pump), and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1; dichloromethane / methanol = 20 / 1 to 5 / 1) to give the product ethyl 4-(2-aminoethyl)-1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxoethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-pyrrole-3-carboxylic acid ester (19.00 g, 33.06 mmol, yield 66.64%), as a yellow oil. LC-MS (ESI) m / z = 575.5 [M+H] +

[0168] Step 5: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydro-5H-pyrido[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0169] A solution of trimethylaluminum (2M, 23.10 mL, 1.5 eq) was added to a toluene (300 mL) solution of ethyl 4-(2-aminoethyl)-1-[2-[(4R,6R)-6-(2-tert-butoxy-2-oxo-ethyl)-2,2-dimethyl-1,3-dioxane-4-yl]ethyl]-5-(4-fluorophenyl)-2-isopropyl-pyrrole-3-carboxylate (17.7 g, 30.80 mmol, 1 eq), and the reaction mixture was stirred at 80 °C for 2 hours.

[0170] TLC (petroleum ether / ethyl acetate = 1 / 1) showed a new spot and complete consumption of the starting material. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (300 mL), and extracted with ethyl acetate (300 mL * 2). The combined organic phases were washed with brine (300 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 0 / 1) to give tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydro-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (12.00 g, 22.70 mmol, yield 73.70%) as a yellow gel.

[0171] Step 6: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydropyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0172] 2.0 g, 3.78 mmol, 1 eq of tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydro-5H-pyrrolo[3,4-c]pyridin-2-yl]ethyl]-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-di Amine (1.86 g, 4.16 mmol, 1.1 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (161.44 mg, 1.13 mmol, 0.3 eq), cuprous iodide (216.15 mg, 1.13 mmol, 0.3 eq), and potassium carbonate (1.57 g, 11.35 mmol, 3 eq) were added to dimethyl sulfoxide (30 mL), and the reaction mixture was stirred at 110 °C under nitrogen protection for 17 hours.

[0173] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 15–25 °C, diluted with water (90 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 0 / 1) to give tert-butyl 2-[(4R,6R)-6-[2-[5-[6-[[[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydropyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (600 mg, 122.06 μmol, yield 3.23%, purity 17.25%), which is a brown gel. LC-MS (ESI) m / z = 848.4 [M+H] +

[0174] Step 7: Synthesis of (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydropyrrolo[3,4-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0175] Hydrochloric acid (102.00 mg, 923.18 μmol, 0.1 mL, 33% purity, 7.56 eq) was added to an anhydrous methanol (5 mL) solution of tert-butyl 2-[(4R,6R)-6-[2-[5-[6-[[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydropyrrolo[3,4-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (600 mg, 122.06 μmol, 1 eq). The reaction mixture was stirred at 15-25 °C for 1 hour.

[0176] LC-MS showed that the starting material was completely consumed. Sodium hydroxide (2M, 0.5 mL, 8.19 eq) was then added to the reaction mixture until the pH was 12–14, and the reaction mixture was stirred at 15–25 °C for 1 hour.

[0177] LC-MS showed that the intermediate reaction was complete and the target product was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase preparation (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mm NH4HCO3)-ACN]; gradient: 20%-50% B over 11.0 min) to give the product (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-6,7-dihydropyrrolo[3,4-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid (78.63 mg).

[0178] LCMS RT=0.462min,MS(ESI)m / z=752.5[M+H] +

[0179] 1 H NMR (400MHz, DMSO-d6): δ8.34-8.11(m,2H),7.86(d,J=2.6Hz,1H),7.46(d,J =7.1Hz,1H),7.40(dd,J=5.6,8.4Hz,2H),7.33-7.23(m,3H),7.23-6.79(m,1 H),6.54(d,J=6.6Hz,1H),6.45(d,J=8.9Hz,1H),4.37-4.19(m,2H),4.10-3. 94(m,1H),3.91-3.75(m,2H),3.73-3.63(m,2H),3.60-3.48(m,1H),2.63(br t,J=6.2Hz,2H),2.28-2.19(m,1H),2.18-2.05(m,3H),1.93-1.80(m,2H),1.75-1.08(m,13H).

[0180] Example 10

[0181] Synthesis of (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0182] Synthesis route:

[0183] Step 1: Synthesis of 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine

[0184] NIS (50.43 g, 224.14 mmol, 1.5 eq) was added in portions to a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (22.8 g, 149.43 mmol, 1 eq) in N,N-dimethylformamide (500 mL) at 0 °C. After addition, the reaction mixture was stirred at 15–25 °C for 16 hours.

[0185] LC-MS indicated that the reaction was complete. The reaction mixture was poured into a saturated sodium sulfite solution (1000 mL), and a white solid was observed to precipitate. The mixture was filtered and the solid was collected. The solid was dried under reduced pressure to give crude product 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (40.0 g, crude product), which is a yellow solid.

[0186] Step 2: Synthesis of 4-chloro-1-(4-fluorophenyl)-3-iodopyrrolo[3,2-c]pyridine

[0187] 4-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (39.0 g, 140.05 mmol, 1 eq), (4-fluorophenyl)boronic acid (58.79 g, 420.14 mmol, 3 eq), copper acetate (50.87 g, 280.10 mmol, 2 eq), 4A molecular sieve (80.0 g), and pyridine (66.47 g, 840.29 mmol, 67.82 mL, 6 eq) were added to anhydrous dichloromethane (800 mL), and the reaction mixture was stirred for 48 hours at 15-25 °C under oxygen (15 psi) protection.

