Pyrimidine compounds and their uses

Abstract

Pyrimidine compounds of formula (I) are provided herein. Pharmaceutical compositions containing one of the pyrimidine compounds and methods of using the pyrimidine compounds for treating or preventing chemotherapy-induced peripheral neuropathy are also disclosed.

Description

[Background technology]

[0001] Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of certain anticancer drugs.

[0002] CIPN affects 30-70% of patients undergoing chemotherapy and is one of the leading reasons for dose reduction or premature interruption of life-saving cancer treatments. Its symptoms include sensory disturbances (e.g., increased sensitivity to pain) that can result in impaired quality of life for many years.

[0003] No drugs have been approved by the U.S. Food and Drug Administration to treat or prevent CIPN. Moreover, recent clinical trials are not promising. See Poupon et al., “Minimizing chemotherapy-induced peripheral neuropathy: Preclinical and clinical development of new perspectives”, Expert Opin. Drug Saf. (2015) 14(8).

[0004] There is a need to develop methods to treat and prevent CIPN. Summary of the Invention

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

[0006] In one aspect, the present invention relates to pyrimidine compounds of formula (I). [ka]

[0007] In this formula, R1, W1, W2 and W3 are each defined as follows. 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 heterocycloalkyl, aryl or heteroaryl. W1 is C 1-10 Heterocycloalkyl or NH-CH2-Ar1-(CH2) m -A1. One of W2 and W3 is NR a R b and the other of W2 and W3 is NH-CH2-Ar2-(CH2) n -A2.

[0008] There, Each of Ar1 and Ar2 is independently a 5-membered heteroaryl; Each of A1 and A2 is independently H, OH, SH, COR 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 and R a and R b each independently represents H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 heterocycloalkyl, or R a and R b Together with the nitrogen atom to which they are attached, C 1-10 is heterocycloalkyl, R c and R deach independently represents H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyloxy, C 1-10 Heterocycloalkyl, C 1-10 Each of heterocycloalkyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, ethanolamino, benzylamino, and carbamido is selected from hydroxyl, halo, nitro, cyano, amino, C 1-6 Alkyl, arylalkyl, C 1-6 Alkoxyl, C 1-6 Carboxyalkyl, aryl, heteroaryl, PO3R e R f , N.C.O.R. e , NC(O)OR e , C(O)OR e , C.O.R. e , (CH2) x -PO3R e R f , (CH2) x -NCOR e or (CH2) x -C(O)OR e and optionally substituted with R e and R f each independently represents H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl; each of m and n is independently 0, 1, 2, 3, 4, or 5; x is 1, 2, 3 or 4.

[0009] Preferred features include R1 being H, W1 being morpholino, and NH-CH2-Ar2-(CH2) n -A2, W2, and NR a Rb and W3, which is. Typically, each of A1 and A2 is independently H, OH, C 1-6 Alkyl, C 1-6 Alkoxy or NCOR c and R a is H or R a and R b together with the nitrogen atom to which they are attached, are 6-membered heterocycloalkyl; R b is a 6-membered heterocycloalkyl, or R b and R a together with the nitrogen atom to which they are attached, are 6-membered heterocycloalkyl; R c is C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-10 Each heterocycloalkyl is selected from the group consisting of hydroxyl, NH2, (CH2), x -PO3R e R f , C(O)OR e or (CH2) x -NCOR e Optionally substituted with R e and R f each independently represents H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl; each of m and n is independently 2, 3, or 4; and x is 1, 2, 3, or 4.

[0010] Another aspect of the present invention relates to a method for treating or preventing chemotherapy-induced peripheral neuropathy, the method comprising administering to a subject in need thereof an effective amount of any one of the above compounds.Optionally, the method further comprises administering to the subject an anti-cancer drug (e.g., paclitaxel), preferably after administration of the compound of the present invention.

[0011] Also within the scope of the present invention are pharmaceutical compositions comprising one of the compounds described above and a pharma- ceutically acceptable carrier.

[0012] The term "alkyl" as used herein refers to a straight or branched chain 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 its halo-substituted derivatives, i.e., haloalkyl, which refers to alkyl substituted with one or more halogen (chlorine, fluorine, bromine, or iodine) atoms. Examples include trifluoromethyl, bromomethyl, and 4,4,4-trifluorobutyl. The term "alkoxy" refers to an -O-alkyl group (e.g., methoxy, ethoxy, propoxy, and isopropoxy). Alkoxy includes haloalkoxy, i.e., alkoxy substituted with one or more halogen atoms, e.g., -O-CH2Cl and O-CHClCH2Cl.

[0013] The term "cycloalkyl" refers to an alkyl group having 3 to 12 carbons (e.g., C 3-10 The term "cycloalkyloxy" refers to saturated and partially unsaturated monocyclic, bicyclic, tricyclic or tetracyclic hydrocarbon groups having the formula (I) and (II). Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. The term "cycloalkyloxy" refers to -O-cycloalkyl groups, such as cyclohexyloxy. Cycloalkyloxy includes halocycloalkyloxy and refers to cycloalkyloxy substituted with one or more halogen atoms.

[0014] The term "heterocycloalkyl" refers to a 3-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic non-aromatic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples of heterocycloalkyl groups include piperazinyl, piperidinyl, imidazolidinyl, azepanyl, pyrrolidinyl, dihydrothiadiazolyl, dioxanyl, morpholinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl, tetrahydropyranyl, and tetrahydrofuranyl. The term "heterocycloalkyloxy" refers to -O-heterocycloalkyl. Each of heterocycloalkyl and heterocycloalkyloxy includes its halogenated form, i.e., having one or more halogen atom substitutions.

[0015] The term "aryl" refers to a monocyclic, C6, bicyclic, or C10, tricyclic, aromatic ring system, each of which may have 1-5 substituents. Examples include phenyl, naphthyl, and anthracenyl. The term "aralkyl" refers to an alkyl substituted with an aryl group. The term "aryloxy" refers to an -O-aryl group, such as phenoxy.

[0016] The term "heteroaryl" refers to a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic aromatic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, carbazolyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group. The term "heteroaryloxy" refers to an -O-heteroaryl group.

[0017] The term "halo" refers to a radical of fluorine, chlorine, bromine or iodine. The term "amino" refers to a radical derived from an amine that is unsubstituted or mono- / di-substituted with alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. The term "alkylamino" refers to alkyl-NH-. The term "dialkylamino" refers to alkyl-N(alkyl)-.

[0018] The alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy, and aryloxy referred to herein include both substituted and unsubstituted moieties. Examples of substituents include halo, hydroxyl, amino, cyano, nitro, mercapto, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, which may be further substituted.

[0019] When referring to a compound of formula (I), the term "compound" also includes its salts, solvates, and prodrugs. A salt can be formed between an anion and a positively charged group (e.g., amino) in the compound. Examples of suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosyl, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate, and maleate. A salt can also be formed between a cation and a negatively charged group. Suitable cations include ammonium cations, such as sodium, potassium, magnesium, calcium, and tetramethylammonium. Additionally, a salt can include a quaternary nitrogen atom. A solvate refers to a complex formed between an active compound and a pharma- ceutically acceptable solvent. Examples of pharma- ceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine. A prodrug refers to a compound that is metabolized into a pharma- ceutically active drug after administration. Examples of prodrugs include esters and other pharma- ceutically acceptable derivatives.

[0020] The compounds may contain one or more non-aromatic double bonds or asymmetric centers. Each of them occurs as a racemate or racemic mixture, a single R enantiomer, a single S enantiomer, an individual diastereomer, a diastereomeric mixture, a cis isomer or a trans isomer. Such isomeric forms of the compounds are within the scope of the present invention. They may be present as a mixture or may be isolated using chiral synthesis or chiral separation techniques.

[0021] The invention also features the use of one or more of the above pyrimidine compounds of formula (I) for the manufacture of a medicament for treating and preventing CIPN.

[0022] The term "treating" or "treatment" refers to administering one or more pyrimidine compounds to a subject undergoing chemotherapy or predisposed to CIPN for the purpose of providing a therapeutic effect, e.g., curing, alleviating, altering, affecting, ameliorating or preventing CIPN, its symptoms or predisposition to it. An "effective amount" refers to the amount of compound required to provide a therapeutic effect. As will be recognized by those skilled in the art, effective doses will vary depending on the type of condition being treated, the route of administration, excipient usage and the possibility of co-administration with other therapeutic treatments.

[0023] To practice the method of the present invention, a composition having one or more of the pyrimidine compounds described above can be administered parenterally, orally, nasally, enterally, topically or bucally. The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection and any suitable infusion technique.

[0024] Sterile injectable compositions may be solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils (e.g., synthetic mono- or di-glycerides) are conventionally employed as solvents or suspending media. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharma-ceutically acceptable oils, such as olive oil and castor oil, particularly in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, carboxymethylcellulose, or similar dispersing agents. Other commonly used surfactants, such as Tweens and Spans, or other similar emulsifying agents, or bioavailability enhancing substances commonly used in the manufacture of pharma-ceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0025] The composition for oral administration can be any orally acceptable dosage form, including capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions.For tablets, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.For oral administration in aqueous suspension or emulsion, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent.If desired, certain sweeteners, flavors, and colorants can be added.

[0026] Nasal aerosol or inhalation compositions can be prepared by techniques known in the art of pharmaceutical formulation. For example, such compositions can be prepared as a solution in saline employing benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons and / or other solubilizing or dispersing agents.

[0027] Compositions having one or more of the pyrimidine compounds described above can also be administered in the form of suppositories for rectal administration.

[0028] A carrier in a pharmaceutical composition must be "acceptable" in the sense that it is compatible with (preferably capable of stabilizing) the active ingredient of the composition and is not harmful to the subject being treated. One or more solubilizing agents may be utilized as pharmaceutical excipients for delivery of the active compound. Examples include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0029] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] The peripheral nervous system ("PNS") consists of sensory neurons and motor neurons. In chemotherapy, anticancer drugs can damage both sensory and motor neurons. Symptoms of CIPN usually begin in the hands / feet and arms / legs and range from numbness or paralysis (e.g., paresthesia) to sharp, stabbing pain or a burning sensation of temperature (e.g., paresthesia, pain, heat hypersensitivity, and temperature hyposensitivity). In certain cases, CIPN results in hearing loss, blurred vision, altered taste, mechanical hypersensitivity, mechanical hyposensitivity, and autonomic neuropathy.

