GLP-1 receptor agonist and application thereof in medicine

Abstract

The invention relates to the technical field of medicine, in particular to a GLP-1 receptor agonist, a preparation method thereof and application of the GLP-1 receptor agonist in medicine. The invention provides a GLP-1 receptor agonist as shown in formula (F) and a composition and application thereof. The compound can be used for treating or preventing GLP-1 receptor mediated diseases or symptoms and related diseases or symptoms.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to GLP-1 receptor agonists, a preparation method thereof and the application thereof in medicine. BACKGROUND

[0002] The glucagon-like peptide-1 (GLP-1) receptor is one of the most concerned drug targets for treating type II diabetes and obesity. GLP-1 receptor agonists not only promote insulin secretion, inhibit glucagon secretion and reduce blood sugar, but also delay gastric emptying and suppress appetite, thereby reducing body weight. The GLP-1 receptor agonist semaglutide can reduce the glycosylated hemoglobin level close to 1.8% and reduce body weight by more than 15%, and is considered to be a revolutionary product for treating obesity. In 2022, the global sales of semaglutide reached 10.8 billion US dollars, and the expected sales in 2023 will exceed 20 billion US dollars.

[0003] However, the existing GLP-1 receptor agonists are all macromolecular polypeptide drugs, which have the limitations of poor medication compliance, low production capacity, high treatment cost, etc. Small molecule drugs can undoubtedly make up for the shortcomings of peptide drugs due to their advantages of convenient oral use, easy production and low price. In recent years, the research on small molecule GLP-1 receptor agonists has become a front hot spot in the pharmaceutical field. However, there is no small molecule GLP-1 receptor agonist on the market yet, so it is still necessary to strengthen the related research to meet the clinical needs. SUMMARY

[0004] In one aspect, the present application provides a compound represented by general formula (F), or a stereoisomer, a tautomer, a deuterated compound or a pharmaceutically acceptable salt thereof:

[0005]

[0006] wherein the ring A is selected from a benzene ring, a 5-6 membered heterocyclyl group, and a 5-6 membered heteroaryl group, and the ring A can be optionally substituted by one or more R a ;

[0007] each R a is independently selected from H, D, oxo, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, a 3-6 membered heterocyclyl group, C 3-6 cycloalkyl, or C 2-6 alkynyl; the C 1-6 alkyl, C 1-6 alkoxy, a 3-6 membered heterocyclyl group, C 3-6The cycloalkyl group may optionally be further surrounded by one or more 3-6 membered heterocyclic groups, C 3-6 cycloalkyl, C 1-6 Alkoxy, hydroxy, amino, cyano, halogen, C 1-6 Haloalkyl, C 1-6 Alkyl or halogen substituted;

[0008] Alternatively, any two Rs substituted on ring A a The atoms to which it is attached can form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups;

[0009] The ring B is selected from phenyl or 5-6 heteroaryl; the ring B may optionally be further converted by one or more R a Replaced;

[0010] X1 is selected from CR2 or N;

[0011] X2 is selected from CR3 or N;

[0012] X3 is selected from CR4 or N;

[0013] X4 is selected from CR5 or N, and at most two of X1, X2, X3, and X4 are N at the same time;

[0014] R2, R3, R4, and R5 are each independently selected from H, D, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 2-4 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0015] Alternatively, R2 and R3, along with the atoms they are attached to, together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group may optionally be further bonded by one or more R... a Replaced;

[0016] Alternatively, R4 and R5, along with the atoms they are attached to, together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group may optionally be further bonded by one or more R4 groups. a Replaced;

[0017] R1 is selected from H, D, halogens, hydroxyl groups, and C. 1-6 Alkyl, amino, or cyano groups;

[0018] R6 and R7 are each independently selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0019] Y1 is selected from N or CR. 17 ;

[0020] The Y2 is selected from N or CR8;

[0021] The Y3 is selected from N or CR9;

[0022] The Y4 is selected from N or CR. 10 ;

[0023] The R8, R9, R 10 R 17 Each group is independently selected from H, D, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0024] The R 11 R 12 R 13 R 14 R 15 R 16 R 18 R 19 Each element is independently selected from H, D, halogens, and C. 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0025] Or, R 11 R 12 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl; the C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a Replaced;

[0026] Or, R 13 R 14 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl; the C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a Replaced;

[0027] Or, R 15 R 16 Together with the C atoms it is attached to, they form C 3-6Cycloalkyl or 3-12 membered heterocycloalkyl; the C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a What it replaced.

[0028] In some embodiments, the general formula (F) is selected from the compounds shown in (F-1), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts:

[0029]

[0030] Among them, ring A, ring B, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R a The definition is as defined in general formula (F).

[0031] In some embodiments, the compound of formula (FI) has the compounds shown in (F-IA), (F-IB), or (F-IC), or stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts thereof:

[0032]

[0033] Among them, ring A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 R 11 R 12 R 13 R 14 R 15 R 16 R a The definition is as defined in general formula (F).

[0034] In some embodiments, the general formula (F) is selected from compounds represented by (F-II), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts:

[0035]

[0036] Among them, ring A, ring B, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14 R15 R 16 R a The definition is as defined in general formula (F).

[0037] In some embodiments, the general formula (F) is selected from compounds represented by (F-III), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts:

[0038]

[0039] Among them, ring A, ring B, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 R 12 R 13 R 14 R 15 R 16 R a The definition is as defined in general formula (F).

[0040] In some implementations, the R 11 R 12 Each is independently selected from H, D, or halogens.

[0041] In some implementations, the R 13 R 14 Each is independently selected from H, D, or halogens.

[0042] In some implementations, the R 15 R 16 Each is independently selected from H, D, or halogens.

[0043] In some implementations, the R 11 R 12 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a Replaced; the R a Selected from H, D or halogens.

[0044] In some implementations, the R 13 R 14 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a Replaced; the R a Selected from H, D or halogens.

[0045] In some implementations, the R 15 R 16 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl, wherein C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a Replaced; the R a Selected from H, D or halogens.

[0046] In some embodiments, the compound of formula (F-IA) has the compound of formula (F-IA-1), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0047]

[0048] Among them, ring A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 The definition is as defined in general formula (F).

[0049] In some embodiments, ring A is selected from phenyl, 5-6 nitrogen-containing heteroaryl, or 5-6 membered nitrogen-containing heterocyclic group, and the phenyl, 5-6 nitrogen-containing heteroaryl, or 5-6 membered nitrogen-containing heterocyclic group can be arbitrarily replaced by one or more R groups. a The R that was replaced a Each group is independently selected from H, D, hydroxyl, amino, cyano, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

[0050] In some implementations, ring A is selected from... The It can be optionally further modified by one or more R a The R that was replaced a Each element is independently selected from H, D, halogens, or C. 1-6 alkyl.

[0051] In some implementations, the Selected from in The B-ring portion in the middle can be optionally further divided by one or more R... a The R that was replaced a Each element is independently selected from H, D, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Haloalkoxy groups, 3-6 membered heterocyclic groups, C 3-6 cycloalkyl or C 2-6 alkynyl group; the C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic group, C 3-6 The cycloalkyl group may optionally be further surrounded by one or more 3-6 membered heterocyclic groups, C 3-6 cycloalkyl, C 1-6 Alkyl groups or halogens are substituted.

[0052] In some embodiments, R1 is selected from H, D, halogens, or C. 1-6 alkyl.

[0053] In some implementations, R2, R3, R4, and R5 are each independently selected from H, D, or halogens.

[0054] In some embodiments, R6 and R7 are each independently selected from H, D, halogens, or C. 1-6 alkyl.

[0055] In some implementations, R8, R9, R 10 Each is independently selected from H, D, or halogens.

[0056] In some embodiments, the compound described in this invention, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, are selected from the following compounds:

[0057]

[0058]

[0059]

[0060] Or its stereoisomers, tautomers, deuterated derivatives, or medicinal salts.

[0061] On the other hand, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (F) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts.

[0062] In another aspect, the present invention provides the use of compounds of formula (F) as described above, or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, in medicaments for the treatment and / or prevention of metabolic-related diseases or conditions, including GLP-1 receptor-mediated diseases or conditions and related diseases or conditions.

[0063] The present invention also provides a method of treating a disease or condition, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (F) as described above or a stereoisomer, tautomer, deuterated compound or pharmaceutical salt thereof, wherein the disease or condition is a GLP-1 receptor-mediated disease or condition and related diseases or conditions.

[0064] In some embodiments, the GLP-1 receptor-mediated disease or condition is diabetes. In some embodiments, diabetes includes, but is not limited to, type 1 diabetes (T1D) and / or type 2 diabetes (T2DM), idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, juvenile atypical diabetes, and gestational diabetes. In some embodiments, the GLP-1 receptor-mediated disease or condition is hyperglycemia, insulin resistance, and impaired glucose tolerance.

[0065] In some implementations, diseases or conditions associated with GLP-1 receptor-mediated diseases or conditions include diabetic nephropathy, diabetic eye complications (diabetic retinopathy, diabetes-associated uveitis, diabetic cataracts), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic neuropathy, obesity, and hypertension.

[0066] In some implementations, the GLP-1 receptor-mediated diseases or conditions and related diseases or conditions include, but are not limited to: diabetes mellitus, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, and hyperinsulinemia. The diabetes mellitus includes, but is not limited to, type 1 diabetes mellitus (T1D) and / or type 2 diabetes mellitus (T2DM), idiopathic T1D, early-onset T2DM, latent autoimmune diabetes mellitus, juvenile atypical diabetes mellitus, and gestational diabetes mellitus.

[0067] The present invention also provides the use of the compound of formula (F) above, or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts thereof, in the preparation of GLP-1 receptor agonist-related drugs.

[0068] In some implementations, the GLP-1 receptor agonist-related drugs are used to treat type II diabetes, type I diabetes, and obesity.

[0069] In another aspect, the present invention provides intermediate compound M9-4 and intermediate compound M9, wherein the chemical name of M9-4 is (4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methanol, and its structural formula is as follows:

[0070]

[0071] The chemical name of M9 is 2-bromo-6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridine, and its structural formula is as follows:

[0072]

[0073] Furthermore, the present invention provides a preparation process for M9-4 and M9, the specific reaction process of which is as follows:

[0074]

[0075] Step 1: Synthesis of methyl 2-fluoro-4-vinylbenzoate (M9-1)

[0076] Methyl 4-bromo-2-fluorobenzoate and potassium vinyltrifluoroborate were added to a solvent system consisting of K2CO3, dioxane, and water. Pd(dppf)Cl2 was added to the reaction system, and the reaction was carried out under nitrogen protection. The compound M9-1 was obtained by separation and purification.

[0077] Step 2: Synthesis of methyl 2-fluoro-4-(3-oxocyclobutyl)benzoate (M9-2)

[0078] The solvent system was DMA and 1,2-dichloroethane. In an ice bath, trifluoromethanesulfonic anhydride was added, followed by the reaction of a mixture of compound M9-1 and 2,4,6-trimethylpyridine. The mixture was then separated and purified to obtain compound M9-2.

[0079] Step 3: Synthesis of methyl 4-(3,3-difluorocyclobutyl)-2-fluorobenzoate (M9-3)

[0080] Compound M9-2 was dissolved in anhydrous dichloromethane, DAST was added, and the reaction was carried out under nitrogen protection. After separation and purification, compound M9-3 was obtained.

[0081] Step 4: Synthesis of (4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methanol (M9-4)

[0082] LiAlH4 and THF were added under nitrogen protection, the mixture was cooled, a THF solution of compound M9-3 was added, the reaction was carried out, and the mixture was separated and purified to obtain compound M9-4.

[0083] Step 5: Synthesis of 2-bromo-6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridine (M9)

[0084] Compound M9-4, 2-bromo-6-fluoropyridine, cesium carbonate and DMF were reacted under elevated temperature, and the mixture was purified to obtain compound M9.

[0085] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0086] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0087] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0088] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0089] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0090] The term "haloalkoxy" refers to a group consisting of -O-haloalkyl groups.

[0091] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0092] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 Cycloalkyl, more preferably C 3-6 Yuan, of which "C" 3-12 The term "cycloalkyl" refers to the fact that a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0093] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0094] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0095] The term "aryl," in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbide ring atom. Preferably C 6-12 aryl, more preferably aryl is C6-10 Aromatic ring groups, either monocyclic or bicyclic. Preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring; non-limiting examples include, but are not limited to, benzocyclopentyl.

[0096] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0097] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-6 membered heterocyclic group, and even more preferably, a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, azacyclic butyl, pyrrolyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazine, oxoperazine, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0098] The term "substituted" refers to a group in which one or more hydrogen atoms are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogens (F, Cl, Br, or I), C... 1-8 Alkyl, C 3-12 cycloalkyl, -OR 1 -SR 1 =O, =S, -C(O)R 1 -C(S)R 1 =NR 1 -C(O)OR 1 -C(S)OR 1 -NR 1 R 2 -C(O)NR 1 R 2 , cyano, nitro, -S(O)2R 1 -OS(O2)OR 1 -OS(O)2R 1 -OP(O)(OR) 1 (OR) 2 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 Cycloalkyl. In some embodiments, the substituents are independently selected from groups comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -C(OCH3), cyano, nitro, -CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0099] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0100] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0101] When the compound provided by this invention is a base, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0102] The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Generally, a drug prodrug refers to a functional derivative that is readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of this application, which, upon administration to a receptor, can directly or indirectly provide the compound of this application or its pharmaceutically active metabolites or residues.

