Potent NF-kb inhibitors for the treatment of inflammatory diseases

Abstract

The application relates to compounds of the general Formulae (I), (II), (III) and (IV) which act as inhibitors of NF-kB useful for the treatment of inflammatory diseases.

Description

Cross Reference to Related Applications This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 614,624, filed December 24, 2023, U.S. Provisional Patent Application No. 63 / 614,625, filed December 24, 2023, and U.S. Provisional Patent Application No. 63 / 614,627, filed December 24, 2023, the contents of each of which are hereby incorporated by reference. Field of the Disclosure The present disclosure provides certain potent compounds that inhibit nuclear factorkappa B (NF-kB) activation induced by inflammatory stimuli. Therefore, the compounds of the present disclosure are useful for the treatment of inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, and inflammatory bowel disease. Also provided are pharmaceutical compositions containing such compounds and methods of using them. Background Inflammation is an important host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation leads to a broad range of pathological processes. Inflammatory disorders include autoimmune diseases, allergies, asthma, chronic obstructive pulmonary disease and sepsis which are a major cause of illness and death. It is also becoming apparent that low-grade chronic inflammation underlies many diseases, including diabetes, cancer, cardiovascular disease and neurodegenerative disorders. Therefore, identifying new drugs to suppress inflammation is an area of intense interest. NF-kB is a ubiquitously expressed transcription factor which regulates the expression of genes involved in inflammation and pain. Activation of NF-kB plays a central role in inflammation through its ability to induce transcription of proinflammatory genes (see Tak et al. NF-kB: a key role in inflammatory diseases. J Clin Inv 2001; 107:7-11; and Liu et al. NF-kB signaling in inflammation. Signal Transduct Target Ther. 2017;2. pii: 17023). Synthesis of proinflammatory cytokines, such as TNF-a, IL-ip, IL-6, and IL-8, is mediated by NF-kB, as is the expression of cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), adhesion molecules (ICAM-1, E-selectin, and VCAM-1), chemokines (MCP-1, KC, MIP-1) and metalloproteinases. Reciprocally, cytokines such as TNF-a and IL-ip or prostaglandins produced by COX-2 trigger NF-kB activation generating an inflammatory cascade. NF-kB is activated at sites of inflammation in diverse diseases including rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, etc (Pai et al. Immune deficiency or hyperactivity-Nf-kappab illuminates autoimmunity. J Autoimmun 2008; 31:245-251; Zhang et al. NFkB in inflammation and renal diseases. Cell Biosci 2015; 5:63; Roman-Blas et al. NF-kB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. OsteoArthritis and Cartilage 2006; 14:839-848). Corticosteroids have been developed to treat inflammatory conditions and have many side effects that can be mild or serious, especially when corticosteroids are used for extended periods of time. For instance, corticosteroids can cause weight gain, edema, high blood pressure, glaucoma, hypokalemia, cataract, psychiatric disturbances, osteoporosis, and weakening of the immune system. Non-steroidal anti-inflammatory drugs (NSAIDs) which act via inhibition of the cyclooxygenase (COX) isozymes are widely prescribed but the chronic use of NSAIDs is associated with common side effects including cardiovascular events (hypertension, myocardial infarction, stroke, and heart failure), gastrointestinal side effects (diffuse gastritis and discrete ulcers both gastric and duodenal) which can be fatal, renal side effects (interstitial nephritis) as well as hepatic adverse reactions (transaminitis, hepatitis). Biologies for targeting inflammatory cytokines have been developed. Although biologies have been shown to ameliorate inflammatory diseases pathology and progression, their use has been limited due to severe adverse reactions and to the fact that they abrogate host defense against infection (Rider et al. Biologies for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations. Int J Cell Biol. 2016; 2016:9259646). Certain NF-kB inhibitors are disclosed in WO / 2020 / 154420. Still, there exists an ongoing need for anti-inflammatory medications with greater potency and efficacy, and fewer side effects, with superior properties over medications known in the art. The present invention fulfills this and related needs. Summary The inventors have surprisingly discovered compounds having unexpectedly superior NF-kB inhibitory properties relative to those known in the art, including the discovery that compounds with particular stereochemistry are markedly superior to their enantiomeric 5 counterparts. Accordingly, in one aspect, provided is a compound of Formula (I): (I) 10 wherein: the dashed line is an optional bond; R1 is C3-C5 alkyl; H , or O; and 15          R2 is H or C3-C7 alkyl; or a pharmaceutically acceptable salt thereof. In a second aspect, provided is a compound of Formula (II): (II) wherein: Y is O or S; and 5          R3 is -H, -F, or -CX3, wherein each X is independently -H or -F; or a pharmaceutically acceptable salt thereof. In a third aspect, provided is a compound of Formula (III): 10 wherein: (HI) Y is O or S; and R4 is -CX3, wherein each X is independently -H or -F; or 15           a pharmaceutically acceptable salt thereof. In a fourth aspect, provided is a compound of Formula (IV): R5 (IV) wherein: Y is O or S; and R5 is C2-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C3-C4 cycloalkyl; or a pharmaceutically acceptable salt thereof. In a fifth aspect, this disclosure is directed to a pharmaceutical composition comprising a compound Formula (I), a compound of Formula (II), a compound of Formula (III), or a compound of Formula (IV) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. In a sixth aspect, this disclosure is directed to a method of treating a disease treatable by inhibiting NF-kB activation comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or a compound of Formula (IV) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or a compound of Formula (IV) (or any of the embodiments thereof described herein) and a pharmaceutically acceptable excipient. In one embodiment the diseases are inflammatory diseases including, autoimmune diseases, pain, allergies, asthma, chronic obstructive pulmonary disease and sepsis. In another embodiment the diseases are rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet’s disease, tuberculosis, Crohn’s disease, colitis, Pagett’s disease, pancreatitis, periodonitis, inflammatory lung disease, and lupus nephritis. In a seventh aspect, the disclosure is directed to a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or a compound of Formula (IV) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment, the compound of Formula (I), a compound of Formula (II), a compound of Formula (III), or a compound of Formula (IV) (and any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof is useful for the treatment of inflammatory diseases including, autoimmune diseases, pain, allergies, asthma, chronic obstructive pulmonary disease and sepsis. In another embodiment the diseases are rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet’s disease, tuberculosis, Crohn’s disease, colitis, Pagett’s disease, pancreatitis, periodonitis, inflammatory lung disease, and lupus nephritis. In a eigth aspect provided a compound Formula (I), a compound of Formula (II), a compound of Formula (III), or a compound of Formula (IV), or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein) for use in treating a disease in a patient in which NF-kB activation contributes to the pathology and / or symptoms of the disease. In one embodiment the diseases are inflammatory diseases including, autoimmune diseases, pain, allergies, asthma, chronic obstructive pulmonary disease and sepsis. In another embodiment the diseases are rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, diabetes, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet’s disease, tuberculosis, Crohn’s disease, colitis, Pagett’s disease, pancreatitis, periodonitis, inflammatory lung disease, and lupus nephritis. Detailed Description Definitions: Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning: “Alkyl” means a linear saturated monovalent hydrocarbon radical of one to eight carbon atoms or a branched saturated monovalent hydrocarbon radical of three to eight carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. In some instances, the number of carbon atoms may be specified. “Alkenyl” means a C2 to C10 radical of carbon and hydrogen having at least one double bond. Unless otherwise specified, alkenyl groups may be linear (i.e. unbranched) or branched, be cyclic, acyclic or part cyclic / acyclic. “Alkynyl” means “alkynyl” means a C2 to C10 radical which includes at least one carbon to carbon triple bond. Unless otherwise specified, alkynyl groups may be linear (i.e. unbranched) or branched, be cyclic, acyclic or part cyclic / acyclic. “Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like. “Patient” means a mammal, preferably a human. The present disclosure also includes protected derivatives of compounds of the present disclosure. For example, when compounds of the present disclosure contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art. The present disclosure also includes polymorphic forms and deuterated forms of the compound of the present disclosure or a pharmaceutically acceptable salt thereof. A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, A-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety. The compounds of the present disclosure have asymmetric centers. Unless otherwise indicated, the stereochemistry for a given compound is as denoted. It will be understood by a person of ordinary skill in the art that when a compound is denoted as an (R) or (S) stereoisomer at a given position, it may contain the corresponding (S) or (R) stereoisomer as an impurity; preferably the undesired enantiomer is present in less than about 10%, preferably less than about 5% w / w. About means + or - 10% of initial value. All chiral, diastereomeric, all mixtures of chiral or diasteromeric forms, and racemic forms are within the scope of this disclosure unless the specific stereochemistry or isomeric form is specifically indicated. Certain compounds of the present disclosure can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Similarly, when the cyclic groups such as aryl, heteroaryl, heterocyclyl are substituted, they include all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of the present disclosure are within the scope of this disclosure. A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier / excipienf ’ as used in the specification and claims includes both one and more than one such excipient. “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. A “therapeutically effective amount” means the amount of a compound of the present disclosure and / or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. When a range is recited herein, it is to be understood that the stated range is meant to additionally encompass any sub-range within the stated range, or any individual number falling within the range, even if not explicitly enumerated herein. Embodiments: Embodiment 1: In embodiment 1, the compounds are of Formula (I), Formula (II), Formula (III), or Formula (IV) as defined in the Summary above. Embodiment 2: In embodiment 2, the compounds of Formula (I) are of Formula (IA): (IA) or a pharmaceutically acceptable salt thereof, wherein R1, L, and R2 are as defined in the Summary above. 5 Embodiment 3: In embodiment 3, the compounds of Formula (I) are of Formula (IB): (IB) or a pharmaceutically acceptable salt thereof, wherein L and R2 are as defined in the 10 Summary above. Embodiment 4: In embodiment 4, the compounds of any of embodiments 1, 2 and 3 are those where L is a bond and R2 is H. Embodiment 5: 15          In embodiment 5, the compounds of Formula (II) are of Formula (IIA): (IIA) or a pharmaceutically acceptable salt thereof, wherein Y and R3 are as defined in the Summary above. 5 Embodiment 6: In embodiment 6, the compounds of any one of embodiments 1 and 5 are those wherein R3 is -CH2F, -CHF2, or -CF3. Embodiment 7: In embodiment 7, the compounds of any one of embodiments 1, 5, and 6 are those 10 wherein R3 is -CHF2. Embodiment 8: In embodiment 8, the compounds of Formula (III) are of Formula (IIIA): (IIIA) 15          or a pharmaceutically acceptable salt thereof, wherein Y and R4 are as defined in the Summary above. Embodiment 9: In embodiment 9, the compounds of any one of embodiments 1 and 8 are those wherein R4 is -CHF2. Embodiment 10: In embodiment 10, the compounds of Formula (IV) are of Formula (IVA): (IVA) or a pharmaceutically acceptable salt thereof, wherein Y and R5 are as defined in the Summary above. Embodiment 11: In embodiment 11, the compounds of embodiments 1 and 10 are those wherein R5 is C2-C3 alkyl. Embodiment 12: In embodiment 12, the compounds of embodiments 1 and 10 are those wherein R5 is C2-C3 alkenyl. Embodiment 13: In embodiment 13, the compounds of embodiments 1 and 10 are those wherein R5 is C2-C3 alkynyl. Embodiment 14: In embodiment 14, the compounds of embodiments 1 and 10 are those wherein R5 is C3-C4 cycloalkyl. Embodiment 15: In embodiment 15, the compounds of embodiments 1,10, and 11 are those wherein R5 is propyl. Embodiment 16: In embodiment 16, the compounds of embodiments 1,10, and 12 are those wherein R5 is C2-C3 propenyl. Embodiment 17: In embodiment 17, the compounds of embodiments 1,10, and 13 are those wherein 5 R5 is ethynyl. Embodiment 18: In embodiment 18, the compounds of embodiments 1,10, and 14 are those wherein R5 is cyclopropanyl. 10          Representative compounds of Formula (I) are as indicated in Table 1 below: Table 1 Representative compounds of Formula (II) are as indicated in Table 2 below: Table 2 Representative compounds of Formula (III) are as indicated in Table 3 below are: Representative compounds of Formula (IV) are as indicated in Table 4 below are: Table 4 Cpd No. Compound 402 H3c ch3 NT „ n T         ri 0 403 h3c ( w C „ ry ^N\ / 0 404 h3c „ fy ^N\ / \            11 o Cpd No. Compound 407 h3c^ C " 13 \                      ri 0 408 h3c^ C " 13 \                TT 0 409 C - JO 11 o General Synthetic Scheme Compounds of this disclosure can be made by the general methods disclosed in WO / 2020 / 154420, the contents of which are hereby incorporated by reference in their 5 entirety. Administration and Pharmaceutical Composition In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar 10 utilities. Therapeutically effective amounts of compounds of this disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg / kg per day; or about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors. In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. The compositions are comprised of, in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. Compressed gases may be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000). The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %. The compounds of this disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of this disclosure or the other drugs may have utility. Such other drug(s) may be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is preferred. However, the combination therapy may also include therapies in which the compound of this disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. Examples The following preparations of compounds of Formulas (I), (II), (III), and (IV) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof. Synthesis of additional compounds within the scope of the disclosure, as well as starting materials and intermediates therefor, will be within the purview of one of skill in the art in view of the syntheses exemplified herein. Synthetic Examples Example 1 Synthesis of (R)-l,2,3f-tetrahydro-2,3'-bipyridine di.»