[0031] These symptoms are induced by anticancer drugs in chemotherapy, so the type and cumulative dose of anticancer drugs (e.g., paclitaxel, oxaliplatin platinum salts, vinca alkaloids, bortezomib, thalidomide, epothilones, and eribulin) may affect the incidence of one or more symptoms and the severity / degree of neuropathy. Furthermore, treatment of different cancers (e.g., colon cancer, lung cancer, breast cancer, and prostate cancer) results in different symptoms and severity, such as neuropathic pain.

[0032] Many anti-cancer drugs cause CIPN. Examples are epothilones (e.g., ixabepilone, available as Ixempra® from Bristol-Myers Squibb, New York, NY), arsenic trioxide (Trisenox®, Teva Pharmaceuticals USA, Parsippany, NJ), cytarabine (Cytosar-U® and Depocyt®), etoposide, hexamethylmelamine, ifosfamide (Ifex®), methotrexate (Trexall®), procarbazine (Matulane®), and vinblastine. The chemotherapy drugs that most commonly cause CIPN include platinum compounds (cisplatin, carboplatin, oxaliplatin), vincristine, taxanes (docetaxel, paclitaxel), bortezomib (Velcade®), thalidomide (Thalomid®), and lenalidomide.

[0033] The compounds of formula (I) are suitable for treating or preventing one or more symptoms of CIPN. [ka]

[0034] The present compounds may be used in conjunction with one of the anti-cancer agents described above, preferably by administering the compound to the patient prior to administration of the anti-cancer agent, for example at least 10 minutes (e.g., at least 30 minutes, at least 1 hour, and at least 2 hours) prior to administration of the anti-cancer agent.

[0035] A preferred subset of compounds having this characteristic are set out below with reference to formula (I) above.

[0036] In one subset of compounds of formula (I), W1 is selected from the group consisting of (i) one or more C 1-6 Morpholino optionally substituted with alkyl, e.g. [ka] (ii) Thiomorpholino or 1,1-dioxidethiomorpholino, for example: [ka] (iii) one or more C 1-6 Piperidino optionally substituted with alkyl and halo, e.g. [ka] and (iv) [ka] One or more C's 1-6 C, including piperazino optionally substituted with alkyl 1-10 (For example, C 4-5 ) nitrogen-containing heterocycloalkyl. Alternatively, W1 is NH-CH2-Ar1-(CH2) m -A1, for example, [ka] It is.

[0037] In another subset of compounds, one of W2 and W3 is NH-CH2-Ar2-(CH2) n -A2. Examples are: [ka] Includes.

[0038] The other of W2 and W3 is NR a R b An example is: [ka] Includes.

[0039] Compounds of formula (II) below are also a preferred subset of compounds of formula (I). [ka]

[0040] R a , R b , Ar2, A2 and n are defined above.

[0041] Rx and Ry, together with the nitrogen atom to which they are attached, are 5-8 membered heterocycloalkyl (eg, morpholino, piperidino, and piperazino).

[0042] Compounds 1-148 are provided below as exemplary compounds of formula (I). [ka] JPEG2024529984000012.jpg206128JPEG2024529984000013.jpg207129JPEG20245299840 00014.jpg217127JPEG2024529984000015.jpg200133JPEG2024529984000016.jpg202139

[0043] The compounds of formula (I) above can be prepared by established methods. The synthetic transformations and protective group methodologies (protection and deprotection) used to prepare these compounds are well known in the art. For example, see R.Larock, Comprehensive Organic Transformations (3rd Edition, Wiley, 2018); PGM Wuts and TW Greene, Greene's Protective Groups in Organic Synthesis (4th Edition, 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 Edition, John Wiley and Sons, 2009) and GJYu et al., J.Med.Chem, 2008, 51, 6044-6054.

[0044] Scheme I below illustrates a 2,4,6-trichloropyrimidine optionally substituted with an R group. [ka] The synthetic route for preparing compounds 1-148 is shown starting from: Each of W1H, W2H and W3H in Scheme I represents an amino compound that is subjected to a substitution reaction in a stepwise manner. [ka]

[0045] In addition to 2,4,6-trichloropyrimidine, its methanesulfonyl derivatives are also useful as starting materials in the preparation of compounds 1 to 148. One example is 4,6-dichloro-2-(methanesulfonyl)pyrimidine, i.e. [ka] It is.

[0046] Some of the compounds 1 to 148 can be prepared using the following moiety (ie, side chain) compounds which correspond to W2 or W3 in formula (I). [ka]

[0047] Other side chain compounds are commercially available or prepared by methods known in the art. The methods may include additional steps, either before or after those specifically described herein, to add or remove appropriate protecting groups, if necessary to facilitate synthesis of the compounds. Additionally, the various synthetic steps may be performed in an alternative order to give the desired compounds.

[0048] The resulting compounds of formula (I) can be initially screened for their neuroprotective efficacy using an in vitro assay, such as the neurite outgrowth assay described in Example 3 below. They can then be evaluated for their effectiveness in treating or preventing symptoms of CIPN using an in vivo animal behavioral model (see, for example, Example 4). Selected compounds can be further tested to confirm their effectiveness, for example, by administering them to animals. Based on the results, appropriate dosage ranges and administration routes can be determined.

[0049] Without further elaboration, it is believed that one skilled in the art can, based on the preceding description, utilize the present disclosure to its fullest extent. Thus, the following specific examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0050] All publications cited herein, including patent documents, are incorporated by reference in their entirety.

[0051] The preparation of moiety compounds 1-17 and pyrimidine compounds 1-148 of the present invention is provided in Examples 1 and 2 below. EXAMPLES

[0052] Example 1: Preparation of partial compounds All chemicals and reagents were purchased from commercial sources unless otherwise noted. Reactions were carried out under a dry nitrogen atmosphere and monitored by thin layer chromatography. Purification was performed using column chromatography. Proton ( 1 H) Nuclear magnetic resonance spectra were measured on a Varian Mercury-300 or Varian Mercury-400 spectrometer. Chemical shifts were reported in parts per million (ppm) on the delta (δ) scale relative to the resonance of the solvent peak. The following abbreviations were used to describe couplings: 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.

[0053] Preparation of part 1 Moiety 1 was prepared according to the following scheme. [ka] 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 warmed to room temperature for 15 h and quenched with NH4Cl(aq.) (100 mL, 2 M) followed by extraction 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 give a residue. Crystallization of the residue using a solvent mixture of n-hexane / dichloromethane ("DCM") at -20 °C gave m1-I (6.42 g, y: 95%). 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).

[0054] In the second step, to a solution of m1-I (6.42 g, 33.9 mmol) and sodium azide (6.42 g, 98.8 mmol) in isopropyl alcohol ("IPA", 150 mL) was added a solution of ZnBr2 (2.5 g, 11.1 mmol) in HO (36 mL). The mixture was stirred at 75 °C for 15 h and concentrated to give a residue that was extracted with DCM (3 x 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give m1-II (4.81 g, y: 61%).

[0055] In the third step, to a solution of m1-II (4.81 g, 20.7 mmol) in acetonitrile ("ACN", 300 mL), 1,2-dibromoethane (4.81 g, 25.6 mmol) and triethylamine ("TEA", 4.81 g, 47.6 mmol) were added. The mixture was refluxed for 15 h and concentrated. The resulting residue was then extracted with DCM (2 x 150 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue, which was purified by column chromatography on silica gel (n-hexane:ethyl acetate = 1:1) to give m1-III (3.63 g, y: 68%).

[0056] In the last step, a solution of m1-III (3.63 g, 14.1 mmol) and 10% Pd / C (0.36 g) in methanol (72 mL) was stirred under H2(g) at 25 °C for 6 h. The reaction mixture was filtered and concentrated to give part 1 (1.52 g, y: 86%).

[0057] Preparation of Part 2 [ka] A solution of bromoacetic acid tert-butyl ester (5.85 g, 30 mmol) and sodium azide (6.56 g, 101 mmol) in acetone / HO (585 mL / 140 mL) was stirred at 25° C. for 15 h and concentrated to give a residue that was extracted with DCM (3×100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give m2-I (3.84 g, y: 81%).

[0058] To a solution of m2-I (3.84 g, 24.4 mmol) and m1-I (4.56 g, 24.1 mmol) in ethanol ("EtOH", 150 mL) was added a solution of CuSO4 (0.41 g, 2.6 mmol), sodium (+)-L-ascorbate (0.56 g, 2.8 mmol), K2CO3 (6.71 g, 48.5 mmol) in HO (36 mL). The mixture was stirred at 25 °C for 15 h and concentrated to give a residue that was extracted with DCM (3 x 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give m2-II (6.02 g, y: 71%).

[0059] A solution of m2-II (3.01 g, 8.7 mmol) and 10% Pd / C (0.3 g) in methanol (60 mL) was stirred under H2(g) (1 atm) at 25 °C for 6 h, and the resulting mixture was filtered. The filtrate was concentrated to give part 2 (1.64 g, y: 89%).

[0060] Preparation of Part 3 [ka] To a solution of (2-bromo-ethyl)-phosphonic acid diethyl ester (2.45 g, 10 mmol) and sodium azide (1.87 g, 28.8 mmol) in acetone / HO (70 mL / 140 mL) was added tetrabutylammonium bromide (1.61 g, 5 mmol). The resulting mixture was stirred at 25° C. for 15 h and concentrated to give a residue that was extracted with DCM (3×100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give m3-I (1.36 g, y: 66%).

[0061] To a solution of m3-I (1.36 g, 6.6 mmol) and m1-I (1.25 g, 6.6 mmol) in EtOH (50 mL) was added a solution of CuSO4 (0.13 g, 0.8 mmol), sodium (+)L-ascorbate (0.14 g, 0.7 mmol), K2CO3 (1.84 g, 13.3 mmol) in HO (36 mL). The mixture was stirred at 25 °C for 15 h and concentrated to give a residue that was extracted with DCM (3 × 50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue that was purified by column chromatography on silica gel (MeOH:Ethyl acetate = 1:19) to give m3-II (2.04 g, y: 77%).