[0103] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0104] When the compounds represented by formula (F) have tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof.

[0105] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0106] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0107] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0108] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0109] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0110] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0111] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0112] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure. Detailed Implementation

[0113] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0114] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0115] The following abbreviations were used in the examples:

[0116] DMF: N,N-dimethylformamide; THF: tetrahydrofuran; Pd / C: palladium on carbon; MeOH: methanol; TsOH: p-toluenesulfonic acid; K2CO3: potassium carbonate; MeCN: acetonitrile; Pd(dppf)Cl2: 1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride; Dioxane / H2O: dioxane / water; PtO2: platinum dioxide; TsOH·H2O: p-toluenesulfonic acid monohydrate; CH3CN: acetonitrile; MeONa: sodium methoxide; DMSO: dimethyl sulfoxide; AcOH: acetic acid; NBS: N-bromosuccinimide; AIBN: azobisisobutyronitrile; 2,4,6-collidine: 2 4,6-Trimethylpyridine; Cs₂CO₃: Cesium carbonate; Tf₂O: Trifluoromethanesulfonic anhydride; DAST: Diethylaminosulfur trifluoride; DCM: Dichloromethane; DCE: 1,2-Dichloroethane; LAH: Lithium aluminum hydride; LiAlD₄: Deuterated lithium aluminum hydride; Pd₂dba₃: Tris(dibenzylacetone)palladium; Xphos: 2-Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; K₂CO₃: Potassium carbonate; Dioxane: Dioxane; LiOH: Lithium hydroxide; EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; EtOAc: Ethyl acetate; PE: Petroleum ether; Flash: Fast column chromatography.

[0117] Synthesis of intermediate M1: (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester

[0118]

[0119] Step 1: Synthesis of (S)-4-nitro-3-((oxetane-2-ylmethyl)amino)benzoate (M1-1)

[0120] Methyl 3-fluoro-4-nitrobenzene (1.0 g, 5.0 mmol), (S)-oxetane-2-ylmethylamine (520 mg, 6 mmol), and potassium carbonate (1.38 g, 10 mmol) were mixed in acetonitrile (10 mL) and stirred overnight at room temperature. Sodium chloride solution (10 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL each time). The organic phases were combined, washed twice with saturated brine (10 mL each time), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound M1-1 (1.3 g, 5 mmol).

[0121] MS(m / z): [M+H] + =267.1.

[0122] Step 2: Synthesis of (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate (M1-2)

[0123] Compound M1-1 (1.3 g, 5 mmol), methanol (50 mL), and wet palladium on carbon (300 mg) were added to the reaction flask. The mixture was purged with nitrogen and then replaced with hydrogen. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound M1-2 (1.0 g, 4.2 mmol).

[0124] Step 3: Synthesis of (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (M1)

[0125] Compound M1-2 (1.0 g, 4.2 mmol), p-toluenesulfonic acid monohydrate (100 mg, 0.5 mmol), 2-chloro-1,1,1-trimethoxyethane (1.0 g, 6 mmol), and acetonitrile (10 mL) were mixed and heated to 60 °C and stirred for 5 hours. The reaction solution was cooled to room temperature, diluted with sodium bicarbonate aqueous solution (20 mL), extracted with ethyl acetate (3 times, 30 mL each time), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Flash column chromatography (0-50% EtOAc / PE) to give compound M1 (800 mg, 2.7 mmol).

[0126] MS(m / z): [M+H] + =295.1.

[0127] Synthesis of intermediate M2: (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[0128]

[0129] Steps 1 and 2: Refer to steps 1 and 2 of the synthesis of intermediate M1.

[0130] Step 3: Synthesis of (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (M2)

[0131] Methyl (S)-5-amino-6-((oxetane-2-ylmethyl)amino)pyridinecarboxylate (M2-2, 500 mg, 2.1 mmol), chloroacetic anhydride (680 mg, 4 mmol), and THF (10 mL) were stirred at 70 °C for 5 hours. The reaction solution was concentrated to obtain a residue, which was extracted with sodium bicarbonate aqueous solution (30 mL) and ethyl acetate (30 mL), repeated 3 times. The combined organic phases were dried over anhydrous sodium sulfate and directly mixed with silica gel. The mixture was purified by Flash column chromatography (0-30% EtOAc / PE) to give compound M2 (450 mg, 1.5 mmol).

[0132] MS(m / z): [M+H] + =296.1.

[0133] Synthesis of intermediates M3 and M4: tert-butyl 6-chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid (M3) and intermediate tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylic acid (M4)

[0134]

[0135] Step 1: Synthesis of tert-butyl 6-chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid (M3)

[0136] N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.0 g, 10 mmol), 2,6-dichloropyridine (2.3 g, 15 mmol), potassium carbonate (2.8 g, 20 mmol), dioxane (50 mL), and water (15 mL) were added to a 100 mL reaction flask. After stirring to dissolve, Pd(dppf)Cl2 (730 mg, 1 mmol) was added. The mixture was gradually heated to 100 °C and stirred for 5 hours. After cooling, the mixture was filtered through diatomaceous earth, extracted twice with ethyl acetate (50 mL each time), washed twice with saturated brine (20 mL each time), and dried over anhydrous sodium sulfate. The solution was purified by Flash column chromatography (0-15% EtOAc / PE) to give compound M3 (2.0 g, 6.8 mmol).

[0137] MS(m / z): [M+H] + =295.1.

[0138] Step 2: Synthesis of tert-butyl 4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (M4)

[0139] PtO2 (220 mg, 1.0 mmol) was added to a methanol (20 mL) solution of compound M3 (2 g, 6.8 mmol), and the mixture was purged with hydrogen. After reacting for 3 hours under a hydrogen atmosphere, the mixture was filtered through diatomaceous earth. The filtrate was concentrated, and the crude product was purified by Flash column chromatography (0-15% EtOAc) to give compound M4 (1.0 g, 3.0 mmol).

[0140] MS(m / z): [M+H] + =297.1.

[0141] Synthesis of intermediate M5: (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0142]

[0143] Step 1: Synthesis of methyl 3,5-difluoro-4-nitrobenzene (M5-1)

[0144] The starting material, 3,5-difluoro-4-nitrobenzene (2 g, 11 mmol), was dissolved in MeOH (20 mL), and 6.5 mL of concentrated sulfuric acid was slowly added. The mixture was heated to 115 °C and stirred overnight. After cooling, the solution was poured into 100 mL of ice water and extracted with ethyl acetate (3 times, 30 mL each time). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by Flash column chromatography (0-10% EtOAc / PE) to give compound M5-1 (1.9 g, 8.7 mmol).

[0145] 1 H NMR (400MHz, CDCl3) δ7.79 (d, 2H), 4.0 (s, 3H).

[0146] Step 2: Synthesis of methyl (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate (M5-2):

[0147] Compound M5-1 (1.9 g, 8.7 mmol), (S)-oxetane-2-methylamine (0.83 g, 9.6 mmol), potassium carbonate (2.4 g, 17 mmol), and acetonitrile (50 mL) were added to a 100 mL reaction flask and stirred. The mixture was heated to 70 °C and reacted overnight. After cooling and filtration, the filtrate was concentrated and purified by Flash column chromatography (0-30% EtOAc / PE) to give compound M5-2 (1.9 g, 6.7 mmol).

[0148] MS(m / z): [M+H] + =285.1.

[0149] Step 3: Synthesis of (S)-4-amino-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate (M5-3)

[0150] Compound M5-2 (1.9 g, 6.7 mmol) was dissolved in MeOH (30 mL), wet Pd / C (400 mg, 10%) was added, hydrogen was added, and the mixture was stirred at room temperature for 5 h until the color completely disappeared. After filtration and concentration, compound M5-3 (1.7 g, 6.7 mmol) was obtained.

[0151] MS(m / z): [M+H] + =255.2.

[0152] Step 4: Synthesis of (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (M5)

[0153] To a solution of compound M5-3 (1.7 g, 6.7 mmol) in acetonitrile (30 mL), 2-chloro-1,1,1-trimethoxyethane (2.1 g, 14 mmol) and p-toluenesulfonic acid monohydrate (250 mg, 1.3 mmol) were added, and the mixture was heated to 70 °C and stirred for 5 hours. After cooling, the mixture was filtered, and the filtrate was directly mixed with silica gel and purified by Flash column chromatography (0-50% EtOAc / PE) to obtain compound M5 (1.5 g, 5 mmol).

[0154] MS(m / z): [M+H] + =313.1.

[0155] Synthesis of intermediate M6: (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (M6)

[0156]

[0157] Step 1: Synthesis of methyl (S)-3-methoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate (M6-1)

[0158] Sodium methoxide (160 mg, 3 mmol) was added to a methanol (10 mL) solution of compound M5-2 (560 mg, 2 mmol), and the mixture was heated to 65 °C and reacted overnight. After cooling, the reaction solution was concentrated, the reaction was quenched with water (20 mL), and extracted twice with ethyl acetate (15 mL each time). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Flash column chromatography (0-30% EtOAc / PE) to give compound M6-1 (450 mg, 1.5 mmol).

[0159] MS(m / z): [M+H] + =297.1.

[0160] Step 2: Synthesis of (S)-4-amino-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate (M6-2)

[0161] The synthesis of intermediate (M6-2) was performed by referring to the synthesis of intermediate (M5-3) to obtain compound M6-2 (400 mg, 1.5 mmol).

[0162] MS(m / z): [M+H] + =267.2.

[0163] Step 3: The synthesis of (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (M6) was performed by referring to the synthesis method of intermediate M5, and finally compound M6 (300 mg, 1 mmol) was obtained.

[0164] MS(m / z): [M+H] + =325.1.

[0165] Synthesis of intermediate M7: tert-butyl 4-(6-chloropyridin-2-yl)piperazine-1-carboxylate

[0166]

[0167] 2,6-Dichloropyridine (3.0 g, 20 mmol), N-Boc piperazine (1.9 g, 10 mmol), DIPEA (2.6 g, 20 mmol), and DMSO (20 mL) were mixed and stirred until dissolved, then heated to 120 °C overnight. The mixture was diluted with water (50 mL), extracted with ethyl acetate (3 times, 20 mL each), and the organic phases were combined. The organic phases were washed with saturated brine (3 times, 10 mL each), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Flash column chromatography (0-50% ethyl acetate / petroleum ether) to give compound M7 (1.2 g, 4 mmol).

[0168] MS(m / z): [M+H] + =298.2.

[0169] Synthesis of intermediate M8: (S)-2-(bromomethyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazolium-5-carboxylic acid methyl ester

[0170]

[0171] Step 1: Synthesis of methyl 4-bromo-5-nitrothiophene-2-carboxylic acid (M8-1)

[0172] Sulfuric acid (20 mL) was added to a dry reaction flask under ice-ethanol bath conditions and stirred. After cooling completely, methyl 4-bromothiophene-2-carboxylic acid (2.2 g, 10 mmol) was added, followed by potassium nitrate (0.4 g / batch, 4 mmol / batch) in three batches, with the addition completed within 10 min. The mixture was stirred at this temperature for 1 h and then poured into ice water. The solid precipitated out, and the solid was collected by filtration. The filter cake was washed with water and dried under vacuum to obtain compound M8-1 (2.6 g, 10 mmol).

[0173] 1 H NMR (400MHz, CDCl3) δ7.28 (s, 1H), 4.0 (s, 3H).

[0174] Step 2: Synthesis of (S)-5-nitro-4-((oxetane-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester (M8-2)

[0175] Compound M8-1 (2.6 g, 10 mmol), (S)-oxetane-2-ylmethylamine (950 mg, 11 mmol), potassium carbonate (2.8 g, 20 mmol), and acetonitrile (100 mL) were added to a reaction flask. The mixture was heated to 60 °C and stirred for 24 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (100 mL) and water (100 mL) were added and separated. The organic phase was washed three times with saturated brine (20 mL each time), dried over anhydrous sodium sulfate, and the crude product obtained after concentration under reduced pressure was purified by Flash column chromatography (0-50% ethyl acetate / petroleum ether) to give compound M8-2 (1.3 g, 5 mmol).

[0176] MS(m / z): [M+H] + =273.1.

[0177] Step 3: Synthesis of (S)-5-amino-4-((oxetane-2-ylmethyl)amino)thiophene-2-carboxylic acid methyl ester (M8-3)

[0178] Compound M8-2 (1.3 g, 5.0 mmol), MeOH (20 mL), and ethyl acetate (60 mL) were added to a reaction flask. Wet Pd / C (1 g) was added under nitrogen atmosphere, and the mixture was purged with hydrogen and reacted for 2 hours under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain compound M8-3, which was used directly as the crude product in the next reaction.

[0179] MS(m / z):[M+H] + =243.1.

[0180] Step 4: Synthesis of (S)-2-methyl-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazolium-5-carboxylic acid methyl ester (M8-4)

[0181] Compound M8-3 (1 g, crude) was dissolved in acetic acid (70 mL), and then 1,1,1-trimethoxyethane (600 mg, 6 mmol) was added. The mixture was heated to 70 °C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by Flash column chromatography (0-100% ethyl acetate / petroleum ether) with silica gel to give compound M8-4 (500 mg, 1.8 mmol).

[0182] MS(m / z): [M+H] + =266.9.