% yiera anatabine freebase                                             R-anatabine freebase To a solution of compound anatibine freebase (500 g, 3.12 mol, 1.00 eq) in i-PrOH (2.50 L) was added compound a (312 g, 1.56 mol, 0.50 eq) at 25°C. The reaction mixture was stirred at 25 °C for 12 hrs. The mixture was filtered, and the filter cake was triturated in IPA (3L) at 60°C for Ihrs. The precipitate was filtered and the filter cake was diluted with H2O (2.00 L), adjust pH to 10~ 11 with NaOH (1 N), extracted with DCM (1.00 L><3), dried over Na2SO4, filtered and concentrated to give R-anatabine freebase (160 g, 993 mmol, 31.8% yield, 99.5% purity, 96.9%ee) as yellow oil. LCMS: EC28826-2-P1C2, Rt = 0.992 min, m / z +1 = 161.1 Example 2 Synthesis of tert-butyl ((S)-2-((R)-3,6-dihydro-[2,3'-bipyridin]-l(2H)-yl)-2-oxo-l-phenyle thy I) carbamate 1001 1002 To a solution of Cpd_1001 (200 g, 796 mmol, 1.00 eq) and R-anatibine freebase (153 g, 955 mmol, 1.20 eq) in DCM (2.00L) was added DIEA (205 g, 1.59 mol, 277 mL, 2.00 eq) and T4P (860 g, 1.19 mol, 50% purity, 1.50 eq) at 0°C. The reaction mixture was stirred at 25°C for 2 hrs. The reaction mixture was washed with water (2.00 L), and dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate =20:1-1:1) to give Cpd_1002 (280 g, 694 mmol, 87.2% yield, 97.5% purity) as yellow oil. LCMS: EC28826-3-P1A1, Rt = 0.335 min, m / z +1 = 394.1 Example 3 Synthesis of (S)-2-amino-l-((R)-3,6-dihydro-[2,3'-bipyridin]-l(2H)-yl)-2-phenylethan-l-one 1002                                          1003 HC1 (10.0 eq) gas was bubbled into a solution of Cpd_1002 (280 g, 711 mmol, 1.00 eq) in DCM (200 mL) and EtOAc (2.00 L) at 0 - 10 °C. After completion, the resulting mixture was stirred for 2 hrs at 25 °C. The reaction mixture was filtered and washed with MTBE (500 mL), the filter cake was dried in vacuo to give the desired product Cpd_1003 (180 g, 540 mmol, 75.9% yield, 99% purity, HC1 salt) as white solid and used to the next step directly. LCMS: EC28826-5-P1A1, Rt = 0.123 min, m / z +1 = 294.0 Example 4 Synthesis of 3-butyramidobenzoic acid 0-25°C, 3 hrs 1004                  66.2% yield                       1005 To a solution of Cpd_1004 (200 g, 1.46 mol, 1.00 eq) in DCM (2.00 L) was added TEA (295 g, 2.92 mol, 406 mL, 2.00 eq) at 25 °C, the mixture was cooled to 0 °C and Cpd_1006 (200 g, 1.88 mol, 196 mL, 1.29 eq) was added dropwise to the reaction mixture at 0 °C. After addition, the mixture was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated to give a residue, the residue was triturated with IN HC1 aqueous for 1 h, filtered and washed with IL water, the filter cake was triturated with EtOAc (1.00 L) at 25 °C for 1 hr, filtered and washed with MTBE (500 mL), the filter cake was dried in vacuo to give compound 1005 (200 g, 965 mmol, 66.2% yield, 100% purity) was obtained as white solid. LCMS: EC28826-4-P1A1, Rt = 0.280 min, m / z +1 = 207.9 Example 5 Synthesis of 3-butyramido-N-((S)-2-((R)-3,6-dihydro-[2,3'-bipyridin]-l(2H)-yl)-2-oxo-l- 1003 phenylethylfbenzamide (Compound 101) Compound 101 To a solution of Cpd_1003 (179 g, 543 mmol, 1.00 eq, HC1 salt) and Cpd_1005 (135 g, 651 mmol, 1.20 eq) in DCM (2.00 L) was added DIEA (210 g, 1.63 mol, 283 mL, 3.00 eq) and T4P (586 g, 814 mmol, 50.0% purity, 1.50 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture was washed with water (1.00 L), the aqueous was extracted with DCM (1.00 L), combined the organic phase and dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (neutral condition) and further purified by SFC (column: Chiral-IK-50-DAICEL CHIRALPAK IK (250mm*50mm,10um); mobile phase: [CO2-IPA: CAN = 7:3 (0.1% NH3H2O)]; B%:40%, isocratic elution mode) to give desired product Compound 101 (106 g, 215 mmol, 39.7% yield, 98.2% purity) was obtained as yellow solid. LCMS: EC28826-6-P1A2, Rt = 1.284 min, m / z +1 = 483.1 LCMS: EC28826-6-P1D1, Rt = 1.312 min, m / z +1 = 483.1 HPLC: EC28826-6-P1D3, purity: 98.2% SFC: EC28826-6-P1D1 and EC28826-6-P1D3, %ee = 99.5%ee HNMR: EC28826-6-P1D2, 400 MHz, CDCW 3 8.70 - 8.29 (m, 2H), 8.06 - 7.90 (m, 1H), 7.87 - 7.54 (m, 4H), 7.54 - 7.44 (m, 3H), 7.41 -7.30 (m, 3H), 7.27 (s, 2H), 6.97 - 6.76 (m, 1H), 6.22 - 6.08 (m, 1H), 6.00 (d, J = 7.4 Hz, 1H), 5.88 (dt, J = 2.8, 5.0 Hz, 1H), 5.70 - 5.36 (m, 1H), 4.86 - 3.94 (m, 1H), 3.70 - 3.12 (m, 1H), 3.00 - 2.54 (m, 2H), 2.33 (br t, J = 7.4 Hz, 2H), 1.74 (sxt, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H) Example 6 Synthesis of tert-butyl ((S)-2-((R)-3,6-dihydro-[2,3'-bipyridin]-l(2H)-yl)-2-oxo-l-phenyle thy I) carbamate OH 1007                               1009 To the solution of 1008 in DCM (60 mL)was added PYBROP (19.26 g, 41.31 mmol, 1.2 eq) ,then added DIEA (4.46 g, 34.48 mmol, 6.01 mL, 1 eq) at 0°C,after 30 min , 1007 was added ,the reaction mixture was stirred for at 25°C for 2 hrs. TLC (PE:EA=1:1) showed that reactant(Rf=0.50) was consumed and new spot(Rf=0.40) was detected. LCMS (EC 10163-76-P1R2) showed that reactant was consumed and the desired MS(Rt=0.315,M+l=394) was given. The reaction mixture was partitioned between EA (60mL*2) and water (60 mL). The organic phase was separated, washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by Prep-HPLC (HC1 condition). From LCMS (EC10163-76-P1A1),HPLC (EC10163-76-P1C4), 1009 as obtained as yellow solid. LC-MS: (EC10163-76-PlAl),RT=0.321,M+l=394 HPLC :EC 10163 -76-P1 C4,RT=0.848 Example 7 Synthesis of (S)-2-amino-l-((R)-3,6-dihydro-[2,3'-bipyridin]-l(2H)-yl)-2-phenylethan-l-one 1009                                  1010 To a solution of 1009 in DCM (50 mL) was added HCl / EtOAc(25ml).The reaction mixture was stirred at 20-25°C for 2 hours. LCMS(EC9891-47-Pl Al 1) showed that reactant 1 was consumed and the desired MS (Rt=0.526 min, M + 1 =294 ) was given. The reaction mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC.column: Agela DuraShell C18 150*25mm*5um;mobile phase: [water(NH3H2O)-ACN];B%: 14%-44%,min From LCMS(EC9891-47-PlAll)HNMR(EC9891-47-P1 A), 1010 was obtained as a red oil. LC-MS: EC9891-47-P1 Al 1, Rt = 0.526 min, m / z (M+l) = 294 Example 8 Synthesis of tert-butyl (4-((3-(((S)-2-((R)-3,6-dihydro-[2,3'-bipyridin]-l(2H)-yl)-2-oxo-l-phenylethyl)carbamoyl)phenyl)amino)-4-oxobutyl)carbamate (Compound 102) 1010                                          Compound 102 To a solution of 1011 (560 mg, 1.74 mmol, 1 eq) in DCM (6 mL) was added DIEA (896 mg, 6.93 mmol, 1.21 mL, 3.99 eq) ,then it was cooled 0-5°C,was added HATU (795 mg, 2.09 mmol, 1.2 eq) ,then was added 1010 (510 mg, 1.74 mmol, 1 eq) .The reaction mixture was stirred at 20-25°Cfor 2 hours. LCMS(EC9891-81-P1A1) showed that reactant 1 was consumed and the desired MS (Rt=0.658 min, M + 1 = 598) was given. The reaction mixture was diluted with DCM (5ml) and H2O(5ml). The organic layer was washed with Saturated NaCl aqueous solution (5 mL), dried over Na2SO4.The organic layer was concentrated under vacuum. The crude product was purified by Prep-HPLC (TFA condition) column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:40%, isocratic elution mode From LCMS (EC9891-81-P1A1), HPLC (EC9891-81-P1HPLC), HNMR (EC9891-81-P1A1), SFC (EC9891-81-P1A1) column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:40%. Compound 102 (520 mg, 870.00 pmol, 50.13% yield) was obtained as a yellow solid. LC-MS: EC9891-50-P1A5, Rt = 0.658 min, m / z (M+l) =598 LC-MS: EC9891-81-P1A1, Rt = 0.658 min, m / z (M+l) = 598 ’H-NMR: EC9891-81-P1A1, 400 MHz, DMSO 3 1.10- 1.26 (m, 1 H), 1.37 (s, 9 H), 1.65 - 1.71 (m, 2 H), 2.30 (brt, 1=7.44 Hz, 2 H), 2.67 (br s, 1 H), 2.93 - 2.97 (m, 2 H), 3.67 - 3.77 (m, 1 H), 4.00 - 4.12 (m, 1 H), 5.44 - 5.65 (m, 1 H), 5.72 - 5.88 (m, 2 H), 5.99 (brt, 1=6.57 Hz, 1 H), 6.77 - 6.90 (m, 1 H), 7.04 - 7.12 (m, 1 H), 7.21 - 7.29 (m, 1 H), 7.33 - 7.43 (m, 4 H), 7.48 - 7.58 (m, 3 H), 7.72 - 7.84 (m, 2 H), 8.00 (s, 1 H), 8.44 - 8.58 (m, 1 H), 8.88 (br d, 1=6.50 Hz, 1 H), 10.02 (s, 1 H) Example 9 Synthesis of 3-(4-butyramidobutanamido)-N-((S)-2-((R)-3,6-dihydro-[2,3'-bipyridin]-l(2H)-yl)-2-oxo-l-phenylethyl)benzamide (Compound 103) 1010 Compound 103 Reagent M.W. Eq P(g / ml) mmol Amount 1010 293.38 1 - 2.653 0.7785g 2 292.34 1 - 2.653 0.7758g EDC HCL 191.71 1.75 - 4.64 0.89g DIPEA 129.25 2 0.742 5.31 0.92ml CH2CL2 - - - - 25ml Reagents were reacted overnight to prepare Compound 103. In the morning, the reaction mixture was washed with H2O, NaHCOs, and pH 6 buffer and then dried over an anhydrous MgSO4 filter. 5 scoops of silica were added and the mixture rotovaped. The product was dry loaded on a 4g silica column and eluted to 100%. After evaporation of all the fractions, the crude purified material was vigorously stirred and dissolved in ethyl acetate (25ml) in ~50ml saturated NaHCOs for several hours. The final product was isolated and dried. Result: White crystalline solid; Mass - 782mg; Yield - 52%; Confirmed via mass spec. Example 10 Synthesis of tert-butyl (4-oxo-4-((3-(((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin-3-yl)piperidin-l- yl)ethyl)carbamoyl)phenyl)amino)butyl)carbamate (Compound 104) Compound 102                                    Compound 104 To a solution of Compound 102 (458 mg, 766.27 pmol, 1 eq) in MeOH (20 mL) ,then was added Pd / C (66.18 mg, 62.19 pmol, 10% purity, 8.12e-2 eq) under Ar.The reaction mixture was stirred at 20°C for 12h. LCMS (EC9891-99 -Pl ACF) showed that reactant 1 was consumed and the desired MS (Rt=0.411 min ) was given. The reaction mixture was concentrated under vacuum. The crude product was separated by SFC column:REGIS(S,S)WHELK01(250mm*25mm,10um);mobilephase:[C02ACN / EtOH(0.1% NH3H2O)];B%:50%, isocratic elution mode. From LCMS (EC9891-99-P1ACF), HPLC (EC9891-99-P1HB2), HNMR (EC9891-99-P1HB HNMR), SFC (EC9891-99-P1A1), Compound 104 (650 mg, 726.17 pmol, 94.77% yield, 67% purity) was obtained as a white solid. LC-MS: EC9891-99-P1 ACF, Rt = 0.411 min, m / z (M+l) = 600 HPLC: EC9891-99-P1ACF2, Rt= 1.661 min ’H-NMR: EC9891-99-P1BU, 400 MHz, DMSO d 1.23 - 1.30 (m, 2 H), 1.37 (s, 9 H), 1.65 - 1.71 (m, 2 H), 2.29 (br t, J= 7.44 Hz, 2 H), 2.81 -2.90 (m, 1 H), 2.95 (q, J= 6.55 Hz, 2 H), 3.85 (br dd, J=14.26, 2.13 Hz, 1 H), 4.34 (t, J= 5.07 Hz, 2 H), 5.86 (br s, 1 H), 6.12 (d, J= 6.88 Hz, 1 H), 6.79 - 6.85 (m, 1 H), 7.06 - 7.22 (m, 1 H), 7.32 - 7.47 (m, 6 H), 7.49 - 7.60 (m, 3 H), 7.71 (br d, J= 7.63 Hz, 1 H), 7.81 (br d, J= 7.75 Hz, 1 H), 8.01 (s, 1 H), 8.43 - 8.58 (m, 2 H), 8.78 (br d, J= 5.88 Hz, 1 H), 10.02 (s, 1H) Example 11 Synthesis of tert-butyl ((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin-3 -yl)piperidin-1-yl)ethyl)carbamate 1012                                        1014 To a solution of compound 1012 (5.00 g, 19.9 mmol, 1.00 eq) in DCM (50.0 mL) was added DIEA (2.60 g, 20.0 mmol, 3.5 mL, 1.00 eq) and PYBROP (11.2 g, 24.0 mmol, 1.20 eq) and compound 1013 (3.23 g, 19.9 mmol, 1.00 eq) at 0 °C stirred for 30 min, then the reaction mixture was stirred at 25 °C for 1.5 hrs. LC-MS (EC7755-2-P1A1) showed the compound 1012 was consumed and the desired mass (RT = 0.354 min, m / z (M+l) = 396.5) was detected. The reaction mixture was partitioned between DCM (100 mL) and water (50.0 mL). The organic phase was separated, washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% HCI condition). From HNMR (EC7755-2-P1A) and LCMS (EC7755-2-P1B2) showed the product compound 1014 (6.20 g, 12.1 mmol, 60.9% yield, 77.3% purity) was obtained as light yellow solid. LC-MS: EC7755-2-P1A1, RT = 0.354 min, m / z (M+l) = 396.5 LC-MS: EC7755-2-P1B2, RT = 0.360 min, m / z (M+l) = 396.4 ’H-NMR: EC7755-2-P1A, 400 MHz, DMSO 5 9.09 - 8.66 (m, 2H), 8.59 - 8.36 (m, 1H), 8.22 - 7.99 (m, 1H), 7.48 - 7.30 (m, 5H), 5.91 -5.62 (m, 3H), 3.98 - 3.55 (m, 1H), 3.41 - 3.10 (m, 1H), 2.95 - 2.82 (m, 1H), 2.43 - 2.27 (m, 1H), 2.03 - 1.84 (m, 1H), 1.77 - 1.73 (m, 22H), 1.64-1.51 (m, 2H), 1.38 (s, 9H), 1.31-1.16 (m, 2H) Example 12 Synthesis of (S)-2-amino-2-phenyl-1-((R)-2-(pyridin-3-yl)piperidin-l-yl)ethan-l-one 1014                                 1015 To a solution of compound 1014 (6.20 g, 15.6 mmol, 1.00 eq) in EtOAc (60.0 mL) was added HCl / EtOAc (4 M, 39.2 mL, 10.0 eq) then the reaction mixture was stirred at 25 °C for 2 hrs. LC-MS (EC7755-4-P1 Al) showed compound 1014 was consumed completely and the desired mass (Rt = 0.198 min, m / z (M+l) = 296.4) was detected. The reaction mixture was concentrated. The residue was used to next step without purification. From HNMR (EC7755-4-P1 A) showed the product compound 1015 (6.00 g, crude, HC1) was obtained as yellow solid. LC-MS: EC7755-4-P1A1, Rt = 0.198 min, m / z (M+l) = 296.4 ’H-NMR: EC7755-4-P1A, 400 MHz, DMSO 5 9.46 - 8.50 (m, 4H), 8.19 - 7.10 (m, 5H), 6.06 - 5.22 (m, 5H), 4.69 - 4.25 (m, 1H), 4.04 -3.54 (m, 1H), 2.97 - 2.78 (m, 1H), 2.68 - 2.55 (m, 1H), 2.43 - 2.30 (m, 1H), 1.67 - 1.53 (m, 1H), 1.45 - 1.17 (m, 2H) Example 13 Synthesis of 3-nitro-N-((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin-3-yl)piperidin-l-yl)ethyl)benzamide 0~20 °C, 2 hrs 29.0% yield 1015                                                1017 To a solution of compound 1016 (3.40 g, 20.3 mmol, 1.02 eq) in DCM (40 mL) was added DIEA (5.19 g, 40.2 mmol, 7.00 mL, 2.01 eq) and HATU (9.10 g, 23.9 mmol, 1.20 eq) at 0 °C stirred for 30 min, then the compound 1015 (5.90 g, 19.9 mmol, 1.00 eq) was added to the solution, then the reaction mixture was stirred at 20 °C for 2 hrs. LCMS (EC7755-6-P1 Al) showed the compound 1015 was consumed and the desired mass (Rt = 0.350 min, m / z (M+l) = 445.4) was detected. The reaction mixture was diluted with EtOAC (150 mL). The organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um;mobile phase: [water(HCl)-ACN];B%: 20%-50%,20min). From HNMR (EC7755-6-P1A) and LCMS (EC7755-6-P1C1) showed the product compound 1017 (3.00 g, 5.79 mmol, 29.0% yield, 85.8% purity) was obtained as white solid. LC-MS: EC7755-6-P1A1, Rt = 0.350 min, m / z (M+l) = 445.4 LC-MS: EC7755-6-P1C1, Rt = 0.351 min, m / z (M+l) = 445.5 ’H-NMR: EC7755-6-P1A, 400 MHz, DMSO 5 9.46 (brd, 7= 6.0 Hz, 1H), 8.85 - 8.75 (m, 2H), 8.51 - 8.31 (m, 3H), 8.11 - 8.00 (m, 1H), 7.78 (t, 7= 8.0 Hz, 1H), 7.61 - 7.11 (m, 4H), 7.24 -7.05 (m, 1H), 6.16 (br d, 7= 6.0 Hz, 1H), 5.94 (br s, 1H), 4.58 - 4.35 (m, 1H), 3.90 (br d, 7= 13.0 Hz, 2H), 3.07 - 2.87 (m, 1H), 2.47 -2.34 (m, 1H), 1.87- 1.69 (m, 1H), 1.46 (br d, 7= 10.6 Hz, 1H), 1.38-1.15 (m, 2H), 0.870.57 (m, 1H) Example 14 Synthesis of 3-amino-N-((S)-2-oxo-1 -phenyl-2-((R)-2-(pyridin-3-yl)piperidin-l-yl)ethyl)benzamide 1017                                              1018 To a solution of compound 1017 (3.00 g, 4.50 mmol, 1.00 eq) in MeOH (10.0 mL) and THF (15.0 mL) was added Pt / C (950 mg, 452 umol, 10% purity, 0.10 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (25 Psi) at 25 °C for 2 hrs. LCMS (EC7755-8-P1 Al) showed the compound 1017 was consumed and the desired mass (Rt = 0.269 min, m / z (M+l) = 415.4) was detected. The reaction mixture was filtered and the filtrate was concentrated. The residue was used to next step without purification. From HNMR (EC7755-8-P1A) and LCMS (EC7755-8-P1B1) showed the product compound 1018 (1.70 g, 3.78 mmol, 84.0% yield, 92.2% purity) was obtained as white solid. LC-MS: EC7755-8-P1A1, Rt = 0.269 min, m / z (M+l) = 415.4 LC-MS: EC7755-8-P1B1, Rt = 0.277 min, m / z (M+l) = 415.4 ’H-NMR: EC7755-8-P1A, 400 MHz, DMSO 5 8.86 - 8.66 (m, 2H), 8.18 (br d, J= 7.6 Hz, 1H), 7.88 - 7.70 (m, 1H), 7.58 - 7.48 (m, 2H), 7.47 - 7.36 (m, 5H), 7.30 (br t, J= 8.0 Hz, 1H), 7.08 (br d, J= 7.2 Hz, 1H), 6.28 - 6.07 (m, 1H), 5.96 - 5.82 (m, 1H), 4.52 - 4.38 (m, 1H), 3.86 (br d, J= 12.4 Hz, 1H), 3.11 - 3.03 (m, 1H), 2.99 - 2.87 (m, 1H), 2.43 - 2.28 (m, 1H), 1.91 - 1.68 (m, 1H), 1.66 - 1.41 (m, 2H), 1.33 -1.14 (m, 2H) Example 15 Synthesis of ethyl 8,8-dimethylnonanoate 20-70 °C, 4 hrs 1019                                 1020 To a solution of compound 1019 (1.00 g, 4.22 mmol, 819 uL, 1.00 eq) and CuCh (11 mg, 81.8 umol, 1.94e-2 eq) and prop-l-ynylbenzene (50.0 mg, 430 umol, 1.02e-l eq) in THF (1 mL) was added and bromo(tert-butyl)magnesium (1 M, 6.5 mL, 1.54 eq) slowly at 20 °C, then the reaction mixture was stirred at 70 °C for 4 hrs. TLC (Petroleum ether : Ethyl acetate = 3:1) indicated compound 1019 (Rf = 0.43) was consumed completely and two new spots (Rf = 0.43, Rf = 0.13) was formed. The reaction mixture was poured into saturated NH4Q aqueous solution (50.0 mL) and extracted with EA (25.0 mL*3). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated. The residue was used to next step without purification. From HNMR (EC7755-22-P1 A) showed the product compound 1020 (1.00 g, crude) was obtained as colorless oil. ’H-NMR: EC7755-22-P1A, 400 MHz, DMSO 5 3.51 (s, 2H), 2.28 - 2.25 (m, 4H), 1.79 (br d, J= 7.2 Hz, 3H), 1.54 - 1.50 (m, 4H), 1.37 (br d, J= 7.2 Hz, 3H), 1.29 (br d, J= 7.2 Hz, 3H), 1.19 - 1.16 (m, 8H), 1.00 - 0.72 (m, 9H) Example 16 Synthesis of 8,8-dimethylnonanoic acid 8,8-dimethylnonanoic acid 1020                                1021 To a solution of compound 1020 (1.00 g, 4.67 mmol, 1.00 eq) in THF (10.0 mL), MeOH (10.0 mL) and H2O (10.0 mL) was added LiOH.H2O (400 mg, 9.53 mmol, 2.04 eq), then the reaction mixture was stirred at 25 °C for 2 hrs. TLC (Dichloromethane : Methanol = 5:1) indicated compound 1020 (Rf = 0.24) was consumed completely and two new spots (Rf=0.38, 0.06) was formed. The reaction mixture was partitioned between ethyl acetate (50.0 mL) and water (25.0 mL). The organic phase was discarded, and the water phase as adjusted to pH = 3 with IM HC1 and diluted with ethyl acetate (50.0 mL), washed with brine (25.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. From HNMR (EC7755-24-P1 A) showed the product compound 1021 (300 mg, crude) was obtained as colorless oil. ’H-NMR: EC7755-24-P1A, 400 MHz, DMSO 5 11.97 (br s, 1H), 2.21 - 2.16 (m, 6H), 1.83 - 1.74 (m, 2H), 1.50- 1.47 (m, 5H), 1.27 (br d, J = 3.6 Hz, 5H), 0.84 (s, 9H) Example 17 Synthesis of 3-(8,8-dimethylnonanamido)-N-((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin-3-yl)piperidin-l-yl)ethyl)benzamide (Compound 105) 1.00 eq 1021              F J 1.20eqHATU                 h 3.00 eq DIEA DCM(10V)                JL 0~25°C, 2 hrs                  f| J 15.9% yield Compound 105 To a solution of compound 1021 (100.00 mg, 536 umol, 1.11 e^)inDCM(l mL) was added DIEA (192 mg, 1.49 mmol, 260 uL, 3.09 eq) and HATU (220 mg, 578 umol, 1.20 eq) at 0 °C stirred for 30 min, compound 1022 (200 mg, 482 umol, 1.00 eq) was added to the solution, then the reaction mixture was stirred at 25 °C for 1.5 hrs. LCMS (EC7755-26-P1 Al) showed the compound 1022 was consumed and the desired mass (Rt = 0.487 min, m / z (M+l) = 583.6) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex C18 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 54%-84%,8min). From HNMR (EC7755-38-P1C), LCMS (EC775-38-P1C1) and HPLC (EC7755-38-P1C2) showed the product Compound 105 (16.88 mg, 28.96 umol, 15.9% yield, 100% purity) was obtained as white solid. LCMS: EC7755-26-P1A1, Rt = 0.487 min, m / z (M+l) = 583.6 LCMS: EC775-38-P1C1, Rt = 0.480 min, m / z (M+l) = 583.6 HPLC: EC7755-38-P1C2, Rt = 2.578 min, 100% purity ’H-NMR: EC7755-38-P1C, 400 MHz, CHLOROFORM-d 5 8.69 - 8.20 (m, 2H), 7.88 - 7.82 (m, 1H), 8.02 - 7.82 (m, 1H), 7.80 - 7.62 (m, 2H), 7.57 -7.48 (m, 3H), 7.47 - 7.29 (m, 5H), 7.22 - 6.93 (m, 1H), 6.18 - 5.84 (m, 2H), 4.89 - 4.58 (m, 1H), 3.93 - 3.71 (m, 1H), 3.04 - 2.50 (m, 1H), 2.46 - 2.24 (m, 3H), 1.77 - 1.66 (m, 3H), 1.61 -1.34 (m, 4H), 1.32 - 1.04 (m, 7H), 0.86 (s, 9H) Example 18 Synthesis of ethyl 4-(3-(tert-butyl)ureido)butanoate OCN 1.00 eq 3.00 eq TEA THE (10 V) 25 °C, 12 hrs 1024 1023 To a solution of compound 1023 (420 mg, 4.24 mmol, 500 uL, N / A purity, 1.42 eq) in THF (5.00 mL) was added TEA (900 mg, 8.89 mmol, 1.24 mL, 2.98 eq) and ethyl 4-aminobutanoate (500 mg, 2.98 mmol, N / A purity, 1.00. eq, HC1). The mixture was stirred at 25 °C for 12 hrs. LCMS (EC7606-21-P1A2) showes that compound 1023 was consumed, and the desired MS (m / z = 231.1, Rt = 0.388 min) was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 250*50mm*10 um;mobile phase: [water(HCl)-ACN];B%: 20%-50%,20min). Compound 1024 (400 mg, 1.74 mmol, 58.2% yield) was obtained as yellow oil LC-MS: EC7606-21-P1A2, RT = 0.388 min, m / z (M+l) = 231.1 Example 19 Synthesis of 4-(3-(tert-butyl)ureido)butanoic acid 1024                                          1025 To a solution of compound 1024 (400 mg, 1.95 mmol, N / A purity, 1.00 eq) in H2O (1.5 mL), MeOH (1.5 mL) THF (1.5 mL) was added LiOH.H2O (165 mg, 3.93 mmol, 2.01 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS (EC7606-25-P1 Al) showes that compound 1024 was consumed, and the desired MS (m / z = 203.3, Rt = 0.216 min) was detected. The mixture was poured into the water (50.0 mL), adjusted to pH = 2-3 with IM HC1, extracted with EtOAc (10.0 mL * 3). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. Compound 1025 (300 mg, 1.48 mmol, 75.9% yield) was obtained as white oil. LC-MS: EC7606-25-P1A1, RT = 0.216 min, m / z (M+l) = 203.3 Example 20 Synthesis of 3f4f3ftertdiutyl)ureidofbutananndo)-N-((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin- 3-yl)piperidin-l-yl)ethyl)benzamide (Compound 106) 1022                                            Compound 106 To a solution of compound 1025 (50 mg, 247 umol, 1.02 eq) in DCM (1 mL) was added HATU (110 mg, 289 umol, 1.20 eq) and DIEA (66.78 mg, 516 umol, 90 uL, 2.14 eq) and compound 1022 (100 mg, 241 umol, 1.00 eq) stirred at 0 °C for 30 min, then the reaction mixture was stirred at 25 °C for 1.5 hrs. LCMS (EC7755-13-P1A1) showed the compound 1022 was consumed and the desired mass (Rt = 0.364 min, m / z (M+l) = 599.6) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (HCl)-ACN]; B%: 20%-50%, 10 min). From HNMR (EC7755-13-P1B), LCMS (EC7755-13-P1C1) and HPLC (EC7755-13-P1C2) showed the product Compound 106 (33.58 mg, 54.1 umol, 22.4% yield, 96.5% purity) was obtained as off-white solid. LCMS: EC7755-13-P1A1, Rt = 0.364 min, m / z (M+l) = 599.6 LCMS: EC7755-13-P1C1, Rt = 0.374 min, m / z (M+l) = 599.6 HPLC: EC7755-13-P1C2, Rt = 1.706 min, 96.5% purity ’H-NMR: EC7755-13-P1B, 400 MHz, DMSO 5 10.08 (s, 1H), 8.78 (br d, J= 6.4 Hz, 1H), 8.58 - 8.38 (m, 1H), 8.09 - 7.95 (m, 1H), 7.81 (br d, J= 8.8 Hz, 1H), 7.78 - 7.65 (m, 1H), 7.58 - 7.33 (m, 7H), 7.28 - 7.05 (m, 1H), 6.12 (d, J= 7.2 Hz, 1H), 5.93 - 5.76 (m, 1H), 5.72 - 5.52 (m, 2H), 4.06 - 3.74 (m, 1H), 3.07 - 2.93 (m, 2H), 2.90 (br s, 1H), 2.40 - 2.26 (m, 3H), 1.71 - 1.56 (m, 3H), 1.48 - 1.26 (m, 2H), 1.20 (s, 9H), 0.68 - 0.43 (m, 1H) Example 21 Synthesis of 6-isopropoxyhexanoic acid o Br 1026 3.00 eq KOH, i-PrOH (10 V) 0~85 °C, 18.5 hrs 49.9% yisid 1027 To a solution of KOH (432 mg, 7.70 mmol, 3.00 eq) in i-PrOH (3.93 g, 65.3 mmol, 5.00 mL, 25.5 eq) stirred at 0 °C for 30 min. Then the solution of compound 1026 (500 mg, 2.56 mmol, 1.00 eq) in i-PrOH (5.00 mL) was added and the resulting solution was stirred at 85 °C for 18 hrs. TLC (Petroleum ether : Ethyl acetate = 3:1) indicated compound 1026 (Rf = 0.24) was consumed completely and two new spots (Rf = 0.43, Rf = 0.10) formed. The reaction mixture was concentrated to remove i-PrOH, then the residue was partitioned between ethyl acetate (100 mL) and water (50.0 mL). The organic phase was separated, washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to the next step without purification. From HNMR (EC7755-20-P1A) showed the product compound 1027 (223 mg, 1.28 mmol, 49.9% yield) was obtained as colorless oil. ’H-NMR: EC7755-20-P1A, 400 MHz, DMSO 5 11.99 (br s, 1H), 5.88 - 5.66 (m, 1H), 5.08-4.91 (m, 1H), 3.52-3.44 (m, 1H), 3.32-3.29 (m, 2H), 2.25 - 2.14 (m, 3H), 2.06 - 1.96 (m, 1H), 1.62 - 1.39 (m, 6H), 1.33 - 1.22 (m, 4H), 1.05 (d, J =6.0 Hz, 6H) Example 22 Synthesis of 3-(6-isopropoxyhexanamido)-N-((S)-2-oxo-1-phenyl-2-((R)-2-(pyridin-3- yl)piperidin-l-yl)ethyl)benzamide (Compound 107) 1022 1.00 eq 1027 1.20 eq HATU 3.00 eq DIEA DCM (10 V) 0~25 °C, 2 hrs 35.7'% yie’d Compound 107 To a solution of compound 1027 (42 mg, 241.05 umol, 9.99e-l eq) in DCM (1 mL) was added DIEA (96.4 mg, 746 umol, 130 uL, 2.09 eq) and HATU (110 mg, 289 umol, 1.20e^) at 0 °C stirred for 30 min, then compound 1022 (100 mg, 241 umol, 1.00 eq) was added to the solution, the reaction mixture was stirred at 25 °C for 1.5 hrs. LCMS (EC7755- 21-P1 Al) showed the compound 1022 was consumed and the desired mass (Rt = 0.399 min, m / z (M+l) = 571.8) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(HCl)-ACN];B%: 17%-47%,10min). From HNMR (EC7755-21-P1A), LCMS (EC7755-21-P1B1) and HPLC (EC7755-21-P1B2) showed the product Compound 107 (51.44 mg, 86.0 umol, 35.7% yield, 95.5% purity) was obtained as colorless oil. LCMS: EC7755-21-P1A1, Rt = 0.399 min, m / z (M+l) = 571.8 LCMS: EC7755-21-P1B1, Rt = 0.402 min, m / z (M+l) = 571.4 HPLC: EC7755-21-P1B2, Rt = 1.940 min, 96.5% purity ’H-NMR: EC7755-21-P1A, 400 MHz, DMSO 5 10.27 - 9.96 (m, 1H), 9.12 - 8.72 (m, 3H), 8.64 - 8.38 (m, 1H), 8.16 - 7.99 (m, 2H), 7.94 -7.65 (m, 2H), 7.61 - 7.48 (m, 3H), 7.48 - 7.29 (m, 4H), 6.26 - 6.08 (m, 1H), 5.97 - 5.79 (m, 1H), 4.58 - 4.40 (m, 1H), 3.89 (br d, J= 14.0 Hz, 2H), 3.49 (br d, J= 6.0 Hz, 1H), 3.32 (t, J= 6.4 Hz, 3H), 3.02 - 2.90 (m, 1H), 2.43 - 2.29 (m, 3H), 1.65 - 1.53 (m, 3H), 1.52 - 1.42 (m, 3H), 1.37 - 1.21 (m, 4H), 1.05 (d, J= 6.0 Hz, 6H) Example 23 Synthesis of 5-(neopentyloxy)pentanenitrile 1028 crude used directly                1030 NaH (300 mg, 7.50 mmol, 60.0% purity, 1.22 eq) was suspended in DMF (20.0 mL) at 0°C under compound 1029 (816 mg, 9.26 mmol, 998 uL, 1.50 eq) was added over approx. 2 minutes. After stirring for a further 15 minutes, compound 1028 (1.00 g, 6.17 mmol, 1.00 eq) was introduced dropwise. Following complete addition, the resulting mixture was warmed to 20 °C and stirred at 20 °C for 8 hrs under N2. TLC (Petroleum ether / Ethyl acetate = 3 / 1) showed the compound 1028 (Rf = 0.70) was consumed completely and one major new spot (Rf = 0.15) was detected. The reaction mixture was quenched with saturated NH4Q (50.0 mL). When suspended solids had dissolved, the solution was extracted with ethyl acetate (3 x 60.0 mL). The organic phases were dried (Na2SO4), filtered and concentrated under vacuum to get a residue. Compound 1030 (250 mg, crude) was obtained as a light yellow oil and confirmed by HNMR (EC9573-6-P1H). ’H-NMR: EC9753-6-P1H, 400 MHz, DMSO 5 = 3.39 (t, J= 5.6 Hz, 2H), 3.02 (s, 2H), 2.61 (s, 1H), 2.57 (s, 1H), 2.33 - 2.30 (m, 2H), 1.63 - 1.60 (m, 2H), 0.93 - 0.84 (m, 9H). Example 24 Synthesis of 5-(neopentyloxy)pentanoic acid 1030 O KOH EtOH / H2O=1 / 1 90 °C, 10 hrs 1031 Compound 1030 (280 mg, 1.65 mmol, 1.00 eq) in to EtOH (1.00 mL) and H2O (1.00 mL) was added KOH (371 mg, 6.62 mmol, 4.00 eq). The mixture was stirred at 85 °C for 3 hrs under N2. LCMS (EC9573-9-P1A2) showed that compound 1030 was consumed, and the desired MS (m / z = 187.1, Rt = 0.613 min) was detected. Upon cooling, all the volatile materials were evaporated and the solid was suspended in water (10.0 ml), the water layers were washed with MBTE (15.0 mL x 2), the pH of the solution was adjusted to 2 with HC1 (IM) at 0 °C. The resulting solution was extracted with Ethyl acetate (10.0 mL x 3), dried over Na2SO4 and concentrated under vacuum. The product used into the next step without further purification. Compound 1031 (60.0 mg, crude) was obtained as a light yellow oil and confirmed by LCMS (EC9573-9-P1B). LCMS: EC9753-9-P1A2, m / z (M-l) = 187.1 LCMS: EC9753-9-P1B, m / z (M-l) = 187.1 Example 25 Synthesis of 3f5fneopentyloxy)pentanamido)-N-((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin-3- yl)piperidin-l-yl)ethyl)benzamide (Compound 108) nh2 1022 1.00 eq 1031 1.20 eq HATU 2.00 eq DIEA DCM (10 V) 0~25 °C, 2 hrs 35.5% yield Compound 108 To a solution of compound 1031 (54.5 mg, 289 umol, 1.00 eq) in DCM (1.00 mL) was added HATU (132 mg, 347 umol, 1.20 eq) and DIEA (74.8 mg, 579 umol, 101 uL, 2.00 eq) at 0 °C stirred for 30 min, then was added compound 1022 (120 mg, 289 umol, 1.00 eq) to the solution and stirred at 25 °C for 5 hrs. LCMS (EC9573-10-P1 A) showed the compound 1022 was consumed completely and 54.9% of desired mass (Rt = 0.429) was detected. The reaction mixture was partitioned between ethyl acetate (6.00 mL x 2) and water (4.00 mL). The organic phase was separated, washed with brine (5.00 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)-ACN];B%: 48%-78%,10min). The fraction was lyophilized. Compound 108 (60.6 mg, 103 umol, 35.5% yield, 99.2% purity) was obtained as a white solid and confirmed by LCMS (EC9573-1O-P1C)(RT = 2.182, 98.5% purity) and HPLC (EC9573-1O-P1CP)(RT = 2.139 min, 99.2% purity), HNMR (EC9573-10-P1CH). LCMS: EC9573-10-P1A, Rt = 0.429 min, m / z (M+l) = 585.9 LCMS: EC9573-10-P1C, Rt = 2.182 min, m / z (M+l) = 585.4 HPLC: EC9573-10-P1CP, Rt = 2.139 min, 99.2% purity ’H NMR: EC9573-10-P1DH1, 400 MHz, DMSO 5 = 10.2 - 9.83 (m, 1H), 9.06 - 7.21 (m, 14H), 6.31 - 5.94 (m, 1H), 5.91 - 5.15 (m, 1H), 4.57 -3.86 (m, 1H), 3.38 (brt, J = 6.2 Hz, 3H), 3.01 (s, 2H), 2.72 - 2.56 (m, 1H), 2.41 -2.27 (m, 3H), 1.70 - 1.49 (m, 6H), 1.39-1.12 (m, 2H), 0.86 (s, 9H). Example 26 Synthesis of ethyl 7, 7-dimethyloctanoate O 1033 o Br 0.02 eq CuCI2 0.10 eq prop-1-ynylbenzene THF (10 V) 20-70 °C, 4 hrs To a solution of compound 1032 (3.00 g, 13.4 mmol, 2.38 mL, 1.00 eq) in THF (10.0 mL) was added bromo(tert-butyl)magnesium (IM, 18 mL, 1.34 eq) at 20 °C, then CuCh (366 mg, 2.72 mmol, 2.02e-l eq) and prop-1-ynylbenzene (160 mg, 1.38 mmol, 1.02e-l eq) was added to the solution, then the reaction mixture was stirred at 70 °C for 4 hrs. TLC (Petroleum ether : Ethyl acetate = 2:1) showed the compound 1032 (Rf= 0.24) was consumed , and two new spots (Rf = 0.43, 0.11) was formed. The reaction mixture was poured into saturated NH4CI aqueous solution (50.0 mL) and extracted with EA (50.0 mL*3). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated. The residue was used to next step without purification. Compound 1033 (3.00 g, crude) was obtained as a colorless oil. Example 27 Synthesis of 7,7-dimethyloctanoic acid To a solution of compound 1033 (3.00 g, 14.98 mmol, 1.00 eq) in THF (10.0 mL) and H2O (10.0 mL) was added LiOH.H2O (1.89 g, 44.93 mmol, 2.00 eq) then the reaction mixture was stirred at 25 °C for 2 hrs. TLC (Dichloromethane : Methanol = 10:1) indicated the compound 1033 was consumed and two new spots (Rf = 0.13, 0.02) was formed. The reaction mixture was partitioned between ethyl acetate (50.0 mL) and water (25.0 mL). The organic phase was discarded, and the water phase as adjusted to pH = 3 with IM HC1 and diluted with ethyl acetate (50.0 mL), washed with brine (25.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. Compound 1034 (2.00 g, 11.6 mmol, 77.5% yield) was obtained as colorless oil. Example 28 Synthesis of 3-(7,7-dimethyloctanamido)-N-((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin-3- yl)piperidin-l-yl)ethyl)benzamide (Compound 109) 1.00 eq 1034 1.20 eq HATU 3.00 eq DIEA DCM (10 V) 0~25 °C, 2 hrs 21.1% yield 1022 Compound 109 To a solution of compound 1034 (150 mg, 870 umol, 1.00 eq) in DCM (3.00 mL) was added DIEA (111 mg, 861 umol, 150 uL, 3.00 eq) and HATU (110 mg, 289 umol, 1.20 eq) at 0 °C stirred for 30 min, compound 1022 (100 mg, 241 umol, 1.00 eq) was added to the solution, then the reaction mixture was stirred at 25 °C for 1.5 hrs. LCMS (EC7755-41- P1 Al) showed the compound 1022 was consumed and the desired mass (Rt = 0.474 min, m / z (M+l) = 569.6) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (HCl)-ACN]; B%: 31%-61%, 10 min). From HNMR (EC7755-41-P1C), LCMS (EC7755-41-P1C1) and HPLC (EC7755-41-P1C2) showed the product Compound 109 (15.19 mg, 50.95 umol, 21.1% yield, 96.6% purity) was obtained as white solid. LCMS: EC7755-41-P1A1, Rt = 0.474 min, m / z (M+l) = 569.6 LCMS: EC7755-41-P1C1, Rt = 0.472 min, m / z (M+l) = 569.6 HPLC: EC7755-41-P1C2, Rt = 2.407 min, 96.6% purity ’H-NMR: EC7755-41-P1C, 400 MHz, DMSO 5 10.06 - 9.94 (m, 1H), 8.92 - 8.62 (m, 1H), 8.57 - 8.45 (m, 1H), 8.24 - 8.00 (m, 1H), 7.98 -7.64 (m, 2H), 7.60 - 7.45 (m, 3H), 7.44 - 7.31 (m, 4H), 7.30 - 7.05 (m, 1H), 6.41 - 6.02 (m, 1H), 6.01 - 5.57 (m, 1H), 4.53 - 3.75 (m, 1H), 3.02 - 2.60 (m, 1H), 2.39 - 2.26 (m, 3H), 1.91 -1.50 (m, 4H), 1.41 (br s, 1H), 1.36- 1.19 (m, 6H), 1.15 (br d, J= 8.6 Hz, 2H), 0.85 (s, 9H), 0.75 - 0.44 (m, 1H) Example 29 Synthesis of ethyl 6,6-dimethylheptanoate THF (10 V) 20-70 °C, 4 hrs 1035                                 1036 To a solution of compound 1035 (1.00 g, 4.78 mmol, 763 uL, 1.00 eq) in THF (10.0 mL) was added bromo(tert-butyl)magnesium (1 M, 6 mL, 1.25 eq) at 20 °C, then CuCh (130 mg, 967 umol, 2.02e-l eq) and prop-l-ynylbenzene (56.0 mg, 482 umol, 1.01e-l eq) was added to the solution, then the reaction mixture was stirred at 70 °C for 4 hrs. TLC (Petroleum ether : Ethyl acetate = 2:1) indicated compound 1035 (Rf= 0.24) was consumed completely and two new spots (Rf = 0.09, 0.43) was formed. The reaction mixture was poured into saturated NH4CI aqueous solution (50.0 mL) and extracted with EA (50.0 mL*3). The combined organic layer was washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated. The residue was used to next step without purification. From HNMR (EC7755-32-P1A) showed the product compound 1036 (1.00 g, crude) was obtained as a brown oil. ’H-NMR: EC7755-32-P1A, 400 MHz, DMSO 5 2.03 (s, 3H), 1.81 (br s, 4H), 1.64 (s, 4H), 1.53 - 1.44 (m, 2H), 1.18 (s, 9H), 0.84 (s, 9H) Example 30 Synthesis of 6,6-dimethylheptanoic acid 1036 0 To a solution of compound 1036 (1.00 g, 5.37 mmol, 1.00 eq) in THF (10.0 mL) and MeOH (10.0 mL) and H2O (10.0 mL) was added LiOH.H2O (455 mg, 10.8 mmol, 2.02 eq), then the reaction mixture was stirred at 25 °C for 2 hrs. TLC (Dichloromethane : Methanol = 10:1) indicated compound 1036 (Rf = 0.24) was consumed completely and two new spots (Rf = 0.06, Rf = 0.40) was formed. The reaction mixture was partitioned between ethyl acetate (50.0 mL) and water (25.0 mL). The organic phase was discarded, and the water phase as adjusted to pH = 3 with IM HC1 and diluted with ethyl acetate (50.0 mL), washed with brine (25.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. Compound 1037 (200 mg, 1.26 mmol, crude) was obtained as a colorless oil. Example 31 3-(6,6-dimethylheptanamido)-N-((S)-2-oxo-l-phenyl-2-(d{)-2-lpyridin-3-y I)piperidin-1- yl)ethyl)benzamide (Compound 110) 1022 1.00 eq 1037 1.20 eq HATU 3.00 eq DIEA --------► DCM (10 V) 0~25 °C, 2 hrs 37.4% yieid Compound 110 To a solution of compound 1037 (150 mg, 947 umol, 1.00 eq) in CH2CI2 (2.00 mL) was added DIEA (89.0 mg, 688 umol, 120 uL, 3.00 eq) and HATU (120 mg, 315 umol, 1.20 eq) stirred at 0 °C for 30 min, compound 1022 (100 mg, 241 umol, 1.00 eq) was added to the mixture, then the reaction mixture was stirred at 25 °C for 1.5 hrs. LCMS (EC8870-3-P1A1) showed that compound 10227 was consumed and the desired mass (Rt = 0.450 min, m / z (M+l) = 555.7) was detected. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Cl8 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 46%-76%, 8 min). From HNMR (EC7755-37-P1B), LCMS (EC7755-37-P1C1) and HPLC (EC7755-37-P1C2) showed the product Compound 110 (41.97 mg, 75.66 umol, 37.4% yield, 99.7% purity) was obtained as white solid. LCMS: EC8870-3-P1A1, Rt = 0.450 min, m / z (M+l) = 555.7 LCMS: EC7755-37-P1C1, Rt = 0.446 min, m / z (M+l) = 555.5 HPLC: EC7755-37-P1C2, Rt = 2.322 min, 99.7% purity ’H-NMR: EC7755-37-P1B, 400 MHz, DMSO 5 10.05 - 9.84 (m, 1H), 8.92 - 8.72 (m, 1H), 8.67 - 8.45 (m, 1H), 8.42 - 8.16 (m, 1H), 8.07 -7.94 (m, 1H), 7.71 (br d, J= 7.2 Hz, 1H), 7.80 (br t, J= 9.2 Hz, 1H), 7.60 - 7.49 (m, 3H), 7.47 - 7.24 (m, 5H), 6.24 - 6.09 (m, 1H), 6.02 - 5.78 (m, 1H), 4.07 - 3.72 (m, 1H), 2.86 (br s, 1H), 2.70 - 2.59 (m, 1H), 2.42 - 2.26 (m, 3H), 1.64 - 1.55 (m, 3H), 1.47 - 1.39 (m, 1H), 1.35 -1.18 (m, 8H), 1.14 (br d, J= 8.8 Hz, 2H), 0.84 (s, 9H), 0.63 - 0.36 (m, 1H) Example 32 Synthesis of N-((S)-2-oxo-l-phenyl-2-((R)-2-(pyridin-3-yl)piperidin-l-yl)ethyl)-3-(4-pivalamidobutanamido)benzamide (Compound 111) 1.00 eq 1038 1.20 eq HATU 3.00 eq DIEA NH2            * DCM (10 V) 0~25 °C, 2 hrs 26.1 % yield Compound 111 1022 To a solution of compound 1038 (4-pivalamidobutanoic acid) (46 mg, 245 umol, 1.02 eq) in DCM (1 mL) was added HATU (110 mg, 289 umol, 1.20 eq) and DIEA (66.7 mg, 516 umol, 90 uL, 2.14 eq) and compound 1022 (100 mg, 241 umol, 1.00 eq) stirred at 0 °C for 30 min, then the reaction mixture was stirred at 25 °C for 1.5 hrs. LCMS (EC7755-14-P1A1) showed the compound 1022 was consumed and the desired mass (Rt = 0.361 min, m / z (M+l) = 584.5) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (HC1)-ACN]; B%: 18%-48%, 10 min). From HNMR (EC7755-14-P1B), LCMS (EC7755-14-P1C1) and HPLC (EC7755-14-P1C2) showed the product Compound 111 (37.63 mg, 63.1 umol, 26.1% yield, 97.8% purity) was obtained as white solid. LCMS: EC7755-14-P1A1, Rt = 0.361 min, m / z (M+l) = 584.5 LCMS: EC7755-14-P1C1, Rt = 0.362 min, m / z (M+l) = 584.6 HPLC: EC7755-14-P1C2, Rt = 1.686 min, 99.8% purity ’H-NMR: EC7755-14-P1B, 400 MHz, DMSO 5 10.13 - 9.96 (m, 1H), 8.92 - 8.72 (m, 1H), 8.63 - 8.46 (m, 1H), 8.07 - 7.93 (m, 1H), 7.87 -7.77 (m, 1H), 7.71 (br d, J= 7.2 Hz, 1H), 7.58 - 7.34 (m, 8H), 7.29 - 7.06 (m, 1H), 6.24 -6.07 (m, 1H), 5.95 - 5.59 (m, 1H), 4.54 - 3.73 (m, 1H), 3.16 - 3.00 (m, 2H), 2.98 - 2.58 (m, 1H), 2.45 - 1.84 (m, 4H), 1.78 - 1.67 (m, 2H), 1.59 (br s, 1H), 1.51 - 1.37 (m, 1H), 1.35-1.17 (m, 2H), 1.08 (s, 9H), 0.74 - 0.31 (m, 1H) Example 33 Synthesis of ethyl 4-(3,3-dimethylbutanamido)butanoate To a solurion of compound 1039 (500 mg, 3.81 mmol, 1.00 eq) in THF (5.00 mL) was added TEA (1.16 g, 11.5 mmol, 1.6 mL, 3.02 eq) and 3,3-dimethylbutanoyl chloride (581 mg, 4.32 mmol, 600 uL, 1.13 eq), the reaction mixture was stirred at 25 °C for 12 hrs. LC-MS (EC7755-1-P1 Al) showed the compound 1039 was consumed and the desired mass (RT = 0.355 min, m / z (M+l) = 230.5) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 8 min). From LCMS (EC7755-1-P1B1) showed the product compound 1040 (280 mg, 1.22 mmol, 30.0% yield, 100% purity) was obtained as colorless oil. LC-MS: EC7755-1-P1A1, RT = 0.355 min, m / z (M+l) = 230.5 LC-MS: EC7755-1-P1B1, RT = 0.339 min, m / z (M+l) = 230.5 Example 34 Synthesis of 4-(3,3-dimethylbutanamido)butanoic acid To a solution of compound 1040 (280 mg, 1.22 mmol, 1.00 eq) in THF (1 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH.H2O (103 mg, 2.45 mmol, 2.01 eq), then the reaction mixture was stirred at 25 °C for 2 hrs. LCMS (EC7755-3-P1 Al) showed the compound 1040 was consumed and the desired mass (RT = 0.268 min, m / z (M+l) = 202.4) was detected. The reaction mixture was partitioned between ethyl acetate (50.0 mL) and water (25.0 mL). The organic phase was separated, washed with brine (25.