Spiro heterocyclic compound and use thereof

Abstract

Disclosed in the present invention are a spiro heterocyclic compound having a structure as shown in formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated compound thereof or a prodrug molecule thereof, and the use thereof. The compound has the effect of antagonizing MC4 receptor activity, can be used for treating various diseases associated with MC4 receptors, and has great application value.

Description

Spiroheterocyclic compounds and their applications Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to a spiro heterocyclic compound and application thereof. Background Art

[0002] Melanocortin receptors (MCRs) are involved in regulating a variety of physiological behaviors in organisms, including energy balance, pigmentation, inflammation, cardiovascular and cerebrovascular function, feeding, and sebaceous gland lipid secretion. MCRs are a subfamily of G-protein coupled receptors (GPCRs) with seven transmembrane spans. Five melanocortin receptor subtypes are known: MC1R, MC2R, MC3R, MC4R, and MC5R. MC3R is primarily expressed in the central nervous system and regulates energy balance; MC4R is widely expressed throughout the central nervous system and is also expressed in peripheral tissues, such as adipose tissue, where it regulates feeding behavior and energy expenditure; other members are primarily expressed in the periphery and are involved in regulating pigmentation (MC1R), adrenal function (MC2R), immune function (MC1R / MC3R), and sebaceous gland activity (MC5R) (Endocr Rev. 2010 Aug; 31(4): 506-43).

[0003] MC4R is a family A G protein-coupled receptor (GPCR) regulated by endogenous MC4R agonist and inverse agonist / antagonist peptides. Its signaling has physiological effects on regulating energy homeostasis, cachexia, cardiovascular function, glycolipid homeostasis, reproductive and sexual function, brain inflammation, and anxiety. Inhibition or antagonism of MC4R signaling leads to increased appetite and food intake (Endocr Rev. 2010 Aug;31(4):506-43).

[0004] To date, a variety of small molecule MC4R antagonists have been reported. These antagonists can reverse or prevent appetite and weight loss in preclinical models of cancer, chronic kidney disease, age-related cachexia or anorexia (Biochim.Biophys.Acta.Mol.Basis.Dis.2017,1863(10),2414–2435;PLoS One 2009,4(3),e4774;J.Med.Chem.2004,47(7),1602-1604). A recent study reported that a MC4R antagonist peptide (TCMCB07) was effective in cachexia models after oral or subcutaneous administration, which can improve appetite and increase weight. It has now entered Phase 1 clinical trials (J Clin Invest.2020Sep 1;130(9):4921-4934). In addition, Pfizer reported a small molecule MC4R antagonist PF-07258669, which has a strong therapeutic effect on the cachexia model of elderly rats and has entered clinical trials (J Med Chem. 2023 Mar 9; 66(5): 3195-3211; patent WO2021250541A1).

[0005] Cachexia is a devastating, multifactorial wasting syndrome characterized by a loss of homeostatic control over energy and protein balance, resulting in involuntary weight loss and a reduction in skeletal muscle mass. Cachexia is highly associated with mortality from various malignant cancers (e.g., pancreatic, esophageal, gastric, lung, liver, and intestinal cancers, which together account for approximately half of all cancer deaths worldwide) (Nat Rev Dis Primers. 2018 Jan 18;4:17105; http: / / www.who.int / mediacentre / factsheets / fs297 / en / ) and is also associated with the further exacerbation of chronic non-malignant diseases (e.g., heart failure, kidney disease, chronic obstructive pulmonary disease, neurological diseases, HIV / AIDS, and rheumatoid arthritis) (Lancet Oncol. 12, 489–495 (2011)). There is currently no effective treatment for cachexia. In addition, it has been observed that when patients with chronic kidney disease (CKD) have more muscle or fat, a better appetite, and eat more, they live longer (J Cachexia Sarcopenia Muscle. 2011; 2(1): 9–25).

[0006] In view of the important role of melanocortin-4 receptor (MC4R) in the above-mentioned diseases, the development of efficient and safe MC4R antagonists has great application value for preventing or treating various diseases related to MC4R.

[0007] Summary of the Invention

[0008] Based on this, the present invention provides a class of spiroheterocyclic compounds, which have the effect of antagonizing the activity of MC4 receptors and can be used to treat various diseases related to MC4 receptors.

[0009] The present invention includes the following technical solutions.

[0010] A spiroheterocyclic compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated product thereof, or a prodrug molecule thereof:

[0011] in:

[0012] R1, R2, R3 and R4 are independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen, halogen-substituted C1-C6 alkyl, hydroxy, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, cyano, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)2R, -S(O)2N(R)2, -N(R)C(O)R;

[0013] R is selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, and alkylamino-substituted C1-C6 alkyl;

[0014] R5 and R6 are independently selected from: H, deuterium, halogen;

[0015] M is selected from: CH, N;

[0016] W is selected from: O, S, NR7;

[0017] Q is selected from the group consisting of CR7R8, NR8, C=O, O, S, or absent;

[0018] R7 and R8 are independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C8 cycloalkyl, hydroxy, cyano, amino, and C1-C6 alkylamino; or R8 and the substituents in A are linked to form a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring;

[0019] A is selected from: R9 and R 10 Substituted or unsubstituted C6-C 10 Aryl, R9 and R 10 substituted or unsubstituted 5-10 membered heteroaryl, R9 and R 10 a substituted or unsubstituted 7-10 membered benzoheterocyclyl group;

[0020] Each R9 and R 10 Each of the following is independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, C3-C8 cycloalkyl, C3-C8 deuterated cycloalkyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 deuterated alkylthio, C3-C8 cycloalkylthio, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, halogen-substituted C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 deuterated cycloalkyloxy, halogen-substituted C3-C8 cycloalkyloxy, and carbamoyl;

[0021] A1 is selected from: R 11 and R 12 Substituted or unsubstituted phenyl, R 11 and R 12 a substituted or unsubstituted 5-6 membered heteroaryl group;

[0022] Each R 11 and R 12 Each is independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, cyano, and C1-C6 alkoxy.

[0023] In some embodiments, A is selected from the group consisting of: R9 and R 10 Substituted or unsubstituted naphthyl, R9 and R 10 Substituted or unsubstituted 9-10 membered heteroaryl, R9 and R 10 A substituted or unsubstituted 9- to 10-membered benzoheterocyclic group.

[0024] In some embodiments, A is selected from:

[0025] Where: the dotted line in the ring represents whether it is a CC single bond or not;

[0026] X1, X2, and X3 are independently selected from: CR9, N.

[0027] In some embodiments, A is selected from:

[0028] In some embodiments, A is selected from: W is O.

[0029] In some embodiments, each of R9 and R 10 Each of the following groups is independently selected from the group consisting of: H, deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, C3-C6 cycloalkyl, C3-C6 deuterated cycloalkyl, C3-C6 cycloalkylmethyl, C1-C3 alkylsulfonyl, C1-C3 alkylthio, C1-C3 deuterated alkylthio, C3-C6 cycloalkylthio, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 deuterated alkoxy, halogen-substituted C1-C3 alkoxy, C3-C6 cycloalkyloxy, C3-C6 deuterated cycloalkyloxy, halogen-substituted C3-C6 cycloalkyloxy, and carbamoyl.

[0030] In some embodiments, each of R9 and R 10 Each of the following groups is independently selected from the group consisting of hydrogen, methoxy, fluorine, difluoromethyl, difluoromethoxy, cyano, methyl, ethynyl, carbamoyl, methylsulfonyl, cyclopropyloxy, methylthio, and chlorine.

[0031] In some embodiments, A is selected from:

[0032] In some embodiments, each R 11 and R 12 Each is independently selected from the group consisting of: H, deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, cyano, and C1-C3 alkoxy.

[0033] In some embodiments, A1 is selected from:

[0034] In some embodiments, A1 is selected from:

[0035] In some embodiments, W is selected from the group consisting of: O, S, NH, NCH3.

[0036] In some embodiments, W is selected from: S, NR7;

[0037] Wherein, R7 in W is selected from the group consisting of: H, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, and halogen-substituted C3-C8 cycloalkyl.

[0038] In some embodiments, R7 and R8 are independently selected from: H, deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl, cyano, amino, C1-C3 alkylamino; or R8 and the substituents in A are linked to form a substituted or unsubstituted 5-6 membered carbocyclic or heterocyclic ring.

[0039] In some embodiments, R7 and R8 are independently selected from: H, deuterium, methyl, hydroxyl, cyano, vinyl, ethynyl, amino, deuterated methyl, or R8 and the substituent in A are connected to form a 5-6 membered carbocyclic or heterocyclic ring.

[0040] In some embodiments, Q is selected from: -N(CH3)-,

[0041] In some embodiments, R4 is selected from the group consisting of: C1-C6 alkyl, C1-C6 deuterated alkyl, and halogen-substituted C1-C6 alkyl.

[0042] In some embodiments, R1, R2, R3 and R4 are independently selected from: H, deuterium, C1-C3 alkyl, C1-C3 deuterated alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, halogen, halogen-substituted C1-C3 alkyl, OH, hydroxy-substituted C1-C3 alkyl, alkoxy-substituted C1-C3 alkyl, cyano.

[0043] In some embodiments, R1 is selected from the group consisting of methyl, hydroxy, difluoromethyl, trifluoromethyl, cyano, chlorine, fluorine, vinyl, ethynyl, cyclopropyl, and deuterated methyl.

[0044] In some embodiments, R2 is selected from the group consisting of: H, fluoro, methyl, chloro, and deuterium.

[0045] In some embodiments, R3 is selected from: H, fluorine.

[0046] In some embodiments, R4 is selected from the group consisting of: H, methyl, methoxymethyl, and monofluoromethyl.

[0047] In some embodiments, the spiro heterocyclic compound is selected from the following compounds:

[0048] The present invention also provides the use of the spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule, including the following technical solutions.

[0049] Use of the spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule in the preparation of MC4 receptor antagonists.

[0050] Use of the spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule in the preparation of a drug for preventing and / or treating diseases and / or symptoms associated with the MC4 receptor.

[0051] In some embodiments, the diseases and / or symptoms associated with the MC4 receptor are selected from: diseases and / or symptoms associated with the MC4 receptor are selected from: cachexia (including cachexia associated with chronic diseases, cancer, acquired immune deficiency syndrome (AIDS), heart failure, chronic kidney disease (CKD)), etc.); anorexia or anorexia nervosa (such as senile anorexia, anorexia associated with chemotherapy and radiotherapy); nausea; vomiting; weight loss (involuntary weight loss); sarcopenia; muscle atrophy; muscle weakness; weakness; bone disease (such as bone loss); pain or neuropathic pain; anxiety (such as post-traumatic stress disorder, PTSD, etc.); sexual dysfunction; and inflammatory diseases (such as inflammatory diseases associated with cachexia, anorexia, sarcopenia, etc.), etc.

[0052] The present invention also provides a pharmaceutical composition for preventing and / or treating diseases and / or symptoms associated with the MC4 receptor, comprising the following technical solutions.

[0053] A pharmaceutical composition for preventing and / or treating diseases and / or symptoms associated with the MC4 receptor, comprising an active ingredient and a pharmaceutically acceptable excipient and / or carrier, wherein the active ingredient comprises the spiroheterocyclic compound or a pharmaceutically acceptable salt or stereoisomer or deuterated product or a prodrug molecule thereof.

[0054] The present invention also provides a method for preventing and / or treating diseases and / or symptoms associated with the MC4 receptor, comprising: administering a safe and effective amount of the spiroheterocyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated substance thereof, or a prodrug molecule thereof; and / or,

[0055] Administer a safe and effective amount of the pharmaceutical composition of the present invention.

[0056] The present invention has the following beneficial effects:

[0057] The spiroheterocyclic compound provided by the present invention, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated product, or its prodrug molecule has the effect of antagonizing the activity of MC4 receptor, can be used to treat various diseases related to MC4 receptor, and has great application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] FIG1 is a plasma drug-dose curve of Compound 100, Compound 104, and PF07258669 after oral administration to mice.

[0059] FIG2 is a drug-dose curve of compound 100, compound 104 and PF07258669 in brain tissue after oral administration to mice. DETAILED DESCRIPTION

[0060] In the compounds described herein, when any variable (e.g., R, etc.) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Likewise, combinations of substituents and variables are permitted so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns in the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0061] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0062] The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, for example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0063] The term "alkoxy" refers to a group in which an alkyl group is directly connected to oxygen, that is, a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0064] The term "heterocyclyl" is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent (acyclic, bridged or spirocyclic) in which one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon atoms, for example: morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothiophenyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, etc., and N-oxides thereof. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom.

[0065] The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S. Heteroaryl within the scope of the present invention includes, but is not limited to, quinolyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuranyl, benzothienyl, benzoxazole, indolyl, and the like; "heteroaryl" is also understood to include any N-oxide derivative of heteroaryl containing nitrogen.

[0066] The term "substituted" refers to the replacement of hydrogen radicals in a specified structure with the radical of a specified substituent.

[0067] As will be understood by those skilled in the art, "halo" or "halo" as used herein refers to chlorine, fluorine, bromine and iodine.

[0068] Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents may be unsubstituted or substituted. For example, C1-C6 alkyl may be substituted by one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclic radicals such as morpholinyl, piperidinyl etc.

[0069] The present invention includes free forms of compounds of Formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. Certain specific exemplary compounds of the present invention are amine compounds in non-salt form, i.e., "free form." Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0070] Therefore, the pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0071] If the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0072] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '1977: 66: 1-19, describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0073] The stereoisomers according to the present invention are, depending on their structure, enantiomers, diastereomers, syn- / anti-isomers, cis- / trans-isomers, epimers and (E)- / (Z)-isomers. The compounds of formula I can be used in the context of the present invention in the form of pure stereoisomers or in the form of any mixture of stereoisomers, in the latter case the racemates being preferred.

[0074] The metabolites of the compounds of the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds of the present invention and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present invention.

[0075] The present invention also provides a pharmaceutical composition for preventing and / or treating diseases and / or symptoms associated with MC4 receptors, which comprises an active ingredient within a safe and effective amount and a pharmaceutically acceptable excipient.

[0076] The "active ingredient" described in the present invention refers to the compound of formula I described in the present invention, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug molecule, or its deuterated substance, or its tritiated substance.

[0077] "Safe and effective amount" means the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0078] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0079] "Pharmaceutically acceptable excipients" refer to: one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0080] "Compatibility" herein means that the components in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0081] Examples of pharmaceutically acceptable excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0082] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or polymer through non-bonding interaction. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be linked to a macromolecular compound or polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, protein, nucleic acid, polypeptide, etc.

[0083] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0084] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0085] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with:

[0086] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0087] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0088] (c) humectants, for example, glycerin;

[0089] (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0090] (e) buffering solvents, such as paraffin;

[0091] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0092] (g) wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0093] (h) adsorbents, for example, kaolin; and

[0094] (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0095] The solid dosage forms can also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0096] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0097] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0098] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0099] Synthetic Methods: In addition to standard methods known in the literature or exemplified in the experimental procedures, the compounds of the present invention may be prepared using the methods described in the following synthetic schemes (Schemes 1-5). The compounds and synthetic methods described herein can be better understood in conjunction with the following synthetic schemes. The synthetic schemes described herein describe methods that can be used to prepare the compounds described herein. The described synthetic schemes are merely illustrative schemes for illustrative purposes and are not intended to limit the scope of the present invention.

[0100] Option 1

[0101] Option 2

[0102] Option 3

[0103] Option 4

[0104] Plan 5

[0105] Example 1: Preparation of (S)-N-(5-fluoro-2-methoxypyridin-4-yl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxamide (Compound 1) (Prepared according to Schemes 1 and 2)

[0106] Step 1a: Preparation of 1-benzyl-3-((trimethylsilyl)ethynyl)pyrrolidin-3-ol (Compound 0102-1): Under nitrogen, n-butyllithium (25.11 mL, 62.78 mmol, 1.1 eq) was added dropwise to a solution of ethynyltrimethylsilane (6.73 g, 68.48 mmol, 1.2 eq) in tetrahydrofuran (50 mL) at -70°C. The mixture was stirred at -70°C for 1.0 hour. A solution of 1-benzylpyrrolidin-3-one (Compound 0101-1) (10.0 g, 57.07 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was then added dropwise to the reaction mixture at -60°C. The cryogenic device was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give 1-benzyl-3-((trimethylsilyl)ethynyl)pyrrolidin-3-ol (12.11 g, yield: 77.63%) as a yellow oily product.

[0107] Step 1b: Preparation of 1-benzyl-3-ethynylpyrrolidin-3-ol (Compound 0103-1): To a solution of 1-benzyl-3-((trimethylsilyl)ethynyl)pyrrolidin-3-ol (0102-1) (12.11 g, 44.36 mmol, 1.0 eq) in methanol (100 mL) was added potassium carbonate (12.24 g, 88.72 mmol, 2.0 eq) under nitrogen. The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified on a silica gel column (ethyl acetate) to afford 1-benzyl-3-ethynylpyrrolidin-3-ol (7.65 g, 85.68% yield) as a yellow oil.

[0108] Step 1c: Preparation of 1-benzyl-3-ethynylpyrrolidin-3-yl acetate (Compound 0104-1): Under nitrogen, to a solution of 1-benzyl-3-ethynylpyrrolidin-3-ol (0103-1) (7.65 g, 38.05 mmol, 1.0 equiv) and N,N-diisopropylethylamine (9.82 g, 76.1 mmol, 2.0 equiv) in dichloromethane (100 mL) at 0°C was added a solution of acetyl chloride (5.08 g, 64.7 mmol, 1.7 equiv) in dichloromethane (6 mL). The mixture was stirred at 0°C for 0.5 h. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give 1-benzyl-3-ethynylpyrrolidin-3-yl acetate (8.94 g, yield: 96.70%) as a yellow oily product.

[0109] Step 1d: Preparation of 1-benzyl-3-ethynyl-N-(4-methoxybenzyl)pyrrolidin-3-amine (Compound 0105-1): To a solution of 4-methoxybenzylamine (10.06 g, 73.32 mmol, 2.0 eq) and cuprous chloride (363 mg, 3.67 mmol, 0.1 eq) in tetrahydrofuran (60 mL) was added a solution of 1-benzyl-3-ethynylpyrrolidin-3-yl acetate (0104-1) (8.92 g, 36.66 mmol, 1.0 eq) in tetrahydrofuran (18 mL) under nitrogen at 70° C. The mixture was stirred at 70° C. for 20 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give 1-benzyl-3-ethynyl-N-(4-methoxybenzyl)pyrrolidin-3-amine (3.5 g, yield: 29.83%) as a yellow oil. LCMS (ESI): m / z = 321 [M+1] + .

[0110] Step 1e: Preparation of 2-chloro-3-iodo-6-methylpyridine (Compound 0107-1): To a mixture of 2-chloro-6-methylpyridin-3-amine (0106-1) (25.0 g, 175.33 mmol, 1.0 eq) in 6 M dilute hydrochloric acid (175 mL) was added dropwise a solution of sodium nitrite (14.52 g, 210.39 mmol, 1.2 eq) in water (50 mL) at 0°C. The mixture was stirred at 0°C for 0.5 h. A solution of potassium iodide (58.18 g, 350.46 mmol, 2.0 eq) in water (100 mL) was added dropwise. The mixture was allowed to warm to room temperature and then stirred overnight. 2 M sodium hydroxide solution was slowly added to adjust the pH to 8, and the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate = 60:1 to 10:1) to give 2-chloro-3-iodo-6-methylpyridine (37.67 g, yield: 85%) as a pale yellow solid. LCMS (ESI): m / z 254 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

[0111] Step 1f: Preparation of 1-benzyl-3-((2-chloro-6-methylpyridin-3-yl)ethynyl)-N-(4-methoxybenzyl)pyrrolidin-3-amine (Compound 0108-1): To a mixture of 2-chloro-3-iodo-6-methylpyridine (0107-1) (35.78 g, 141.43 mmol, 1.0 equiv), bistriphenylphosphine palladium dichloride (4.96 g, 7.1 mmol, 0.05 equiv) and cuprous iodide (1.35 g, 7.1 mmol, 0.05 equiv) in triethylamine (220 ml) was added 1-benzyl-3-ethynyl-N-(4-methoxybenzyl)pyrrolidin-3-amine (0105-1) (45.25 g, 141.43 mmol, 1.0 equiv). The mixture was stirred at 80° C. overnight under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 10:1 to 1:2) to give 1-benzyl-3-((2-chloro-6-methylpyridin-3-yl)ethynyl)-N-(4-methoxybenzyl)pyrrolidin-3-amine (54.66 g, yield: 87%) as a brown oil. LCMS (ESI): m / z 446 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=2:1).

[0112] Step 1g: Preparation of 1-benzyl-3-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-N-(4-methoxybenzyl)pyrrolidin-3-amine (Compound 0109-1): To a mixture of 1-benzyl-3-((2-chloro-6-methylpyridin-3-yl)ethynyl)-N-(4-methoxybenzyl)pyrrolidin-3-amine (0108-1) (54.66 g, 122.56 mmol, 1.0 equiv) in methanol (300 mL) was added platinum dioxide (4.17 g, 18.38 mmol, 0.15 equiv). The mixture was stirred at room temperature under hydrogen balloon pressure for 10 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure to give 1-benzyl-3-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-N-(4-methoxybenzyl)pyrrolidin-3-amine (53.5 g, crude) as a brown oil. LCMS (ESI): m / z 450 [M+1] + ; TLC: Rf 0.3 (petroleum ether:ethyl acetate=2:1).