[0183] Step 5: Synthesis of (S)-2-(bromomethyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazolium-5-carboxylic acid methyl ester (M8)

[0184] Compound M8-4 (130 mg, 0.5 mmol), NBS (107 mg, 0.6 mmol), AIBN (16 mg, 0.1 mmol), and dichloroethane were added to a reaction flask, and the mixture was heated to 70 °C and stirred for 5 hours. The reaction solution was added directly to silica gel without further treatment, and purified by Flash column chromatography (0-50% ethyl acetate / petroleum ether) to obtain compound M8 (68 mg, 0.43 mmol).

[0185] MS(m / z): [M+H] + =344.9.

[0186] Synthesis of intermediate M9: 2-bromo-6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridine

[0187]

[0188] Step 1: Synthesis of methyl 2-fluoro-4-vinylbenzoate (M9-1)

[0189] Methyl 4-bromo-2-fluorobenzoate (2.3 g, 10 mmol), potassium vinyltrifluoroborate (1.95 g, 15 mmol), K₂CO₃ (2.7 g, 20 mmol), dioxane (100 mL), and water (30 mL) were added to a reaction flask and stirred until dissolved. Pd(dppf)Cl₂ (730 mg, 1 mmol) was then added. The mixture was purged with nitrogen three times and stirred at 100 °C for 6 hours under nitrogen protection. Extraction was performed twice with ethyl acetate (50 mL each time). The organic phase was dried over anhydrous sodium sulfate, mixed with silica gel, and purified by flash column chromatography (0-50% ethyl acetate / petroleum ether) to give compound M9-1 (1.6 g, 9 mmol).

[0190] 1 H NMR (400MHz, CDCl3) δ7.89 (t, J=7.8Hz, 1H), 7.25-7.11 (m, 2H), 6.69 (dd, J=17 .6,10.9Hz,1H),5.86(d,J=17.6Hz,1H),5.43(d,J=10.9Hz,1H),3.92(s,3H).

[0191] Step 2: Synthesis of methyl 2-fluoro-4-(3-oxocyclobutyl)benzoate (M9-2)

[0192] Add DMA (1.1 mL, 12 mmol) and 1,2-dichloroethane (30 mL) to a dry reaction flask, cool the solution in an ice bath, and slowly add trifluoromethanesulfonic anhydride (2.2 mL, 13 mmol). After the addition is complete, move the reaction solution to room temperature, stir for about 15 min, and continue cooling. Slowly add a mixture of compound M9-1 (1.8 g, 10 mmol) and 2,4,6-trimethylpyridine (1.8 mL, 14 mmol). After the addition is complete, heat to 80 °C and react overnight. Concentrate under reduced pressure to remove dichloroethane, add carbon tetrachloride (20 mL) and water (20 mL), and reflux overnight. After cooling, separate the liquid phase directly. The organic phase is dried over anhydrous sodium sulfate and purified by flash column chromatography (0-50% ethyl acetate / petroleum ether) to give compound M9-2 (600 mg, 3.0 mmol).

[0193] 1 H NMR (400MHz, CDCl3) δ7.96 (t, J=7.8Hz, 1H), 7.17 (dd, J=8.1, 1.8Hz, 1H), 7.10 (dd, J=1 1.7,1.8Hz,1H),3.96(s,3H),3.81-3.68(m,1H),3.64-3.50(m,2H),3.37-3.22(m,2H).

[0194] Step 3: Synthesis of methyl 4-(3,3-difluorocyclobutyl)-2-fluorobenzoate (M9-3)

[0195] Compound M9-2 (600 mg, 2.7 mmol) was dissolved in anhydrous dichloromethane (20 mL), and DAST (4.2 mL, 31 mmol) was added. The mixture was stirred overnight at room temperature under nitrogen protection. The reaction was quenched by slowly adding sodium carbonate solution to the solution in an ice bath. The mixture was separated, and the organic phase was washed three times with 10 mL of brine, then dried over anhydrous sodium sulfate. The solution was concentrated to dryness under reduced pressure to give compound M9-3 (700 mg, 2.86 mmol).

[0196] 1 H NMR (400MHz, CDCl3) δ7.91 (t, J = 7.8Hz, 1H), 7.11-6.97 (m, 2H), 3.49-3.36 (m, 1H), 3.93 (s, 3H), 3.13-2.90 (m, 2H), 2.79-2.58 (m, 2H).

[0197] Step 4: Synthesis of (4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methanol (M9-4)

[0198] Under nitrogen protection, LiAlH4 (60 mg, 1.5 mmol) and THF (2 mL) were added to a dry reaction flask. The mixture was cooled to approximately 0 °C, and a THF solution of compound M9-3 (240 mg, 1 mmol) in 2 mL portions was added. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. The reaction solution was cooled again, and the reaction was quenched with dilute hydrochloric acid (1 N, 0.5 mL). Anhydrous sodium sulfate was added and stirred. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain compound M9-4 (200 mg, 0.93 mmol).

[0199] 1 H NMR (400MHz, CDCl3) δ7.38(t,J=7.8Hz,1H),7.02(dd,J=7.8,1.8Hz,1H),6.93(dd,J =11.0,1.8Hz,1H),4.73(s,2H),3.37(m,1H),3.09-2.92(m,2H),2.74-2.55(m,2H).

[0200] Step 5: Synthesis of 2-bromo-6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridine (M9)

[0201] Compound M9-4 (220 mg, 1.0 mmol), 2-bromo-6-fluoropyridine (170 mg, 1.0 mmol), cesium carbonate (650 mg, 2.0 mmol), and DMF (5 mL) were added to a reaction flask, and the mixture was heated to 80 °C and stirred overnight. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (3 times, 10 mL each time), the organic phases were combined, washed with brine (3 times, 5 mL each time), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by Flash purification (0-10% ethyl acetate / petroleum ether) to give compound M9 (200 mg, 0.54 mmol).

[0202] MS(m / z): [M+H] + =372.1.

[0203] Synthesis of intermediates (4-(3,3-difluoro-1-methylcyclobutyl)-2-fluorophenyl)methanol (M10) and 2-bromo-6-((4-(3,3-difluoro-1-methylcyclobutyl)-2-fluorobenzyl)oxy)pyridine (M11):

[0204]

[0205] Intermediate M10 was synthesized by referring to the synthesis of intermediate M9-4, except that potassium vinyltrifluoroborate was replaced with potassium propenyltrifluoroborate; intermediate M11 was synthesized by referring to the synthesis of intermediate M9.

[0206] M10: 1 H NMR (600MHz, DMSO-d6) δ7.45-7.40(m,1H),7.12-7.04(m,2H),5.21(t,J=5.7Hz,1H),4.52

[0207] (d,J=5.7Hz,2H),2.97-2.87(m,2H),2.79-2.70(m,2H),1.45(s,3H).

[0208] M11: MS(m / z): [M+H] + =386.1.

[0209] Synthesis of intermediates (4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methane-d2-ol (M12) and 2-bromo-6-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyridine (M15):

[0210]

[0211] Intermediate M12 was synthesized by referring to the synthesis of M9-4, with the reducing agent LiAlH4 replaced by LiAlD4; intermediate M15 was synthesized by referring to the synthesis of intermediate M9.

[0212] M12: 1 H NMR (400MHz, CDCl3) δ7.37 (t, J=7.8Hz, 1H), 7.01 (dd, J=7.8, 1.8Hz, 1H), 6.9 2(dd,J=11.0,1.8Hz,1H),3.37(m,1H),3.09-2.92(m,2H),2.74-2.55(m,2H).

[0213] M15: MS(m / z): [M+H] + =374.1.

[0214] Synthesis of intermediates (4-(3,3-difluorocyclobutyl)-2,5-difluorophenyl)methane-d2-ol (M13) and 2-bromo-6-((4-(3,3-difluorocyclobutyl)-2,5-difluorophenyl)methoxy-d2)pyridine (M14):

[0215]

[0216] Intermediate M13 was synthesized by referring to the synthesis of intermediate M9-4, except that the starting material methyl 4-bromo-2-fluorobenzoate was replaced with methyl 4-bromo-2,5-difluorobenzoate, and the reducing agent LiAlH4 was replaced with LiAlD4; intermediate M14 was synthesized by referring to the synthesis of intermediate M9.

[0217] M13: 1 H NMR (600MHz, CDCl3) δ7.14 (dd, J = 10.0, 6.0 Hz, 1H), 6.92 (dd, J = 10.0, 6.0 Hz, 1H), 3.57-3.48 (m, 1H), 3.07-2.97 (m, 2H), 2.74-2.62 (m, 2H).

[0218] M14: MS(m / z): [M+H] + =392.1.

[0219] Synthesis of intermediates (4-(3,3-difluorocyclobutyl)-3,5-difluorophenyl)methanol (M16) and M16-4

[0220]

[0221] Intermediate M16-4 was synthesized by referring to the synthesis of intermediate M9-4, except that the starting material methyl 4-bromo-2-fluorobenzoate was replaced with methyl 4-bromo-3,5-difluorobenzoate; intermediate M16 was synthesized by referring to the synthesis of intermediate M9.

[0222] M16-4: 1 H NMR (600MHz, DMSO-d6) δ7.04-6.95 (m, 2H), 5.41 (t, J = 5.8Hz, 1H), 4.48 (d, J = 5.7Hz, 2H), 3.55 (qd, J = 9.2, 2.2Hz, 1H), 3.07-2.85 (m, 4H).

[0223] M16: MS(m / z): [M+H] + =390.1.

[0224] Example 1: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 1)

[0225]

[0226] Step 1: Synthesis of tert-butyl 6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (1-5)

[0227] Compounds M9-4 (110 mg, 0.5 mmol), M3 (150 mg, 0.5 mmol), cesium carbonate (330 mg, 1 mmol), and dioxane (10 mL) were added to a 100 mL reaction flask and stirred. Pd2dba3 (46 mg, 0.05 mmol) and Xphos (48 mg, 0.1 mmol) were added, and nitrogen was used for purging. The mixture was heated to 110 °C and stirred for 18 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (10 mL), filtered, and the filtrate was directly purified by silica gel flash column chromatography (0-30% EtOAc) to obtain compounds 1-5 (190 mg, 0.4 mmol).

[0228] MS(m / z): [M+H] + =475.2.

[0229] Step 2: Synthesis of trifluoroacetate (1-6) of 6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine

[0230] Add 0.5 mL of trifluoroacetic acid to a 2 mL solution of dichloromethane containing 100 mg (0.21 mmol) of compound 1-5, stir at room temperature for 1 hour, and concentrate under reduced pressure to dryness to obtain compound 1-6 (150 mg), which can be used directly in the next reaction.

[0231] Step 3: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1-7)

[0232] Compounds 1-6 (crude product 150 mg, 0.21 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (138 mg, 1.0 mmol) and M2 (60 mg, 0.2 mmol) were added. The mixture was heated to 60 °C and stirred for 5 hours. The reaction solution was filtered, and the filtrate was directly purified by Flash column chromatography (20% methanol / dichloromethane) to give compounds 1-7 (100 mg, 0.15 mmol).

[0233] MS(m / z): [M+H] + =634.2.

[0234] Step 4: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 1)

[0235] Compounds 1-7 (100 mg, 0.15 mmol) were dissolved in methanol (5 mL), lithium hydroxide (46 mg, 2 mmol) and water (1 mL) were added, and the mixture was stirred overnight at room temperature. The reaction solution was then acidified to neutral, concentrated under reduced pressure, and purified by HPLC to obtain compound 1 (50 mg, 0.08 mmol).

[0236] MS(m / z): [M+H] + =620.2;

[0237] 1 H NMR (400MHz, Methanol-d4) δ8.17-8.08(m,2H),7.60(t,J=7.8Hz,1H),7.44(t,J=7.8Hz,1H),7.05(m 3H),6.75-6.71(m,1H),6.66(d,J=8.2Hz,1H).,5.41(s,2H),5.31-5.22(m,1H),5.05-4.95(m,2H),4.64-4.54(m,1H),4.47-4.37( m,1H),4.32(d,J=14.1Hz,1H),4.21(d,J=14.1Hz,1H),3.45-3.32(m,3H),3.03-2.88(m,4H),2.83-2.58(m,5H),2.54-2.44(m,1H).

[0238] Example 2: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 2)

[0239]

[0240] Compound 2 was synthesized using the same method as compound 1, except that M2 was replaced with M5, resulting in compound 2 (10 mg, 0.015 mmol).

[0241] MS(m / z): [M+H] + =637.3;

[0242] 1 H NMR(400MHz, DMSO-d6)δ8.16(d,J=1.3Hz,1H),7.68(t,J=7.8Hz,1H),7.56-7.47(m,2H),7.22(dd,J= 11.4,1.7Hz,1H),7.15(dd,J=7.9,1.7Hz,1H),7.08(d,J=7.5Hz,1H),6.76(d,J=4.0Hz,1H),6.71(d,J =8.2Hz,1H),5.39(s,2H),5.12-5.03(m,1H),4.84(m,1H),4.69(m,1H),4.51-4.43(m,1H),4.41-4.3 3(m,1H),4.10(d,J=13.6Hz,1H),3.99-3.89(m,1H),3.48-3.40(m,2H),3.25(d,J=9.2Hz,2H),2.97(m 2H),2.80-2.63(m,5H),2.45-2.32(m,2H).