[0188] LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give the product 4-chloro-1-(4-fluorophenyl)-3-iodopyrrolo[3,2-c]pyridine (40.0 g, 107.36 mmol, yield 76.66%) as a yellow solid.

[0189] Step 3: Synthesis of 4-chloro-1-(4-fluorophenyl)-3-ethylpropenyl-pyrrolo[3,2-c]pyridine

[0190] 4-Chloro-1-(4-fluorophenyl)-3-iodopyrrolo[3,2-c]pyridine (27 g, 72.47 mmol, 1 eq), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (12.79 g, 76.09 mmol, 1.05 eq), Pd(dppf)Cl2 (5.30 g, 7.25 mmol, 0.1 eq), and potassium carbonate (30.05 g, 217.41 mmol, 3 eq) were added to a mixture of dioxane (600 mL) and water (100 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred at 110 °C under nitrogen for 3 hours.

[0191] LC-MS indicated that the reaction was complete. The crude reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give the product 4-chloro-1-(4-fluorophenyl)-3-isopropenyl-pyrrolo[3,2-c]pyridine (21.0 g, crude), which is a yellow oil.

[0192] Step 4: Synthesis of 4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrrolo[3,2-c]pyridine

[0193] Solution S1: {4-chloro-1-(4-fluorophenyl)-3-isopropenyl-pyrrolo[3,2-c]pyridine, 1 eq, 2.0 g} dissolved in {THF, 200 mL}, a fixed bed (named FLR1, volume 15 mL) completely filled with 10 g of 5% Ru / Al2O3 particulate catalyst. The H2 back pressure regulator was adjusted to 0.3 mPa {H2, flow rate}, and then solution S1 was pumped into the fixed bed {FLR1, SS, fixed bed, 12.700(1 / 2") mm, 3 mL, 25 °C} through pump 1 {S1, P1, 0.909 mL / min}. The reaction mixture was then collected from the reactor effluent.

[0194] LC-MS showed that the desired product was detected. The reaction mixture was concentrated under reduced pressure to give crude product 4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrrolo[3,2-c]pyridine (1.0 g, crude product), which is a yellow oil.

[0195] Step 5: Synthesis of 2-bromo-4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrrolo[3,2-c]pyridine

[0196] NBS (2.22 g, 12.47 mmol, 1.2 eq) was added to a solution of 4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrrolo[3,2-c]pyridine (3.0 g, 10.39 mmol, 1 eq) in N,N-dimethylformamide (40 mL), and the mixture was stirred at 15-25 °C for 16 hours under nitrogen atmosphere.

[0197] LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 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 silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to give the product 2-bromo-4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrrolo[3,2-c]pyridine (3.0 g, 8.16 mmol, yield 78.54%) as a yellow solid.

[0198] Step 6: Synthesis of 2-bromo-1-(4-fluorophenyl)-3-isopropyl-5H-pyrrole[3,2-c]pyridin-4-one

[0199] 2-Bromo-4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrrolo[3,2-c]pyridine (3.0 g, 8.16 mmol, 1 eq) and ammonium acetate (14.47 g, 187.68 mmol, 23 eq) were added to acetic acid (50 mL), and the reaction mixture was stirred at 120 °C for 18 hours under nitrogen protection.

[0200] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 15-25°C and then poured into water (200 mL). The mixture was filtered, and the filter cake was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 3 / 1) to give the product 2-bromo-1-(4-fluorophenyl)-3-isopropyl-5H-pyrrolo[3,2-c]pyridin-4-one (2.5 g, crude product), as a yellow solid.

[0201] Step 7: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,2-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0202] 2-Bromo-1-(4-fluorophenyl)-3-isopropyl-5H-pyrrolo[3,2-c]pyridin-4-one (2.5 g, 7.16 mmol, 1 eq), tert-butyl-2-[(4R,6S)-2,2-dimethyl-6-vinyl-1,3-dioxane-4-yl]acetate (3.67 g, 14.32 mmol, 2 eq), Pd(PPh3)4 (827.30 mg, 715.93 μmol, 0.1 eq) and sodium carbonate (2.28 g, 21.48 mmol, 3 eq) were added to anhydrous DMF (100 mL), and the reaction mixture was stirred at 110 °C under nitrogen protection for 1 hour.

[0203] LC-MS showed the desired product was detected. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (300 mL). The mixture was washed with water (300 mL) and brine (300 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (column: Phenomenex luna C18 (250*70mm, 10μm); mobile phase: [H2O (10mm NH4HCO3)-ACN]; gradient: 55%-85% B over 20.0 min) to obtain tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,2-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (850 mg, 1.44 mmol, yield 50.20%, purity 88.59%), which is a yellow solid.

[0204] Step 8: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,2-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0205] Solution 1: {tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,2-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxa-4-yl]acetate, 1 eq, 0.5 g, 100%, 0.5 g} and {NH3H2O, 20 eq, 0.668 g, 0.734 mL, 100%, 0.668 g} were dissolved in a fixed bed (named FLR1, volume 5 mL) completely filled with 5% Pd / Al2O3 granular catalyst (0.65 g). The H2 back pressure regulator was adjusted to 2 mPa, and the H2 flow rate was 30 mL / min. Then, solution S1 is pumped into the fixed bed {FLR1,SS, fixed bed, 6.350(1 / 4") mm, 1 mL, 90℃} using pump 1 {S1,P1,0.3 mL / min}.

[0206] The reaction mixture was filtered and concentrated under reduced pressure to give crude product tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,2-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (450 mg, crude product), which is a yellow oil.