[0113] Step 1h: Preparation of 1-benzyl-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro(pyrrolidine-3,2'-[1,8]naphthyridine (Compound 0110-1): To a mixture of 1-benzyl-3-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-N-(4-methoxybenzyl)pyrrolidin-3-amine (0109-1) (42.18 g, 93.94 mmol, 1.0 equiv), palladium acetate (1.05 g, 4.70 mmol, 0.05 equiv) and RuPhos (4.38 g, 1.0 mmol, 0.1 equiv) in dioxane (420 ml) was added sodium tert-butoxide (18.04 g, 1 87.88 mmol, 2.0 equiv). The mixture was heated to 115°C under a nitrogen atmosphere and reacted overnight. The solvent was removed under reduced pressure. The residue was diluted with water (200 ml). The aqueous layer was extracted with ethyl acetate (150 ml × 3). The combined organic layers were washed with saturated brine (100 ml × 1), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain 1-benzyl-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] (21.0 g, yield: 54%) as a light yellow solid. LCMS (ESI): m / z 414 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=5:1).

[0114] Step 1i: Preparation of 1-benzyl-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] (Compound 0111-1): To a mixture of 1-benzyl-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] (0110-1) (21.0 g, 50.85 mmol, 1.0 equiv) in dichloromethane (150 mL) was added dropwise trifluoroacetic acid (57.98 g, 508.5 mmol, 10.0 equiv) at 0°C. The mixture was warmed to room temperature and stirred for 6 hours. The solvent was removed under reduced pressure. The mixture was diluted with water (200 mL). Solid sodium carbonate was added to adjust the pH to 10, and the aqueous layer was then extracted with dichloromethane (100 ml x 3). The combined organic layers were washed with saturated brine (100 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (dichloromethane:methanol = 80:1 to 20:1) to obtain 1-benzyl-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] (14.9 g, yield: 100%) as a pale yellow oil. LCMS (ESI): m / z 294 [M+1]+ ; TLC: Rf 0.5 (dichloromethane:methanol=20:1).

[0115] Step 1j: Preparation of tert-butyl 7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0112-1): To a mixture of 1-benzyl-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] (0111-1) (14.9 g, 50.85 mmol, 1.0 equiv) and di-tert-butyl dicarbonate (22.2 g, 101.7 mmol, 2.0 equiv) in tetrahydrofuran (150 mL) was added palladium hydroxide on carbon (10%, 3.73 g). The mixture was heated to 60°C under hydrogen balloon pressure for 40 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (dichloromethane:ethyl acetate 10:1 to 1:1) to give (S)-tert-butyl 7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (13.5 g, yield: 87%) as a pale yellow solid. LCMS (ESI): m / z 305 [M+1] + ; TLC: Rf 0.5 (dichloromethane:ethyl acetate=1:1).

[0116] Step 1k: Preparation of (S)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (Compound 0113-1) and (R)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (0114-1): Separation of the enantiomers of 7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (0112-1) was performed by supercritical fluid chromatography (column: ChiralPak IC, 250×30 mm ID, 10 μm; mobile phase: A is carbon dioxide, B is ethanol; eluent: 30% B; flow rate: 150 ml / min; back pressure: 100 bar; column temperature: 38°C). The first eluting enantiomer was (R)-tert-butyl 7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (compound 0114-1) (6.32 g, yield: 47%), and the second eluting enantiomer was (S)-tert-butyl 7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (compound 0113-1) (6.29 g, yield: 47%). Analytical conditions (Chromatographic column: ChiralPak IC, 100 × 4.6 mm ID, 3 μm; mobile phase: A is carbon dioxide, B is ethanol (0.05% diethylamine); eluent: 40% B; flow rate: 2.5 mL / min; back pressure: 100 bar; column temperature: 35°C)

[0117] Step 11: Preparation of (S)-tert-butyl 6'-bromo-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0116-1): To a mixture of (S)-tert-butyl 7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0113-1) (6.29 g, 20.76 mmol, 1.0 equiv) in dichloromethane (60 mL) was added dibromohydantoin (2.97 g, 10.38 mmol, 0.5 equiv) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction was quenched by the addition of saturated aqueous sodium sulfite (50 mL). The aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated to afford (S)-tert-butyl 6'-bromo-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (7.74 g, yield: 98%) as a pale yellow solid. LCMS (ESI): m / z 382 [M+1] +; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0118] Step 1m: Preparation of (S)-(1-(tert-Butyloxycarbonyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (Compound 0118-1): To (S)-6'-bromo-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (0116-1) (5.75 g, 15.05 mmol, 1.0 equiv), To a mixture of Xphos-Pd-G2 (237 mg, 0.30 mmol, 0.02 eq), Xphos (215 mg, 0.45 mmol, 0.03 eq), potassium acetate (3.69 g, 37.63 mmol, 2.5 eq), and sodium tert-butoxide (36 mg, 0.38 mmol, 0.025 eq) was added tetrahydroxydiboron (3.37 g, 37.63 mmol, 2.5 eq) in methanol (60 ml) and ethylene glycol (6 ml). Under a nitrogen atmosphere, the mixture was stirred at 53°C overnight. The solvent was removed under reduced pressure. The residue was diluted with water (50 ml). 2M sodium hydroxide solution was added to adjust the pH to 12, and the mixture was then washed with methyl tert-butyl ether (30 ml x 3). 2M dilute hydrochloric acid solution was added to the aqueous layer to adjust the pH to 8, and the mixture was then extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and concentrated to afford (S)-(1-(tert-butyloxycarbonyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-6'-yl)boronic acid (3.58 g, yield: 69%) as a white solid. LCMS (ESI): m / z 348 [M+1] + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0119] Step 1n: Preparation of (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (Compound 0120-1): To (S)-(1-(tert-Butyloxycarbonyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (0118-1) (3.58 g, 10. To a mixture of toluene (25 mL), ethanol (25 mL), and water (10 mL) was added 2-bromopyrimidine (1.80 g, 11.34 mmol, 1.1 eq). Under a nitrogen atmosphere, the mixture was stirred at 55°C overnight. The solvent was removed under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 4:1 to 1:1) to give (S)-tert-butyl 7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (2.94 g, yield: 75%) as a white solid. LCMS (ESI): m / z 382 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

[0120] Step 1o: Preparation of (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (0120-1) (1.07 g, 3.08 mmol, 1.0 equiv) in methanolic hydrogen chloride (4 M solution, 10 ml) was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (1.09 g, crude) as a pale yellow solid. LCMS (ESI): m / z 282 [M+1] + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0121] Step 1p: Preparation of 5-fluoro-4-iodo-2-methoxypyridine (Compound 0202-1): To a mixture of 2,5-difluoro-4-iodopyridine (Compound 0201-1) (25.0 g, 103.74 mmol, 1.0 equiv) in methanol (70 mL) was added sodium methoxide (5.4 M in methanol, 57.6 mL, 311.23 mmol, 3.0 equiv) at 0°C. The mixture was heated to 60°C under a nitrogen atmosphere and stirred for 1.5 hours. The solvent was removed under reduced pressure. The residue was diluted with saturated ammonium chloride solution (150 mL) and then extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether: ethyl acetate = 50:1) to give 5-fluoro-4-iodo-2-methoxypyridine (22.06 g, yield: 84%) as a white solid. LCMS (ESI): m / z 254 [M+1] + ; TLC: Rf 0.6 (petroleum ether:ethyl acetate=20:1).

[0122] Step 1q: Preparation of 5-fluoro-2-methoxy-N-(4-methoxybenzyl)-N-methylpyridin-4-amine (Compound 0203-1): To a mixture of 5-fluoro-4-iodo-2-methoxypyridine (0202-1) (1.0 g, 3.95 mmol, 1.0 equiv), tris(dibenzylideneacetone)palladium (109 mg, 0.119 mmol, 0.03 equiv), RuPhos (111 mg, 0.237 mmol, 0.06 equiv) and sodium tert-butoxide (1.14 g, 11.85 mmol, 3.0 equiv) in toluene (15 ml) was added 1-(4-methoxyphenyl)-N-methylmethanamine (0.72 g, 4.74 mmol, 1.2 equiv). The mixture was heated to 120° C. under nitrogen and stirred overnight. The solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate = 30:1 to 10:1) to give 5-fluoro-2-methoxy-N-(4-methoxybenzyl)-N-methylpyridin-4-amine (630 mg, yield: 58%) as a pale yellow oil. LCMS (ESI): m / z 277 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

[0123] Step 1r: Preparation of 5-fluoro-2-methoxy-N-methylpyridin-4-amine (Compound 0204-1): To a mixture of 5-fluoro-2-methoxy-N-(4-methoxybenzyl)-N-methylpyridin-4-amine (0203-1) (630 mg, 2.28 mmol, 1.0 equiv) in dichloromethane (12 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 mL). Solid sodium bicarbonate was added to adjust the pH to 8, and the aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated to afford 5-fluoro-2-methoxy-N-methylpyridin-4-amine (204 mg, yield: 57%) as a light yellow oil. LCMS (ESI): m / z 157 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=8:1).

[0124] Step 1s: Preparation of (S)-N-(5-fluoro-2-methoxypyridin-4-yl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxamide (Compound 1): To a mixture of 5-fluoro-2-methoxy-N-methylpyridin-4-amine (0204-1) (20 mg, 0.13 mmol, 2.0 equiv) and triethylamine (53 mg, 0.52 mmol, 8.0 equiv) in dichloromethane (2.5 mL) was added triphosgene (19 mg, 0.065 mmol, 1.0 equiv) at 0°C. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was diluted with water (15 mL) and then extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with saturated brine (15 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in dichloromethane (2.5 ml), and (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (23 mg, 0.065 mmol, 1.0 equiv) and N,N-diisopropylethylamine (54 mg, 0.46 mmol, 7.0 equiv) were added. The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:aqueous ammonia = 80:4.5:0.8) to give (S)-N-(5-fluoro-2-methoxypyridin-4-yl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxamide (15 mg, yield: 50%) as a white solid. LCMS (ESI): m / z 464 [M+1] +; TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500MHz, MeOD) δ8.81(d,J=4.9Hz,2H),8.00(d,J=2.8Hz,1H),7.87(s,1H),7.30(t,J=4.9Hz,1H),6.64(d,J=5.5Hz,1H),3.88(s,3H),3.5 5–3.37(m,2H),3.26(d,J=11.0Hz,2H),3.21(s,3H),2.90–2.65(m,2H) ,2.58(s,3H),2.01(dtd,J=20.0,13.0,7.3Hz,2H),1.92–1.74(m,2H).

[0125] Example 2: Preparation of (S)-N-(5-fluoro-2-methoxypyridin-4-yl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carbothioamide (Compound 2) (Prepared according to Scheme 3)

[0126] To a mixture of 5-fluoro-2-methoxy-N-methylpyridin-4-amine (0204-1) (51.5 mg, 0.33 mmol, 1.0 equiv) in tetrahydrofuran (1 ml) was added lithium bistrimethylsilylamide (1 M solution in tetrahydrofuran, 0.99 ml, 0.99 mmol, 3.0 equiv) at 0°C. The mixture was stirred for 10 minutes. Thiophosgene (114 mg, 0.99 mmol, 3.0 equiv) was added. The mixture was warmed to room temperature and stirred for 1 hour. Water (20 ml) was added to quench the reaction. The aqueous layer was extracted with dichloromethane (10 ml x 3). The combined organic layers were washed with saturated brine (10 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate=10:1) to give (5-fluoro-2-methoxypyridin-4-yl)(methyl)aminothioyl chloride (33 mg, yield: 43%) as a pale yellow oil. LCMS (ESI): m / z 235 [M+1] +TLC: Rf 0.5 (petroleum ether:ethyl acetate = 10:1). (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (50 mg, 0.14 mmol, 1.0 equiv) was added to a mixture of (5-fluoro-2-methoxypyridin-4-yl)(methyl)aminothioyl chloride (33 mg, 0.14 mmol, 1.0 equiv) and N,N-diisopropylethylamine (90 mg, 0.70 mmol, 5.0 equiv) in dichloromethane (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (ethyl acetate:dichloromethane:methanol=20:20:1) to give (S)-N-(5-fluoro-2-methoxypyridin-4-yl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carbothioamide (59 mg, yield: 88%) as a white solid. LCMS (ESI): m / z 480 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=15:1). 1 H NMR(500MHz,MeOD)δ8.80(d,J=4.9Hz,2H),7.99(d,J=3.1Hz,1H),7.85(s,1H),7.30(t,J=4.9Hz,1H),6.50(d,J=5.6Hz,1H),3 .88(s,3H),3.80–3.44(m,4H),3.36(d,J=11.3Hz,3H),2.92–2.69(m,2H),2.57(s,3H),2.19–2.00(m,2H),1.93–1.72(m,2H).

[0127] Example 3: Preparation of (S)-N-(3,4-difluorophenyl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxamide (Compound 3) (Prepared according to Scheme 2)

[0128] Step 3a: Preparation of 3,4-difluoro-N-methylaniline (Compound 0204-3):

[0129] Under nitrogen, sodium methoxide (5.4 mol / L, 7.17 mL, 38.75 mmol, 5.0 equiv) was added to a solution of 3,4-difluoroaniline (1.0 g, 7.75 mmol, 1.0 equiv) and paraformaldehyde (2.1 g, 23.25 mmol, 3.0 equiv) in methanol (10 mL). The mixture was stirred at room temperature overnight. Sodium borohydride (879 mg, 23.25 mmol, 3.0 equiv) was added to the reaction solution, and the mixture was stirred at 65°C for 2.0 hours. The mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 6 / 1) to afford 3,4-difluoro-N-methylaniline (600 mg, yield: 54.15%) as a yellow oil. LCMS (ESI): m / z = 144 [M+1] + .

[0130] Step 3b: Preparation of (S)-N-(3,4-difluorophenyl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxamide (Compound 3): Under nitrogen protection, triphosgene (37.4 mg, 0.126 mmol, 0.9 equiv) was added to a solution of 3,4-difluoro-N-methylaniline (0204-3) (20 mg, 0.14 mmol, 1.0 equiv) and triethylamine (56 mg, 0.56 mmol, 4.0 equiv) in dichloromethane (5 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with dichloromethane (8 ml). The organic phase was dried. 7'-Methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (49.4 mg, 0.14 mmol, 1.0 eq) and N,N-diisopropylethylamine (63.21 mg, 0.49 mmol, 3.5 eq) were added to the above solution, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 15 / 1, 4% aqueous ammonia) to give (S)-N-(3,4-difluorophenyl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxamide (30 mg, yield: 62.94%) as a yellow solid. LCMS (ESI): m / z = 451 [M+1] + . 1H NMR(500MHz,MeOD)δ8.80(d,J=4.9Hz,2H),7.81(s,1H),7.33–7.25(m,2H),7.20(ddd,J=11.4,7.0,2.5Hz,1H), 7.01(d,J=8.8Hz,1H),3.41–3.32(m,2H),3.23–3.10(m,5H),2.88–2.63(m,2H),2.56(s,3H),2.00–1.71(m,4H).

[0131] Example 4: Preparation of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione (Compound 7) (Prepared according to Schemes 4 and 5)

[0132] Step 4a: Preparation of dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)malonate (Compound 0403-7): To a mixture of 5-fluoro-4-iodo-2-methoxypyridine (0202-1) (22.06 g, 87.19 mmol, 1.0 eq), cuprous iodide (1.66 g, 8.72 mmol, 0.1 eq), 2-picolinic acid (2.15 g, 17.44 mmol, 0.2 eq) and cesium carbonate (85.27 g, 261.57 mmol, 3.0 eq) in tetrahydrofuran (130 mL) was added dibenzyl malonate (34.70 g, 12.21 mmol, 1.4 eq). The mixture was heated to 70° C. under a nitrogen atmosphere and stirred overnight. The mixture was diluted with water (200 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, and concentrated to give dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)malonate (46.1 g, crude) as a brown oil. LCMS (ESI): m / z 410 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

[0133] Step 4b: Preparation of dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methylmalonate (Compound 0404-7): To a mixture of dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)malonate (0403-7) (35.70 g, 87.19 mmol, 1.0 equiv) and potassium carbonate (36.10 g, 261.57 mmol, 3.0 equiv) in acetonitrile (80 mL) was added iodomethane (24.75 g, 174.38 mmol, 2.0 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was diluted with water (150 mL) and then extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was diluted with petroleum ether (120 ml) and then stirred at 0°C for 1 hour. The mixture was filtered. The solid was washed with petroleum ether and then dried under vacuum to give dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methylmalonate (24.5 g, yield: 68%) as a pale yellow solid. LCMS (ESI): m / z 414 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1).

[0134] Step 4c: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (Compound 0405-7): To a mixture of dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methylmalonate (0404-7) (24.5 g, 59.32 mmol, 1.0 equiv) in ethyl acetate (100 mL) was added palladium on carbon (10%, 4.0 g). The mixture was stirred at 55°C under hydrogen balloon pressure for two days. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 6:1 to 3:1) to afford 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (8.86 g, 75% yield) as a white solid. LCMS (ESI): m / z 200 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=2:1).

[0135] Step 4d: Preparation of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (compound 0406-7) and (S)-2-(5-fluoro-2-methylpyridin-4-yl)propanoic acid (0407-7): Separation of the enantiomers of 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0405-7) (8.86 g, 44.52 mmol) was performed by supercritical fluid chromatography (column: ChiralPak IG, 250×30 mm ID, 10 μm; mobile phase: A is carbon dioxide, B is methanol; eluent: 10% B; flow rate: 60 ml / min; back pressure: 100 bar; column temperature: 38°C. The first eluting enantiomer is (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0406-7) (3.75 g, yield: 42%), and the second eluting enantiomer is (S)-2-(5-fluoro-2-methylpyridin-4-yl)propanoic acid (0407-7) (3.86 g, yield: 44%). Analytical conditions (chromatographic column: ChiralPak IG, 100×4.6 mm ID, 5 μm; mobile phase: A is carbon dioxide, B is methanol (0.05% diethylamine); eluent: 5% B; flow rate: 2.5 ml / min; back pressure: 100 bar; column temperature: 35°C)

[0136] Step 4e: Preparation of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (Compound 0413-7): To a mixture of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (Compound 0406-7) (66 mg, 0.33 mmol, 1.0 equiv) in acetonitrile (3 mL) were added imidazole triflate (108 mg, 0.50 mmol, 1.5 equiv) and carbonyldiimidazole (64 mg, 0.40 mmol, 1.2 equiv). The mixture was stirred at room temperature for 2 hours. (S)-7'-Methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0122-1) (117 mg, 0.33 mmol, 1.0 equiv) and N,N-diisopropylethylamine (213 mg, 1.65 mmol, 5.0 equiv) were added. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:aqueous ammonia = 80:4:0.8) to give (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (80 mg, yield: 52%) as a white solid. LCMS (ESI): m / z 463 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

[0137] Step 4f: Preparation of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione (Compound 7): To (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-( To a mixture of (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (Compound 0413-7) (80 mg, 0.18 mmol, 1.0 equiv) in toluene (5 mL) was added Lawesson's reagent (85 mg, 0.21 mmol, 1.2 equiv). The mixture was heated in a microwave reactor at 125°C for 40 minutes. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:aqueous ammonia = 80:3.5:0.8) to give (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propane-1-thione (30 mg, yield: 36%) as a white solid. LCMS (ESI): m / z 479 [M+1] + ; TLC: Rf 0.6 (dichloromethane:methanol=10:1). 1 HNMR(500MHz,MeOD)δ8.81(t,J=4.4Hz,2H),7.88(dt,J=41.5,18.1Hz,2H),7.30(t,J=4.1Hz,1H),6.95–6.81(m,1H),4.54(dt,J=14.2, 6.8Hz,1H),4.18–3.66(m,7H),2.97–2.76(m,2H),2.58(dd,J=9.6,4.7Hz,3H),2.32–2.06(m,2H),2.05–1.78(m,2H),1.63–1.51(m,3H).

[0138] Example 5: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one-3,3,3-d3 (Compound 57) (Prepared according to Schemes 1 and 4)

[0139] Step 5a: Preparation of dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-(methyl-d3)malonate (Compound 0404-57): Under nitrogen, to a solution of dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)malonate (0403-7) (500 mg, 1.22 mmol, 1.0 eq) and potassium carbonate (507 mg, 3.67 mmol, 3.0 eq) in N,N-dimethylformamide (5 mL) was added deuterated iodomethane (355 mg, 2.44 mmol, 2.0 eq). The mixture was stirred at room temperature for three hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-(methyl-d3)malonate (510 mg, yield: 98.07%) as a white oil. LCMS (ESI): m / z = 427 [M+1] + .

[0140] Step 5b: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid-3,3,3-d3-acid (Compound 0405-57): Under hydrogen protection, palladium on carbon (102 mg, 20% mass fraction) was added to a mixture of dibenzyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-(methyl-d3)malonate (Compound 0404-57) (510 mg, 1.19 mmol, 1.0 equiv) in ethyl acetate (5 mL). The mixture was stirred at 55°C overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid-3,3,3-d3-acid (120 mg, yield: 49.38%) as a white oil. LCMS (ESI): m / z=203[M+1] + .

[0141] Step 5c: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7′-methyl-6′-(pyrimidin-2-yl)-3′,4′-dihydro-1′H-spiro[pyrrolidin-3,2′-[1,8]naphthyridin]-1-yl)propan-1-one-3,3,3-d3 (Compound 57 (0412-57)): 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0405-57) A solution of 7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (50 mg, 0.143 mmol, 1.0 equiv), and N,N-diisopropylethylamine (74 mg, 0.571 mmol, 4.0 equiv) in dichloromethane (3 ml) was stirred at room temperature for 10 minutes. 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (66 mg, 0.171 mmol, 1.2 equiv) was then added to the mixture and stirred at room temperature for one hour. The reaction solution was diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol / aqueous ammonia = 80 / 4.5 / 0.8) to give 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one-3,3,3-d3 (40 mg, yield: 60.61%) as a yellow solid. LCMS (ESI): m / z = 466 [M+1] + . 1 HNMR(500MHz,MeOD)δ8.87–8.74(m,2H),8.02–7.80(m,2H),7.31(s,1H),6.82–6.67(m,1H),4.21(dd,J=42.9,6.0 Hz,1H),3.93–3.82(m,3H),3.76–3.33(m,4H),2.98–2.75(m,2H),2.59(dd,J=12.9,4.1Hz,3H),2.21–1.76(m,4H).