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. From LCMS (EC7755-3-P1B1) showed the product compound 1041 (200 mg, 952 umol, 78.0% yield, 95.8% purity) was obtained as colorless oil. LC-MS: EC7755-3-P1A1, RT = 0.268 min, m / z (M+l) = 202.4 LC-MS: EC7755-3-P1B1, RT = 0.269 min, m / z (M+l) = 202.4 Example 35 Synthesis of 3-(4-(3,3-dimethylbutanamido)butanamido)-N-((S)-2-oxo-1 -phenyl-2-((R)-2- (pyridin-3-yl)piperidin-l-yl)ethyl)benzamide (Compound 112) 1022 1.00 eq 1041 1.20 eq HATU 3.00 eq DIEA ------► DCM (10 V) 0~25 °C, 2 hrs '15 4% yieid Compound 112 To a solution of compound 1041 (50 mg, 248 umol, 1.03 eq) in DCM (2.00 mL) was added DIEA (66.7 mg, 516 umol, 90 uL, 2.14 eq) and HATU (110 mg, 289 umol, 1.20 eq) at 0 °C stirred for 30 min, then compound 1022 (100 mg, 241 umol, 1.00 eq) was added to the reaction mixture and then the reaction was stirred at 25 °C for 1.5 hrs. LCMS (EC7755-9-P1 Al) showed the compound 1022 was consumed and the desired mass (Rt = 0.368 min, m / z (M+l) = 598.5) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna Cl8 150*25mm* lOum; mobile phase: [water (HC1)-ACN];B%: 20%-50%, 10 min). From HNMR (EC7755-9-P1C), LCMS (EC7755-9-P1D1) and HPLC (EC7755-9-P1D2) showed the product Compound 112 (22.78 mg, 37.04 umol, 15.4% yield, 97.2% purity) was obtained as white solid. LCMS: EC7755-9-P1A1, Rt = 0.368 min, m / z (M+l) = 598.5 LCMS: EC7755-9-P1D1, Rt = 0.379 min, m / z (M+l) = 598.5 HPLC: EC7755-9-P1D2, Rt = 1.760 min, 97.2% purity ’H-NMR: EC7755-9-P1C, 400 MHz, DMSO 5 = 10.30 - 10.04 (m, 1H), 8.85 - 8.70 (m, 2H), 8.25 (br s, 1H), 8.07 (br s, 1H), 7.87 - 7.78 (m, 2H), 7.54 (br d, J= 6.4 Hz, 2H), 7.44 (br d, J= 6.4 Hz, 3H), 7.38 - 7.33 (m, 3H), 7.20 (br d, J= 7.2 Hz, 2H), 6.22 - 5.79 (m, 2H), 3.91 - 3.84 (m, 1H), 3.10-3.04 (m, 2H), 2.97 - 2.88 (m, 1H), 2.73 - 2.62 (m, 1H), 2.33 (br t, J= 7.6 Hz, 2H), 1.95 (s, 2H), 1.79 - 1.59 (m, 3H), 1.50 - 1.38 (m, 1H), 1.35 - 1.20 (m, 2H), 0.94 (s, 9H), 0.68 - 0.54 (m, 1H) Example 36 Synthesis of tert-butyl ((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(p-tolyl)propan-2- yl)carbamate 0~25 °C, 2 hrs 49.5% 2001                                       2002 To a solution of compound 2001 (200 mg, 716 umol, 1.00 eq) and compound 2001a (120 mg, 739 umol, 1.03 eq) in DCM (5.0 mL) was added DIEA (185 mg, 1.43 mmol, 249 uL, 2.00 eq) and HATU (327 mg, 860 umol, 1.20 eq) at 0°C, then the mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 2001 was consumed and desired MS (Rt = 0.428 min, m / z = 424.2) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (TFA)-ACN]; B%: 25%-55%, lOmin). Compound 2002 (150 mg, 354 umol, 49.5% yield) was obtained as a white solid. LC-MS (reaction mixture): Rt = 0.428 min, m / z = 424.2 Example 37 Synthesis of (S)-2-amino-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(p-tolyl)propan-l-one 2002                               2003 To a solution of compound 2002 (150 mg, 354 umol, 1.00 eq) in EtOAc (5.0 mL) was added HCl / EtOAc (4 M, 2.0 mL, 22.5eq) at 25 °C, then, the mixture was stirred at 25°C for 2 hrs. LCMS showed compound 2002 was consumed and desired MS (Rt = 0.299 min, m / z = 324.2, M+l) was detected. The reaction solution was concentrated. The residue was used for next step without purification. Compound 2003 (127 mg, 352 umol, 99.6% yield, HC1) was obtained as a white solid. LC-MS (reaction mixture): Rt = 0.299 min, m / z = 324.2, M+l Example 38 Synthesis of N-((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(p-tolyl)propan-2-yl)thiophene-2-carboxamide (Compound 203) 1.10eq o 0~25 °C, 2 hrs 2003 4.00 eq TEA DMF (20 V) Compound 203 78.4% yieid To a solution of compound 2003 (127 mg, 352 umol, 1.00 eq, HC1) and TEA (145 mg, 1.44 mmol, 0.20 mL, 4.07 eq) in DCM (2 mL) was added thiophene-2-carbonyl chloride (57 mg, 388 umol, 41.61 uL, 1.10 eq) at 0 °C, then the mixture was stirred at 25°C for 2 hrs. LCMS showed compound 2003 was consumed and desired MS (Rt = 0.448 min, m / z = 434.0, M+l) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; B%: 19%-49%, min). LCMS and HPLC showed the product Compound 203 (120.94 mg, 278.94 umol, 78.4% yield, 99.5% purity) was obtained as white solid. LC-MS (reaction mixture): Rt = 0.448 min, m / z = 434.0, M+l LC-MS: Rt = 0.425 min, m / z = 434.3, M+l HPLC: Rt = 1.639 min, 99.5% purity ’H-NMR: 400 MHz, DMSO: 5 9.07 - 8.87 (m, 1H), 8.48 - 8.40 (m, 2H), 7.93 (d, J= 3.1 Hz, 1H), 7.81 -7.73 (m, 1H), 7.61 (br d, J= 7.9 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.23 (br d, J= 7.8 Hz, 2H), 7.18 - 7.09 (m, 3H), 6.96 (s, 1H), 5.74 (br s, 1H), 5.17 - 5.02 (m, 1H), 3.90 (br d, J= 13.6 Hz, 1H), 3.12-3.00 (m, 2H), 2.37 - 2.32 (m, 1H), 2.26 (s, 3H), 1.65 - 1.34 (m, 4H), 1.28 - 1.15 (m, 1H), 1.00 - 0.75 (m, 1H) Example 39 Synthesis of tert-butyl ((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(4- (trifluoromethyl)phenyl)propan-2-yl)carbamate To a solution of compound 2007 (400 mg, 1.20 mmol, 1.00 eq) and compound 2001a (200 mg, 1.23 mmol, 1.03 eq) in DCM (5.0 mL) was added DIEA (310 mg, 2.40 mmol, 417 uL, 2.00 eq) and HATU (548 mg, 1.44 mmol, 1.20 eq) at 0°C, then the mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 2007 was consumed and desired MS (Rt = 0.466 min, m / z = 478.2) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 10 min). Compound 2008 (250 mg, 523 umol, 43.6% yield) was obtained as a yellow solid. LC-MS (reaction mixture): Rt = 0.466 min, m / z = 478.2 Example 40 Synthesis of (S)-2-amino-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(4-(trijluoromethyl)phenyl)propan-l-one 2008                                2009 To a solution of compound 2008 (250 mg, 523 umol, 1.00 eq) in EtOAc (5 mL) was added HCl / EtOAc (4 M, 5 mL, 38.2 eq) at 25 °C, then the mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 2008 was consumed and desired MS (Rt = 0.327 min, m / z = 378.1, M+l) was detected. The reaction solution was concentrated. The residue was used for next step without purification. Compound 2009 (216 mg, 521 umol, 99.7% yield, HC1) was obtained as a yellow solid. LC-MS (reaction mixture): Rt = 0.327 min, m / z = 378.1, M+l Example 41 Synthesis of N-((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(4-(trifluoromethyl)phenyl)propan-2-yl)thiophene-2-carboxamide (Compound 205) 4.00 eq TEA DCM (20 V) 0~25 °C, 2 hrs 36.3% yield ci 1.10 eq Compound 205 To a solution of compound 2009 (100 mg, 264 umol, 1.00 eq) and TEA (110 mg, 1.09 mmol, 151 uL, 4.10 eq) in DCM (2 mL) was added thiophene-2-carbonyl chloride (43 mg, 293 umol, 31.4 uL, 1.11 eq) at 0°C, then, the mixture was stirred at 25°C for 2 hrs. LCMS showed compound 2009 was consumed and desired MS (Rt = 0.472 min, m / z = 488.0, M+l) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Phenomenex luna Cl8 150*25mm* lOum; mobile phase: [water (FA)- ACN]; B%: 22%-52%, min). From HNMR, LCMS and HPLC showed the product Compound 205 (50.40 mg, 96.1 umol, 36.3% yield) was obtained as a off-white gum. LC-MS (reaction mixture): Rt = 0.472 min, m / z = 488.0, M+l LC-MS: Rt = 0.453 min, m / z = 488.4, M+l HPLC: Rt = 1.773 min, 97.8% purity ’H-NMR: 400 MHz, DMSO: 5 9.22 - 8.94 (m, 1H), 8.42 (br s, 2H), 7.92 (d, J= 3.1 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.68 (br d, J= 8.0 Hz, 2H), 7.62 - 7.46 (m, 3H), 7.43 - 7.23 (m, 2H), 7.16 (t, J= 4.3 Hz, 1H), 5.84 - 5.54 (m, 1H), 5.31 - 4.98 (m, 1H), 3.92 (br d, J= 14.0 Hz, 1H), 3.21 (br d, J= 7.3 Hz, 2H), 2.84 (br t, J= 12.4 Hz, 1H), 2.37 - 2.31 (m, 1H), 1.58 -1.38 (m, 3H), 1.30-1.13 (m, 1H), 0.97 - 0.75 (m, 1H). Example 42 Synthesis of N-((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(4-(trijluoromethyl)phenyl)propan-2-yl)furan-2-carboxamide (Compound 208) 2009                                    Compound 208 To a solution of compound 2009 (113 mg, 274.83 umol, 1.00 eq, HC1) and TEA (114 mg, 1.13 mmol, 156 uL, 4.10 eq) in DCM (2 mL) was added furan-2-carbonyl chloride (39.4 mg, 302 umol, 29.8 uL, 1.10 eq) at 0 °C, then, the mixture was stirred at 25 °C for 2 hrs. LCMS showed reactant 2009 was consumed and desired MS (Rt = 0.460 min, m / z = 472.1, M+l) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; B%: 21%-51%, min). From HNMR, LCMS and HPLC showed the product Compound 208 (78.38 mg, 166.25 umol, 60.49% yield) was obtained as a white solid. LC-MS (reaction mixture): Rt = 0.460 min, m / z = 472.1, M+l LC-MS: Rt = 0.438 min, m / z = 472.3, M+l HPLC: Rt = 1.687 min, 97.1% purity ’H-NMR: 400 MHz, DMSO: 5 8.81 (br d, J= 2.3 Hz, 1H), 8.54 - 8.32 (m, 2H), 7.85 (s, 1H), 7.76 - 7.47 (m, 5H), 7.42 - 7.16 (m, 3H), 6.68 - 6.56 (m, 1H), 5.80 - 5.56 (m, 1H), 5.20 (br d, J= 7.4 Hz, 1H), 3.91 (br d, J= 13.1 Hz, 1H), 3.20 (br d, J= 7.3 Hz, 2H), 2.84 (br t, J= 12.4 Hz, 1H), 2.38 - 2.32 (m, 1H), 1.59 - 1.39 (m, 3H), 1.30-1.16 (m, 1H), 1.02 - 0.76 (m, 1H). Example 43 Synthesis of tert-butyl ((S)-3-(4-fluorophenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l- yl)propan-2-yl)carbamate To a solution of compound 2010 (400 mg, 1.41 mmol, 1.00 eq) and compound 2001a (236 mg, 1.45 mmol, 1.03 eq) in DCM (5 mL) was added DIEA (365 mg, 2.82 mmol, 491 uL, 2.00 eq) and HATU (645 mg, 1.70 mmol, 1.20 eq) at 0 °C, the mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 2010 was consumed and desired MS (RT = 0.417 min, m / z = 428.1) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 10 min) to give compound 2011 (300 mg, 701 umol, 49.7% yield) as a yellow solid. LCMS (reaction mixture): RT = 0.417min, m / z (M+l) = 428.1 Example 44 Synthesis of (S)-2-amino-3-(4-fluorophenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-l- one 2011                                 2012 To a solution of compound 2011 (250 mg, 584 umol, 1.00 eq) in EtOAc (5 mL) was added HCl / EtOAc (4 M, 5 mL, 34.2 eq) at 25 °C, the mixture was stirred at 25°C for 2 hrs. LCMS showed compound 2012 was consumed and desired MS (RT = 0.266 min, m / z = 328.1) was detected. The reaction solution was concentrated to give (212 mg, 582.65 umol, 99.64% yield, HC1) as a yellow solid. LCMS (reaction mixture): RT=0.334 min, m / z (M+l) = 394.2 Example 45 Synthesis of N-((S)-3-(4-fluorophenyl)-l-oxo-l-((R)CC(pyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 206) 2012                               Compound 206 To a solution of compound 2012 (100 mg, 274 umol, 1.00 eq, HC1) and TEA (114 mg, 1.13 mmol, 156.81 uL, 4.10 eq) in DCM (2 mL) was added thiophene-2-carbonyl chloride (44 mg, 300 umol, 32.1 uL, 1.09 eq) at 0°C, the mixture was stirred at 25°C for 2 hrs. LCMS showed compound 2012 was consumed and desired MS (RT = 0.427 min, m / z = 438.0) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; B%: 16%-46%, min) to afford Compound 206 (110 mg, 251.41 umol, 91.48% yield) as a off-white solid. LCMS (reaction mixture): RT=0.427 min, m / z (M+l) = 438.0 ‘HNMR: CDCh 400 MHz: 5 8.63 - 8.32 (m, 2H), 7.52 (dd, J= 4.4, 10.4 Hz, 2H), 7.45 (br d, J= 8.0 Hz, 1H), 7.29 - 7.23 (m, 3H), 7.11 - 6.93 (m, 4H), 6.00 - 5.22 (m, 2H), 3.78 (br d, J= 13.6 Hz, 1H), 3.37 - 2.89 (m, 3H), 2.38 (br d, J= 13.8 Hz, 1H), 1.70 - 1.36 (m, 4H), 0.92 - 0.69 (m, 1H) LCMS: RT = 0.403 min, m / z (M+l) = 438.3 HPLC: RT = 1 552 min Example 46 Synthesis of N-((S)-3-(4-fluorophenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 209) To a solution of compound 2012 (100 mg, 274.83 umol, 1.00 eq, HC1) and TEA (114 mg, 1.13 mmol, 156 uL, 4.10 eq) in DCM (2 mL) was added furan-2-carbonyl chloride (39.4 mg, 302 umol, 29.8 uL, 1.10 eq) at 0°C, the mixture was stirred at 25 °C for 2 hrs. LCMS showed compound 2012 was consumed and desired MS (RT = 0.410 min, m / z=422.1) was detected. The reaction solution was concentrated. The residue was purified by pre-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; B%: 22%-52%, min) to give Compound 209 (110 mg, 261.00 umol, 94.97% yield) as a yellow solid. LCMS (reaction mixture): RT = 0.410 min, m / z (M+l) = 422.1 ‘HNMR: CDCh 400 MHz : 5 8.54 - 8.34 (m, 2H), 7.54 - 7.39 (m, 2H), 7.33 - 7.18 (m, 4H), 7.17 - 6.84 (m, 4H), 6.52 (dd, J= 1.6, 3.3 Hz, 1H), 6.06 - 5.54 (m, 1H), 5.48 - 5.22 (m, 1H), 4.59 - 4.46 (m, 1H), 3.77 (br d, J = 12.8 Hz, 1H), 3.34 - 2.80 (m, 3H), 2.36 (br d, J = 14.0 Hz, 1H), 1.99 - 1.87 (m, 1H), 1.76 - 1.25 (m, 5H), 0.89 - 0.61 (m, 1H) LCMS: RT = 0.419 min, m / z (M+l) = 422.1 HPLC: RT = 0 821 min Example 47 Synthesis of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(p-tolyl)propanoate 2013 2015 To a solution of compound 2013 (10.0 g, 35.8 mmol, 1.00 eq) in DCM (100 mL) was added compound 2014 (31.3 g, 143 mmol, 25.7 mL, 4.01 eq). The mixture was stirred at 25 °C for 12 hrs. LCMS showed the main peak with desired MS (RT = 0.610 min, M-155 = 180) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, PE: EA=20:1-5:1), the fraction (Plate 1, Rf = 0.75) was collected. Compound 2015 (11.59 g, 34.30 mmol, 95.8% yield, 99.3% purity) was obtained as colourless oil, checked by LCMS and HNMR. LCMS (reaction mixture): RT=0.601 min, m / z (M-155) = 180.1 LCMS (compound 2015): RT=0.603 min, m / z (M-155) = 180.1 ’H NMR: 400 MHz, CDCh: 5 7.08 (q, J= 8.1 Hz, 4H), 5.07 - 4.63 (m, 1H), 4.50 - 4.17 (m, 1H), 3.02 (br s, 2H), 2.32 (s, 3H), 1.43 (d, 7=2.5 Hz, 18H) Example 48 Synthesis of tert-butyl (S)-3-(4-(bromomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate To a solution of compound 2015 (7.00 g, 20.9 mmol, 1.00 eq) in CHCh (70.0 mL) was added AIBN (461 mg, 2.81 mmol, 0.14 eq) and NBS (3.34 g, 18.8 mmol, 0.90 eq), and then the reaction mixture was stirred at 50 °C for 12 hrs. TLC (Petroleum ether : Ethyl acetate = 10:1) indicated Reactant 2015 (Rf = 0.54) was consumed completely and two new spots (Rf = 0.43, Rf = 0.30) formed. The reaction mixture was concentrated to remove CHCI3, The reaction mixture was diluted with DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 50 / 1 to 10 / 1, Rf = 0.30 was collected). From HNMR showed the product compound 20161 (2.60 g, 5.25 mmol, 25.1% yield, 83.6% purity) was obtained as white solid. ’H NMR: 400 MHz, DMSO: 5 7.35 (br d, J= 7.9 Hz, 2H), 7.24 - 7.15 (m, 2H), 4.67 (s, 2H), 4.08 - 3.92 (m, 1H), 3.08 - 2.67 (m, 2H), 1.34 (s, 18H). Example 49 Synthesis of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(fluoromethyl)phenyl)propanoate 2016                                   2017 Under N2 to a solution of compound 2016 (2.50 g, 6.03 mmol, 1.00 eq) in MeCN (25.0 mL) was added TBAF (1.00 M, 12.5 mL, 2.07 eq) at 25 °C, and then the mixture was stirred at 70 °C for 2 hrs. LCMS, product: Ret. Time = 0.657 min, m / z - 100 - 56 + 1= 198.1) and HPLC, product: Ret. Time = 1.970 min) showed the starting material compound 2016 was consumed completely and desired mass was detected. The reaction mixture was quenched by addition H2O 30.0 mL at 25 °C, and then extracted with EA 90 mL (30.0 mL * 3). The combined organic layers were washed with NaCl 100 mL (100 mL * 1), dried over NaSO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: 330g Flash Coulmn Welch Ultimate XB_C18 20 - 40pm; 120 A; mobile phase: [water (TFA) - ACN]; B%: 44% 33min). From HNMR and FNMR showed the product compound 2017 (1.30 g, 3.68 mmol, 61.0% yield) was obtained as a white solid. LC-MS (reaction mixture): Ret. Time = 0.657 min, m / z - 100 - 56 + 1= 198.1 ’H NMR: 400 MHz, MeOD: 5 7.31 (s, 2H), 7.29 - 7.20 (m, 2H), 5.38 (s, 1H), 5.26 (s, 1H), 4.24 (brt,7=7.3 Hz, 1H), 3.13 - 3.01 (m, 1H), 2.92 (br dd, J= 8.6, 13.6 Hz, 1H), 1.40 (d, 7= 5.8 Hz, 18H). 19F NMR: 377 MHz, MeOD: 5 -212.70 (s, IF). Example 50 Synthesis of (S)-2-amino-3-(4-(fluoromethyl)phenyl)propanoic acid o                          0 2017                            2018 To a solution of compound 2017 (0.50 g, 1.41 mmol, 1.00 eq) in EA (5.00 mL) was added HCl / EtOAc (4.00 M, 19.0 mL, 53.7 eq), and then the mixture was stirred at 25 °C for 1 hr. LCMS, product: Ret. Time = 0.290, m / z + 1= 198.1) showed the starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was used to the next step without purification. Compound 2018 (400 mg, crude) was obtained as a white solid. LC-MS (reaction mixture): Ret. Time = 0.290, m / z + 1= 198.1 Example 51 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(fluoromethyl)phenyl)propanoic acid 2018 2.00 TEA 2.00 eq Boc2O THF (10 V) 25 °C,3 hrs 2019 To a solution of compound 2018 (400 mg, 1.71 mmol, 1.00 eq, HC1) in THF (4.00 mL) and H2O (4.00 mL) was added BOC2O (950 mg, 4.35 mmol, 1.00 mL, 2.54 eq) and NaHCOs (440 mg, 5.24 mmol, 204 uL, 3.06 eq), and then the mixture was stirred at 25 °C for 16 hrs. LCMS, product 1: Ret. Time = 0.507 min, m / z + 23 = 320.1 and product 2: Ret. Time = 0.665 min, m / z + 23 = 376.2) showed the starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate Cl8 150 * 25mm * 5um; mobile phase: [water (TFA) - ACN]; B%: 28% - 58%, 10 min). From HNMR, LCMS, HPLC and FNMR showed compound 2019 (173 mg, 448 umol, 26.2% yield, 77% purity) was obtained as a white solid. LC-MS (reaction mixture): Ret. Time = 0.507 min, m / z + 23 = 320.1 ’H NMR: 400 MHz, MeOD: 5 7.41 - 7.19 (m, 4H), 5.40 (s, 1H), 5.28 (s, 1H), 4.37 (br dd, J= 5.0, 8.9 Hz, 1H), 3.24 - 3.10 (m, 1H), 2.95 (br dd, J= 8.9, 13.8 Hz, 1H), 1.40 (s, 10H). 