Pyrimidine Compounds and Their Uses

Abstract

A pyrimidine compound of chemical formula (I) as shown herein. Additionally, a pharmaceutical composition containing one of the pyrimidine compounds and a method of using the pyrimidine compound to treat or prevent chemotherapy-induced peripheral neuropathy are also disclosed.

Description

Background Technology

[0001] Chemotherapy-induced peripheral neuropathy ("CIPN") is a side effect of certain anticancer drugs.

[0002] Affecting 30–70% of patients undergoing chemotherapy, CIPN is one of the leading reasons for dose reduction or early discontinuation in life-saving cancer treatments. Symptoms include sensory disturbances (e.g., increased sensitivity to pain), which impair the quality of life for years.

[0003] There are no drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment or prevention of CIPN. Furthermore, recent clinical trials are not promising. Poupon et al., "Minimizing Chemotherapy-Induced Peripheral Neuropathy: A Novel Perspective on Preclinical and Clinical Development," Expert Opinion. Drug Safety. (2015) 14(8) is referenced.

[0004] The development of methods to treat and prevent CIPN is necessary. means of solving the problem

[0005] The present invention is based on the unexpected discovery that certain pyrimidine compounds are effective in treating and preventing CIPN.

[0006] In one aspect, the present invention relates to a pyrimidine compound of the following formula (I):

[0007] .

[0008] In this equation, R1, W1, W2, and W3 are each defined as follows.

[0009] R1 is H, halo, nitro (i.e., -NO2), cyano (-CN), amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-10 It is a heterocycloalkyl, aryl, or heteroaryl.

[0010] W1 is C 1-10 Heterocycloalkyl or NH―CH2―Ar1―(CH2) m It is A1.

[0011] One of W2 and W3 is NR a R b And, the other one of W2 and W3 is NH―CH2―Ar2―(CH2) n It is A2.

[0012] Here,

[0013] Ar1 and Ar2 are each independently pentagonal heteroaryls;

[0014] A1 and A2 are independently H, OH, SH, CO2R c , PO3R c R d , NH2, benzylamino, isopropylamino, ethanolamino, carbamido (i.e., -NHCONH2), guanidinyl (i.e., -NHC(NH)NH2), C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyloxy, C 1-10 Heterocycloalkyl, C 1-10 Heterocycloalkyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, or NCOR c is;

[0015] R a and R b H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 It is hetero-cycloalkyl, or R a and R b is, together with the nitrogen atoms to which they are bonded, C 1-10 It is heterocycloalkyl;

[0016] R c and R d H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 It is a hetero-cycloalkyl, aryl, or heteroaryl;

[0017] C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyloxy, C 1-10 Heterocycloalkyl, C 1-10 Heterocycloalkyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, ethanolamino, benzylamino, and carbamido are, respectively, hydroxyl, halo, nitro, cyano, amino, C 1-6 Alkyl, arylalkyl, C 1-6 Alkoxyl, C 1-6 Carboxyalkyl, aryl, heteroaryl, PO3R e R f , NCOR e , NC(O)OR e , C(O)OR e , COR e , (CH2) x ―PO3R e R f , (CH2) x ―NCOR e , or (CH2) x ―C(O)OR e It is optionally replaced with;

[0018] R e and R f H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 It is a hetero-cycloalkyl, aryl, or heteroaryl;

[0019] m and n are independently 0, 1, 2, 3, 4 or 5, respectively; and

[0020] x is 1, 2, 3, or 4.

[0021] Desirable characteristics include R1 being H, W1 being morpholino, and W2 being NH-CH2-Ar2-(CH2) n ―A2 and W3 is NR a R bIt includes that. Typically, A1 and A2 each independently consist of H, OH, and C 1-6 Alkyl, C 1-6 Alkoxy or NCOR c and; R a is H, or R a and R b is a hexavalent heterocycloalkyl, together with the nitrogen atoms to which they are bonded; R b is a 6-membered heterocycloalkyl, or R b and R a is a hexavalent heterocycloalkyl, together with the nitrogen atoms to which they are bonded; R c is C 1-6 It is alkyl; C 1-6 Alkyl, C 1-6 Alkoxy and C 1-10 Hetero-cycloalkyl groups are hydroxyl, NH2, (CH2), respectively x ―PO3R e R f , C(O)OR e , or (CH2) x ―NCOR e Optionally substituted as; R e and R f H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 It is a heterocycloalkyl, aryl, or heteroaryl; m and n are each independently 2, 3, or 4; and x is 1, 2, 3, or 4.

[0022] Another aspect of the present invention relates to a method for treating or preventing chemotherapy-induced peripheral neuropathy. The method comprises administering an effective amount of any one of the compounds described above to a subject requiring treatment or prevention of chemotherapy-induced peripheral neuropathy. Optionally, the method comprises an additional step of administering an anticancer agent (e.g., paclitaxel) to the subject, preferably comprising an additional step of administering an anticancer agent (e.g., paclitaxel) to the subject after administering the compounds of the present invention.

[0023] Additionally, the scope of the present invention includes a pharmaceutical composition containing one of the compounds described above and a pharmaceutically acceptable carrier.

[0024] In this document, the term "alkyl" means a linear or branched hydrocarbon group containing 1 to 20 (e.g., 1 to 10 and 1 to 6) carbon atoms. Exemplary alkyl groups are methyl ("Me"), ethyl ("Et"), n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. Alkyl includes haloalkyls, which refer to alkyls substituted with one or more halogen atoms (chloro, fluoro, bromo, or iodo). Examples include trifluoromethyl, bromomethyl, and 4,4,4-trifluorobutyl. The term "alkoxy" means an -O-alkyl group (e.g., methoxy, ethoxy, propoxy, and isopropoxy). Alkoxys include haloalkoxys, that is, alkoxys substituted with one or more halogen atoms, for example, -O-CH2Cl and -O-CHClCH2Cl.

[0025] The term "cycloalkyl" refers to 3 to 12 carbons (e.g., C 3-10 It refers to saturated and partially unsaturated monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon groups having ). Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyloxy" refers to an -O-cycloalkyl group, e.g., cyclohexyloxy. Cycloalkyloxy includes halocycloalkyloxy, which means a cycloalkyloxy substituted with one or more halogen atoms.

[0026] The term "heterocycloalkyl" refers to a non-aromatic 3-8-membered monocyclic, 8-12-membered bicyclic, or 11-14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples of heterocycloalkyl groups include piperazinyl, piperidinyl, imidazolidinyl, azephanyl, pyrrolidinyl, dihydrothiazolyl, dioxanyl, morpholinyl, thiomophorinyl, 1,1-dioxide thiomophorinyl, tetrahydropyranyl, and tetrahydrofuranyl. The term "heterocycloalkyloxy" refers to -O-heterocycloalkyl. Each of heterocycloalkyl and heterocycloalkyloxy comprises a halogenated version, i.e., having substitution of one or more halogen atoms.

[0027] The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system in which each ring may have 1 to 5 substituents. Examples include phenyl, naphthyl, and anthracenyl. The term "arylkyll" refers to an alkyl group substituted with an aryl group. The term "aryloxy" refers to an -O-aryl group, e.g., phenoxy.

[0028] The term "heteroaryl" means an aromatic 5-8-membered monocyclic, 8-12-membered bicyclic, or 11-14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, oxazolyl, isooxazolyl, pyrazolyl, pyridyl, carbazolyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl. The term "heteroaryl alkyl" means an alkyl group substituted with a heteroaryl group. The term "heteroaryloxy" means an -O-heteroaryl group.

[0029] The term "halo" means a fluoro, chloro, bromo, or iodo radical. The term "amino" means a radical derived from an amine that is unsubstituted or monosubstituted / dissubstituted with an alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl amine. The term "alkylamino" means alkyl-NH-. The term "dialkylamino" means alkyl-N(alkyl)-.

[0030] The alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aracleyl, heteroaracleyl, alkoxy, and aryloxy mentioned herein include both substituted moiety and unsubstituted moiety. Examples of substituents include halo, hydroxyl, amino, cyano, nitro, mercapto, alkoxycarbonyl, amido, carboxyl, alkansulfonyl, alkylcarbonyl, carbamido, carbamyl, carboxyl, thiouredo, thiocyanato, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl may be further substituted.

[0031] When referring to the compound of chemical formula (I), the term “compound” includes its salt, solvate, and prodrug. A salt can be formed between the anion of the compound and a positively charged group (e.g., amino). Examples of suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate. A salt can also be formed between a cation and a negatively charged group. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations, such as tetramethylammonium ions. Additionally, salts may contain a quaternary nitrogen atom. A solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine. A prodrug refers to a compound that is metabolized into a pharmaceutically active drug after administration. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives.

[0032] The compound may contain one or more non-aromatic double bonds or asymmetric centers. Each of these occurs as a racemate or racemic mixture, a single R enantiomer, a single S enantiomer, individual diastereomers, a mixture of diastereomers, a cis-isomer, or a trans-isomer. Compounds in these isomer forms are within the scope of the present invention. They may exist as a mixture or may be isolated using chiral synthesis or chiral separation techniques.

[0033] The present invention also features one or more uses of the pyrimidine compound of the formula (I) described above for the manufacture of a drug for treating and preventing CIPN.

[0034] The terms “therapeutic” or “therapeutic” mean administering one or more pyrimidine compounds to a subject receiving chemotherapy or predisposed to CIPN for the purpose of conferring a therapeutic effect, for example, to cure, alleviate, correct, affect, improve, or prevent CIPN, its symptoms, or predisposition to it. “Effective dose” means the amount of compound required to confer a therapeutic effect. As recognized by those skilled in the art, the effective dose may vary depending on the type of symptom being treated, the route of administration, the use of excipients, and the possibility of concomitant use with other therapies.

[0035] To carry out the method of the present invention, a composition having one or more of the pyrimidine compounds described above may be administered parenterally, orally, nasally, rectally, topically, or buccally. As used herein, the term “parenterally” means subcutaneously, intradermally, intravenously, intraperitoneally, intramuscularly, intra-articularly, intra-arterially, intrasynovially, intrasternally, intrathecally (intraspinal), intralesionally, or intracranially, as well as any suitable injection technique.

[0036] Sterile injectable compositions may be solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, fixed oils are generally used as solvents or suspending media (e.g., synthetic monoglycerides or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives, are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil and castor oil, particularly in their polyoxyethylated versions. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, carboxymethyl cellulose, or similar dispersants. Other commonly used surfactants such as tweens and spans, or other similar emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0037] Compositions for oral administration may be any orally acceptable dosage forms, including capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in aqueous suspensions or emulsions, the active ingredient may be suspended or dissolved in an oil phase combined with an emulsifying agent or suspending agent. If desired, specific sweeteners, flavorings, or colorings may be added.

[0038] Nasal aerosols or inhalation compositions may be prepared according to techniques well known in the field of pharmaceutical formulations. For example, such compositions may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other solubilizing agents or dispersants.

[0039] A composition having one or more of the pyrimidine compounds described above may also be administered in the form of a suppository for rectal administration.

[0040] In a pharmaceutical composition, the carrier must be "acceptable" in the sense that it is compatible with the active ingredient of the composition (and preferably can stabilize the active ingredient) and is not harmful to the subject to be treated. One or more solubilizers may be utilized as pharmaceutical excipients for the delivery of the active compound. Examples include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0041] Details of one or more embodiments of the present invention are described below. Other features, objects, and advantages of the present invention will become apparent from the description and claims. Specific details for implementing the invention

[0042] The peripheral nervous system ("PNS") consists of sensory and motor neurons. In chemotherapy, anticancer drugs can damage both sensory and motor neurons. Symptoms of CIPN typically begin in the hands or feet and spread to the arms or legs, ranging from tingling or numbness (e.g., paresthesia) to sharp, stabbing pain or a burning sensation to temperature (e.g., dysesthesia, pain, heat hypersensitivity, thermal hyposensitivity). In some cases, CIPN causes hearing loss, vision loss, changes in taste, mechanical hypersensitivity, mechanical hyposensitivity, and autonomic dysfunction.

[0043] Since these symptoms are triggered by anticancer agents during chemotherapy, the type of anticancer agent (e.g., paclitaxel, oxaliplatin platinum salt, vinca alkaloid, bortezomib, thalidomide, epotillone, and eribulin) and the cumulative dose may affect the occurrence of one or more symptoms and the severity / grade of neuropathy. Additionally, treatment for various cancers (e.g., colorectal cancer, lung cancer, breast cancer, and prostate cancer) leads to other symptoms and severity, e.g., neuropathic pain.

[0044] Numerous anticancer drugs cause CIPN. Examples include epotillon (e.g., ixabepilon available as Ixempra® at Bristol-Myers Squibb, NY), arsenic trioxide (Trisenox®, Teva Pharmaceuticals USA, Parsifane, NY), cytarabine (Cytosar-U® and Depocyt®), etoposide, hexamethylmelamine, ifosfamide (Ifex®), methotrexate (Trexall®), procarbazine (Matulane®), and vinblastine. Chemotherapy drugs that most commonly cause CIPN include platinum compounds (cisplatin, carboplatin, oxaliplatin), vincristine, taxanes (docetaxel, paclitaxel), bortezomib (Velcade®), thalidomide (Thalomid®), and lenalidomide.

[0045] Compounds of chemical formula (I) are suitable for treating or preventing one or more symptoms of CIPN.

[0046] .

[0047] The above compound may be used in combination with one of the aforementioned anticancer agents, preferably by administering the compound to a patient at least 10 minutes (e.g., at least 30 minutes, at least 1 hour, at least 2 hours) before administering the anticancer agent.

[0048] Referring to the above chemical formula (I), there is a preferred subset of compounds having the characteristics described below.

[0049] In one subset of compounds of chemical formula (I), W1 comprises (i) one or more C 1-6 Morpolinos selectively substituted with alkyl groups, e.g., and , (ii) thiomofolino or 1,1-dioxide thiomofolino, e.g., and , (iii) one or more C 1-6Piperidinos selectively substituted with alkyl and halo groups, e.g., , and , and (iv) one or more C 1-6 Piperazinos selectively substituted with alkyl groups, for example and C including 1-10 (Yes, C 4-5 ) is a nitrogen-containing heterocycloalkyl. Alternatively, W1 is NH―CH2―Ar1―(CH2) m ―A1, for example, am.

[0050] In another subset of compounds, one of W2 and W3 is NH―CH2―Ar2―(CH2) n ―It is A2. Examples include the following:

[0051]

[0052] .

[0053] The other one of W2 and W3 is NR a R b is. Examples include the following:

[0054]

[0055] .

[0056] The compound of the following chemical formula (II) is also a preferred subset of the compound of chemical formula (I).

[0057]

[0058] R a , R b , Ar2, A2 and n are defined above.

[0059] Rx and Ry are 5 to 8 heterocycloalkyls (e.g., morpholino, piperidino, and piperazino) together with the nitrogen atom to which they are bonded.

[0060] Compound 1-148 is provided below as an exemplary compound of chemical formula (I):

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] The compounds of formula (I) described above can be prepared according to established methods. The synthetic modifications and protecting group methodologies (protection and deprotection) used to prepare these compounds are well known in the art. For example, R. Larock, Comprehensive Organic Transformations (3rd Ed., Wiley 2018); PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis (4th Ed., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2nd ed., John Wiley and Sons 2009); and GJ Yu et al., J. Med. Chem. 2008, 51, 6044-6054 are referenced.

[0070] 2,4,6-trichloropyrimidine selectively substituted with an R1 group A synthetic route for preparing compound 1-148 starting from is shown in Scheme I below. In Scheme I, W1H, W2H, and W3H are each amino compounds, which are substituted stepwise.

[0071] Scheme I

[0072]

[0073] Not only 2,4,6-trichloropyrimidine, but also its methanesulfonyl derivatives are useful as starting materials for the preparation of compound 1-148. One example is 4,6-dichloro-2-(methanesulfonyl)pyrimidine, namely am.

[0074] Some of the compounds 1-148 can be prepared using the following moiety (i.e., side chain) compounds that become the moiety corresponding to W2 or W3 in chemical formula (I).

[0075]

[0076] .

[0077] Other side-chain compounds are prepared by methods that are commercially available or known in the art. The method may also include additional steps, either before or after the steps specifically described herein, to add or remove suitable protecting groups if necessary to facilitate the synthesis of the compound. Additionally, the desired compound can be obtained by performing various synthesis steps alternately.

[0078] The compound of chemical formula (I) prepared in this way is in a test tube ( in vitro) Neuroprotective efficacy can be initially screened using an assay, for example, the neurite outgrowth assay described in Example 3 below. In vivo ( in vivo)Subsequent evaluation can be performed using an animal behavioral model (e.g., see Example 4). The selected compound may be further tested to verify its efficacy, for example, by administering it to animals. Based on the results, an appropriate dosage range and route of administration can be determined.