[0142] Example 6: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione-3,3,3-d3 (Compound 58) (Prepared according to Scheme 5)

[0143] A mixed solution of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one-3,3,3-d3(0412-57) (50 mg, 0.107 mmol, 1.0 eq) and Lawesson's reagent (53 mg, 0.129 mmol, 1.2 eq) in toluene (2.5 ml) was stirred at 125°C in a microwave reactor for one hour. The reaction solution was diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol / aqueous ammonia = 80 / 4.5 / 0.8) to give 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione-3,3,3-d3 (33 mg, yield: 63.46%) as a yellow solid. LCMS (ESI): m / z = 484 [M+1] + . 1 HNMR(500MHz,MeOD)δ8.82(t,J=4.2Hz,2H),7.99–7.76(m,2H),7.31(t,J=4.8Hz,1H),6.96–6.83(m,1H),4.52 (dd,J=48.3,6.5Hz,1H),4.22–3.90(m,3H),3.86(dd,J=15.1,5.9Hz,3H),3.82–3.62(m,1 H),2.97–2.77(m,2H),2.59(dd,J=9.7,7.2Hz,3H),2.34–2.09(m,2H),2.07–1.77(m,2H).

[0144] Example 7: Preparation of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 34) (Prepared according to Schemes 1 and 4)

[0145] Step 7a: Preparation of tert-butyl 3-hydroxy-3-((trimethylsilyl)ethynyl)pyrrolidine-1-carboxylate (Compound 0102-34): Under nitrogen, n-butyl lithium (9.5 mL, 23.8 mmol, 1.1 eq) was added dropwise to a solution of ethynyltrimethylsilane (2.55 g, 25.9 mmol, 1.2 eq) in tetrahydrofuran (40 mL) at -70°C, and the mixture was stirred at -70°C for 1.0 hour. A solution of 1-tert-butoxycarbonyl-3-pyrrolidone (0101-34) (4.0 g, 21.6 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was then added dropwise to the reaction mixture at -60°C. The cryogenic device was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give a crude yellow oily product, tert-butyl 3-hydroxy-3-((trimethylsilyl)ethynyl)pyrrolidine-1-carboxylate (6.04 g). The crude product was used directly in the next step without further purification.

[0146] Step 7b: Preparation of tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (Compound 0103-34): To a solution of tert-butyl 3-hydroxy-3-((trimethylsilyl)ethynyl)pyrrolidine-1-carboxylate (0102-34) (6.00 g, 21.2 mmol, 1.0 equiv) in methanol (100 mL) was added potassium carbonate (5.80 g, 42.3 mmol, 2.0 equiv) under nitrogen. The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to afford tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (4.43 g, 97.1% yield over two steps) as a yellow oil.

[0147] Step 7c: Preparation of tert-butyl 3-acetoxy-3-ethynyl-pyrrolidine-1-carboxylate (Compound 0104-34): Under nitrogen, acetyl chloride (1.98 g, 25.2 mmol, 1.2 eq) was added to a solution of tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (0103-34) (4.43 g, 21.0 mmol, 1.0 eq) and N,N-diisopropylethylamine (4.06 g, 31.5 mmol, 1.5 eq) in dichloromethane (100 mL) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give 3-acetoxy-3-ethynyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.07 g, yield: 57.8%) as a yellow oily product.

[0148] Step 7d: Preparation of tert-butyl 3-ethynyl-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0105-34): Under nitrogen, to a solution of 4-methoxybenzylamine (3.07 g, 22.3 mmol, 2.0 eq) and cuprous chloride (111 mg, 1.1 mmol, 0.1 eq) in tetrahydrofuran (30 mL) at 70° C. was added a solution of tert-butyl 3-acetoxy-3-ethynyl-pyrrolidine-1-carboxylate (0104-34) (2.83 g, 11.2 mmol, 1.0 eq) in tetrahydrofuran (10 mL). The mixture was stirred at 70° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give tert-butyl 3-ethynyl-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (2.56 g, yield: 69.4%) as a yellow oily product.

[0149] Step 7e: Preparation of 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (Compound 0107-34): To a mixture of 2-chloro-6-(trifluoromethyl)pyridin-3-amine (0106-34) (1.5 g, 7.63 mmol, 1.0 eq) and 6 M dilute hydrochloric acid (7.6 mL, 45.78 mmol, 6.0 eq) in acetonitrile (5 mL) was added dropwise a solution of sodium nitrite (0.63 g, 9.16 mmol, 1.2 eq) in water (503 mL) at 0°C. The mixture was stirred at 0°C for 35 minutes. A solution of potassium iodide (2.53 g, 15.26 mmol, 2.0 eq) in water (5 mL) was added. The mixture was allowed to warm to room temperature and then stirred overnight. 2 M sodium hydroxide solution was slowly added to adjust the pH to 8, and the aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 100:1) to give 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (1.77 g, yield: 76%) as a white solid. LCMS (ESI): m / z 308 [M+1] + ; TLC: Rf 0.8 (petroleum ether).

[0150] Step 7f: Preparation of tert-butyl 3-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0108-34): To a mixture of 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (0107-34) (1.0 g, 3.26 mmol, 1.08 equiv), bistriphenylphosphine palladium dichloride (106 mg, 0.15 mmol, 0.05 equiv) and cuprous iodide (29 mg, 0.15 mmol, 0.05 equiv) in triethylamine (10 ml) was added tert-butyl 3-ethynyl-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (0105-34) (1.0 g, 3.03 mmol, 1.0 equiv). The mixture was heated to 80°C under a nitrogen atmosphere and reacted overnight. The solvent was removed under reduced pressure. The residue was diluted with water (30 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain tert-butyl 3-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (1.36 g, yield: 88%) as a light yellow oil. LCMS (ESI): m / z 511 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0151] Step 7g: Preparation of tert-butyl 3-(2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0109-34): To a mixture of tert-butyl 3-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (0108-34) (1.33 g, 2.61 mmol, 1.0 equiv) in methanol (10 mL) was added platinum dioxide (118 mg, 0.52 mmol, 0.2 equiv). The mixture was stirred at room temperature under hydrogen balloon pressure for 2 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3-(2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (1.29 g, yield: 96%) as a pale yellow oil. LCMS (ESI): m / z 515 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0152] Step 7h: Preparation of tert-butyl 1'-(4-methoxybenzyl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0110-34): To a mixture of tert-butyl 3-(2-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (0109-34) (1.29 g, 2.51 mmol, 1.0 equiv), palladium acetate (28 mg, 0.13 mmol, 0.05 equiv) and RuPhos (117 mg, 0.25 mmol, 0.1 equiv) in dioxane (12 mL) was added sodium tert-butoxide (0.48 g, 5.02 mmol, 2.0 equiv). The mixture was heated to 115°C in a microwave reactor for 1 hour. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 8:1 to 3:1) to obtain tert-butyl 1'-(4-methoxybenzyl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (724 mg, yield: 60%) as a pale yellow oil. LCMS (ESI): m / z 478 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=5:1).

[0153] Step 7i: Preparation of tert-butyl 7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0112-34): A mixture of tert-butyl 1'-(4-methoxybenzyl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0110-34) (724 mg, 1.52 mmol, 1.0 equiv) in methanolic hydrogen chloride (4 M solution, 7.5 mL) was heated to 70°C for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and water (10 mL). Solid sodium carbonate was added to adjust the pH to 9. Di-tert-butyl dicarbonate (332 mg, 1.52 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 ml) and then extracted with ethyl acetate (10 ml x 3). The combined organic layers were washed with saturated brine (10 ml x 1), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (610 mg, crude) as a pale yellow oil. LCMS (ESI): m / z 358 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=4:1).

[0154] Step 7j: Preparation of tert-butyl 6'-bromo-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0115-34): To a mixture of tert-butyl 7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0112-34) (543 mg, 1.52 mmol, 1.0 equiv) in dichloromethane (10 mL) was added dibromohydantoin (261 mg, 0.91 mmol, 0.6 equiv) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction was quenched by the addition of saturated aqueous sodium sulfite (20 mL). The aqueous layer was extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with saturated brine (10 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 6:1) to obtain tert-butyl 6'-bromo-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (659 mg, yield: 99%) as a pale yellow oil. LCMS (ESI): m / z 436 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=4:1).

[0155] Step 7k: Preparation of (1-(tert-Butyloxycarbonyl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (Compound 0117-34): To tert-butyl 6'-bromo-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0115-34) (250 mg, 0.57 mmol, 1.0 equiv) was added. ), Xphos-Pd-G2 (9 mg, 0.011 mmol, 0.02 eq), Xphos (8 mg, 0.017 mmol, 0.03 eq), potassium acetate (140 mg, 1.43 mmol, 2.5 eq) and sodium tert-butoxide (1.4 mg, 0.014 mmol, 0.025 eq) were added to a mixture of methanol (6 ml) and ethylene glycol (0.6 ml) with tetrahydroxydiboron (129 mg, 1.43 mmol, 2.5 eq). The mixture was heated to 53° C. under a nitrogen atmosphere for 10 hours. The solvent was removed under reduced pressure. The residue was diluted with water (20 ml). 2M sodium hydroxide solution was added to adjust the pH to 12, and then the mixture was washed with methyl tert-butyl ether (8 ml×3). 2M dilute hydrochloric acid solution was added to the aqueous layer to adjust the pH to 7, and then extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated to afford (1-(tert-butyloxycarbonyl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-6'-yl)boronic acid (151 mg, yield: 66%) as a white solid. LCMS (ESI): m / z 402 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

[0156] Step 71: Preparation of tert-butyl 6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0119-34): To (1-(tert-butyloxycarbonyl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (0117-34) (151 mg, To a mixture of toluene (2.5 ml), ethanol (2.5 ml) and water (1 ml) was added 2-bromopyrimidine (66 mg, 0.42 mmol, 1.1 eq). The mixture was heated to 55° C. under a nitrogen atmosphere for 6 hours. The solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel (dichloromethane:methanol = 100:1 to 50:1) to afford tert-butyl 6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (115 mg, yield: 70%) as a pale yellow oil. LCMS (ESI): m / z 436 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=20:1).

[0157] Step 7m: Preparation of 6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0121-34): A mixture of tert-butyl 6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0119-34) (49 mg, 0.113 mmol, 1.0 equiv) in methanolic hydrogen chloride (4 M solution, 1.5 mL) was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give 6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (46 mg, crude) as a pale yellow oil. LCMS (ESI): m / z 336 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

[0158] Step 7n: Preparation of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (Compound 34): To a mixture of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (Compound 0406-7) (22.5 mg, 0.113 mmol, 1.0 equiv) in acetonitrile (3 mL) were added imidazole triflate (37 mg, 0.17 mmol, 1.5 equiv) and carbonyldiimidazole (22 mg, 0.14 mmol, 1.2 equiv). The mixture was stirred at room temperature for 1.5 hours. 6'-(Pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0121-34) (46 mg, 0.113 mmol, 1.0 equiv) and N,N-diisopropylethylamine (73 mg, 0.57 mmol, 5.0 equiv) were added. The mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:3) to give (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6'-(pyrimidin-2-yl)-7'-(trifluoromethyl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (16 mg, yield: 28%) as a white solid. LCMS (ESI): m / z 517 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:3). 1 HNMR(500MHz,MeOD)δ8.83(s,2H),7.95(t,J=22.6Hz, 1H),7.62(d,J=10.2Hz,1H),7.43(d,J=2.1Hz,1H),6.81–6.70(m,1H),4.34–4.14(m,1H),3.86(d,J=10.8Hz,3H), 3.78–3.38(m,4H),3.00–2.62(m,2H),2.00(dddd,J=47.1,41.6,24.0,15.9Hz,4H),1.46(dd,J=11.5,5.9Hz,3H).

[0159] Example 8: Preparation of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 37) (Prepared according to Schemes 1 and 4)

[0160] Step 8a: Preparation of tert-butyl 3-((2,6-difluoropyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0108-37): To a mixture of 2,6-difluoro-3-iodopyridine (422 mg, 1.75 mmol, 1.05 equiv), bistriphenylphosphine palladium dichloride (59 mg, 0.084 mmol, 0.05 equiv), and cuprous iodide (16 mg, 0.084 mmol, 0.05 equiv) in triethylamine (8 mL) was added tert-butyl 3-ethynyl-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0105-34) (550 mg, 1.67 mmol, 1.0 equiv). The mixture was heated to 80° C. under a nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain tert-butyl 3-((2,6-difluoropyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (600 mg, yield: 81%) as a pale yellow oil. LCMS (ESI): m / z 444 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0161] Step 8b: Preparation of tert-butyl 7'-fluoro-1'-(4-methoxybenzyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0110-37): To a mixture of tert-butyl 3-((2,6-difluoropyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (0108-37) (600 mg, 1.35 mmol, 1.0 equiv) in methanol (10 mL) was added platinum dioxide (62 mg, 0.27 mmol, 0.2 equiv). The mixture was stirred at room temperature under hydrogen balloon pressure for 2.5 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate = 5:1 to 3:1) to afford tert-butyl 7'-fluoro-1'-(4-methoxybenzyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (315 mg, yield: 55%) as a pale yellow oil. LCMS (ESI): m / z 428 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0162] Step 8c: Preparation of tert-butyl 7'-fluoro-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0112-37): To a mixture of tert-butyl 7'-fluoro-1'-(4-methoxybenzyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0110-37) (315 mg, 0.74 mmol, 1.0 equiv) in dichloromethane (6 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 4.5 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (10 mL) and tetrahydrofuran (10 mL). Solid sodium carbonate was added to adjust the pH to 9. Di-tert-butyl dicarbonate (403 mg, 1.84 mmol, 2.5 eq) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate = 5:1) to obtain tert-butyl 7'-fluoro-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (227 mg, yield: 100%) as a pale yellow oil. LCMS (ESI): m / z 308 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0163] Step 8d: Preparation of tert-butyl 7'-fluoro-6'-iodo-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0115-37): To a mixture of tert-butyl 7'-fluoro-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0112-37) (227 mg, 0.74 mmol, 1.0 equiv) in acetonitrile (3.5 mL) at 0°C was added N-iodosuccinimide (166 mg, 0.74 mmol, 1.0 equiv). The mixture was stirred at 0°C for 1 hour. The reaction was quenched by the addition of saturated aqueous sodium sulfite (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 7'-fluoro-6'-iodo-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (277 mg, yield: 87%) as a pale yellow oil. LCMS (ESI): m / z 434 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0164] Step 8e: Preparation of tert-butyl 7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0119-37): To tert-butyl 7'-fluoro-6'-iodo-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0115-37) (240 mg, 0.55 mmol, 1.0 equiv), Xphos- To a mixture of Pd-G3 (23 mg, 0.028 mmol, 0.05 eq), Xphos (13.3 mg, 0.028 mmol, 0.05 eq), cuprous iodide (10.5 mg, 0.055 mmol, 0.1 eq), and cesium fluoride (167 mg, 1.10 mmol, 2.0 eq) in N,N-dimethylformamide (6 ml) was added 2-(tributyltinyl)pyrimidine (406 mg, 1.10 mmol, 2.0 eq). The mixture was heated to 100°C in a microwave reactor for 50 minutes. The mixture was diluted with water (30 ml) and then extracted with ethyl acetate (10 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate:petroleum ether = 3:2) to give tert-butyl 7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (43 mg, yield: 20%) as a pale yellow oil. LCMS (ESI): m / z 386 [M+1]+ ; TLC: Rf 0.5 (ethyl acetate: petroleum ether = 3:2).

[0165] Step 8f: Preparation of 7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0121-37): A mixture of tert-butyl 7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0119-37) (42 mg, 0.11 mmol, 1.0 equiv) in hydrogen chloride in ethyl acetate (4 M solution, 2.5 mL) was stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give 7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (39 mg, crude) as a pale yellow solid. LCMS (ESI): m / z 286 [M+1] + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0166] Step 8g: Preparation of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 37): To (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (Compound 0406-7) (22 mg, 0.11 mmol, 1.0 equiv), 2-(7-azabenzotriazole To a mixture of 7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0121-37) (39 mg, 0.11 mmol, 1.0 equiv) and N,N'-diisopropylethylamine (71 mg, 0.55 mmol, 5.0 equiv) in dichloromethane (3 ml) was added 7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0121-37) (39 mg, 0.11 mmol, 1.0 equiv). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 ml) and then extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:ethyl acetate:methanol=10:10:1) to give (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7'-fluoro-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one as a white solid (25 mg, yield: 48%). LCMS (ESI): m / z 476 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=15:1). 1 HNMR(500MHz,MeOD)δ8.77(s,2H),8.13(d,J=9.2Hz,1H),7.91(d,J=64.6Hz,1H),7.28(s,1H),6.75(d,J=22.1Hz,1H),4.22(d,J= 36.4Hz,1H),3.87(d,J=12.1Hz,3H),3.77–3.36(m,4H),2.72(d,J=114.3Hz,2H),2.16–1.71(m,4H),1.43(dd,J=13.0,6.6Hz,3H).

[0167] Example 9: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)-3-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)-3-oxopropionitrile (Compound 41)

[0168] Under nitrogen, a solution of 5-fluoro-4-iodo-2-methoxypyridine (0202-1) (500 mg, 1.98 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added dropwise to a solution of ethyl 2-cyanoacetate (335 mg, 2.96 mmol, 1.5 equiv), picolinic acid (50 mg, 0.40 mmol, 0.2 equiv), cuprous iodide (37.5 mg, 0.20 mmol, 0.1 equiv), and cesium carbonate (730 mg, 2.24 mmol, 1.1 equiv) in tetrahydrofuran (20 mL). The reaction was stirred at 70°C overnight. After completion of the reaction, the mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL x 3). The combined filtrates were washed sequentially with saturated aqueous ammonium chloride (100 mL) and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% to 20% ethyl acetate in petroleum ether) to give ethyl 2-cyano-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (355 mg, yield: 75.2%) as a white solid. LCMS (ESI): m / z = 239 [M+1] + Under nitrogen, to a solution of ethyl 2-cyano-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (43 mg, 0.16 mmol, 1.0 equiv) and 7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0122-1) (50 mg, 0.18 mmol, 1.0 equiv) in toluene (10 mL) was added N,N-diisopropylethylamine (0.5 mL, 2.87 mmol, 18 equiv). The reaction was stirred at 120°C overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure at 45°C. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2-(5-fluoro-2-methoxypyridin-4-yl)-3-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-3-oxopropionitrile (15 mg, yield: 17.6%) as a white solid. LCMS (ESI): m / z = 474.30 [M+1] + . 1HNMR(500MHz,DMSO)δ8.88(d,J=4.6Hz,2H),8.38– 8.25(m,1H),7.97(d,J=6.3Hz,1H),7.48–7.31(m,2H),6.99–6.88(m,1H),5.92–5.80(m,1H),4.08–3.90(m,4H),3.83–3.69(m,2H), 3.58(d,J=9.9Hz,2H),2.83(dd,J=16.2,6.3Hz,2H),2.65(d,J=8.4Hz,3H),2.15–2.04(m,2H),1.85(tdd,J=21.6,15.6,8.4Hz,2H).

[0169] Example 10: Preparation of 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 31) (Prepared according to Scheme 4)

[0170] Step 10a: Preparation of dimethyl 2-(2-methoxy-5-(methylthio)pyridin-4-yl)malonate (Compound 0403-31): To a mixture of 6-methoxy-4-methylpyridin-3-amine (1 g, 7.2 mmol, 1.0 eq) in dimethyl disulfide (10 mL) was added tert-butyl nitrite (5.96 g, 57.9 mmol, 8.0 eq) and the mixture was stirred at 50°C for half an hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give a crude oil. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to give 2-methoxy-4-methyl-5-(methylthio)pyridine (710 mg, 59% yield) as a yellow oil. MS (ES) + ):m / z=170(M+H) +Under nitrogen protection, a tetrahydrofuran solution of lithium diisopropylamide (1.6 M, 6.7 ml, 10.8 mmol, 3.0 eq) was added dropwise to a tetrahydrofuran (5 ml) solution of 2-methoxy-4-methyl-5-(methylthio)pyridine (610 mg, 3.6 mmol, 1.0 eq) at -30°C. After the reaction mixture was stirred at -30°C for 1 hour, dimethyl carbonate (975 mg, 10.8 mmol, 3.0 eq) was added dropwise. After the addition was complete, the reaction mixture was heated to 25°C and stirred for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1) to give dimethyl 2-(2-methoxy-5-(methylthio)pyridin-4-yl)malonate (290 mg, 29% yield) as a yellow oil. LCMS (ESI): m / z = 286 [M+1] + .

[0171] Step 10b: Preparation of dimethyl 2-(2-methoxy-5-(methylthio)pyridin-4-yl)-2-methylmalonate (Compound 0404-31): To a mixture of dimethyl 2-(2-methoxy-5-(methylthio)pyridin-4-yl)malonate (0403-31) (290 mg, 1.0 mmol, 1.0 equiv) and cesium carbonate (501 mg, 1.5 mmol, 1.5 equiv) in N,N-dimethylformamide (5 ml) was added iodomethane (145 mg, 1.0 mol, 1.0 equiv) under nitrogen, and the mixture was stirred at 35°C overnight. After cooling to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to give dimethyl 2-(2-methoxy-5-(methylthio)pyridin-4-yl)-2-methylmalonate (275 mg, 95% yield) as a yellow oil. LCMS (ESI): m / z = 300 [M+1] + .

[0172] Step 10c: Preparation of 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)propanoic acid (Compound 0405-31): A mixture of dimethyl 2-(2-methoxy-5-(methylthio)pyridin-4-yl)-2-methylmalonate (0404-31) (275 mg, 0.9 mmol, 1.0 eq) and sodium hydroxide (183.8 mg, 4.6 mmol, 5.0 eq) in 5 / 1 ethanol / water (10 mL / 2 mL) was stirred at 85°C overnight. The reaction mixture was adjusted to pH 2-3 with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to afford 2-(5-fluoro-2-methylbenzofuran-6-yl)propanoic acid (160 mg, 76.9% yield) as a yellow oil. LCMS (ESI): m / z = 228 [M+1]. + . A mixture of 2-(2-methoxy-5-(methylthio)pyridin-4-yl)propanoic acid (160 mg, 0.7 mmol, 1.0 eq) and potassium peroxymonosulfonate (866.6 mg, 1.4 mmol, 2 eq) in ethanol (5 ml) was stirred at room temperature overnight. The reaction solution was diluted with ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure to obtain a crude oil. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)propanoic acid (160 mg, yield 87.9%). LCMS (ESI): m / z = 260 [M+1] + .