[0062] A solution of m3-II (2.04 g, 5.1 mmol) and 10% Pd / C (0.2 g) in methanol (40 mL) was stirred under H2(g) (1 atm) at 25 °C for 6 h. The reaction mixture was then filtered. The filtrate was concentrated to give part 3 (1.18 g, y: 87%).

[0063] Preparation of Part 4 [ka] A solution of 2-(3-bromo-propyl)-isoindole-1,3-dione (1.5 g, 5.6 mmol), K2CO3 (2 g, 14.5 mmol) and 2-piperazin-1-yl-ethanol (2.5 g, 19.2 mmol) in ACN (120 mL) was stirred at 65 °C for 15 h and concentrated to give a residue which was extracted with DCM (3 x 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give m4-I (0.98 g, y: 55%).

[0064] A solution of m4-I (0.98 g, 3.1 mmol) and hydrazine monohydrate (0.4 g, 8 mmol) in DCM (20 mL) was stirred at 25° C. for 15 h and then filtered. The filtrate was concentrated to give part 4 (0.52 g, y: 90%).

[0065] Preparation of Part 5 [ka] To a solution of 1-aminopropanol (2.25 g, 30 mmol) in DCM was added tert-butoxycarbonyl ("Boc") anhydride ("Boc2O", 7.81 g, 35.7 mmol) and TEA (3.6 g, 35.6 mmol). The mixture was stirred at room temperature for 15 h and concentrated to give a crude residue, which was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give m5-I (4.11 g, y:78%).

[0066] To a solution of m5-I (4.11 g, 23.4 mmol) and TEA (3.22 g, 31.7 mmol) in DCM (180 mL) was added methanesulfonyl chloride ("MsCl", 5.41 g, 47.2 mmol) dropwise at 5-10 °C. The resulting mixture was warmed to room temperature for 15 h and then quenched with NH4Cl(aq.) (50 mL, 2 M) followed by extraction with DCM. The combined organic phase was washed with NaHCO3(aq.) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give m5-II (4.12 g, y: 70%).

[0067] To a solution of m5-II (4.12 g, 16.3 mmol) and sodium azide (5.41 g, 83.2 mmol) in MeOH (300 mL) was added tetrabutylammonium bromide (1.61 g, 5 mmol). The resulting mixture was stirred at 65° C. for 15 h and concentrated to give a residue that was extracted with DCM (3×100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give m5-III (2.41 g, y: 74%).

[0068] To a solution of m5-III (2.41 g, 12 mmol) and m1-I (2.41 g, 12.7 mmol) in EtOH (160 mL) was added a solution of CuSO4 (0.2 g, 1.3 mmol), sodium (+)-L-ascorbate (0.24 g, 1.2 mmol), K2CO3 (2.24 g, 16.2 mmol) in HO (40 mL). The mixture was stirred at 25 °C for 15 h and concentrated to give a residue that was extracted with DCM (3 x 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give m5-IV (3.12 g, y: 67%).

[0069] A solution of m5-IV (3.12 g, 8 mmol) and 10% Pd / C (0.6 g) in methanol (40 mL) was stirred under H(g) (1 atm) at 25 °C for 6 h and then filtered. The filtrate was concentrated to give part 5 (1.82 g, y: 89%).

[0070] Preparation of Part 6 [ka] To a solution of 3-bromo-1-propanol (20 g, 144 mmol) in water / acetone (100 mL / 35 mL) was added NaN3 (11.3 g, 174 mmol) and KI (2.02 g, 12.2 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 15 h and concentrated. The resulting residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m6-I (14.12 g, y: 97%).

[0071] To a solution of m1-I (15.4 g, 81.4 mmol) and m6-I (8.23 g, 81.4 mmol) in EtOH (690 mL) was added 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 HO (69 mL). The reaction mixture was stirred at 25 °C for 15 h and concentrated. The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate = 1:3) to give m6-II (19.74 g, y: 84%).

[0072] A solution of m6-II (2 g, 6.9 mmol) and 10% Pd / C (0.6 g) in IPA (40 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and filtered. The filtrate was concentrated to give part 6 (1 g, y: 93%).

[0073] Preparation of Part 7 [ka] To a solution of m6-II (5 g, 17.2 mmol) in dry DCM (100 mL) was added TEA (2.6 g, 25.7 mmol) and MsCl (2.37 g, 20.7 mmol) at 5° C. The reaction mixture was stirred at 60° C. for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m7-I (4.56 g, y: 72%).

[0074] To a solution of m7-I (4.56 g, 12.4 mmol) in dry THF (50 mL) was added isopropylamine (5.6 g, 94.7 mmol) at 5° C. The reaction mixture was stirred at room temperature for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined extracts were 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 h and concentrated to give a crude residue which was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give m7-II (3.51 g, y: 66%).

[0075] A solution of m7-II (3.51 g, 8.1 mmol) and 10% Pd / C (1.05 g) in IPA (100 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and filtered. The filtrate was concentrated to give part 7 (2.2 g, y: 91%).

[0076] Preparation of Part 8 [ka] To a solution of m6-I (5 g, 49.5 mmol) in a solution of dry dimethylformamide ("DMF", 40 mL) was added KOH (11 g, 196.4 mmol) at 5° C. The reaction mixture was stirred at 5° C. for 0.5 h. Then, iodomethane (14 g, 98.6 mmol) was added to the solution. The mixture was stirred at room temperature for 15 h and concentrated. The resulting residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m8-I (1.62 g, y: 28%).

[0077] To a solution of m8-I (1.62 g, 14.1 mmol) and m1-I (2.67 g, 14.1 mmol) in EtOH (60 mL) was added 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 HO (15 mL). The reaction mixture was stirred at 25 °C for 15 h and concentrated. The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate = 1:2) to give m8-II (3.03 g, y: 71%).

[0078] A solution of m8-II (3.03 g, 10 mmol) and 10% Pd / C (0.9 g) in IPA (60 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and filtered. The filtrate was concentrated to give part 8 (1.66 g, y: 98%).

[0079] Preparation of Part 9 [ka] To a solution of 1-bromopropan-2-ol (1.51 g, 10.8 mmol) in DMF (16 mL) was added NaN3 (3.01 g, 46.2 mmol) and Na2CO3 (2.32 g, 21.7 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 15 h and concentrated. The resulting residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m9-I (0.87 g, y: 80%).

[0080] To a solution of m9-I (0.75 g, 7.4 mmol) and m1-I (1.7 g, 9 mmol) in EtOH (38 mL) was added 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 HO (19 mL). The reaction mixture was stirred at 25 °C for 15 h and concentrated. The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate = 1:3) to give m9-II (1.61 g, y: 75%).

[0081] A solution of m9-II (1.61 g, 5.5 mmol) and 10% Pd / C (0.48 g) in IPA (32 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and filtered. The filtrate was concentrated to give part 9 (0.79 g, y: 92%).

[0082] Preparation of Part 10 [ka] To a solution of 4-bromo-butan-2-one (1.51 g, 10 mmol) in dimethylformamide (16 mL) was added NaN3 (3.01 g, 46.2 mmol) and KI (0.23 g, 1.4 mmol) at room temperature. The reaction mixture was stirred at 25° C. for 15 h and concentrated. The resulting residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m10-I (0.87 g, y: 77%).

[0083] To a solution of m10-I (0.87 g, 7.7 mmol) and m1-I (1.7 g, 9 mmol) in EtOH (38 mL) was added 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). The reaction mixture was stirred at 25 °C for 15 h and concentrated. The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue from the previous step was purified by column chromatography on silica gel (n-hexane:ethyl acetate = 1:3) to give m10-II (1.98 g, y: 85%).

[0084] To a solution of m10-II (1.98 g, 6.5 mmol) in dry MeOH (30 mL) was added NaBH4 (0.72 g, 19 mmol) at 5° C. The reaction mixture was stirred at 5° C. for 3 h and quenched with aqueous NH4Cl. The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m10-III (1.61 g, y: 81%).

[0085] A solution of m10-III (1.61 g, 5.3 mmol) and 10% Pd / C (0.32 g) in 2-propanol (32 mL) was stirred at 60 °C under H (1 atm) for 15 h and filtered. The filtrate was concentrated to give part 10 (0.83 g, y: 93%).

[0086] Preparation of part 11 [ka] To a solution of ethyl 3-bromopropanoate (2 g, 11 mmol) in dry THF (45 mL) was added a solution of methylmagnesium bromide (8 mL, 3 M in THF). The mixture was stirred at 25° C. for 4 h and 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 to give m11-I (1.21 g, y: 65%).

[0087] To a solution of m11-I (1.21 g, 7.2 mmol) in DMF (12 mL) was added NaN3 (2.31 g, 35.4 mmol) and Na2CO3 (2.02 g, 19.1 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 15 h and concentrated. The resulting residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m11-II (0.72 g, y: 78%).

[0088] To a solution of m11-II (0.72 g, 5.6 mmol) and m1-I (1.56 g, 8.2 mmol) in EtOH (19 mL) was added 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 HO (8.4 mL). The reaction mixture was stirred at 25 °C for 15 h and concentrated. The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH: ethyl acetate = 1: 19) to give m11-III (1.2 g, y: 68%).

[0089] A solution of m11-III (1.2 g, 3.8 mmol) and 10% Pd / C (0.36 g) in IPA (24 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and then filtered. The filtrate was concentrated to give part 11 (0.61 g, y: 88%).

[0090] Preparation of Part 12 Moiety 12 was prepared from 1-bromo-3-methylsulfanyl-propane following a procedure similar to that used to prepare moiety 6. [ka]

[0091] Preparation of Portions 13 and 14 Moieties 13 and 14 were prepared from aminoacetonitrile following a procedure similar to that used to prepare moiety 1. [ka]

[0092] Preparation of Part 15 [ka] To a solution of sodium methoxide (0.1 mL, 5.4 M in MeOH) in DCM (100 mL) and MeOH (10 mL) at 0° C. was added dichloroacetonitrile (5.02 g, 45.7 mmol) over 45 min. The mixture was stirred at 0° C. for 1 h, after which L-serine methyl ester hydrochloride (7.91 g, 50.8 mmol) was added. The reaction mixture was stirred at 25° C. for 15 h and quenched with water. The resulting solution was concentrated and extracted with DCM (3×150 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude residue. A mixture of the residue and N,N-diisopropylethylamine (8.91 g, 68.9 mmol) in DCM (150 mL) was stirred at 50° C. for 15 h and 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, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (n-hexane:ethyl acetate = 4:1) to give m15-I (7.85 g, y: 98%). 1 H NMR (CDCl3, 300 MHz) δ 8.25 (s, 1H), 4.64 (s, 2H), 3.93 (s, 3H).