[0207] Step 9: Synthesis of tert-butyl 2-[(4R,6R)-6-[2-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0208] tert-butyl 2-[(4R,6R)-6-[2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,2-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (450 mg, 854.48 μmol, 1 eq), (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine (382.14 m 854.48 μmol (1 eq) of copper iodide (48.82 mg, 256.34 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (36.46 mg, 256.34 μmol, 0.3 eq) and potassium carbonate (354.29 mg, 2.56 mmol, 3 eq) were added to dimethyl sulfoxide (10 mL). The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 110 °C for 2 hours under nitrogen protection.

[0209] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 15-25°C, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 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 tert-butyl-2-[(4R,6R)-6-[2-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (700 mg, crude), which is a brown solid.

[0210] Step 10: Synthesis of (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid

[0211] Add 0.2 mL of hydrochloric acid to a methanol (5 mL) solution of tert-butyl 2-[(4R,6R)-6-[2-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (700 mg, 827.48 μmol, 1 eq), and stir the mixture at 15-25 °C for 1 hour.

[0212] LC-MS showed that the starting material was completely consumed and intermediates were detected. Sodium hydroxide (2M, 1 mL, 2.42 eq) was then added to the reaction mixture, and the reaction mixture was stirred at 15–25 °C for 16 hours.

[0213] LC-MS showed that the intermediate reaction was complete and the target product was detected. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase preparation (column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [H2O(10mm NH4HCO3)-ACN]; gradient: 15%-45% B, 14.0 min) to give the product (3R,5R)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]-3,5-dihydroxy-heptanoic acid (252 mg).

[0214] LCMS RT=0.983min,MS(ESI)m / z=750.5[M+H] +

[0215] 1H NMR (400MHz, DMSO-d6): δ8.23(s,2H),7.88(d,J=2.5Hz,1H),7.53-7.38(m,5H),7.36(dd,J=2 .6,8.8Hz,1H),7.26-6.78(m,3H),6.53(d,J=8.9Hz,1H),5.90(d,J=7.3Hz,1H),4.43-4.20(m, 2H),3.88-3.73(m,1H),3.51-3.43(m,2H),3.24-3.18(m,2H),2.72-2.57(m,1H),2.27-2.19(m ,1H),2.18-2.06(m,3H),1.89(qt,J=6.7,13.6Hz,2H),1.61-1.44(m,2H),1.42-1.15(m,10H).

[0216] Example 11

[0217] Synthesis of (E,3R,5S)-7-[5-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]-3,5-dihydroxy-heptyl-6-enoic acid

[0218] Synthesis route:

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

[0220] 200 mg, 381.23 μmol, 1 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[1-(4-fluorophenyl)-3-isopropyl-4-oxo-5H-pyrrolo[3,2-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (170 mg, 381.23 μmol, 1 eq), and (1S,3S)-N3-[5-(difluoromethoxy)pyrimidin-2-yl]-N1-(5-iodo-2-pyridyl)cyclopentane-1,3-diamine (170 mg, 381.23 μmol, 1 eq) were added. 49 mg (381.23 μmol, 1 eq), cuprous iodide (21.78 mg, 114.37 μmol, 0.3 eq), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (16.27 mg, 114.37 μmol, 0.3 eq), and potassium carbonate (158.06 mg, 1.14 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 1 hour.

[0221] LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 15-25°C, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 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 crude product tert-butyl-2-[(4R,6S)-6-[(E)-2-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (320 mg, crude product), which is a yellow solid.

[0222] Step 2: Synthesis of (E,3R,5S)-7-[5-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]-3,5-dihydroxy-heptyl-6-enoic acid

[0223] Acetic acid (5.25 g, 87.34 mmol, 5 mL, 230.34 eq) was added to a methanol (5 mL) solution of tert-butyl 2-[(4R,6S)-6-[(E)-2-[5-[6-[[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (320 mg, 379.18 μmol, 1 eq) at 0 °C, and the mixture was stirred at 50 °C for 16 hours.

[0224] LC-MS indicated that the reaction was complete and the desired product intermediate was detected.

[0225] Add sodium hydroxide solution (2M) to the reaction solution until the pH is 12-14, and stir the reaction mixture at 15-25°C for 5 minutes.

[0226] LC-MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product (containing a large amount of inorganic salts) was purified by reverse-phase chromatography (mainly to remove inorganic salts): 1000g Flash column, Welch Ultimate XB_C18 20-40μm; 120A. Approximately 12.00g of sample was dissolved in 50mL MeOH at a flow rate of 200mL / min. Mobile phase: MeCN / H2O gradient B% 60% 10min; %min. Instrument: 3mPa. The resulting product was then lyophilized and purified again by reverse-phase chromatography (column: Waters Xbridge C18 150*25mm*5μm; mobile phase: [H2O (10mm)...). NH4HCO3)-ACN]; gradient: 8%-38% B) within 15.0 min to obtain product (E,3R,5S)-7-[5-[6-[[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridyl]-1-(4-fluorophenyl)-3-isopropyl-4-oxo-pyrrolo[3,2-c]pyridin-2-yl]-3,5-dihydroxy-heptyl-6-enoic acid (70 mg).

[0227] LCMS RT=0.978min,MS(ESI)m / z=748.4[M+H] +

[0228] The NMR data for compound 3-19 are as follows:

[0229] Example 20

[0230] Synthesize (3R,5S,E)-7-(2-cyclopentyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)-3,5-dihydroxyhept-6-enoic acid.