[0243] Example 3: Synthesis of (S)-2-((4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 3)

[0244]

[0245] Compound 3 was synthesized using the same method as compound 1, except that M3 was replaced with M4 and M2 with M5, resulting in compound 3 (30 mg, 0.047 mmol).

[0246] MS(m / z): [M+H] + =639.3;

[0247] 1H NMR (400MHz, DMSO-d6) δ13.08(s,1H),8.17(d,J=1.3Hz,1H),7.62(dd,J=8.2,7.3Hz,1H),7.55-7.46(m,2H),7.21(dd,J =11.4,1.7Hz,1H),7.13(dd,J=7.9,1.7Hz,1H),6.87(d,J=7.3Hz,1H),6.66(d,J=8.1Hz,1H),5.37(s,2H),5.12(m,1H),4 .85(dd,J=15.2,7.3Hz,1H),4.70(dd,J=15.2,2.7Hz,1H),4.52-4.45(m,1H),4.43-4.36(m,1H),3.98(d,J=13.6Hz,1H), 3.80(d,J=13.6Hz,1H),3.44-3.38(m,1H),3.05-2.82(m,4H),2.67(m,4H),2.45(m,1H),2.25(m,2H),1.87-1.66(m,4H).

[0248] Example 4: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 4)

[0249]

[0250] Compound 4 was synthesized using the same method as compound 1, except that M2 was replaced with M6, resulting in compound 4 (12 mg, 0.018 mmol).

[0251] MS(m / z): [M+H] + =649.2;

[0252] 1H NMR (400MHz, DMSO-d6) δ7.89(d,J=1.3Hz,1H),7.68(t,J=7.8Hz,1H),7.49(t,J=7.9Hz,1H),7.27(d,J=1.3Hz,1H),7.22(dd,J=11.4 ,1.7Hz,1H),7.15(dd,J=7.9,1.7Hz,1H),7.08(d,J=7.4Hz,1H),6.76(d,J=3.5Hz,1H),6.71(d,J=8.2Hz,1H),5.39(s,2H),5.10-5. 01(m,1H),4.76(dd,J=15.2,7.1Hz,1H),4.63(dd,J=15.2,2.9Hz,1H),4.51-4.41(m,1H),4.34(dt,J=8.9,5.9Hz,1H),4.04(d,J=13 .4Hz,1H),3.97(s,3H),3.90(d,J=13.5Hz,1H),3.43(m,2H),3.26-3.15(m,2H),3.05-2.90(m,2H),2.79-2.60(m,5H),2.38(m,2H).

[0253] Example 5: Synthesis of (S)-2-((4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid

[0254]

[0255] Compound 5 was synthesized using the same method as compound 1, except that M2 was replaced with M6 and M3 with M4, resulting in compound 5 (23 mg, 0.035 mmol).

[0256] MS(m / z): [M+H] + =651.3;

[0257] 1H NMR (400MHz, DMSO-d6) δ12.82(s,1H),7.91(d,J=1.3Hz,1H),7.62(dd,J=8.2,7.3Hz,1H),7.50(t,J=7.9Hz,1H),7.26(d,J=1.3Hz,1H) ,7.20(dd,J=11.3,1.7Hz,1H),7.13(dd,J=8.1,1.7Hz,1H),6.87(d,J=7.2Hz,1H),6.65(d,J=8.1Hz,1H),5.37(s,2H),5.11(m,1H),4. 77(dd,J=15.2,7.1Hz,1H),4.68-4.61(m,1H),4.50-4.43(m,1H),4.39-4.33(m,1H),3.96(s,3H),3.91(s,1H),3.76(d,J=13.4Hz,1H) ,3.45-3.39(m,1H),3.03-2.90(m,3H),2.85(d,J=11.1Hz,1H),2.75-2.57(m,4H),2.49-2.40(m,1H),2.16(m,2H),1.84-1.66(m,4H).

[0258] Example 6: Synthesis of (S)-2-((4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 6)

[0259]

[0260] Compound 6 was synthesized using the same method as compound 1, except that M2 was replaced with M1 and M3 with M4, resulting in compound 6 (89 mg, 0.14 mmol).

[0261] MS(m / z): [M+H] + =621.2;

[0262] 1H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.28(d,J=1.6Hz,1H),7.81(dd,J=8.4,1.6Hz,1H),7.63(dd,J=15.2,8.0Hz,2H),7.50(t ,J=7.9Hz,1H),7.20(dd,J=11.3,1.7Hz,1H),7.13(dd,J=7.9,1.7Hz,1H),6.87(d,J=7.3Hz,1H),6.65(d,J=8.1Hz,1H),5.37(s, 2H),5.13(m,1H),4.81(dd,J=15.2,7.2Hz,1H),4.67(dd,J=15.2,2.8Hz,1H),4.52-4.43(m,1H),4.39(m,1H),3.97(d,J=13.4H z,1H),3.78(d,J=13.4Hz,1H),3.46-3.37(m,1H),3.07-2.81(m,4H),2.77-2.56(m,4H),2.45(m,1H),2.22(m,2H),1.75(m,4H).

[0263] Example 7: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 7)

[0264]

[0265] Compound 7 was synthesized using the same method as compound 1, except that M2 was replaced with M1, resulting in compound 7 (52 mg, 0.084 mmol).

[0266] MS(m / z): [M+H] + =619.2;

[0267] 1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.28(s,1H),7.81(s,1H),7.68(d,J=8.1Hz,2H),7.50 (s,1H),7.18(m,3H),6.75(d,J=17.1Hz,2H),5.39(s,2H),5.06(m,1H),4.81(dd,J=15.4,7.2 Hz,1H),4.66(d,J=15.1Hz,1H),4.47(d,J=7.1Hz,1H),4.36(d,J=8.6Hz,1H),3.94(s,1H),3. 46-3.40(m,2H),3.28-3.15(m,2H),3.05-2.91(m,3H),2.80-2.62(m,5H),2.45-2.31(m,2H).

[0268] Example 8: Synthesis of (S)-2-((4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 8)

[0269]

[0270] Compound 8 was synthesized using the same method as compound 1, except that M3 was replaced with M7 and M2 with M1, resulting in compound 8 (30 mg, 0.048 mmol).

[0271] MS(m / z): [M+H] + =622.2;

[0272] 1 H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.33(s,1H),7.92-7.80(m,1H),7.79-7.64(m,1H),7.51-7.4 1(m,2H),7.17(dd,J=24.3,10.1Hz,2H),6.37(s,1H),6.11(d,J=6.5Hz,1H),5.30(s,2H),5.09-5.0 4(m,1H),4.87-4.77(m,1H),4.71-4.63(m,1H),4.48(q,J=7.0Hz,1H),4.40-4.33(m,1H),3.81-3.5 0(m,3H),3.50-3.34(m,5H),3.30(s,1H),3.05-2.90(m,3H),2.79-2.61(m,4H),2.46-2.27(m,1H).

[0273] Example 9: Synthesis of (S)-2-((4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxacyclobutane-2-ylmethyl)-1H-thieno[2,3-d]imidazolium-5-carboxylic acid (compound 9)

[0274]

[0275] Compound 9 was synthesized using the same method as compound 1, except that M3 was replaced with M4 and M2 with M8, resulting in compound 9 (30 mg, 0.048 mmol).

[0276] MS(m / z): [M+H] + =627.1;

[0277] 1 H NMR (400MHz, DMSO-d6) δ13.0(s,1H),7.85(s,1H),7.63(t,J=7.7Hz,1H),7.51(t,J=7.8Hz,1H),7.24- 7.19(m,1H),7.15(d,J=7.5Hz,1H),6.87(d,J=7.3Hz,1H),6.67(d,J=8.2Hz,1H),5.37(s,2H),5.13-5 .05(m,1H),4.72-4.63(m,1H),4.60-4.43(m,2H),4.43-4.33(m,1H),3.89-3.67(m,2H),3.47-3.36(m ,1H),3.05-2.90(m,3H),2.78-2.60(m,4H),2.45-2.31(m,2H),2.25-2.08(m,2H),1.90-1.65(m,4H).

[0278] Example 10: Synthesis of (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 10)

[0279]

[0280] Step 1: Synthesis of (S)-4-(2-(4-bromophenyl)acetamido)-3-((oxetane-2-ylmethyl)amino)benzoate (10-1)

[0281] Compound M1-2 (2.36 g, 10 mmol) was dissolved in bromophenylacetic acid (2.3 g, 11 mmol) in dichloromethane (20 mL) and stirred until dissolved. EDCI (2.5 g, 13 mmol) and DMAP (1.2 g, 10 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Ammonium chloride solution (50 mL) was added, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and purified by flash column chromatography (0-10% MeOH / DCM) to give compound 10-1 (3.8 g, 8.7 mmol).

[0282] MS(m / z): [M+H] + =433.1.

[0283] Step 2: Synthesis of (S)-2-(4-bromobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (10-2)

[0284] Compound 10-1 (430 mg, 1 mmol) was dissolved in 1,2-dichloroethane (10 mL), and acetic acid (1 mL) was added. The mixture was heated to 60 °C and stirred overnight. After cooling to room temperature, the acetic acid was removed by concentration under reduced pressure. The crude product was purified by Flash column chromatography (0-50% EtOAc / PE) to give compound 10-2 (280 mg, 0.67 mmol).

[0285] MS(m / z): [M+H] + =415.2.

[0286] Step 3: Synthesis of (S)-1-(oxecyclobutane-2-ylmethyl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzyl)-1H-benzo[d]imidazolium-6-carboxylate (10-3)

[0287] Compound 10⁻² (280 mg, 0.67 mmol), potassium acetate (100 mg, 1.0 mmol), pinacol diboronate (250 mg, 1.0 mmol), Pd(dppf)Cl₂ (73 mg, 0.1 mmol), and dioxane (10 mL) were mixed and stirred. After purging with nitrogen, the mixture was stirred overnight at 100 °C under nitrogen protection. The mixture was cooled, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by flash column chromatography (0-50% EtOAc / PE) to give compound 10⁻³ (140 mg, 0.3 mmol).

[0288] Step 4: Synthesis of (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (10-4)

[0289] Compound 10⁻³ (140 mg, 0.3 mmol), M9 (110 mg, 0.3 mmol), potassium carbonate (140 mg, 1 mmol), dioxane (10 mL), and water (3 mL) were mixed and stirred until dissolved. Pd(dppf)Cl₂ (22 mg, 0.03 mmol) was added, and the mixture was purged with nitrogen. The mixture was heated to 100 °C overnight under nitrogen protection. After cooling, the mixture was filtered through diatomaceous earth and extracted twice with ethyl acetate (20 mL each time). The organic phase was directly mixed with silica gel and purified by Flash column chromatography (0-50% ethyl acetate / petroleum ether) to give compound 10⁻⁴ (90 mg, 0.14 mmol).

[0290] Step 5: Synthesis of (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (10)

[0291] Compound 10-4 (90 mg, 0.14 mmol) was dissolved in a mixed solution of methanol (5 mL) and water (1 mL), and lithium hydroxide (46 mg, 2.0 mmol) was added. The mixture was stirred for 18 hours, neutralized to approximately neutral with dilute hydrochloric acid (1 N), and the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (elution buffer: water / acetonitrile, 0.1% formic acid, systematic gradient elution) to obtain compound 10 (30 mg, 0.048 mmol).

[0292] MS(m / z): [M+H] + =614.2;

[0293] 1 H NMR (600MHz, DMSO-d6) δ12.78(s,1H),8.25(s,1H),8.06(d,J=8.0Hz,2H),7.83-7.77(m,2H),7.64(d,J=8 .4Hz,1H),7.59-7.51(m,2H),7.43(d,J=8.0Hz,2H),7.23(d,J=11.3Hz,1H),7.16(d,J=7.9Hz,1H),6.81(d ,J=8.1Hz,1H),5.49(s,2H),4.96-4.92(m,1H),4.68(dd,J=15.5,7.3Hz,1H),4.57-4.52(m,1H),4.51-4. 42(m,2H),4.39-4.33(m,1H),3.47-3.40(m,1H),3.02-2.92(m,2H),2.77-2.59(m,3H),2.39-2.30(m,2H).

[0294] Example 11: Synthesis of (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 11)

[0295]

[0296] The synthesis of compound 11 was performed using the same method as that used for compound 10, except that 4-bromophenylacetic acid in step 1 was replaced with 2-(4-bromo-2,5-difluorophenyl)acetic acid, and compound 11 (12 mg, 0.018 mmol) was finally obtained.

[0297] MS(m / z): [M+H] + =650.1;

[0298] 1 H NMR (600MHz, DMSO-d6) δ12.80(s,1H),8.25(s,1H),7.88-7.76(m,3H),7.59(d,J=8.4Hz,1H),7.55-7.48(m,2H),7. 38(dd,J=11.5,6.0Hz,1H),7.23(d,J=9.5Hz,1H),7.16(d,J=8.0Hz,1H),6.91(d,J=8.2Hz,1H),5.48(s,2H),5.07( m,1H),4.74(dd,J=15.6,7.1Hz,1H),4.62(dd,J=15.6,2.7Hz,1H),4.55-4.46(m,2H),4.46-4.40(m,1H),4.35(dt, J=9.0,5.9Hz,1H),3.48-3.41(m,1H),3.03-2.93(m,2H),2.76-2.64(m,2H),2.53-2.49(m,1H),2.43-2.34(m,1H).