[0093] A mixture of m15-I (8.01 g, 45.6 mmol) and sodium azide (10 g, 153.8 mmol) in DMF (240 mL) was stirred at 25° C. for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting solution was extracted with diethyl ether. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give m15-II (6.91 g, y:83%). 1 H NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 4.46 (s, 2H), 3.90 (s, 3H).

[0094] A mixture of m15-II (6.91 g, 37.9 mmol) and triphenylphosphine (10.42 g, 39.7 mmol) in water (105 mL) / THF (210 mL) was stirred at 25° C. for 15 h. The resulting mixture was concentrated to remove THF. The resulting residue was washed with ethyl acetate. The 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 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give m15-III (7.13 g, y: 65% over two steps). 1H 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).

[0095] To a solution of m15-III (3 g, 10.3 mmol) in THF (40 mL) was added LiOH(aq.) (20 mL, 1N). The mixture was stirred at 25° C. for 16 h and 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 to give m15-IV (2.25 g, y: 79%).

[0096] To m15-IV (2.25 g, 8.1 mmol) was added BocO (2.61 g, 11.9 mmol) and 4-dimethylaminopyridine (1.4 g, 11.5 mmol). The resulting mixture was stirred at room temperature for 15 h and concentrated to give a crude residue, which was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give m15-V (2.06 g, y:76%).

[0097] A solution of m15-V (2.06 g, 6.2 mmol) and 10% Pd / C (0.6 g) in IPA (40 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and filtered. The filtrate was concentrated to give part 15 (1.11 g, y: 90%).

[0098] Preparation of Part 16 [ka] 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 h and quenched with NH4Cl(aq.) (100 mL, 2 M). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give m16-I (15.49 g, y: 98%).

[0099] To a solution of m16-I (15.49 g, 65.8 mmol) in EtOH / H2O (20 mL / 40 mL) was added HCl (aq.) (120 mL, 6N). The mixture was heated at 80 °C for 16 h and 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 to give m16-II (6.26 g, y: 50%).

[0100] To a solution of m16-II (6.26 g, 33.1 mmol) and TEA (10 g, 99.4 mmol) in DCM (100 mL) at 5-10 °C was added hydroxylamine hydrochloride (2.53 g, 36.4 mmol). The mixture was stirred at room temperature for 15 h and 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 to give m16-III (4.01 g, y: 59%).

[0101] A solution of m16-III (4 g, 19.6 mmol) and N-chlorosuccinimide (2.75 g, 20.6 mmol) in DMF (100 mL) was heated at 50° C. for 5 h and poured into water. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give m16-IV (3.64 g, y: 78%).

[0102] To a solution of m16-IV (2.38 g, 10 mmol) and pent-4-yn-1-ol (2.6 g, 30.9 mmol) in diethyl ether (66 mL) was added Na2CO3 (3.3 g, 31.1 mmol) in H2O / chloroform (33 mL / 30 mL) at 5 °C for 5 h. 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 on silica gel with (n-hexane:ethyl acetate = 1:4) to give m16-V (1.25 g, y: 44%).

[0103] A solution of m16-V (0.9 g, 3.1 mmol) and hydrazine monohydrate (0.2 g, 6 mmol) in MeOH / DCM (20 mL / 20 mL) was stirred at 25° C. for 15 h and then filtered. The filtrate was concentrated to give part 16 (0.41 g, y: 84%).

[0104] Preparation of Part 17 [ka] To a solution of m15-III (10.02 g, 34.5 mmol) in a mixture of EtOH (200 mL) and THF (100 mL) at 0-5 °C, CaCl2 (4.01 g, 36.1 mmol) and NaBH4 (7.01 g, 185.3 mmol) were added in one portion. The resulting solution was then stirred at 30 °C for 2 h, quenched with sat. NH4Cl(aq), and subsequently extracted with DCM (3 x 150 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. MnO2 (36.31 g, 417.8 mmol) was added to the filtrate with stirring at 25 °C for 2 h. Filtration and concentration gave the crude product, which was purified chromatographically to give m17-I (5.31 g, y: 59% over two steps).

[0105] A solution of m17-I (3.63 g, 13.9 mmol), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (7.21 g, 16.8 mmol) and t-BuOK (1.92 g, 17.1 mmol) in THF (100 mL) was stirred at 5 °C for 2 h. HCl (aq) (50 mL, 2N) was added to the resulting mixture, stirred at 10-15 °C for 2 h, and quenched with sat.NaHCO3 (aq). The mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with n-hexane / ethyl acetate (3:1) to give product m17-II (3.54 g, y: 89%).

[0106] To a magnetically stirred solution of m17-II (3.54 g, 12.4 mmol) in dry MeOH (100 mL) was added a solution of NaBH4 (0.69 g, 18.3 mmol) in MeOH (20 mL). The mixture was stirred at 10° C. for 1 h and concentrated. The residue was dissolved in DCM (150 mL), washed with NH4Cl, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give m17-III (3.14 g, y: 88%).

[0107] A mixture of m17-III (3.14 g, 10.9 mmol) and 10% Pd / C (0.62 g) in isopropanol (62 mL) was stirred under H2(g) at 50 °C for 15 h. The resulting mixture was filtered and the filtrate was concentrated to give portion 17 (1.53 g, y: 90%). EXAMPLES

[0108] Example 2: Preparation of Compounds 1-148 Compounds 1-148 of the present invention were prepared according to the procedures provided below. Unless otherwise noted above, such as the preparation of partial compounds, all side chain compounds and other reagents are commercially available from a variety of sources.

[0109] Preparation of Compound 1 The following scheme illustrates the synthesis of compound 1. [ka] To a solution of 4,6-dichloro-2-methanesulfonylpyrimidine (1.02 g, 4.5 mmol) in THF (50 mL) was added portion 1 (0.85 g, 6.7 mmol) at -70 °C. The mixture was stirred at 25 °C for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate = 2:1) to give 1-I (0.81 g, y: 66%).

[0110] A solution of 1-I (0.81 g, 3 mmol) in isopropanol ("IPA", 4 mL) was mixed with morpholine (1.2 g, 13.8 mmol). The mixture was stirred at 140° C. for 4 h and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:4) to give 1-II (0.72 g, y:65%).

[0111] A solution of 2N HCl / diethyl ether (2 mL, 4 mmol) was added to a solution of 1-II (360 mg, 1 mmol) in DCM (3.6 mL). The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 1 (381 mg, y: 96%). EI-MS: 375.2 (M+1).

[0112] Preparation of compounds 97-98 Compounds 97-98 were prepared in a manner similar to that used to prepare compound 1. Compound 97 EI-MS: 376.2 (M+1). 1H-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). 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).

[0113] Preparation of compound 2 [ka] A solution of 1-I (1.27 g, 4.6 mmol) and phenethylamine (1.27 g, 10.5 mmol) in 1-pentanol (4 mL) was heated at 150° C. for 15 h, and then the resulting mixture was concentrated. The resulting residue was purified by column chromatography with ethyl acetate to give 2-I (1.1 g, y: 66%).

[0114] To a solution of 2-I (1.1 g, 3.1 mmol) in IPA (4 mL) was added morpholine (1.2 g, 13.8 mmol). The mixture was stirred at 140° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:9) to give 2-II (0.98 g, y:78%).

[0115] A solution of 2N HCl in diethyl ether (2 mL, 4 mmol) was added to a solution of 2-II (360 mg, 0.9 mmol) in DCM (3.6 mL). The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 2 (341 mg, y: 87%). EI-MS: 409.2 (M+1).

[0116] Preparation of compound 3 [ka] Portion 2 (1.43 g, 6.7 mmol) was added to a solution of 4,6-dichloro-2-methanesulfonylpyrimidine (1.02 g, 4.5 mmol) in THF (50 mL) at -70 °C. The mixture was stirred at 25 °C for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate = 2:1) to give 3-I (0.91 g, y: 56%) as a solid.

[0117] To a solution of 3-I (0.91 g, 2.5 mmol) in IPA (4 mL) was added morpholine (1.1 g, 12.6 mmol). The mixture was stirred at 140° C. for 4 h and concentrated. The resulting residue was purified by column chromatography on silica gel with ethyl acetate to give 3-II (0.84 g, y: 72%).

[0118] A solution of 2N HCl in diethyl ether (2 mL, 4 mmol) was added to a solution of 3-II (360 mg, 0.8 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 3 (282 mg, y: 82%). EI-MS: 405.2 (M+1).

[0119] Preparation of compound 4 [ka] A solution of 3-I (1.02 g, 2.8 mmol) and phenethylamine (0.81 g, 6.6 mmol) in 1-pentanol (4 mL) was heated at 120° C. for 15 h. The resulting mixture was then concentrated. The resulting residue was purified by column chromatography with ethyl acetate to give 4-I (0.85 g, y: 67%).

[0120] To a solution of 4-I (0.85 g, 1.9 mmol) in IPA (4 mL) was added morpholine (0.85 g, 9.8 mmol). The mixture was stirred at 140° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:9) to give 4-II (0.76 g, y:80%).

[0121] A solution of 2N HCl in diethyl ether (1.5 mL, 3 mmol) was added to a solution of 4-II (300 mg, 0.6 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 4 (254 mg, y: 88%). EI-MS: 439.2 (M+1).

[0122] Preparation of compound 5 [ka] A solution of 3-I (1.02 g, 2.8 mmol) and 1-benzyl-piperidin-4-ylamine (1.06 g, 5.6 mmol) in 1-pentanol (4 mL) was heated at 120° C. for 15 h. The resulting mixture was then concentrated. The resulting residue was purified by column chromatography with ethyl acetate to give 5-I (0.96 g, y: 66%).

[0123] To a solution of 5-I (0.96 g, 1.9 mmol) in IPA (4 mL) was added morpholine (0.82 g, 9.4 mmol). The mixture was stirred at 140° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:9) to give 5-II (0.81 g, y:77%).