[0079] It is believed that those skilled in the art will be able to make the most of the present invention based on the foregoing description without further explanation. Accordingly, the following specific embodiments should be interpreted merely as illustrative and not as limiting the remainder of the disclosure in any way.

[0080] All publications, including patent documents cited herein, are incorporated by reference in their entirety.

[0081] The preparation of the moiety compound 1-17 and pyrimidine compound 1-148 of the present invention is provided in the following Examples 1 and 2.

[0082] Example 1 : Preparation of moiety compounds

[0083] Unless otherwise provided, all chemicals and reagents were purchased from commercial suppliers. Reactions were carried out under a dry nitrogen atmosphere and monitored by thin-layer chromatography. Purification was performed using column chromatography. Protons ( 1H) Nuclear magnetic resonance spectra were measured using a Varian Mercury-300 or Varian Mercury-400 spectrometer. Chemical shifts were recorded in parts per million (ppm) on a delta (δ) scale relative to the resonance of the solvent peaks. The following abbreviations were used to describe coupling: s = singlet; d = doublet; t = triplet; q = quartet; quin = quintet; br = broad; and m = multiplet. LCMS data were measured on an Agilent 6125B Single Quadrupole LC / MS system.

[0084] Manufacturing of Moiety 1

[0085] Moiety 1 was manufactured according to the scheme below:

[0086]

[0087] In the first step, benzyl chloroformate (6.07 g, 35.6 mmol) was added to a solution of prop-2-ynylamine (1.97 g, 35.8 mmol) and potassium carbonate (10.11 g, 73.3 mmol) in a mixture of tetrahydrofuran ("THF") and water (20 mL / 40 mL) at 5-10 °C. The resulting mixture was heated to room temperature for 15 hours, then quenched with NH4Cl (aq.) (100 mL, 2 M), and subsequently extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Crystallize the residue using a solvent mixture of n-hexane / dichloromethane ("DCM") at -20℃. m1-I (6.42g, y: 95%) was obtained.

[0088] 1 H NMR (CDCl3, 400 MHz) δ 7.38-7.32 (m, 5H), 5.13 (s, 2H), 3.99 (m, 2H), 2.24 (dd, 1H).

[0089] In the second step, in isopropyl alcohol ("IPA", 150 mL) m1-I A solution of ZnBr2 (2.5 g, 11.1 mmol) in H2O (36 mL) was added to a solution of sodium azide (6.42 g, 98.8 mmol) and (6.42 g, 33.9 mmol). The mixture was stirred at 75°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. m1-II (4.81g, y: 61%) was obtained.

[0090] In the third step, in acetonitrile ("ACN", 300 mL) m1-II 1,2-dibromoethane (4.81 g, 25.6 mmol) and triethylamine ("TEA", 4.81 g, 47.6 mmol) were added to a solution of (4.81 g, 20.7 mmol). The mixture was refluxed for 15 hours and concentrated. Subsequently, the resulting residue was extracted with DCM (2 x 150 mL). The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude residue, which was purified by column chromatography (n-hexane:ethyl acetate = 1:1) on silica gel. m1-III (3.63 g, y: 68%) was obtained.

[0091] In the final step, in methanol (72 mL) m1-III Solutions of (3.63 g, 14.1 mmol) and 10% Pd / C (0.36 g) were stirred under H2 (g) at 25°C for 6 hours. The reaction mixture was filtered and concentrated to form a moiety 1(1.52g, y: 86%) was obtained.

[0092] Manufacturing of Moiety 2

[0093]

[0094] A solution of bromo-acetate tert-butyl ester (5.85 g, 30 mmol) and sodium azide (6.56 g, 101 mmol) in acetone / H2O (585 mL / 140 mL) was stirred at 25°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. m2-I (3.84g, y: 81%) was obtained.

[0095] in ethanol ("EtOH", 150mL) m2-I (3.84g, 24.4mmol) and m1-I A solution of CuSO4 (0.41 g, 2.6 mmol), (+)-sodium L-ascorbate (0.56 g, 2.8 mmol), and K2CO3 (6.71 g, 48.5 mmol) in H2O (36 mL) was added to a solution of (4.56 g, 24.1 mmol). The mixture was stirred at 25°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated m2-II (6.02 g, y: 71%) was obtained.

[0096] in methanol (60 mL) m2-II Solutions of (3.01 g, 8.7 mmol) and 10% Pd / C (0.3 g) were stirred at 25°C for 6 hours under H2 (g) (1 atm). Afterward, the resulting mixture was filtered. The filtrate was concentrated to form a moiety 2 (1.64g, y: 89%) was obtained.

[0097] Manufacturing of Moiety 3

[0098]

[0099] Tetrabutylammonium bromide (1.61 g, 5 mmol) was added to a solution of (2-bromoethyl)-phosphonic acid diethyl ester (2.45 g, 10 mmol) and sodium azide (1.87 g, 28.8 mmol) in acetone / H2O (70 mL / 140 mL). The resulting mixture was stirred at 25°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated m3-I (1.36g, y: 66%) was obtained.

[0100] in EtOH (50 mL) m3-I (1.36g, 6.6mmol) and m1-I A solution of CuSO4 (0.13 g, 0.8 mmol), (+) sodium L-ascorbate (0.14 g, 0.7 mmol), and K2CO3 (1.84 g, 13.3 mmol) in H2O (36 mL) was added to a solution of (1.25 g, 6.6 mmol). The mixture was stirred at 25°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 50 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue, which was purified by column chromatography (MeOH:ethyl acetate = 1:19) on silica gel. m3-II (2.04 g, y: 77%) was obtained.

[0101] in methanol (40 mL) m3-II A solution of (2.04 g, 5.1 mmol) and 10% Pd / C (0.2 g) was stirred at 25°C for 6 hours under H2 (g) (1 atm). Afterward, the reaction mixture was filtered. The filtrate was concentrated to form a moiety 3 (1.18g, y: 87%) was obtained.

[0102] Manufacturing of Moiety 4

[0103]

[0104] A solution of 2-(3-bromopropyl)-isoindole-1,3-dione (1.5 g, 5.6 mmol), K2CO3 (2 g, 14.5 mmol), and 2-piperazine-1-yl-ethanol (2.5 g, 19.2 mmol) in ACN (120 mL) was stirred at 65°C for 15 hours and then concentrated to obtain the residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated m4-I (0.98 g, y: 55%) was obtained.

[0105] in DCM (20 mL) m4-I Solutions of (0.98 g, 3.1 mmol) and hydrazine monohydrate (0.4 g, 8 mmol) were stirred at 25°C for 15 hours and then filtered. The filtrate was concentrated and moiety 4 (0.52g, y: 90%) was obtained.

[0106] Manufacturing of Moiety 5

[0107]

[0108] Tert-butoxycarbonyl ("Boc") anhydride ("Boc2O", 7.81 g, 35.7 mmol) and TEA (3.6 g, 35.6 mmol) were added to a solution of 1-aminopropanol (2.25 g, 30 mmol) in DCM. The mixture was stirred at room temperature for 15 hours and then concentrated to obtain a crude residue, which was purified by column chromatography (n-hexane:ethyl acetate = 1:3) in silica gel. m5-I (4.11 g, y: 78%) was obtained.

[0109] in DCM (180 mL) m5-IMethanesulfonyl chloride ("MsCl", 5.41 g, 47.2 mmol) was added dropwise to a solution of (4.11 g, 23.4 mmol) and TEA (3.22 g, 31.7 mmol) at 5-10°C. The resulting mixture was heated to room temperature for 15 hours, quenched with NH4Cl (aq.) (50 mL, 2 M), and then extracted with DCM. The combined organic phase was washed with NaHCO3 (aq.) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated m5-II (4.12 g, y: 70%) was obtained.

[0110] in MeOH (300 mL) m5-II Tetrabutylammonium bromide (1.61 g, 5 mmol) was added to a solution of (4.12 g, 16.3 mmol) and sodium azide (5.41 g, 83.2 mmol). The resulting mixture was stirred at 65°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated m5-III (2.41g, y: 74%) was obtained.

[0111] in EtOH (160 mL) m5-III (2.41 g, 12 mmol) and m1-I A solution of CuSO4 (0.2 g, 1.3 mmol), (+)-sodium L-ascorbate (0.24 g, 1.2 mmol), and K2CO3 (2.24 g, 16.2 mmol) in H2O (40 mL) was added to a solution of (2.41 g, 12.7 mmol). The mixture was stirred at 25°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated m5-IV (3.12g, y: 67%) was obtained.

[0112] in methanol (40 mL) m5-IVA solution of (3.12 g, 8 mmol) and 10% Pd / C (0.6 g) was stirred at 25°C for 6 hours under H₂ (g) (1 atm) and then filtered. The filtrate was concentrated and moiety 5 (1.82g, y: 89%) was obtained.

[0113] Manufacturing of Moiety 6

[0114]

[0115] NaN3 (11.3 g, 174 mmol) and KI (2.02 g, 12.2 mmol) were added to a solution of 3-bromo-1-propanol (20 g, 144 mmol) in water / acetone (100 mL / 35 mL) at room temperature. The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m6-I (14.12 g, y: 97%) was obtained.

[0116] in EtOH (690 mL) m1-I (15.4 g, 81.4 mmol) and m6-I A solution of CuSO4 (2.01 g, 12.6 mmol), (+)-sodium L-ascorbate (4 g, 20.2 mmol), and K2CO3 (11.31 g, 81.8 mmol) in H2O (69 mL) was added to a solution of (8.23 g, 81.4 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on silica gel by column chromatography (n-hexane:ethyl acetate = 1:3) m6-II (19.74 g, y: 84%) was obtained.

[0117] in IPA (40 mL) m6-IIA solution of (2 g, 6.9 mmol) and 10% Pd / C (0.6 g) was stirred at 60°C for 15 hours under H2 (g) (1 atm) and filtered. The filtrate was concentrated and moiety 6 (1g, y: 93%) was obtained.

[0118] Manufacturing of Moiety 7

[0119]

[0120] in dry DCM (100mL) m6-II TEA (2.6 g, 25.7 mmol) and MsCl (2.37 g, 20.7 mmol) were added to a solution of (5 g, 17.2 mmol) at 5 °C. The reaction mixture was stirred at 60 °C for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m7-I (4.56g, y: 72%) was obtained.

[0121] in dry THF (50 mL) m7-I Isopropylamine (5.6 g, 94.7 mmol) was added to a solution of (4.56 g, 12.4 mmol) at 5°C. The reaction mixture was stirred at room temperature for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in DCM (50 mL) and mixed with Boc2O (3.4 g, 15.6 mmol) and TEA (1.6 g, 15.8 mmol). The mixture was stirred at room temperature for 15 hours and then concentrated to obtain a crude residue, which was purified by column chromatography (n-hexane:ethyl acetate = 1:3) on silica gel. m7-II (3.51 g, y: 66%) was obtained.

[0122] in IPA (100mL) m7-II Solutions of (3.51 g, 8.1 mmol) and 10% Pd / C (1.05 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm) and filtered. The filtrate was concentrated and moiety 7 (2.2g, y: 91%) was obtained.

[0123] Manufacturing of Moiety 8

[0124]

[0125] in a dry dimethylformamide ("DMF", 40 mL) solution m6-I KOH (11 g, 196.4 mmol) was added to a solution of (5 g, 49.5 mmol) at 5°C. The reaction mixture was stirred at 5°C for 0.5 hours. Subsequently, iodomethane (14 g, 98.6 mmol) was added to the solution. The mixture was stirred at room temperature for 15 hours and concentrated. The resulting residue was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m8-I (1.62g, y: 28%) was obtained.

[0126] in EtOH (60 mL) m8-I (1.62 g, 14.1 mmol) and m1-I A solution of CuSO4 (0.34 g, 2.1 mmol), (+)-sodium L-ascorbate (0.84 g, 4.2 mmol), and K2CO3 (1.94 g, 14 mmol) in H2O (15 mL) was added to a solution of (2.67 g, 14.1 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (n-hexane:ethyl acetate = 1:2) on silica gel, m8-II(3.03g, y:71%) was obtained.

[0127] in IPA (60 mL) m8-II A solution of (3.03 g, 10 mmol) and 10% Pd / C (0.9 g) was stirred at 60°C for 15 hours under H₂ (g) (1 atm) and filtered. The filtrate was concentrated and moiety 8 (1.66g, y: 98%) was obtained.

[0128] Manufacturing of Moiety 9

[0129]

[0130] NaN3 (3.01 g, 46.2 mmol) and Na2CO3 (2.32 g, 21.7 mmol) were added at room temperature to a solution of 1-bromopropan-2-ol (1.51 g, 10.8 mmol) in DMF (16 mL). The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m9-I (0.87g, y: 80%) was obtained.

[0131] in EtOH (38 mL) m9-I (0.75 g, 7.4 mmol) and m1-I A solution of CuSO4 (0.4 g, 2.5 mmol), (+)-sodium L-ascorbate (0.75 g, 3.8 mmol), and K2CO3 (1.2 g, 8.7 mmol) in H2O (19 mL) was added to a solution of (1.7 g, 9 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (n-hexane:ethyl acetate = 1:3) on silica gel, m9-II (1.61 g, y: 75%) was obtained.

[0132] in IPA (32 mL) m9-II Solutions of (1.61 g, 5.5 mmol) and 10% Pd / C (0.48 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm) and filtered. The filtrate was concentrated and moiety 9 (0.79g, y: 92%) was obtained.

[0133] Manufacturing of Moiety 10

[0134]

[0135] NaN3 (3.01 g, 46.2 mmol) and KI (0.23 g, 1.4 mmol) were added at room temperature to a solution of 4-bromo-butan-2-one (1.51 g, 10 mmol) in dimethylformamide (16 mL). The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m10-I (0.87g, y: 77%) was obtained.

[0136] in EtOH (38 mL) m10-I (0.87 g, 7.7 mmol) and m1-I A solution of CuSO4 (0.4 g, 2.5 mmol), (+)-sodium L-ascorbate (0.75 g, 3.8 mmol), and K2CO3 (1.2 g, 8.7 mmol) in H2O (19 mL) was added to a solution of (1.7 g, 9 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained from the previous step was purified on silica gel by column chromatography (n-hexane:ethyl acetate = 1:3) and m10-II (1.98 g, y: 85%) was obtained.

[0137] in dry MeOH (30 mL) m10-II NaBH4 (0.72 g, 19 mmol) was added to a solution of (1.98 g, 6.5 mmol) at 5°C. The reaction mixture was stirred at 5°C for 3 hours and then quenched with aqueous NH4Cl. The resulting mixture was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m10-III (1.61g, y: 81%) was obtained.

[0138] in 2-propanol (32 mL) m10-III Solutions of (1.61 g, 5.3 mmol) and 10% Pd / C (0.32 g) were stirred at 60°C under H2 (1 atm) for 15 hours and filtered. The filtrate was concentrated and moiety 10 (0.83g, y: 93%) was obtained.

[0139] Manufacturing of Moiety 11

[0140]

[0141] A solution of methyl magnesium bromide (8 mL, 3 M in THF) was added to a solution of ethyl 3-bromopropanoate (2 g, 11 mmol) in dry THF (45 mL). The mixture was stirred at 25°C for 4 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated m11-I (1.21g, y: 65%) was obtained.

[0142] in DMF (12 mL) m11-INaN3 (2.31 g, 35.4 mmol) and Na2CO3 (2.02 g, 19.1 mmol) were added to a solution of (1.21 g, 7.2 mmol) at room temperature. The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m11-II (0.72g, y: 78%) was obtained.

[0143] in EtOH (19 mL) m11-II (0.72 g, 5.6 mmol) and m1-I A solution of CuSO4 (0.24 g, 1.5 mmol), (+)-sodium L-ascorbate (0.48 g, 2.4 mmol), and K2CO3 (0.84 g, 6.1 mmol) in H2O (8.4 mL) was added to a solution of (1.56 g, 8.2 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated. The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on silica gel by column chromatography (MeOH:ethyl acetate = 1:19). m11-III (1.2 g, y: 68%) was obtained.

[0144] in IPA (24 mL) m11-III A solution of (1.2 g, 3.8 mmol) and 10% Pd / C (0.36 g) was stirred at 60°C for 15 hours under H₂ (g) (1 atm) and then filtered. The filtrate was concentrated and moiety 11 (0.61g, y: 88%) was obtained.

[0145] Manufacturing of Moiety 12

[0146] Moiety 12 was prepared from 1-bromo-3-methylsulfanyl-propane according to a procedure similar to that used to prepare Moiety 6.

[0147]

[0148] Manufacture of Moiety 13 and 14

[0149] Moiety 13 and 14 were prepared from amino-acetonitrile according to a procedure similar to that used to prepare Moiety 1.