[0173] Step 10d: Preparation of 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 31, 0412-31): To 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)propanoic acid (0405-31) (50 mg, 0.2 mmol, 1.05 mmol), 7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one To a mixture of (pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (65 mg, 0.18 mmol, 1.0 mmol) and N,N-diisopropylethylamine (94.5 mg, 0.7 mmol, 4.0 mmol) in N,N-dimethylformamide (5 ml) was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (90.5 mg, 0.24 mmol, 1.3 mmol). The reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thick column chromatography (eluent: petroleum ether / ethyl acetate / aqueous ammonia = 1 / 10 / 1 drop) to afford 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (44 mg, 45.8% yield) as a yellow solid. LCMS (ESI): m / z = 523 [M+1]. + . 1 H NMR(500MHz,MeOD)δ8.81(s,2H),8.70(dd,J=28.5,23.2Hz,1H),7.92(d,J=60.3Hz,1H),7.34–7.22(m,1H),6.97(dd,J=15.9,7.4Hz,1H),4.02(s, 3H),3.95–3.80(m,1H),3.76–3.39(m,4H),3.24–3.15(m,3H),2.84(d,J= 15.8Hz,2H),2.58(d,J=5.9Hz,3H),2.23–1.78(m,4H),1.61–1.47(m,3H).

[0174] Example 11: Preparation of 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione (Compound 70) (Prepared according to Scheme 5)

[0175] A mixture of 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3'-dihydro-1'-pyrrolidin-3,2'-[1,8]naphthyridine)-1-yl)propan-1-one (0412-31) (15 mg, 0.03 mmol, 1.0 eq) and Lawesson's reagent (17 mg, 0.04 mmol, 1.2 eq) in toluene (1 ml) was stirred in a microwave reactor at 125°C for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure to obtain a crude oil. The crude product was purified by thick column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2-(2-methoxy-5-(methylsulfonyl)pyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propane-1-thione (9 mg, 60% yield). LCMS (ESI): m / z = 539 [M+1]. + . 1 H NMR (500MHz, CDCl3) δ8.76–8.63(m,2H),8.02–7.81(m,1H),7.17(s,1H),7.11–7.00(m,1 H),6.90(dd,J=20.4,4.6Hz,1H),5.35–5.00(m,1H),4.46–3.97(m,2H),3.94(d,J=13.1Hz ,3H),3.91–3.51(m,2H),3.04(dd,J=28.4,7.2Hz,3H),2.80(t,J=10.7Hz,2H),2.64(dd, J=16.3,9.1Hz,3H),2.37–2.07(m,2H),1.99(dd,J=32.6,16.3Hz,2H),1.55–1.46(m,3H).

[0176] Example 12: Preparation of 2-(5-fluorobenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 14)

[0177] Step 12a: Preparation of 4-fluoro-2-iodo-5-methylphenol: A mixture of 4-fluoro-3-methylphenol (5.0 g, 39.6 mmol, 1.0 equiv), p-toluenesulfonic acid monohydrate (7.5 g, 39.6 mmol, 1.0 equiv), and N-iodosuccinimide (9.8 g, 43.6 mmol, 1.1 equiv) in acetonitrile (50 mL) was stirred at room temperature for 2 hours. The reaction mixture was quenched with sodium sulfite solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to provide 4-fluoro-2-iodo-5-methylphenol (7.65 g, yield: 75.6%) as a yellow oil.

[0178] Step 12b: Preparation of 4-fluoro-5-methyl-2-(trimethylsilyl)ethynyl)phenol: To a mixture of 4-fluoro-2-iodo-5-methylphenol (4.19 g, 16.7 mmol, 1.0 eq), bistriphenylphosphine palladium dichloride (292 mg, 0.42 mmol, 0.025 eq), and cuprous iodide (79.3 mg, 0.42 mmol, 0.025 eq) in triethylamine / tetrahydrofuran (3.6 mL / 5 mL) was added ethynyltrimethylsilane (8.2 g, 83 mmol, 5.0 eq) under nitrogen. The mixture was stirred at 90° C. for four hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)phenol (crude product) as a yellow oil.

[0179] Step 12c: Preparation of 5-fluoro-6-methylbenzofuran: A solution of 4-fluoro-5-methyl-2-((trimethylsilyl)ethynyl)phenol (crude), cuprous iodide (3.59 g, 18.9 mmol, 1.0 eq), and N,N-diisopropylethylamine (4.9 g, 37.7 mmol, 2.0 eq) in methanol (40 mL) was heated to 60°C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, and tetrabutylammonium fluoride trihydrate (6 g, 20.8 mol, 1.1 eq) was added to the solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to give 5-fluoro-6-methylbenzofuran (1.5 g, yield: 60%) as a yellow oil.

[0180] Step 12d: Preparation of 6-(bromomethyl)-5-fluorobenzofuran: Under nitrogen, a mixture of 5-fluoro-6-methylbenzofuran (1.5 g, 9.99 mmol, 1.0 eq), azobisisobutyronitrile (328.3 mg, 1.99 mmol, 0.2 eq), and N-bromosuccinimide (2.13 g, 11.99 mmol, 1.2 eq) in dichloroethane (15 mL) was stirred at 72°C overnight. The reaction mixture was cooled to room temperature, quenched with sodium sulfite solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to afford 6-(bromomethyl)-5-fluorobenzofuran (1.37 g, 59.5% yield) as a yellow oil.

[0181] Step 12e: Preparation of 2-(5-fluorobenzofuran-6-yl)acetonitrile: Under nitrogen, a mixture of 6-(bromomethyl)-5-fluorobenzofuran (2 g, 8.7 mmol, 1.0 eq), trimethylsilyl cyanide (1.7 g, 17.4 mmol, 2.0 eq), tetrabutylammonium fluoride in tetrahydrofuran (17 mL, 17.4 mmol, 2.0 eq), and potassium carbonate (1.1 g, 8.7 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was stirred at 60° C. overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(5-fluorobenzofuran-6-yl)acetonitrile (crude) as a yellow oil.

[0182] Step 12f: Preparation of 2-(5-fluorobenzofuran-6-yl)acetic acid: A mixture of 2-(5-fluorobenzofuran-6-yl)acetonitrile (crude) and potassium hydroxide (2.4 g, 43.5 mmol, 5 eq) in 1 / 1 ethanol / water (5 mL / 5 mL) was stirred at 90°C overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The aqueous phase was adjusted to pH 2-3 with dilute sulfuric acid solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 2-(5-fluorobenzofuran-6-yl)acetic acid (210 mg, 21% yield) as a yellow solid. MS (ES+): m / z = 193 (M+H)+.

[0183] Step 12g: Preparation of 2-(5-fluorobenzofuran-6-yl)propanoic acid: To a solution of 2-(5-fluorobenzofuran-6-yl)acetic acid (210 mg, 1.03 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added n-butyllithium (1.38 mL, 2.06 mmol, 2.0 eq) at -70°C under nitrogen, and the mixture was stirred at -70°C for 30 minutes. Diisopropylamine (21.9 mg, 0.22 mmol, 0.2 eq) was then added, and the mixture was stirred for 15 minutes. Methyl iodide (307 mg, 2.2 mmol, 2.0 eq) was then added at -30°C, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(5-fluorobenzofuran-6-yl)propanoic acid (20 mg, 8.8% yield) as a yellow oil. MS (ES+): m / z = 209 (M+H)+.

[0184] Step 12h: Preparation of 2-(5-fluorobenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 14): To 2-(5-fluorobenzofuran-6-yl)propanoic acid (20 mg, 0.096 mmol, 1.0 equiv), 7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro To a mixture of 1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (34 mg, 0.096 mmol, 1.0 equiv) and N,N-diisopropylethylamine (50 mg, 0.38 mmol, 4.0 equiv) in N,N-dimethylformamide (5 ml) was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (47.5 mg, 0.12 mmol, 1.3 equiv). The mixture was stirred at room temperature for two hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thick column chromatography (eluent: petroleum ether / ethyl acetate / ammonia water = 1 / 100 / 1) to give 2-(5-fluorobenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (22 mg, 47.2% yield) as a yellow solid. MS(ES+): m / z=486(M+H)+.1H NMR(500MHz,MeOD)δ8.80(s,2H),7.79(t,J=22.6Hz,2H),7.36(dd,J=38.6,33.6Hz,3H),6.79(d,J=44.9Hz,1H),4.31(d,J=53 .9Hz,1H),3.69–3.43(m,4H),2.81(d,J=3.9Hz,2H),2.61–2.43(m,3H),1.99(dd,J=60.7,30.0Hz,4H),1.47(d,J=5.6Hz,3H).

[0185] Example 13: Preparation of 6-methoxy-4-(1-(S)-7'-methyl-6'(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-thiopropan-2-yl)nicotinonitrile (Compound 11) (Prepared according to Schemes 4 and 5)

[0186] Step 13a: Preparation of methyl 2-(5-bromo-2-methoxypyridin-4-yl)acetate (Compound 0409-11): Under nitrogen, a solution of lithium diisopropylamide in tetrahydrofuran (0.9 mol, 67 mL, 60.00 mmol, 3.0 equiv) was added dropwise to a -30°C solution of 5-bromo-2-methoxy-4-methylpyridine (0408-11) (4.04 g, 20.00 mmol, 1.0 equiv) in tetrahydrofuran (40 mL). The reaction mixture was stirred at -30°C for 1 hour, and then dimethyl carbonate (5.40 g, 60.00 mmol, 3.0 equiv) was added dropwise. At the end of the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with 0.5 mol hydrochloric acid solution (120 mL, 60.00 mmol) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether to petroleum ether / ethyl acetate = 20 / 1) to obtain methyl 2-(5-bromo-2-methoxypyridin-4-yl)acetate (3.84 g, yield: 73.82%) as a yellow oil. LCMS (ESI): m / z = 260 (M+H) + .

[0187] Step 13b: Preparation of methyl 2-(5-cyano-2-methoxypyridin-4-yl)propanoate (Compound 0410-11): Under nitrogen, a solution of methyl 2-(5-bromo-2-methoxypyridin-4-yl)acetate (0409-11) (3.71 g, 14.27 mmol, 1.0 eq) in tetrahydrofuran (60 mL) at -70°C was added lithium bis(trimethylsilyl)amide (1 mol, 16 mL, 15.98 mmol, 1.12 eq) and stirred for 1 hour. A solution of iodomethane (2.23 g, 15.70 mmol, 1.1 eq) in tetrahydrofuran (5 mL) was added dropwise to the reaction mixture and stirred at -70°C for 2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether to petroleum ether / ethyl acetate = 35 / 1) to give methyl 2-(5-bromo-2-methoxypyridin-4-yl)propanoate (3.38 g, yield: 86.45%) as a yellow oil. LCMS (ESI): m / z = 274 (M+H) +. A mixture of methyl 2-(5-bromo-2-methoxypyridin-4-yl)propanoate (1.37 g, 5.00 mmol, 1.0 eq) and cuprous cyanide (2.68 g, 30.00 mmol, 6.0 eq) in N-methylpyrrolidone (15 ml) was stirred at 180°C for 1.5 hours. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give methyl 2-(5-cyano-2-methoxypyridin-4-yl)propanoate (434 mg, yield: 39.45%) as a yellow oily product. LCMS (ESI): m / z = 221 (M+H) + .

[0188] Step 13c: Preparation of 2-(5-cyano-2-methoxypyridin-4-yl)propanoic acid (Compound 0405-11): Under nitrogen, a mixture of methyl 2-(5-cyano-2-methoxypyridin-4-yl)propanoate (0410-11) (434 mg, 1.97 mmol, 1.0 eq) and potassium trimethylsilanol (380 mg, 2.96 mmol, 1.5 eq) in tetrahydrofuran (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was quenched with monomol hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to ethyl acetate) to give 2-(5-cyano-2-methoxypyridin-4-yl)propanoic acid (269 mg, yield: 66.42%) as a yellow solid. LCMS (ESI): m / z=207 (M+H) + .

[0189] Step 13d: Preparation of 6-methoxy-4-(1-(S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-oxopropan-2-yl)nicotinonitrile (Compound 0412-11): 2-(5-cyano-2-methoxypyridin-4-yl)propanoic acid (0405-11) (20.6 mg, 0.10 mmol, 1.0 equiv), (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-oxopropan-2-yl)nicotinonitrile (Compound 0412-11) A mixture of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (40 mg, 0.105 mmol, 1.05 equiv) in dichloromethane (2 ml) was stirred for 30 minutes. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 20 / 1) to afford 6-methoxy-4-(1-(S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-oxopropan-2-yl)nicotinonitrile (45 mg, yield: 95.74%) as a white solid. LCMS (ESI): m / z = 470 (M+H) + .

[0190] Step 13e: Preparation of 6-methoxy-4-(1-(S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-thiopropan-2-yl)nicotinonitrile (Compound 11): 6-methoxy-4-(1-(S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-thiopropan-2-yl)nicotinonitrile A mixture of 4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-oxopropan-2-yl)nicotinonitrile (0412-11) (19.7 mg, 0.042 mmol, 1.0 eq) and Lawesson's reagent (20.4 mg, 0.05 mmol, 1.2 eq) in toluene (1.5 ml) was stirred in a microwave reactor at 125°C for 40 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 20 / 1) to afford 6-methoxy-4-(1-(S)-7'-methyl-6'(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-thiopropan-2-yl)nicotinonitrile (13 mg, yield: 63.73%) as a yellow solid. LCMS (ESI): m / z = 486 (M+H) + . 1 H NMR(500MHz,MeOD)δ8.72(t,J=5.4Hz,2H),8.32(dd,J=36.1,30.8Hz,1H),7.7 8(d,J=6.3Hz,1H),7.22(q,J=5.0Hz,1H),6.89(dd,J=26.3,11.2Hz,1H),4.49( dd,J=28.2,6.7Hz,1H),4.09–3.74(m,7H),2.85–2.69(m,2H),2.51–2.42(m,3 H),2.31–2.00(m,2H),1.87(ddd,J=20.0,14.3,7.4Hz,2H),1.58–1.46(m,3H).

[0191] Example 14: Preparation of (S)-N-(3,4-difluorophenyl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carbothioamide (Compound 4) (prepared according to Scheme 3):

[0192] Under nitrogen, to a mixture of 3,4-difluoro-N-methylaniline (0204-3) (14 mg, 0.10 mmol, 1.0 eq.), triethylamine (60.6 mg, 0.60 mmol, 6.0 eq.) in dichloromethane (3 ml) was added dichlorocarbonyl sulfide (11.5 mg, 0.10 mmol, 1.0 eq.), and the mixture was stirred at room temperature for one hour. The mixture was quenched with 1M hydrochloric acid solution, diluted with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue (crude product) was used directly in the next step without further purification.

[0193] Under nitrogen, to a mixture of (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine](0122-1) (31.7 mg, 0.09 mmol, 0.9 equiv) and triethylamine (60.6 mg, 0.60 mmol, 6.0 equiv) in dichloromethane (2 ml) was added (3,4-difluorophenyl)(methyl)aminothioyl chloride (crude product). The mixture was stirred at room temperature for one hour. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by thick preparative thin-layer chromatography (eluent: dichloromethane / methanol / aqueous ammonia = 80 / 3.5 / 0.8) to afford (S)-N-(3,4-difluorophenyl)-N,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carbothioamide (30 mg, yield: 64.38%) as a yellow solid. LCMS (ESI): 467 [M+H] + . 1 H NMR(500MHz,MeOD)δ8.79(t,J=5.3Hz,2H),7.87–7.52(m,3H),7.50–7.36(m,1H),7.31–7.09(m,2H),6.77(dd,J=45.1,2.5Hz,1H ),4.14–3.94(m,1H),3.93–3.37(m,4H),2.90–2.67(m,2H),2.53(dd,J=34.4,13.4Hz,4H),2.21–1.65(m,4H),1.50–1.40(m,3H).

[0194] Example 15: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one-2-deuterium (Compound 67) (Prepared according to Schemes 4 and 5)

[0195] Step 15a: Preparation of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)propanoate (Compound 0410-67)

[0196] Under nitrogen, oxalyl chloride (1.5 mL, 1 M solution in dichloromethane, 1.5 mmol, 1.5 eq) was added dropwise to a solution of 2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0405-7) (200 mg, 1.0 mmol, 1.0 eq) and N,N-dimethylformamide (two drops) in dichloromethane (5 mL) at -78°C. The mixture was stirred at -78°C for 1.0 hour. Methanol (0.5 mL) was then added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 to 1 / 2) to obtain methyl 2-(5-fluoro-2-methoxypyridin-4-yl)propanoate (177 mg, yield: 82.7%) as a yellow oil.

[0197] Step 15b: Preparation of 2-deuterio-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (Compound 0405-67): To a solution of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)propanoate (0410-67) (50 mg, 0.23 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added dropwise lithium bis(trimethylsilylamide) (0.35 mL, 1 M solution in tetrahydrofuran, 0.35 mmol, 1.4 equiv) under nitrogen at -78°C. The mixture was stirred at -78°C for 1.0 hour. Deuterium hydroxide (0.2 mL) was then added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. The mixture was diluted with methyl tert-butyl ether and washed with water. The aqueous phase was acidified with 1 M hydrochloric acid, extracted with ethyl acetate, and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 2-deuterio-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (50 mg, crude) as a yellow oil.

[0198] Step 15c: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one-2-deuterium (Compound 67): Under nitrogen protection, at 0°C, to (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl To a solution of [1,8]naphthyridine](0122-1) (50 mg, 0.14 mmol, 1.0 equiv), 2-deuterio-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0405-67) (23 mg, 0.14 mmol, 1.00 equiv), and N,N-diisopropylethylamine (55 mg, 0.42 mmol, 1.05 equiv) in acetonitrile (5 ml) was added N'N-carbonyldiimidazole (25 mg, 0.15 mmol, 1.1 equiv). The mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one-2-deuterium (47.6 mg, yield: 72.6%) as a white solid product. LCMS (ESI): m / z = 454 [M+1]. + . 1 H NMR (500MHz, MeOD) δ8.81(t,J=3.8Hz,2H),7.96(t,J=20.7Hz,1H),7.84(d,J=14.8Hz,1H),7.35–7.21(m,1H),6.83–6.67(m,1H),3.87( dd,J=10.5,4.2Hz,3H),3.76–3.34(m,4H),2.92–2.72(m,2H),2.57(d,J=12.7Hz,3H),2.19–1.74(m,4H),1.44(dt,J=12.5,6.4Hz,3H).

[0199] Example 16: Preparation of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione-2-deuterium (Compound 75) (Prepared according to Scheme 5)

[0200] Under nitrogen, Lawesson's reagent (47 mg, 0.12 mmol, 1.2 eq) was added to a solution of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one-2-deuterium (Compound 67) (45 mg, 0.10 mmol, 1.0 eq) in toluene (2 ml). The mixture was heated to 100°C overnight. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione-2-deuterium (26.0 mg, yield: 55.7%) as a white solid product. LCMS (ESI): m / z = 481 [M+1]. + . 1 HNMR(500MHz,MeOD)δ8.81(t,J=4.6Hz,2H),7.98–7.74(m,2H),7.30(t,J=3.9Hz,1H),6.97–6.80(m,1H),4.21–3.95(m,2H), 3.95–3.63(m,5H),2.95–2.67(m,2H),2.57(dd,J=10.2,3.4Hz,3H),2.34–2.09(m,2H),2.08–1.85(m,2H),1.61–1.51(m,3H).

[0201] Example 17: Preparation of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 59) (Prepared according to Schemes 1 and 4)

[0202] Step 17a: Preparation of 2-chloro-6-(methyl-d3)pyridin-3-amine 2-chloro-6-(methyl-d3)pyridin-3-amine (Compound 0106-59):

[0203] Under nitrogen, sodium hydride (2.41 g, 60.25 mmol, 2.5 eq) was added to a solution of 6-bromo-2-chloropyridin-3-amine (5.00 g, 24.10 mmol, 1.0 eq) in N,N-dimethylformamide (25 ml) at 0°C, and the reaction was stirred at 0°C for one hour. 4-Methoxybenzyl chloride (7.93 g, 50.61 mmol, 2.1 eq) was added to the reaction mixture at 0°C, and stirred at room temperature for one hour. The reaction was quenched with ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 6-bromo-2-chloro-N,N-bis(4-methoxybenzyl)pyridin-3-amine (11 g, yield: 100%) as a yellow solid. LCMS (ESI): m / z = 447 [M+H] + .

[0204] To a solution of 6-bromo-2-chloro-N,N-bis(4-methoxybenzyl)pyridin-3-amine (19.98 g, 44.80 mmol, 1.0 eq) in tetrahydrofuran (200 mL) was added dropwise tert-butyllithium (1.3 M, 51.69 mL, 67.20 mmol, 1.5 eq) at -70°C under nitrogen and stirred for 1 hour. A solution of dry iodomethane (9.74 g, 67.20 mmol, 1.5 eq) in tetrahydrofuran (10 mL) was added to the reaction mixture at -70°C and stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give 2-chloro-N,N-bis(4-methoxybenzyl)-6-(methyl-d3)pyridin-3-amine (9.0 g, yield: 52.05%) as a yellow oil. LCMS (ESI): m / z = 386 [M+H] + .

[0205] To a mixture of 2-chloro-N, N-bis(4-methoxybenzyl)-6-(methyl-d3)pyridin-3-amine (9.0 g, 23.32 mmol, 1.0 eq) in dichloromethane (80 ml) was added trifluoroacetic acid (20 ml) and stirred at room temperature overnight. The solvent was removed under vacuum. The pH of the residue was adjusted to 13 with a 2M sodium hydroxide solution. The product was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give a yellow oily product, 2-chloro-6-(methyl-d3)pyridin-3-amine (3.38 g, yield: 100%). LCMS (ESI): m / z = 146 [M+H]+ .