[0124] A solution of 2N HCl / diethyl ether (1 mL, 2 mmol) was added to a solution of 5-II (304 mg, 0.5 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 5 (268 mg, y: 86%). EI-MS: 508.2 (M+1). 1 H 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).

[0125] Preparation of compound 6 [ka] A solution of 5-II (1 g, 1.8 mmol) and 10% Pd / C (0.2 g) in 2-propanol (20 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h. The resulting mixture was filtered. The filtrate was concentrated to give 6-I (0.75 g, y: 89%). 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).

[0126] A solution of 6-I (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) in MeOH (18 mL) was stirred at 60° C. for 16 h and concentrated. The resulting residue was purified on silica gel (MeOH:ethyl acetate=1:4) to give 6-II (0.67 g, y:70%).

[0127] A solution of 2N HCl in diethyl ether (1.5 mL, 3 mmol) was added to a solution of 6-II (412 mg, 0.7 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 6 (306 mg, y: 79%). EI-MS: 490.2 (M+1).

[0128] Preparation of compounds 99-104 Compounds 99-104 were prepared similarly to compound 6. Compound 99 EI-MS: 389.2 (M+1). 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). Compound 101 EI-MS: 461.2 (M+1). Compound 102 EI-MS: 497.2 (M+1). Compound 103 EI-MS: 568.2 (M+1). Compound 104 EI-MS: 418.2 (M+1).

[0129] Preparation of compound 7 [ka] To a solution of 4,6-dichloro-2-methanesulfonylpyrimidine (2.04 g, 9 mmol) in THF (100 mL) was added portion 3 (2.51 g, 9.6 mmol) at -70 °C. The mixture was stirred at 25 °C for 15 h and quenched with NH4Cl (aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate = 1:19) to give 7-I (2.35 g, y: 64%).

[0130] A solution of 7-I (1.2 g, 2.9 mmol) and 1-benzyl-piperidin-4-ylamine (1.06 g, 5.6 mmol) in 1-pentanol (4 mL) was heated at 150° C. for 15 h. The resulting mixture was concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:4) to give 7-II (0.77 g, y:47%).

[0131] To a solution of 7-II (0.77 g, 1.4 mmol) in IPA (4 mL) was added morpholine (0.7 g, 8 mmol). The mixture was stirred at 120° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel with ethyl acetate to give 7-III (0.34 g, y: 41%).

[0132] To a solution of 7-III (340 mg, 0.6 mmol) in DCM (1.5 mL) was added bromotrimethylsilane ("TMSBr", 510 mg, 3.3 mmol). The reaction mixture was stirred at 25° C. for 4 h and concentrated to give the hydrobromide salt of compound 7 (310 mg, y: 78%). EI-MS: 558.2 (M+1).

[0133] Preparation of compound 8 [ka] A solution of 7-I (1.02 g, 2.5 mmol) and portion 4 (0.5 g, 2.6 mmol) in 1-pentanol (4 mL) was heated at 150° C. for 15 h. The resulting mixture was concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 8-I (0.61 g, y:44%).

[0134] To a solution of 8-I (0.61 g, 1.1 mmol) in IPA (8 mL) was added morpholine (0.52 g, 6 mmol). The mixture was stirred at 140° C. for 4 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:DCM=3:7) to give 8-II (0.21 g, y:32%).

[0135] To a solution of 8-II (211 mg, 0.3 mmol) in DCM (1 mL) was added TMSBr (0.42 g, 2.7 mmol). The reaction mixture was stirred at 25° C. for 6 h and concentrated to give the hydrobromide salt of compound 8 (242 mg, y: 80%). EI-MS: 555.3 (M+1). 1 H-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).

[0136] Preparation of compound 9 [ka] A solution of 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) and 1-benzyl-piperidin-4-ylamine (2.71 g, 14.2 mmol) in THF (100 mL) was heated at 60° C. for 15 h. The resulting mixture was concentrated. The resulting residue was purified by column chromatography (n-hexane:ethyl acetate=1:1) to give 9-I (1.83 g, y:54%).

[0137] To a solution of 9-I (1.83 g, 5.4 mmol) in 1-pentanol (4 mL) was added portion 5 (1.41 g, 5.5 mmol). The mixture was stirred at 150° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel with ethyl acetate to give 9-II (2.01 g, y: 67%) as a solid.

[0138] To a solution of 9-II (2.01 g, 3.6 mmol) in IPA (4 mL) was added morpholine (1.42 g, 16.1 mmol). The mixture was stirred at 120° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:19) to give 9-III (1.58 g, y:72%).

[0139] 2N HCl in diethyl ether (1.2 mL, 2.4 mmol) was added to a solution of 9-III (350 mg, 0.6 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 9 (325 mg, y: 91%). EI-MS: 507.3 (M+1). 1 H-NMR (D2O, 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).

[0140] Preparation of compound 17 Compound 17 was prepared in a manner similar to that used to prepare compound 9. EI-MS: 549.3 (M+1).

[0141] Preparation of Compound 10 [ka] A solution of 9-III (1 g, 1.6 mmol) and 10% Pd / C (0.3 g) in 2-propanol (20 mL) was stirred under H2(g) (1 atm) at 60 °C for 15 h. The resulting mixture was filtered and concentrated to give 10-I (0.74 g, y: 87%).

[0142] A solution of 10-I (0.74 g, 1.4 mmol), diethyl vinylphosphonate (0.41 g, 2.5 mmol) and TEA (3 drops) in MeOH (18 mL) was stirred at 60° C. for 16 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:9) to give 10-II (0.63 g, y:65%).

[0143] A solution of 2N HCl in diethyl ether (1 mL, 2 mmol) was added to a solution of 10-II (330 mg, 0.5 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 10 (305 mg, y: 91%). EI-MS: 581.3 (M+1).

[0144] Preparation of compounds 18-19, 36, 109, 122, 125, 131, 132 and 145 Compounds 18-19, 36, 109, 122, 125, 131, 132 and 145 were prepared in a manner similar to that used to prepare compound 10. Compound 18 EI-MS: 459.3 (M+1). Compound 19 EI-MS: 531.3 (M+1). Compound 36 EI-MS: 567.3 (M+1). 1 H-NMR (D2O, 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). Compound 109 EI-MS: 651.3 (M+1). Compound 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). Compound 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). Compound 131 EI-MS: 595.3 (M+1). 1H-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). Compound 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). Compound 145 EI-MS: 747.3 (M+1).

[0145] Preparation of compound 11 [ka] To a solution of 10-II (302 mg, 0.4 mmol) in DCM (1 mL) was added TMSBr (0.40 g, 2.6 mmol). The reaction mixture was stirred at 25° C. for 5 h and concentrated to give the hydrobromide salt of compound 11 (263 mg, y: 77%). EI-MS: 525.3 (M+1). 1H-NMR (D2O, 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).

[0146] Preparation of compound 12 [ka] To a solution of 10-I (0.61 g, 1.2 mmol) in DCM (25 mL) was added 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) at 25° C. The reaction mixture was stirred for 15 h and poured into water. The resulting mixture was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:DCM=1:19) to give 12-I (0.55 g, y:62%).

[0147] A solution of 2N HCl / diethyl ether (0.75 mL, 1.5 mmol) was added to a solution of 12-I (300 mg, 0.4 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 12 (240 mg, y: 91%). EI-MS: 546.3 (M+1). 1H-NMR (D2O, 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).

[0148] Preparation of Compounds 13-15, 23-26, 33-34, 73-74, and 77-80 Compounds 13-15, 23-26, 33-34, 73-74 and 77-80 were prepared following a procedure similar to that used to prepare compound 12. Compound 13 EI-MS: 567.3 (M+1). 1 H-NMR (D2O, 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). Compound 14 EI-MS: 577.3 (M+1). Compound 15 EI-MS: 662.3 (M+1). 1 H-NMR (D2O, 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). Compound 23 EI-MS: 806.4 (M+1). 1 H-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). Compound 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). Compound 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). Compound 26 EI-MS: 691.4 (M+1). Compound 33 EI-MS: 675.4 (M+1). 1 H-NMR (D2O, 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). Compound 34 EI-MS: 791.4 (M+1). Compound 73 EI-MS: 646.3 (M+1). 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, 1.21 (t, 3H). 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). Compound 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). Compound 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). Compound 80 EI-MS: 566.3 (M+1).

[0149] Modulation of compound 16 [ka] To a solution of 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) in THF (54 mL) was added portion 6 (2.41 g, 15.4 mmol) and TEA (2 g, 19.8 mmol). The mixture was stirred at 25° C. for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 16-I (1.03 g, y:34%).

[0150] To a solution of 16-I (1.03 g, 3.4 mmol) in IPA (10 mL) was added morpholine (1.4 g, 16.1 mmol). The mixture was stirred at 120° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:9) to give 16-II (1.2 g, y: 87%).

[0151] To a solution of 16-II (1.2 g, 3 mmol) in dry DCM (40 mL) was added TEA (0.45 g, 4.5 mmol) and MsCl (0.45 g, 3.9 mmol) at 5° C. The reaction mixture was stirred at room temperature for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 16-III (1.04 g, y: 73%).

[0152] To a solution of 16-III (1.04 g, 2.2 mmol) in dry THF (30 mL) was added benzylamine (0.28 g, 2.6 mmol) at 5° C. The reaction mixture was stirred at room temperature for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. To the resulting residue were added DCM (50 mL), Boc2O (0.65 g, 3 mmol) and TEA (0.41 g, 4.1 mmol). The mixture was stirred at room temperature for 15 h and concentrated to give a crude residue which was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 16-IV (0.56 g, y:44%).

[0153] A solution of 2N HCl / diethyl ether (2 mL, 4 mmol) was added to a solution of 16-IV (562 mg, 0.9 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 16 (451 mg, y: 84%). EI-MS: 494.3 (M+1). 1 H-NMR (D2O, 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).

[0154] Preparation of Compounds 21-22 and 50-52 Compounds 21-22 and 50-52 were prepared in a manner similar to that used to prepare compound 16. 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). Compound 22 EI-MS: 565.3 (M+1). Compound 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). Compound 51 EI-MS: 693.3 (M+1). Compound 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).

[0155] Modulation of Compound 20

change

[0156] To a solution of 20-I (1.54 g, 3.4 mmol) in IPA (45 mL) was added morpholine (1.4 g, 16.1 mmol). The mixture was stirred at 120° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:4) to give 20-II (1.2 g, y:70%).