[0150]

[0151] Manufacturing of Moiety 15

[0152]

[0153] Dichloroacetonitrile (5.02 g, 45.7 mmol) was added over 45 minutes to a solution of sodium methoxide (0.1 mL, 5.4 M in MeOH) in MeOH (10 mL) and DCM (100 mL) at 0°C. After stirring the mixture at 0°C for 1 hour, L-serine methyl ester hydrochloride (7.91 g, 50.8 mmol) was added. The reaction mixture was stirred at 25°C for 15 hours and then quenched with water. The resulting solution was concentrated and then extracted with DCM (3 x 150 mL). The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude residue. A mixture of the residue in DCM (150 mL) and N,N-diisopropylethylamine (8.91 g, 68.9 mmol) was stirred at 50°C for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The aqueous phase was separated and extracted with DCM (2 x 50 mL). The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (n-hexane:ethyl acetate = 4:1) and m15-I (7.85g, y: 98%) was obtained.

[0154] 1H NMR (CDCl3, 300 MHz) δ 8.25 (s, 1H), 4.64 (s, 2H), 3.93 (s, 3H).

[0155] in DMF (240 mL) m15-I A mixture of (8.01 g, 45.6 mmol) and sodium azide (10 g, 153.8 mmol) was stirred at 25°C for 15 hours and then quenched with NH4Cl(aq.)(50%) (50 mL, 2 M). The resulting solution was extracted with diethyl ether. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (n-hexane:ethyl acetate = 4:1) on silica gel, m15-II (6.91 g, y: 83%) was obtained.

[0156] 1 H NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 4.46 (s, 2H), 3.90 (s, 3H).

[0157] in water (105 mL) / THF (210 mL) m15-IIA mixture of (6.91 g, 37.9 mmol) and triphenylphosphine (10.42 g, 39.7 mmol) was stirred at 25°C for 15 hours. The resulting mixture was concentrated to remove THF. The resulting residue was washed with ethyl acetate. An amino product was obtained and remained in the aqueous phase, to which NaHCO3 (6.37 g, 75.8 mmol), THF (105 mL), and benzyl chloroformate (5.81 g, 34 mmol) were introduced at 5-10°C. The mixture was stirred at room temperature for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue obtained in this way is purified in silica gel by column chromatography (n-hexane:ethyl acetate = 3:1). m15-III (7.13g, y: 65% over 2 steps) was obtained.

[0158] 1 H NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.35-7.28 (m, 5H), 5.69 (br s, NH), 5.11 (s, 2H), 4.53 (d, 2H), 3.88 (s, 3H).

[0159] in THF (40 mL) m15-III LiOH (aq.) (20 mL, 1 N) was added to a solution of (3 g, 10.3 mmol). The mixture was stirred at 25 °C for 16 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. m15-IV (2.25g, y: 79%) was obtained.

[0160] m15-IVBoc2O (2.61 g, 11.9 mmol) and 4-dimethylaminopyridine (1.4 g, 11.5 mmol) were added to (2.25 g, 8.1 mmol). The resulting mixture was stirred at room temperature for 15 hours and then concentrated to obtain a crude residue, which was purified by column chromatography (n-hexane:ethyl acetate = 1:1) in silica gel. m15-V (2.06 g, y: 76%) was obtained.

[0161] in IPA (40 mL) m15-V A solution of (2.06 g, 6.2 mmol) and 10% Pd / C (0.6 g) was stirred at 60°C for 15 hours under H2 (g) (1 atm) and filtered. The filtrate was concentrated and moiety 15 (1.11g, y: 90%) was obtained.

[0162] Manufacturing of Moiety 16

[0163]

[0164] A solution of phthalic anhydride (10 g, 67.5 mmol), aminoacetaldehyde (7.81 g, 74.3 mmol), and N,N-diisopropylethylamine (13.09 g, 101.3 mmol) in toluene was heated at 120°C for 16 hours and then quenched with NH4Cl(aq.) (100 mL, 2 M). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m16-I (15.49g, y: 98%) was obtained.

[0165] in EtOH / H2O (20mL / 40mL) m16-IHCl (aq.) (120 mL, 6N) was added to a solution of (15.49 g, 65.8 mmol). The mixture was heated at 80°C for 16 hours and then concentrated. The residue was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with NaHCO3 (aq.) and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m16-II (6.26g, y: 50%) was obtained.

[0166] in DCM (100 mL) at 5-10℃ m16-II Hydroxylamine hydrochloride (2.53 g, 36.4 mmol) was added to a solution of (6.26 g, 33.1 mmol) and TEA (10 g, 99.4 mmol). The mixture was stirred at room temperature for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phase was washed with NaHCO3 (aq.) and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m16-III (4.01g, y: 59%) was obtained.

[0167] in DMF (100 mL) m16-III Solutions of (4 g, 19.6 mmol) and N-chlorosuccinimide (2.75 g, 20.6 mmol) were heated at 50°C for 5 hours and then poured into water. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated m16-IV (3.64g, y: 78%) was obtained.

[0168] in diethyl ether (66 mL) m16-IVNa2CO3 (3.3 g, 31.1 mmol) in H2O / chloroform (33 mL / 30 mL) was added to a solution of (2.38 g, 10 mmol) and pent-4-yn-1-ol (2.6 g, 30.9 mmol) at 5°C for 5 hours. The aqueous phase was extracted with diethyl ether (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (n-hexane:ethyl acetate = 1:4) on silica gel, m16-V (1.25g, y:44%) was obtained.

[0169] in MeOH / DCM (20mL / 20mL) m16-V Solutions of (0.9 g, 3.1 mmol) and hydrazine monohydrate (0.2 g, 6 mmol) were stirred at 25°C for 15 hours and then filtered. The filtrate was concentrated and moiety 16 (0.41g, y: 84%) was obtained.

[0170] Manufacturing of Moiety 17

[0171]

[0172] in a mixture of EtOH (200 mL) and THF (100 mL) at 0-5°C m15-III CaCl2 (4.01 g, 36.1 mmol) and NaBH4 (7.01 g, 185.3 mmol) were added as a single fraction to a solution of (10.02 g, 34.5 mmol). Subsequently, the resulting solution was stirred at 30°C for 2 hours, quenched with saturated (sat.) NH4Cl(aq), and then extracted with DCM (3 x 150 mL). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. MnO2 (36.31 g, 417.8 mmol) was added to the filtrate at 25°C while stirring for 2 hours. The crude product was obtained by filtration and concentration, which was purified by chromatography m17-I(5.31 g, y: 59% over two steps) was obtained.

[0173] in THF (100 g) m17-I Solutions of (3.63 g, 13.9 mmol), (1,3-dioxolane-2-ylmethyl)triphenylphosphonium bromide (7.21 g, 16.8 mmol), and t-BuOK (1.92 g, 17.1 mmol) were stirred at 5°C for 2 hours. HCl (aq) (50 mL, 2 N) was added to the resulting mixture and stirred at 10–15°C for 2 hours, after which it was quenched with saturated NaHCO3(aq). The mixture was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel using n-hexane / ethyl acetate (3:1) to obtain the product m17-II (3.54g, y: 89%) was obtained.

[0174] in dry MeOH (100 mL) m17-II A solution of NaBH4 (0.69 g, 18.3 mmol) in MeOH (20 mL) was added to a magnetically stirred solution of (3.54 g, 12.4 mmol). The mixture was stirred at 10°C for 1 hour and then concentrated. The residue was dissolved in DCM (150 mL), washed with NH4Cl and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. m17-III (3.14g, yield: 88%) was obtained.

[0175] in isopropanol (62 mL) m17-III A mixture of (3.14 g, 10.9 mmol) and 10% Pd / C (0.62 g) was stirred at 50°C under H2 (g) for 15 hours. The resulting mixture was filtered, and the filtrate was concentrated to form a moiety 17 (1.53g, y: 90%) was obtained.

[0176] Example 2 : Preparation of Compound 1-148

[0177] Compounds 1-148 of the present invention were prepared according to the procedure provided below. Unless otherwise described above, such as the preparation of moiety compounds, all side-chain compounds and other reagents are commercially available from various suppliers.

[0178] compound 1 manufacturing

[0179] The following scheme is a compound 1 It represents the synthesis of.

[0180]

[0181] Moiety in a solution of 4,6-dichloro-2-methanesulfonylpyrimidine (1.02 g, 4.5 mmol) in THF (50 mL) 1 (0.85 g, 6.7 mmol) was added at -70°C. The mixture was stirred at 25°C for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on silica gel by column chromatography (n-hexane:ethyl acetate = 2:1). 1-I (0.81g, y:66%) was obtained.

[0182] in isopropanol ("IPA", 4 mL) 1-I A solution of (0.81 g, 3 mmol) was mixed with morpholine (1.2 g, 13.8 mmol). The mixture was stirred at 140°C for 4 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (n-hexane:ethyl acetate = 1:4). 1-II (0.72g, y:65%) was obtained.

[0183] A solution of 2N HCl / diethyl ether (2 mL, 4 mmol) in DCM (3.6 mL) 1-IIIt was added to a solution of (360 mg, 1 mmol). The reaction mixture was stirred at 25°C for 15 hours and concentrated to obtain the compound. 1 The hydrochloride salt (381 mg, y: 96%) of was obtained.

[0184] EI-MS: 375.2(M+1).

[0185] Preparation of Compounds 97-98

[0186] Compounds 97-98 were prepared in a manner similar to that used to prepare Compound 1.

[0187] Compound 97 EI-MS: 376.2 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 5.12 (s, 1H), 4.97 (d, 2H), 4.45 (q, 2H), 3.73 (m, 8H), 3.47 (m, 8H), 1.49 (t, 3H).

[0188] Compound 98 EI-MS: 376.2 (M+1). 1 H-NMR (CDCl3, 300 MHz, free form) δ 5.10 (s, 1H), 4.82 (d, 2H), 4.61 (q, 2H), 3.74 (m, 8H), 3.48 (m, 8H), 1.61 (t, 3H).

[0189] Preparation of Compound 2

[0190]

[0191] in 1-pentanol (4 mL) 1-I Solutions of (1.27 g, 4.6 mmol) and phenethylamine (1.27 g, 10.5 mmol) were heated at 150°C for 15 hours, and the resulting mixture was concentrated. The residue thus obtained was purified by ethyl acetate column chromatography. 2-I (1.1g, y:66%) was obtained.

[0192] in IPA (4 mL) 2-IMorpholine (1.2 g, 13.8 mmol) was added to a solution of (1.1 g, 3.1 mmol). The mixture was stirred at 140°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:9). 2-II (0.98g, y:78%) was obtained.

[0193] A solution of 2N HCl in diethyl ether (2 mL, 4 mmol) in DCM (3.6 mL) 2-II It was added to a solution of (360 mg, 0.9 mmol). The reaction mixture was stirred at 25°C for 15 hours and concentrated to obtain the compound. 2 The hydrochloride salt (341 mg, y: 87%) of was obtained.

[0194] EI-MS: 409.2(M+1).

[0195] Preparation of Compound 3

[0196]

[0197] Moiety in a solution of 4,6-dichloro-2-methanesulfonylpyrimidine (1.02 g, 4.5 mmol) in THF (50 mL) 2 (1.43 g, 6.7 mmol) was added at -70°C. The mixture was stirred at 25°C for 15 hours and then quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on silica gel by column chromatography (n-hexane:ethyl acetate = 2:1). 3-I (0.91g, y: 56%) was obtained as a solid.

[0198] in IPA (4 mL) 3-IMorpholine (1.1 g, 12.6 mmol) was added to a solution of (0.91 g, 2.5 mmol). The mixture was stirred at 140°C for 4 hours and then concentrated. The resulting residue was purified by column chromatography in silica gel using ethyl acetate. 3-II (0.84g, y:72%) was obtained.

[0199] A solution of 2N HCl in diethyl ether (2 mL, 4 mmol) 3-II It was added to a DCM solution (360 mg, 0.8 mmol). The reaction mixture was stirred at 25°C for 15 hours, then concentrated to obtain the compound. 3 The hydrochloride salt (282 mg, y: 82%) of was obtained.

[0200] EI-MS: 405.2(M+1).

[0201] Preparation of Compound 4

[0202]

[0203] in 1-pentanol (4 mL) 3-I Solutions of (1.02 g, 2.8 mmol) and phenethylamine (0.81 g, 6.6 mmol) were heated at 120°C for 15 hours. Afterward, the resulting mixture was concentrated. The resulting residue was purified by column chromatography using ethyl acetate. 4-I (0.85g, y:67%) was obtained.

[0204] in IPA (4mL) 4-I Morpholine (0.85 g, 9.8 mmol) was added to a solution of (0.85 g, 1.9 mmol). The mixture was stirred at 140°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:9). 4-II (0.76g, y:80%) was obtained.

[0205] 2N HCl solution in diethyl ether (1.5 mL, 3 mmol) 4-IIIt was added to a DCM solution (300 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 4 The hydrochloride salt (254 mg, y: 88%) of was obtained.

[0206] EI-MS: 439.2(M+1).

[0207] Preparation of Compound 5

[0208]

[0209] in 1-pentanol (4 mL) 3-I Solutions of (1.02 g, 2.8 mmol) and 1-benzyl-piperidine-4-ylamine (1.06 g, 5.6 mmol) were heated at 120°C for 15 hours. Afterward, the resulting mixture was concentrated. The resulting residue was purified by ethyl acetate column chromatography. 5-I (0.96g, y:66%) was obtained.

[0210] in IPA (4 mL) 5-I Morpholine (0.82 g, 9.4 mmol) was added to a solution of (0.96 g, 1.9 mmol). The mixture was stirred at 140°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:9). 5-II (0.81g, y:77%) was obtained.

[0211] A solution of 2N HCl / diethyl ether (1 mL, 2 mmol) 5-II It was added to a DCM solution (304 mg, 0.5 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 5 The hydrochloride salt (268 mg, y: 86%) of was obtained.

[0212] EI-MS: 508.2 (M+1). 1H NMR (CD3OD, 400 MHz) δ 8.17 (s, 1H), 7.62-7.58 (m, 2H), 7.53-7.50 (m, 3H), 5.36 (s, 2H), 4.75 (s, 2H), 4.38 (s, 2H), 4.01 (m, 1H), 3.78-3.70 (m, 8H), 3.64 (m, 2H), 3.26 (m, 2H), 2.24 (m, 2H), 1.88 (m, 2H).

[0213] Preparation of Compound 6

[0214]

[0215] in 2-propanol (20 mL) 5-II Solutions of (1 g, 1.8 mmol) and 10% Pd / C (0.2 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm). The resulting mixture was filtered. The filtrate was concentrated 6-I (0.75g, yield: 89%) was obtained.

[0216] 1 H-NMR (CDCl3, 400 MHz) δ 7.58 (s, 1H), 5.00 (s, 2H), 4.94 (s, 1H), 4.69 (d, 2H), 3.74 (m, 4H), 3.62 (m, 1H), 3.47 (m, 4H), 3.07 (m, 2H), 2.70 (m, 2H), 1.96 (m, 2H), 1.47 (s, 9H), 1.34 (m, 2H).

[0217] in MeOH (18 mL) 6-I Solutions of (0.75 g, 1.6 mmol), acrylic acid tert-butyl ester (0.41 g, 3.2 mmol), and TEA (0.65 g, 6.4 mmol) were stirred at 60°C for 16 hours and then concentrated. The resulting residue was purified in silica gel (MeOH:ethyl acetate = 1:4) and 6-II (0.67g, y:70%) was obtained.

[0218] A solution of 2N HCl in diethyl ether (1.5 mL, 3 mmol) 6-II It was added to a DCM solution (412 mg, 0.7 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 6 The hydrochloride salt (306 mg, y: 79%) of was obtained.

[0219] EI-MS:490.2(M+1).

[0220] Preparation of Compound 99-104

[0221] Compounds 99-104 were prepared similarly to compound 6.

[0222] Compound 99 EI-MS: 389.2 (M+1).

[0223] Compound 100 EI-MS: 475.3 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 4.93 (s, 1H), 4.81 (d, 2H), 4.61 (q, 2H), 3.71 (m, 4H), 3.67 (s, 3H), 3.56 (m, 1H), 3.46 (m, 4H), 2.82 (m, 2H), 2.70 (t, 2H), 2.52 (t, 2H), 2.18 (m, 2H), 1.99 (m, 2H), 1.60 (t, 3H), 1.48 (m, 2H).

[0224] Compound 101 EI-MS: 461.2 (M+1).

[0225] Compound 102 EI-MS: 497.2 (M+1).

[0226] Compound 103 EI-MS: 568.2 (M+1).

[0227] Compound 104 EI-MS: 418.2 (M+1).