[0206] Step 17b: Preparation of 2-chloro-3-iodo-6-(methyl-d3)pyridine (Compound 0107-59): To a solution of 2-chloro-6-(methyl-d3)pyridin-3-amine (0106-59) (3.38 g, 23.32 mmol, 1.0 eq) in concentrated hydrochloric acid / water (25 mL / 25 mL) was added 24 mL of sodium nitrite solution (2.41 g, 34.98 mmol, 1.5 eq) and stirred at 0°C for 30 minutes. Methyl tert-butyl ether (15 mL) was then added to the reaction, and 80 mL of potassium iodide solution (7.74 g, 46.64 mmol, 2.0 eq) was added dropwise at 0°C. The mixture was stirred at room temperature overnight. The reaction was quenched with sodium sulfite solution. The pH of the residue was adjusted to 7 with 2 M sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1) to give 2-chloro-3-iodo-6-(methyl-d3)pyridine (4.68 g, yield: 72.24%) as a yellow solid product.

[0207] Step 17c: Preparation of tert-butyl 3-hydroxy-3-((trimethylsilyl)ethynyl)pyrrolidine-1-carboxylate (Compound 0102-59): To a solution of ethynyltrimethylsilane (2.55 g, 25.9 mmol, 1.2 eq) in tetrahydrofuran (40 mL) was added dropwise n-butyllithium (9.5 mL, 23.8 mmol, 1.1 eq) under nitrogen at -70°C, and the mixture was stirred at -70°C for 1.0 hour. A solution of 1-tert-butoxycarbonyl-3-pyrrolidone (0101-59) (4.0 g, 21.6 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was then added dropwise at -60°C, the cryogenic device was removed, and the mixture was stirred overnight. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give a crude yellow oily product, tert-butyl 3-hydroxy-3-((trimethylsilyl)ethynyl)pyrrolidine-1-carboxylate (6.04 g). The crude product was used directly in the next step without further purification.

[0208] Step 17d: Preparation of tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (Compound 0103-59): To a solution of tert-butyl 3-hydroxy-3-((trimethylsilyl)ethynyl)pyrrolidine-1-carboxylate (0102-59) (6.00 g, 21.2 mmol, 1.0 eq) in methanol (100 mL) was added potassium carbonate (5.80 g, 42.3 mmol, 2.0 eq) under nitrogen. The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (4.43 g, two-step yield: 97.1%) as a yellow oil.

[0209] Step 17e: Preparation of tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (0104-59): To a solution of tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (0103-59) (4.43 g, 21.0 mmol, 1.0 eq) and N,N-diisopropylethylamine (4.06 g, 31.5 mmol, 1.5 eq) in dichloromethane (100 mL) was added acetyl chloride (1.98 g, 25.2 mmol, 1.2 eq) under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (3.07 g, yield: 57.8%) as a yellow oily product.

[0210] Step 17f: Preparation of tert-butyl 3-ethynyl-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0105-59): To a solution of 4-methoxybenzylamine (3.07 g, 22.3 mmol, 2.0 equiv) and cuprous chloride (111 mg, 1.1 mmol, 0.1 equiv) in tetrahydrofuran (30 mL) was added a solution of tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylate (0104-59) (2.83 g, 11.2 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) under nitrogen at 70° C. The mixture was stirred at 70° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give tert-butyl 3-ethynyl-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (2.56 g, yield: 69.4%) as a yellow oily product.

[0211] Step 17g: Preparation of tert-butyl 3-((2-chloro-6-(methyl-d3)pyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0108-59): Under nitrogen protection, 2-chloro-3-iodo-6-(methyl-d3)pyridine (0107-59) (1.30 g, 5.07 mmol, 1.0 equiv), 3-ethynyl A mixture of tert-butyl 3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (0105-59) (1.69 g, 5.07 mmol, 1.0 eq), cuprous iodide (96 mg, 0.51 mmol, 0.1 eq), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (356 mg, 0.51 mmol, 0.1 eq) was stirred at 90°C for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give tert-butyl 3-((2-chloro-6-(methyl-d3)pyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (1.90 g, yield: 81.90%) as a yellow oil. LCMS (ESI): m / z = 459 [M+H] + .

[0212] Step 17h: Preparation of tert-butyl 3-(2-(2-chloro-6-(methyl-d3)pyridin-3-yl)ethyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (Compound 0109-59): A mixture of tert-butyl 3-((2-chloro-6-(methyl-d3)pyridin-3-yl)ethynyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (0108-59) (1.90 g, 4.126 mmol, 1.0 equiv), platinum dioxide (187 mg, 0.825 mmol, 0.2 equiv) in methanol (20 mL) was stirred at room temperature overnight under a hydrogen atmosphere. The mixture was filtered through celite, the filter cake was washed with methanol, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give tert-butyl 3-(2-(2-chloro-6-(methyl-d3)pyridin-3-yl)ethyl)-3-(((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (1.30 g, yield: 68.42%) as a yellow oil. LCMS (ESI): m / z = 463 [M+H] + .

[0213] Step 17i: Preparation of tert-butyl 1'-(4-methoxybenzyl)-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0110-59): Under nitrogen protection, tert-butyl 3-(2-(2-chloro-6-(methyl-d3)pyridin-3-yl)ethyl)-3-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate A mixture of butyl ester (0109-59) (1.30 g, 2.81 mmol, 1.0 eq), palladium acetate (63 mg, 0.28 mmol, 0.1 eq), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (262 mg, 0.56 mmol, 0.2 eq) and sodium tert-butoxide (540 mg, 5.62 mmol, 2.0 eq) was stirred in a microwave apparatus for 1 hour. The mixture was diluted with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to give tert-butyl 1'-(4-methoxybenzyl)-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (945 mg, yield: 78.95%) as a yellow oil. LCMS (ESI): m / z = 427 M+H + .

[0214] Step 17j: Preparation of tert-butyl 7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0112-59): To a mixture of tert-butyl 1'-(4-methoxybenzyl)-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0110-59) (945 mg, 2.22 mmol, 1.0 equiv) in dichloromethane (8 mL) was added trifluoroacetic acid (4 mL) and stirred at room temperature for 4 hours. The solvent was removed under vacuum and the pH of the residue was adjusted to 8 with sodium bicarbonate solution. A solution of di-tert-butyl dicarbonate (485 mg, 2.22 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added and stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane to dichloromethane / methanol = 10 / 1) to obtain tert-butyl 7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (580 mg, yield: 85.46%) as a yellow oil. LCMS (ESI): m / z = 307 [M+H] + .

[0215] Step 17k: Preparation of tert-butyl 6'-bromo-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0115-59): To a solution of tert-butyl 7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0112-59) (550 mg, 1.80 mmol, 1.0 equiv) in dichloromethane (10 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (309 mg, 1.08 mmol, 0.6 equiv) under nitrogen and stirred at 0°C for 30 min. The reaction was quenched with sodium sulfite solution. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1 to 30 / 1) to obtain a yellow solid product, 6'-bromo-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (720 mg, yield: 100%). (ESI): m / z = 386 [M+H] + .

[0216] Step 171: Preparation of (1-(tert-Butyloxycarbonyl)-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (Compound 0117-59): Under nitrogen protection, tert-butyl 6'-bromo-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0115-59) (690 mg, 1.79 mmol, 1.0 equiv), tetrahydroxydiboron ( A mixture of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (402 mg, 4.48 mmol, 2.5 eq), Xphos-Pd-G2 (30 mg, 0.036 mmol, 0.02 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (26 mg, 0.054 mmol, 0.03 eq), potassium acetate (439 mg, 4.48 mmol, 2.5 eq) and sodium tert-butoxide (4.3 mg, 0.045 mmol, 0.025 eq) in methanol / ethylene glycol (20 ml / 1 ml) was stirred at 55° C. for 1 hour. The mixture was diluted with water and extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1 to 10 / 1) to give (1-(tert-butoxycarbonyl)-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridin]-6'-yl)boronic acid (360 mg, yield: 57.46%) as a yellow oil. LCMS (ESI): m / z = 351 M+H + .

[0217] Step 17m: Preparation of tert-butyl (7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0119-59): Under nitrogen protection, (1-(tert-butyloxycarbonyl)-7'-(methyl-d3)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate alkyl-3,2'-[1,8]naphthyridin-6'-yl)boronic acid (0117-59) (360 mg, 1.03 mmol, 1.0 equiv), 2-bromopyrimidine (213 mg, 1.34 mmol, 1.3 equiv), Xphos-Pd-G2 (30 mg, 0.036 mmol, 0.02 equiv), 2-dicyclohexylphosphino-2',4',6'-triisopropylamine A mixture of propylbiphenyl (15 mg, 0.031 mmol, 0.03 eq) and sodium carbonate (328 mg, 3.09 mmol, 3.0 eq) in toluene / ethanol / water (4 ml / 2 ml / 2 ml) was stirred at 60°C for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1 to 20 / 1) to give tert-butyl 7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (290 mg, yield: 73.42%). LCMS (ESI): m / z = 385 [M+H] + .

[0218] Step 17n: Preparation of (methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0121-59): A solution of tert-butyl 7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (77 mg, 0.20 mmol, 1.0 equiv) in hydrogen chloride-methanol (2 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The residue was used in the next step without purification. (Crude) LCMS (ESI): m / z = 285 [M+H] + .

[0219] Step 17o: Preparation of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 59): To a mixture of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0406-7) (40 mg, 0.20 mmol, 1.0 equiv) in acetonitrile (2 ml) were added pyridine trifluoromethanesulfonate (92 mg, 0.4 mmol, 2.0 equiv) and N,N'-carbonyldiimidazole (36 mg, 0.22 mmol, 1.1 equiv) and the mixture was stirred at room temperature for 1 hour. (Methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (77 mg, 0.60 mmol, 3.0 equiv) was added to the reaction mixture and stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol / aqueous ammonia = 80 / 3.5 / 0.8) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 59) (40 mg, yield: 43.01%) as a white solid. LCMS (ESI): m / z = 466 [M+H] + . 1 HNMR(500MHz,MeOD)δ8.71(t,J=3.8Hz,2H),7.81(dd,J=75.5,11.1Hz,2H),7.24–7.13(m,1H),6.72–6.52(m,1H),4.22–3 .99(m,1H),3.77(t,J=7.6Hz,3H),3.64–3.25(m,4H),2.85–2.38(m,2H),2.10–1.62(m,5H),1.35(dt,J=12.9,6.8Hz,3H).

[0220] Example 18: Preparation of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 101):

[0221] Compound 59 (31 mg) was separated by chiral high performance liquid chromatography (Chromatographic column: ChiralPak AD-H, 10×250 mm). The first eluting enantiomer was a white solid product (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-7'-(methyl-d3)-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 101) (19 mg, yield: 62.50%). LCMS (ESI): 466 [M+H] + . 1 H NMR (500MHz, DMSO) δ8.80(d,J=2.6Hz,2H),8.11(d,J=5.7Hz,1H),7.89(d,J=11.6Hz,1H),7.23(d,J=50.3Hz,2H),6.72(dd,J=30.7,4 .6Hz,1H),4.12(dd,J=26.8,6.9Hz,1H),3.83(s,3H),3.61–3.37(m,4H),2.85–2.59(m,2H),2.05–1.62(m,4H),1.33(t,J=6.7Hz,3H).

[0222] Example 19: Preparation of 2-(5-fluorobenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione (Compound 12) (prepared according to Scheme 5):

[0223] A mixture of 2-(5-fluorobenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (Compound 14) (30 mg, 0.064 mmol, 1.0 eq) and Lawesson's reagent (49 mg, 0.12 mmol, 1.89 eq) in toluene (2 ml) was stirred and heated in a microwave at 125°C for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to obtain a crude oil. The crude product was purified by thick column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2-(5-fluorobenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridin]-1-yl)propane-1-thione (17 mg, 54.8% yield). LCMS (ESI): m / z = 488 [M+1] + .1 H NMR(500MHz,MeOD)δ8.78–8.67(m,2H),7.85–7.62(m,2H),7.61–7.49(m,1H),7.31–6.97(m,2H),6.78–6.56(m,1H),4.56(d,J=7.2H z,1H),3.93–3.61(m,4H),2.75(ddd,J=19.9,14.6,5.6Hz,2H),2.57–2.41(m,3H),2.15–1.83(m,4H),1.51(dd,J=12.8,6.5Hz,3H).

[0224] Example 20: Preparation of 2-(4-methoxybenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 87):

[0225] Step 20a: Preparation of 4-bromo-2,6-dimethoxybenzaldehyde: To a mixture of 4-bromo-2,6-difluorobenzaldehyde (3.5 g, 15.84 mmol, 1.0 eq) in methanol (20 mL) was added sodium methoxide (5.4 M in methanol, 5.87 mL, 31.67 mmol, 2.0 eq). The mixture was heated to 65°C under a nitrogen atmosphere for 3.5 hours. The solvent was removed under reduced pressure. The residue was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate 8:1) to afford 4-bromo-2,6-dimethoxybenzaldehyde (2.89 g, 74% yield) as a white solid. LCMS (ESI): m / z 245 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=4:1).

[0226] Step 20b: Preparation of 4-bromo-2-hydroxy-6-methoxybenzaldehyde: To a mixture of aluminum chloride (3.54 g, 26.53 mmol, 1.0 eq) and sodium iodide (3.98 g, 26.53 mmol, 2.0 eq) in acetonitrile (16 mL) at 0°C was added dropwise a solution of 4-bromo-2,6-dimethoxybenzaldehyde (3.25 g, 13.27 mmol, 1.0 eq) in dichloromethane (16 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched by the addition of 1N dilute hydrochloric acid (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether: ethyl acetate 30:1) to give 4-bromo-2-hydroxy-6-methoxybenzaldehyde (2.87 g, yield: 94%) as a white solid. LCMS (ESI): m / z 231 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=20:1).

[0227] Step 20c: Preparation of 6-bromo-4-methoxybenzofuran: To a mixture of 4-bromo-2-hydroxy-6-methoxybenzaldehyde (2.87 g, 12.42 mmol, 1.0 eq) and cesium carbonate (10.12 g, 31.05 mmol, 2.5 eq) in N,N-dimethylformamide (20 mL) was added ethyl bromoacetate (2.49 g, 14.91 mmol, 1.2 eq). The mixture was heated to 120°C under a nitrogen atmosphere for 8 hours. The mixture was diluted with water (80 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate 50:1) to afford 6-bromo-4-methoxybenzofuran (0.492 g, 17% yield) as a white solid. LCMS (ESI): m / z 227[M+1] + ; TLC: Rf 0.8 (petroleum ether:ethyl acetate=10:1).

[0228] Step 20d: Preparation of tert-butyl 2-(4-methoxybenzofuran-6-yl)propanoate: To a mixture of 6-bromo-4-methoxybenzofuran (100 mg, 0.44 mmol, 1.0 eq), Pd(dba)2 (25 mg, 0.044 mmol, 0.1 eq), and X-Phos (42 mg, 0.088 mmol, 0.2 eq) in tetrahydrofuran (1 mL) was added (1-(tert-butoxy)-1-oxopropan-2-yl)zinc bromide (0.96 M in tetrahydrofuran, 2 mL, 1.92 mmol, 4.4 eq). The mixture was heated to 65°C under a nitrogen atmosphere for 1.5 hours. The mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate=50:1) to give tert-butyl 2-(4-methoxybenzofuran-6-yl)propanoate (79 mg, yield: 65%) as a pale yellow oil. LCMS (ESI): m / z 277 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=50:1).

[0229] Step 20e: Preparation of 2-(4-methoxybenzofuran-6-yl)propanoic acid: A mixture of tert-butyl 2-(4-methoxybenzofuran-6-yl)propanoate (70 mg, 0.254 mmol, 1.0 equiv) in hydrogen chloride / dioxane (4 M, 1 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dried under vacuum to give a pale yellow oil (2-(4-methoxybenzofuran-6-yl)propanoic acid (56 mg, crude). LCMS (ESI): m / z 221 [M+1]. + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0230] Step 20f: Preparation of 2-(4-methoxybenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 87): To 2-(4-methoxybenzofuran-6-yl)propanoic acid (23 mg, 0.105 mmol, 1.0 equiv), 2-(7-azobenzotriazole)-N,N,N',N'- To a mixture of tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol, 1.05 equiv) and N,N-diisopropylethylamine (68 mg, 0.525 mmol, 5.0 equiv) in dichloromethane (2.5 mL) was added (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (37 mg, 0.105 mmol, 1.0 equiv). The mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:aqueous ammonia=80:3.5:0.8) to give a white solid mixture of two diastereoisomers, 2-(4-methoxybenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 87) (34 mg, yield: 67%). 1 H NMR(500MHz,MeOD)δ8.81(dd,J=7.3,4.8Hz,2H),7.82(d,J=72.9Hz,1H),7.57(d,J=56 .2Hz,1H),7.30(d,J=3.9Hz,1H),7.07(dd,J=25.2,11.8Hz,1H),6.89–6.61(m,2H),4. 03(dd,J=25.4,19.3Hz,1H),3.91(dd,J=30.5,17.0Hz,3H),3.75–3.36(m,4H),2.83(d ,J=20.9Hz,2H),2.56(dd,J=33.0,14.8Hz,3H),2.23–1.71(m,4H),1.50–1.42(m,3H).

[0231] Example 21: Preparation of (R)-2-(4-methoxybenzofuran-6-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 102):

[0232] Compound 87 diastereomers (20 mg) were separated using chiral high-performance liquid chromatography (column: ChiralPak AD-H, 10×250 mm). The second eluting enantiomer was (R)-2-(4-methoxybenzofuran-6-yl)-1-((S)-7′-methyl-6′-(pyrimidin-2-yl)-3′,4′-dihydro-1′H-spiro[pyrrolidin-3,2-[1,8]naphthyridin]-1-yl)propan-1-one (Compound 102) (5.6 mg, yield: 28%) as a white solid. LCMS (ESI): m / z 484 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=20:1). 1 H NMR (500MHz, MeOD) δ8.79(d,J=4.8Hz,2H),7.75(d,J=70.3Hz,1H),7.63(d,J=1.7Hz,1H),7.29( dd,J=6.4,3.2Hz,1H),7.08(d,J=28.7Hz,1H),6.84(s,1H),6.72(d,J=17.3Hz,1H),4.51(s,4H), 4.12–3.86(m,4H),3.76–3.35(m,4H),2.85(d,J=6.3Hz,1H),2.59–2.49(m,3H),2.22–1.79(m,4H),1.47–1.39(m,3H).

[0233] Example 22: Preparation of 6-(1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-oxopropan-2-yl)benzofuran-5-carbonitrile (Compound 77):

[0234] Step 22a: Preparation of 1-bromo-2-bromomethyl-4-methoxybenzene: Under nitrogen, a mixture of 1-bromo-4-methoxy-2-methylbenzene (2.5 g, 12.44 mmol, 1.0 eq), N-bromosuccinimide (2.22 g, 12.44 mmol, 1.0 eq) and azobisisobutyronitrile (409 mg, 2.49 mmol, 0.2 eq) in 1,2-dichloroethane (25 ml) was stirred at 72 ° C overnight. Dichloromethane was added and the mixture was washed with sodium thiosulfate solution and saturated brine. The organic phase was dried and concentrated under reduced pressure to give a yellow

[0235] Oily product 1-bromo-2-bromomethyl-4-methoxybenzene (4.08 g, crude product). LCMS (ESI): m / z=279[M+1] + .

[0236] Step 22b: Preparation of 2-(2-bromo-5-methoxyphenyl)acetonitrile: Under nitrogen, a mixture of 1-bromo-2-bromomethyl-4-methoxybenzene (4.08 g, 12.44 mmol, 1.0 eq), trimethylsilyl cyanide (1.85 g, 18.66 mmol, 1.5 eq), and tetrabutylammonium fluoride (1 M in tetrahydrofuran, 18.7 mL, 18.66 mmol, 1.5 eq) in acetonitrile (30 mL) was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure to give 2-(2-bromo-5-methoxyphenyl)acetonitrile (5.61 g, crude) as a brown oil. LCMS (ESI): m / z = 226 [M+1] + .

[0237] Step 22c: Preparation of 2-(2-bromo-5-methoxyphenyl)acetic acid: To a solution of 2-(2-bromo-5-methoxyphenyl)acetonitrile (5.61 g, 12.44 mmol, 1.0 eq) in ethanol (50 mL) was added a solution of potassium hydroxide (2.09 g, 37.32 mmol, 3.0 eq) in water (50 mL). The mixture was stirred at 85°C overnight. The mixture was concentrated to 75 mL and washed with ethyl acetate. The aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid. Ethyl acetate was added for extraction, and the mixture was washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure to give 2-(2-bromo-5-methoxyphenyl)acetic acid (1.86 g, yield: 60.7%) as a yellow oil. LCMS (ESI): m / z = 245 [M+1] + .

[0238] Step 22d: Preparation of methyl 2-(2-bromo-5-methoxyphenyl)acetate: Under nitrogen, oxalyl chloride (2M solution in dichloromethane, 7.56 mL, 15.12 mmol, 2.0 eq) was added dropwise to a mixture of 2-(2-bromo-5-methoxyphenyl)acetic acid (1.86 g, 7.56 mmol, 1.0 eq) and N,N-dimethylformamide (0.1 mL) in 10 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours. 2 mL of methanol was added dropwise, and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to give methyl 2-(2-bromo-5-methoxyphenyl)acetate (1.8 g, yield: 91.3%) as a yellow oil. MS (ES) + ):m / z=259(M+H) + .