[0299] Example 12: Synthesis of (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 12)

[0300]

[0301] The synthesis of compound 12 was performed using the same method as that used for compound 10, except that 4-bromophenylacetic acid in step 1 was replaced with 2-(4-bromo-2-fluorophenyl)acetic acid, and compound 12 (32 mg, 0.05 mmol) was finally obtained.

[0302] MS(m / z): [M+H] + =632.1;

[0303] 1H NMR (600MHz, DMSO-d6) δ12.85(s,1H),8.30(d,J=1.5Hz,1H),7.96-7.90(m,2H),7.82(t,J=7.9Hz,2H),7.63(dd,J=1 2.4,7.9Hz,2H),7.54(t,J=7.8Hz,1H),7.45(t,J=8.0Hz,1H),7.23(dd,J=11.4,1.7Hz,1H),7.16(dd,J=7.9,1.7Hz,1 H),6.86(d,J=8.2Hz,1H),5.51(s,2H),5.05(m,1H),4.77(dd,J=15.6,7.2Hz,1H),4.64(dd,J=15.6,2.7Hz,1H),4.5 7(d,J=16.8Hz,1H),4.54-4.46(m,2H),4.37(m,1H),3.47-3.39(m,1H),2.97(m,2H),2.76-2.64(m,3H),2.39(m,1H).

[0304] Example 13: Synthesis of (S)-2-((4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 13)

[0305]

[0306] The synthesis of compound 13 followed the same method as compound 6, with M9-4 replaced by M12, finally yielding compound 13 (S)-2-((4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxacyclobutyl-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (57 mg, 0.091 mmol).

[0307] MS(m / z): [M+H] + =623.2;

[0308] 1H NMR(600MHz,DMSO-d6)δ12.78(s,1H),8.28(s,1H),7.80(s,1H),7.64(s,2H),7.50(s,1H),7.20( d,J=11.1Hz,1H),7.14(s,1H),6.87(s,1H),5.11(s,1H),4.81(dd,J=15.1,7.2Hz,1H),4.67(d,J =15.1Hz,1H),4.47(d,J=7.3Hz,1H),4.37(s,1H),3.96(d,J=13.2Hz,1H),3.77(d,J=14.6Hz,1H) ,3.41(s,1H),2.96(s,5H),2.77-2.56(m,4H),2.48-2.42(m,1H)2.31-2.02(m,3H),1.77(s,3H).

[0309] Example 14: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 14)

[0310]

[0311] The synthesis of compound 14 was performed using the same method as compound 1, except that M9-4 was replaced with M12, resulting in compound 14.

[0312] MS(m / z): [M+H] + =622.2;

[0313] 1 H NMR (400MHz, Methanol-d4) δ8.17-8.08(m,2H),7.60(t,J=7.8Hz,1H),7.44(t,J=7.8Hz,1H),7.05(m 3H),6.75-6.71(m,1H),6.66(d,J=8.2Hz,1H),5.31-5.22(m,1H),5.05-4.95(m,2H),4.64-4.54(m,1H),4.47-4.37(m,1H), 4.32(d,J=14.1Hz,1H), 4.21(d,J=14.1Hz,1H), 3.45-3.32(m,3H), 3.03-2.88(m,4H), 2.83-2.58(m,5H), 2.54-2.44(m,1H).

[0314] Example 16: Synthesis of compound (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2,5-difluorophenyl)methoxy-d2)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 16)

[0315]

[0316] The synthesis of compound 16 was performed using the same method as compound 1, except that M9-4 was replaced with M13, resulting in compound 16.

[0317] MS(m / z): [M+H] + =640.2;

[0318] 1 H NMR (600MHz, DMSO-d6) δ13.29(s,1H),8.32(d,J=8.3Hz,1H),8.11(d,J=8.3Hz,1H),7.78(t,J=7.8Hz,1H),7.37(dd d,J=12.4,10.2,6.1Hz,2H),7.22(d,J=7.5Hz,1H),6.84(d,J=8.2Hz,1H),6.79(s,1H),5.14-5.07(m,1H),5.05-4. 87(m,2H),4.80(dd,J=15.2,6.3Hz,1H),4.67(dd,J=15.2,3.3Hz,1H),4.53-4.44(m,1H),4.32-4.26(m,1H),4.19( s,2H),3.70-3.65(m,1H),3.57-3.46(m,2H),3.04-2.94(m,2H),2.89(s,2H),2.85-2.67(m,3H),2.41-2.33(m,1H).

[0319] Example 17: Synthesis of compound (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 17)

[0320]

[0321] The synthesis of compound 17 was performed using the same method as compound 1, with M9-4 replaced by M12 and M2 replaced by M1, resulting in compound 17.

[0322] MS(m / z): [M+H] + =621.2;

[0323] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.28(s,1H),7.81(s,1H),7.68(d,J=8.1Hz,2H),7. 50(s,1H),7.18(m,3H),6.75(d,J=17.1Hz,2H),5.06(m,1H),4.81(dd,J=15.4,7.2Hz,1H) ,4.66(d,J=15.1Hz,1H),4.47(d,J=7.1Hz,1H),4.36(d,J=8.6Hz,1H),3.94(s,1H),3.46- 3.40(m,2H),3.28-3.15(m,2H),3.05-2.91(m,3H),2.80-2.62(m,5H),2.45-2.31(m,2H).

[0324] Example 32: Synthesis of compound (S)-2-((4-(6-((2-fluoro-4-(1,3,3-trifluorocyclobutyl)phenyl)methoxy-d2)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 32)

[0325]

[0326] Step 1: Synthesis of (4-bromo-2-fluorophenyl)methane-2-ol (32-1)

[0327] Methyl 4-bromo-2-fluorobenzoate (3.2 g, 13.7 mmol) was dissolved in 20 mL of ultra-dry THF and cooled in an ice bath. LiAlD4 (580 mg, 13.7 mmol) was then added in portions. The ice bath was removed, and the mixture was stirred at room temperature for 30 min. After the reaction was complete as monitored by TLC, methanol was added to quench the reaction. The mixture was then directly stirred with silica gel and purified by Flash column chromatography to obtain compound 32-1 (2.8 g, 13.6 mmol).

[0328] Step 2: Synthesis of ((4-bromo-2-fluorophenyl)methoxy-d2)(tert-butyl)dimethylsilane (32-2)

[0329] Compound 32-1 (2.8 g, 13.6 mmol) was dissolved in DCM (30 mL), TEA (4 g, 40 mmol), and DMAP (1.66 g, 13.6 mmol), followed by the addition of TBSCl (2.4 g, 16.3 mmol). The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was washed three times with NH4Cl aqueous solution, dried over anhydrous sodium sulfate, mixed with silica gel, and purified by Flash column chromatography to obtain compound 32-2 (3.6 g, 11.2 mmol).

[0330] Step 3: Synthesis of 1-(4-(((tert-butyldimethylsiloxy)methyl-d2)-3-fluorophenyl)-3,3-difluorocyclobutane-1-ol (32-3):

[0331] Compound 32-2 (3.0 g, 9.3 mmol) and ultra-dry THF (20 mL) were added to a dried three-necked flask. Under nitrogen protection, the mixture was cooled to -78 °C for 10 min, followed by slow dropwise addition of n-butyllithium (4.5 mL, 11.2 mmol). The mixture was stirred at -78 °C for 30 min. Then, 3,3-difluorocyclohexanone (1 g, 10 mmol) was slowly added. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 3 h. After the reaction was monitored by TLC until complete, the reaction was quenched with ammonium chloride aqueous solution (10 mL), and extracted with ethyl acetate (twice, 30 mL each time). The combined organic phases were washed twice with saturated brine (10 mL each time). The organic phase was dried over anhydrous sodium sulfate and purified by Flash column chromatography to give compound 32-3 (500 mg, 1.43 mmol).

[0332] 1 H NMR (600MHz, DMSO-d6) δ7.44(t,J=7.9Hz,1H),7.30(dd,J=7.9,1.8Hz,1H),7.23(dd,J=11.6,1.8 Hz, 1H), 6.16 (s, 1H), 3.11-3.04 (m, 2H), 2.88 (td, J = 14.3, 10.7Hz, 2H), 0.89 (s, 9H), 0.20 (s, 6H).

[0333] Step 4: Synthesis of tert-butyl((2-fluoro-4-(1,3,3-trifluorocyclobutyl)phenyl)methoxy-d2)dimethylsilane (32-4)

[0334] Compound 32-3 (500 mg, 1.43 mmol) was dissolved in anhydrous DCM (5 mL) and cooled in an ice bath for 5 min. DAST (1.15 g, 7.15 mmol) was slowly added dropwise, and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was monitored by TLC until complete, the reaction was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL). The organic phase was washed twice with saturated brine (5 mL each time), dried over anhydrous sodium sulfate, and purified by Flash column chromatography to give compound 32-4 (285 mg, 0.81 mmol).

[0335] Step 5: Synthesis of (2-fluoro-4-(1,3,3-trifluorocyclobutyl)phenyl)methane-d2-ol (32-5)

[0336] Compound 32-4 (285 mg, 0.81 mmol) was dissolved in DMF (2 mL), and CsF (370 mg, 2.43 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction mixture was diluted with ethyl acetate (30 mL), washed three times with saturated brine (5 mL each time), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 32-5 (190 mg, 0.8 mmol).

[0337] Steps 6 to 9 were performed using the same synthetic method as compound 1 to obtain compound 32.

[0338] MS(m / z): [M+H] + =642.2;

[0339] 1 H NMR(600MHz,DMSO-d6)δ13.08(s,1H),8.16(s,1H),8.03(s,1H),7.64(s,2H),7.40(d,J= 10.9Hz,1H),7.34(d,J=8.0Hz,1H),6.95-6.85(m,1H),6.70(s,1H),5.17(s,1H),4.86(dd ,J=14.7,6.3Hz,1H),4.73(d,J=14.2Hz,1H),4.49(q,J=7.2Hz,1H),4.36(s,1H),3.96(m, 2H),3.42-3.37(m,3H),3.26(m,2H),2.95(m,2H),2.71(m,2H),2.17(m,3H),1.79(m,3H).

[0340] Example 34: Synthesis of compound (S)-2-(4-(6-((4-(3,3-difluoro-1-methylcyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-3-(oxacyclobutane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 34)

[0341]

[0342] The synthesis of compound 34 was performed by referring to the synthesis method of compound 10, except that M1-2 was replaced with M2-2, p-bromophenylacetic acid was replaced with 2-(4-bromo-2-fluorophenyl)acetic acid, and M9 was replaced with M11, thus obtaining compound 34.

[0343] MS(m / z): [M+H] + =647.1;

[0344] 1 H NMR(600MHz,DMSO-d6)δ8.03(d,J=8.2Hz,1H),7.97(d,J=8.2Hz,1H),7.95-7.88(m,2H),7.86-7.80 (m,1H),7.64(d,J=7.5Hz,1H),7.59-7.53(m,1H),7.49-7.43(m,1H),7.21-7.16(m,1H),7.15-7.11 (m,1H),6.86(d,J=8.2Hz,1H),5.51(s,2H),5.17-5.14(m,1H),4.76-4.58(m,3H),4.54-4.48(m,2H ),4.37-4.30(m,1H),2.94(q,J=14.5Hz,2H),2.79-2.69(m,3H),2.43(d,J=9.6Hz,1H),1.45(s,3H).

[0345] Example 35: Synthesis of compound (S)-2-(4-(6-((4-(3,3-difluoro-1-methylcyclobutyl)-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 35)

[0346]

[0347] The synthesis of compound 35 was performed using the same method as compound 10, with M9 replaced by M11, resulting in compound 35.

[0348] MS(m / z): [M+H] + =646.2;

[0349] 1 H NMR (600MHz, DMSO-d6) δ12.75(s,1H),8.25(d,J=1.6Hz,1H),7.94-7.88(m,2H),7.86-7.80(m,1H),7.79(dd,J=8.4,1.6Hz, 1H),7.64(d,J=7.5Hz,1H),7.61-7.53(m,2H),7.46-7.40(m,1H),7.19(dd,J=11.4,1.8Hz,1H),7.13(dd,J=7.8,1.8Hz,1H), 6.86(d,J=8.1Hz,1H),5.51(s,2H),5.08-5.01(m,1H),4.73(dd,J=15.6,7.2Hz,1H),4.60(dd,J=15.6,2.8Hz,1H),4.55-4. 47(m,2H),4.44(d,J=16.6Hz,1H),4.39-4.32(m,1H),2.99-2.88(m,2H),2.79-2.66(m,3H),2.42-2.34(m,1H),1.45(s,3H).

[0350] Example 36: Synthesis of compound (S)-2-((6-((4-(3,3-difluoro-1-methylcyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 36)

[0351]

[0352] The synthesis of compound 36 was performed using the same method as compound 1, with M9-4 replaced by M10, resulting in compound 36.

[0353] MS(m / z): [M+H] + =634.2;

[0354] 1H NMR (600MHz, DMSO-d6) δ8.32(d,J=8.3Hz,1H),8.11(d,J=8.3Hz,1H),7.79-7.74(m,1H),7.56-7.50(m,1H ),7.23-7.15(m,2H),7.12(dd,J=7.9,1.8Hz,1H),6.83-6.78(m,2H),5.42(s,2H),5.15-5.08(m,1H),5.0 0-4.97(m,2H),4.81(dd,J=15.2,6.3Hz,1H),4.68(dd,J=15.2,3.3Hz,1H),4.51-4.44(m,1H),4.33-4.26 (m,1H),4.17(s,2H),2.94-2.91(m,4H),2.80-2.67(m,3H),2.54(s,2H),2.42-2.33(m,1H),1.46(s,3H).