[0231] Synthesis route:

[0232] Step 1: Synthesis of 2-chloro-4-iodonicotinic acid

[0233] 2-Chloro-4-iodopyridine (80.0 g, 334 mmol, 1.00 eq) was dissolved in tetrahydrofuran (400 mL) and cooled to -70 °C. Then, lithium diisopropylamine (2 M, 184 mL, 1.10 eq) was slowly added dropwise to the reaction mixture, maintaining the temperature at approximately -70 °C throughout the addition. After the addition was complete, the reaction mixture was stirred at -70 °C for 1 hour. Next, dry ice (73.5 g, 1.67 mol, 5.00 eq) was slowly added to the reaction mixture. After the addition was complete, the reaction mixture was slowly heated to 20 °C and stirred for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.356 min). The reaction mixture was quenched with a saturated ammonium chloride aqueous solution (200 mL). When the quenched mixture was concentrated to remove most of the tetrahydrofuran, a solid precipitated. This solid was then filtered, and the resulting filter cake was dried and concentrated to obtain 2-chloro-4-iodonicotinic acid (65.0 g). This was not purified and was used directly in the next step. LCMS RT=0.356min,MS(ESI)m / z=283.9[M+1] +

[0234] Step 2: Synthesize tert-butyl (2-chloro-4-iodopyridin-3-yl) carbamate.

[0235] 2-Chloro-4-iodonicotinic acid (65.0 g, 229 mmol, 1.00 eq) and triethylamine (69.6 g, 688 mmol, 3.00 eq) were dissolved in tert-butanol (550 mL) and N,N-dimethylformamide (100 mL). Then, diphenyl azide phosphate (189 g, 688 mmol, 3.00 eq) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 90 °C for 12 hours. The MS value of the product was monitored by LC-MS (RT = 0.552 min). The reaction mixture was concentrated to remove most of the solvent, then diluted with water (600 mL) and extracted with ethyl acetate (200 mL x 2). The concentrated organic phase was washed with saturated brine (500 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 tert-butyl(2-chloro-4-iodopyridin-3-yl)carbamate (65.5 g). LC-MS RT = 0.556 min, MS (ESI) m / z = 355.0 [M+1] +

[0236] Step 3: Synthesis of tert-butyl (2-chloro-4-(4-fluorobenzoyl)pyridin-3-yl)carbamate

[0237] tert-butyl(2-chloro-4-iodopyridin-3-yl)carbamate (65.5 g, 185 mmol, 1.00 eq) was dissolved in tetrahydrofuran (650 mL) and cooled to -70 °C. Then, a 1.3 M tetrahydrofuran solution of isopropyl magnesium lithium chloride complex (1.3 M, 426 mL, 3.00 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. Next, 4-fluoro-N-methoxy-N-methylbenzamide (50.8 g, 277 mmol, 1.50 eq) was slowly added to the reaction solution. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.597 min). The reaction solution was quenched with a saturated ammonium chloride aqueous solution (500 mL) and extracted with ethyl acetate (200 mL x 2). The concentrated organic phase was washed with saturated brine (300 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 tert-butyl(2-chloro-4-(4-fluorobenzoyl)pyridin-3-yl)carbamate (20.0 g). LCMS RT = 0.597 min, MS (ESI) m / z = 351.1 [M+1] +

[0238] Step 4: Synthesis of (3-amino-2-chloropyridin-4-yl)(4-fluorophenyl)methyl ketone

[0239] 20.0 g (57.0 mmol, 1.00 eq) of tert-butyl(2-chloro-4-(4-fluorobenzoyl)pyridin-3-yl)carbamate was dissolved in 200 mL of dichloromethane, and then trifluoroacetic acid (32.51 g, 285 mmol, 5.00 eq) was added dropwise. After the addition was complete, the reaction mixture was stirred at 20 °C for 8 hours. The MS value of the product was monitored by LCMS (RT = 0.570 min). The pH of the reaction mixture was adjusted to approximately 8–9 with saturated sodium bicarbonate, and the mixture was extracted with 100 mL (2) of dichloromethane. The concentrated organic phase was washed with 200 mL (2) of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (3-amino-2-chloropyridin-4-yl)(4-fluorophenyl)methyl ketone (13.0 g). This was used directly in the next step without purification. LCMS RT=0.570min,MS(ESI)m / z=251.0[M+1] +

[0240] Step 5: Synthesis of ethyl 8-chloro-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthyl-3-carboxylate

[0241] (3-Amino-2-chloropyridin-4-yl)(4-fluorophenyl) methyl ketone (13.0 g, 51.9 mmol, 1.00 eq) and ethyl 3-cyclopropyl-3-oxopropionate (10.5 g, 67.4 mmol, 1.30 eq) were dissolved in ethanol (130 mL), followed by the addition of ytterbium trifluoromethanesulfonate (3.22 g, 5.19 mmol, 0.10 eq). The reaction mixture was stirred at 20 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.686 min). The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain ethyl 8-chloro-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthyl-3-carboxylic acid (17.0 g). LCMS RT = 0.686 min, MS (ESI) m / z = 371.1 [M+1] +

[0242] Step 6: Synthesis of ethyl 2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthyl-3-carboxylate

[0243] Ethyl 8-chloro-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidine-3-carboxylate (17.0 g, 45.9 mmol, 1.00 eq) was dissolved in acetic acid (170 mL), followed by the addition of ammonium acetate (70.7 g, 917 mmol, 20.0 eq). The reaction mixture was stirred at 120 °C for 2 hours. The MS value of the product was monitored by LC-MS (RT = 0.552 min). The reaction mixture was concentrated to remove most of the solvent, then diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The concentrated organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidine-3-carboxylate (15.0 g). This was used directly in the next step without purification. LCMS RT=0.552min,MS(ESI)m / z=353.1[M+1] +