[0239] Step 22e: Preparation of methyl 2-(2-bromo-5-methoxyphenyl)propanoate: To a solution of methyl 2-(2-bromo-5-methoxyphenyl)acetate (437 mg, 1.68 mmol, 1.0 eq) in tetrahydrofuran was added dropwise lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 1.71 mL, 1.71 mmol, 1.02 eq) under nitrogen at -70°C. The mixture was stirred for 1.5 hours. A solution of iodomethane (429 mg, 3.02 mmol, 1.8 eq) in tetrahydrofuran was added dropwise and the mixture was stirred at -70°C for 1 hour. The mixture was then stirred at room temperature for 45 minutes. The reaction was quenched by the addition of ammonium chloride solution. The mixture was extracted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give methyl 2-(2-bromo-5-methoxyphenyl)propanoate (350 mg, yield: 75.9%) as a colorless oil. LCMS (ESI): m / z = 273 [M+H] +.

[0240] Step 22f: Preparation of methyl 2-(2-cyano-5-methoxyphenyl)propanoate: A mixture of methyl 2-(2-bromo-5-methoxyphenyl)propanoate (719 mg, 2.63 mmol, 1.0 eq) and cuprous cyanide (1.42 g, 15.80 mmol, 6.0 eq) in 8 mL of N-methylpyrrolidone was stirred and heated in a microwave at 180°C for 2 hours. The mixture was filtered through celite. The filtrate was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give methyl 2-(2-cyano-5-methoxyphenyl)propanoate (364 mg, yield: 63.1%) as a yellow oil. MS (ES) + ):m / z=220(M+H) + .

[0241] Step 22g: Preparation of methyl 2-(2-cyano-4-iodo-5-methoxyphenyl)propanoate: To a solution of methyl 2-(2-cyano-5-methoxyphenyl)propanoate (331 mg, 1.51 mmol, 1.0 eq) in trifluoroacetic acid (5 mL) was added N-iodosuccinimide (340 mg, 1.51 mmol, 1.0 eq) at room temperature and stirred for 6 hours. The mixture was concentrated and sodium carbonate solution was added. The mixture was extracted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 80 / 1 to 5 / 1) to give methyl 2-(2-cyano-4-iodo-5-methoxyphenyl)propanoate (355 mg, yield: 68.0%) as a yellow oil. LCMS (ESI): m / z = 346 [M+1] + .

[0242] Step 22h: Preparation of 2-(2-cyano-5-hydroxy-4-iodophenyl)propanoic acid: Under nitrogen, sodium hydride (145 mg, 3.63 mmol, 1.0 equiv) was added to a solution of ethanethiol (225 mg, 3.63 mmol, 5.0 equiv) in N,N-dimethylformamide (5 mL) at 0°C. The mixture was stirred at room temperature for 30 minutes. A solution of methyl 2-(2-cyano-4-iodo-5-methoxyphenyl)propanoate (250 mg, 0.725 mmol, 1.0 equiv) in N,N-dimethylformamide was added. The mixture was stirred at 155°C for 1 hour and quenched by the addition of dilute hydrochloric acid. The mixture was extracted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to 1 / 10) to give 2-(2-cyano-5-hydroxy-4-iodophenyl)propanoic acid (173 mg, yield: 75.1%) as a yellow oil. LCMS (ESI): m / z = 318 [M+1]+ .

[0243] Step 22i: Preparation of methyl 2-(2-cyano-5-hydroxy-4-iodophenyl)propanoate: Under nitrogen, to a mixture of 2-(2-cyano-5-hydroxy-4-iodophenyl)propanoic acid (160 mg, 0.505 mmol, 1.0 equiv) and N,N-dimethylformamide (0.05 mL) in 5 mL of dichloromethane was added dropwise oxalyl chloride (2 M in dichloromethane, 0.76 mL, 1.52 mmol, 3.00 equiv). The mixture was stirred at room temperature for 1.5 hours. 2 mL of methanol was added dropwise, and the mixture was stirred for 15 minutes. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 to 1 / 5) to give methyl 2-(2-cyano-5-hydroxy-4-iodophenyl)propanoate (145 mg, yield: 86.8%) as a yellow oil. MS (ES + ):m / z=332(M+H) + .

[0244] Step 22j: Preparation of methyl 2-(5-cyanobenzofuran-6-yl)propanoate: Under nitrogen, a mixture of methyl 2-(2-cyano-5-hydroxy-4-iodophenyl)propanoate (130 mg, 0.393 mmol, 1.0 equiv), trimethylsilylacetylene (192 mg, 0.393 mmol, 1.0 equiv), cuprous iodide (38 mg, 0.197 mmol, 0.5 equiv), dichlorobistriphenylphosphine palladium (28 mmol, 0.04 mmol, 0.1 equiv), and N,N-diisopropylethylamine (253 mg, 1.96 mmol, 5.0 equiv) in 15 mL of tetrahydrofuran was stirred at 66° C. for 1.5 hours. The mixture was filtered through celite. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 10 ml of methanol, and then cuprous iodide (75 mg, 0.393 mmol, 1.0 eq) and N,N-diisopropylethylamine (253 mg, 1.96 mmol, 2.5 eq) were added. The mixture was stirred at 72°C for 2 hours. The mixture was diluted with dichloromethane and washed with ammonium chloride solution and saturated brine. The organic phase was dried and concentrated to dryness under reduced pressure. The residue was dissolved in 12 ml of tetrahydrofuran, and tetrabutylammonium fluoride (100 mg, 0.32 mmol, 0.8 eq) was added. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried and concentrated to dryness under reduced pressure. The residue was purified by thick preparative thin layer chromatography (developing solvent: petroleum ether / ethyl acetate = 20 / 1) to give methyl 2-(5-cyanobenzofuran-6-yl)propanoate (46 mg, yield: 51.1%) as a colorless oil. MS (ES + ):m / z=230(M+H) + .

[0245] Step 22k: Preparation of 2-(5-cyanobenzofuran-6-yl)propanoic acid: To a solution of methyl 2-(5-cyanobenzofuran-6-yl)propanoate (46 mg, 0.2 mmol, 1.0 eq) in tetrahydrofuran / water (2 mL / 0.5 mL) was added lithium hydroxide (17 mg, 0.4 mmol, 2.0 eq). The mixture was stirred at room temperature for 1 hour. The mixture was acidified with dilute hydrochloric acid. Ethyl acetate was added for extraction, and the mixture was washed with water and saturated brine. The organic phase was dried and concentrated under reduced pressure to give 2-(5-cyanobenzofuran-6-yl)propanoic acid (30 mg, yield: 69.7%) as a yellow solid. LCMS (ESI): m / z = 216 [M+1] + .

[0246] Step 221: Preparation of 6-(1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)-1-oxopropan-2-yl)benzofuran-5-carbonitrile (Compound 77): (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122- A mixture of 2-(5-cyanobenzofuran-6-yl)propanoic acid (30 mg, 0.1 mmol, 1.0 equiv), N,N-diisopropylethylamine (40 mg, 0.3 mmol, 3.0 equiv), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol, 1.1 equiv) in dichloromethane (2 ml) was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol = 20 / 1) to obtain 6-(1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-oxopropan-2-yl)benzofuran-5-carbonitrile (38 mg, yield: 88.3%) as a yellow solid. LCMS (ESI): m / z = 465 [M+H] + . 1H NMR(500MHz,MeOD)δ8.81(dt,J=8.6,4.4Hz,2H),8.15–7.62(m,4H),7.33–7.12(m,1H),6.93(dd,J=37.9,1.3Hz,1H) ,4.57–4.30(m,1H),4.04–3.42(m,4H),2.92–2.61(m,2H),2.63–2.42(m,3H),2.20–1.69(m,4H),1.64–1.49(m,3H).

[0247] Example 23: Preparation of (2R)-1-(5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Compound 55) (Prepared according to Schemes 1 and 4)

[0248] Step 23a: Preparation of 1-(tert-butyl)-2-methyl-4-hydroxy-4-(trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (Compound 0102-55): To a mixture of ethynyltrimethylsilane (4.85 g, 49.33 mmol, 1.2 eq) in tetrahydrofuran (60 mL) at -78°C was added n-butyllithium (2.5 M in hexanes, 17.3 mL, 43.16 mmol, 1.05 eq) dropwise. The mixture was stirred at -78°C under nitrogen for 1 hour. A solution of tert-butyl 2-acetoxy-4-oxopyrrolidine-1-carboxylate (0101-55) (10.0 g, 41.11 mmol, 1.0 eq) in tetrahydrofuran (40 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding saturated ammonium chloride solution (60 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 1-(tert-butyl)-2-methyl-4-hydroxy-4-(trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (12.2 g, yield: 87%) as a brown oil. LCMS (ESI): m / z 342 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=60:1).

[0249] Step 23b: Preparation of 1-(tert-butyl)-2-methyl-4-ethynyl-4-hydroxypyrrolidine-1,2-dicarboxylate (Compound 0103-55): To a mixture of 1-(tert-butyl)-2-methyl-4-hydroxy-4-(trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (0102-55) (12.2 g, 35.78 mmol, 1.0 eq) in methanol (50 mL) was added potassium carbonate (7.4 g, 53.67 mmol, 1.5 eq). The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was diluted with water (60 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 1-(tert-butyl)-2-methyl-4-ethynyl-4-hydroxypyrrolidine-1,2-dicarboxylate (5.61 g, yield: 58%) as a brown oil. LCMS (ESI): m / z 270 [M+1] + ; TLC: Rf 0.4 (petroleum ether:ethyl acetate=3:1).

[0250] Step 23c: Preparation of 1-(tert-butyl)-2-methyl-4-acetoxy-4-ethynylpyrrolidine-1,2-dicarboxylate (Compound 0104-55): To a mixture of 1-(tert-butyl)-2-methyl-4-ethynyl-4-hydroxypyrrolidine-1,2-dicarboxylate (0103-55) (5.61 g, 20.86 mmol, 1.0 equiv) and N,N-diisopropylethylamine (9.2 mL, 52.14 mmol, 2.5 equiv) in dichloromethane (50 mL) was added acetyl chloride (2.68 mL, 35.46 mmol, 1.7 equiv) dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate 5:1) to give 1-(tert-butyl)-2-methyl-4-acetoxy-4-ethynylpyrrolidine-1,2-dicarboxylate (4.92 g, yield: 76%) as a pale yellow oil. LCMS (ESI): m / z 312 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0251] Step 23d: Preparation of 1-(tert-butyl)-2-methyl-4-ethynyl-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (Compound 0105-55): To a mixture of p-methoxybenzylamine (4.16 g, 30.35 mmol, 2.0 equiv) and cuprous chloride (0.15 g, 1.52 mmol, 0.1 equiv) in tetrahydrofuran (50 mL) was added dropwise a solution of 1-(tert-butyl)-2-methyl-4-acetoxy-4-ethynylpyrrolidine-1,2-dicarboxylate (0104-55) (4.72 g, 15.18 mmol, 1.0 equiv) in tetrahydrofuran (30 mL) at 70°C. The mixture was stirred at 70°C under a nitrogen atmosphere for 1.5 hours. The mixture was diluted with water (50 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate 8:1) to afford 1-(tert-butyl)-2-methyl-4-ethynyl-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (2.06 g, yield: 35%) as a pale yellow oil. LCMS (ESI): m / z 389 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=4:1).

[0252] Step 23e: Preparation of 1-(tert-butyl)-2-methyl-4-((2-chloro-6-methylpyridin-3-yl)ethynyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (Compound 0108-55): To 2-chloro-3-iodo-6-methylpyridine (0107-1) (1.41 g, 5.57 mmol, 1.05 equiv), bistriphenylphosphine palladium dichloride (0 To a mixture of 1-(tert-butyl)-2-methyl-4-ethynyl-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (0105-55) (2.06 g, 5.31 mmol, 1.0 equiv) and cuprous iodide (51 mg, 0.266 mmol, 0.05 equiv) in triethylamine (25 ml) was added 1-(tert-butyl)-2-methyl-4-ethynyl-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (0105-55) (2.06 g, 5.31 mmol, 1.0 equiv). The mixture was heated to 80°C under a nitrogen atmosphere for 3.5 hours. The solvent was removed under reduced pressure. The residue was diluted with water (50 ml) and then extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 6:1 to 2:1) to give 1-(tert-butyl)2-methyl-4-((2-chloro-6-methylpyridin-3-yl)ethynyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (2.10 g, yield: 77%) as a pale yellow oil. LCMS (ESI): m / z 514 [M+1] + ; TLC: Rf 0.4 (petroleum ether:ethyl acetate=3:1).

[0253] Step 23f: Preparation of 1-(tert-butyl)-2-methyl-4-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (Compound 0109-55): To a mixture of 1-(tert-butyl)-2-methyl-4-((2-chloro-6-methylpyridin-3-yl)ethynyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (0108-55) (2.1 g, 4.09 mmol, 1.0 equiv) in methanol (20 mL) was added platinum dioxide (0.186 g, 0.82 mmol, 0.2 equiv). The mixture was stirred at room temperature under hydrogen balloon pressure for 40 h. The mixture was filtered. The filtrate was concentrated under reduced pressure to give 1-(tert-butyl)-2-methyl-4-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (2.14 g, crude) as a pale yellow oil. LCMS (ESI): m / z 518 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=2:1).

[0254] Step 23g: Preparation of tert-butyl 1'-(4-methoxybenzyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0110-55):

[0255] To a mixture of 1-(tert-butyl)-2-methyl-4-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (0109-55) (2.14 g, 4.14 mmol, 1.0 eq), palladium acetate (46 mg, 0.21 mmol, 0.05 eq), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (191 mg, 0.41 mmol, 0.1 eq) in N-methylpyrrolidone (20 ml) was added sodium tert-butoxide (0.795 g, 8.28 mmol, 2.0 eq). The mixture was heated to 100°C in a microwave reactor for 1 hour. The mixture was diluted with water (40 ml). 2M sodium hydroxide solution was added to adjust the pH to 12, and the mixture was then washed with methyl tert-butyl ether (15 ml x 2). 1M dilute hydrochloric acid solution was added to the aqueous layer to adjust the pH to 7, and then extracted with ethyl acetate (20 ml x 4). The combined organic layers were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated to give 1-(tert-butyloxycarbonyl)-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-5-carboxylic acid (2.13 g, crude) as a brown oil. LCMS (ESI): m / z 468 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=10:1).

[0256] To a mixture of 1-(tert-butyloxycarbonyl)-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-5-carboxylic acid (1.63 g, 3.49 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was added borane dimethyl sulfide complex (10 M solution in dimethyl sulfide, 0.87 mL, 8.73 mmol, 2.5 equiv). The mixture was heated to 65°C under a nitrogen atmosphere for 1.5 hours. The reaction was quenched by the addition of water (50 mL). The aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 5-(hydroxymethyl)-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (1.39 g, yield: 88%) as a pale yellow oil. LCMS (ESI): m / z 454 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=20:1).

[0257] To a mixture of tert-butyl 5-(hydroxymethyl)-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0.79 g, 1.74 mmol, 1.0 equiv) and N,N-diisopropylethylamine (449 mg, 3.48 mmol, 2.0 equiv) in dichloromethane (10 mL) was added methanesulfonyl chloride (0.2 mL, 2.62 mmol, 1.5 equiv) dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 22 hours. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate 3:1) to give tert-butyl 1'-(4-methoxybenzyl)-7'-methyl-5-(((methylsulfonyl)oxy)methyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0.545 g, yield: 59%) as a pale yellow oil. LCMS (ESI): m / z 532 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=20:1).

[0258] To a mixture of tert-butyl 1'-(4-methoxybenzyl)-7'-methyl-5-(((methylsulfonyl)oxy)methyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0.545 g, 1.03 mmol, 1.0 equiv) in tetrahydrofuran (6 mL) was added dropwise lithium triethylborohydride (1 M solution in tetrahydrofuran, 3.09 mL, 3.09 mmol, 3.0 equiv) at 0°C. The mixture was allowed to warm to room temperature and then stirred for 6 hours. The reaction was quenched by the addition of water (30 mL). The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl 1'-(4-methoxybenzyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (480 mg, crude) as a pale yellow oil. LCMS (ESI): m / z 438 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=5:1).

[0259] Step 23h: Preparation of tert-butyl 5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0112-55): To a mixture of tert-butyl 1'-(4-methoxybenzyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0110-55) (450 mg, 1.03 mmol, 1.0 equiv) in dichloromethane (6 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (10 mL) and tetrahydrofuran (10 mL). Solid sodium carbonate was added to adjust the pH to 9. Di-tert-butyl dicarbonate (449 mg, 2.06 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate 3:1) to obtain tert-butyl 5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (193 mg, yield: 59%) as a pale yellow oil. LCMS (ESI): m / z 318 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

[0260] Step 23i: Preparation of tert-butyl 6'-bromo-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0115-55): To a mixture of tert-butyl 5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0112-55) (193 mg, 0.61 mmol, 1.0 equiv) in dichloromethane (5 mL) at 0°C was added dibromohydantoin (96 mg, 0.34 mmol, 0.55 equiv). The mixture was stirred at 0°C for 20 minutes. The reaction was quenched by the addition of saturated aqueous sodium sulfite (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 6'-bromo-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (255 mg, crude) as a pale yellow oil. LCMS (ESI): m / z 396 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0261] Step 23j: Preparation of (1-(tert-Butyloxycarbonyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (Compound 0117-55): To tert-butyl 6'-bromo-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0115-55) (242 mg, 0.61 mmol, 1.0 equiv), Xphos-Pd-G To a mixture of 2 (9.6 mg, 0.012 mmol, 0.02 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (8.7 mg, 0.018 mmol, 0.03 eq), potassium acetate (424 mg, 4.32 mmol, 2.5 eq), and sodium tert-butoxide (4.2 mg, 0.043 mmol, 0.025 eq) was added tetrahydroxydiboron (137 mg, 1.532 mmol, 2.5 eq) in methanol (6 ml) and ethylene glycol (0.6 ml). The mixture was heated to 55°C under a nitrogen atmosphere for 1.5 hours. The solvent was removed under reduced pressure. The residue was diluted with water (20 ml). 2M sodium hydroxide solution was added to adjust the pH to 12, and the mixture was then washed with methyl tert-butyl ether (10 ml x 2). 2M dilute hydrochloric acid solution was added to the aqueous layer to adjust the pH to 8, followed by extraction with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (15 ml), dried over anhydrous sodium sulfate, and concentrated to afford (1-(tert-butyloxycarbonyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridin]-6'-yl)boronic acid (165 mg, yield: 75%) as a colorless oil. LCMS (ESI): m / z 362 [M+1] + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0262] Step 23k: Preparation of tert-butyl 5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0119-55): To (1-(tert-butyloxycarbonyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (0117-55) (165 mg, 0.457 mmol, 1.0 To a mixture of toluene (2.5 ml), ethanol (2.5 ml) and water (1 ml) was added 2-bromopyrimidine (76 mg, 0.480 mmol, 1.05 equiv), Xphos-Pd-G2 (10.8 mg, 0.014 mmol, 0.03 equiv), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (6.7 mg, 0.014 mmol, 0.03 equiv), and sodium carbonate (145 mg, 1.37 mmol, 3.0 equiv). The mixture was heated to 55°C under a nitrogen atmosphere for 4 hours. The mixture was diluted with water (20 ml) and then extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate:petroleum ether = 5:1) to give tert-butyl 5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (109 mg, yield: 60%) as a pale yellow solid. LCMS (ESI): m / z 396 [M+1] + ; TLC: Rf 0.5 (ethyl acetate:petroleum ether=5:1).

[0263] Step 231: Preparation of 5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (Compound 0121-55): A mixture of tert-butyl 5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0119-55) (109 mg, 0.276 mmol, 1.0 equiv) in hydrogen chloride / methanol solution (4 M solution, 2 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give 5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (105 mg, crude) as a pale yellow solid. LCMS (ESI): m / z 296 [M+1] + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0264] Step 23m: Preparation of (2R)-1-(5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Compound 55): To (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0406-7) (27.5 mg, 0.138 mmol, 1.0 equiv), benzotriazole-N,N,N',N'-tetramethyluronium hexafluoro To a mixture of phosphate (63 mg, 0.166 mmol, 1.2 eq), 1-hydroxybenzotriazole (20 mg, 0.152 mmol, 1.1 eq), and N,N-diisopropylethylamine (89 mg, 0.69 mmol, 5.0 eq) in dichloromethane (3 ml) was added 5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0121-55) (51 mg, 0.138 mmol, 1.0 eq). The mixture was stirred at room temperature overnight. The mixture was diluted with water (20 ml) and then extracted with ethyl acetate (10 ml x 3). The combined organic layers were washed with saturated brine (15 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:aqueous ammonia = 80:3:0.8) to give (2R)-1-(5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (51 mg, yield: 78%) as a white solid. LCMS (ESI): m / z 477 [M+1] + ; TLC: Rf 0.5 (dichloromethane: methanol = 20:1). 1 H NMR(500MHz,MeOD)δ8.82(dt,J=9.0,5.0Hz,2H),7.88(ddd,J=127.8,64.9,35.9Hz,2H),7.34–7.24(m,1H),6.93–6.66(m,1H),4.43–4.06(m,2H), 3.87(dd,J=19.4,11.6Hz,3H),3.75–3.45(m,2H),2.93–2.68(m,2H),2.6 3–2.53(m,3H),2.38–2.13(m,1H),2.01–1.61(m,3H),1.45–1.31(m,6H).

[0265] Example 24: Preparation of (R)-1-((3R,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Compound 100) (Prepared according to Schemes 4 and 5)

[0266] Step 24a: Preparation of tert-butyl (3S,5S)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0113-100):

[0267] To a mixture of ethynyltrimethylsilane (7.27 g, 73.99 mmol, 1.2 eq) in tetrahydrofuran (70 mL) was added n-butyllithium (2.5 M in hexane, 25.90 mL, 64.74 mmol, 1.05 eq) dropwise at -78°C. The mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour. A solution of (S)-tert-butyl 2-acetoxy-4-oxopyrrolidine-1-carboxylate (15.0 g, 61.66 mmol, 1.0 eq) in tetrahydrofuran (50 mL) was added dropwise. The mixture was allowed to warm to room temperature and then stirred overnight. The reaction was quenched by the addition of saturated ammonium chloride solution (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to afford 1-(tert-butyl)-2-methyl (2R)-4-hydroxy-4-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (17.5 g, yield: 83%) as a brown solid. LCMS (ESI): m / z 342 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=60:1).