[0355] Example 37: Synthesis of compound (S)-2-((6-((4-(3,3-difluoro-1-methylcyclobutyl)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 37)

[0356]

[0357] The synthesis of compound 37 was performed using the same method as compound 1, with M9-4 replaced by M10 and M2 replaced by M1, resulting in compound 37.

[0358] MS(m / z): [M+H] + =633.1;

[0359] 1H NMR(600MHz,DMSO-d6)δ8.39(d,J=1.6Hz,1H),7.92(dd,J=8.4,1.5Hz,1H),7.83-7.74(m,2H),7.56-7 .50(m,1H),7.24-7.15(m,2H),7.12(dd,J=7.9,1.9Hz,1H),6.84-6.79(m,2H),5.42(s,2H),5.08-5.01 (m,1H),4.95(q,J=15.7Hz,2H),4.85-4.79(m,1H),4.71-4.66(m,1H),4.51-4.45(m,1H),4.36-4.30(m ,1H),4.21(s,2H),3.73(s,2H),2.99-2.93(m,4H),2.80-2.67(m,3H),2.37-2.28(m,1H),1.46(s,3H).

[0360] Example 38: Synthesis of compound (S)-2-((6-((4-(3,3-difluorocyclobutyl)-2,5-difluorophenyl)methoxy-d2)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 38)

[0361]

[0362] The synthesis of compound 38 was performed using the same method as compound 1, with M9-4 replaced by M13 and M2 replaced by M1, resulting in compound 38.

[0363] MS(m / z): [M+H] + =639.2;

[0364] 1 H NMR(600MHz, DMSO-d6)δ8.39(s,1H),7.92(dd,J=8.5,1.6Hz,1H),7.83-7.75(m,2H),7.37(ddd,J=13 .2,10.2,6.1Hz,2H),7.22(d,J=7.5Hz,1H),6.84(d,J=8.2Hz,1H),6.81-6.78(m,1H),5.08-5.01(m,

[0365] 1H),5.00-4.87(m,2H),4.86-4.78(m,1H),4.68(dd,J=15.7,2.7Hz,1H),4.50-4.44(m,1H),4.36-4.27(m,1H),4.21 (s,2H),3.81-3.63(m,2H),3.57-3.48(m,1H),3.04-2.94(m,2H),2.90(s,2H),2.85-2.67(m,3H),2.37-2.28(m,1H).

[0366] Example 39: Synthesis of compound (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2,5-difluorophenyl)methoxy-d2)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 39)

[0367]

[0368] The synthesis of compound 39 was performed by referring to the synthesis method of compound 10, except that M1-2 was replaced with M2-2, p-bromophenylacetic acid was replaced with 2-(4-bromo-2-fluorophenyl)acetic acid, and M9 was replaced with M14, thus obtaining compound 39.

[0369] MS(m / z): [M+H] + =653.1;

[0370] 1 H NMR (600MHz, Methanol-d4) δ8.14(d,J=8.2Hz,1H),8.07(d,J=8.2Hz,1H),7.86-7.82(m,2H),7.78-7.72(m,1H ),7.53-7.48(m,1H),7.38(t,J=7.9Hz,1H),7.27-7.21(m,1H),7.14(dd,J=10.3,6.2Hz,1H),6.82(d,J=8.2Hz ,1H),5.28-5.22(m,1H),4.80-4.76(m,1H),4.73-4.67(m,2H),4.66-4.59(m,1H),4.56(d,J=17.0Hz,1H),4.4 8-4.42(m,1H),3.56-3.48(m,1H),3.01-2.91(m,2H),2.83-2.76(m,1H),2.76-2.66(m,2H),2.54-2.45(m,1H).

[0371] Example 40: Synthesis of compound (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyridin-2-yl)-2-fluorobenzyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 40)

[0372]

[0373] The synthesis of compound 40 was performed by referring to the synthesis method of compound 10, except that M1-2 was replaced with M2-2, p-bromophenylacetic acid was replaced with 2-(4-bromo-2-fluorophenyl)acetic acid, and M9 was replaced with M15, thus obtaining compound 40.

[0374] MS(m / z):[M+H] + =635.2;

[0375] 1 H NMR (600MHz, DMSO-d6) δ8.07(d,J=8.2Hz,1H),7.98(d,J=8.1Hz,1H),7.92(t,J=9.2Hz,2H),7.82(t,J=7.9Hz, 1H),7.64(d,J=7.4Hz,1H),7.54(t,J=7.7Hz,1H),7.46(t,J=8.0Hz,1H),7.23(d,J=11.1Hz,1H),7.16(d,J=7.9 Hz,1H),6.86(d,J=8.1Hz,1H),5.17-5.14(m,1H),4.74(dd,J=15.2,6.5Hz,1H),4.66-4.60(m,2H),4.53(d,J=1 6.1Hz,2H),4.40-4.34(m,1H),3.46-3.40(m,1H),3.00-2.95(m,2H),2.75-2.69(m,3H),2.45(d,J=7.6Hz,1H).

[0376] Example 41: Synthesis of compound (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 41)

[0377]

[0378] The synthesis of compound 41 was performed using the same method as compound 10, except that p-bromophenylacetic acid was replaced with 2-(4-bromo-2,5-difluorophenyl)acetic acid and M9 was replaced with M15, thus yielding compound 41.

[0379] MS(m / z):[M+H] + =652.1;

[0380] 1 H NMR (600MHz, DMSO-d6) δ8.39 (s, 1H), 7.91-7.84 (m, 3H), 7.68 (d, J = 8.5Hz, 1H), 7.54-7.44 (m, 3H), 7.2 4(d,J=11.3Hz,1H),7.17(d,J=8.0Hz,1H),6.93(d,J=8.2Hz,1H),5.13-5.06(m,1H),4.87(dd,J=15.5, 7.3Hz,1H),4.72(dd,J=15.6,2.7Hz,1H),4.64(d,J=17.0Hz,1H),4.57(d,J=17.0Hz,1H),4.54-4.48( m,1H),4.45-4.36(m,1H),3.48-3.40(m,1H),3.03-2.93(m,2H),2.78-2.65(m,3H),2.46-2.37(m,1H).

[0381] Example 43: Synthesis of compound (S)-2-((4-(2-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 43)

[0382]

[0383] Step 1: Synthesis of tert-butyl 4-(2-chloropyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (43-1)

[0384] 2,4-Dichloropyrimidine (2 g, 13.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4.15 g, 13.4 mmol), Pd(dppf)Cl2 (390 mg, 0.53 mmol), and NaHCO3 (1.7 g, 20 mmol) were dissolved in a mixed solvent of dioxane (25 mL) and water (5 mL). The mixture was purged with nitrogen and protected, and the reaction was carried out at 90 °C for 4 h. After the reaction was completed by TLC monitoring, the mixture was diluted with EA (100 mL), washed twice with saturated brine (20 mL each time), and the organic phase was dried over anhydrous sodium sulfate. The mixture was purified by Flash column chromatography (0-50% EA / PE) to give compound 43-1 (2.4 g, 8.1 mmol).

[0385] MS(m / z): [M+H] + =296.2.

[0386] Step 2: Synthesis of tert-butyl 4-(2-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (43-2)

[0387] Compound 43-1 (136 mg, 0.46 mmol), M12 (100 mg, 0.46 mmol), Pd2(dba)3 (142 mg, 0.16 mmol), RuPhos (42 mg, 0.1 mmol), and Cs2CO3 (300 mg, 0.92 mmol) were dissolved in toluene (5 mL), purged with nitrogen for protection, and heated to 110 °C with stirring overnight. After the reaction was complete as monitored by TLC, the toluene was removed by concentration, and the mixture was purified by Flash column chromatography (0-50% EA / PE) to give compound 43-2 (140 mg, 0.29 mmol).

[0388] MS(m / z): [M+H] + =478.2.

[0389] The synthesis of compound 43 was prepared by referring to the synthesis method of compound 1 in steps 3 to 5.

[0390] MS(m / z): [M+H] + =622.2;

[0391] 1H NMR (600MHz, DMSO-d6) δ12.91(s,1H),8.61(d,J=5.1Hz,1H),8.35(s,1H),7.88(d,J=8.4Hz,1H),7.76(d,J=8 .2Hz,1H),7.51(t,J=7.8Hz,1H),7.34(s,1H),7.24(d,J=11.2Hz,1H),7.17(d,J=7.9Hz,1H),7.03(d,J=3.8Hz ,1H),5.04(qd,J=7.2,2.6Hz,1H),4.81(dd,J=15.5,7.2Hz,1H),4.67(dd,J=15.6,2.8Hz,1H),4.50-4.43(m,1 H), 4.34 (dt, J = 9.1, 6.0Hz, 1H), 3.46-3.43 (m, 4H), 2.99 (m, 3H), 2.85-2.65 (m, 5H), 2.35 (m, 2H), 1.99 (m, 1H).

[0392] Example 44: Synthesis of compound (S)-2-((4-(4-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 44)

[0393]

[0394] Step 1: Synthesis of 2-chloro-4-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidine (44-1)

[0395] M12 (110 mg, 0.5 mmol), 2,4-dichloropyrimidine (75 mg, 0.5 mmol), cesium carbonate (330 mg, 1 mmol), and DMF (5 mL) were added to a dried single-necked flask. The mixture was reacted at 90 °C for 4 hours under nitrogen protection. Water (10 mL) and EA (10 mL) were added, and the mixture was stirred and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Flash column chromatography to give compound 44-1 (100 mg, 0.3 mmol).

[0396] MS(m / z): [M+H] + =331.2.

[0397] Step 2: Synthesis of tert-butyl 4-(4-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (44-2)

[0398] Compound 44-1 (100 mg, 0.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (90 mg, 0.3 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), cesium carbonate (200 mg, 0.6 mmol), dioxane (5 mL), and H2O (1 mL) were added to a single-necked flask. The mixture was purged with nitrogen three times and reacted at 100 °C for 6 hours under nitrogen protection. After the reaction was complete as monitored by TLC, the mixture was diluted with EA (10 mL), washed three times with 10 mL of brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was purified by Flash column chromatography (0-50% EA / PE) to give compound 44-2 (100 mg, 0.2 mmol).

[0399] MS(m / z): [M+H] + =478.2;

[0400] The synthesis of compound 44 was prepared by referring to the synthesis method of compound 1 in steps 3 to 5.

[0401] MS(m / z): [M+H] + =622.1;

[0402] 1 H NMR (600MHz, DMSO-d6) δ8.49(d,J=6.0Hz,1H),8.25(s,1H),7.81(d,J=12.0Hz,1H),7.65(d,J=6.0Hz,1H),7.52(t,J=6.0Hz, 1H),7.23(d,J=12.0Hz,1H),7.20-7.13(m,2H),6.78(d,J=6.0Hz,1H),5.07(d,J=6.0Hz,1H),4.80(dd,J=12.0,6.0Hz,1H),4 .65(d,J=18.0Hz,1H),4.51-4.43(m,1H),4.41-4.33(m,1H),4.09(d,J=12.0Hz,1H),3.93(d,J=18.0Hz,1H),3.44(q,J=12.0 ,6.0Hz,2H),3.24(s,1H),2.97(tdd,J=18.0,12.0,6.0Hz,2H),2.79-2.62(m,5H),2.60(s,2H),2.40(dt,J=18.0,6.0Hz,1H).

[0403] Example 45: Synthesis of compound (S)-2-((4-(6-((4-(3,3-difluorocyclobut-1-en-1-yl)-2-fluorophenyl)methoxy-d2)pyridin-2-yl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 45)

[0404]

[0405] The synthesis of compound 45 is based on the synthesis method of compound 32, wherein intermediate 45-1 is another product of step 6 in the synthesis of compound 32.

[0406] MS(m / z): [M+H] + =622.3;

[0407] 1 H NMR (600MHz, DMSO-d6) δ13.17(s,1H),8.30(s,1H),8.08(s,1H),7.68(d,J=11.8Hz,2H),7.50( d,J=10.5Hz,1H),7.40(d,J=7.8Hz,1H),6.92(s,1H),6.75(s,1H),6.67(s,1H),5.13(s,1H),4. 92(s,2H),4.84(dd,J=15.5,6.0Hz,1H),4.70(d,J=16.3Hz,1H),4.48(t,J=7.4Hz,1H),4.32(s, 1H),3.88(m,3H),2.94(m,2H),2.71(m,2H),2.45-2.32(m,1H),2.10(m,3H),2.02-1.84(m,2H).

[0408] Example 46: Synthesis of compound (S)-2-((4-(4-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 46)

[0409]

[0410] Compound 46 was synthesized using the same method as compound 44, except that M1 was replaced with M2, resulting in compound 46.