[0244] Step 7: Synthesis of 2-cyclopropyl-4-(4-fluorophenyl)-3-(hydroxymethyl)-1,7-naphthidium-8(7H)-one

[0245] Ethyl 2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidine-3-carboxylic acid (7.5 g, 21.3 mmol, 1.00 eq) was dissolved in dichloromethane (75 mL) and cooled to -70 °C. Then, diisobutylaluminum hydride (1 M, 85.1 mL, 4.00 eq) was slowly added dropwise to the reaction solution while maintaining the temperature at approximately -70 °C. After the addition was complete, the reaction solution was stirred at -70 °C for 4 hours. The MS value of the product was monitored by LC-MS (RT = 0.485 min). The reaction solution was heated to approximately 0 °C and quenched with a saturated potassium sodium tartrate solution (200 mL), resulting in the precipitation of a yellow solid. The solid was filtered, and the filter cake was collected and dried to obtain 2-cyclopropyl-4-(4-fluorophenyl)-3-(hydroxymethyl)-1,7-naphthidine-8(7H)-one (9.00 g). Two batches were reacted simultaneously. No purification was performed; the product was used directly in the next step. LCMS RT = 0.485 min, MS (ESI) m / z = 311.0 [M+1] +

[0246] Step 8: Synthesis of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidium-8(7H)-one

[0247] 2-Cyclopropyl-4-(4-fluorophenyl)-3-(hydroxymethyl)-1,7-naphthidium-8(7H)-one (9.00 g, 29.0 mmol, 1.00 eq) was dissolved in dichloromethane (90 mL) and cooled to 0 °C. Phosphorus tribromide (11.8 g, 43.5 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 LCMS (RT = 0.567 min). The reaction mixture 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 9.55 g of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidium-8(7H)-one. It was used directly in the next step without purification. LCMS RT = 0.567 min, MS (ESI) m / z = 375.0 [M+1] +

[0248] Step 9: Synthesis of ((2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthid-3-yl)methyl)triphenylphosphine; bromide

[0249] 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidium-8(7H)-one (9.55 g, 25.6 mmol, 1.00 eq) and triphenylphosphine (8.05 g, 30.7 mmol, 1.20 eq) were dissolved in toluene (100 mL), and the reaction mixture was stirred at 100 °C for 2 h. The MS value of the product was monitored by LCMS (RT = 0.518 min). The reaction mixture was concentrated to give ((2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidium-3-yl)methyl)triphenylphosphine; bromide (16.0 g). No purification was performed; it was used directly in the next step. LCMS RT = 0.518 min, MS(ESI) m / z = 555.3 [M+1] +

[0250] Step 10: Synthesis of tert-butyl 2-[(4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7H-1,7-naphthid-3-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0251] ((2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthid-3-yl)methyl)triphenylphosphine; bromide (16.0 g, 25.2 mmol, 1.00 eq), tert-butyl-2-(((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl)acetate (7.15 g, 27.7 mmol, 1.10 eq) and potassium carbonate (6.96 g, 50.4 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (160 mL), and the reaction mixture was stirred at 110 °C for 2 hours. The product was monitored by LCMS. MS value (RT = 0.634 min). The reaction solution was cooled to room temperature, then diluted with water (400 mL) and extracted with ethyl acetate (150 mL * 2). The concentrated organic phase was washed with saturated brine (500 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-[2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7H-1,7-naphthid-3-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (6.00 g), LCMS RT = 0.634 min, MS (ESI) m / z = 535.3 [M+1]. +

[0252] Step 11: Synthesis of tert-butyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate

[0253] 4.00 g, 7.48 mmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7H-1,7-naphthidin-3-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-Diamine (3.35 g, 7.48 mmol, 1.00 eq), cuprous iodide (427 mg, 2.24 mmol, 0.30 eq), potassium carbonate (3.10 g, 22.5 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (319 mg, 2.24 mmol, 0.30 eq) were dissolved in dimethyl sulfoxide (40 mL) and stirred at 110 °C for 2 h. The MS value of the product was monitored by LCMS (RT = 0.619 min). The reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (80 mL * 2). The concentrated organic phase was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate (6.00 g). It was used directly in the next step without purification. LCMS RT = 0.619 min, MS (ESI) m / z = 854.5 [M+1] +

[0254] Step 12: Synthesis of 2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-3-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1,7-naphthidium-8(7H)-one

[0255] 6.00 g (7.03 mmol, 1.00 eq) of tert-butyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate was dissolved in dichloromethane (30 mL), followed by the addition of trifluoroacetic acid (16.0 g, 141 mmol, 20.0 eq). The reaction mixture was stirred at 20 °C for 0.5 h. The MS value of the product was monitored by LCMS (RT = 0.504 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*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 20%-50% B over 15.0 min) to obtain 2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-3-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1,7-naphthidium-8(7H)-one (4.00 g). LCMS RT=0.504min,MS(ESI)m / z=740.3[M+1] +

[0256] 1 H NMR (400MHz, DMSO-d6): δ8 8.23(s,2H),7.97(d,J=2.5Hz,1H),7.53-7.42(m,2H),7.40-7.27(m,5H),7.03(t,J=74. 0Hz,2H),6.67-6.53(m,2H),5.91(d,J=7.6Hz,1H),5.70(dd,J=6.5,16.1Hz,1H),5.24(br s,1H),5.13-5.04(m,1H),4.38-4.25(m,2H),4.05-3.98(m,1H),2.61(dd,J=4.6,17.4Hz,1H),2.42-2.3 2(m,2H),2.21-2.05(m,2H),1.98-1.82(m,2H),1.65-1.45(m,4H),1.20-1.14(m,2H),1.08-1.00(m,2H).