[0228] Preparation of Compound 7

[0229]

[0230] Moiety in a solution of 4,6-dichloro-2-methanesulfonylpyrimidine (2.04 g, 9 mmol) in THF (100 mL) 3 (2.51 g, 9.6 mmol) was added at -70°C. The mixture was stirred at 25°C for 15 hours and then quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (MeOH:ethyl acetate = 1:19) on silica gel, 7-I (2.35g, y: 64%) was obtained.

[0231] in 1-pentanol (4 mL) 7-I Solutions of (1.2 g, 2.9 mmol) and 1-benzyl-piperidine-4-ylamine (1.06 g, 5.6 mmol) were heated at 150°C for 15 hours. The resulting mixture was concentrated. The residue obtained was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:4). 7-II (0.77g, y:47%) was obtained.

[0232] in IPA (4 mL) 7-II Morpholine (0.7 g, 8 mmol) was added to a solution of (0.77 g, 1.4 mmol). The mixture was stirred at 120°C for 15 hours and then concentrated. The resulting residue was purified by column chromatography in silica gel using ethyl acetate. 7-III (0.34g, y:41%) was obtained.

[0233] in DCM (1.5 mL) 7-III Bromotrimethylsilane ("TMSBr", 510 mg, 3.3 mmol) was added to a solution of (340 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 4 hours and then concentrated to obtain the compound 7Hydrobromide salt (310 mg, y: 78%) was obtained.

[0234] EI-MS: 558.2(M+1).

[0235] compound 8 manufacturing

[0236]

[0237] in 1-pentanol (4 mL) 7-I (1.02g, 2.5mmol) and moiety 4 A solution of (0.5 g, 2.6 mmol) was heated at 150°C for 15 hours. The resulting mixture was concentrated. The residue obtained in this way was purified in silica gel by column chromatography (n-hexane:ethyl acetate = 1:3). 8-I (0.61g, y:44%) was obtained.

[0238] in IPA (8 mL) 8-I Morpholine (0.52 g, 6 mmol) was added to a solution of (0.61 g, 1.1 mmol). The mixture was stirred at 140°C for 4 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:DCM = 3:7). 8-II (0.21g, y:32%) was obtained.

[0239] DCM (1 mL) 8-II TMSBr (0.42 g, 2.7 mmol) was added to a solution of (211 mg, 0.3 mmol). The reaction mixture was stirred at 25°C for 6 hours and then concentrated to obtain the compound 8 The hydrobromide salt (242 mg, y: 80%) of was obtained.

[0240] EI-MS: 555.3 (M+1). 1H-NMR (CD3OD, 400 MHz) δ 8.24 (s, 1H), 4.76-4.67 (m, 4H), 3.94 (m, 2H), 3.90 (m, 2H), 3.78-3.62 (m, 9H), 3.60-3.43 (m, 9H), 3.23 (m, 2H), 2.42 (m, 2H), 2.20 (m, 2H).

[0241] Preparation of Compound 9

[0242]

[0243] A solution of 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) and 1-benzyl-piperidine-4-ylamine (2.71 g, 14.2 mmol) in THF (100 mL) was heated at 60°C for 15 hours. The resulting mixture was concentrated. The residue thus obtained was purified by column chromatography (n-hexane:ethyl acetate = 1:1) and 9-I (1.83g, y:54%) was obtained.

[0244] in 1-pentanol (4 mL) 9-I Moiety in a solution of (1.83 g, 5.4 mmol) 5 (1.41g, 5.5mmol) was added. The mixture was stirred at 150°C for 15 hours and then concentrated. The resulting residue was purified by column chromatography in silica gel using ethyl acetate. 9-II (2.01 g, y: 67%) was obtained as a solid.

[0245] in IPA (4 mL) 9-II Morpholine (1.42 g, 16.1 mmol) was added to a solution of (2.01 g, 3.6 mmol). The mixture was stirred at 120°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:19). 9-III (1.58g, y:72%) was obtained.

[0246] 2N HCl solution in diethyl ether (1.2 mL, 2.4 mmol) 9-III It was added to a DCM solution (350 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 15 hours, then concentrated to obtain the compound. 9 The hydrochloride salt (325 mg, y: 91%) of was obtained.

[0247] EI-MS: 507.3 (M+1). 1 H-NMR (DO, 300 MHz) δ 7.87 (s, 1H), 7.42-7.30 (m, 5H), 4.53 (s, 2H), 4.39 (t, 2H), 4.20 (s, 2H), 3.70 (m, 1H), 3.62 (m, 4H), 3.48-3.44 (m, 6H), 3.02 (m, 2H), 2.87 (m, 2H), 2.20-2.04 (m, 4H), 1.60 (m, 2H).

[0248] Preparation of Compound 17

[0249] Compound 17 was prepared in a similar manner to that used to prepare Compound 9.

[0250] EI-MS: 549.3(M+1).

[0251] Preparation of Compound 10

[0252]

[0253] in 2-propanol (20 mL) 9-III Solutions of (1 g, 1.6 mmol) and 10% Pd / C (0.3 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm). The resulting mixture was filtered and concentrated 10-I (0.74g, y: 87%) was obtained.

[0254] in MeOH (18 mL) 10-IA solution of (0.74 g, 1.4 mmol), diethyl vinylphosphonate (0.41 g, 2.5 mmol), and TEA (3 drops) was stirred at 60 °C for 16 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:9). 10-II (0.63g, y:65%) was obtained.

[0255] A solution of 2N HCl in diethyl ether (1 mL, 2 mmol) 10-II It was added to a DCM solution (330 mg, 0.5 mmol). The reaction mixture was stirred at 25°C for 15 hours, then concentrated to obtain the compound. 10 The hydrochloride salt (305 mg, y: 91%) of was obtained.

[0256] EI-MS: 581.3 (M+1).

[0257] Preparation of compounds 18-19, 36, 109, 122, 125, 131, 132, and 145

[0258] Compounds 18-19, 36, 109, 122, 125, 131, 132, and 145 were prepared in a manner similar to that used to prepare compound 10.

[0259] Compound 18 EI-MS: 459.3 (M+1).

[0260] Compound 19 EI-MS: 531.3 (M+1).

[0261] Compound 36 EI-MS: 567.3 (M+1). 1 H-NMR (DO, 400 MHz) δ 7.88 (s, 1H), 4.53 (d, 2H), 4.37 (t, 2H), 3.75 (m, 1H), 3.61-3.40 (m, 10H), 3.28 (m, 2H), 3.05-3.00 (m, 4H), 2.20-1.90 (m, 6H), 1.62 (m, 2H).

[0262] Compound 109 EI-MS: 651.3 (M+1).

[0263] 화합물 122 EI-MS: 651.4 (M+1). 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.75 (s, 1H), 4.55 (s, 2H), 4.42 (t, 2H), 4.13 (q, 4H), 3.68-3.62 (m, 9H), 3.40 (m, 4H), 2.88 (m, 2H), 2.64 (m, 2H), 2.34 (m, 4H), 2.28-2.15 (m, 4H), 2.10-2.02 (m, 4H), 1.93 (m, 2H), 1.51 (m, 2H), 1.35 (t, 6H).

[0264] 화합물 125 EI-MS: 699.3 (M+1). 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.77 (s, 1H), 4.58 (s, 2H), 4.46 (t, 2H), 4.15 (q, 4H), 3.73-3.70 (m, 5H), 3.42 (m, 4H), 3.02 (m, 4H), 2.88 (m, 2H), 2.82 (m, 4H), 2.66 (m, 2H), 2.33 (t, 2H), 2.24 (m, 2H), 2.16-2.04 (m, 4H), 1.91 (m, 2H), 1.51 (m, 2H), 1.35 (t, 6H).

[0265] 화합물 131 EI-MS: 595.3 (M+1). 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.80 (s, 1H), 4.58 (s, 2H), 4.49 (t, 2H), 4.13 (q, 4H), 3.71 (m, 1H), 3.57-3.53 (m, 6H), 2.92 (m, 2H), 2.70 (m, 2H), 2.53 (m, 4H), 2.37 (s, 3H), 2.26 (m, 2H), 2.14-2.08 (m, 4H), 1.95 (m, 2H), 1.52 (m, 2H), 1.37 (t, 6H).

[0266] 화합물 132 EI-MS: 639.4 (M+1).1 H-NMR (CD3OD, 400 MHz, free form) δ 7.81 (s, 1H), 4.57 (s, 2H), 4.46 (t, 2H), 4.16 (q, 4H), 3.70 (m, 1H), 3.60 (t, 2H), 3.53 (m, 4H), 3.36 (s, 3H), 3.30 (t, 2H), 3.21 (m, 4H), 3.00 (m, 2H), 2.75 (m, 2H), 2.64 (m, 2H), 2.33 (m, 2H), 2.10-2.02 (m, 6H), 1.53 (m, 2H), 1.31 (t, 6H).

[0267] Compound 145 EI-MS: 747.3 (M+1).

[0268] Preparation of Compound 11

[0269]

[0270] DCM (1 mL) 10-II TMSBr (0.40 g, 2.6 mmol) was added to a solution of (302 mg, 0.4 mmol). The reaction mixture was stirred at 25°C for 5 hours and then concentrated to obtain the compound 11 The hydrobromide salt (263 mg, y: 77%) of was obtained.

[0271] EI-MS: 525.3 (M+1). 1 H-NMR (DO, 400 MHz) δ 7.92 (s, 1H), 4.53 (s, 2H), 4.40 (t, 2H), 3.78 (m, 1H), 3.58 (m, 4H), 3.54 (m, 2H), 3.48 (m, 4H), 3.23 (m, 2H), 3.00 (m, 2H), 2.87 (t, 2H), 2.13 (m, 2H), 2.09-1.97 (m, 4H), 1.61 (m, 2H).

[0272] Preparation of Compound 12

[0273]

[0274] in DCM (25 mL)10-I 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide ("EDCI", 0.35 g, 1.8 mmol), hydroxybenzotriazole ("HOBt", 0.28 g, 1.8 mmol), and 3-[tert-butoxycarbonyl-(2-hydroxy-propyl)-amino]-propionic acid (0.42 g, 1.7 mmol) were added to a solution of (0.61 g, 1.2 mmol) at 25 °C. The reaction mixture was stirred for 15 hours and then poured into water. The resulting mixture was extracted with DCM. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (MeOH:DCM = 1:19) on silica gel, 12-I (0.55g, y:62%) was obtained.

[0275] A solution of 2N HCl / diethyl ether (0.75 mL, 1.5 mmol) 12-I It was added to a DCM solution (300 mg, 0.4 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 12 The hydrochloride salt (240 mg, y: 91%) of was obtained.

[0276] EI-MS: 546.3 (M+1). 1 H-NMR (DO, 300 MHz) δ 7.83 (s, 1H), 4.51 (s, 2H), 4.37 (t, 2H), 4.13 (m, 1H), 3.97 (m, 1H), 3.78-3.57 (m, 6H), 3.43 (m, 4H), 3.30-3.02 (m, 4H), 2.90-2.67 (m, 6H), 2.16 (m, 2H), 1.93 (m, 2H), 1.38 (m, 2H), 1.06 (d, 3H).

[0277] Preparation of compounds 13-15, 23-26, 33-34, 73-74 and 77-80

[0278] Compounds 13-15, 23-26, 33-34, 73-74, and 77-80 were prepared according to a procedure similar to that used to prepare compound 12.

[0279] Compound 13 EI-MS: 567.3 (M+1). 1 H-NMR (DO, 400 MHz) δ 7.85 (s, 1H), 6.78-6.70 (m, 3H), 4.47 (s, 2H), 4.36 (t, 2H), 4.15 (m, 1H), 3.66 (s, 3H), 3.65-3.36 (m, 10H), 3.06 (m, 1H), 2.87-2.83 (m, 3H), 2.14 (m, 2H), 1.89 (m, 1H), 1.70 (m, 1H), 1.37 (m, 2H).

[0280] Compound 14 EI-MS: 577.3 (M+1).

[0281] Compound 15 EI-MS: 662.3 (M+1). 1 H-NMR (DO, 300 MHz) δ 7.90 (s, 1H), 4.52 (s, 2H), 4.40 (t, 2H), 4.16-4.04 (m, 2H), 3.95 (m, 1H), 3.77 (m, 1H), 3.65-3.55 (m, 5H), 3.47-3.30 (m, 7H), 3.16 (m, 1H), 2.86 (m, 2H), 2.78 (m, 1H), 2.60 (m, 2H), 2.14 (m, 2H), 1.93-1.70 (m, 6H), 1.40 (m, 1H), 1.26 (m, 1H).

[0282] Compound 23 EI-MS: 806.4 (M+1). 1H-NMR (CD3OD, 400 MHz, free form) δ 7.80(s, 1H), 4.57 (s, 2H), 4.43-4.39 (m, 4H), 4.16-4.13 (m, 2H), 4.00 (m, 1H), 3.85 (m, 1H), 3.73-3.64 (m, 5H), 3.61 (m, 2H), 3.50-3.30 (m, 9H), 3.16 (m, 1H), 2.84 (m, 1H), 2.62 (m, 2H), 2.14 (m, 2H), 1.99-1.86 (m, 6H), 1.43-1.40 (m, 11H).

[0283] 화합물 24 EI-MS: 706.3 (M+1). 1 H-NMR (D2O, 400 MHz) δ 7.86 (s, 1H), 4.52 (s, 2H), 4.41-4.38 (m, 4H), 4.06-4.04 (m, 2H), 3.88 (m, 1H), 3.81-3.78 (m, 2H), 3.62-3.60 (m, 4H), 3.60 (m, 2H), 3.50-3.30 (m, 6H), 3.10-2.96 (m, 4H), 2.78 (m, 1H), 2.58 (m, 2H), 2.20 (m, 2H), 1.90-1.64 (m, 6H), 1.41 (m, 2H).

[0284] 화합물 25 EI-MS: 762.4 (M+1). 1 H-NMR (CD3OD, 300 MHz, free form) δ 7.84 (s, 1H), 4.59 (s, 2H), 4.39 (t, 2H), 4.16 (m, 1H), 3.98 (m, 1H), 3.84 (m, 1H), 3.71-3.68 (m, 5H), 3.50-3.40 (m, 6H), 3.22 (m, 1H), 3.03 (t, 2H), 2.82 (m, 1H), 2.62 (t, 2H), 2.04-1.86 (m, 10H), 1.42 (s, 9H), 1.38 (m, 2H).

[0285] 화합물 26 EI-MS: 691.4 (M+1).

[0286] Compound 33 EI-MS: 675.4 (M+1). 1 H-NMR (DO, 400 MHz, free form) δ 7.84 (s, 1H), 4.50 (s, 2H), 4.29 (t, 2H), 4.10 (m, 1H), 3.98-3.95 (m, 2H), 3.78-3.65 (m, 2H), 3.57 (m, 4H), 3.42 (m, 4H), 3.23-3.10 (m, 5H), 3.06-2.96 (m, 4H), 2.86-2.77 (m, 5H), 2.55 (t, 2H), 2.00-1.73 (m, 4H), 1.41 (m, 1H), 1.34 (m, 1H), 1.08-1.06 (m, 6H).

[0287] Compound 34 EI-MS: 791.4 (M+1).

[0288] Compound 73 EI-MS: 646.3 (M+1).

[0289] Compound 74 EI-MS: 661.3 (M+1). 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.79 (s, 1H), 4.60 (s, 2H), 4.45-4.40 (m, 3H), 4.18 (q, 2H), 4.00 (s, 2H), 3.98 (m, 1H), 3.81-3.75 (m, 5H), 3.68 (s, 3H), 3.57-3.52 (m, 4H), 3.20 (m, 1H), 3.06 (m, 4H), 2.79-2.61 (m, 5H), 2.48 (t, 2H), 2.10-1.83 (m, 6H), 1.21 (t, 3H).

[0290] Compound 77 EI-MS: 792.4 (M+1). 1H-NMR (CD3OD, 400 MHz, free form) δ 7.86 (s, 1H), 4.60 (s, 2H), 4.54 (t, 2H), 4.39 (m, 1H), 4.10 (m, 1H), 3.95 (m, 1H), 3.86 (m, 1H), 3.81 (t, 2H), 3.68-3.62 (m, 5H), 3.56-3.40 (m, 7H), 3.22 (m, 1H), 3.13 (t, 2H), 2.84 (m, 1H), 2.62 (t, 2H), 1.98-1.83 (m, 8H), 1.42 (s, 9H), 1.38 (m, 2H).

[0291] 화합물 78 EI-MS: 692.3 (M+1). 1 H-NMR (D2O, 400 MHz) δ 7.86 (s, 1H), 4.53-4.46 (m, 4H), 4.16-4.05 (m, 2H), 3.95 (m, 1H), 3.81-3.77 (m, 3H), 3.65-3.54 (m, 5H), 3.48-3.30 (m, 7H), 3.15 (m, 1H), 3.01 (m, 2H), 2.80 (m, 1H), 2.56 (m, 2H), 1.93-1.70 (m, 8H), 1.40 (m, 1H), 1.26 (m, 1H).