[0411] MS(m / z): [M+H] + =623.2;

[0412] 1 H NMR (600MHz, DMSO-d6) δ8.49(d,J=6.0Hz,1H),8.11(d,J=6.0Hz,1H),8.00(d,J=12.0Hz,1H),7.52(t,J=6.0Hz,1H), 7.23(d,J=6.0Hz,1H),7.19(s,1H),7.16(d,J=6.0Hz,1H),6.79(d,J=6.0Hz,1H),5.16(s,1H),4.82(dd,J=12.0,6.0 Hz,1H),4.72(d,J=12.0Hz,1H),4.47(q,J=6.0Hz,1H),4.31(d,J=12.0Hz,1H),4.11(d,J=18.0Hz,1H),4.04(d,J=12 .0Hz,1H),3.48-3.41(m,2H),2.97(m,3H),2.76(q,J=6.0Hz,2H),2.73-2.63(m,3H),2.61(s,2H),2.48-2.43(m,1H).

[0413] Example 47: Synthesis of compound (S)-2-(4-(2-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-4-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 47)

[0414]

[0415] Step 1: Synthesis of (S)-2-(4-(2-chloropyrimidin-4-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (47-1)

[0416] 2,4-Dichloropyrimidine (120 mg, 0.8 mmol), intermediate 10⁻³ (380 mg, 0.8 mmol), Pd(dppf)Cl₂ (60 mg, 0.08 mmol), NaHCO₃ (170 mg, 2 mmol), Dioxane (5 mL), and H₂O (1 mL) were added to a single-necked flask and stirred. The mixture was then purged with nitrogen and heated to 100 °C overnight under nitrogen protection. After cooling, the mixture was filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (15 mL) were added. The mixture was stirred and separated. The organic phase was washed three times with 5 mL of brine, dried over anhydrous sodium sulfate, and purified by Flash column chromatography (0-50% ethyl acetate / petroleum ether) to give compound 47⁻¹ (140 mg, 0.3 mmol).

[0417] MS(m / z): [M+H]+ =467.1;

[0418] Step 2: Synthesis of (S)-2-(4-(2-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-4-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (47-2)

[0419] Compound 47-1 (140 mg, 0.3 mmol), M12 (65 mg, 0.3 mmol), Pd2dba3 (27 mg, 0.03 mmol), RuPhos (28 mg, 0.06 mmol), Cs2CO3 (200 mg, 0.6 mmol), and Dioxane (5 mL) were added to a dried single-necked flask. The mixture was purged with nitrogen and heated to 110 °C under nitrogen protection with stirring overnight. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (10 mL), filtered, and the filtrate was directly purified by flash column chromatography (0-60% EtOAc) to obtain compound 47-2 (90 mg, 0.14 mmol).

[0420] MS(m / z): [M+H] + =649.2;

[0421] The synthesis of step 3 followed the synthesis of compound 1, yielding compound 47 (20 mg, 0.03 mmol).

[0422] MS(m / z): [M+H] + =635.2;

[0423] 1H NMR (600MHz, DMSO-d6) δ12.96(s,1H),8.73(d,J=5.0Hz,1H),8.36(s,1H),8.11-8.04(m,2H),7.88(d,J=8.4Hz,1H),7.81(d,J=5. 1Hz,1H),7.65(d,J=8.5Hz,1H),7.56(td,J=7.8,3.6Hz,2H),7.25(dd,J=11.3,1.7Hz,1H),7.18(dd,J=7.9,1.7Hz,1H),5.07(qd, J=7.2,2.6Hz,1H),4.83(dd,J=15.5,7.3Hz,1H),4.73-4.62(m,2H),4.58(d,J=16.9Hz,1H),4.53-4.47(m,1H),4.38(dt,J=9.1,6 .1Hz,1H),3.45(dq,J=17.5,8.8,8.3Hz,1H),2.99(dtt,J=14.1,9.0,5.1Hz,2H),2.77-2.65(m,3H),2.40(dq,J=12.0,7.7Hz,1H).

[0424] Example 48. Synthesis of compound (S)-2-(4-(2-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-4-yl)-2-fluorobenzyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (48)

[0425]

[0426] The synthesis of compound 48 was performed with reference to the synthesis of compound 47, except that intermediate 10-3 was replaced with 39-3, and compound 48 was finally obtained.

[0427] MS(m / z): [M+H] + =636.1;

[0428] 1H NMR(600MHz,DMSO-d6)δ13.02(s,1H),8.72(d,J=5.1Hz,1H),8.10-8.02(m,3H),7.98(d,J=8.2Hz,1H),7 .80(d,J=5.3Hz,1H),7.55(q,J=7.8Hz,2H),7.25(dd,J=11.3,1.7Hz,1H),7.19(dd,J=7.9,1.7Hz,1H),5 .15(qd,J=6.6,3.4Hz,1H),4.75(dd,J=15.1,6.5Hz,1H),4.69-4.61(m,2H),4.59-4.55(m,1H),4.53-4. 48(m,1H),4.39-4.29(m,1H),3.45(dd,J=12.4,5.4Hz,1H),2.99(m,2H),2.71(m,3H),2.47-2.40(m,1H).

[0429] Example 50: Synthesis of compound (S)-2-(4-(4-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 50)

[0430]

[0431] Step 1: Synthesis of (S)-2-(4-(4-((4-(3,3-difluorocyclobutyl)-2-fluorophenyl)methoxy-d2)pyrimidin-2-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (50-1)

[0432] Intermediate 10⁻³ (120 mg, 0.24 mmol), 44⁻¹ (66 mg, 0.2 mmol), Pd(dppf)Cl₂ (15 mg, 0.02 mmol), NaHCO₃ (42 mg, 0.5 mmol), Dioxane (5 mL), and H₂O (1 mL) were added sequentially to a single-necked flask and stirred. The mixture was then purged with nitrogen and heated to 100 °C overnight under nitrogen protection. After cooling, the mixture was filtered through diatomaceous earth, and ethyl acetate (10 mL) and water (15 mL) were added. The mixture was stirred and separated. The organic phase was washed three times with 5 mL of brine, dried over anhydrous sodium sulfate, and purified by Flash column chromatography (0-50% ethyl acetate / petroleum ether) to give compound 50⁻¹ (60 mg, 0.09 mmol).

[0433] MS(m / z): [M+H] + =649.2.

[0434] Step 2: Following the synthesis method of compound 1, compound 50 (18 mg, 0.03 mmol) was prepared.

[0435] MS(m / z): [M+H] + =635.2;

[0436] 1 H NMR (600MHz, DMSO-d6) δ8.65(d,J=6.0Hz,1H),8.22(d,J=12.0Hz,2H),8.14(d,J=12.0Hz,1H),7.79(d,J=6. 0Hz,1H),7.60-7.54(m,2H),7.49(t,J=6.0Hz,1H),7.26(d,J=12.0Hz,1H),7.19(d,J=6.0Hz,1H),6.95(d,J= 6.0Hz,1H),5.05(q,J=12.0,6.0Hz,1H),4.71(dd,J=12.0,6.0Hz,1H),4.62-4.52(m,2H),4.52-4.43(m,2H) ,4.38-4.32(m,1H),3.46(m,1H),2.98(tdd,J=18.0,12.0,6.0Hz,2H),2.76-2.66(m,3H),2.42-2.34(m,1H).

[0437] Example 51: Synthesis of compound (S)-2-((6-((4-(3,3-difluorocyclobutyl)-3,5-difluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxacyclobutane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 51)

[0438]

[0439] The synthesis of compound 51 was performed by referring to the synthesis of compound 1, except that M9-4 was replaced with M16, and compound 51 was finally obtained.

[0440] MS(m / z): [M+H] + =638.2;

[0441] 1H NMR (600MHz, DMSO-d6) δ13.05(s,1H),8.23(s,1H),8.07-8.03(m,1H),7.73(t,J=7.9H z,1H),7.27-7.03(m,3H),6.89-6.69(m,2H),5.38(s,2H),5.14(s,1H),4.84(dd,J=14 .9,6.5Hz,1H),4.71(d,J=15.0Hz,1H),4.504.44(m,1H),4.39-3.99(m,3H),3.61-3.5 0(m,1H),3.31-3.16(m,4H),3.09-2.84(m,5H),2.77-2.59(m,2H),2.45-2.42(m,1H).

[0442] Example 52: Synthesis of compound (S)-2-((6-((4-(3,3-difluorocyclobutyl-1-d)-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 52)

[0443]

[0444] Step 1: Synthesis of 3-(benzyloxy)cyclobut-1-d-1-ol (52-1)

[0445] Add LAD (305 mg, 7.3 mmol) and ultra-dry THF (10 mL) to a dried single-necked flask, cool in an ice bath, and slowly add a THF (5 mL) solution of 3-(benzyloxy)cyclobutanone (1.0 g, 5.6 mmol). Stir overnight after the addition is complete. The next day, cool the reaction solution, add water (1 mL) to quench the reaction, add anhydrous sodium sulfate, stir for 30 min, filter with diatomaceous earth, and wash the filter cake with ethyl acetate. Collect the filtrate and concentrate under reduced pressure to obtain compound 52-1 (1 g, 5.5 mmol).

[0446] 1 H NMR (600MHz, DMSO-d6) δ7.39-7.20(m,5H),4.99(s,1H),4.33(s,2H),3.58-3.49(m,1H),2.55-2.48(m,2H),1.76-1.70(m,2H).

[0447] Step 2: Synthesis of ((3-iodocyclobutoxy-3-d)methyl)benzene (52-2)

[0448] Compound 52-1 (1 g, 5.5 mmol), imidazole (1.1 g, 17 mmol), PPh3 (2.88 g, 11 mmol), elemental iodine (2.1 g, 8.25 mmol), and toluene (20 mL) were added to a dried single-necked flask. The mixture was stirred and heated to 100 °C for 2 hours. After cooling, ethyl acetate and water were added, stirred, and separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting semi-solid mixture was then slurried with methyl tert-butyl ether, filtered to remove most of the triphenylphosphine oxide, and the filtrate was purified by Flash column chromatography to give compound 52-2 (1.1 g, 4 mmol, cis-trans isomer mixture).

[0449] 1 H NMR(600MHz,DMSO-d6)δ7.39-7.26(m,5H),4.48-4.41(m,0.6H),4.37(s,1.2H),4.36(s,0.8H),4.05- 3.98(m,0.4H),3.01-2.95(m,0.8H),2.69-2.63(m,1.2H),2.62-2.56(m,1.2H),2.45-2.38(m,0.8H).

[0450] Step 3: Synthesis of methyl 4-(3-(benzyloxy)cyclobutyl-1-d)-2-fluorobenzoate (52-3)

[0451] Compound 52-2 (290 mg, 1 mmol), NiI2 (62 mg, 0.2 mmol), pyridinium amidine hydrochloride (31 mg, 0.2 mmol), zinc powder (112 mg, 2 mmol), and DMA (5 mL) were added to a dried, pressure-resistant reaction tube. After bubbling with nitrogen for 5 min, ((3-iodocyclobutoxy-3-d)methyl)benzene (230 mg, 1 mmol), NaI (75 mg, 0.5 mmol), and TFA (70 mg) were added. After the addition was complete, the reaction tube was sealed and stirred at 100 °C for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate (10 mL), filtered through diatomaceous earth, and the filtrate was washed with brine (3 times, 10 mL each time). Flash purification (0-15% EA / PE) was performed to obtain compound 52-3 (150 mg, 0.47 mmol, cis-trans isomer mixture).

[0452] MS(m / z): [M+H] + =316.0;

[0453] 1H NMR (600MHz, DMSO-d6) δ7.85-7.79(m,1H),7.38-7.32(m,4H),7.31-7.26(m,1H),7.26-7.18(m,2H),4.43-4.39(m,2H),4.24(tt,J=6.9,5.2 Hz, 0.5H), 4.02 (tt, J = 7.9, 6.6 Hz, 0.5H), 3.83 (d, J = 1.8 Hz, 3H), 2.67-2.61 (m, 1H), 2.46-2.40 (m, 1H), 2.39-2.32 (m, 1H), 1.99-1.93 (m, 1H).

[0454] Step 4: Synthesis of methyl 2-fluoro-4-(3-hydroxycyclobutyl-1-d)benzoate (52-4)

[0455] Nitrogen gas was introduced into a single-necked flask, and compound 52-3 (150 mg, 0.47 mmol), methanol (5 mL), and wet palladium on carbon (30 mg) were added. A hydrogen balloon was placed on top, and the mixture was purged with hydrogen three times. The reaction was carried out under a hydrogen atmosphere for 18 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 52-4 (95 mg, 0.42 mmol, a mixture of cis and trans isomers).

[0456] 1 H NMR(600MHz,DMSO-d6)δ7.85-7.79(m,1H),7.24-7.17(m,2H),5.15-5.11(m,1H),4.35-4.27(m,0 .4H),4.08-3.99(m,0.6H),3.83(s,3H),2.63-2.57(m,1H),2.36-2.26(m,2H),1.92-1.86(m,1H).

[0457] Step 5: Synthesis of methyl 2-fluoro-4-(3-oxocyclobutyl-1-d)benzoate (52-5)

[0458] DCM (15 mL) and DMP (1.0 g, 2.4 mmol) were added to a single-necked flask containing compound 52-4 (450 mg, 2.0 mmol). The mixture was stirred at room temperature for 2 hours. Sodium sulfite solution (15 mL) and sodium bicarbonate solution (15 mL) were added, and the mixture was stirred for 30 minutes before separation. The organic phase was dried over anhydrous sodium sulfate and purified by Flash column chromatography (0-50% EA / PE) to give compound 52-5 (400 mg, 1.8 mmol).