[0257] Step 13: Synthesis of (3R,5S,E)-7-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)-3,5-dihydroxyhept-6-enoic acid

[0258] 2-Cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-3-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1,7-naphthidium-8(7H)-one (25.0 mg, 33.8 μmol, 1.00 eq) was dissolved in MeOH (3 mL), and then sodium hydroxide (1 M, 67.59 μL, 2.00 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 = 0.506 min). The reaction solution was concentrated to obtain a crude product, which was then subjected to two reverse-phase column chromatography tests (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H2O(0.05% NH3H2O)-ACN]; gradient: 5%-35% B over 12.0min) and (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 15%-45% B over (10.0 min) Purification yielded (3R,5S,E)-7-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)-3,5-dihydroxyhept-6-enoic acid (7.80 mg).

[0259] LCMS RT=0.506min,MS(ESI)m / z=758.3[M+1] +

[0260] 1H NMR (400MHz, DMSO-d6): δ8.23(s,2H),7.95(d,J=2.6Hz,1H),7.59(br s,1H),7.51-7.41(m,2H),7.38-7.24(m,5H),7.22-6.83(m,2H),6.54(d,J=8.9Hz,1 H),6.48-6.40(m,1H),5.87(d,J=7.5Hz,1H),5.67(dd,J=5.5,16.3Hz,1H),5.03(br s,1H),4.38-4.26(m,2H),4.18-4.09(m,1H),3.55-3.46(m,1H),2.19-2.07(m,2H),1.97-1.86 (m,3H),1.72(dd,J=8.3,14.9Hz,1H),1.57-1.46(m,2H),1.36(td,J=7.9,13.5Hz,1H),1.14(br d,J=4.4Hz,2H),1.11-0.97(m,3H).

[0261] Example 21

[0262] Synthesize 2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-3-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1,7-naphthidium-8(7H)-one.

[0263] Synthesis route:

[0264] Step 1: Synthesis of 2-chloro-4-iodonicotinic acid

[0265] 2-Chloro-4-iodopyridine (80.0 g, 334 mmol, 1.00 eq) was dissolved in tetrahydrofuran (400 mL) and cooled to -70 °C. Then, lithium diisopropylamine (2 M, 184 mL, 1.10 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 1 hour. Next, dry ice (73.5 g, 1.67 mol, 5.00 eq) was slowly added to the reaction solution. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.356 min). The reaction solution was quenched with a saturated ammonium chloride aqueous solution (200 mL). After quenching, the mixture was concentrated to remove most of the tetrahydrofuran, resulting in a solid precipitation. This was then filtered, and the resulting filter cake was dried and concentrated to obtain 2-chloro-4-iodonicotinic acid (65.0 g, 229 mmol, 68.6% yield). It was not purified and used directly in the next step. LCMS RT = 0.356 min, MS (ESI) m / z = 283.9 [M+1] +

[0266] Step 2: Synthesize tert-butyl (2-chloro-4-iodopyridin-3-yl) carbamate.

[0267] 2-Chloro-4-iodonicotinic acid (65.0 g, 229 mmol, 1.00 eq) and triethylamine (69.6 g, 688 mmol, 3.00 eq) were dissolved in tert-butanol (550 mL) and N,N-dimethylformamide (100 mL). Then, diphenyl azide phosphate (189 g, 688 mmol, 3.00 eq) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at 90 °C for 12 hours. The MS value of the product was monitored by LC-MS (RT = 0.552 min). The reaction mixture was concentrated to remove most of the solvent, then diluted with water (600 mL) and extracted with ethyl acetate (200 mL x 2). The concentrated organic phase was washed with saturated brine (500 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 tert-butyl(2-chloro-4-iodopyridin-3-yl)carbamate (65.5 g). LC-MS RT = 0.556 min, MS (ESI) m / z = 355.0 [M+1] +

[0268] Step 3: Synthesis of tert-butyl (2-chloro-4-(4-fluorobenzoyl)pyridin-3-yl)carbamate

[0269] tert-butyl(2-chloro-4-iodopyridin-3-yl)carbamate (65.5 g, 185 mmol, 1.00 eq) was dissolved in tetrahydrofuran (650 mL) and cooled to -70 °C. Then, a 1.3 M tetrahydrofuran solution of isopropyl magnesium lithium chloride complex (1.3 M, 426 mL, 3.00 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. Next, 4-fluoro-N-methoxy-N-methylbenzamide (50.8 g, 277 mmol, 1.50 eq) was slowly added to the reaction solution. After the addition was complete, the reaction solution was slowly heated to 20 °C and stirred for 2 hours. The MS value of the product was monitored by LCMS (RT = 0.597 min). The reaction solution was quenched with a saturated ammonium chloride aqueous solution (500 mL) and extracted with ethyl acetate (200 mL x 2). The concentrated organic phase was washed with saturated brine (300 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 tert-butyl(2-chloro-4-(4-fluorobenzoyl)pyridin-3-yl)carbamate (20.0 g). LCMS RT = 0.597 min, MS (ESI) m / z = 351.1 [M+1] +

[0270] Step 4: Synthesis of (3-amino-2-chloropyridin-4-yl)(4-fluorophenyl)methyl ketone