19F NMR: 400 MHz, MeOD: 5 -223.12 (s, IF). LC-MS (compound 2019): Ret. Time = 0.499 min, m / z + 23 = 320.1 HPLC: Ret. Time = 1.03 min, 77.0% purity Example 52 Synthesis of tert-butyl ((S)-3-(4-(fluoromethyl)phenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-y I) carbamate To a solution of compound 2019 (140 mg, 471 umol, 1.00 eq) and compound 2001a (84.0 mg, 518 umol, 1.10 eq) in DCM (2.00 mL) was added DIEA (148 mg, 1.15 mmol, 200 uL, 2.44 eq) and HATU (217 mg, 571 umol, 1.21 eq) at 0 °C, and then the mixture was stirred at 25 °C for 2 hrs. LCMS, product: Ret. Time = 0.478 min, m / z + 1= 442.1) showed starting material was consumed completely and desired mass was detected. The reaction mixture was quenched by addition DCM 2.00 mL at 25°C, and then diluted with H2O 5.00 mL and extracted with DCM 15.0 mL (5.00 mL * 3). The combined organic layers were washed with NaCl 20.0 mL (20.0 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150 * 25mm * 5um; mobile phase: [water(TFA) - ACN]; B%: 21% -51%, lOmin). From HNMR, FNMR showed the product compound 2020 (47.0 mg, 107 umol, 22.6% yield) was obtained as a light yellow oil. LC-MS (reaction mixture): Ret. Time = 0.478 min, m / z + 1= 442.1 ’H NMR: 400 MHz, MeOD: 5 8.69 (br d, J= 6.5 Hz, 2H), 8.46 (br d, J= 8.0 Hz, 1H), 8.02 - 7.85 (m, 1H), 7.50 - 7.24 (m, 4H), 5.86 (br s, 1H), 5.47 - 5.23 (m, 2H), 3.85 (br d, J= 14.0 Hz, 1H), 3.10 - 2.87 (m, 3H), 2.34 (br d, J= 13.9 Hz, 1H), 1.72 - 1.58 (m, 1H), 1.53 - 1.23 (m, 13H), 0.67 - 0.33 (m, 1H). 19F NMR: 400 MHz, MeOD: 5 -73.81 (s, IF). Example 53 Synthesis of (S)-2-amino-3-(4-(fluoromethyl)phenyl)-l-(^R)-2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 2020                                  2021 To a solution of compound 2020 (47.0 mg, 107 umol, 1.00 eq) in EA (0.50 mL) was added HClZEtOAc (4 M, 1.50 mL, 56.4 eq), and then the mixture was stirred at 25 °C for 1 hr. LCMS, product: Ret. Time = 0.314 min, m / z + 1 = 342.1) showed the starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was used to the next step without purification. From HNMR showed that compound 2021 (36.0 mg, crude) was obtained as a light yellow solid. LC-MS (reaction mixture): Ret. Time = 0.314 min, m / z + 1 = 342.1 ’H NMR: 400 MHz, MeOD: 8 8.89 (s, 1H), 8.79 (br d, J= 5.5 Hz, 1H), 8.62 (br d, J = 8.3 Hz, 1H), 8.10 (dd, J= 6.0, 7.9 Hz, 1H), 7.55 - 7.30 (m, 4H), 5.47 - 5.28 (m, 2H), 3.68 (br d, J= 13.6 Hz, 1H), 3.27 - 3.19 (m, 1H), 3.30 - 3.15 (m, 1H), 3.08 - 2.97 (m, 1H), 2.47 -2.29 (m, 1H), 2.04 - 1.96 (m, 1H), 1.85 - 1.69 (m, 1H), 1.58 - 1.21 (m, 4H), 0.65 - 0.47 (m, 1H). Example 54 Synthesis ofN-((S)-3-(4-(fluoromethyl)phenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l- yl)propan-2-yl)thiophene-2-carboxamide (Compound 204) 2021 DMF (10 V) 5.00 eq TEA 0~25 °C, 2 hrs Compound 204 To a solution of compound 2021 (18.0 mg, 52.7 umol, 1.00 eq) in DMF (0.50 mL) was added TEA (29.1 mg, 287 umol, 40.0 uL, 5.45 eq) and compound 2022 (9.59 mg, 65.4 umol, 7.00 uL, 1.24 eq) at 0 °C, and then the mixture was stirred at 25 °C for 2 hrs. LCMS, product: Ret. Time = 0.457 min, m / z + 1 = 452.1) showed the starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate C18 150 * 25 mm * 5 um; mobile phase: [water (TFA) - ACN]; B%: 16% - 46%, 2 min). From HNMR, FNMR, LCMS and HPLC showed that Compound 204 (13.0 mg, 26.7 umol, 50.6% yield, 92.7% purity) was obtained as a yellow gum. LC-MS (reaction mixture): Ret. Time = 0.457 min, m / z + 1 = 452.1 LC-MS: Ret. Time = 0.455 min, m / z + 1 = 452.1 HPLC: Ret. Time = 1.563 min, 92.7% purity ’H NMR: 400 MHz, MeOD: 5 8.62 (br d, J= 10.1 Hz, 2H), 8.29 (br d, J= 8.9 Hz, 1H), 7.84 (br s, 2H), 7.69 (d, J= 5.0 Hz, 1H), 7.42 (br s, 4H), 7.15 (t, J= 4.4 Hz, 1H), 5.85 (br s, 1H), 5.49 - 5.27 (m, 3H), 5.25 - 5.11 (m, 1H), 4.01 - 3.78 (m, 1H), 3.27 - 3.21 (m, 2H), 3.03 - 2.90 (m, 1H), 2.40 - 2.30 (m, 1H), 1.67 - 1.57 (m, 1H), 1.50 - 1.21 (m, 4H), 0.63 - 0.41 (m, 1H). 19F NMR: 400 MHz, MeOD: 5 -207.17 (s, IF). Example 55 Synthesis ofN-((S)-3-(4-(fluoromethyl)phenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-y l)propan-2-y I)furan-2-carboxamide (Compound207) 2021                                    Compound 207 To a solution of compound 2021 (18.0 mg, 52.7 umol, 1.00 eq) in DMF (0.50 mL) was added TEA (29.1 mg, 287 umol, 40.0 uL, 5.45 eq) and compound 2023 (9.24 mg, 70.8 umol, 7.00 uL, 1.34 eq) at 0 °C, and then the mixture was stirred at 25 °C for 2 hrs. LCMS, product: Ret. Time = 0.452 min, m / z + 1 = 436.1) showed the starting material was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate C18 150 * 25mm * 5um; mobile phase: [water(TFA) - ACN]; B%: 16% - 46%, 2min). From HNMR, FNMR, LCMS and HPLC showed Compound 207 (18.3 mg, 41.2 umol, 78.1% yield, 98.1% purity) was obtained as a yellow gum. LC-MS (reaction mixture): Ret. Time = 0.452 min, m / z + 1 = 436.1 LC-MS: Ret. Time = 0.435 min, m / z + 1 = 436.2 HPLC: Ret. Time = 1.458 min, 98.1% purity ’H NMR: 400 MHz, MeOD: 5 8.80 - 8.67 (m, 2H), 8.52 (br d, J= 8.1 Hz, 1H), 8.12 -7.94 (m, 1H), 7.72 (s, 1H), 7.51 - 7.36 (m, 4H), 7.23 (br d, J= 3.3 Hz, 1H), 6.61 (dd, J= 1.8, 3.4 Hz, 1H), 5.86 (br s, 1H), 5.48 - 5.26 (m, 2H), 5.19 (dd, J= 6.1, 9.7 Hz, 1H), 3.92 (br d, J = 14.0 Hz, 1H), 3.29-3.17 (m, 2H), 2.98 (br t, J= 12.2 Hz, 1H), 2.35 (br d, J= 13.4 Hz, 1H), 1.77 - 1.56 (m, 1H), 1.51 - 1.31 (m, 2H), 1.31-1.20 (m, 1H), 0.61 - 0.40 (m, 1H). 19F NMR: 400 MHz, MeOD: 5 -207.20 (br s, IF). Example 56 Synthesis of (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide -o                          H I     M                                             N 3.00 eq Zn, 0.10 eq l2 (Ty "Boe 0 jT B0C DMF(10V)          L I                                    Zn I          25-50 °C, 6 hrs                | I 2024                                2025 To a solution of I2 (1.62 g, 6.38 mmol, 1.29 mL, 0.10 eq) in DMF (84.0 mL) was added Zn (12.5 g, 191 mmol, 3.00 eq) at 25 °C. The mixture was stirred at 50 °C for 3 hrs. Then the mixture cooled to 25 °C, the compound 20241 (21.0 g, 63.8 mmol, 1.00 eq) in DMF (120 mL) was added. The mixture was stirred at 25 °C for 3 hrs. TLC (Petroleum ether: Ethyl acetate = 5:1) showed compound 2024 (Rf= 0.40) was consumed and the one new spot (Rf = 0.50) was formed. The reaction mixture was filtered, the filtrate was used to next step. The filtrate was used to next step without purification. Compound 2025 (24.8 g, 62.8 mmol, 98.5% yield) was obtained as a gray liquid and dissolved in DMF (300 mL). Example 57 Synthesis of Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(difluoromethyl)phenyl)propanoate 60 °C, 12 hrs 65.3% yield 2026                                     2027 To a solution of compound 2025 (24.8 g, 62.8 mmol, 1.3 eq) in DMF (300 mL) was added compound 2026 (10.0 g, 48.3 mmol, 1.00 eq), SPhos (1.98 g, 4.83 mmol, 0.10 eq), and Pd2(dba)3 (1.33 g, 1.45 mmol, 0.03 eq). The mixture was stirred at 60 °C for 12 hrs under N2. LCMS showed the compound 2026 was consumed and the desired mass (RT = 0.521 min, m / z (M-99) = 230.1) was detected. The reaction mixture was filtered, the filtrate was diluted with Ethyl acetate (400 mL) and H2O (500 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 30 / 1 to 5 / 1, Rf = 0.30 was collected). From HNMR and LCMS showed the compound 2027 (11.0 g, 31.5 mmol, 65.3% yield, 94.4% purity) was obtained as brown yellow oil. LC-MS (reaction mixture): RT = 0.521 min, m / z (M-99) = 230.1 LC-MS (compound 2027): RT = 0.525 min, m / z (M-99) = 230.1 ’H-NMR: 400 MHz, DMSO-t / e: 5 7.56 - 7.30 (m, 2H), 7.12 (s, 1H), 6.98 (s, 1H), 6.84 (s, 1H), 7.15 - 6.77 (m, 1H), 4.27 - 3.97 (m, 1H), 3.62 (s, 3H), 3.22 - 2.77 (m, 2H), 1.39 -1.26 (m, 9H) Example 58 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(dijluoromethyl)phenyl)propanoic acid 2027                                   2028 To a solution of compound 2027 (11.0 g, 31.5 mmol, 94.4% purity, 1.00 eq) in MeOH (100 mL) was added the solution of LiOH.H2O (3.97 g, 94.6 mmol, 3.00 eq) in H2O (100 mL) at 0 °C, then the reaction mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 2027 was consumed and the desired mass (RT = 0.466 min, m / z (M-99) = 216.1) was detected. The reaction mixture was adjusted to pH = 5 with IM HC1, and the reaction mixture was partitioned between ethyl acetate (250 mL) and water (150 mL). The organic phase was separated, washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. From LCMS and HNMR showed the product compound 2028 (10.0 g, 30.9 mmol, 98.1% yield, 97.5% purity) was obtained as gray solid. LC-MS (rection mixture): RT = 0.466 min, m / z (M-99) = 216.1 LC-MS (compound 2028): RT = 0.468 min, m / z (M-99) = 216.1 ’H-NMR: 400 MHz, CDCh: 5 7.46 (d, J= 8.0 Hz, 2H), 7.29 (br d, J= 7.6 Hz, 2H), 6.64 (t, J= 56.4 Hz, 1H), 4.97 (br d, J= 7.6 Hz, 1H), 4.65 (br d, J= 6.4 Hz, 1H), 3.34 - 2.95 (m, 2H), 1.45 - 1.25 (m, 9H) Example 59 Synthesis of tert-butyl ((2S)-3-(4-(difluoromethyl)phenyl)-l-oxo-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-2-y I) carbamate F 2028                                            2030 To a solution of compound 2028 (10.0 g, 30.9 mmol, 97.5% purity, 1.00 eq) and compound 2029 (5.02 g, 30.9 mmol, 1.00 eq) in DCM (100 mL) was added T3P (23.5 g, 36.9 mmol, 22.0 mL, 50% purity, 1.20 eq) and DIEA (8.16 g, 63.1 mmol, 11.0 mL, 2.04 eq), then the reaction mixture was stirred at 25 °C for 2 hrs. LCMS showed the compound 2028 was consumed and the desired mass (RT = 0.441 min, m / z (M+l) = 460.3) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 10 um); mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-70%, 20 min). From HNMR and LCMS showed the product compound 2030 (2.70 g, 4.96 mmol, 16.0% yield, 84.4% purity) was obtained as white solid. LC-MS (reaction mixture): RT = 0.441 min, m / z (M+l) = 460.3 LC-MS (compound 2030): RT = 0.430 min, m / z (M+l) = 460.4 ’H-NMR: 400 MHz, DMSO-t / e: 5 8.50 - 8.31 (m, 2H), 7.65 - 7.22 (m, 7H), 7.15 -6.86 (m, 1H), 5.73 (brd,J= 15.6 Hz, 1H), 4.92 - 4.56 (m, 1H), 4.06 - 3.68 (m, 1H), 3.172.64 (m, 3H), 2.41 - 2.30 (m, 1H), 1.81 - 1.43 (m, 3H), 1.41 - 1.24 (m, 9H), 1.05 (br s, 2H). Example 60 Synthesis of (2S)-2-amino-3-(4-(dijluoromethyl)phenyl)-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 2030                                   2031 To a solution of compound 2030 (2.70 g, 4.96 mmol, 84.4% purity, 1.00 eq) in EtOAc (27.0 mL) was added HC1 / EtOAc (4 M, 27.0 mL, 18.3 eq), then the reaction mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 2030 was consumed and the desired mass (RT = 0.251 min, m / z (M-99) = 360.2) was detected. The reaction mixture was concentrated. The residue was used to next step without purification. From HNMR showed the product compound 2031 (2.50 g, crude, HC1) was obtained as light brown solid. LC-MS (reaction mixture): RT = 0.250 min, m / z (M-99) = 360.2 ’H-NMR: 400 MHz, DMSO-t / 6; 5 9.03 - 8.63 (m, 2H), 8.59 (br d, J= 5.2 Hz, 1H), 8.05 - 7.67 (m, 1H), 7.64 - 7.30 (m, 3H), 7.27 - 6.83 (m, 1H), 5.74 (br d, J= 26.8 Hz, 1H), 4.93 - 4.60 (m, 1H), 4.50 - 3.96 (m, 3H), 3.36 - 2.99 (m, 2H), 2.92 - 2.56 (m, 1H), 2.46 - 2.22 (m, 1H), 1.95 - 1.35 (m, 2H), 1.27 - 1.08 (m, 1H). Example 61 Synthesis of N-((2S)-3-(4-(dijluoromethyl)phenyl)-l-oxo-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 201) 2031                                 Compound 201 To a solution of compound 2031 (2.30 g, 6.40 mmol, 1.00 eq) in DCM (25.0 mL)was added TEA (2.18 g, 21.5 mmol, 3 mL, 3.00 eq) and compound 2032 (924 mg, 7.08 mmol, 700 uL, 1.11 eq) at 0 °C, and then the reaction mixture stirred at 25 °C for 30 min. LCMS showed the compound 2031 was consumed and the desired mass (RT = 0.385 min, m / z (M+l) = 454.3) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: YMC Triart Cl8 250*50mm*7um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 20 min). From HNMR, LCMS and HPLC showed the product Compound 201 (1.60 g, 3.41 mmol, 53.3% yield, 96.6% purity) was obtained as gray solid. LC-MS (reaction mixture): RT = 0.385 min, m / z (M+l) = 454.3 LC-MS: RT = 0.389 min, m / z (M+l) = 454.2 HPLC: RT =1.428 min, 96.5% purity ’H-NMR: 400 MHz, DMSO-t / e: 5 9.02 - 8.65 (m, 1H), 8.59 - 8.29 (m, 2H), 7.93 -7.68 (m, 1H), 7.65 - 7.40 (m, 4H), 7.33 - 7.20 (m, 2H), 7.16 - 6.80 (m, 1H), 6.67 - 6.43 (m, 1H), 5.87 - 5.55 (m, 1H), 5.42 - 5.02 (m, 1H), 4.53 - 3.72 (m, 1H), 3.26 - 3.05 (m, 2H), 2.94 -2.59 (m, 1H), 2.40 - 2.30 (m, 1H), 1.78 - 0.86 (m, 5H) Example 62 Synthesis of N-((S)-3-(4-(difluoromethyl)phenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l- yl)propan-2-yl)thiophene-2-carboxamide (Compound 202) To a solution of compound 2033 (80.0 mg, 202 umol, 1.00 eq, HC1) in DCM (2 mL) was added TEA (62.0 mg, 613 umol, 85.3 uL, 3.03 eq) and compound 2034 (30.0 mg, 205 umol, 21.9 uL, 1.01 eq) at 0 °C, and then the reaction mixture stirred at 20 °C for 4 hrs. LCMS showed that compound 2033 was consumed and the desired mass (RT = 0.366 min, m / z = 470.2) was detected. The reaction mixture was concentrated under vacuum. The crude product was purified by reversed-phase HPLC (column: Welch Xtimate Cl8 150*25mm*5um; mobile phase: [water (0.05%HCl)-ACN]; B%: 15%-45%, lOmin). From HNMR, FNMR, LCMS, HPLC and SFC, Compound 202 (62.68 mg, 127 umol, 62.8% yield, 95.1% purity) was obtained as an off-white solid. LC-MS (reaction mixture): RT = 0.366 min, m / z =470.2 LC-MS: RT = 0.370 min, m / z = 470.1 HPLC: RT = 1.610 min, 95.1% purity SFC: 92.0% ee ’H-NMR: 400 MHz, DMSO: 5 9.03 (br d, J= 6.4 Hz, 1H), 8.74 - 8.52 (m, 2H), 8.21 - 8.05 (m, 1H), 7.93 (d, J= 3.0 Hz, 1H), 7.79 (br d, J= 4.8 Hz, 2H), 7.57 - 7.43 (m, 4H), 7.21 -7.12(m, 1H), 7.03 - 6.84 (m, 1H), 5.82 - 5.70 (m, 1H), 5.21 - 5.05 (m, 1H), 3.89 (br dd, J= 2.1, 13.6 Hz, 1H), 3.21 - 3.13 (m, 4H), 2.97 - 2.82 (m, 2H), 1.65 - 1.10 (m, 6H), 0.85 - 0.66 (m, 1H). Example 63 Synthesis of tert-butyl ((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(o-tolyl)propan-2-yl)carbamate 2035                                        2037 To a solution of Compound 2035 (100 mg, 358 umol, N / A purity, 1.00 eq) and Compound 2036 (64 mg, 395 umol, N / A purity, 1.10 eq) in DCM (1.00 mL) was added HATU (164 mg, 431 umol, 1.20 eq) and DIEA (96.5 mg, 746 umol, 130 uL, 2.08 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS (EC5857-2-P1R1, product: Ret. Time = 0.403 min, m / z +1 = 424.3) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition H2O 3 mL at 25 °C, and extracted with DCM 6 mL (2 mL * 3). The combined organic layers were washed with NaCl 6 mL,dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to the next step without the further puriffication. From LCMS (EC5857-2-P1A1) showed that the product Compound 2037 (150 mg, crude) was obtained as a yellow oil. LCMS: EC5857-2-P1R1, Ret. Time = 0.403 min, m / z +1 = 424.3 LCMS: EC5857-2-P1A1, Ret. Time = 0.456 min, m / z +1 = 424.3 Example 64 Synthesis of (S)-2-amino-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(o-tolyl)propan-l-one 2037                          2038 To a solution of Compound 2037 (150 mg, 354 umol, N / A purity, 1.00 eq) in EtOAc (2.00 mL) was added HCl / EtOAc (4.00 M, 6.00 mL, 67.8 eq) .The mixture was stirred at 25 °C for 2 hrs. LCMS (EC5857-4-P1R1, product: Ret. Time = 0.297 min, m / z +1 = 324.3) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was used to the next step without further purification. From HNMR (EC5857-4-P1C2) showed that the product Compound 2038 (120 mg, crude) was obtained as a yellow oil. LCMS: EC5857-4-P1R1, Ret. Time = 0.297 min, m / z +1 = 324.3 ‘HNMR: EC5857-4-P1C2 (400 MHz, MeOD) 3 8.75 (d, J= 1.1 Hz, 1H), 8.63 (d, J= 5.6 Hz, 1H), 8.47 (td, J= 0.9, 8.3 Hz, 1H), 7.94 (dd, J = 5.8, 8.3 Hz, 1H), 7.16 - 7.07 (m, 4H), 5.73 (brs, 1H), 3.94 (q, J=1A Hz, 1H), 3.57 (td, J= 6.6, 13.3 Hz, 1H), 3.10 - 3.00 (m, 2H), 2.78 (dt, J= 3.0, 13.4 Hz, 1H), 2.28 (s, 3H), 1.57 -1.42 (m, 1H), 1.25 (brs, 1H), 1.19 - 0.99 (m, 4H). Example 65 Synthesis of N-((S)-l-oxo-l-((R)Clfpyridin-3-yl)piperidin-l-yl)-3fo-tolyl)propan-2-yl)furan-2-carboxamide (Compound 210) ci 1.20 eq 5.00 eq TEA DMF, 0~25 °C, 2 hrs 2038                                     Compound 210 To a solution of Compound 2038 (60.0 mg, 186 umol, 1.00 eq) and Compound 2039 (25.1 mg, 192 umol, 19.0 uL, 1.04 eq) in DMF (1.00 mL) was added TEA (94.5 mg, 934 umol, 130 uL, 5.03 eq) at 0 °C. The mixture was stirred at 25 °Cfor 2 hrs. LCMS (EC5857-8-P1R1, product: Ret. Time = 0.364 min, m / z +1 = 418.2) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition). From HNMR (EC5857-8-P1C1), LCMS (EC5857-8-P1A2) and HPLC (EC5857-8-P1B1) showed that the product Compound 210 (25.69 mg, 61.2 umol, 33.0% yield, 99.4% purity) was obtained as a white solid. LCMS: EC5857-8-P1R1, product: Ret. Time = 0.364 min, m / z +1 = 418.2 ‘HNMR: EC5857-8-P1C1 (400 MHz, CDCh) 5 8.54 (brs, 2H), 7.84 (d, J= 6.8 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.50 (d, J= 0.9 Hz, 1H), 7.24 (d, J= 3.1 Hz, 1H), 7.21 (d, J= 1.8 Hz, 1H), 7.18 (d, J= 3.4 Hz, 2H), 6.53 (dd, J= 1.8, 3.5 Hz, 1H), 5.97 (s, 1H), 5.39 (ddd,J = 5.4, 7.7, 9.9 Hz, 1H), 3.66 - 3.55 (m, 1H), 3.30 - 3.15 (m, 2H), 2.86 - 2.74 (m, 1H), 2.48 (s, 3H), 2.26 (br d, J= 14.5 Hz, 1H), 1.67 - 1.57 (m, 2H), 1.51 - 1.39 (m, 2H), 1.25 (d, J= 12.6 Hz, 2H). LCMS: EC5857-8-P1A2, product: Ret. Time = 0.462 min, m / z +1 = 418.2 HPLC: EC5857-8-P1B1, product: Ret. Time = 1.542 min Example 66 Synthesis of N-((S)-l-oxo-l-((R)-2fpyridin-3-yl)piperidin-l-yl)-3fo-tolyl)propan-2-yl)thiophene-2-carboxamide (Compound 211) 2038                                     Compound 211 To a solution of Compound 2038 (60.0 mg, 186 umol, 1.00 eq) and Compound 2040 (27.4 mg, 187 umol, 20.0 uL, 1.01 eq) in DMF (1.00 mL) was added TEA (94.5 mg, 934 umol, 130 uL, 5.03 eq) at 0 °C. The mixture was stirred at 25 °Cfor 2 hrs. LCMS (EC5857-7-P1R1, product: Ret. Time = 0.375 min, m / z +1 = 434.2) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. From HNMR (EC5857-7-P1C1), LCMS (EC5857-7-P1A1) and HPLC(EC5857-7-P1B1) showed that the product Compound 211 (66.93 mg, 122 umol, 65.6% yield, 99.5% purity, TFA) was obtained as a yellow solid. LCMS: EC5857-7-P1R1, product: Ret. Time = 0.375 min, m / z +1 = 434.2 ‘HNMR: EC5857-7-P1C1 (400 MHz, CDCh) 5 8.76 (s, 1H), 8.67 (d, J= 5.4 Hz, 1H), 8.17 (d, J= 7.8 Hz, 1H), 7.80 (dd, J= 5.5, 8.1 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.56 - 7.52 (m, 1H), 7.26 - 7.19 (m, 4H), 7.12 (dd, J= 3.9, 4.9 Hz, 1H), 6.91 (d, J= 7.1 Hz, 1H), 5.98 (d, J= 3.0 Hz, 1H), 5.39 - 5.28 (m, 1H), 3.71 - 3.63 (m, 2H), 3.28 - 3.20 (m, 2H), 2.86 - 2.76 (m, 1H), 2.27 (d, J= 15.0 Hz, 1H), 1.73 - 1.60 (m, 1H), 1.55 - 1.46 (m, 1H), 1.34 - 1.23 (m, 2H) LCMS: EC5857-7-P1A1, product: Ret. Time = 0.466 min, m / z +1 = 434.2 HPLC: EC5857-7-P1B1, product: Ret. Time = 1.635 min Example 67 Synthesis of tert-butyl ((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(m-tolyl)propan-2-yl)carbamate 2041                                        2043 To a solution of Compound 2041 (100 mg, 358 umol, N / A purity, 1.00 eq) and Compound 2042 (64 mg, 395 umol, N / A purity, 1.10 eq) in DCM (1 mL) was added HATU (164 mg, 431 umol, 1.20 eq) and DIEA (96.5 mg, 746 umol, 130 uL, 2.08 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS (EC5857-1-P1R1, product: Ret. Time = 0.407 min, m / z +1 = 424.3) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was quenched by addition H2O 3 mL at 25 °C, and extracted with DCM 6 mL (2 mL * 3). The combined organic layers were washed with NaCl 6 mL,dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to the next step without the further puriffication. From LCMS (EC5857-1-P1A1) showed that the product Compound 2043 (150 mg, crude) was obtained as a yellow oil. LCMS: EC5857-1-P1R1, Ret. Time = 0.407 min, m / z +1 = 424.3 LCMS: EC5857-1-P1A1, Ret. Time = 0.455 min, m / z +1 = 424.3 Example 68 Synthesis of (S)-2-amino-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(m-tolyl)propan-l-one 2043                          2044 To a solution of Compound 2043 (150 mg, 354 umol, N / A purity, 1.00 eq) in EtOAc (2.00 mL) was added HCl / EtOAc (4.00 M, 6.00 mL, 67.8 eq) .The mixture was stirred at 25 °C for 2 hrs. LCMS (EC5857-3-P1R1, product: Ret. Time = 0.302 min, m / z +1 = 324.3) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was used to the next step without further purification. From HNMR (EC5857-3-P1C2) showed that the product Compound 2044 (120 mg, crude) was obtained as a yellow oil. LCMS: EC5857-3-P1R1, Ret. Time = 0.302 min, m / z +1 = 324.3 ‘HNMR: EC5857-3-P1C2 (400 MHz, MeOD) 5 8.90 (s, 1H), 8.79 (d, 7= 5.8 Hz, 1H), 8.64 (d, 7=8.3 Hz, 1H), 8.11 (dd, 7=5.8, 8.3 Hz, 1H), 7.34 -7.28 (m, 1H), 7.23-7.11 (m, 3H), 5.90 (brs, 1H), 3.73 (td, 7= 6.6, 13.3 Hz, 1H), 3.31 (td, 7= 1.6, 3.3 Hz, 5H), 3.27 - 3.17 (m, 2H), 3.16 - 3.07 (m, 1H), 3.05 - 2.95 (m, 1H), 2.39 - 2.36 (m, 3H), 1.79 - 1.65 (m, 1H), 1.57 - 1.44 (m, 1H), 1.38 (d, 7= 1.9 Hz, 4H). Example 69 Synthesis of N-((S)-l-oxo-l-(fl)-2-(pyridin-3-yl)piperidin-l-yl)-3-(m-tolyl)propan-2-yl)furan-2-carboxamide (Compound 212) 2044                                     Compound 212 To a solution of Compound 2044 (60.0 mg, 186 umol, 1.00 eq) and Compound 2045 (25.1 mg, 192 umol, 19.0 uL, 1.04 eq) in DMF (1.00 mL) was added TEA (94.5 mg, 934 umol, 130 uL, 5.03 eq) at 0 °C. The mixture was stirred at 25 °Cfor 2 hrs. LCMS (EC5857-6-P1R1, product: Ret. Time = 0.367 min, m / z +1 = 418.2) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition). From HNMR (EC5857-6-P1C1), LCMS (EC5857-6-P1A1) and HPLC (EC55857-P1B1) showed that the product Compound 212 (38.88 mg, 72.7 umol, 39.2% yield, 99.4% purity, TFA) was obtained as a colorless oil. LCMS: EC5857-6-P1R1, product: Ret. Time = 0.367 min, m / z +1 = 418.2 ‘HNMR: EC5857-6-P1C1 (400 MHz, CDCh) 5 8.75 - 8.67 (m, 1H), 8.62 (d, J= 4.6 Hz, 1H), 8.05 (d, J= 7.9 Hz, 1H), 7.74 - 7.64 (m, 1H), 7.45 - 7.37 (m, 1H), 7.15 - 7.09 (m, 1H), 7.04 (brs, 4H), 6.51 - 6.43 (m, 1H), 5.96 - 5.82 (m, 1H), 5.31 - 5.15 (m, 1H), 3.73 (d, J= 14.1 Hz, 1H), 3.16-3.00 (m, 2H), 2.77 (t,J = 12.6 Hz, 1H), 2.29 (s, 3H), 2.26 - 2.16 (m, 1H), 1.67 - 1.55 (m, 1H), 1.47 (d, J= 12.4 Hz, 1H), 1.35 -1.17 (m, 2H), 0.50 - 0.34 (m, 1H). LCMS: EC5857-6-P1A1, product: Ret. Time = 0.450 min, m / z +1 = 418.2 HPLC: EC5857-6-P1B1, product: Ret. Time = 1.526 min Example 70 Synthesis of N-((S)-l-oxo-l-(fl)-2-(pyridin-3-yl)piperidin-l-yl)-3-(m-tolyl)propan-2-yl)thiophene-2-carboxamide (Compound 213) 2044                                    Compound 213 To a solution of Compound 2044 (60.0 mg, 186 umol, 1.00 eq) and Compound 2046 (27.4 mg, 187 umol, 20.0 uL, 1.01 eq) in DMF (1.00 mL) was added TEA (94.5 mg, 934 umol, 130 uL, 5.03 eq) at 0 °C. The mixture was stirred at 25 °Cfor 2 hrs. LCMS (EC5857-5-P1R1, product: Ret. Time = 0.380 min, m / z +1 = 434.2) showed that the reactant was consumed completely and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (neutral condition). From HNMR (EC5857-5-P1C1), LCMS (EC5857-5-P1A1) and HPLC (EC5857-5-P1B4) showed that the product Compound 212 (15.96 mg, 36.2 umol, 19.5% yield, 98.3% purity) was obtained as a white solid. The residue was purified by prep-HPLC (neutral condition). From HNMR (EC5857-12-P1C3), LCMS (EC5857-12-P1A1) and HPLC (EC5857-12-P1B1) showed that the product Compound 212 (11.65 mg, 26.9 umol, 38.8% yield) was obtained as a yellow gum. LCMS: EC5857-5-P1R1, product: Ret. Time = 0.380 min, m / z +1 = 434.2 ‘HNMR: EC5857-5-P1C1 (400 MHz, CDCh) and EC5857-12-P1C3 (400 MHz, CDCk) 5 8.62 - 8.48 (m, 2H), 7.87 (dd, J= 2.4, 5.3 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.15 - 7.09 (m, 4H), 6.84 (d, 7= 7.4 Hz, 1H), 5.98 (d, 7=3.1 Hz, 1H), 5.42 - 5.33 (m, 1H), 3.82 - 3.72 (m, 1H), 3.22 - 3.13 (m, 2H), 2.94 - 2.83 (m, 1H), 2.40 - 2.36 (m, 3H), 2.33 (d, J= 16.0 Hz, 1H), 1.58 -1.53 (m, 2H), 1.42 - 1.35 (m, 2H), 0.62 - 0.50 (m, 1H). LCMS: EC5857-5-P1A1 and EC5857-12-P1A1, product: Ret. Time = 0.481 min, m / z +1 =434.2 HPLC: EC5857-5-P1B4 and EC5857-12-P1B1, product: Ret. Time = 1.587 min Example 71 Synthesis of tert-butyl ((2S)-l-oxo-3-phenyl-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)carbamate To a solution of compound 2047 (300 mg, 1.13 mmol, 1.00 eq) in DCM (2 mL) was added T3P (864 mg, 1.36 mmol, 808 uL, 50% purity, 1.20 eq) and TEA (229 mg, 2.26 mmol, 315 uL, 2.00 eq), compound 2048 (183 mg, 1.13 mmol, 9.98e-l eq) at under N2. The mixture was stirred at 15 °C for 8 hrs. LCMS (EC1956-3-P1A1) showed that the compound 2047 was consumed completely and the desired mass (RT = 0.399 min, M+l = 410.4) was detected. The residue was diluted with H2O (15.0 mL) and extracted with DCM 30 mL (10mL x3). The combined organic layers were washed with brine 20 mL (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 2049 (400 mg, 976 umol, 86.3% yield) as a yellow solid. LCMS: EC1956-3-P1A1, RT = 0.399 min, m / z (M+l) = 410.4 Example 72 Synthesis of (2S)-2-amino-3-phenyl-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 2049                                  2050 To a solution of compound 2049 (400 mg, 976 umol, 1.00 eq) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 4 mL, 16.3 eq). The mixture was stirred at 15 °C for Ihr. LCMS (EC1956-4-P1 Al) showed that the compound 2049 was consumed completely and the desired mass (RT = 0.373 min, M+l = 310.2) was detected. The reaction mixture was concentrated under vacuum to give compound 2050 (300 mg, 969.60 umol, 99.27% yield) as a yellow solid. LCMS: EC1956-4-P1A1, RT = 0.373 min, m / z (M+l) = 310.2 Example 73 Synthesis of N-((2S)-l-oxo-3-phenyl-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 217) To a solution of compound 2050 (300 mg, 969 umol, 1.00 eq) in DCM (2 mL) was added TEA (196 mg, 1.94 mmol, 270 uL, 2.00 eq) and compound 2051 (142 mg, 971 umol, 104 uL, 1.20 eq). The mixture was stirred at 15 °C for 3 hrs. LCMS (EC1956-5-P1A1) showed that the compound 2050 was consumed completely and the desired mass (RT = 0.345 min, M+l = 420.3) was detected. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7um;mobile phase: [water(0.1%TFA)-ACN];B%: 23%-53%,10min) to afford the Compound 217 (169 mg, 395.57 umol, 40.8% yield, 98.2% purity) as a white solid. LCMS: EC1956-5-P1A1 , RT = 0.345 min, m / z (MS+1 = 420.3) LCMS: EC1956-5-P1B2, RT = 0.359 min, m / z (M+l) = 420.1 HPLC: EC1956-5-P1B4, RT = 0.853 min, 1H NMR: EC1956-5-P1B1 (400 MHz, DMSO) 3 9.06 - 8.93 (m, 1H), 8.76 - 8.65 (m, 1H), 8.60 (s, 1H), 8.21 (br d, J= 8.0 Hz, 1H), 7.98 -7.65 (m, 3H), 7.40 - 7.15 (m, 6H), 5.88 - 5.70 (m, 1H), 5.17 - 4.97 (m, 1H), 3.88 (br d, J= 14.6 Hz, 2H), 3.16-3.07 (m, 2H), 2.96 - 2.81 (m, 1H), 1.62-0.60 (m, 6H) Example 74 Synthesis of (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide H .A N 3.00 eq Zn, 0.10 eq l2               Boc DMF(10V)          C Zn 25-50 °C, 6 hrs                | I 2052                                 2053 To a solution of I2 (1.62 g, 6.38 mmol, 1.29 mL, 0.10 eq) in DMF (84.0 mL) was added Zn (12.5 g, 191 mmol, 3.00 eq) at 25 °C. The mixture was stirred at 50 °C for 3 hrs. Then the mixture cooled to 25 °C, the compound 2052 (21.0 g, 63.8 mmol, 1.00 eq) in DMF (120 mL) was added. The mixture was stirred at 25 °C for 3 hrs. TLC (Petroleum ether: Ethyl acetate = 5:1) showed compound 2052 (Rf= 0.40) was consumed and the one new spot (Rf = 0.50) was formed. The reaction mixture was filtered, the filtrate was used to next step. The filtrate was used to next step without purification. Compound 2053 (24.8 g, 62.8 mmol, 98.5% yield) was obtained as a gray liquid and dissolved in DMF (300 mL). Example 75 Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(difluoromethyl)phenyl)propanoate DMF(10v)         F 60 °C, 12 hrs 65,3% yield 2054                                     2056 To a solution of compound 2055 (24.8 g, 62.8 mmol, 1.3 eq) in DMF (300 mL) was added compound 2054 (10.0 g, 48.3 mmol, 1.00 eq), SPhos (1.98 g, 4.83 mmol, 0.10 eq), and Pd2(dba)3 (1.33 g, 1.45 mmol, 0.03 eq). The mixture was stirred at 60 °C for 12 hrs under N2. LCMS (EC2762-2-P1 Al) showed the compound 2054 was consumed and the desired mass (RT = 0.521 min, m / z (M-99) = 230.1) was detected. The reaction mixture was filtered, the filtrate was diluted with Ethyl acetate (400 mL) and H2O (500 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 30 / 1 to 5 / 1, Rf = 0.30 was collected). From HNMR (EC2762-2-P1A) and LCMS (EC2762-2-P1C1) showed the compound 2056 (11.0 g, 31.5 mmol, 65.3% yield, 94.4% purity) was obtained as brown yellow oil. LC-MS: EC2762-2-P1A1, RT = 0.521 min, m / z (M-99) = 230.1 LC-MS: EC2762-2-P1C1, RT = 0.525 min, m / z (M-99) = 230.1 ’H-NMR: EC2762-2-P1A, 400 MHz, DMSO-t / e 5 7.56 - 7.30 (m, 2H), 7.12 (s, 1H), 6.98 (s, 1H), 6.84 (s, 1H), 7.15 - 6.77 (m, 1H), 4.27 - 3.97 (m, 1H), 3.62 (s, 3H), 3.22 - 2.77 (m, 2H), 1.39 - 1.26 (m, 9H) Example 76 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(dijluoromethyl)phenyl)propanoic acid F Boc F MeOH:H2O=1:1 0~25 °C, 12 hrs 98 1 % yield OH 3.00 eq LiOH.H2O F B oc 2056 2057 To a solution of compound 2056 (11.0 g, 31.5 mmol, 94.4% purity, 1.00 eq) in MeOH (100 mL) was added the solution of LiOH.H2O (3.97 g, 94.6 mmol, 3.00 eq) in H2O (100 mL) at 0 °C, then the reaction mixture was stirred at 25 °C for 12 hrs. LCMS (EC2762-3-P1 Al) showed the compound 2056 was consumed and the desired mass (RT = 0.466 min, m / z (M-99) = 216.1) was detected. The reaction mixture was adjusted to pH = 5 with IM HC1, and the reaction mixture was partitioned between ethyl acetate (250 mL) and water (150 mL). The organic phase was separated, washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. From LCMS (EC2762-3-P1B1) and HNMR (EC2762-3-P1A) showed the product compound 2057 (10.0 g, 30.9 mmol, 98.1% yield, 97.5% purity) was obtained as gray solid. LC-MS: EC2762-3-P1A1, RT = 0.466 min, m / z (M-99) = 216.1 LC-MS: EC2762-3-P1B1, RT = 0.468 min, m / z (M-99) = 216.1 ’H-NMR: EC2762-3-P1A, 400 MHz, CDCh 5 7.46 (d, J= 8.0 Hz, 2H), 7.29 (br d, J= 7.6 Hz, 2H), 6.64 (t, J= 56.4 Hz, 1H), 4.97 (br d, J = 7.6 Hz, 1H), 4.65 (br d, J= 6.4 Hz, 1H), 3.34 - 2.95 (m, 2H), 1.45 - 1.25 (m, 9H) Example 77 Synthesis of tert-butyl ((2S)-3-(4-(difluoromethyl)phenyl)-l-oxo-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-2-y I) carbamate F 2057                                           2059 To a solution of compound 2057 (10.0 g, 30.9 mmol, 97.5% purity, 1.00 eq) and compound 2058 (5.02 g, 30.9 mmol, 1.00 eq) in DCM (100 mL) was added T3P (23.5 g, 36.9 mmol, 22.0 mL, 50% purity, 1.20 eq) and DIEA (8.16 g, 63.1 mmol, 11.0 mL, 2.04 eq), then the reaction mixture was stirred at 25 °C for 2 hrs. LCMS (EC2762-4-P1 Al) showed the compound 2057 was consumed and the desired mass (RT = 0.441 min, m / z (M+l) = 460.3) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 10 um); mobile phase: [water ( NH4HCO3)-ACN]; B%: 45%-70%, 20 min). From HNMR (EC2762-4-P1 A) and LCMS (EC2762-4-P1B1) showed the product compound 2059 (2.70 g, 4.96 mmol, 16.0% yield, 84.4% purity) was obtained as white solid. LC-MS: EC2762-4-P1A1, RT = 0.441 min, m / z (M+l) = 460.3 LC-MS: EC2762-4-P1B1, RT = 0.430 min, m / z (M+l) = 460.4 ’H-NMR: EC2762-4-P1A, 400 MHz, DMSO-t / e 5 8.50 - 8.31 (m, 2H), 7.65 - 7.22 (m, 7H), 7.15 - 6.86 (m, 1H), 5.73 (br d, J= 15.6 Hz, 1H), 4.92 - 4.56 (m, 1H), 4.06 - 3.68 (m, 1H), 3.17 - 2.64 (m, 3H), 2.41 - 2.30 (m, 1H), 1.81 - 1.43 (m, 3H), 1.41 - 1.24 (m, 9H), 1.05 (br s, 2H) Example 78 Synthesis of (2S)-2-amino-3-(4-(dijluoromethyl)phenyl)-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 2059                                 2060 To a solution of compound 2059 (2.70 g, 4.96 mmol, 84.4% purity, 1.00 eq) in EtOAc (27.0 mL) was added HC1 / EtOAc (4 M, 27.0 mL, 18.3 eq), then the reaction mixture was stirred at 25 °C for 12 hrs. LCMS (EC2762-5-P1A1) showed the compound 2059 was consumed and the desired mass (RT = 0.251 min, m / z (M-99) = 360.2) was detected. The reaction mixture was concentrated. The residue was used to next step without purification. From HNMR (EC2762-5-P1A) showed the product compound 2060 (2.50 g, crude, HC1) was obtained as light brown solid. LC-MS: EC2762-5-P1A1, RT = 0.250 min, m / z (M-99) = 360.2 ’H-NMR: EC2762-5-P1A, 400 MHz, DMSO-t / e 5 9.03 - 8.63 (m, 2H), 8.59 (br d, J= 5.2 Hz, 1H), 8.05 - 7.67 (m, 1H), 7.64 - 7.30 (m, 3H), 7.27 - 6.83 (m, 1H), 5.74 (br d, J= 26.8 Hz, 1H), 4.93 - 4.60 (m, 1H), 4.50 - 3.96 (m, 3H), 3.36 - 2.99 (m, 2H), 2.92 - 2.56 (m, 1H), 2.46 - 2.22 (m, 1H), 1.95 - 1.35 (m, 2H), 1.27 - 1.08 (m, 1H) Example 79 Synthesis of N-((2S)-3-(4-(difluoromethyl)phenyl)-l-oxo-l-(2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 220) 2060                               Compound 220 To a solution of compound 2060 (2.30 g, 6.40 mmol, 1.00 eq) in DCM (25.0 mL)was added TEA (2.18 g, 21.5 mmol, 3 mL, 3.00 eq) and compound 2061 (924 mg, 7.08 mmol, 700 uL, 1.11 eq) at 0 °C, and then the reaction mixture stirred at 25 °C for 30 min. LCMS (EC2762-7-P1A2) showed the compound 2060 was consumed and the desired mass (RT = 0.385 min, m / z (M+l) = 454.3) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 20 min). From HNMR (EC2762-7-P1B), LCMS (EC2762-7-P1B1) and HPLC (EC2762-7-P1B2) showed the product Compound 220 (1.60 g, 3.41 mmol, 53.3% yield, 96.6% purity) was obtained as gray solid. LC-MS: EC2762-7-P1A2, RT = 0.385 min, m / z (M+l) = 454.3 LC-MS: EC2762-7-P1B1, RT = 0.389 min, m / z (M+l) = 454.2 HPLC: EC2762-7-P1B2, RT =1.428 min, 96.5% purity ’H-NMR: EC2762-7-P1B, 400 MHz, DMSO-t / e 5 9.02 - 8.65 (m, 1H), 8.59 - 8.29 (m, 2H), 7.93 - 7.68 (m, 1H), 7.65 - 7.40 (m, 4H), 7.33 -7.20 (m, 2H), 7.16 - 6.80 (m, 1H), 6.67 - 6.43 (m, 1H), 5.87 - 5.55 (m, 1H), 5.42 - 5.02 (m, 1H), 4.53 - 3.72 (m, 1H), 3.26 - 3.05 (m, 2H), 2.94 - 2.59 (m, 1H), 2.40 - 2.30 (m, 1H), 1.78 -0.86 (m, 5H) Example 80 Synthesis of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(fluoromethoxy)phenyl)propanoate 2.00 eq Br'^F 1.00 eqNaH DMF (10 V) 0~25 °C, 5 hrs 3001 O 3002 98.6% yieid To a solution of compound 3001 (5.00 g, 14.8 mmol, 1.00 eq) in THF (50.0 mL) was added NaH (600 mg, 15.0 mmol, 60% purity, 1.01 eq) at 25 °C and the mixture was stirred at this temperature for 0.5 hr. Then bromo (fluoro) methane (3.35 g, 29.64 mmol, 2.00 eq) in THF (10 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 2 hrs. The resulting mixture was warmed to 25 °C and stirred at 25°C for 2 hrs. LCMS showed that compound 3001 (m / z=337.4) was consumed completely the desired MS (Rt = 0.657 min, M-155 = 214.1) was found. TLC (Plate 1, PE: EA = 5:1) showed the consumption of compound 3001 (Rf = 0.45) and the one large new spot (Rf = 0.65) was formed. The reaction mixture was poured into saturated NH4Q aqueous solution (100 mL) and extracted with EtOAc (50.0 mL*3). The combined organic layer was washed with brine (50.0 mL*2), dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, PE: EA=20:l-5:l), the fraction (Plate 1, Rf = 0.65) was collected. Compound 3002 (5.40 g, 14.6 mmol, 98.6% yield) was obtained as yellow oil, checked by LCMS and HNMR. LC-MS (reaction mixture): RT = 0.657 min, m / z (M-155) = 214.1 LC-MS (compound 3002): RT = 0.651 min, m / z (M-155) = 214.1 ’H-NMR: 400 MHz, CDCh: 5 7.25 - 6.86 (m, 4H), 5.89 - 5.51 (m, 2H), 5.00 (br s, 1H), 4.43 (br s, 1H), 3.02 (br s, 2H), 1.42 (br d, J= 3.8 Hz, 18H) Example 81 Synthesis of (S)-2-amino-3-(4-(fluoromethoxy)phenyl)propanoic acid To a solution of compound 3002 (5.50 g, 14.8 mmol, 1.00 eq) in EtOAc (20.0 mL) was added HCl / EtOAc (4 M, 30.0 mL, 8.06 eq). The mixture was stirred at 25 °C for 3 hrs. LCMS showed compound 3002 (m / z=369) was consumed completely and the main peak with desired MS (RT = 0.246 min, M-155 = 214.0) was found. The reaction mixture was concentrated under vacuum. No need further purification to give compound 3003 (3.90 g, crude, HC1) as white solid and used to the next step. Compound 3003 (3.90 g, crude, HC1) was obtained as white solid, checked by HNMR. LC-MS (reaction mixture): RT = 0.246 min, m / z (M-155) = 214.0 ’H-NMR: 400 MHz, DMSO-t / e: 5 14.10 - 13.61 (m, 1H), 8.35 (br s, 2H), 7.26 (d, J= 8.5 Hz, 2H), 7.07 (d, J= 8.5 Hz, 2H), 6.04 - 5.65 (m, 2H), 4.15 (br s, 1H), 3.09 (br d, J= 6.1 Hz, 2H) Example 82 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(fluoromethoxy)phenyl)propanoic acid 3003                                3004 To a solution of compound 3003 (3.07 g, 14.40 mmol, 1.00 eq) in THF (40.0 mL) was added (Boc)2O (12.8 g, 58.7 mmol, 13.5 mL, 4.08 eq) and TEA (5.82 g, 57.5 mmol, 8 mL, 3.99 eq). The mixture was stirred at 25 °C for 4 hrs. LCMS showed that compound 3003 (m / z = 214) was consumed completely and the desired MS (Rt = 0.488 min, M+23 = 336) was found. The reaction mixture was filtered, and the filter liquor was collected and concentrated. The crude product was purified by prep-HPLC (column: YMC Triart Cl8 70*250mm*7um; mobile phase: [water (NH4HCO3)-ACN]; B%: 13%-43%, 20 min). Compound 3004 (1.47 g, 4.60 mmol, 31.9% yield, 98% purity) was obtained as yellow oil, checked by