[0292] 화합물 79 EI-MS: 584.3 (M+1). 1 H-NMR (CDCl3, 300 MHz, free form) δ 7.46 (s, 1H), 7.32-7.22 (m, 7H), 6.97 (t, 1H), 6.86 (t, 2H), 4.92 (s, 1H), 4.65 (d, 2H), 4.52 (t, 2H), 3.97-3.92 (m, 3H), 3.72 (m, 4H), 3.51 (s, 2H), 3.44 (m, 4H), 2.82 (m, 2H), 2.36 (m, 2H), 2.15 (m, 2H), 1.96 (m, 2H), 1.48 (m, 2H).

[0293] 화합물 80 EI-MS: 566.3 (M+1).

[0294] Preparation of Compound 16

[0295]

[0296] Moiety 6 (2.41 g, 15.4 mmol) and TEA (2 g, 19.8 mmol) were added to a solution of 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) in THF (54 mL). The mixture was stirred at 25°C for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on silica gel by column chromatography (n-hexane:ethyl acetate = 1:3). 16-I (1.03g, y:34%) was obtained.

[0297] in IPA (10 mL) 16-I Morpholine (1.4 g, 16.1 mmol) was added to a solution of (1.03 g, 3.4 mmol). The mixture was stirred at 120°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (n-hexane:ethyl acetate = 1:9). 16-II (1.2g, y:87%) was obtained.

[0298] in dry DCM (40mL) 16-II TEA (0.45 g, 4.5 mmol) and MsCl (0.45 g, 3.9 mmol) were added to a solution of (1.2 g, 3 mmol) at 5 °C. The reaction mixture was stirred at room temperature for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated 16-III (1.04g, y: 73%) was obtained.

[0299] in dry THF (30 mL) 16-III Benzylamine (0.28 g, 2.6 mmol) was added to a solution of (1.04 g, 2.2 mmol) at 5°C. The reaction mixture was stirred at room temperature for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting residue was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. DCM (50 mL), Boc2O (0.65 g, 3 mmol), and TEA (0.41 g, 4.1 mmol) were added to the obtained residue. The mixture was stirred at room temperature for 15 hours and then concentrated to obtain a crude residue, which was purified by column chromatography (n-hexane:ethyl acetate = 1:3) on silica gel. 16-IV (0.56g, y: 44%) was obtained.

[0300] A solution of 2N HCl / diethyl ether (2 mL, 4 mmol) 16-IV It was added to a DCM solution (562 mg, 0.9 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 16 The hydrochloride salt (451 mg, y: 84%) of was obtained.

[0301] EI-MS: 494.3 (M+1). 1 H-NMR (DO, 400 MHz) δ 7.83 (s, 1H), 7.30-7.15 (m, 5H), 4.50 (s, 2H), 4.37 (t, 2H), 3.97 (s, 2H), 3.70-3.57 (m, 8H), 3.40 (m, 8H), 2.84 (m, 2H), 2.15 (m, 2H).

[0302] Preparation of Compounds 21-22 and 50-52

[0303] Compounds 21-22 and 50-52 were prepared in a manner similar to that used to prepare compound 16.

[0304] Compound 21 EI-MS: 655.4 (M+1). 1H-NMR (D2O, 400 MHz) δ 7.87 (s, 1H), 7.83 (s, 1H), 7.49 (m, 1H), 7.40-7.35 (m, 6H), 4.49 (s, 2H), 4.38 (t, 2H), 4.21 (s, 2H), 4.08 (s, 2H), 3.80 (s, 3H), 3.68 (m, 1H), 3.60 (m, 4H), 3.53-3.40 (m, 6H), 3.02 (m, 2H), 2.88 (m, 2H), 2.22-2.06 (m, 4H), 1.58 (m, 2H).

[0305] 화합물 22 EI-MS: 565.3 (M+1).

[0306] 화합물 50 EI-MS: 405.2 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 7.45 (s, 1H), 5.07 (s, 1H), 4.62 (d, 2H), 4.41 (t, 2H), 3.69 (m, 8H), 3.54 (t, 2H), 3.44 (m, 8H), 2.03 (m, 2H).

[0307] 화합물 51 EI-MS: 693.3 (M+1).

[0308] 화합물 52 EI-MS: 433.2 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 7.41 (s, 1H), 5.08 (s, 1H), 4.63 (d, 2H), 4.27 (t, 2H), 3.70 (m, 8H), 3.58 (t, 2H), 3.45 (m, 8H), 1.87 (m, 2H), 1.54 (m, 2H), 1.35 (m, 2H).

[0309] Preparation of Compound 20

[0310]

[0311]

[0312] IPA(10 mL) 중의 16-I1-benzyl-piperidine-4-ylamine (1.35 g, 7.1 mmol) was added to a solution of (1.52 g, 5 mmol). The mixture was stirred at 150°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:9). 20-I (1.54g, y:67%) was obtained.

[0313] in IPA (45mL) 20-I Morpholine (1.4g, 16.1mmol) was added to a solution of (1.54g, 3.4mmol). The mixture was stirred at 120°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:4). 20-II (1.2g, y:70%) was obtained.

[0314] in dry DCM (40mL) 20-II TEA (0.4 g, 4 mmol) and MsCl (0.4 g, 3.5 mmol) were added to a solution of (1.2 g, 2.4 mmol) at 5 °C. The reaction mixture was stirred at room temperature for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting residue was extracted with DCM. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated 20-III (0.95g, yield: 69%) was obtained.

[0315] in dry THF (25 mL) 20-IIIPiperidine (0.28 g, 3.3 mmol) was added to a solution of (0.95 g, 1.6 mmol) at 5 °C. The reaction mixture was stirred at room temperature for 15 hours and quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting residue was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on silica gel by column chromatography (MeOH:ethyl acetate = 1:1) 20-IV (0.56g, y:60%) was obtained.

[0316] in 2-propanol (2 mL) 20-IV Solutions of (0.56 g, 1 mmol) and 10% Pd / C (0.17 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm). The resulting mixture was filtered. The filtrate was concentrated 20-V (0.42g, y: 89%) was obtained.

[0317] 2N HCl solution in diethyl ether (1.2 mL, 2.4 mmol) 20-V It was added to a DCM solution of (310 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 20 The hydrochloride salt (359 mg, y: 95%) of was obtained.

[0318] EI-MS: 485.3(M+1).

[0319] Preparation of compounds 120, 121, 124, 127 and 144

[0320] Compounds 120, 121, 124, 127, and 144 were prepared in a manner similar to that used to prepare compound 20.

[0321] Compound 120 EI-MS: 665.4 (M+1).

[0322] Compound 121 EI-MS: 577.3 (M+1). 1H NMR (CD3OD, 400 MHz, free form) δ 7.75 (s, 1H), 7.35-7.28 (m, 5H), 4.55 (s, 2H), 4.41 (t, 2H), 3.75-3.62 (m, 11H), 3.40 (m, 4H), 2.89 (m, 2H), 2.34 (m, 4H), 2.29 (m, 2H), 2.24 (m, 2H), 2.06 (m, 2H), 1.94 (m, 2H), 1.52 (m, 2H).

[0323] Compound 124 EI-MS: 625.3 (M+1).

[0324] Compound 127 EI-MS: 725.4 (M+1). 1 H NMR (CDCl3, 400 MHz, free form) δ 7.55 (s, 1H), 4.96 (s, 1H), 4.71 (d, 2H), 4.32 (t, 2H), 4.11 (q, 4H), 3.75-3.70 (m, 6H), 3.56-3.50 (m, 5H), 3.31 (m, 4H), 2.82 (m, 2H), 2.65 (m, 2H), 2.16-2.12 (m, 4H), 2.05-1.96 (m, 4H), 1.50 (m, 2H), 1.46 (s, 9H), 1.31 (t, 6H).

[0325] Compound 144 EI-MS: 673.3 (M+1).

[0326] Preparation of Compound 27

[0327]

[0328] Compounds in DCM (18 mL) 10EDCI (0.21 g, 1.1 mmol), HOBt (0.19 g, 1.2 mmol), TEA (0.3 g, 3.0 mmol), and Levulinic acid (0.14 g, 1.2 mmol) were added to a solution of (0.53 g, 0.8 mmol) at 25°C. The reaction mixture was stirred for 15 hours and then poured into water. The resulting mixture was extracted with DCM. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (MeOH:DCM = 1:19) on silica gel, 27-I (0.38g, y:73%) was obtained.

[0329] A solution of 2N HCl / diethyl ether (1.2 mL, 2.4 mmol) 27-I It was added to a DCM solution (382 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 27 The hydrochloride salt (359 mg, y: 90%) of was obtained.

[0330] EI-MS: 679.3(M+1).

[0331] Preparation of Compounds 28-32

[0332] Compounds 28-32 were prepared in a manner similar to that used to prepare compound 27.

[0333] Compound 28 EI-MS: 609.3 (M+1).

[0334] Compound 29 EI-MS: 738.4 (M+1). 1H-NMR (D2O, 400 MHz, free form) δ 7.79 (s, 1H), 4.46 (s, 2H), 4.28 (t, 2H), 4.05 (q, 4H), 3.61 (m, 1H), 3.57 (s, 3H), 3.55 (m, 4H), 3.42 (m, 4H), 3.23-3.18 (m, 6H), 3.02 (m, 2H), 2.76-2.68 (m, 4H), 2.53 (t, 2H), 2.28 (m, 2H), 2.16 (m, 2H), 1.96-1.86 (m, 4H), 1.61 (m, 2H), 1.17 (t, 6H).

[0335] 화합물 30 EI-MS: 682.3 (M+1).

[0336] 화합물 31 EI-MS: 710.4 (M+1). 1 H-NMR (CD3OD, 300 MHz, free form) δ 7.81 (s, 1H), 4.47 (s, 2H), 4.32 (t, 2H), 4.02 (q, 4H), 3.97 (m, 1H), 3.64 (m, 1H), 3.57 (m, 4H), 3.42 (m, 4H), 3.33 (m, 2H), 3.20 (m, 2H), 3.02 (m, 4H), 2.83 (m, 2H), 2.58 (t, 2H), 2.36 (m, 2H), 2.17 (m, 2H), 2.00-1.92 (m, 4H), 1.62 (m, 2H), 1.20 (t, 6H), 1.09 (d, 3H).

[0337] 화합물 32 EI-MS: 654.3 (M+1). 1 H-NMR (D2O, 300 MHz) δ 7.98 (s, 1H), 4.46 (s, 2H), 4.34 (t, 2H), 3.96 (m, 1H), 3.64 (m, 1H), 3.57-3.50 (m, 6H), 3.36-3.31 (m, 6H), 3.08 (m, 4H), 2.83 (m, 2H), 2.58 (t, 2H), 2.00-1.92 (m, 8H), 1.62 (m, 2H), 1.09 (d, 3H).

[0338] Preparation of Compound 35

[0339]

[0340] Compound in MeOH (5 mL) 10 N,N'-di-Boc-1H-pyrazole-1-carboxamidine (0.28 g, 0.9 mmol) and TEA (0.37 g, 3.7 mmol) were added to a solution of (0.5 g, 0.7 mmol). The mixture was stirred at room temperature for 15 hours and then concentrated to obtain a crude residue, which was purified by column chromatography (n-hexane:ethyl acetate = 1:3) on silica gel. 35-I (0.40g, y: 67%) was obtained.

[0341] A solution of 2N HCl / diethyl ether (1 mL, 2 mmol) 35-I It was added to a DCM solution (310 mg, 0.4 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 35 The hydrochloride salt (261 mg, y: 90%) of was obtained.

[0342] EI-MS: 623.3 (M+1).

[0343] 1 H-NMR (DO, 400 MHz) δ 7.84 (s, 1H), 4.52 (d, 2H), 4.36 (t, 2H), 4.03 (q, 4H), 3.72 (m, 1H), 3.61-3.40 (m, 10H), 3.28 (m, 2H), 3.05-3.00 (m, 4H), 2.30 (m, 2H), 2.20-1.98 (m, 4H), 1.64 (m, 2H), 1.32 (t, 6H).

[0344] Preparation of Compound 37

[0345]

[0346] 1-benzyl-piperidine-4-ylamine (6.3 g, 33.1 mmol) and TEA (4.5 g, 44.6 mmol) were added to a solution of 2,4,6-trichloropyrimidine (5.4 g, 29.4 mmol) in THF under a nitrogen atmosphere. The mixture was stirred at 60°C for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on silica gel by column chromatography (n-hexane:ethyl acetate = 1:4) 37-I (5.60g, y:56%) was obtained.

[0347] in IPA (40 mL) 37-I (2 g, 5.9 mmol) and moiety 6 A solution of (1.08 g, 6.9 mmol) was heated at 145°C for 15 hours. The resulting mixture was concentrated. The residue obtained was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:9). 37-II (1.6g, y:59%) was obtained.

[0348] in IPA (40 mL) 37-II Solutions of (1.2 g, 2.6 mmol) and piperidine (1 g, 11.7 mmol) were sealed and heated at 120°C for 15 hours. The resulting mixture was concentrated. The residue thus obtained was purified in silica gel by column chromatography (MeOH:ethyl acetate = 3:7). 37-III (1.19g, y:89%) was obtained.

[0349] 1H NMR (CD3OD, 400 MHz, free form) δ 7.81 (s, 1H), 7.41-7.30 (m, 5H), 4.57 (s, 2H), 4.44 (t, 2H), 3.75 (s, 2H), 3.71 (m, 1H), 3.53 (t, 2H), 3.47 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.46 (m, 2H), 2.07 (m, 2H), 2.01 (m, 2H), 1.80 (m, 2H), 1.70-1.51 (m, 6H).

[0350] 2N HCl solution in diethyl ether (1.2 mL, 2.4 mmol) 37-III It was added to a DCM solution (305 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 37 The hydrochloride salt (320 mg, y: 92%) of was obtained.

[0351] EI-MS:506.3(M+1).

[0352] Preparation of compounds 38-44, 112, 115, 133, 136, 138 and 141

[0353] Compounds 38-44, 112, 115, 133, 136, 138, and 141 were prepared in a manner similar to that used to prepare compound 37.

[0354] Compound 38 EI-MS: 416.3 (M+1).

[0355] Compound 39 EI-MS: 502.3 (M+1).

[0356] Compound 40 EI-MS: 493.3 (M+1).

[0357] Compound 41 EI-MS: 431.3 (M+1).

[0358] Compound 42 EI-MS: 439.2 (M+1).

[0359] Compound 43 EI-MS: 502.3 (M+1).

[0360] Compound 44 EI-MS: 430.3 (M+1).

[0361] Compound 112 EI-MS: 494.3 (M+1). 1 H NMR (CDCl3, 400 MHz, free form) δ 7.60 (s, 1H), 7.35-7.24 (m, 5H), 4.95 (s, 1H), 4.63 (d, 2H), 4.42 (t, 2H), 4.01 (t, 2H), 3.73 (m, 4H), 3.54 (s, 2H), 3.48-4.40 (m, 5H), 2.85 (m, 2H), 2.19 (m, 2H), 1.97 (m, 2H), 1.55 (m, 2H).

[0362] Compound 115 EI-MS: 522.3 (M+1). 1 H NMR (CDCl3, 400 MHz, free form) δ 7.49 (s, 1H), 7.30-7.23 (m, 5H), 4.95 (s, 1H), 4.70 (s, 2H), 4.31 (t, 2H), 3.73 (m, 4H), 3.54 (t, 2H), 3.48 (s, 2H), 3.47-4.40 (m, 5H), 2.77 (m, 2H), 2.11 (m, 2H), 2.01-1.93 (m, 4H), 1.56 (m, 2H).

[0363] Compound 133 EI-MS: 516.3 (M+1).

[0364] Compound 136 EI-MS: 542.3 (M+1).

[0365] Compound 138 EI-MS: 524.3 (M+1). 1H NMR (CDCl3, 600 MHz, free form) δ 7.51 (s, 1H), 7.36-7.27 (m, 5H), 4.92 (s, 1H), 4.70 (s, 2H), 4.48 (t, 2H), 3.88 (m, 4H), 3.66 (t, 2H), 3.58 (s, 2H), 3.56 (m, 1H), 2.80 (m, 2H), 2.56 (m, 4H), 2.21 (m, 2H), 2.04 (m, 2H), 1.98 (m, 2H), 1.56 (m, 2H).

[0366] Compound 141 EI-MS: 556.2 (M+1).