[0268] To a mixture of 1-(tert-butyl)-2-methyl(2R)-4-hydroxy-4-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (17.5 g, 51.32 mmol, 1.0 eq) in methanol (45 mL) was added potassium carbonate (10.6 g, 76.98 mmol, 1.5 eq). The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was diluted with water (80 mL) and then extracted with ethyl acetate (50 mL x 4). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 1-(tert-butyl)-2-methyl(2R)-4-ethynyl-4-hydroxypyrrolidine-1,2-dicarboxylate (9.74 g, yield: 71%) as a brown oil. LCMS (ESI): m / z 270 [M+1] +; TLC: Rf 0.4 (petroleum ether:ethyl acetate=3:1).

[0269] To a mixture of 1-(tert-butyl)-2-methyl(2R)-4-ethynyl-4-hydroxypyrrolidine-1,2-dicarboxylate (9.74 g, 36.21 mmol, 1.0 eq) and N,N-diisopropylethylamine (11.68 g, 90.52 mmol, 2.5 eq) in dichloromethane (100 mL) was added acetyl chloride (4.65 mL, 61.56 mmol, 1.7 eq) dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was diluted with water (60 mL) and then extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate 4:1) to give 1-(tert-butyl)-2-methyl (2R)-4-acetoxy-4-ethynylpyrrolidine-1,2-dicarboxylate (9.50 g, yield: 84%) as a pale yellow oil. LCMS (ESI): m / z 312 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0270] To a mixture of p-methoxybenzylamine (20.29 g, 147.9 mmol, 2.0 eq) and cuprous chloride (0.732 g, 7.40 mmol, 0.1 eq) in tetrahydrofuran (250 ml) at 70°C was added dropwise a solution of 1-(tert-butyl)-2-methyl(2R)-4-acetoxy-4-ethynylpyrrolidine-1,2-dicarboxylate (23 g, 73.95 mmol, 1.0 eq) in tetrahydrofuran (100 ml). The mixture was stirred at 70°C under a nitrogen atmosphere for 1.5 hours. The mixture was diluted with water (150 ml) and then extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate 8:1) to give 1-(tert-butyl)-2-methyl(2R)-4-ethynyl-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (9.26 g, yield: 32%) as a pale yellow oil. LCMS (ESI): m / z 389 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=4:1).

[0271] To a mixture of 2-chloro-3-iodo-6-methylpyridine (0107-1) (6.33 g, 25.06 mmol, 1.05 eq), bistriphenylphosphine palladium dichloride (0.838 g, 1.19 mmol, 0.05 eq), and cuprous iodide (0.227 g, 1.19 mmol, 0.05 eq) in triethylamine (100 ml) was added 1-(tert-butyl)-2-methyl(2R)-4-ethynyl-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (9.26 g, 23.87 mmol, 1.0 eq). The mixture was heated to 80°C under a nitrogen atmosphere for 8 hours. The solvent was removed under reduced pressure. The residue was diluted with water (50 ml) and then extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate 6:1 to 3:1) to afford 1-(tert-butyl)-2-methyl (2R)-4-((2-chloro-6-methylpyridin-3-yl)ethynyl)-4-(4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (10.02 g, yield: 82%) as a pale yellow oil. LCMS (ESI): m / z 514 [M+1]. + ; TLC: Rf 0.4 (petroleum ether:ethyl acetate=3:1).

[0272] To a mixture of 1-(tert-butyl)-2-methyl (2R)-4-((2-chloro-6-methylpyridin-3-yl)ethynyl)-4-(4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (10.02 g, 19.53 mmol, 1.0 equiv) in methanol (80 mL) was added platinum dioxide (0.887 g, 39.06 mmol, 0.2 equiv). The mixture was stirred at room temperature under hydrogen balloon pressure for 40 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure to give 1-(tert-butyl)-2-methyl (2R)-4-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (9.56 g, crude) as a pale yellow oil. LCMS (ESI): m / z 518 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=2:1).

[0273] To a mixture of 1-(tert-butyl)-2-methyl(2R)-4-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1,2-dicarboxylate (9.0 g, 17.41 mmol, 1.0 eq) in tetrahydrofuran (60 ml) at 0°C was slowly added lithium aluminum tetrahydride (2.65 g, 69.63 mmol, 4.0 eq). The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was cooled to 0°C. Water (10.5 ml) and 15% sodium hydroxide solution (2.65 ml) were added. The mixture was allowed to warm to room temperature and stirred for 10 minutes. The mixture was diluted with ethyl acetate (50 ml) and then filtered. The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl (2R)-4-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-2-(hydroxymethyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (8.05 g, yield: 95%) as a pale yellow oil. LCMS (ESI): m / z 490 [M+1]. + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=2:1).

[0274] To a mixture of tert-butyl (2R)-4-(2-(2-chloro-6-methylpyridin-3-yl)ethyl)-2-(hydroxymethyl)-4-((4-methoxybenzyl)amino)pyrrolidine-1-carboxylate (8.05 g, 16.46 mmol, 1.0 equiv), palladium acetate (0.184 g, 0.82 mmol, 0.05 equiv), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.77 g, 1.65 mmol, 0.1 equiv) in N-methylpyrrolidone (50 ml) was added sodium tert-butoxide (3.16 g, 32.92 mmol, 2.0 equiv). The mixture was heated to 100°C in a microwave reactor for 1 hour. The mixture was diluted with water (20 ml) and tetrahydrofuran (20 ml). Di-tert-butyl dicarbonate (4.67 g, 21.40 mmol, 1.3 eq) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (60 mL) and then extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (petroleum ether:ethyl acetate 8:1 to 3:1) to give (3S,5R)-5-(hydroxymethyl)-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (833 mg, yield: 11%) as a pale yellow oil. LCMS (ESI): m / z 454 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=2:1).

[0275] To a mixture of tert-butyl (3S,5R)-5-(hydroxymethyl)-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (833 mg, 1.84 mmol, 1.0 equiv) and N,N-diisopropylethylamine (475 mg, 3.68 mmol, 2.0 equiv) in dichloromethane (10 mL) was added methanesulfonyl chloride (0.21 mL, 2.76 mmol, 1.5 equiv) dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (15 mL x 4). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate 3:1) to give (3S,5R)-1'-(4-methoxybenzyl)-7'-methyl-5-(((methylsulfonyl)oxy)methyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (0.92 g, yield: 94%) as a pale yellow oil. LCMS (ESI): m / z 532 [M+1]. + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=2:1).

[0276] To a mixture of tert-butyl (3S,5R)-1'-(4-methoxybenzyl)-7'-methyl-5-(((methylsulfonyl)oxy)methyl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0.92 g, 1.73 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added dropwise lithium triethylborohydride (1 M solution in tetrahydrofuran, 6.93 mL, 6.93 mmol, 4.0 equiv) at 0°C. The mixture was allowed to warm to room temperature and then stirred overnight. The reaction was quenched by the addition of water (30 mL). The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl (3S,5S)-1'-(4-methoxybenzyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (800 mg, crude) as a pale yellow oil. LCMS (ESI): m / z 438 [M+1]. + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=5:1).

[0277] To a mixture of tert-butyl (3S,5S)-1'-(4-methoxybenzyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (756 mg, 1.73 mmol, 1.0 eq) in dichloromethane (12 ml) was added trifluoroacetic acid (3 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (10 ml) and tetrahydrofuran (10 ml). Solid sodium carbonate was added to adjust the pH to 9. Di-tert-butyl dicarbonate (566 mg, 2.60 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 ml) and then extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate 3:1) to give (3S,5S)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (548 mg, yield: 100%) as a pale yellow oil. LCMS (ESI): m / z 318 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1).

[0278] Step 24b: Preparation of tert-butyl (3S,5S)-6'-bromo-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (Compound 0116-100): To a mixture of tert-butyl (3S,5S)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (0113-100) (548 mg, 1.73 mmol, 1.0 equiv) in dichloromethane (10 mL) at 0°C was added dibromohydantoin (272 mg, 0.95 mmol, 0.55 equiv). The mixture was stirred at 0°C for 0.5 h. The reaction was quenched by the addition of saturated aqueous sodium sulfite (15 mL). The aqueous layer was extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow oily substance, tert-butyl (3S,5S)-6'-bromo-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (754 mg, crude product). LCMS (ESI): m / z 396 [M+1] + ; TLC: Rf 0.5 (petroleum ether:ethyl acetate=3:1).

[0279] Step 24c: Preparation of ((3S,5S)-1-(tert-Butyloxycarbonyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (Compound 0118-100): To (3S,5S)-6'-bromo-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (0116-100) (685 mg, 1.73 mmol, 1.0 equiv) , Xphos-Pd-G2 (27 mg, 0.035 mmol, 0.02 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (25 mg, 0.052 mmol, 0.03 eq), potassium acetate (424 mg, 4.32 mmol, 2.5 eq) and sodium tert-butoxide (4.2 mg, 0.043 mmol, 0.025 eq) were added to a mixture of methanol (10 ml) and ethylene glycol (1 ml). Tetrahydroxydiboron (388 mg, 4.32 mmol, 2.5 eq) was added. The mixture was heated to 55° C. under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml). 2M sodium hydroxide solution was added to adjust the pH to 12, and then the mixture was washed with methyl tert-butyl ether (10 ml×2). 2M dilute hydrochloric acid solution was added to the aqueous layer to adjust the pH to 8, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to afford ((3S,5S)-1-(tert-butyloxycarbonyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridin]-6'-yl)boronic acid (299 mg, yield: 48%) as a white solid. LCMS (ESI): m / z 362 [M+1] + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0280] Step 24d: Preparation of (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (Compound 0120-100): To ((3S,5S)-1-(tert-Butyloxycarbonyl)-5,7'-dimethyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-6'-yl)boronic acid (0118-100) (299 mg, 0. To a mixture of toluene (5 ml), ethanol (5 ml) and water (2 ml) was added 2-bromopyrimidine (151 mg, 0.95 mmol, 1.15 equiv), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (11.9 mg, 0.025 mmol, 0.03 equiv), and sodium carbonate (263 mg, 2.48 mmol, 3.0 equiv). The mixture was heated to 55°C under a nitrogen atmosphere for 5 hours. The solvent was removed under reduced pressure. The residue was diluted with water (20 ml) and then extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (15 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography on silica gel (dichloromethane:methanol 50:1 to 25:1) to afford tert-butyl (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (270 mg, yield: 83%) as a pale yellow solid. LCMS (ESI): m / z 396 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=20:1).

[0281] Step 24e: Preparation of (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (0120-100) (270 mg, 0.68 mmol, 1.0 equiv) in hydrogen chloride / methanol solution (4 M solution, 2 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dried under vacuum to give (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (270 mg, crude) as a pale yellow solid. LCMS (ESI): m / z 296 [M+1] + ; TLC: Rf 0.3 (dichloromethane:methanol=10:1).

[0282] Step 24f: Preparation of (R)-1-((3R,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Compound 100): To (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0406-7) (95 mg, 0.476 mmol, 1.0 equiv), 6-chlorobenzotriazole-1, To a mixture of 1,3,3-tetramethyluronium hexafluorophosphate (217 mg, 0.524 mmol, 1.1 eq) and N,N-diisopropylethylamine (196 mg, 1.523 mmol, 3.2 eq) in dichloromethane (7 mL) was added (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-100) (175 mg, 0.476 mmol, 1.0 eq). The mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:aqueous ammonia = 80:2.5:0.8) to give (R)-1-((3R,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (152 mg, yield: 67%) as a white solid. LCMS (ESI): m / z 477 [M+1] + ; TLC: Rf 0.5 (dichloromethane:methanol=15:1). 1H NMR(500MHz,MeOD)δ8.81(d,J=4.9Hz,2H),7.93(d,J=31.5Hz,2H),7.31(t,J=4.9Hz, 1H),6.70(d,J=4.8Hz,1H),4.46–4.30(m,1H),4.16(d,J=6.9Hz,1H),3.88(d,J =9.9Hz,3H),3.73(d,J=10.8Hz,1H),3.24(d,J=11.0Hz,1H),2.90–2.68(m,2H), 2.57(d,J=19.3Hz,3H), 2.33(dd,J=12.7,8.2Hz,1H), 1.89(dd,J=14.9,7.6Hz, 2H), 1.69 (dd, J=13.2, 8.7Hz, 1H), 1.40 (d, J=6.9Hz, 3H), 1.31 (d, J=6.1Hz, 3H).

[0283] Example 25: Preparation of 4-(1-((3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)-1-oxopropan-2-yl)-6-methoxynicotinonitrile (Compound 96) (Prepared according to Scheme 4):

[0284] (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-1 λ 2A mixture of 2-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-100) (88 mg, 0.24 mmol, 1.0 eq), 2-(5-cyano-2-methoxypyridin-4-yl)propanoic acid (0405-11) (59 mg, 0.29 mmol, 1.2 eq), N,N-diisopropylethylamine (186 mg, 1.44 mmol, 6.0 eq) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol, 1.2 eq) in dichloromethane (4 ml) was stirred for one hour. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol / aqueous ammonia = 80 / 4.5 / 0.8) to afford 4-(1-((3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)-1-oxopropan-2-yl)-6-methoxynicotinonitrile (20 mg, yield: 17.24%) as a pale yellow solid. LCMS (ESI): m / z = 484 [M+H] + . 1 H NMR(500MHz,MeOD)δ8.82(dd,J=14.2,4.9Hz,2H),8.32(d,J=184.6Hz,1H),7.84(d,J=22.5 Hz,1H),7.31(dt,J=9.7,4.9Hz,1H),6.89(d,J=31.8Hz,1H),4.45–4.32(m,1H),4.13(dd,J= 77.8,6.8Hz,1H),3.98(d,J=6.6Hz,3H),3.71(dd,J=74.4,10.3Hz,1H),3.51(dd,J=40.4,10 .8Hz,1H),2.91–2.82(m,2H),2.52(d,J=13.6Hz,3H),2.09–1.66(m,4H),1.49–1.34(m,6H).

[0285] Example 26: Preparation of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((3S,5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 103):

[0286] Step 26a: Preparation of (9H-fluoren-9-yl)methyl (3S,5R)-5-(hydroxymethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate: A solution of tert-butyl (3S,5R)-5-(hydroxymethyl)-1'-(4-methoxybenzyl)-7'-methyl-3',4'-dihydro-1'-H-pyrrolo[3,2'-[1,8]naphthyridine]-1-carboxylate (500 mg, 1.10 mmol, 1.0 equiv) in hydrogen chloride / dioxane (5 mL) was stirred at room temperature for one hour. The reaction was concentrated under vacuum. The residue was added with tetrahydrofuran (10 ml), 9-fluorenylmethyl chloroformate (424 mg, 1.66 mmol, 1.5 eq), and triethylamine (335 mg, 3.30 mmol, 3.0 eq). The mixture was then stirred at room temperature for two hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain a yellow solid product, (9H-fluoren-9-yl)methyl (3S,5R)-5-(hydroxymethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (380 mg, yield: 75.55%). LCMS (ESI): m / z = 456 [M+1] + .

[0287] Step 26b: Preparation of (9H-fluoren-9-yl)methyl (3S,5R)-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate: Under nitrogen, to a solution of (9H-fluoren-9-yl)methyl (3S,5R)-5-(hydroxymethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (380 mg, 0.83 mmol, 1.0 equiv) in dichloromethane (5 ml) was added diethylaminosulfur trifluoride (269 mg, 1.67 mmol, 2.0 equiv) at 0°C, and the mixture was stirred at 0°C for 1.0 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified on a silica gel column (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain a yellow solid product, (9H-fluoren-9-yl)methyl (3S,5R)-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (278 mg, yield: 72.97%). LCMS (ESI): m / z = 458 [M+1] + .

[0288] Step 26c: Preparation of (9H-fluoren-9-yl)methyl (3S,5R)-6'-bromo-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'-pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate: Under nitrogen protection at 0°C, to (9H-fluoren-9-yl)methyl (3S,5R)-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'-pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (87 mg, 0.303 mmol, 0.5 eq) was added dropwise to a solution of 4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (278 mg, 0.61 mmol, 1.0 eq) in dichloromethane (5 ml), and the mixture was stirred at 0°C for 1.0 hour. The reaction solution was quenched with sodium carbonate solution and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give (9H-fluoren-9-yl)methyl (3S,5R)-6'-bromo-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'-pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate as a yellow solid (230 mg, yield: 70.77%). LCMS (ESI): m / z = 537 [M+1] + .

[0289] Step 26d: Preparation of tert-butyl (3S,5R)-6'-bromo-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate: A solution of (9H-fluoren-9-yl)methyl (3S,5R)-6'-bromo-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'-pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (230 mg, 0.43 mmol, 1.0 equiv) in piperidine / dichloromethane (1 mL / 4 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. To the residue was added di-tert-butyl dicarbonate (188 mg, 0.86 mmol, 2.0 equiv) and tetrahydrofuran (5 mL). The mixture was stirred at room temperature for one hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain a yellow oily product (3S,5R)-6'-bromo-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylic acid tert-butyl ester (150 mg, yield: 84.75%). LCMS (ESI): m / z = 414 [M+1] + .

[0290] Step 26e: Preparation of tert-butyl (3S,5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-pyrrolo[3,2'-[1,8]naphthyridine]-1-carboxylate: Under nitrogen protection, tert-butyl (3S,5R)-6'-bromo-5-(fluoromethyl)-7'-methyl-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-carboxylate (150 mg, 0.36 mmol, 1.0 equiv), 2-(tributyltinyl)pyrimidine (268 mg, 0.72 mmol, 2.0 equiv), iodide A mixture of copper (I) (7 mg, 0.036 mmol, 0.1 eq), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (16 mg, 0.018 mmol, 0.05 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (18 mg, 0.036 mmol, 0.1 eq), and cesium fluoride (111 mg, 0.72 mmol, 3.0 eq) in N,N-dimethylformamide (5 ml) was stirred and heated in a microwave at 100°C for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain tert-butyl (3S,5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-pyrrolo[3,2'-[1,8]naphthyridine]-1-carboxylate as a yellow solid (64 mg, yield: 42.67%). LCMS (ESI): m / z = 414 [M+1] + .

[0291] Step 26f: Preparation of (3S,5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-pyrrolo[3,2'-[1,8]naphthyridine] dihydrochloride: A mixture of tert-butyl (3S,5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-pyrrolo[3,2'-[1,8]naphthyridine]-1-carboxylate (64 mg, 0.15 mmol, 1.0 equiv) in hydrogen chloride in dioxane (4 M solution, 2.5 mL) was stirred at room temperature for 1.0 h. The solvent was removed under reduced pressure and the residue was dried under vacuum. The residue was used in the next step without further purification. LCMS (ESI): m / z = 314 [M+1]. + .

[0292] Step 26g: Preparation of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((3S,5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (Compound 103): To (R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (0406-7) (31 mg, 0.155 mmol, 1.0 equiv), (3S, To a solution of 5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-H-pyrrolo[3,2'-[1,8]naphthyridine] dihydrochloride (crude product) and N,N-diisopropylethylamine (50 mg, 0.388 mmol, 2.5 eq) in dichloromethane (3 ml) was added 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (77 mg, 0.186 mmol, 1.2 eq). The mixture was stirred at room temperature for 1.0 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((3S,5R)-5-(fluoromethyl)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'-pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (32 mg, 42.11% yield) as a yellow solid. LCMS (ESI): m / z = 495 [M+1] + . 1 H NMR (500MHz, MeOD) δ8.82(t,J=6.2Hz,2H),7.96(s,1H),7.86(s,1H),7.30(t,J=4.9Hz,1H),6.69( d,J=4.9Hz,1H),4.93(dd,J=9.3,3.2Hz,1H),4.61–4.37(m,2H),4.20(q,J=6.8Hz,1H),3.88(d,J=1 3.8Hz,3H),3.76(d,J=10.7Hz,1H),3.13(d,J=10.8Hz,1H),2.93–2.72(m,2H),2.56(d,J=16.9Hz, 3H),2.31–2.15(m,1H),2.10(dd,J=13.3,9.0Hz,1H),1.90(t,J=6.4Hz,2H),1.41(d,J=6.9Hz,3H).

[0293] Example 27: Preparation of 2-(5-chloro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione (Compound 10) (prepared according to Schemes 4 and 5):

[0294] Step 27a: Preparation of methyl 2-(5-chloro-2-methoxypyridin-4-yl)acetate (0409-10): Under nitrogen, to a solution of diisopropylamine (1.23 g, 12.22 mmol, 3.2 eq) in tetrahydrofuran (5 mL) at -30°C was added dropwise a solution of n-butyllithium in n-hexane (2.5 mol, 4.7 mL, 11.84 mmol, 3.1 eq). The mixture was stirred at -30°C for 1 hour, and then a solution of 5-chloro-2-methoxy-4-methylpyridine (0408-10) (600 mg, 3.82 mmol, 0.2 eq) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at -30°C for 1 hour, and then dimethyl carbonate (1.03 g, 11.46 mmol, 3 eq) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to afford methyl 2-(5-chloro-2-methoxypyridin-4-yl)acetate (600 mg, yield: 73.08%) as a clear oil. LCMS (ESI): m / z = 216 [M+1] + .

[0295] Step 27b: Preparation of methyl 2-(5-chloro-2-methoxypyridin-4-yl)propanoate (Compound 0410-10): To a solution of methyl 2-(5-chloro-2-methoxypyridin-4-yl)acetate (0409-10) (550 mg, 2.56 mmol, 1 eq) in tetrahydrofuran (5 mL) at 0°C was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 2.86 mL, 2.86 mmol, 1.2 eq) dropwise. The mixture was stirred at 0°C for 1 hour, then a solution of iodomethane (327 mg, 2.3 mmol, 0.9 eq) in tetrahydrofuran (1 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give methyl 2-(5-chloro-2-methoxypyridin-4-yl)propanoate (320 mg, yield: 54.61%) as a yellow oily product. LCMS (ESI): m / z = 230 [M+1] +.