[0271] 20.0 g (57.0 mmol, 1.00 eq) of tert-butyl(2-chloro-4-(4-fluorobenzoyl)pyridin-3-yl)carbamate was dissolved in 200 mL of dichloromethane, and then trifluoroacetic acid (32.51 g, 285 mmol, 5.00 eq) was added dropwise. After the addition was complete, the reaction mixture was stirred at 20 °C for 8 hours. The MS value of the product was monitored by LCMS (RT = 0.570 min). The pH of the reaction mixture was adjusted to approximately 8–9 with saturated sodium bicarbonate, and the mixture was extracted with 100 mL (2) of dichloromethane. The concentrated organic phase was washed with 200 mL (2) of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (3-amino-2-chloropyridin-4-yl)(4-fluorophenyl)methyl ketone (13.0 g). This was used directly in the next step without purification. LCMS RT=0.570min,MS(ESI)m / z=251.0[M+1] +

[0272] Step 5: Synthesis of ethyl 8-chloro-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthyl-3-carboxylate

[0273] (3-Amino-2-chloropyridin-4-yl)(4-fluorophenyl) methyl ketone (13.0 g, 51.9 mmol, 1.00 eq) and ethyl 3-cyclopropyl-3-oxopropionate (10.5 g, 67.4 mmol, 1.30 eq) were dissolved in ethanol (130 mL), followed by the addition of ytterbium trifluoromethanesulfonate (3.22 g, 5.19 mmol, 0.10 eq). The reaction mixture was stirred at 20 °C for 12 hours. The MS value of the product was monitored by LCMS (RT = 0.686 min). The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain ethyl 8-chloro-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthyl-3-carboxylic acid (17.0 g). LCMS RT = 0.686 min, MS (ESI) m / z = 371.1 [M+1] +

[0274] Step 6: Synthesis of ethyl 2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthyl-3-carboxylate

[0275] Ethyl 8-chloro-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidine-3-carboxylate (17.0 g, 45.9 mmol, 1.00 eq) was dissolved in acetic acid (170 mL), followed by the addition of ammonium acetate (70.7 g, 917 mmol, 20.0 eq). The reaction mixture was stirred at 120 °C for 2 hours. The MS value of the product was monitored by LC-MS (RT = 0.552 min). The reaction mixture was concentrated to remove most of the solvent, then diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The concentrated organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidine-3-carboxylate (15.0 g). This was used directly in the next step without purification. LCMS RT=0.552min,MS(ESI)m / z=353.1[M+1] +

[0276] Step 7: Synthesis of 2-cyclopropyl-4-(4-fluorophenyl)-3-(hydroxymethyl)-1,7-naphthidium-8(7H)-one

[0277] Ethyl 2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidine-3-carboxylic acid (7.5 g, 21.3 mmol, 1.00 eq) was dissolved in dichloromethane (75 mL) and cooled to -70 °C. Then, diisobutylaluminum hydride (1 M, 85.1 mL, 4.00 eq) was slowly added dropwise to the reaction solution while maintaining the temperature at approximately -70 °C. After the addition was complete, the reaction solution was stirred at -70 °C for 4 hours. The MS value of the product was monitored by LC-MS (RT = 0.485 min). The reaction solution was heated to approximately 0 °C and quenched with a saturated potassium sodium tartrate solution (200 mL), resulting in the precipitation of a yellow solid. The solid was filtered, and the filter cake was collected and dried to obtain 2-cyclopropyl-4-(4-fluorophenyl)-3-(hydroxymethyl)-1,7-naphthidine-8(7H)-one (9.00 g). Two batches were reacted simultaneously. No purification was performed; the product was used directly in the next step. LCMS RT = 0.485 min, MS (ESI) m / z = 311.0 [M+1] +

[0278] Step 8: Synthesis of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidium-8(7H)-one

[0279] 2-Cyclopropyl-4-(4-fluorophenyl)-3-(hydroxymethyl)-1,7-naphthidium-8(7H)-one (9.00 g, 29.0 mmol, 1.00 eq) was dissolved in dichloromethane (90 mL) and cooled to 0 °C. Phosphorus tribromide (11.8 g, 43.5 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 LCMS (RT = 0.567 min). The reaction mixture 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 9.55 g of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidium-8(7H)-one. It was used directly in the next step without purification. LCMS RT = 0.567 min, MS (ESI) m / z = 375.0 [M+1] +

[0280] Step 9: Synthesis of ((2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthid-3-yl)methyl)triphenylphosphine; bromide

[0281] 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)-1,7-naphthidium-8(7H)-one (9.55 g, 25.6 mmol, 1.00 eq) and triphenylphosphine (8.05 g, 30.7 mmol, 1.20 eq) were dissolved in toluene (100 mL), and the reaction mixture was stirred at 100 °C for 2 h. The MS value of the product was monitored by LCMS (RT = 0.518 min). The reaction mixture was concentrated to give ((2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidium-3-yl)methyl)triphenylphosphine; bromide (16.0 g). No purification was performed; it was used directly in the next step. LCMS RT = 0.518 min, MS(ESI) m / z = 555.3 [M+1] +

[0282] Step 10: Synthesis of butyl 2-[(4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7H-1,7-naphthid-3-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate

[0283] ((2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthid-3-yl)methyl)triphenylphosphine; bromide (16.0 g, 25.2 mmol, 1.00 eq), tert-butyl-2-(((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl)acetate (7.15 g, 27.7 mmol, 1.10 eq) and potassium carbonate (6.96 g, 50.4 mmol, 2.00 eq) were dissolved in dimethyl sulfoxide (160 mL), and the reaction mixture was stirred at 110 °C for 2 hours. The product was monitored by LCMS. MS value (RT = 0.634 min). The reaction solution was cooled to room temperature, then diluted with water (400 mL) and extracted with ethyl acetate (150 mL * 2). The concentrated organic phase was washed with saturated brine (500 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-[2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7H-1,7-naphthid-3-yl]vinyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate (6.00 g). LC-MS RT = 0.634 min, MS (ESI) m / z = 535.3 [M+1] +