LCMS and HNMR. LC-MS (reaction mixture): RT = 0.488 min, m / z (M+23) = 336 LC-MS (compound 22): RT = 0.468 min, m / z (M-99) = 216.1 ’H-NMR: 400 MHz, CDCh: 5 7.15 (d, J = 8.4 Hz, 2H), 6.94 (d, J= 8.5 Hz, 2H), 5.76 -5.67 (m, 1H), 5.62 - 5.55 (m, 1H), 5.42 (br d, J= 7.1 Hz, 1H), 4.28 (br d, J= 6.1 Hz, 1H), 3.15 (brdd, 7=4.9, 13.8 Hz, 1H), 1.38 (s, 8H) Example 83 Synthesis of tert-butyl ((S)-3-(4-(fluoromethoxy)phenyl)-l-oxo-l-((R)-2-(pyridin-3- yl)piperidin-l-yl)propan-2-yl)carbamate 3004                                      3006 To a solution of compound 3004 (1.10 g, 3.51 mmol, 1.00 eq) in DCM (20.0 mL) was added compound 3005 (570 mg, 3.51 mmol, 1.00 eq) and DIEA (890 mg, 6.89 mmol, 1.2 mL, 1.96 eq). Then HATU (1.65 g, 4.34 mmol, 1.24 eq) was added at 0 °C. The mixture was stirred at 25 °C for 2 hr. LCMS showed that compound 3004 (m / z = 313) was consumed completely and the desired MS (Rt = 0.455 min, M+l = 458.3) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7um; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 24min). Compound 3006 (323 mg, 670 umol, 19.1% yield, 95% purity) was obtained as yellow oil, checked by LCMS and HNMR. LC-MS (reaction mixture): RT = 0.441 min, m / z (M+l) = 460.3 LC-MS (compound 23): RT = 0.430 min, m / z (M+l) = 460.4 ’H-NMR: 400 MHz, CDCh: 5 8.52 (br s, 1H), 8.13 (br s, 1H), 7.68 (br d, J= 7.9 Hz, 1H), 7.46 - 7.36 (m, 1H), 7.23 (br d, J= 8.4 Hz, 2H), 7.08 - 7.00 (m, 2H), 5.94 (br d, J= 1.4 Hz, 1H), 5.77 (s, 1H), 5.63 (s, 1H), 5.52 (br d, J= 8.6 Hz, 1H), 4.95 - 4.84 (m, 1H), 3.78 -3.65 (m, 1H), 3.07 - 2.95 (m, 2H), 2.53 - 2.20 (m, 2H), 1.82 - 1.57 (m, 2H), 1.57 - 1.49 (m, 2H), 1.44 (s, 9H) Example 84 Synthesis of (S)-2-amino-3-(4-(fluoromethoxy)phenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 3006                                3007 To a solution of compound 3006 (0.53 g, 1.16 mmol, 1.00 eq) in EtOAc (5 mL) was added HCl / EtOAc (4 M, 5 mL, 17.2 eq). The mixture was stirred at 25 °C for 1 hrs. LCMS 5 showed that compound 3006 (m / z = 457) was consumed completely and the desired MS (Rt = 0.317min, M+l = 358.1) was found. The reaction mixture was concentrated under vacuum. No need further purification to give compound 3007 as white solid and used to the next step. Compound 3007 (0.528 g, crude, HC1) was obtained as white solid, checked by HNMR. LC-MS (reaction mixture): RT = 0.317 min, m / z (M+l) = 358.1 10          ’H-NMR: 400 MHz, DMSO-t / e: 5 8.91 (s, 1H), 8.75 (br d, J= 5.4 Hz, 1H), 8.70 - 8.58 (m, 3H), 8.52 (br d, J= 7.9 Hz, 1H), 7.92 (dd, J= 5.5, 8.0 Hz, 1H), 7.30 (br d, J= 8.5 Hz, 2H), 7.13 (d, J= 8.4 Hz, 2H), 5.95 - 5.88 (m, 1H), 5.80 - 5.76 (m, 1H), 5.73 (br s, 1H), 4.83 -4.68 (m, 1H), 3.67 (br d, J= 13.6 Hz, 1H), 3.17 (br dd, J= 5.1, 13.1 Hz, 1H), 2.96 (br dd, J= 9.3, 13.1 Hz, 1H), 2.42 - 2.26 (m, 2H), 1.91 (s, 1H), 1.55 - 1.21 (m, 3H) 15 Example 85 Synthesis of N-((S)-3-(4-(fluoromethoxy)phenyl)-l-oxo-l-((R)-2fpyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 301) 0-25 °C, 2 hrs 26.4% yieid 3007                                    Compound 301 20         To a solution of compound 3007 (0.25 g, 634.71 umol, 1.00 eq, HC1) in DCM (5 mL) was added thiophene-2-carboxylic acid (82 mg, 639.88 umol, 1.01 eq) and DIEA (244 mg, 1.89 mmol, 330 uL, 2.98 eq). Then HATU (290 mg, 762.70 umol, 1.20 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 hr. LCMS showed that compound 3007 (m / z = 457) was consumed completely and the desired MS (Rt = 0.429min, M+l = 468.3) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: YMC Triart Cl8 250*50mm*7um; mobile phase: [water ( NH4HCO3)-ACN];B%: 27%-57%,20min). Compound 301 (86 mg, 167.38 umol, 26.4% yield, 91.0% purity) was obtained as white solid, checked by LCMS, HPLC and HNMR. LC-MS (reaction mixture): RT = 0.429 min, m / z (M+l) = 468.3 LC-MS: RT = 1.625 min, m / z (M+l) = 468.2 HPLC: RT =1.652 min, 91.0% purity ’H-NMR: 400 MHz, CDCh: 5 8.49 (br s, 2H), 7.59 - 7.44 (m, 3H), 7.25 (br s, 1H), 7.15 - 7.01 (m, 3H), 6.99 - 6.86 (m, 2H), 5.95 (br d, J= 2.8 Hz, 1H), 5.78 (s, 1H), 5.64 (s, 1H), 5.51 - 5.37 (m, 1H), 3.82 - 3.73 (m, 1H), 3.28 - 3.09 (m, 2H), 2.96(brt,J= 13.4 Hz, 1H), 2.38 (br d, J= 13.0 Hz, 1H), 1.86 - 1.52 (m, 6H), 0.93 - 0.64 (m, 1H) Example 86 Synthesis of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- (dijluoromethoxy)phenyl)propanoate 80 °C, 3 hrs 3009            26.i%ywto               3010 To a solution of compound 3009 (10.0 g, 29.6 mmol, 1.00 eq) in DMF (100 mL) was added CS2CO3 (11.5 g, 35.5 mmol, 1.20 eq) and (2-chloro-2,2-difluoro-acetyl)oxysodium (5.42 g, 35.5 mmol, 1.20 eq), then the reaction mixture was stirred at 80 °C for 3 hrs. LCMS showed 30% of the Reactant 1 (RT=0.578 min, m / z (M-155) = 182.2) remained and the desired mass (RT = 0.667 min, m / z (M-155) = 232.1) was detected. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% TFA condition). From HNMR showed the product compound 3010 (3.00 g, 7.74 mmol, 26.1% yield) was obtained as gray solid. LC-MS (reaction mixture): RT = 0.667 min, m / z (M-155) = 232.1 ’H-NMR: 400 MHz, DMSO: 5 7.39 - 7.25 (m, 2H), 7.19 - 7.14 (m, 1H), 7.08 (br d, J = 8.4 Hz, 2H), 4.12 - 3.76 (m, 1H), 3.03 - 2.73 (m, 2H), 1.37-1.31 (m, 18H) Example 87 Synthesis of (S)-2-amino-3-(4-(difluoromethoxy)phenyl)propanoic acid To a solution of compound 3010 (600 mg, 2.09 mmol, 1.00 eq) in TFA (5 mL) then the reaction mixture was stirred at 25 °C for 2 hrs. LCMS showed the compound 3010 was consumed and the desired mass (RT = 0.288 min, m / z (M+l) = 232.1) was detected. The reaction mixture was concentrated. The residue was used to next step without purification. From HNMR showed the product compound 3011 (500 mg, 1.45 mmol, 69.4% yield, TFA) was obtained as gray solid. LC-MS (reaction mixture): RT = 0.288 min, m / z (M+l) = 232.1 ’H-NMR: 400 MHz, DMSO: 5 8.33 (s, 3H), 7.37 - 7.00 (m, 5H), 4.17(s, 1H), 3.13 -3.08 (m, 2H) Example 88 Syntheis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(difluoromethoxy)phenyl)propanoic acid To a solution of compound 3011 (500 mg, 2.16 mmol, 1.00 eq) in THF (5 mL) and H2O (5 mL) was added NaHCOs (545 mg, 6.49 mmol, 252 uL, 3.00 eq) and BOC2O (475 mg, 2.18 mmol, 500 uL, 1.01 eq) and then the reaction mixture was stirred at 25 °C for 12 hrs. LC-MS showed the compound 3011 was consumed and the desired mass (RT = 0.532 min, m / z (M-99) = 232.1) was detected. The reaction mixture was poured into H2O (50.0 mL) and adjusted to pH = 5 with citirc acid, and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (20.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated. The residue was used to next step without purification. From HNMR and LCMS showed the product compound 3012 (500 mg, 1.37 mmol, 63.3% yield, 90.7% purity) was obtained as colourless oil. LC-MS (reaction mixture): RT = 0.532 min, m / z (M-99) = 232.1 LC-MS: RT = 0.537 min, m / z (M-99) = 232.1 ’H-NMR: 400 MHz, DMSO: 5 7.25 - 6.95 (m, 4H), 6.49 (t, J= 74.0 Hz, 1H), 5.01 (br d, J= 7.1 Hz, 1H), 4.75 - 3.94 (m, 2H), 3.38 - 2.86 (m, 2H), 1.48- 1.31 (m, 9H) Example 89 Synthesis of tert-butyl ((S)-3-(4-(dijluoromethoxy)phenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)carbamate 3012                                      3014 To a solution of compound 3012 (500 mg, 1.51 mmol, 1.00 eq) and compound 3013 (250 mg, 1.54 mmol, 1.02 eq) in DCM (3 mL) was added DIEA (393 mg, 3.04 mmol, 530 uL, 2.02 eq) and HATU (689 mg, 1.81 mmol, 1.20 eq) at 0 °C, and then the reaction mixture was stirred at 25 °C for 12 hrs. LCMS showed the compound 3012 was consumed and the desired mass (RT = 0.493 min, m / z (M+l) = 476.4) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl8 200*40mm*10um; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 10 min). From HNMR and LCMS showed the product compound 3014 (290 mg, 453 umol, 30.0% yield, 74.3% purity) was obtained as colorless oil. LC-MS (reaction mixture): RT = 0.493 min, m / z (M+l) = 476.4 LC-MS (compound 3014): RT = 0.498 min, m / z (M+l) = 476.3 ’H-NMR: 400 MHz, DMSO: 5 8.58 - 8.48 (m, 1H), 7.85 (br d, J= 7.6 Hz, 1H), 7.59 -7.24 (m, 4H), 7.22 - 6.95 (m, 3H), 5.74 (br s, 1H), 4.91 - 4.44 (m, 1H), 2.98 - 2.71 (m, 3H), 2.45 - 2.23 (m, 2H), 1.78 - 1.44 (m, 2H), 1.43 - 1.27 (m, 9H), 1.25 - 0.65 (m, 3H) Example 90 Synthesis of (S)-2-amino-3-(4-(dijluoromethoxy)phenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l- yl)propan-l-one 3014                                   3015 To a solution of compound 3014 (290 mg, 609 umol, 1.00 eq) in EtOAC (2 mL) was added HCl / EtOAc (4 M, 2.07 mL, 13.5eq) then the reaction mixture was stirred at 25 °C for 0.5 hrs. LCMS showed the compound 3014 was consumed and the desired mass (RT = 0.361 min, m / z (M+) = 376.3) was detected. The reaction mixture was concentrated. The residue was used to next step without purification. Compound 3015 (300 mg, crude, HC1) was obtained as colorless oil. LCMS (reaction mixture): RT = 0.361 min, m / z (M+) = 376.3. Example 91 Synthesis of N-((S)-3-(4-(difluoromethoxy)phenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 302) 3015                                 Compound 302 To a solution of compound 3015 (150 mg, 399 umol, 1.00 eq) in DCM (2 mL) was added DIEA (103 mg, 803 umol, 140 uL, 2.01 eq) and thiophene-2-carbonyl chloride (61.6 mg, 420 umol, 45 uL, 1.05 eq) at 0 °C, and then the reaction mixture was stirred at 25 °C for 1 hr. LCMS showed the compound 3015 was consumed and the desired mass (RT = 0.479 min, m / z (M+l) = 486.4) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 min). From HNMR, LCMS and HPLC showed the product Compound 302 (58.44 mg, 118 umol, 29.7% yield, 98.7% purity) was obtained as white solid. LCMS (reaction mixture): RT = 0.479 min, m / z (M+l) = 486.4 LCMS: RT = 0.473 min, m / z (M+l) = 486.3 HPLC: RT = 1.661min, 98.7% purity ’H-NMR: 400 MHz, MeOD: 5 8.45 - 8.27 (m, 2H), 7.79 - 7.53 (m, 2H), 7.39 - 7.28 (m, 4H), 7.20 - 6.92 (m, 4H), 6.86 - 6.53 (m, 1H), 5.89 - 5.30 (m, 2H), 4.60 - 3.98 (m, 1H), 3.27 - 3.09 (m, 2H), 2.84 - 2.34 (m, 2H), 2.02 - 1.84 (m, 1H), 1.75 - 1.32 (m, 4H) Example 92 Synthesis of N-((S)-3-(4-(difluoromethoxy)phenyl)-l-oxo-l-(^R)-2-(pyridin-3-yl)piperidin-l-y l)propan-2-y I)furan-2-carboxamide (Compound 304) 3015                                 Compound 304 To a solution of compound 3015 (100 mg, 266 umol, 1.00 eq) in DCM (2 mL) was added TEA (58.1 mg, 574 umol, 80 uL, 2.16 eq) and furan-2-carbonyl chloride (39.6 mg, 303.38 umol, 30 uL, 1.14 eq) at 0 °C, and then the reaction mixture was stirred at 25 °C for 1 hr. LC-MS showed the compound 3015 was consumed and the desired mass (RT = 0.465 min, m / z (M+l) = 470.3) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (HCl)-ACN]; B%: 19%-49%, 10 min). From HNMR, LCMS and HPLC showed the product Compound 204 (25.84 mg, 53.99 umol, 20.3% yield, 98.1% purity) was obtained as colorless oil. LC-MS (reaction mixture): RT = 0.465 min, m / z (M+l) = 470.3 LC-MS: RT = 0.473 min, m / z (M+l) = 470.3 HPLC: RT = 1.592 min, 98.1% purity ’H-NMR: 400 MHz, MeOD: 5 8.92 - 8.45 (m, 3H), 8.16 - 8.00 (m, 1H), 7.72 (d, J= 0.8 Hz, 1H), 7.50 - 7.07 (m, 5H), 7.03 - 6.59 (m, 2H), 5.87 (br s, 1H), 5.27 - 5.12 (m, 1H), 3.94 (br d, J= 14.0 Hz, 1H), 3.28-3.12 (m, 2H), 2.99 (br t, J= 12.2 Hz, 1H), 2.46 - 2.27 (m, 1H), 1.79 - 1.04 (m, 5H), 0.77 - 0.42 (m, 1H) Example 93 Synthesis of tert-butyl ((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(4- (trifhioromethoxy)phenyl)propan-2-yl)carbamate 1.08 eq 2.00 eq TEA, 1.22 eq HATU DCM (8 V), 25 °C, 3 hrs 94.3% yield 3016                                                  3018 To the solution of compound 3016 (300 mg, 858 umol, 1.00 eq) in DCM (2 mL) was added HATU (397 mg, 1.04 mmol, 1.22 eq), TEA (174 mg, 1.72 mmol, 240 uL, 2.01 eq) and compound 3017 (150 mg, 924 umol, 1.08 eq) was added the reaction mixture was stirred at 25 °C for 3 hours. LCMS showed that compound 3016 was consumed and the desired mass (RT = 0.467 min, M+l = 494.5) was given. Crude reaction mixtures were combined for workup. The combined reaction mixture was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL x 2), the combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10um;mobile phase: [water(HCl)-ACN];B%: 35%-65%,10min) to afford compound 3018 (400 mg, 810.51 umol, 94.37% yield) ) was obtained as a yellow solid. LCMS (reaction mixture): RT=0.467min, m / z (M+l) = 494.5 Example 94 Synthesis of (S)-2-amino-1-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(4- (trifluoromethoxy)phenyl)propan-l-one 3018                                     3019 To the solution of compound 3018 (400 mg, 810 umol, 1.00 eq) in EtOAc (2 mL) was added HClZEtOAc (4 M, 2 mL, 9.87 eq). The reaction mixture was stirred at 20 °C for 1 hr. LCMS showed that compound 3018 was consumed and the desired mass (RT = 0.334 min, M+l = 394.2) was given. The reaction mixture was concentrated under vacuum. Compound 3019 (300 mg, 762 umol, 94.0% yield) was obtained as a yellow oil. LCMS (reaction mixture): RT=0.334 min, m / z (M+l) = 394.2 Example 95 Synthesis of N-((S)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)-3-(4-(trijluoromethoxy)phenyl)propan-2-yl)thiophene-2-carboxamide (Compound 303) 3019                                         Compound 303 To the solution of compound 3019 (200 mg, 508 umol, 1.00 eq) in DMF (2 mL) was added TEA (218 mg, 2.16 mmol, 300 uL, 4.24 eq) and thiophene-2-carbonyl chloride (75.3 mg, 514 umol, 55 uL, 1.01 eq) was added the reaction mixture was stirred at 25 °C for 3 hours. LCMS showed that compound 3019 was consumed and the desired mass (RT = 0.492 min, M+l = 504.3) was given. The reaction mixture was partitioned between 20.0 mL H2O and 60.0 mL EtOAc and separated. The aqueous layer was then extracted with (2x30.0 mL) EtOAc. The organic layers were combined dried over MgSO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna Cl8 150*25mm* lOum; mobile phase: [water (HCl)-ACN]; B%: 26%-56%, 10 min) to afford Compound 303 (47 mg, 93.25 umol, 18.3% yield, 99.9% purity) as a off-white gum. LCMS (reaction mixture): RT=0.492 min, m / z (M+l) = 504.3. ‘HNMR CDCh 400 MHz: 5 8.60 - 8.52 (m, 2H), 7.89 (br dd, J= 1.6, 4.2 Hz, 1H), 7.66 - 7.43 (m, 3H), 7.35 (br d, J= 8.4 Hz, 2H), 7.26 - 7.20 (m, 2H), 7.13 - 7.03 (m, 2H), 6.93 (br d, J= 6.8 Hz, 1H), 5.94 (br d, J= 1.2 Hz, 1H), 5.44 - 5.24 (m, 1H), 3.93 - 3.63 (m, 1H), 3.31 - 3.15 (m, 2H), 3.05 - 2.85 (m, 1H), 2.39 - 2.26 (m, 1H), 1.70 - 1.27 (m, 5H), 0.95 -0.43 (m, 1H) LCMS: RT = 0.463 min, m / z (M+l) = 504.4 HPLC: RT = 1.838 min Synthesis of N-((5)-3-(4-(fluoromethoxy)phenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 305) 3020                                      Compound 305 To a solution of compound 3020 (0.165 g, 461.64 umol, 1.00 eq) in DCM (3 mL) was added DIEA (148.40 mg, 1.15 mmol, 200 uL, 2.49 eq). Then compound 3021 (60.72 mg, 465.18 umol, 46 uL, 1.01 eq) was added at 0°C. The mixture was stirred at 25 °C hr for 3 hrs. LCMS (EC3956-24-P1A1) showed that reactant l(m / z = 357) was consumed completely and the desired MS (Rt = 0.439 min, M+l = 452.4) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water (FA)-ACN]; B%: 12%-42%, 9 min). Compound 305 (0.035 g, 67.44 umol, 14.6% yield, 87.8% purity) was obtained as white solid, checked by HPLC (EC3956-24-P1A9), LCMS (EC3956-24-P1A7) and HNMR (EC3956-24-P1A1) LCMS: EC3956-24-P1A1, RT=0.439 min, m / z (M+l) = 452.4 LCMS: EC1557-136-P1A4, RT= 1.575 min, m / z (M+l) = 452.3 HPLC: EC1557-136-P1A5, RT = 1.549 min, 87.8% purity ’H NMR: EC1557-136-P1A1, 400 MHz, CDCh 5 8.60 - 8.34 (m, 2H), 7.57 - 7.43 (m, 2H), 7.32 (br s, 1H), 7.22 (br d, J= 8.3 Hz, 1H), 7.15 (br d, J= 3.5 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.95 - 6.84 (m, 1H), 6.52 (dd, J= 1.7, 3.4 Hz, 1H), 5.95 (br d, J= 2.8 Hz, 1H), 5.80- 5.74 (m, 1H), 5.66-5.61 (m, 1H), 5.41 (dt, J= 5.5, 8.4 Hz, 1H), 3.85 - 3.68 (m, 1H), 3.32 - 3.03 (m, 2H), 3.00 - 2.87 (m, 1H), 2.40 - 2.18 (m, 4H), 1.78 - 1.34 (m, 5H), 0.83 - 0.61 (m, 1H) Example 97 Synthetic Protocol for Compound 401 and Compound 402 4001                                4003                         4004                             Compound 401 4004                           Compound A'2 Example 98 5 Synthesis of tert-butyl ((S)-3-(4-isopropylphenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l- yl)propan-2-yl)carbamate NHBoc 4001                                  4003 To a solution of compound 4001 (300 mg, 975 umol, 1.00 eq) and compound 4002 10   (160 mg, 986 umol, 1.01 eq) in DCM (3.00 mL) was added DIEA (256 mg, 1.98 mmol, 345 uL, 2.03 eq) and HATU (450 mg, 1.18 mmol, 1.21 eq) at 0 °C. The mixture was stirred at 25°C for 2 hrs. LCMS (EC5892-20-P1A1) showed that compound 4001 (m / z=307) was consumed completely and the desired MS (Rt =0.502 min, M+l=452.4) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep- 15 HPLC (column: Phenomenex C18 250*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 46%-76%, 8 min). Compound 4003 (0.36 g, 805 umol, 82.4% yield, 99.6% purity) was obtained as yellow oil, checked by LCMS (EC5892-20-P1 Al) and HNMR (EC5892-20-P1A1). LCMS: EC5892-20-P1A1, Rt = 0.502 min, m / z +1 = 452.4 HNMR: EC5892-20-P1A1, (400 MHz, CDCh) 3 = 8.48 (br s, 2H), 7.62 - 7.43 (m, 1H), 7.20 (s, 4H), 7.12 - 6.90 (m, 1H), 5.93 (br d, J= 1.1 Hz, 1H), 5.37 (br d, J= 8.0 Hz, 1H), 4.91 (q, J = 7.9 Hz, 1H), 3.63 (br d, J= 13.9 Hz, 1H), 3.09 - 2.96 (m, 2H), 2.94 - 2.77 (m, 2H), 2.27 (br d, J= 14.3 Hz, 1H), 1.64 - 1.54 (m, 1H), 1.46 (s, 9H), 1.41 (br s, 2H), 1.36 - 1.29 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H), 0.41 - 0.19 (m, 1H) Example 99 Synthesis of (S)-2-amino-3-(4-isopropylphenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-1-one 4003                         4004 To a solution of compound 4003 (360 mg, 797.17 umol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 1.73 mL, 8.67 eq). The mixture was stirred at 25°C for 2 hrs. LCMS (EC5892-21-P1A1) showed that compound 4003 (m / z=451) was consumed completely and the desired MS (Rt =0.375 min, M+l=352.3) was found. The reaction mixture was concentrated under vacuum. No need further purification to give compound 4004 (335 mg, crude, HC1) as white solid and used to the next step. Compound 4004 (335 