[0157] To a solution of 20-II (1.2 g, 2.4 mmol) in dry DCM (40 mL) was added TEA (0.4 g, 4 mmol) and MsCl (0.4 g, 3.5 mmol) at 5° C. The reaction mixture was stirred at room temperature for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting residue was extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 20-III (0.95 g, y: 69%).

[0158] To a solution of 20-III (0.95 g, 1.6 mmol) in dry THF (25 mL) was added piperidine (0.28 g, 3.3 mmol) at 5° C. The reaction mixture was stirred at room temperature for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:1) to give 20-IV (0.56 g, y:60%).

[0159] A solution of 20-IV (0.56 g, 1 mmol) and 10% Pd / C (0.17 g) in 2-propanol (2 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h. The resulting mixture was filtered. The filtrate was concentrated to give 20-V (0.42 g, y: 89%).

[0160] A solution of 2N HCl in diethyl ether (1.2 mL, 2.4 mmol) was added to a solution of 20-V (310 mg, 0.6 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 20 (359 mg, y: 95%). EI-MS: 485.3 (M+1).

[0161] Preparation of Compounds 120, 121, 124, 127 and 144 Compounds 120, 121, 124, 127 and 144 were prepared in a manner similar to that used to prepare compound 20. Compound 120 EI-MS: 665.4 (M+1). Compound 121 EI-MS: 577.3 (M+1). 1 H 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). Compound 124 EI-MS: 625.3 (M+1). Compound 127 EI-MS: 725.4 (M+1). 1H 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). Compound 144 EI-MS: 673.3 (M+1).

[0162] Preparation of compound 27 [ka] To a solution of compound 10 (0.53 g, 0.8 mmol) in DCM (18 mL) was added EDCI (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) at 25° C. The reaction mixture was stirred for 15 h and poured into water. The resulting mixture was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:DCM=1:19) to give 27-I (0.38 g, y:73%).

[0163] A solution of 2N HCl / diethyl ether (1.2 mL, 2.4 mmol) was added to a solution of 27-I (382 mg, 0.6 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 27 (359 mg, y: 90%). EI-MS: 679.3 (M+1).

[0164] Preparation of compounds 28-32 Compounds 28-32 were prepared in a manner similar to that used to prepare compound 27. Compound 28 EI-MS: 609.3 (M+1). Compound 29 EI-MS: 738.4 (M+1). 1 H-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). Compound 30 EI-MS: 682.3 (M+1). Compound 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). Compound 32 EI-MS: 654.3 (M+1). 1H-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).

[0165] Preparation of compound 35 [ka] To a solution of compound 10 (0.5 g, 0.7 mmol) in MeOH (5 mL) was added N,N'-di-Boc-1H-pyrazole-1-carboxamidine (0.28 g, 0.9 mmol) and TEA (0.37 g, 3.7 mmol). The mixture was stirred at room temperature for 15 h and concentrated to give a crude residue, which was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 35-I (0.40 g, y:67%).

[0166] A solution of 2N HCl / diethyl ether (1 mL, 2 mmol) was added to a solution of 35-I (310 mg, 0.4 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 35 (261 mg, y: 90%). EI-MS: 623.3 (M+1). 1 H-NMR (D2O, 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).

[0167] Preparation of compound 37 [ka] To a solution of 2,4,6-trichloropyrimidine (5.4 g, 29.4 mmol) in THF was added 1-benzyl-piperidin-4-ylamine (6.3 g, 33.1 mmol) and TEA (4.5 g, 44.6 mmol) under nitrogen atmosphere. The mixture was stirred at 60° C. for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:4) to give 37-I (5.60 g, y:56%).

[0168] A solution of 37-I (2 g, 5.9 mmol) and portion 6 (1.08 g, 6.9 mmol) in IPA (40 mL) was heated at 145° C. for 15 h. The resulting mixture was concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:9) to give 37-II (1.6 g, y:59%).

[0169] A solution of 37-II (1.2 g, 2.6 mmol) and piperidine (1 g, 11.7 mmol) in IPA (40 mL) was sealed and heated at 120° C. for 15 h. The resulting mixture was concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=3:7) to give 37-III (1.19 g, y:89%). 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).

[0170] 2N HCl in diethyl ether (1.2 mL, 2.4 mmol) was added to a solution of 37-III (305 mg, 0.6 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 37 (320 mg, y: 92%). EI-MS: 506.3 (M+1).

[0171] Preparation of compounds 38-44, 112, 115, 133, 136, 138 and 141 Compounds 38-44, 112, 115, 133, 136, 138 and 141 were prepared in a manner similar to that used to prepare compound 37. Compound 38 EI-MS: 416.3 (M+1). Compound 39 EI-MS: 502.3 (M+1). Compound 40 EI-MS: 493.3 (M+1). Compound 41 EI-MS: 431.3 (M+1). Compound 42 EI-MS: 439.2 (M+1). Compound 43 EI-MS: 502.3 (M+1). Compound 44 EI-MS: 430.3 (M+1). Compound 112 EI-MS: 494.3 (M+1). 1H 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). 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). Compound 133 EI-MS: 516.3 (M+1). Compound 136 EI-MS: 542.3 (M+1). Compound 138 EI-MS: 524.3 (M+1). 1 H 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). Compound 141 EI-MS: 556.2 (M+1).

[0172] Modulation of Compound 45 [ka] A solution of compound 37-II (1.2 g, 2.6 mmol) and morpholine (1 g, 11.5 mmol) in IPA (40 mL) was sealed and heated at 120° C. for 15 h. The resulting mixture was concentrated. The resulting residue was purified by flash chromatography on silica gel (MeOH:ethyl acetate=1:3) to give 45-I (1.08 g, y: 81%).

[0173] A solution of 45-I (1.08 g, 2.1 mmol) and 10% Pd / C (0.3 g) in 2-propanol (20 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h. The resulting mixture was filtered. The filtrate was concentrated to give 45-II (0.81 g, y: 91%). 1 H-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).

[0174] A solution of 2N HCl / diethyl ether (1.5 mL, 3 mmol) was added to a solution of 45-II (310 mg, 0.7 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 45 (331 mg, y: 91%). EI-MS: 418.2 (M+1).

[0175] Preparation of Compounds 49, 53, 54, 61, 81, 82, 85, 86 and 89-94 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. 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). Compound 53 EI-MS: 418.2 (M+1). Compound 54 EI-MS: 508.3 (M+1). Compound 61 EI-MS: 432.2 (M+1). Compound 81 EI-MS: 538.3 (M+1). Compound 82 EI-MS: 548.3 (M+1). 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). Compound 86 EI-MS: 448.2 (M+1). Compound 89 EI-MS: 537.3 (M+1). Compound 90 EI-MS: 447.2 (M+1). Compound 91 EI-MS: 551.3 (M+1). Compound 92 EI-MS: 461.3 (M+1). Compound 93 EI-MS: 536.3 (M+1). Compound 94 EI-MS: 446.3 (M+1).

[0176] Preparation of compound 46 [ka] A solution of 45-II (0.51 g, 1.2 mmol), diethyl vinylphosphonate (0.4 g, 2.4 mmol) and TEA (3 drops) in MeOH (18 mL) was stirred at 60° C. for 16 h and concentrated. The resulting residue was purified by flash chromatography on silica gel (MeOH:ethyl acetate=3:7) to give 46-I (0.42 g, y:59%). 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).

[0177] A solution of 2N HCl in diethyl ether (0.5 mL, 1 mmol) was added to a solution of 46-I (150 mg, 0.3 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 46 (152 mg, y: 90%). EI-MS: 582.3 (M+1).

[0178] Preparation of Compounds 48, 55, 57, 59, 62, 63, 83, 87, 95, 113, 116, 118, 134, 137, 139, 142 and 147 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. Compound 48 EI-MS: 504.3 (M+1). 1 H 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). Compound 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). Compound 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). Compound 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). 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). Compound 63 EI-MS: 596.3 (M+1). Compound 83 EI-MS: 610.3 (M+1). Compound 87 EI-MS: 612.3 (M+1). Compound 95 EI-MS: 610.3 (M+1). Compound 113 EI-MS: 568.3 (M+1). Compound 116 EI-MS: 596.3 (M+1). 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). Compound 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). Compound 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). Compound 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). 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). Compound 147 EI-MS: 582.3 (M+1).

[0179] Preparation of compound 47 [ka] To a solution of 46-I (243 mg, 0.4 mmol) in DCM (0.5 mL) was added TMSBr (0.36 g, 2.4 mmol). The mixture was stirred at 25° C. for 4 h and concentrated to give the hydrobromide salt of compound 47 (240 mg, y: 84%). EI-MS: 526.2 (M+1). 1H-NMR (D2O, 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).

[0180] Preparation of Compounds 56, 58, 60, 64, 84, 88, 96, 114, 117, 119, 123, 126, 128, 130, 135, 140, 143, 146 and 148 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 to prepare compound 47. 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). 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). 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). Compound 64 EI-MS: 540.2 (M+1). 1 H NMR (D2O, 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). Compound 84 EI-MS: 554.2 (M+1). Compound 88 EI-MS: 556.2 (M+1). Compound 96 EI-MS: 554.3 (M+1). Compound 114 EI-MS: 512.2 (M+1). 1 H NMR ((D2O, 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). 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). Compound 119 EI-MS: 528.2 (M+1). 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). 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). Compound 128 EI-MS: 569.3 (M+1). 1 H-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). Compound 130 EI-MS: 752.3 (M+1). 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). 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). Compound 143 EI-MS: 574.2 (M+1). 1 H 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). Compound 146 EI-MS: 691.2 (M+1). Compound 148 EI-MS: 526.2 (M+1).

[0181] Modulation of Compound 65

change

[0182] 2N HCl in diethyl ether (0.75 mL, 1.5 mmol) was added to a solution of 65-I (302 mg, 0.5 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 65 (312 mg, y: 92%). EI-MS: 594.3 (M+1).

[0183] Preparation of compound 66 [ka] A solution of 65-I (1.7 g, 2.9 mmol) and 10% Pd / C (0.51 g) in 2-propanol (34 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and then filtered. The filtrate was concentrated to give 66-I (1.34 g, y: 93%).