[0459] 1H NMR(600MHz,DMSO-d6)δ7.86(t,J=7.9Hz,1H),7.43(dd,J=12.3,1.7Hz,1H),7 .35(dd,J=8.0,1.7Hz,1H),3.84(s,3H),3.47-3.40(m,2H),3.31-3.25(m,2H).

[0460] Following the synthetic steps of compound 1 in steps 6-9, compound 52 was prepared.

[0461] MS(m / z): [M+H] + =621.2;

[0462] 1 H NMR (600MHz, Methanol-d4) δ8.30-8.25(m,1H),8.25-8.20(m,1H),7.70(t,J=7.8Hz,1H),7.46(t,J=7 .8Hz,1H),7.19(d,J=7.4Hz,1H),7.12-7.04(m,2H),6.81-6.76(m,2H),5.46(s,2H),5.25-5.18(m,1H) ,5.04(s,2H),4.85-4.73(m,2H),4.66-4.59(m,1H),4.41-4.32(m,1H),4.32-4.23(m,2H),3.89-3.72( m,2H),3.07-3.04(m,2H),3.03-2.93(m,2H),2.83-2.74(m,1H),2.71-2.59(m,2H),2.53-2.45(m,1H).

[0463] Example 54: Synthesis of (S)-2-(4-(6-((4-(3,3-difluorocyclobutyl)-3,5-difluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 54)

[0464]

[0465] The synthesis of compound 54 was based on the synthesis of compound 10, except that M9 was replaced with M16 and p-bromophenylacetic acid was replaced with 2-(4-bromo-2-fluorophenyl)acetic acid, thus yielding compound 54.

[0466] MS(m / z): [M+H] + =650.1;

[0467] 1H NMR(600MHz,DMSO-d6)δ8.24(s,1H),7.90-7.82(m,3H),7.79(d,J=8.4Hz,1 H),7.64(d,J=7.5Hz,1H),7.58(d,J=8.4Hz,1H),7.42(t,J=7.9Hz,1H),7.2 3(d,J=8.9Hz,2H),6.92(d,J=8.2Hz,1H),5.48(s,2H),5.04(d,J=7.6Hz,1H ),4.75-4.68(m,1H),4.59(d,J=15.3Hz,1H),4.54-4.46(m,2H),4.43(d,J=

[0468] 16.8Hz, 1H), 4.35 (q, J = 6.6Hz, 1H), 3.62-3.53 (m, 1H), 3.03-2.89 (m, 4H), 2.74-2.66 (m, 1H), 2.42-2.33 (m, 1H).

[0469] Example 55: Synthesis of (S)-2-((6-((4-(3,3-difluorocyclobutyl)-3,5-difluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (compound 55)

[0470]

[0471] The synthesis of compound 55 was performed by referring to the synthesis of compound 1, except that M9-4 was replaced with M16-4 and M2 was replaced with M1, thus obtaining compound 55.

[0472] MS(m / z): [M+H] + =637.2;

[0473] 1H NMR(600MHz,DMSO-d6)δ12.98(s,1H),8.34(s,1H),7.87(d,J=8.5Hz,1H),7.76-7.73(m,2 H),7.18(d,J=8.8Hz,3H),6.89-6.68(m,2H),5.38(s,2H),5.07-5.03(m,1H),4.88-4.82( m,1H),4.73-4.67(m,1H),4.50-4.43(m,1H),4.38-4.32(m,1H),4.01-3.81(m,2H),3.61- 3.52(m,1H),3.33-3.17(m,3H),3.05-2.86(m,5H),2.84-2.61(m,3H),2.40-2.34(m,1H).

[0474] Biological tests

[0475] Example 1: Evaluation of GLP-1 receptor agonist activity

[0476] 1) Testing Principle

[0477] This experiment uses cAMP Hunter TM The CHO-K1 GLP1R Gs cell line (DiscoverX, 95-0062C2) overexpresses wild-type GPCRs coupled to Gs. Under the influence of the compound, the downstream signaling pathway of GLP-1R is activated, leading to an increase in cAMP levels. CAMP levels in the cells were detected using an HTRF (uniform time-resolved fluorescence) cAMP assay kit (CisBio) to reflect the activity of the compound in activating the GLP-1 receptor. This method involves a competitive immunoassay between naturally occurring cAMP produced by the cells and exogenous cAMP labeled with dye d2. Tracker binding is indicated by anti-cAMP activity using a cryptotate-labeled mAb. A specific signal (i.e., energy transfer) is inversely proportional to the cAMP concentration in the standard live assay sample.

[0478] 2) Test methods

[0479] The test compound was dissolved in DMSO to prepare a stock solution with an initial concentration of 10 mM. For small molecule compounds, the initial concentration was 0.2 mM, diluted 4-fold, and diluted 10 times. DMSO was used as a solvent control. 100 nL of the test sample (Echo) at different concentrations was added to each well of a 384-well plate, with two replicates for each sample.

[0480] cAMP Hunter TMCHO-K1 GLP1R Gs cells were digested, centrifuged, and resuspended in analytical buffer (5 mM HEPES, 0.01 mM IBMX, 0.1% BSA, 1×HBSS). The viable cell density was adjusted to 1 x 10⁻⁶ cells / cells. 5 Cells / mL. Add 10 μL of cells to each well of a 384-well plate, centrifuge at 600 rpm for 3 min, and incubate at room temperature for 60 min.

[0481] Add 5 μL of 4X Eu-cAMP tracer solution and 5 μL of 4X ULight to each well. TM - Anti-cAMP solution. After centrifugation at 600 rpm for 3 min, incubate at room temperature for 60 min. Use an Envision multi-label plate reader to read changes in the HTRF signal using 330 nm excitation and 615 nm luminescence.

[0482] Raw data were converted to nM cAMP by interpolation from the cAMP standard curve, and the percentage of effect relative to the saturation concentration of the full agonist GLP-17-37 (10 nM) contained in each plate was determined. EC50 was performed on the agonist dose-response curves analyzed using a curve fitting procedure with a four-parameter logarithmic dose-response equation. 50 Confirmed, results are shown in Table 1.

[0483] Table 1 EC50 of the compounds of the present invention against GLP-1 receptor agonists 50 value

[0484]

[0485]

[0486] As can be seen from Table 1, the compounds of the present invention have a potent agonistic effect on the GLP-1 receptor.

[0487] Example 2: Pharmacokinetic Characteristics of Rats

[0488] Experimental materials:

[0489] SD rats (SPF grade, male) were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. The experimental animals weighed between 180-260g and were 6-10 weeks old.

[0490] Danuglipron (PF-06882961): Purchased from Shanghai Loulan Biotechnology Co., Ltd.

[0491] Experimental methods:

[0492] The pharmacokinetic characteristics of the test compound in rats after intravenous and oral administration were investigated. The compound was administered to rats via single gavage and single intravenous injection in a solvent of 10% DMSO + 50% PEG400 + 40% Saline, with three animals per route of administration. The gavage dose was 5 mg / kg, and the intravenous dose was 1 mg / kg. Whole blood samples were collected within 24 hours. Plasma samples were obtained by centrifugation at 2000 g / min for 10 min at 4℃. 50 μL of plasma sample was taken, and 5 μL of internal standard solution (100 ng / mL rameltein 50% methanol aqueous solution) was added. A certain amount of methanol was added to precipitate proteins, followed by vortexing at 2500 rpm for 1 min. Finally, the mixture was centrifuged at 17000 g for 10 min at 4℃, and 180 μL of the supernatant was collected for quantitative analysis of plasma drug concentration using LC-MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.4 software based on the plasma drug concentration data at different time points, providing T0. 1 / 2 C max AUC last The parameters Cl_obs, Cl_F_obs, F, and their average values ​​are shown in Table 2 below.

[0493] Table 2

[0494]

[0495]

[0496] As can be seen from Table 2, compared with Danuglipron, compound 1 of the present invention has a lower clearance rate, higher exposure and better oral bioavailability.

[0497] While the invention has been fully described through its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims.

Claims

1. A compound represented by general formula (F), or a stereoisomer, tautomer, deuterated derivative, or pharmaceutical salt thereof: in, The ring A is selected from benzene, 5-6 membered heterocyclic groups, and 5-6 membered heteroaryl groups. The ring A can be arbitrarily divided by one or more R groups. a Replaced; The R a Each group is independently selected from H, D, oxo group, hydroxyl group, amino group, cyano group, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, 3-6 membered heterocyclic groups, C 3-6 cycloalkyl or C 2-6 alkynyl group; the C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic group, C 3-6 The cycloalkyl group may optionally be further surrounded by one or more 3-6 membered heterocyclic groups, C 3-6 cycloalkyl, C 1-6 Alkoxy, hydroxy, amino, cyano, halogen, C 1-6 Haloalkyl, C 1-6 Alkyl or halogen substituted; Alternatively, any two Rs substituted on ring A a The atoms to which it is attached can form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups; The ring B is selected from phenyl or 5-6 heteroaryl; the ring B may be further arbitrarily converted by one or more R a Replaced; X1 is selected from CR2 or N; X2 is selected from CR3 or N; X3 is selected from CR4 or N; X4 is selected from CR5 or N, and at most two of X1, X2, X3, and X4 are N at the same time; R2, R3, R4, and R5 are each independently selected from H, D, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 2-4 alkynyl group, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Alternatively, R2 and R3, along with the atoms they are attached to, together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group may optionally be further bonded by one or more R... a Replaced; Alternatively, R4 and R5, along with the atoms they are attached to, together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group may optionally be further bonded by one or more R4 groups. a Replaced; R1 is selected from H, D, halogens, hydroxyl groups, and C. 1-6 Alkyl, amino, or cyano groups; R6 and R7 are each independently selected from H, D, halogens, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Y1 is selected from N or CR. 17 ; The Y2 is selected from N or CR8; The Y3 is selected from N or CR9; The Y4 is selected from N or CR. 10 ; The R8, R9, R 10 R 17 Each group is independently selected from H, D, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; The R 11 R 12 R 13 R 14 R 15 R 16 R 18 R 19 Each element is independently selected from H, D, halogens, and C. 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Or, R 11 R 12 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl; the C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a Replaced; Or, R 13 R 14 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl; the C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a Replaced; Or, R 15 R 16 Together with the C atoms it is attached to, they form C 3-6 Cycloalkyl or 3-12 membered heterocycloalkyl; the C 3-6 Cycloalkyl or 3-12-membered heterocycloalkyl groups may optionally be further reacted with one or more R a What it replaced.

2. The compound represented by general formula (F) according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The general formula (F) is selected from the compounds shown in (FI), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts: Among them, ring A, ring B, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R a The definition is as described in claim 1.

3. The compound of formula (FI) according to claim 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, Compounds of formula (FI) are selected from compounds of formula (F-IA), (F-IB), or (F-IC), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts: Among them, ring A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 R 11 R 12 R 13 R 14 R 15 R 16 R a The definition is as described in claim 1.

4. The compound represented by general formula (F) according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The general formula (F) is selected from compounds represented by (F-II), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts: Among them, ring A, ring B, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R a The definition is as described in claim 1.

5. The compound represented by general formula (F) according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The general formula (F) is selected from compounds represented by (F-III), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts: Among them, ring A, ring B, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 R 12 R 13 R 14 R 15 R 16 R a The definition is as described in claim 1.

6. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound of formula (F-IA) is selected from the compound of formula (F-IA-1), or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts: Among them, ring A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 The definition is as described in claim 1.

7. The compound according to any one of claims 1-6, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The ring A is selected from phenyl, 5-6 nitrogen-containing heteroaryl, or 5-6 membered nitrogen-containing heterocyclic group. The phenyl, 5-6 nitrogen-containing heteroaryl, or 5-6 membered nitrogen-containing heterocyclic group can be arbitrarily replaced by one or more R groups. a The R that was replaced a Each group is independently selected from H, D, hydroxyl, amino, cyano, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

8. The compound according to claim 7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The ring A is selected from The It can be optionally further modified by one or more R a The R that was replaced a Each element is independently selected from H, D, halogens, or C. 1-6 alkyl.

9. The compound according to any one of claims 1-8, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The Selected from in The B-ring portion in the middle can be optionally further divided by one or more R... a The R that was replaced a Each element is independently selected from H, D, halogens, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, 3-6 membered heterocyclic groups, C 3-6 cycloalkyl or C 2-6 alkynyl group; the C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic group, C 3-6 The cycloalkyl group may optionally be further surrounded by one or more 3-6 membered heterocyclic groups, C 3-6 cycloalkyl, C 1-6 Alkyl groups or halogens are substituted.

10. The compound according to any one of claims 1-9, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, R1 is selected from H, D, halogen, or C. 1-6 alkyl.

11. The compound according to any one of claims 1-10, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, R2, R3, R4, and R5 are each independently selected from H, D, or halogens.

12. The compound according to any one of claims 1-11, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, R6 and R7 are each independently selected from H, D, halogens, or C. 1-6 alkyl.

13. The compound according to any one of claims 1-12, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R8, R9, R 10 Each is independently selected from H, D, or halogens.

14. The compound according to claims 1-13, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound is selected from the following compounds:

15. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of any one of claims 1-14, or a stereoisomer, tautomer, deuterated compound, or pharmaceutical salt thereof.

16. Use of the compound of any one of claims 1-14, or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof, or the pharmaceutical composition of claim 15, in the preparation of a medicament for treating GLP-1 receptor-mediated diseases or conditions and related diseases or conditions.

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