[0296] Step 27c: Preparation of 2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (Compound 0405-10): To a solution of methyl 2-(5-chloro-2-methoxypyridin-4-yl)propanoate (0410-10) (320 mg, 1.4 mmol, 1 eq) in tetrahydrofuran / water (5 / 1 ml) was added lithium hydroxide monohydrate (12 mg, 0.28 mmol, 0.2 eq). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The aqueous residue was poured into water and washed with methyl tert-butyl ether. The pH of the aqueous layer was then adjusted to 4 by the addition of 3M hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (106 mg, yield: 35.33%) as a clear oily product. LCMS (ESI): m / z = 216 [M+1] + .

[0297] Step 27d: Preparation of 2-(5-chloro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 0412-10): To 2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (0405-10) (18 mg, 0.085 mmol, 1 eq), (S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one was added. To a solution of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (36 mg, 0.094 mmol, 1.1 eq) in dichloromethane (5 ml) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (36 mg, 0.094 mmol, 1.1 eq) of 3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-1) (30 mg, 0.085 mmol, 1 eq) and N,N-diisopropylethylamine (22 mg, 0.17 mmol, 2 eq). The mixture was stirred at room temperature for 1.0 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give 2-(5-chloro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (12 mg, yield: 30%) as a yellow oily product. LCMS (ESI): m / z = 479 [M+1] + .

[0298] Step 27e: Preparation of 2-(5-chloro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione (Compound 10): 2-(5-chloro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propane-1-thione A mixture of 1'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (0412-10) (36 mg, 0.075 mmol, 1.0 equiv) and Lawesson's reagent (36 mg, 0.09 mmol, 1.2 equiv) was stirred and heated in a microwave at 125°C for 45 minutes. The reaction was cooled to room temperature and quenched with water. The reaction solution was extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol / aqueous ammonia = 80 / 4.5 / 0.8) to give 2-(5-chloro-2-methoxypyridin-4-yl)-1-((S)-7'-methyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propane-1-thione (21 mg, yield: 56.3%) as a yellow solid. LCMS (ESI): m / z = 495 [M+1]. + . 1 H NMR(500MHz,MeOD)δ8.81(t,J=5.0Hz,2H),8.03(t,J=43.5Hz,1H),7.86(dd,J=13.1,9 .3Hz,1H),7.32–7.23(m,1H),6.94(dd,J=15.6,13.9Hz,1H),4.57–4.37(m,1H),4.14– 3.93(m,2H),3.91–3.85(m,3H),3.86–3.57(m,2H),2.96–2.72(m,2H),2.57(dd,J=9.6 ,4.8Hz,3H),2.31–2.08(m,2H),2.06–1.75(m,2H),1.54(ddd,J=15.7,9.2,6.9Hz,3H).

[0299] Example 28: Preparation of 2-(5-chloro-2-methoxypyridin-4-yl)-1-((3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 104):

[0300] (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-100) (66 mg, 0.181 mmol, 1.0 equiv), 2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (0405-10) (38 mg, 0.181 mmol, 1.0 equiv) A mixture of 1,2-diisopropylethylamine (94 mg, 0.724 mmol, 4.0 equiv), 1-hydroxybenzotriazole (29 mg, 0.217 mmol, 1.2 equiv), and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (82 mg, 0.217 mmol, 1.2 equiv) in dichloromethane (2 ml) was stirred at room temperature for 2 hours. The reaction solution was diluted with water (15 ml) and extracted with ethyl acetate (5 ml x 3). The organic phase was washed with saturated brine (15 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 8 / 1) to give 2-(5-chloro-2-methoxypyridin-4-yl)-1-((3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (48.3 mg, yield: 97.3%) as a white solid. LCMS (ESI): m / z = 494 [M+1] + . 1 HNMR(500MHz,MeOD)δ8.82(dd,J=6.9,5.0Hz,2H),8.18–7.70(m,2H),7.31(t,J=4.0Hz ,1H),6.76(d,J=54.1Hz,1H),4.38(dd,J=14.4,7.8Hz,1H),4.16(dd,J=38.3,6.9Hz,1 H),3.89(d,J=4.2Hz,3H),3.72–3.32(m,2H),2.91–2.69(m,2H),2.31(ddd,J=21.4,12 .6,7.9Hz,1H),1.98–1.61(m,3H),1.38(d,J=6.6Hz,3H),1.34(dd,J=16.4,6.6Hz,3H).

[0301] Example 29: Preparation of (R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 105) (Prepared according to Schemes 1 and 4)

[0302] Step 29a: Preparation of (R)-2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid: Separation of the enantiomers of 2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (0405-10) (12.5 g, 57.98 mmol) was carried out by supercritical fluid chromatography (column: ChiralPak IG, 300×50 mm ID, 10 μm; mobile phase: A is carbon dioxide, B is methanol; gradient: 15% B; flow rate: 200 ml / min; back pressure: 100 bar; column temperature: 38°C). The first eluting enantiomer was (R)-2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (5.29 g, yield: 42%), and the second eluting enantiomer was (S)-2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (4.81 g, yield: 38%). Analytical conditions: Column: ChiralPak IG, 100×4.6 mm ID, 3 μm; Mobile phase: A: carbon dioxide, B: methanol (0.05% diethylamine); Gradient: 5-40% B; Flow rate: 2.5 ml / min; Back pressure: 100 bar; Column temperature: 35°C.

[0303] Step 29b: Preparation of (R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one (Compound 105): (R)-2-(5-chloro-2-methoxypyridin-4-yl)propanoic acid (154 mg, 0.712 mmol, 1.05 equiv), (3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridine]-1-yl)propan-1-one were added to the mixture at 0°C. '-Dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidine-3,2'-[1,8]naphthyridine] dihydrochloride (0122-100) (247 mg, 0.678 mmol, 1.0 equiv) and N-methylimidazole (228 mg, 2.78 mmol, 4.1 equiv) were added to a mixture of acetonitrile (2 ml) and dichloromethane (2 ml). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (247 mg, 0.881 mmol, 1.3 equiv) was added. The mixture was stirred at 0°C for 1.5 hours. The mixture was diluted with water (30 ml) and then extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (dichloromethane:methanol 30:1) to give (R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((3S,5S)-5,7'-dimethyl-6'-(pyrimidin-2-yl)-3',4'-dihydro-1'H-spiro[pyrrolidin-3,2'-[1,8]naphthyridin]-1-yl)propan-1-one (290 mg, yield: 84%) as a white solid. LCMS (ESI): m / z 493 [M+1] + ; TLC: Rf 0.5 (ethyl acetate:dichloromethane=1:1). 1H NMR(500MHz,MeOD)δ8.82(d,J=4.9Hz,2H),8.12(s,1H),7.92(s,1H),7.31(t,J=4.9Hz,1H),6.71(s ,1H),4.38(d,J=6.4Hz,1H),4.20(d,J=6.9Hz,1H),3.89(s,3H),3.69(d,J=10.9Hz,1H),3.22(d,J= 11.0Hz,1H),2.81(ddd,J=24.1,14.6,7.9Hz,2H),2.61(s,3H),2.34(dd,J=13.2,7.8Hz,1H),1.90( dd,J=13.4,7.3Hz,2H),1.70(dd,J=13.3,8.6Hz,1H),1.38(d,J=6.8Hz,3H),1.33(d,J=6.2Hz,3H).

[0304] Example 30 Biological Activity Test

[0305] The reference compound used in the present invention is PF-07258669 (Journal of Medicinal Chemistry, 66(5), 3195-3211, 2023, WO 2021250541), and its structure is as follows:

[0306] 1. MC4R Antagonist Activity

[0307] The time-resolved fluorescence resonance energy transfer (TR-FRET) method was used to detect the antagonistic activity of the test compounds against human melanocortin-4-receptor (MC4R) stably expressed in cell lines.

[0308] 1 Experimental materials and instruments

[0309] 2 Experimental steps

[0310] 2.1 Preparation and handling of test compounds

[0311] 2.1.1 Preparation of test compound stock solutions

[0312] 1) Dissolve the test compound in DMSO to prepare a 10 mM stock solution;

[0313] 2) Melanotan I was dissolved in H2O to prepare a 1 mM stock solution.

[0314] 2.1.2 Storage of compound stock solutions

[0315] After the compound was dissolved, it was stored in a -20°C refrigerator.

[0316] 2.1.3 Preparation of working solution

[0317] 1) The test compound was diluted 5-fold with DMSO, with 10 or 5 concentration gradients;

[0318] 2) Prepare Melanotan I at 800 pM using assay buffer.

[0319] 2.2 Determination of the antagonistic activity of the test compounds on MC4R

[0320] 2.2.1 Cell lines, culture media, and buffers

[0321] 1) Cell line: Flp-In-293-Human MC4R

[0322] Complete culture medium: DMEM + 10% fetal bovine serum + 1% penicillin-streptomycin + 200 μg / mL hygromycin

[0323] 2) Experimental buffer: HBSS + 20 mM HEPES + 10% FBS + 500 μM IBMX

[0324] 2.2.2 Cell culture and plating

[0325] 1) Culture Flp-In-293-MC4R in complete medium at 37°C and 5% CO2.

[0326] 2) After trypsin digestion, the cells were resuspended in experimental buffer and seeded into 384 cell culture plates at a seeding density of 2000 cells per well and a seeding volume of 15 μl per well.

[0327] 2.2.3 Determination of the activity of test compounds on human MC4R receptors

[0328] 1) Add 2.5 μl of 8X diluted test compound to each well and incubate at 37°C for 10 minutes.

[0329] 2) Add 2.5 μl of diluted 8X Melanotan I (800 pM) to each well and incubate at 37°C for 30 minutes.

[0330] 3) Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP and dilute them with lysis buffer.

[0331] 4) First add 10 μl Eu-cAMP tracer to the experimental wells, and then add 10 μl Ulight-anti-cAMP to the experimental wells.

[0332] 5) The reaction plate was centrifuged at 1000 g for 1 min at room temperature and allowed to stand at 25°C for 1 h. Data were collected using Envision, with excitation at 340 nm and emission at 665 nm and 615 nm.

[0333] 2.3 Data Analysis

[0334] 1) Calculate the ratio of the acceptor and donor excitation signals for each well using the formula Ratio = Signal 665nm / Signal 620nm, and calculate the inhibition rate at different concentrations. Calculate the compound IC using the GraphPad nonlinear fitting formula. 50 :

[0335] Y=Bottom﹢(Top﹣Bottom) / (1﹢10^((LogIC 50 ﹣X)×HillSlope))

[0336] X: log value of compound concentration; Y: Inhibition%

[0337] 3. Experimental Results

[0338] Calculate the half-maximal inhibitory concentration (IC 50 ), the results are shown in Table 1.

[0339] Table 1. Antagonistic activity of compounds on MC4R

[0340] 2. Pharmacokinetic (PK) Experiment

[0341] 1. Experimental Methods

[0342] Female C57 mice weighing 18-20 g were enrolled. The test compound was dissolved in 30% sulfobutyl β-cyclodextrin and administered orally at 10 mg / kg. Blood was collected from the heart at 15 and 30 minutes, and 1, 2, 4, 7, and 24 hours after administration. The mice were then euthanized and brain tissue was collected. Approximately 0.3 ml of whole blood and 50-100 mg of brain tissue were collected at each time point. The whole blood was placed in a centrifuge tube containing K2-EDTA and centrifuged (3000 g, 10 minutes, 4°C) to obtain plasma. Plasma and brain tissue were stored at -40°C until use. Pre-weighed brain tissue was homogenized in 0.9% NaCl solution at a ratio of 1:3 (g / ml). 50 μL of plasma sample or brain tissue homogenate was vortexed with 135 μL of acetonitrile (containing 0.1 μg / mL internal standard) for protein precipitation. The supernatant was then centrifuged and analyzed by LC-MS / MS.

[0343] 2. Experimental Results

[0344] Compounds 100 and 104 provided by the present invention were well absorbed after oral administration to mice, with high exposure levels in the blood and brain. The results are shown in Figures 1-2 and Table 2. The T values ​​of the spiro heterocyclic compounds of the present invention in plasma were max 0.25 hours, C max 1243.33–1593.33 ng / ml, AUC 0-24 The T in the brain is 1448.77–1649.36 hr*ng / mL. max 0.25-0.50 hours, C max 413.20–512.00 ng / ml, AUC 0-24 The pharmacokinetic properties of the compound of the present invention are better in the brain than those of the control compound PF07258669, and the compound of the present invention has a greater therapeutic potential in treating MC4 receptor-related diseases and / or symptoms such as cachexia and anorexia. max Refers to the maximum blood drug concentration, T 1 / 2 is half-life, AUC 0-24 Refers to the area under the time-concentration curve from 0 to 24 hours, AUC 0-inf It refers to the area under the 0-Inf time-concentration curve.

[0345] Table 2. Pharmacokinetic parameters of mice after oral administration (10 mg / kg)

[0346] 3. In vitro metabolic stability test

[0347] 1. Experimental Methods

[0348] The test compound was dissolved in DMSO and diluted with acetonitrile. 2 μL of the acetonitrile-diluted test compound and 300 μL of potassium phosphate buffer containing human liver microsomes were added to a centrifuge tube. After mixing, 30 μL was transferred to each of six centrifuge tubes. After preheating at 37°C for 10 minutes, 15 μL of 6 mM NADPH solution (except for the time point 0) was added and mixed. The reaction was terminated by adding 135 μL of acetonitrile (containing 0.1 μg / mL internal standard) after 30 and 60 minutes of incubation. The 0-minute sample was first terminated by adding 135 μL of acetonitrile (containing 0.1 μg / mL internal standard) and then 15 μL of 6 mM NADPH solution (duplicate samples were prepared for each time point). After mixing, the mixture was centrifuged at 15,000 g for 10 minutes, and the supernatant was analyzed by LC-MS / MS.

[0349] The experimental results are expressed as half-life (T 1 / 2)=0.693 / K (K is the rate constant obtained by linear regression with the logarithm of the relative remaining percentage of the test compound as the ordinate and the incubation time as the abscissa).

[0350] 2. Experimental Results

[0351] Calculate the half-life (T 1 / 2 ), the results are shown in Table 3. The results show that Compound 100 and Compound 105 have better metabolic stability in human liver microsomes than PF07258669 and longer metabolic half-lives. This suggests that the compounds of the present invention may have a longer drug elimination half-life in humans, thereby reducing the frequency of dosing.

[0352] Table 3 Metabolic stability results of compounds in human liver microsomes

[0353] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A spiroheterocyclic compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated product thereof or a prodrug molecule thereof: in: R1, R2, R3 and R4 are independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen, halogen-substituted C1-C6 alkyl, hydroxy, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, cyano, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)2R, -S(O)2N(R)2, -N(R)C(O)R; R is selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, alkylamino-substituted C1-C6 alkyl; R5 and R6 are independently selected from: H, deuterium, halogen; M is selected from: CH, N; W is selected from: O, S, NR7; Q is selected from: CR7R8, NR8, C=O, O, S, or absent; R7 and R8 are independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C8 cycloalkyl, hydroxy, cyano, amino, C1-C6 alkylamino; or R8 and the substituent in A are linked to form a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring; A is selected from: R9 and R 10 Substituted or unsubstituted C6-C 10 Aryl, R9 and R 10 Substituted or unsubstituted 5-10 membered heteroaryl, R9 and R 10 a substituted or unsubstituted 7-10 membered benzoheterocyclyl group; Each R9 and R 10 Each of the following is independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, C3-C8 cycloalkyl, C3-C8 deuterated cycloalkyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 deuterated alkylthio, C3-C8 cycloalkylthio, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, halogen-substituted C1-C6 alkoxy, C3-C8 cycloalkyloxy, C3-C8 deuterated cycloalkyloxy, halogen-substituted C3-C8 cycloalkyloxy, and carbamoyl; A1 is selected from: R 11 and R 12 Substituted or unsubstituted phenyl, R 11 and R 12 a substituted or unsubstituted 5-6 membered heteroaryl group; Each R n and R 12 Each of them is independently selected from the group consisting of: H, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, cyano, and C1-C6 alkoxy.

2. The spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule according to claim 1, characterized in that: A is selected from: R9 and R 10 Substituted or unsubstituted naphthyl, R9 and R 10 Substituted or unsubstituted 9-10 membered heteroaryl, R9 and R 10 A substituted or unsubstituted 9- to 10-membered benzoheterocyclic group.

3. The spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule according to claim 1, characterized in that: A is selected from: Among them: the dotted line in the ring represents that it is a CC single bond or not; X1, X2, and X3 are independently selected from: CR9, N.

4. The spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule according to claim 3, characterized in that: A is selected from:

5. The spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule according to claim 4, characterized in that: A is selected from: W is O.

6. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: Each R9 and R 10 Each of the following is independently selected from the group consisting of: H, deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyano, C3-C6 cycloalkyl, C3-C6 deuterated cycloalkyl, C3-C6 cycloalkylmethyl, C1-C3 alkylsulfonyl, C1-C3 alkylthio, C1-C3 deuterated alkylthio, C3-C6 cycloalkylthio, halogen-substituted C1-C3 alkyl, C1-C3 alkoxy, C1-C3 deuterated alkoxy, halogen-substituted C1-C3 alkoxy, C3-C6 cycloalkyloxy, C3-C6 deuterated cycloalkyloxy, halogen-substituted C3-C6 cycloalkyloxy, and carbamoyl.

7. The spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule according to claim 6, characterized in that: Each R9 and R i0 Each of the following is independently selected from the group consisting of hydrogen, methoxy, fluorine, difluoromethyl, difluoromethoxy, cyano, methyl, ethynyl, carbamoyl, methylsulfonyl, cyclopropyloxy, methylthio and chlorine.

8. The spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule according to claim 3, characterized in that: A is selected from:

9. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: Each R 11 and R 12 Each of the following is independently selected from the group consisting of: H, deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, cyano, and C1-C3 alkoxy.

10. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: A1 is selected from:

11. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to claim 10, characterized in that: A1 is selected from:

12. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: W is selected from: S, NR7; Wherein, R7 in W is selected from: H, C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, halogen-substituted C3-C8 cycloalkyl.

13. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated product thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: R7 and R8 are independently selected from the group consisting of: H, deuterium, halogen, C1-C3 alkyl, C1-C3 deuterated alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, halogen-substituted C1-C3 alkyl, halogen-substituted C3-C6 cycloalkyl, hydroxyl, cyano, amino, C1-C3 alkylamino; or R8 and the substituents in A are linked to form a substituted or unsubstituted 5-6 membered carbocyclic or heterocyclic ring.

14. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to claim 13, characterized in that: R7 and R8 are independently selected from: H, deuterium, methyl, hydroxyl, cyano, vinyl, ethynyl, amino, deuterated methyl, or R8 and the substituent in A are connected to form a 5-6 membered carbocyclic or heterocyclic ring.

15. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: Q is selected from: -N(CH3)-, 16. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: R4 is selected from the group consisting of: C1-C6 alkyl, C1-C6 deuterated alkyl, and halogen-substituted C1-C6 alkyl.

17. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 1 to 5, characterized in that: R1, R2, R3 and R4 are independently selected from the group consisting of: H, deuterium, C1-C3 alkyl, C1-C3 deuterated alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, halogen-substituted C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, halogen, halogen-substituted C1-C3 alkyl, OH, hydroxy-substituted C1-C3 alkyl, alkoxy-substituted C1-C3 alkyl, and cyano.

18. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to claim 17, characterized in that: R1 is selected from the group consisting of: methyl, hydroxy, difluoromethyl, trifluoromethyl, cyano, chlorine, fluorine, vinyl, ethynyl, cyclopropyl, deuterated methyl.

19. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 17, characterized in that: R2 is selected from: H, fluorine, methyl, chlorine, deuterium.

20. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 17, characterized in that: R3 is selected from: H, fluorine.

21. The spiroheterocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a deuterated substance thereof or a prodrug molecule thereof according to any one of claims 17, characterized in that: R4 is selected from the group consisting of: H, methyl, methoxymethyl, and monofluoromethyl.

22. The spiroheterocyclic compound or its pharmaceutically acceptable salt or its stereoisomer or its deuterated product or its prodrug molecule according to claim 1, characterized in that: Selected from the following compounds:

23. Use of the spiroheterocyclic compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated product thereof, or a prodrug molecule thereof in the preparation of an MC4 receptor antagonist.

24. Use of the spiroheterocyclic compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated product thereof, or a prodrug molecule thereof, in the preparation of a medicament for preventing and / or treating diseases and / or symptoms associated with MC4 receptors.

25. The use according to claim 24, characterized in that Diseases and / or symptoms associated with the MC4 receptor are selected from the group consisting of: cachexia, anorexia, nausea, vomiting, involuntary weight loss, sarcopenia, muscle atrophy, muscle weakness, asthenia, bone diseases, pain or neuropathic pain, anxiety, sexual dysfunction, inflammatory diseases.

26. The use according to claim 25, characterized in that The cachexia includes cachexia associated with chronic diseases, cancer, acquired immunodeficiency syndrome, heart failure and / or chronic kidney disease; the anorexia includes anorexia nervosa, senile anorexia, and anorexia associated with chemotherapy and radiotherapy; the bone disease includes bone loss; the anxiety includes post-traumatic stress disorder and PTSD; the inflammatory disease includes inflammatory diseases associated with cachexia, anorexia, and sarcopenia.

27. A pharmaceutical composition for preventing and / or treating diseases and / or symptoms associated with MC4 receptor, characterized in that: The invention comprises an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the spiroheterocyclic compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated product thereof, or a prodrug molecule thereof.

28. A method for preventing and / or treating diseases and / or symptoms associated with MC4 receptor, characterized in that: The method comprises: administering a safe and effective amount of the spiroheterocyclic compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated substance thereof, or a prodrug molecule thereof; and / or, Administer a safe and effective amount of the pharmaceutical composition of claim 27.

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