[0367] Preparation of Compound 45

[0368]

[0369] Compounds in IPA (40 mL) 37-II Solutions of (1.2 g, 2.6 mmol) and morpholine (1 g, 11.5 mmol) were sealed and heated at 120°C for 15 hours. The resulting mixture was concentrated. The residue thus obtained was purified by flash chromatography (MeOH:ethyl acetate = 1:3) in silica gel. 45-I (1.08g, y:81%) was obtained.

[0370] in 2-propanol (20 mL) 45-I Solutions of (1.08 g, 2.1 mmol) and 10% Pd / C (0.3 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm). The resulting mixture was filtered. The filtrate was concentrated 45-II (0.81g, y: 91%) was obtained.

[0371] 1H-NMR (CD3OD, 400 MHz, free form) δ 7.76 (s, 1H), 4.81 (s, 1H), 4.55 (s, 2H), 4.45 (t, 2H), 3.89 (m, 1H), 3.68 (m, 4H), 3.53 (t, 2H), 3.40 (m, 4H), 3.10 (m, 2H), 2.76 (m, 2H), 2.05 (m, 2H), 1.95 (m, 2H), 1.40 (m, 2H).

[0372] A solution of 2N HCl / diethyl ether (1.5 mL, 3 mmol) 45-II It was added to a DCM solution (310 mg, 0.7 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 45 The hydrochloride salt (331 mg, y: 91%) of was obtained.

[0373] EI-MS: 418.2(M+1).

[0374] Preparation of compounds 49, 53, 54, 61, 81, 82, 85, 86 and 89-94

[0375] Compounds 49, 53, 54, 61, 81, 82, 85, 86 and 89-94 were prepared in a manner similar to that used to prepare compound 45.

[0376] Compound 49 EI-MS: 508.3 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 7.52 (s, 1H), 7.35-7.24 (m, 5H), 4.92 (d, 1H), 4.65 (d, 2H), 4.46 (t, 2H), 3.76-3.71 (m, 5H), 3.59 (t, 2H), 3.55 (s, 2H), 3.48 (m, 4H), 2.83 (m, 2H), 2.13 (m, 2H), 2.06 (m, 2H), 1.95 (m, 2H), 1.54 (m, 2H).

[0377] Compound 53 EI-MS: 418.2 (M+1).

[0378] Compound 54 EI-MS: 508.3 (M+1).

[0379] Compound 61 EI-MS: 432.2 (M+1).

[0380] Compound 81 EI-MS: 538.3 (M+1).

[0381] Compound 82 EI-MS: 548.3 (M+1).

[0382] Compound 85 EI-MS: 538.3 (M+1). 1 H NMR (CDCl 3, 400 MHz, free form) δ 7.46 (s, 1H), 7.32-7.24 (m, 5H), 4.94 (s, 1H), 4.65 (d, 2H), 4.43 (t, 2H), 3.74 (m, 4H), 3.54 (m, 1H), 3.52 (s, 2H), 3.48 (m, 4H), 2.81 (m, 2H), 2.46 (t, 2H), 2.20-2.14 (m, 4H), 2.08 (s, 3H), 1.96 (m, 2H), 1.51 (m, 2H).

[0383] Compound 86 EI-MS: 448.2 (M+1).

[0384] Compound 89 EI-MS: 537.3 (M+1).

[0385] Compound 90 EI-MS: 447.2 (M+1).

[0386] Compound 91 EI-MS: 551.3 (M+1).

[0387] Compound 92 EI-MS: 461.3 (M+1).

[0388] Compound 93 EI-MS: 536.3 (M+1).

[0389] Compound 94 EI-MS: 446.3 (M+1).

[0390] Preparation of Compound 46

[0391]

[0392] in MeOH (18 mL) 45-II A solution of (0.51 g, 1.2 mmol), diethyl vinylphosphonate (0.4 g, 2.4 mmol), and TEA (3 drops) was stirred at 60°C for 16 hours and then concentrated. The resulting residue was purified by flash chromatography (MeOH:ethyl acetate = 3:7) on silica gel. 46-I (0.42g, y: 59%) was obtained.

[0393] 1 H-NMR (CDCl3, 300 MHz, free form) δ 7.48 (s, 1H), 4.93 (s, 1H), 4.64 (d, 2H), 4.46 (t, 2H), 4.09 (q, 4H), 3.73 (m, 4H), 3.61 (t, 2H), 3.56 (m, 1H), 3.46 (m, 4H), 2.83 (m, 2H), 2.66 (m, 2H), 2.13 (t, 2H), 2.06 (m, 2H), 2.10-1.93 (m, 4H), 1.47 (m, 2H), 1.32 (t, 6H).

[0394] A solution of 2N HCl in diethyl ether (0.5 mL, 1 mmol) 46-I It was added to a DCM solution (150 mg, 0.3 mmol). The reaction mixture was stirred at 25°C for 15 hours and concentrated to obtain the compound. 46 The hydrochloride salt (152 mg, y: 90%) of was obtained.

[0395] EI-MS: 582.3(M+1).

[0396] Preparation of compounds 48, 55, 57, 59, 62, 63, 83, 87, 95, 113, 116, 118, 134, 137, 139, 142 and 147

[0397] Compounds 48, 55, 57, 59, 62, 63, 83, 87, 95, 113, 116, 118, 134, 137, 139, 142, and 147 were prepared in a manner similar to that used to prepare compound 46.

[0398] Compound 48 EI-MS: 504.3 (M+1). 1H NMR (CDCl3, 400 MHz, free form) δ 7.53 (s, 1H), 4.93 (s, 1H), 4.66 (d, 2H), 4.48 (t, 2H), 3.75 (m, 4H), 3.70 (s, 3H), 3.60 (t, 2H), 3.52-3.46 (m, 5H), 2.84 (m, 2H), 2.71 (t, 2H), 2.52 (t, 2H), 2.16 (m, 2H), 2.09 (m, 2H), 1.98 (m, 2H), 1.50 (m, 2H).

[0399] 화합물 55 EI-MS: 582.3 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 7.63 (s, 1H), 4.92 (s, 1H), 4.65 (d, 2H), 4.39 (dd, 1H), 4.20 (dd, 1H), 4.08-4.03 (m, 5H), 3.73 (m, 4H), 3.58 (m, 1H), 3.48 (m, 4H), 2.85 (m, 2H), 2.68 (m, 2H), 2.21 (t, 2H), 2.02-1.96 (m, 4H), 1.53 (m, 2H), 1.32 (t, 6H), 1.24 (d, 3H).

[0400] 화합물 57 EI-MS: 596.3 (M+1). 1 H NMR (CD3OD, 400 MHz, free form) δ 7.88 (s, 1H), 4.57 (s, 2H), 4.47 (t, 2H), 4.14 (q, 4H), 3.75-3.65 (m, 6H), 3.42 (m, 4H), 2.91 (m, 2H), 2.64 (m, 2H), 2.21 (m, 2H), 2.07-1.86 (m, 6H), 1.51 (m, 2H), 1.35 (t, 6H), 1.19 (d, 3H).

[0401] 화합물 59 EI-MS: 610.3 (M+1). 1H-NMR (CD3OD, 400 MHz, free form) δ 7.78 (s, 1H), 5.13 (s, 1H), 4.62 (d, 2H), 4.48 (t, 2H), 4.12 (q, 4H), 3.71 (m, 4H), 3.69 (m, 1H), 3.45 (m, 4H), 2.85 (m, 2H), 2.66 (m, 2H), 2.20 (t, 2H), 2.12-2.06 (m, 4H), 1.93 (m, 2H), 1.47 (m, 2H), 1.32 (t, 6H), 1.22 (s, 6H).

[0402] Compound 62 EI-MS: 518.3 (M+1). 1 H NMR (CDCl3, 400 MHz, free form) δ 7.55 (s, 1H), 4.93 (s, 1H), 4.68 (d, 2H), 4.42 (t, 2H), 3.74 (m, 4H), 3.60 (s, 3H), 3.56-3.52 (m, 5H), 3.35 (t, 2H), 3.32 (s, 3H), 2.93 (m, 2H), 2.80 (t, 2H), 2.57 (t, 2H), 2.33 (m, 2H), 2.13 (m, 2H), 2.00 (m, 2H), 1.63 (m, 2H).

[0403] Compound 63 EI-MS: 596.3 (M+1).

[0404] Compound 83 EI-MS: 610.3 (M+1).

[0405] Compound 87 EI-MS: 612.3 (M+1).

[0406] Compound 95 EI-MS: 610.3 (M+1).

[0407] Compound 113 EI-MS: 568.3 (M+1).

[0408] Compound 116 EI-MS: 596.3 (M+1).

[0409] Compound 118 EI-MS: 584.3 (M+1). 1 H-NMR (CDCl 3,400 MHz, free form) δ 7.44 (s, 1H), 4.90 (s, 1H), 4.59 (s, 2H), 4.38 (t, 2H), 3.32 (m, 2H), 4.06 (q, 4H), 3.69 (m, 4H), 3.45-3.41 (m, 5H), 2.79 (m, 2H), 2.62 (m, 2H), 2.25-1.84 (m, 8H), 1.45 (m, 2H), 1.28 (t, 6H).

[0410] 화합물 134 EI-MS: 580.3 (M+1). 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.80 (s, 1H), 4.57 (s, 2H), 4.46 (t, 2H), 4.17 (q, 4H), 3.65 (m, 1H), 3.55 (t, 2H), 3.49 (m, 4H), 2.91 (m, 2H), 2.70 (m, 2H), 2.26 (t, 2H), 2.10-2.07 (m, 4H), 1.97 (m, 2H), 1.65 (m, 2H), 1.57-1.55 (m, 6H), 1.31 (t, 6H).

[0411] 화합물 137 EI-MS: 616.3 (M+1). 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.79 (s, 1H), 4.58 (s, 2H), 4.47 (t, 2H), 4.14 (q, 4H), 3.64 (m, 1H), 3.62 (m, 4H), 3.55 (t, 2H), 2.93 (m, 2H), 2.68 (m, 2H), 2.23 (m, 2H), 2.09-2.06 (m, 4H), 1.97-1.82 (m, 6H), 1.51 (m, 2H), 1.35 (t, 6H).

[0412] 화합물 139 EI-MS: 598.3 (M+1). 1H-NMR (CDCl3, 400 MHz, free form) δ 7.50 (s, 1H), 4.88 (s, 1H), 4.61 (s, 2H), 4.44 (t, 1H), 4.11 (q, 4H), 3.86 (m, 4H), 3.57 (t, 2H), 3.52 (m, 1H), 2.80 (m, 2H), 2.64 (m, 2H), 2.56 (m, 4H), 2.15-1.95 (m, 8H), 1.53 (m, 2H), 1.48 (m, 2H), 1.32 (t, 6H).

[0413] Compound 142 EI-MS: 630.3 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 7.50 (s, 1H), 5.06 (s, 1H), 4.63 (s, 2H), 4.50 (t, 1H), 4.17 (q, 4H), 4.06 (m, 4H), 3.70-3.61 (m, 3H), 2.98 (m, 4H), 2.83 (m, 2H), 2.71 (m, 2H), 2.20-1.96 (m, 8H), 1.51 (m, 2H), 1.31 (t, 6H).

[0414] Compound 147 EI-MS: 582.3 (M+1).

[0415] Preparation of Compound 47

[0416]

[0417] in DCM (0.5 mL) 46-I TMSBr (0.36 g, 2.4 mmol) was added to a solution of (243 mg, 0.4 mmol). The mixture was stirred at 25°C for 4 hours and then concentrated to obtain the compound. 47 Hydrobromide salt (240 mg, y: 84%) was obtained.

[0418] EI-MS: 526.2 (M+1).

[0419] 1H-NMR (DO, 400 MHz) δ 7.88 (s, 1H), 5.33 (s, 1H), 4.56 (s, 2H), 4.40 (t, 2H), 3.76 (m, 1H), 3.63 (m, 4H), 3.57 (m, 2H), 3.48 (m, 4H), 3.42 (t, 2H), 3.24 (m, 2H), 3.02 (t, 2H), 2.17 (m, 2H), 2.07-1.95 (m, 4H), 1.65 (m, 2H).

[0420] Preparation of compounds 56, 58, 60, 64, 84, 88, 96, 114, 117, 119, 123, 126, 128, 130, 135, 140, 143, 146 and 148

[0421] Compounds 56, 58, 60, 64, 84, 88, 96, 114, 117, 119, 123, 126, 128, 130, 135, 140, 143, 146, and 148 were prepared in a manner similar to that used in the preparation of compound 47.

[0422] Compound 56 EI-MS: 526.2 (M+1). 1 H-NMR (CD3OD, 400 MHz) δ 8.29 (s, 1H), 4.79 (d, 2H), 4.54 (dd, 1H), 4.38 (dd, 1H), 4.17 (m, 1H), 3.79-3.57 (m, 11H), 3.42 (m, 2H), 3.32 (m, 2H), 2.36-2.20 (m, 4H), 1.84 (m, 2H), 1.21 (d, 3H).

[0423] Compound 58 EI-MS: 540.2 (M+1). 1 H NMR (CD3OD, 400 MHz) δ 8.17 (s, 1H), 4.75 (s, 2H), 4.58 (t, 2H), 4.10 (m, 1H), 3.80-3.70 (m, 10H), 3.47-3.43 (m, 3H), 3.31 (m, 2H), 2.36-2.25 (m, 4H), 2.08 (m, 2H), 1.96 (m, 2H), 1.22 (d, 3H).

[0424] Compound 60 EI-MS: 554.3 (M+1). 1H NMR (CD3OD, 400 MHz) δ 8.12 (s, 1H), 4.73 (s, 2H), 4.57 (dd, 2H), 4.11 (m, 1H), 3.80-3.64 (m, 10H), 3.44 (m, 2H), 3.31 (m, 2H), 2.33-2.22 (m, 4H), 2.08 (m, 2H), 1.90 (m, 2H). 1.27 (s, 6H).

[0425] Compound 64 EI-MS: 540.2 (M+1). 1 H NMR (DO, 600 MHz) δ 8.06 (s, 1H), 4.75 (s, 2H), 4.53 (t, 2H), 3.92 (m, 1H), 3.75-3.50 (m, 10H), 3.39 (m, 2H), 3.29 (t, 2H), 3.27 (s, 3H), 3.17 (m, 2H), 2.30 (m, 2H), 2.23-2.08 (m, 4H), 1.79 (m, 2H).

[0426] Compound 84 EI-MS: 554.2 (M+1).

[0427] Compound 88 EI-MS: 556.2 (M+1).

[0428] Compound 96 EI-MS: 554.3 (M+1).

[0429] Compound 114 EI-MS: 512.2 (M+1). 1 H NMR ((DO, 600 MHz) δ 8.08 (s, 1H), 4.62 (s, 2H), 4.48 (t, 2H), 3.87 (t, 2H), 3.80 (m, 1H), 3.70-3.40 (m, 10H), 3.28 (m, 2H), 3.07 (m, 2H), 2.25-2.10 (m, 4H), 1.69 (m, 2H).

[0430] Compound 117 EI-MS: 540.2 (M+1). 1H NMR (D2O, 400 MHz) δ 7.87 (s, 1H), 4.55 (s, 2H), 4.33 (t, 2H), 3.75 (m, 1H), 3.65-3.40 (m, 12H), 3.24 (m, 2H), 3.02 (m, 2H), 2.17 (m, 2H), 1.99 (m, 2H), 1.81 (m, 2H), 1.64 (m, 2H), 1.32 (m, 2H).

[0431] compound 119 EI-MS: 528.2 (M+1).

[0432] compound 123 EI-MS: 595.3 (M+1). 1 H-NMR (CD3OD, 400 MHz) δ 8.37 (s, 1H), 4.77 (s, 2H), 4.66 (t, 2H), 4.13 (m, 1H), 4.04 (m, 4H), 3.92-3.61 (m, 12H), 3.51-3.44 (m, 4H), 3.27-3.23 (m, 4H), 2.60 (m, 2H), 2.46-2.30 (m, 4H), 1.93 (m, 2H).

[0433] compound 126 EI-MS: 643.3 (M+1). 1 H-NMR (CD3OD, 400 MHz) δ 8.30 (s, 1H), 4.76 (s, 2H), 4.62 (t, 2H), 4.10 (m, 1H), 3.98 (m, 4H), 3.86-3.60 (m, 12H), 3.50-3.31 (m, 6H), 3.25 (m, 2H), 2.61 (m, 2H), 2.46-2.31 (m, 4H), 1.89 (m, 2H).

[0434] compound 128 EI-MS: 569.3 (M+1). 1H-NMR (CD3OD, 400 MHz) δ 8.30 (s, 1H), 4.76 (s, 2H), 4.61 (t, 2H), 4.12 (m, 1H), 3.70-3.63 (m, 12H), 3.42 (m, 2H), 3.20-3.08 (m, 6H), 2.41-2.28 (m, 6H), 1.86 (m, 2H).