[0284] Step 11: Synthesis of tert-butyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate

[0285] 4.00 g, 7.48 mmol, 1.00 eq of tert-butyl 2-[(4R,6S)-6-[(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-8-oxo-7H-1,7-naphthidin-3-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-Diamine (3.35 g, 7.48 mmol, 1.00 eq), cuprous iodide (427 mg, 2.24 mmol, 0.30 eq), potassium carbonate (3.10 g, 22.5 mmol, 3.00 eq), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (319 mg, 2.24 mmol, 0.30 eq) were dissolved in dimethyl sulfoxide (40 mL) and stirred at 110 °C for 2 h. The MS value of the product was monitored by LCMS (RT = 0.619 min). The reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (80 mL * 2). The concentrated organic phase was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate (6.00 g). It was used directly in the next step without purification. LCMS RT = 0.619 min, MS (ESI) m / z = 854.5 [M+1] +

[0286] Step 12: Synthesis of 2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-3-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1,7-naphthidium-8(7H)-one

[0287] 6.00 g (7.03 mmol, 1.00 eq) of tert-butyl 2-((4R,6S)-6-((E)-2-(2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-8-oxo-7,8-dihydro-1,7-naphthidin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate was dissolved in dichloromethane (30 mL), followed by the addition of trifluoroacetic acid (16.0 g, 141 mmol, 20.0 eq). The reaction mixture was stirred at 20 °C for 0.5 h. The MS value of the product was monitored by LCMS (RT = 0.504 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*25mm*10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient: 20%-50% B over 15.0 min) to obtain 2-cyclopropyl-7-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-(4-fluorophenyl)-3-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-1,7-naphthidium-8(7H)-one (4.00 g).

[0288] LCMS RT=0.504min,MS(ESI)m / z=740.3[M+1] + : 1 H NMR (400MHz, DMSO-d6): δ8 8.23 ​​(s, 2H), 7.97 (d,

[0289] J=2.5Hz,1H),7.53-7.42(m,2H),7.40-7.27(m,5H),7.03(t,J=74.0Hz,2H),6 .67-6.53(m,2H),5.91(d,J=7.6Hz,1H),5.70(dd,J=6.5,16.1Hz,1H),5.24(br s,1H),5.13-5.04(m,1H),4.38-4.25(m,2H),4.05-3.98(m,1H),2.61(dd,J=4.6,17.4Hz,1H),2.42-2.3 2(m,2H),2.21-2.05(m,2H),1.98-1.82(m,2H),1.65-1.45(m,4H),1.20-1.14(m,2H),1.08-1.00(m,2H).

[0290] Identification data for compounds 22-25:

[0291] Example 26: Affinity test of the compound with PCSK9 protein

[0292] The binding affinity of the compounds of the present invention to PCSK9 protein was determined by fluorescence polarization method.

[0293] 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).

[0294] Table 1. FP-IC 50 data

[0295] A<300nm.

[0296] 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.

[0297] Example 27 Test for inhibition of human HMG-CoA reductase activity

[0298] 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.

[0299] The specific experiments were conducted according to the reagent instructions.

[0300] Reagent preparation:

[0301] HMG-CoA reductase: original concentration 0.214 mg / ml, total 20 μg. 10 μl / tube, store frozen at -80℃.

[0302] 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.

[0303] 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.

[0304] Assay buffer: 50mM Tris, 500mM KCl, 1mg / ml BSA, pH 7.0. Used for dilution of enzymes and substrates.

[0305] Experimental steps:

[0306] 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.

[0307] 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). 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.

[0308] Table 2. HMG-CoA reductase activity data

[0309] B < 300nm.

[0310] 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.

[0311] 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 with or without R1 substitution. The heterocycle can be monocyclic, bicyclic, or tricyclic, and 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 heterobicycles with or without R3 substitution; R2 can be one or more, each independently selected from hydrogen, halogen, alkyl, cycloalkyl, or cyano; R3 is one or more, each independently selected from hydrogen, alkyl, oxo, halogen, cycloalkyl, cycloalkylalkyl, 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; T is selected from CH or N.

2. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, Ring A is selected from 3. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, Compounds selected from those represented by formula (II) or (III), or their isomers, racemates, or pharmaceutically acceptable salts thereof:

4. The compound according to any one of claims 1-3, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that, Ring B is selected from: Indicates a connection key.

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, 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.

6. 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, The halogen is selected from fluorine, chlorine, bromine, and iodine.

7. 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, R1 is selected from H, F, Cl, Br, methyl, cyclopropyl, -OCHF2, cyano; and / or R2 is selected from H, F, Cl, Br, methyl, cyclopropyl.

8. The compound according to any one of claims 1-3, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R3 can be one or more, each independently selected from hydrogen, methyl, ethyl, chlorine, ...

9. The compound according to any one of claims 1-3, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: R5 is selected from: Furthermore, Preferred from 10. The compound according to any one of claims 1-3, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The replaced A ring is selected from 11. 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, Selected from:

12. A pharmaceutical composition, characterized in that, The compound comprising a therapeutically effective amount of any one of claims 1-11, or an isomer thereof, a racemic mixture thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

13. The pharmaceutical use of the compound of any one of claims 1-11, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically usable salt thereof, or the pharmaceutical composition of claim 12, specifically, in the preparation of a medicament for treating a disease, said disease being a PCSK9 and / or HMG-CoA reductase inhibitor-related disease, preferably from conditions such as hypercholesterolemia.

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