[0184] A solution of 66-I (0.3 g, 0.6 mmol), acrylic acid methyl ester (0.15 g, 1.8 mmol) and TEA (0.38 g, 3.8 mmol) in MeOH (18 mL) was stirred at 60° C. for 16 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:4) to give 66-II (0.23 g, y:65%). 1 H 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).

[0185] A solution of 2N HCl in diethyl ether (1 mL, 2 mmol) was added to a solution of 66-II (231 mg, 0.4 mmol) in DCM. The reaction mixture was stirred at 25° C. for 2 h and concentrated to give the hydrochloride salt of compound 66 (241 mg, y: 93%). EI-MS: 590.3 (M+1).

[0186] Preparation of compound 67 Compound 67 was prepared in a manner similar to that used to prepare compound 66. EI-MS: 668.3 (M+1). 1H-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).

[0187] Preparation of compound 68 [ka] A solution of 66-I (0.4 g, 0.8 mmol), 3-bromomethyl-benzoic acid methyl ester (0.6 g, 2.6 mmol) and TEA (0.3 g, 3 mmol) in THF (12 mL) was stirred at 25° C. for 16 h and quenched with NH4Cl(aq.) (20 mL, 2 M). The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:4) to give 68-I (0.34 g, y:66%). 1H-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).

[0188] 2N HCl in diethyl ether (0.75 mL, 1.5 mmol) was added to a solution of 68-I (0.34 g, 0.5 mmol) in DCM. The reaction mixture was stirred at 25° C. for 2 h and concentrated to give the hydrochloride salt of compound 68 (0.35 g, y: 93%). EI-MS: 652.3 (M+1).

[0189] Preparation of Compounds 70, 71, 72, 75 and 76 Compounds 70, 71, 72, 75 and 76 were prepared in a manner similar to that used to prepare compound 68. 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). 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). Compound 72 EI-MS: 619.3 (M+1). Compound 75 EI-MS: 644.3 (M+1). 1 H-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). Compound 76 EI-MS: 669.3 (M+1).

[0190] Modulation of Compound 69

change

[0191] A solution of 69-I (0.52 g, 0.8 mmol) and 10% Pd / C (0.15 g) in 2-propanol (10 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h. The resulting mixture was filtered. The filtrate was concentrated to give 69-II (0.41 g, y: 92%).

[0192] A solution of 69-II (0.41 g, 0.8 mmol), diethyl vinylphosphonate (0.26 g, 1.6 mmol) and TEA (1 drop) in MeOH (12 mL) was stirred at 60° C. for 16 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=3:7) to give 69-III (0.31 g, y:58%).

[0193] 2N HCl in diethyl ether (0.75 mL, 1.5 mmol) was added to a solution of 69-III (0.31 g, 0.4 mmol) in DCM. The reaction mixture was stirred at 25° C. for 2 h and concentrated to give the hydrochloride salt of compound 69 (0.28 g, y: 88%). EI-MS: 654.3 (M+1).

[0194] Preparation of Compound 105 [ka] To a solution of 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) in THF (54 mL) was added portion 6 (2.41 g, 15.4 mmol) and TEA (2 g, 19.8 mmol). The mixture was stirred at 25° C. for 15 h and quenched with NH4Cl(aq.) (50 mL, 2 M). The resulting solution was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give 105-I (0.76 g, y:25%).

[0195] To a solution of 105-I (0.76 g, 2.5 mmol) in IPA (25 mL) was added morpholine (1.4 g, 16.1 mmol). The mixture was stirred at 120° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give 105-II (0.67 g, y: 66%).

[0196] A solution of 2N HCl in diethyl ether (1.2 mL, 2.4 mmol) was added to a solution of 105-II (0.31 g, 0.8 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 105 (0.32 g, y: 95%). EI-MS: 405.2 (M+1).

[0197] Preparation of compounds 106-107 Compounds 106-107 were prepared in a manner similar to that used to prepare compound 105. Compound 106 EI-MS: 433.2 (M+1). Compound 107 EI-MS: 418.2 (M+1).

[0198] Preparation of Compound 108 [ka] A solution of 37-II (1.4 g, 3.1 mmol), tetrabutylammonium bromide (1 g, 3.1 mmol) and portion 6 (0.7 g, 4.5 mmol) in 2-pentanol (30 mL) was stirred at 140° C. for 15 h and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:ethyl acetate=1:3) to give 108-I (0.48 g, y: 27%).

[0199] A solution of 108-I (0.48 g, 0.8 mmol) and 10% Pd / C (0.15 g) in 2-propanol (10 mL) was stirred at 60 °C under H2(g) (1 atm) for 15 h and then filtered. The filtrate was concentrated to give 108-II (0.36 g, y: 89%).

[0200] A solution of 2N HCl in diethyl ether (0.5 mL, 1 mmol) was added to a solution of 108-II (0.15 g, 0.3 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 108 (0.17 g, y: 93%). EI-MS: 487.3 (M+1).

[0201] Preparation of Compound 110 [ka] A solution of 45-II (0.51 g, 1.2 mmol), acrylonitrile (0.3 g, 5.7 mmol) and TEA (0.2 g, 2 mmol) in MeOH (15 mL) was stirred at 60° C. for 6 h and concentrated. The resulting residue was purified by flash chromatography on silica gel (MeOH:ethyl acetate=3:7) to give 110-I (0.42 g, y:73%). 1H-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).

[0202] A solution of 2N HCl in diethyl ether (0.5 mL, 1 mmol) was added to a solution of 110-I (200 mg, 0.3 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 110 (210 mg, y: 91%). EI-MS: 471.3 (M+1).

[0203] Preparation of Compound 111 [ka] To a solution of 110-I (1.51 g, 3.2 mmol) and sodium azide (1.01 g, 15.4 mmol) in isopropyl alcohol (75 mL) was added a solution of ZnBr2 (0.36 g, 1.6 mmol) in H2O (15 mL). The mixture was stirred at 100 °C for 15 h and concentrated to give a residue, which was extracted with DCM (3 × 100 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (MeOH: ethyl acetate = 3: 7) to give 111-I (1.28 g, y: 78%). 1H-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).

[0204] A solution of 2N HCl in diethyl ether (1 mL, 2 mmol) was added to a solution of 111-I (310 mg, 0.6 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 111 (315 mg, y: 84%). EI-MS: 514.3 (M+1).

[0205] Preparation of Compound 129 [ka] To a solution of compound 46-I (301 mg, 0.5 mmol) in DMF (11 mL) was added EDCI (265 mg, 1.4 mmol), DMAP (28 mg, 0.2 mmol) and biotin (337 mg, 1.4 mmol). The reaction mixture was stirred at 25° C. for 72 h and poured into water. The resulting mixture was extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (MeOH:DCM=1:19) to give 129-I (242 mg, y:57%). 1H-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).

[0206] A solution of 2N HCl / diethyl ether (0.5 mL, 1 mmol) was added to a solution of 129-I (242 mg, 0.3 mmol) in DCM. The reaction mixture was stirred at 25° C. for 15 h and concentrated to give the hydrochloride salt of compound 129 (237 mg, y: 90%). EI-MS: 808.4 (M+1). EXAMPLES

[0207] Example 3: Neurite outgrowth assay Compounds of the invention were evaluated using a neurite outgrowth assay as described in Chen et al., Scientific Reports, 7, 45366, DOI:10.1038 / srep45366 (2017).

[0208] cell culture For primary culture, dorsal root ganglia ("DRG") were removed from 7-week-old C57BL / 6J mice and digested with 0.1% collagenase (Sigma-Aldrich, St. Louis, MO) for 1 h, followed by 0.25% trypsinization for 25 min. Dissociated neuronal cultures were plated at 2.5 × 10 cells per well onto 96-well optical plates (CLS3614, Sigma-Aldrich) precoated with 1 mg / mL poly-D-lysine (A-003-M, Sigma-Aldrich) for 3 h. 4Primary DRG cells were grown in DMEM-F12 (11320033, Gibco®, ThermoFisher Scientific, Waltham, MA) supplemented with 10% fetal bovine serum (FBS, 26140079, Gibco®, ThermoFisher Scientific). The cells were maintained at 37°C in an environment containing 5% CO2.

[0209] Neurite outgrowth assay (Group A) Primary DRG cells were incubated with one of the compounds of Example 2 at 1 μM for 24 hours, and then treated with 0.05 μM paclitaxel for another 24 hours. After paclitaxel treatment, primary DRG cells were washed with PBS and fixed with 4% paraformaldehyde (PFA, P6148, Sigma-Aldrich) for 15 minutes. The resulting 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, DRG cells were stained with rabbit anti-βIII tubulin antibody (1:600, Cell Signaling, USA) and mouse anti-NeuN monoclonal antibody (1:400, Millipore, USA) at 4° C. overnight. Then, the samples were washed with PBS and reacted with secondary antibodies (Alexa-488 and Alexa-594, 1:600, Invitrogen, CA) for 1 hour at room temperature. For image acquisition and analysis of DRG neurite outgrowth, images of stained cells were automatically acquired by Image Xpress Micro wide-field fluorescence microscope (Molecular Devices, USA) using a 10x objective. Controls were obtained following the same procedure, except that DRG cells were not treated with compounds or paclitaxel. Neurite outgrowth was measured as the percentage of outgrowth compared to the control.

[0210] It was found that paclitaxel inhibits neurite outgrowth due to its neurotoxicity. The compounds of the present invention effectively protect DRG cells from paclitaxel-induced neurotoxicity. The results are shown in Table 1 below. In Table 1, column A shows the neurite outgrowth of DRG cells treated with 1 μM of the compounds of the present invention and 0.05 μM of paclitaxel, and column B shows the neurite outgrowth of DRG cells treated with 0.05 μM of paclitaxel. The difference between A and B shows the degree of protection provided by the compound. Table 1. Neurite outgrowth (%) [Table 1]

[0211] As shown in Table 1, 0.05 μM paclitaxel inhibited DRG neurite outgrowth by 50% to 69%. 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 over 18% (i.e., 65% outgrowth compared to 47% in paclitaxel-treated cells).

[0212] Neurite outgrowth assay (Group B) Primary DRG cells were incubated with compounds 17, 47, 97, 98, 101, 104 at 1 μM for 24 hours and then treated with 100 μM oxaliplatin for an additional 48 hours. Treatment was performed following the same procedure as in Group A, except that DRG cells were treated with oxaliplatin. Neurite outgrowth was measured as a percentage of outgrowth compared to the control.