[0435] compound 130 EI-MS: 752.3 (M+1).

[0436] compound 135 EI-MS: 524.3 (M+1). 1 H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H), 4.73 (s, 2H), 4.57 (t, 2H), 4.11 (m, 1H), 3.75-3.59 (m, 6H), 3.58 (t, 2H), 3.43 (m, 2H), 3.28 (m, 2H), 2.36-2.12 (m, 6H), 1.91 (m, 2H), 1.75-1.60 (m, 6H).

[0437] compound 140 EI-MS: 542.2 (M+1). 1 H NMR (D2O, 400 MHz) δ 7.91 (s, 1H), 4.54 (s, 2H), 4.39 (t, 2H), 3.80-3.70 (m, 5H), 3.58 (m, 2H), 3.42 (t, 2H), 3.27 (m, 2H), 3.04 (m, 2H), 2.50 (m, 4H), 2.17 (m, 2H), 2.06-1.98 (m, 4H), 1.68 (m, 2H).

[0438] compound 143 EI-MS: 574.2 (M+1). 1H NMR (CD3OD, 400 MHz) δ 8.00 (s, 1H), 4.71 (s, 2H), 4.52 (t, 2H), 4.24 (m, 4H), 4.11 (m, 1H), 3.74 (m, 2H), 3.57 (t, 2H), 3.43 (m, 2H), 3.33 (m, 2H), 3.18 (m, 4H), 2.34-2.24 (m, 4H), 2.12 (m, 2H), 1.91 (m, 2H).

[0439] Compound 146 EI-MS: 691.2 (M+1).

[0440] Compound 148 EI-MS: 526.2 (M+1).

[0441] Preparation of Compound 65

[0442]

[0443] in MeOH (50 mL) 45-I Solutions of (2.38 g, 4.7 mmol), methyl acrylate (1.28 g, 15 mmol), and TEA (3.8 g, 37.6 mmol) were stirred at 60°C for 16 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:4). 65-I (2.01g, y:72%) was obtained.

[0444] 1 H-NMR (CDCl3, 300 MHz, free form) δ 7.50 (s, 1H), 7.38-7.20 (m, 5H), 4.88 (d, 1H), 4.63 (d, 2H), 4.45 (t, 2H), 3.92 (m, 1H), 3.75 (m, 4H), 3.70 (s, 3H), 3.67 (t, 2H), 3.51 (s, 2H), 3.03 (m, 4H), 2.83 (m, 2H), 2.66 (t, 2H), 2.45 (t, 2H), 2.13 (m, 2H), 2.06 (m, 2H), 1.95 (m, 2H), 1.54 (m, 2H).

[0445] 2N HCl solution in diethyl ether (0.75 mL, 1.5 mmol) 65-I It was added to a DCM solution (302 mg, 0.5 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 65 The hydrochloride salt (312 mg, y: 92%) of was obtained.

[0446] EI-MS: 594.3(M+1).

[0447] Preparation of Compound 66

[0448]

[0449] in 2-propanol (34 mL) 65-I Solutions of (1.7 g, 2.9 mmol) and 10% Pd / C (0.51 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm) and then filtered. The filtrate was concentrated 66-I (1.34g, y: 93%) was obtained.

[0450] in MeOH (18 mL) 66-I Solutions of (0.3 g, 0.6 mmol), methyl acrylate (0.15 g, 1.8 mmol), and TEA (0.38 g, 3.8 mmol) were stirred at 60°C for 16 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:4). 66-II (0.23g, y:65%) was obtained.

[0451] 1H NMR (CDCl3, 400 MHz, free form) 7.53 (s, 1H), 4.92 (d, 1H), 4.64 (d, 2H), 4.48 (t, 2H), 3.91 (m, 1H), 3.78 (m, 4H), 3.71 (s, 3H), 3.69 (s, 3H), 3.63 (t, 2H), 3.05 (m, 4H), 2.84 (m, 2H), 2.73-2.65 (m, 4H), 2.54-2.48 (m, 4H), 2.21-2.10 (m, 4H), 1.97 (m, 2H), 1.49 (m, 2H).

[0452] A solution of 2N HCl in diethyl ether (1 mL, 2 mmol) 66-II It was added to a DCM solution (231 mg, 0.4 mmol). The reaction mixture was stirred at 25°C for 2 hours and then concentrated to obtain the compound. 66 The hydrochloride salt (241 mg, y: 93%) of was obtained.

[0453] EI-MS: 590.3(M+1).

[0454] Preparation of Compound 67

[0455] Compound 67 was prepared in a manner similar to that used to prepare Compound 66.

[0456] EI-MS: 668.3 (M+1). 1 H-NMR (CDCl3, 300 MHz, free form) δ 7.50 (s, 1H), 4.97 (d, 1H), 4.62 (d, 2H), 4.45 (t, 2H), 4.07 (q, 4H), 3.89 (m, 1H), 3.75 (m, 4H), 3.68 (s, 3H), 3.59 (t, 2H), 3.02 (m, 4H), 2.85 (m, 2H), 2.76-2.60 (m, 4H), 2.47 (t, 2H), 2.18 (m, 2H), 2.10-1.93 (m, 6H), 1.47 (m, 2H), 1.31 (t, 6H).

[0457] Preparation of Compound 68

[0458]

[0459] in THF (12 mL) 66-I Solutions of (0.4 g, 0.8 mmol), 3-bromomethyl-benzoate methyl ester (0.6 g, 2.6 mmol), and TEA (0.3 g, 3 mmol) were stirred at 25°C for 16 hours and then quenched with NH4Cl(aq.) (20 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined extract was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on silica gel by column chromatography (MeOH:ethyl acetate = 1:4). 68-I (0.34g, y: 66%) was obtained.

[0460] 1 H-NMR (CDCl3, 300 MHz, free form) δ 7.94 (s, 1H), 7.89 (d, 1H), 7.51 (d, 1H), 7.50 (s, 1H), 7.36 (t, 1H), 4.93 (d, 1H), 4.60 (d, 2H), 4.43 (t, 2H), 3.88 (m, 1H), 3.87 (s, 3H), 3.73 (m, 4H), 3.67 (s, 3H), 3.57 (t, 2H), 3.52 (s, 2H), 3.00 (m, 4H), 2.78 (m, 2H), 2.64 (t, 2H), 2.46 (t, 2H), 2.13 (m, 2H), 2.03 (m, 2H), 1.92 (m, 2H), 1.48 (m, 2H).

[0461] A solution of 2N HCl in diethyl ether (0.75 mL, 1.5 mmol) 68-I It was added to a DCM solution (0.34 g, 0.5 mmol). The reaction mixture was stirred at 25°C for 2 hours and then concentrated to obtain the compound. 68 Hydrochloride salt (0.35g, y: 93%) was obtained.

[0462] EI-MS: 652.3(M+1).

[0463] Preparation of compounds 70, 71, 72, 75, and 76

[0464] Compounds 70, 71, 72, 75, and 76 were prepared in a manner similar to that used to prepare compound 68.

[0465] Compound 70 EI-MS: 662.3 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 7.53 (d, 2H), 7.50 (s, 1H), 7.43 (d, 2H), 4.57 (s, 2H), 4.37 (t, 2H), 3.95 (m, 1H), 3.70 (m, 4H), 3.64 (s, 3H), 3.62 (s, 2H), 3.52 (t, 2H), 3.01 (m, 4H), 2.87 (m, 2H), 2.60 (t, 2H), 2.42 (t, 2H), 2.23 (m, 2H), 2.04 (m, 2H), 1.88 (m, 2H), 1.54 (m, 2H).

[0466] Compound 71 EI-MS: 652.3 (M+1). 1 H-NMR (CDCl3, 400 MHz, free form) δ 8.02 (d, 2H), 7.64 (s, 1H), 7.48 (d, 2H), 4.65 (s, 2H), 4.48 (t, 2H), 3.98 (m, 1H), 3.78 (s, 3H), 3.76 (s, 2H), 3.67 (m, 4H), 3.65 (s, 3H), 3.57 (t, 2H), 3.12 (m, 4H), 3.00 (m, 2H), 2.67 (t, 2H), 2.52 (t, 2H), 2.43 (m, 2H), 2.04 (m, 2H), 1.97 (m, 2H), 1.68 (m, 2H).

[0467] Compound 72 EI-MS: 619.3 (M+1).

[0468] Compound 75 EI-MS: 644.3 (M+1). 1H-NMR (CD3OD, 400 MHz, free form) δ 8.04 (s, 1H), 7.99-7.90 (m, 3H), 7.78 (s, 1H), 7.64 (d, 1H), 7.56-7.53 (m, 2H), 4.56 (s, 2H), 4.42 (t, 2H), 4.36 (s, 2H), 3.92 (m, 1H), 3.75 (m, 4H), 3.63 (s, 3H), 3.48 (t, 2H), 3.37 (m, 2H), 3.03 (m, 2H), 3.01 (m, 4H), 2.70 (t, 2H), 2.46 (t, 2H), 2.08-2.01 (m, 4H), 1.78 (m, 2H).

[0469] Compound 76 EI-MS: 669.3 (M+1).

[0470] Preparation of Compound 69

[0471]

[0472] in MeOH (20 mL) 45-I Solutions of (0.53 g, 1 mmol), tert-butyl acrylate (0.45 g, 3.5 mmol), and TEA (0.35 g, 3.5 mmol) were stirred at 60°C for 16 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:4). 69-I (0.52g, y:78%) was obtained.

[0473] in 2-propanol (10 mL) 69-I Solutions of (0.52 g, 0.8 mmol) and 10% Pd / C (0.15 g) were stirred at 60°C for 15 hours under H₂ (g) (1 atm). The resulting mixture was filtered. The filtrate was concentrated 69-II (0.41g, y: 92%) was obtained.

[0474] in MeOH (12 mL) 69-IIA solution of (0.41 g, 0.8 mmol), diethyl vinylphosphonate (0.26 g, 1.6 mmol), and TEA (1 drop) was stirred at 60°C for 16 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 3:7). 69-III (0.31g, y:58%) was obtained.

[0475] A solution of 2N HCl in diethyl ether (0.75 mL, 1.5 mmol) 69-III It was added to a DCM solution (0.31 g, 0.4 mmol). The reaction mixture was stirred at 25°C for 2 hours and then concentrated to obtain the compound. 69 Hydrochloride salt (0.28g, y: 88%) was obtained.

[0476] EI-MS:654.3(M+1).

[0477] Preparation of Compound 105

[0478]

[0479] Moiety in a solution of 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) in THF (54 mL) 6 (2.41 g, 15.4 mmol) and TEA (2 g, 19.8 mmol) were added. The mixture was stirred at 25°C for 15 hours and then quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified on silica gel by column chromatography (n-hexane:ethyl acetate = 1:1) 105-I (0.76g, y:25%) was obtained.

[0480] in IPA (25 mL) 105-IMorpholine (1.4 g, 16.1 mmol) was added to a solution of (0.76 g, 2.5 mmol). The mixture was stirred at 120°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (n-hexane:ethyl acetate = 1:3). 105-II (0.67g, y:66%) was obtained.

[0481] 2N HCl solution in diethyl ether (1.2 mL, 2.4 mmol) 105-II It was added to a DCM solution (0.31 g, 0.8 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 105 Hydrochloride salt (0.32g, y: 95%) was obtained.

[0482] EI-MS: 405.2(M+1).

[0483] Preparation of Compounds 106-107

[0484] Compounds 106-107 were prepared in a manner similar to that used to prepare compound 105.

[0485] Compound 106 EI-MS: 433.2(M+1).

[0486] Compound 107 EI-MS: 418.2(M+1).

[0487] Preparation of Compound 108

[0488]

[0489] in 2-pentanol (30 mL) 37-II (1.4g, 3.1mmol), tetrabutylammonium bromide (1g, 3.1mmol) and moiety 6 A solution of (0.7 g, 4.5 mmol) was stirred at 140°C for 15 hours and then concentrated. The resulting residue was purified in silica gel by column chromatography (MeOH:ethyl acetate = 1:3). 108-I (0.48g, y: 27%) was obtained.

[0490] in 2-propanol (10 mL) 108-I A solution of (0.48 g, 0.8 mmol) and 10% Pd / C (0.15 g) was stirred at 60°C for 15 hours under H₂ (g) (1 atm) and then filtered. The filtrate was concentrated 108-II (0.36g, y: 89%) was obtained.

[0491] 2N HCl solution in diethyl ether (0.5 mL, 1 mmol) 108-II It was added to a DCM solution (0.15 g, 0.3 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 108 Hydrochloride salt (0.17g, y: 93%) was obtained.

[0492] EI-MS: 487.3(M+1).

[0493] Preparation of Compound 110

[0494]

[0495] in MeOH (15 mL) 45-II A solution of (0.51 g, 1.2 mmol), acrylonitrile (0.3 g, 5.7 mmol), and TEA (0.2 g, 2 mmol) was stirred at 60°C for 6 hours and then concentrated. The resulting residue was purified by flash chromatography (MeOH:ethyl acetate = 3:7) on silica gel. 110-I (0.42g, y: 73%) was obtained.

[0496] 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.78 (s, 1H), 4.58 (s, 2H), 4.47 (t, 2H), 3.73-3.66 (m, 5H), 3.56 (t, 2H), 3.42 (m, 4H), 2.90 (m, 2H), 2.69 (m, 2H), 2.66 (m, 2H), 2.26 (m, 2H), 2.20 (m, 2H), 1.92 (m, 2H), 1.51 (m, 2H).

[0497] 2N HCl solution in diethyl ether (0.5 mL, 1 mmol) 110-I It was added to a DCM solution (200 mg, 0.3 mmol). The reaction mixture was stirred at 25°C for 15 hours and concentrated to obtain the compound. 110 Hydrochloride salt (210 mg, y: 91%) was obtained.

[0498] EI-MS: 471.3(M+1).

[0499] Preparation of Compound 111

[0500]

[0501] in isopropyl alcohol (75 mL) 110-I A solution of ZnBr2 (0.36 g, 1.6 mmol) in H2O (15 mL) was added to a solution of (1.51 g, 3.2 mmol) and sodium azide (1.01 g, 15.4 mmol). The mixture was stirred at 100°C for 15 hours and then concentrated to obtain a residue, which was extracted with DCM (3 x 100 mL). The combined extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography (MeOH:ethyl acetate = 3:7) on silica gel, 111-I (1.28g, y:78%) was obtained.

[0502] 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.80 (s, 1H), 4.58 (s, 2H), 4.47 (t, 2H), 3.74-3.68 (m, 5H), 3.55 (t, 2H), 3.43 (m, 4H), 3.10-3.08 (m, 4H), 2.94 (m, 2H), 2.43 (m, 2H), 2.09 (m, 2H), 1.92 (m, 2H), 1.57 (m, 2H).

[0503] A solution of 2N HCl in diethyl ether (1 mL, 2 mmol) 111-IIt was added to a DCM solution (310 mg, 0.6 mmol). The reaction mixture was stirred at 25°C for 15 hours and concentrated to obtain the compound. 111 The hydrochloride salt (315 mg, y: 84%) of was obtained.

[0504] EI-MS: 514.3(M+1).

[0505] Preparation of Compound 129

[0506]

[0507] Compound in DMF (11 mL) 46-I EDCI (265 mg, 1.4 mmol), DMAP (28 mg, 0.2 mmol), and biotin (337 mg, 1.4 mmol) were added to a solution of (301 mg, 0.5 mmol). The reaction mixture was stirred at 25°C for 72 hours and then poured into water. The resulting mixture was extracted with DCM. The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (MeOH:DCM = 1:19) on silica gel, 129-I (242 mg, y: 57%) was obtained.

[0508] 1 H-NMR (CD3OD, 400 MHz, free form) δ 7.76 (s, 1H), 4.56 (s, 2H), 4.46 (t, 2H), 4.30 (m, 1H), 4.13 (q, 4H), 4.06 (t, 2H), 3.77-3.66 (m, 6H), 3.42 (m, 4H), 3.25 (m, 1H), 2.90-2.80 (m, 3H), 2.70-2.63 (m, 3H), 2.28 (t, 2H), 2.23-2.20 (m, 4H), 2.06 (m, 2H), 1.96 (m, 2H), 1.75-1.46 (m, 8H), 1.32 (t, 6H).

[0509] A solution of 2N HCl / diethyl ether (0.5 mL, 1 mmol)129-I It was added to a DCM solution (242 mg, 0.3 mmol). The reaction mixture was stirred at 25°C for 15 hours and then concentrated to obtain the compound. 129 The hydrochloride salt (237 mg, y: 90%) of was obtained.

[0510] EI-MS: 808.4(M+1).

[0511] Example 3 Neuroite outgrowth assay

[0512] The compounds of the present invention were evaluated using a neurite proliferation assay as described in Chen et al., Scientific Reports, 7, 45366, DOI: 10.1038 / srep45366 (2017).

[0513] cell culture For primary culture, dorsal root ganglia ("DRGs") were removed from 7-week-old C57BL / 6 J mice and digested with 0.1% collagenase (Sigma-Aldrich, St. Louis, MO) for 1 hour, followed by treatment with 0.25% trypsin for 25 minutes. The dissociated neuron cultures were deposited at 2.5 x 10⁶ per well on 96-well optical plates (CLS3614, Sigma-Aldrich) pre-coated with 1 mg / mL poly-D-lysine (A-003-M, Sigma-Aldrich) for 3 hours. 4 The cells were plated at a density of dog cells. Primary DRG cells were grown in DMEM-F12 (11320033; Gibco®, ThermoFisher Scientific (Waltham, MA)) supplemented with 10% fetal bovine serum (FBS, 26140079; Gibco®, ThermoFischer). These cells were maintained at 37°C in an environment containing 5% CO2.

[0514] Analysis of neurite proliferation (Group A)Primary DRG cells were incubated with one of the compounds from Example 2 at 1 μM for 24 hours, and then treated with 0.05 μM paclitaxel for an additional 24 hours. After paclitaxel treatment, the primary DRG cells were washed with PBS and fixed with 4% paraformaldehyde (PFA, P6148; Sigma-Aldrich) for 15 minutes. The fixed DRG cells were permeabilized with 0.05% Triton X-100 in PBS for 20 minutes and blocked with 3% bovine serum albumin (BSA; Sigma-Aldrich, USA) at room temperature for 1 hour. Subsequently, the DRG cells were stained with rabbit anti-β III tubulin (1:600; Cell Signaling, USA) and mouse anti-NeuN monoclonal antibody (1:400; Millipore, USA) overnight at 4°C. The samples were then washed with PBS and incubated with secondary antibodies (Alexa-488 and Alexa-594 1:600, Invitrogen, CA) at room temperature for 1 hour. For the image acquisition and analysis of DRG neurite proliferation, images of stained cells were automatically acquired using an Image Xpress Micro wide-field fluorescent microscope (Molecular Devices, USA) with a 10X objective lens. A control group was obtained following the same procedure, except that DRG cells were not treated with the compound or paclitaxel. Neuroite proliferation was measured as a percentage of proliferation compared to the control group.

[0515] Paclitaxel has been found to inhibit neurite proliferation due to its neurotoxicity. The compound of the present invention effectively protected DRG cells from paclitaxel-induced neurotoxicity. The results are provided in Table 1 below. In Table 1, Column A represents the neurite proliferation of DRG cells treated with 1 μM of the compound of the present invention and 0.05 μM of paclitaxel, and Column B represents the neurite proliferation of DRG cells treated with 0.05 μM of paclitaxel. The difference between A and B indicates the degree of protection provided by the compound.

[0516] Table 1. Neurodegeneration (%)

[0517] compound A B AB p value potential for neuroprotective effects 6 46 43 3 * ++ 15 35 32 3 * ++ 17 50 47 3 + 18 50 47 3 + 21 45 42 3 + 28 53 50 3 * ++ 38 37 32 5 + 41 34 31 3 + 42 34 31 3 + 46 55 47 8 ** +++ 47 65 47 18 * +++ 48 58 47 11 + 53 47 45 2 ** ++ 59 47 42 5 * ++ 60 40 44 4 ** +++ 61 52 49 3 + 62 50 47 3 + 63 42 40 2 *** ++ 66 52 47 5 + 67 43 40 3 ** +++ 68 41 40 1 * ++ 69 41 40 1 * ++ 72 45 42 3 + 73 45 42 3 + 74 45 42 3 * ++ 77 48 42 6 + 78 35 32 3 * ++ 81 52 50 2 * ++ 97 45 40 5 * ++ 98 45 40 5 + 100 52 49 3 + 101 53 47 6 + 104 45 40 5 * ++ 108 41 50 9 ** +++ 109 41 51 10 * +++ 114 55 47 8 ** ++ 117 58 47 11 ** +++ 135 56 50 6 * + 140 54 50 4 + 143 57 50 7 +

[0518] *: p < 0.05, **: p < 0.01, and ***: p < 0.001.

[0519] As shown in Table 1, 0.05 μM paclitaxel inhibited 50%–69% of DRG neurite proliferation. Unexpectedly, neuroprotection was found to be provided by compounds 6, 15, 17, 18, 21, 28, 38, 41, 42, 46, 47, 48, 53, 59, 60, 61, 62, 65, 66, 67, 68, 69, 72, 73, 74, 75, 78, 81, 97, 98, 100, 101, 104, 108, 109, 114, 117, 135, 140, and 143. In particular, compound 47 showed an improvement of more than 18% (i.e., 65% proliferation compared to 47% of paclitaxel-treated cells).

[0520] Analysis of neurite proliferation (Group B)Primary DRG cells were cultured with 1 μM compounds 17, 47, 97, 98, 101, and 104 for 24 hours, and then treated with 100 μM oxaliplatin for an additional 48 hours. Treatment was performed according to the same procedure as Group A, except that the DRG cells were treated with oxaliplatin. Neurodegeneration was measured as a percentage of proliferation compared to the control group.

[0521] Oxaliplatin has been found to inhibit neurite proliferation due to its neurotoxicity. The compound of the present invention effectively protected DRG cells from oxaliplatin-induced neurotoxicity. The results are provided in Table 2 below.

[0522] Table 2. Neurodegeneration (%)

[0523] compound A B AB p value Potential for neuroprotective effects 17 26 29 -3 47 47 40 7 ** ++ 97 31 29 2 + 98 26 29 -3 101 31 29 2 + 104 34 29 5 * ++

[0524] *: p < 0.05 and **: p < 0.01

[0525] As shown in Table 2, 100 μM oxaliplatin inhibited DRG neurite proliferation by 60%–71%. Unexpectedly, neuroprotection was found to be provided by compounds 47, 97, 101, and 104. In particular, compound 47 showed an improvement of more than 7% (i.e., 47% proliferation compared to 40% in oxaliplatin-treated cells).

[0526] Example 4 : In vivo mouse behavioral model

[0527] compound 47 It was used in in vivo mouse behavioral studies to treat paclitaxel-induced neuropathy according to the procedure described in Chen et al., Scientific Reports, 7, 45366, DOI: 10.1038 / srep45366 (2017).

[0528] After housing acclimatization, 7-week-old female C57BL / 6J mice (body weight range: 18–20 g) were treated as follows: paclitaxel (4.5 mg / kg, Bristol-Myers Squibb (NY, NY)), vehicle (saline), or compound. 47 (5, 10, or 20 mg / kg) was administered intraperitoneally every other day on days 4 (days 0, 2, 4, and 6). Two behavioral tests were performed: (1) mechanical hyperalgesia was evaluated using a von Frey filament (Part #2390, IITC Inc., CA), and (2) thermal sensitivity was studied using a tail immersion assay (water temperature: 48–49°C). Chen et al., Mol. Cancer. Ther. Reference is made to 14, 2206-14 (2015). Baseline measurements for each behavioral test were established before treatment. Five sessions were measured per week.

[0529] Compounds in mouse models 47 The neuroprotective effects were measured according to a protocol including predetermined drug administration and behavioral tests. The baseline level for each behavioral analysis was obtained prior to treatment. During the first week, paclitaxel 4.5 mg / kg was administered intraperitoneally every other day, and the vehicle or compound was administered 1 hour prior to paclitaxel treatment. 47 (5, 10, and 20 mg / kg) was administered by intraperitoneal injection. After 4 treatment cycles, behavioral tests were performed weekly.

[0530] The von Frey filament test was performed to detect allodynia. Pressure was applied due to contact until the foot was withdrawn. Heat sensation was evaluated using a tail immersion test to check tail withdrawal latency.

[0531] Eight groups of mice were treated separately.

[0532] Compounds in saline solution to mice of groups 1, 2, and 3 47 It was injected at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg, respectively. One hour later, 4.5 mg / kg of paclitaxel was injected into the mice.

[0533] As a control group, mice in group 4 were injected with saline, and 4.5 mg / kg of paclitaxel was injected 1 hour later.

[0534] The compounds in the mice of control group 5 47 and saline solution was injected twice instead of paclitaxel.

[0535] Mice in control groups 6, 7, and 8 were injected with compound 47 at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg, respectively, followed by injection of saline solution.

[0536] The results showed that mice in Group 4 had a very low pain threshold due to paclitaxel toxicity. In Groups 1-3, the compound 47 It provided protection even at a low dose of 5 mg / kg. After administration of Compound 47 at 10 mg / kg and 20 mg / kg, mice in both groups exhibited pain thresholds similar to the control group, indicating that the compound is effective in protecting against paclitaxel-induced neuropathy. 47 Its high efficacy has been proven.

[0537] Similar results were observed in tail immersion analysis, which is a compound 47 It demonstrates the neuroprotective efficacy of again.

[0538] All features disclosed herein may be combined in any combination. Each feature disclosed herein may be replaced by an alternative feature that serves the same, equivalent, or similar purpose. Accordingly, unless otherwise explicitly stated, each disclosed feature is merely an example of a general series of equivalent or similar features.

[0539] From the foregoing description, those skilled in the art can easily identify the essential features of the present invention, and various changes and modifications may be made to adapt the present invention to various uses and conditions without departing from the spirit and scope thereof. Accordingly, other embodiments are also within the scope of the following claims.

Claims

Claim 1 Compound of chemical formula (I) or its salt: ,(here, R1 is H, halo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 It is an aryl or 5- to 14-membered heteroaryl; W1 is a morpholino or NH―CH2―Ar1―(CH2) m ―A1 and; one of W2 and W3 is NR a R b And the other one of W2 and W3 is NH―CH2―Ar2―(CH2) n ―A2, where Ar1 and Ar2 are each independently pentomer heteroaryls; A1 and A2 are each independently H, OH, SH, CO2R c , P(=O)(OR c )(OR d ), NH2, isopropylamino, ethanolamino, C 1-6 Alkoxy, or NHCOR c is;R a and R b H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, or, (CH2) x ―P(=O)(OR e )(OR f It is piperidine substituted with ) and R c and R d H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 It is an aryl or 5- to 14-membered heteroaryl; R1, W1, A1, A2, R a , R b , R c , and R d C in the middle 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 Aryl, 5- to 14-membered heteroaryl, morpholino, and ethanolamino are, respectively, hydroxyl, halo, nitro, cyano, amino, C 1-6 Alkyl, arylalkyl, C 1-6 Alkoxyl, C 1-6 Carboxyalkyl, C 6-14 Aryl, 5- to 14-membered heteroaryl, P(=O)(OR e )(OR f ), NHCOR e , NHC(O)OR e , C(O)OR e , COR e , (CH2) x ―P(=O)(OR e )(OR f ), (CH2) x ―NHCOR e , or (CH2) x ―C(O)OR e It is optionally replaced with;R e and R f H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 It is an aryl or a 5- to 14-membered heteroaryl; R e and R f C in the middle 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 Aryl, and 5- to 14-membered heteroaryls are each hydroxyl, halo, nitro, cyano, amino, C 1-6 Alkyl, arylalkyl, C 1-6 Alkoxyl, C 1-6 Carboxyalkyl, C 6-14 aryl, or optionally substituted with a 5- to 14-membered heteroaryl; C 1-10 The hetero-cycloalkyl and 5- to 14-membered heteroaryls each independently have one or more heteroatoms selected from O, N, P, and S; m and n are each independently 0, 1, 2, 3, 4, or 5; and x is 1, 2, 3, or 4.) Claim 2 In paragraph 1, R1 is H and W1 is a morpholinoin compound or its salt. Claim 3 In paragraph 2, W2 is NH―CH2―Ar2―(CH2) n ―A2, a compound or its salt in which n is 2, 3, or 4. Claim 4 In paragraph 3, W3 is NR a R b and; R a is H and; R b is (CH2) x ―P(=O)(OR e )(OR f It is piperidine substituted with ), and R e and R f H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 A compound or its salt that is an aryl or 5- to 14-membered heteroaryl and x is 2 or 3. Claim 5 In paragraph 1, R1 is H; W1 is morpholino or NH―CH2―Ar1―(CH2) m ―A1 and;W2 is NH―CH2―Ar2―(CH2) n ―A2 is and; W3 is NR a R b And; A1 and A2 are independently H, OH, C 1-6 Alkoxy or NHCOR c Igo;R a is H and;R b is (CH2) x ―P(=O)(OR e )(OR f It is piperidine substituted with ) and R c is C 1-6 It is alkyl; W1, A1, A2, and R c C in the middle 1-6 Alkyl, C 1-6 Alkoxy and morpholino are, respectively, hydroxyl, NH2, (CH2) x ―P(=O)(OR e )(OR f ), C(O)OR e , or (CH2) x ―NHCOR e Optionally substituted as; R e and R f H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 It is an aryl or a 5- to 14-membered heteroaryl; R e and R f C in the middle 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 Aryl, and 5- to 14-membered heteroaryls are each hydroxyl, halo, nitro, cyano, amino, C 1-6 Alkyl, arylalkyl, C 1-6 Alkoxyl, C 1-6 Carboxyalkyl, C 6-14 A compound or its salt, optionally substituted with an aryl or 5- to 14-membered heteroaryl, wherein m and n are each 2, 3, or 4; and x is 1, 2, 3, or 4. Claim 6 In paragraph 1, W2 is NH―CH2―Ar2―(CH2) n ―A2, a compound or its salt in which n is 2, 3, or 4. Claim 7 In paragraph 1, W3 is NR a R b and; R a is H and; R b is (CH2) x ―P(=O)(OR e )(OR f It is piperidine substituted with ), and R e and R f H and C are independently 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 It is an aryl or a 5- to 14-membered heteroaryl, and R e and R f C in the middle 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 Hetero-cycloalkyl, C 6-14 Aryl, and 5- to 14-membered heteroaryls are each hydroxyl, halo, nitro, cyano, amino, C 1-6 Alkyl, arylalkyl, C 1-6 Alkoxyl, C 1-6 Carboxyalkyl, C 6-14 A compound or its salt thereof that is optionally substituted with an aryl, or a 5- to 14-membered heteroaryl; where x is 2 or 3. Claim 8 In paragraph 1, R1 is H; W1 is morpholino; and W2 is NH―CH2―Ar2―(CH2) n ―A2, where Ar2 is a triazole, n is 2 or 3, A2 is OH; and W3 is NR a R b and, here R a is H and R b is (CH2) x ―P(=O)(OR e )(OR f It is piperidine substituted with ), and R e and R f Each independently H or C 1-6 It is alkyl; R e and R f C in the middle 1-6 Alkyl groups are hydroxyl, halo, nitro, cyano, amino, C 1-6 Alkyl, arylalkyl, C 1-6 Alkoxyl, C 1-6 Carboxyalkyl, C 6-14 A compound or its salt thereof that is optionally substituted with an aryl, or a 5- to 14-membered heteroaryl; where x is 2 or 3. Claim 9 In claim 1, the compound is any one selected from the group consisting of compounds having the structure shown below, or a salt thereof: . Claim 10 In claim 9, the compound is any one selected from the group consisting of compounds 28, 46, 47, 58, 67, 69, 109, 114 and 117, or a salt thereof. Claim 11 In paragraph 9, the compound is a compound that is compound 47 or a salt thereof. Claim 12 A compound for use in the treatment of chemotherapy-induced peripheral neuropathy, wherein the compound is the compound of claim 1 or a salt thereof, administered in an effective amount to a subject requiring treatment for chemotherapy-induced peripheral neuropathy, wherein the chemotherapy-induced peripheral neuropathy is allodynia or heat-sensitive. Claim 13 In Clause 12, a compound in which the subject receives an additional anticancer agent. Claim 14 In paragraph 13, a compound in which the compound of paragraph 1 or its salt is administered prior to the administration of an anticancer agent. Claim 15 In paragraph 13, the compounds in which the anticancer agents are paclitaxel and oxaliplatin. Claim 16 In paragraph 12, the compound of paragraph 1 or its salt is any one selected from the group consisting of compounds 28, 46, 47, 58, 67, 69, 109, 114 and 117 shown below: Claim 17 A pharmaceutical composition for treating chemotherapy-induced peripheral neuropathy comprising the compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier thereof. Claim 18 A pharmaceutical composition according to claim 17, wherein the compound of claim 1 or its salt is any one selected from the group consisting of compounds 28, 46, 47, 58, 67, 69, 109, 114 and 117 shown below: Claim 19 A compound in which the chemotherapy-induced peripheral neuropathy is allodynia. Claim 20 A compound in which the chemotherapy-induced peripheral neuropathy is heat-sensitive, as described in paragraph 12.

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