[0213] Oxaliplatin was found to inhibit neurite outgrowth due to its neurotoxicity. Compounds of the present invention effectively protected DRG cells from oxaliplatin-induced neurotoxicity. The results are shown in Table 2 below. Table 2. Neurite outgrowth (%) [Table 2]

[0214] As shown in Table 2, 100 μM oxaliplatin inhibited DRG neurite outgrowth by 60%-71%. Unexpectedly, neuroprotection was found to be provided by compounds 47, 97, 101 and 104. In particular, compound 47 showed a greater than 7% improvement (i.e., 47% outgrowth compared to 40% in oxaliplatin-treated cells). EXAMPLES

[0215] Example 4: In vivo mouse behavioral model Following the procedures described in Chen et al., Scientific Reports, 7, 45366, DOI:10.1038 / srep45366 (2017), compound 47 was used in an in vivo mouse behavioral study to treat paclitaxel-induced neuropathy.

[0216] After breeding adaptation, 7-week-old C57BL / 6J female mice (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) were injected intraperitoneally on alternate days for four times (days 0, 2, 4, and 6). Two behavioral tests were performed: (1) mechanical hyperalgesia was assessed using von Frey filaments (Part#2390, IITC, CA), and (2) temperature sensitivity was studied using a tail immersion assay (water temperature, 48-49°C). See Chen et al., Mol. Cancer. Ther. 14, 2206-14 (2015). Baseline measurements for each behavioral test were established before treatment. Five sessions were measured weekly.

[0217] The neuroprotective effect of compound 47 in mouse model was measured according to a protocol of prescribed drug administration and behavioral test. Baseline level of each behavioral assay was obtained before treatment. In the first week, paclitaxel was intraperitoneally injected at 4.5mg / kg every other day, and vehicle or compound 47 (5, 10 and 20mg / kg) was administered by intraperitoneal injection 1 hour before paclitaxel treatment. After four courses of treatment, behavioral test was performed every week.

[0218] The von Frey filament test was performed to detect allodynia. Touch pressure was exerted until paw withdrawal. Temperature sensation was assessed using the tail immersion test by determining the tail withdrawal latency.

[0219] Eight groups of mice were treated individually.

[0220] Mice in groups 1, 2 and 3 were injected with Compound 47 in saline at doses of 5 mg / kg, 10 mg / kg and 20 mg / kg, respectively. One hour later, mice were injected with 4.5 mg / kg paclitaxel.

[0221] As a comparison group, mice in group 4 were injected with saline and, 1 hour later, with 4.5 mg / kg paclitaxel.

[0222] Mice in control group 5 were injected twice with saline instead of compound 47 and paclitaxel.

[0223] In control groups 6, 7 and 8, mice were injected with Compound 47 at 5 mg / kg, 10 mg / kg and 20 mg / kg, respectively, followed by saline injection.

[0224] The results showed that mice in group 4 had a very low pain threshold due to paclitaxel toxicity. In groups 1-3, compound 47 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 had similar pain thresholds to the control group, indicating the high efficacy of compound 47 in protecting against paclitaxel-induced neuropathy.

[0225] Similar results were observed in the tail immersion assay, again demonstrating the neuroprotective efficacy of compound 47.

[0226] Other embodiments All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

[0227] From the above description, those skilled in the art can easily ascertain the essential features of the present invention, and can make various changes and modifications to the present invention to adapt it to various applications and conditions without departing from the spirit and scope of the present invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

1. A compound of formula (I) 【Chemical 1】 R １ is H, halo, nitro, cyano, amino, C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ Cycloalkyl, C １－１０ heterocycloalkyl, aryl, or heteroaryl; W １ is C １－１０ Heterocycloalkyl or NH—CH ２ -Ar1-(CH ２ ) ｍ -A1, W ２ and W ３ One of them is NR ａ R ｂ and W ２ and W ３ The other is NH-CH ２ -Ar2-(CH ２ ) ｎ -A2, each of Ar1 and Ar2 is independently a 5-membered heteroaryl; Each of A1 and A2 independently represents H, OH, SH, CO ２ R ｃ , P.O. ３ R ｃ R ｄ , N.H. ２ , benzylamino, isopropylamino, ethanolamino, carbamide, guanidinyl, 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 and R ａ and R ｂ each independently represents H, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－１０ heterocycloalkyl, or R ａ and R ｂ together with the nitrogen atom to which they are attached, １－１０ is heterocycloalkyl, R ｃ and R ｄ each independently represents H, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－１０ heterocycloalkyl, aryl, or heteroaryl; C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ Cycloalkyl, C ３－１０ Cycloalkyloxy, C １－１０ Heterocycloalkyl, C １－１０ Each of heterocycloalkyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, ethanolamino, benzylamino, and carbamido is selected from hydroxyl, halo, nitro, cyano, amino, C １－６ Alkyl, arylalkyl, C １－６ Alkoxyl, C １－６ Carboxyalkyl, aryl, heteroaryl, PO ３ R ｅ R ｆ , N.C.O.R. ｅ , NC(O)OR ｅ , C(O)OR ｅ , C.O.R. ｅ , (CH ２ ) ｘ -PO ３ R ｅ R ｆ , (CH ２ ) ｘ -NCOR ｅ or (CH ２ ) ｘ -C(O)OR ｅ optionally substituted with R ｅ and R ｆ each independently represents H, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－１０ heterocycloalkyl, aryl, or heteroaryl; each of m and n is independently 0, 1, 2, 3, 4, or 5; x is 1, 2, 3 or 4.

2. R １ is H and W １ The compound of claim 1 , wherein is morpholino.

3. W ２ is NH-CH ２ -Ar2-(CH ２ ) ｎ -A2 and n is 2, 3 or 4.

4. W ３ is NR ａ R ｂ and R ａ is H and R ｂ is hydroxyl, (CH ２ ) ｘ -PO ３ R ｅ R ｆ or (CH ２ ) ｘ -NCOR ｅ and R is a 6-membered heterocycloalkyl optionally substituted with ｅ and R ｆ each independently represents H, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－１０ The compound of claim 3, wherein x is 2 or 3 and is heterocycloalkyl, aryl, or heteroaryl.

5. R １ is H, W １ is C １－１０ Heterocycloalkyl or NH—CH ２ -Ar1-(CH ２ ) ｍ -A1, W ２ is NH-CH ２ -Ar2-(CH ２ ) ｎ -A2, W ３ is NR ａ R ｂ and Each of A1 and A2 is independently H, OH, C １－６ Alkyl, C １－６ Alkoxy or NCOR ｃ and R ａ is H, or R ａ and R ｂ together with the nitrogen atom to which they are attached are a 6-membered heterocycloalkyl; R ｂ is a 6-membered heterocycloalkyl, or R ｂ and R ａ together with the nitrogen atom to which they are attached are a 6-membered heterocycloalkyl; R ｃ is C １－６ is alkyl, C １－６ Alkyl, C １－６ Alkoxy and C １－１０ Each heterocycloalkyl can be selected from the group consisting of hydroxyl, NH ２ , (CH ２ ) ｘ -PO ３ R ｅ R ｆ , C(O)OR ｅ or (CH ２ ) ｘ -NCOR ｅ optionally substituted with R ｅ and R ｆ each independently represents H, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－１０ heterocycloalkyl, aryl, or heteroaryl; 2. The compound of claim 1, wherein each of m and n is 2, 3, or 4; and x is 1, 2, 3, or 4.

6. W ２ is NH-CH ２ -Ar2-(CH ２ ) ｎ -A2 and n is 2, 3 or 4.

7. W ３ is NR ａ R ｂ and R ａ is H and R ｂ is hydroxyl, (CH ２ ) ｘ -PO ３ R ｅ R ｆ or (CH ２ ) ｘ -NCOR ｅ and R is a 6-membered heterocycloalkyl optionally substituted with ｅ and R ｆ each independently represents H, C １－６ Alkyl, C ３－１０ Cycloalkyl, C １－１０ 2. The compound of claim 1, wherein x is 2 or 3 and is heterocycloalkyl, aryl, or heteroaryl.

8. R １ is H and W １ is a morpholino, and W ２ is NH-CH ２ -Ar2-(CH ２ ) ｎ -A2, wherein Ar2 is triazole, n is 2 or 3, A2 is OH, and W ３ is NR ａ R ｂ and R ａ is H and R ｂ But, R ｅ and R ｆ each independently represents H or C １－６ alkyl, and x is 2 or 3 (CH ２ ) ｘ -PO ３ R ｅ R ｆ 2. The compound of claim 1, wherein the compound is a piperidine moiety optionally substituted with

9. The compound of claim 1 selected from the group consisting of compounds 1 to 148 having the chemical structures shown below. 【Chemistry 2】 【change】 【change】 【change】 【change】 【change】 【change】

10. 10. The compound of claim 9 selected from the group consisting of compounds 28, 46, 47, 58, 67, 69, 78, 97, 104, 109, 114 and 117.

11. The compound of claim 9, which is compound 47.

12. 10. The compound of claim 1 for use in treating chemotherapy-induced peripheral neuropathy, wherein the compound is administered in an effective amount to a subject in need thereof, and the chemotherapy-induced peripheral neuropathy is allodynia or thermosensitivity.

13. The compound for use according to claim 12, wherein the subject is further administered an anti-cancer drug.

14. 14. The compound for use according to claim 13, wherein the compound according to claim 1 is administered prior to administration of the anti-cancer drug.

15. 14. The compound for use according to claim 13, wherein the anti-cancer drugs are paclitaxel and oxaliplatin.

16. 13. The compound for use according to claim 12, wherein the compound according to claim 1 is selected from the group consisting of compounds 28, 46, 47, 58, 67, 69, 78, 97, 104, 109, 114 and 117.

17. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier thereof.

18. 18. The pharmaceutical composition of claim 17, wherein the compound of claim 1 is selected from the group consisting of compounds 28, 46, 47, 58, 67, 69, 78, 97, 104, 109, 114 and 117.

19. A compound for use as described in claim 12, wherein the chemotherapy-induced peripheral neuropathy is allodynia.

20. A compound for use as described in claim 12, wherein the chemotherapy-induced peripheral neuropathy is temperature sensitive.

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