mg, crude, HC1) was obtained as white solid, checked by HNMR (EC5892-21-P1A1). LCMS: EC5892-21-P1A1, Ret. Time = 0.375 min, m / z +1 = 352.3 ‘HNMR: EC5857-3-P1 Al (400 MHz, DMSO) 3 = 8.93 - 8.83 (m, 1H), 8.72 (br d, J= 5.1 Hz, 1H), 8.62 (br s, 2H), 8.53 - 8.37 (m, 1H), 7.88 (br d, J= 5.4 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.23 - 7.17 (m, 2H), 5.72 (br s, 1H), 4.78 - 4.70 (m, 1H), 3.58 (br d, J= 13.0 Hz, 1H), 3.18 (br dd, J= 4.6, 12.8 Hz, 1H), 2.94 - 2.85 (m, 2H), 2.80 - 2.69 (m, 1H), 2.37 - 2.26 (m, 1H), 2.04 - 1.84 (m, 1H), 1.45 - 1.34 (m, 1H), 1.23 (br s, 1H), 1.18 (d, J= 6.9 Hz, 6H), 1.15- 1.05 (m, 2H) Synthesis of N-((8)-3-(4-isopropylphenyl)-l-oxo-1 -(d{)-2-lpyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 401) 4004                           Compound 401 To a solution of compound 4004 (165 mg, 469 umol, 1.00 eq) and TEA (95.2 mg, 941 umol, 131 uL, 2.00 eq) in DCM (3.00 mL) was added compound 4005 (62.0 mg, 475 umol, 47.0 uL, 1.01 eq) at 0°C. The mixture was stirred at 25 °C for 2 hr. LCMS (EC5892-22-P1A1) showed that compound 4004 (m / z=351) was consumed completely and the desired MS (Rt =0.475 min, M+l=446.2) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 9min). Compound 401 (140 mg, 313 umol, 66.6% yield, 99.6% purity) was obtained as yellow solid, checked by LCMS(EC5892-22-PlA4), HPLC(EC5892-22-PlA2), HNMR(EC5892-22-P1A1) and Chiral SFC(EC5892-22-PlA3) LCMS: EC5892-22-P1A1, product: Ret. Time = 0.475 min, m / z +1 = 446.2 ‘HNMR: EC5892-22-P1 Al (400 MHz, CDCk) 5= 8.56 - 8.37 (m, 2H), 7.50 - 7.41 (m, 2H), 7.24 (s, 2H), 7.23 - 7.19 (m, 2H), 7.16 - 7.10 (m, 1H), 7.09 - 6.90 (m, 1H), 6.51 (dd, J= 1.7, 3.4 Hz, 1H), 5.94 (br d, J= 3.4 Hz, 1H), 5.53 - 5.20 (m, 1H), 4.95 - 4.92 (m, 1H), 3.68 (br d, J = 13.6 Hz, 1H), 3.17 (d, J= 7.4 Hz, 2H), 3.00-2.74 (m, 2H), 2.29 (br d, J= 14.4 Hz, 1H), 1.62 (tt, J= 4.8, 13.5 Hz, 1H), 1.47- 1.31 (m, 2H), 1.23 (d, J= 6.9 Hz, 7H), 0.41 - 0.21 (m, 1H) LCMS: EC5892-22-P1A4, product: Ret. Time = 1.776 min, m / z +1 = 446.4 HPLC: EC5892-22-P1A2, product: Ret. Time = 2.065 min Chiral SFC: EC5892-22-P1A3, ee%=100 Example 101 Synthesis of N-((S)-3-(4-isopropylphenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 402) 4004                           Compound 402 To a solution of compound 4004 (165 mg, 425 umol, 1 eq, HC1) and TEA (87.2 mg, 862 umol, 120 uL, 2.03 eq) in DCM (3.00 mL) was added compound 4006 (63.0 mg, 430 umol, 46.0 uL, 1.01 eq) at 0°C. The mixture was stirred at 25 °C for 2 hrs. LCMS (EC5892-23-P1A1) showed that compound 4004 (m / z=351) was consumed completely and the desired MS (Rt =0.496 min, M+l=462.4) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 9 min). Compound 402 (110 mg, 237 umol, 55.9% yield, 99.8% purity) was obtained as yellow solid, checked by LCMS(EC5892-23-PlA3), HPLC(EC5892-23-PlA2), HNMR(EC5892-23-P1A1) and Chiral SFC(EC5892-23-PlA3). LCMS: EC5892-23-P1A1, product: Ret. Time = 0.496 min, m / z +1 = 462.4 ‘HNMR: EC5892-23-P1 Al (400 MHz, CDCk) 5= 8.48 (br s, 2H), 7.56 - 7.53 (m, 1H), 7.50 (d, J= 4.1 Hz, 1H), 7.30 (br dd, J= 5.1, 7.9 Hz, 1H), 7.26 - 7.23 (m, 2H), 7.23 - 7.18 (m, 2H), 7.09 - 7.01 (m, 2H), 6.03 - 5.58 (m, 1H), 5.49 -5.25 (m, 1H), 3.69 (br d, J= 13.9 Hz, 1H), 3.27 - 3.07 (m, 2H), 2.98 - 2.79 (m, 2H), 2.31 (br d, J= 14.5 Hz, 1H), 1.78 - 1.53 (m, 1H), 1.50 - 1.32 (m, 2H), 1.24 (d, J= 6.9 Hz, 7H), 0.47 -0.26 (m, 1H) LCMS: EC5892-23-P1A3, product: Ret. Time = 1.882 min, m / z +1 = 462.5 HPLC: EC5857-6-P1A2, product: Ret. Time = 2.152 min Chiral SFC: EC5892-23-PlA3, ee%= 100 Example 102 Synthetic Protocol for Compound 403, Compound 404, Compound 405, and Compound 406 4007 4009 4010 Compound 403 4016 1.00 eq 1,20 eq HATU, 2.00 eq DIEA DCM, 0-25 °C, 2 hrs HCI / EtOAc EtOAc, 25 °C 5.00 eq TEA DMF , 0-25 °C, 2 hrs 4017                                      4018 Compound 405 2.00 eq TEA 0-25 °C, 2 hrs 39.y% yield 1.00 eq 4018                                  Compound 406 4010                                   Compound 404 Example 103 5 Synthesis of tert-butyl ((5)-3-(4-ethylphenyl)-l-oxo-l-((A)-2-(pyri din-3-yl)piperi din-1- yl)propan-2-yl)carbamate NHBoc 4007 45.5% yield 4009 To a solution of compound 4007 (4 .00 g, 13.6 mmol, 1.00 eq) and DIEA (3.52 g, 27.3 mmol, 4.75 mL, 2.00 eq) and HATU (6.22 g, 16.4 mmol, 1.20 eq) in DCM (40.0 mL) 10 was added compound 4008 (2.21 g, 13.6 mmol, 1.00 eq) at 0 °C, and then the reaction mixture was stirred at 20 °C for 3 hrs. LCMS (EC7706-1-P1 Al) showed the compound 4007 was consumed and the desired mass (RT = 0.396min, m / z (M+l) = 438.9) was detected. The reaction mixture was concentrated. The crude product was purified by reversed-phase HPLC (0.1%HCI condition). Compound 4009 (2.80 g, 6.21 mmol, 45.5% yield, 97.0% purity) was obtained as brown solid. LC-MS: EC7706-1-P1A1, RT = 0.396min, m / z (M+l) = 438.9 LC-MS: EC7706-1-P1B1, RT = 0.396min, m / z (M+l) = 438.9 ’H-NMR: EC7706-1-P1A, 400 MHz, DMSO 6 8.91 (s, 1H), 8.78 - 8.77 (m, 1H), 8.78 - 8.65 (m, 3H), 8.53 - 8.24 (m, 1H), 7.99 - 7.88 (m, 1H), 7.45 (br d, J= 6.4 Hz, 1H), 7.46 - 7.21 (m, 2H), 5.78 - 5.71 (m, 1H), 4.86 - 4.54 (m, 2H), 3.85 - 3.57 (m, 2H), 3.26 - 3.07 (m, 1H), 2.96 - 2.71 (m, 3H), 2.62 - 2.55 (m, 2H), 2.36 -2.29 (m, 1H), 1.59 (s, 2H), 1.60 - 1.58 (m, 1H), 1.38 (s, 3H), 1.17 - 1.12 (m, 4H) Example 104 Synthesis of (S)-2-amino-3-(4-ethylphenyl)-l-((R)-2fpyridin-3-yl)piperidin-l-yl)propan-l- one 4009                           4010 To a solution of compound 4009 (2.80 g, 6.40 mmol, 1.00 eq) in EtOAc (28.0 mL) was HClZEtOAc (4 M, 16.0 mL, 10.0 eq), then the reaction mixture was stirred at 25 °C for 2 hrs. LCMS (EC7706-5-P1 Al) showed the compound 4009 was consumed and the desired mass (RT = 0.293 min, m / z (M+l) = 338.4) was detected. The reaction mixture was concentrated. The residue was used to next step without purification. From HNMR (EC7706-5-P1 A) showed the product compound 4010 (2.40 g, crude, HC1) was obtained as brown solid. LC-MS: EC7706-5-P1A1, RT = 0.293 min, m / z (M+l) = 338.4 ’H-NMR: EC7706-5-P1A, 400 MHz, DMSO 6 8.91 (s, 1H), 8.75 (d, J= 5.6 Hz, 1H), 8.67 (br s, 3H), 8.54 (br d, J= 8.2 Hz, 1H), 7.98 -7.90 (m, 1H), 7.24 - 7.16 (m, 4H), 5.72 (br s, 1H), 4.87 - 4.52 (m, 2H), 3.43 (d, J= 7.0 Hz, 1H), 3.20 - 3.16 (m, 1H), 3.00 - 2.83 (m, 2H), 2.81 - 2.72 (m, 1H), 1.50 - 1.37 (m, 1H), 1.33 - 1.17 (m, 2H), 1.16- 1.12 (m, 3H), 1.11 - 1.02 (m, 2H), 0.27--0.07 (m, 1H) Example 105 Synthesis of N-((S)-3-(4-ethylphenyl)-l-oxo-l-((R)CC(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 403) 4010                                 Compound 403 To a solution of compound 4010 (2.00 g, 5.93 mmol, 1.00 eq) in DCM (10.0 mL) was added TEA (1.89 g, 18.7 mmol, 2.60 mL, 3.15 eq) and compound 4011 (792 mg, 6.07 mmol, 600 uL, 1.02 eq) at 0 °C, then the reaction mixture was stirred at 25 °C for 3 hrs. LCMS (EC7706-19-P1 Al) showed the compound 4010 was consumed and the desired mass (Rt = 0.379 min, m / z (M+l) = 433.0) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water (NH4HCO3)-ACN];B%: 30%-50%,20min). Compound 403 (1.11 g, 2.57 mmol, 43.3% yield, 99.6% purity) was obtained as white solid. LC-MS: EC7706-19-P1A1, Rt = 0.379 min, m / z (M+l) = 433.0 LC-MS: EC7706-19-B1, Rt = 0.376 min, m / z (M+l) = 432.8 HPLC: EC7706-19-P1B2, Rt = 1.799 min, 99.6% purity ’H-NMR: EC7706-19-P1A, 400 MHz, DMSO 6 8.68 (br d, J= 7.2 Hz, 1H), 8.51 - 8.29 (m, 2H), 7.85 (s, 1H), 7.59 (br d, J= 8.0 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.25 - 7.22 (m, 2H), 7.15 (br d, J= 8.0 Hz, 2H), 6.99 (br s, 1H), 6.70 -6.54 (m, 1H), 5.82 - 5.57 (m, 1H), 5.20 - 4.92 (m, 1H), 3.86 (br d, J= 13.3 Hz, 1H), 3.06 (br d, J= 7.6 Hz, 2H), 2.83 (br t, J= 12.4 Hz, 1H), 2.63 - 2.52 (m, 2H), 2.32 (br d, J= 13.2 Hz, 1H), 1.59 - 1.47 (m, 1H), 1.37 (br s, 2H), 1.27 - 1.09 (m, 4H), 0.83 - 0.62 (m, 1H) Example 106 Synthesis of N-((S)-3-(4-ethylphenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2- y I) thiophene-2-carboxamide (Compound 404) Cl 2.00 eq TEA 0~25 °C, 2 hrs 39.9% yield 4010                                   Compound 404 To a solution of compound 4010 (2.00 g, 5.93 mmol, 1.00 eq) in DCM (10.0 mL) was added TEA (1.89 g, 18.7 mmol, 2.60 mL, 3.15 eq) and compound 4019 (869 mg, 5.93 mmol, 635 uL, 1.00 eq) at 0 °C, then the reaction mixture was stirred at 25 °C for 2 hrs. LCMS (EC7706-20-P1 Al) showed the compound 4010 was consumed and the desired mass (Rt = 0.385 min, m / z (M+l) = 448.9) was detected. The reaction mixture was concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(NH4HCO3)-ACN];B%: 35%-65%,31min). Compound 404 (1.09 g, 2.36 mmol, 39.9% yield, 97.4% purity) was obtained as off-white solid. LC-MS: EC7706-20-P1 Al, Rt = 0.385 min, m / z (M+l) = 448.9 LC-MS: EC7706-20-P1B2, Rt = 0.393 min, m / z (M+l) = 448.8 HPLC: EC7706-20-P1B1, Rt = 1.897 min, 97.4% purity ’H-NMR: EC7706-20-P1A, 400 MHz, DMSO 5 9.14 - 8.85 (m, 1H), 8.52 - 8.33 (m, 2H), 8.02 - 7.87 (m, 1H), 7.77 (d, J= 4.8 Hz, 1H), 7.59 (br d, J= 8.0 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.25 (br d, J= 8.0 Hz, 2H), 7.18-7.14 (m, 2H), 6.99 (br s, 1H), 5.80 - 5.50 (m, 1H), 5.22 - 4.84 (m, 1H), 3.86 (br d, J= 12.4 Hz, 1H), 3.07 (brd, J =5.6 Hz, 2H), 2.82 (br t, J= 12.4 Hz, 1H), 2.60 - 2.53 (m, 2H), 2.31 (br d, J= 13.2 Hz, 1H), 1.59 - 1.46 (m, 1H), 1.36 (br s, 2H), 1.26 - 1.07 (m, 4H), 0.79 - 0.56 (m, 1H) Example 107 Synthesis of methyl (S)-3-(4-allylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate OMe                                     OMe 4012                                            4014 To a solution of compound 4012 (38.0 g, 93.7 mmol, N / A purity, 1.00 eq) in IPA (275 mL) / H2O (125 mL) was added potassium;allyl(trifluoro)boranuide (34.6 g, 234 mmol, 2.50 eq) and K2CO3 (39.5 g, 286 mmol, 3.00 eq) then added Pd(dppf).CH2C12 (3.06 g, 3.75 mmol, 0.04 eq) at 25 °C. The mixture was stirred at 90 °C for 2 hrs. LCMS (EC7606-10-P1A1) showed that compound 4012 was consumed, and the desired MS (m / z (M+l) = 220.1, Rt = 0.588 min) was detected. The mixture was poured into the water (100 mL), extracted with EtOAc (150 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 50: 1 to 5: 1), the fraction (Plate 1, Rf= 0.40) was collected. Compound 4014 (20.0 g, 60.7 mmol, 64.7% yield, 97.0% purity) was obtained as a yellow solid. LC-MS: EC7606-10-P1A1, Rt = 0.588 min, m / z (M+l) = 220.1 LC-MS: EC7606-10-P1ACP, Rt = 0.509 min, m / z (M+l) = 220.5 HPLC: EC7606-10-P1BCP2, Rt = 2.856 min, 97.1% purity ’H-NMR: EC7606-10-P1N1, 400 MHz, CDC13 6 7.40 (d, J = 8.4 Hz, 1H), 7.19 - 7.01 (m, 4H), 6.05 - 5.87 (m, 1H), 5.13 - 5.01 (m, 2H), 4.64 - 4.51 (m, 1H), 4.13 (q, J= 7.2 Hz, 1H), 3.72 (s, 3H), 3.36 (d, J= 6.6 Hz, 2H), 3.08 (dt, J= 5.6, 13.8 Hz, 2H), 1.42 (s, 9H), 1.27 (t, J = 7.2Hz, 1H) Example 108 Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-propylphenyl)propanoate OMe                         OMe 4014                                  4015 To a solution of compound 4014 (20.0 g, 62.6 mmol, N / A purity, 1.00 eq) in MeOH (150 mL) was added Pd / C (62.6 mmol, 10.0% purity, 1.00 eq). The mixture was stirred at 20 °C for 2 hrs. LCMS (EC7606-13-P1 Al) showed that reactant 4014 was consumed, and the desired MS (m / z (M+l) = 222.2, Rt = 0.504 min) was detected. The reaction mixture was filtered through kieselguhr, the filtrate was concentrated under reduced pressure. The residue was used for next step directly. Compound 4015 (20.0 g, 62.2 mmol, 99.3% yield) was obtained as yellow oil. LC-MS: EC7606-10-P1ACP, Rt = 0.504 min, m / z (M+l) = 222.3 ’H-NMR: EC7606-13-P1N1, 400 MHz, CDC13 5 7.18 - 7.09 (m, 2H), 7.08 - 7.01 (m, 2H), 4.98 (br d, J= 7.6 Hz, 1H), 4.57 (br d, J= 7.6 Hz, 1H), 3.73 - 3.70 (m, 3H), 3.05 (dq, J= 6.0, 13.6 Hz, 2H), 2.62 - 2.50 (m, 2H), 1.67 - 1.59 (m, 2H), 1.42 (s, 9H), 0.94 (t, J= 7.2 Hz, 3H) Example 109 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-propylphenyl)propanoic acid OMe                             OH 4015                                   4016 To the solution of compound 4015 (20.0 g, 62.2 mmol, N / A purity, 1.00 eq) in THF (150 mL) and MeOH (50.0 mL) and H2O (50.0 mL) was added LiOH.H2O (5.22 g, 124 mmol, 2.00 eq) at 0 °C and the mixture was stirred at 0 °C for 1 hr. LCMS (EC7606-20-P1 Al) showed that compound 4015 was consumed, and the desired MS (m / z (M+l) = 208.2, Rt = 0.500 min) was detected. The mixture was poured into the water (100 mL), adjusted to pH = 5~6 with IM HC1, extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used to next step without purification. Compound 4016 (19.0 g, 52.5 mmol, 84.4% yield, 85.0% purity) was obtained as white oil. LC-MS: EC7606-20-P1 Al, Rt = 0.500 min, m / z (M+l) = 208.2 HPLC: EC7606-20-P1B1, Rt = 2.567 min, 85.6% purity ’H-NMR: EC7606-20-P1NCP, 400 MHz, CDC13 5 7.22 - 7.07 (m, 5H), 6.06 (br s, 1H), 4.94 (br d, J= 7.4 Hz, 1H), 4.60 (br d, J= 5.4 Hz, 1H), 3.20 - 3.13 (m, 1H), 3.11 - 3.01 (m, 1H), 2.62 - 2.53 (m, 2H), 1.63 (sxt, J= 7.4 Hz, 2H), 1.43 (br s, 9H), 0.95 (t, J= 7.2 Hz, 3H) Example 110 Synthesis of tert-butyl ((S)-l-oxo-3-(4-propylphenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)carbamate 4016                                               4017 To the solution of compound 4016 (5.00 g, 16.2 mmol, N / A purity, 1.00 eq) in DCM (60 mL) was added DIEA (4.21 g, 32.5 mmol, 5.67 mL, 2.00 eq) at 25 °C and then HATU (7.43 g, 19.5 mmol, 1.20 eq) was added at 0 °C. Then added compound 4008 (2.91 g, 17.9 mmol, N / A purity, 1.00 eq) at 0 °C. And the mixture was stirred at 25 °C for 2 hrs under N2. LCMS (EC7606-23-P1 Al) showed that compound 4016 was consumed, and the desired MS (m / z (M+l) = 452.3, Rt = 0.504 min) was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase HPLC (0.10% HC1 condition). Compound 4017 (6.50 g, 12.9 mmol, 79.6% yield, 90.0% purity) was obtained as a white solid. LC-MS: EC7606-23-P1 Al, Rt = 0.504 min, m / z (M+l) = 452.3 HPLC: EC7606-23-P1BCP1, Rt = 2.141 min, 90.4% purity Example 111 Synthesis of (S)-2-amino-3-(4-propylphenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-l-one ^NHBoc N CT 4017 HCI / EtOAc       L l| J Nh --------►    N EtOAc, 25 °C 92.1% yield            F J 4018 To a solution of compound 4017 (5.00 g, 11.0 mmol, N / A purity, 1.00 eq) was added HCl / EtOAc (4.00 M, 2.77 mL, 1.00 eq). The mixture was stirred at 25 °C for 6 hrs. LCMS (EC7606-28-P1A2) showed that compound 4017 was consumed, and the desired MS (m / z (M+l) = 352.4, Rt = 0.317 min) was detected. The reaction mixture was concentrated under reduced pressure to remove HCl / EtOAc. The residue was used to next step without purification. Compound 4018 (4.30 g, 10.2 mmol, 92.1% yield, 92.0% purity, HC1) was obtained as a yellow solid. LC-MS: EC7606-28-P1A2, Rt = 0.317 min, m / z (M+l) = 352.4 Example 112 Synthesis of N-((S)-l-oxo-3-(4-propylphenyl)-l-((R)CC(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 405) Compound 405 To the solution of compound 4018 (3.00 g, 7.73 mmol, N / A purity, 1.00 eq, HC1) in DCM (30 mL) was added TEA (3.91 g, 38.7 mmol, 5.39 mL, 5.00 eq) at 25 °C, and compound 4011 (1.21 g, 9.31 mmol, 920 uL, 1.20 eq) was added at 0 °C and the mixture was stirred at 25 °C for 2 hrs. LCMS (EC7606-32-P1 Al) showed that compound 4018 was consumed, and the desired MS (m / z (M+l) = 446.2, Rt = 0.403 min) was detected. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC Triart C18 70*250mm*7um; mobile phase: [water (NH4HCO3) - ACN]; B%: 45%-75%, 15min). Compound 405 (807 mg, 1.65 mmol, 91.0% purity) was obtained as a yellow solid. LC-MS: EC7606-32-P1 Al, Rt = 0.412 min, m / z (M+l) = 446.2 Special LC-MS: EC8519-3-P1S1, Rt = 10.514 min, m / z (M+l) = 446.4 HPLC: EC8519-3-P1B1, Rt = 1.875 min, 94.7% purity SFC: EC8519-3-P1X1 ’H-NMR: EC8519-3-P1N1, 400 MHz, CDC13 6 8.68 (br d, J= 7.0 Hz, 1H), 8.45 - 8.35 (m, 2H), 7.85 (s, 1H), 7.59 (br d, J= 7.8 Hz, 1H), 7.33 (br dd, J= 4.8, 7.6 Hz, 1H), 7.27 - 7.17 (m, 3H), 7.16 - 7.06 (m, 2H), 7.05 - 6.90 (m, 1H), 6.66 - 6.59 (m, 1H), 5.80 - 5.58 (m, 1H), 5.10 (q, J= 7.2 Hz, 1H), 3.86 (br d, J= 13.4 Hz, 1H), 3.06 (br d, J= 7.2 Hz, 2H), 2.82 (br t, J= 12.2 Hz, 1H), 2.31 (br d, J= 13 Hz, 1H), 1.62 - 1.23 (m, 6H), 1.17 (br d, J= 7.0 Hz, 1H), 0.87 (br t, J= 7.2 Hz, 3H), 0.67 (br d, J= 12.6 Hz, 1H). Example 113 Synthesis of N-((S)-l-oxo-3-(4-propylphenyl)-l-((R)CC(pyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 406) 4018                                  Compound 406 To the solution of compound 4018 (3.00 g, 7.73 mmol, N / A purity, 1.00 eq, HC1) in DCM (30.0 mL) was added TEA (3.91 g, 38.7 mmol, 5.39 mL, 5.00 eq) at 25 °C, and compound 4019 (1.36 g, 9.31 mmol, 996 uL, N / A purity, 1.20 eq) was added at 0 °C and the mixture was stirred at 25 °C for 2 hrs. LCMS (EC7606-33-P1 Al) showed that compound 4018 was consumed, and the desired MS (m / z (M+l) = 462.3, Rt = 0.413 min) was detected. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: YMC Triart Cl8 70*250mm*7um; mobile phase: [water (NH4HCO3)-ACN]; B%: 47%-77%, 15min). Compound 406 (1.05 g, 2.12 mmol, 93.0% purity) was obtained as a yellow solid. LC-MS: EC7606-33-P1A1, Rt = 0.413 min, m / z (M+l) = 462.3. Special LC-MS: EC8519-4-P1S1, Rt = 11.186 min, m / z (M+l) = 462.3 HPLC: EC8519-4-P1B1, Rt = 1.972 min, 94.1% purity SFC: EC8519-4-P1X1 ’H-NMR: EC8519-4-P1N1, 400 MHz, CDC13 6 8.95 (br d, J= 7.0 Hz, 1H), 8.41 (s, 2H), 7.94 (d, J= 3.0 Hz, 1H), 7.77 (d, J= 4.4 Hz, 1H), 7.59 (br d, J= 8.0 Hz, 1H), 7.32 (br dd, J= 4.8, 7.6 Hz, 1H), 7.24 (br d, J= 7.8 Hz, 2H), 7.13 (br d, J= 8.0 Hz, 3H), 6.98 (br s, 1H), 5.73 (br s, 1H), 5.11 (br d, J= 7.2 Hz, 1H), 3.86 (br d, J= 13.0 Hz, 1H), 3.22 - 2.89 (m, 3H), 2.82 (br t, J= 12.4 Hz, 1H), 2.30 (br d, J= 14.2 Hz, 5   1H), 1.58 - 1.45 (m, 3H), 1.40- 1.09 (m, 3H), 0.87 (br t, J= 7.2 Hz, 3H), 0.73 -0.55 (m, 1H). Example 114 Synthetic Protocol for Compound 407 and Compound 408 4020 4022 4024                                     4025 1.00 eq 5.00 eq TEA DMF, 0-25 °C, 2 hrs 4027                                4028 Compound 407 1.20 eq HATU, 2.00 eq DIEA DCM, 0-25 °C, 2 hrs 5.00 eq TEA DMF, 0-25 °C, 2 hrs 4028                                      Compound 408 10 Example 115 Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-vinylphenyl)propanoate 2.50 eq 4021, 3.00 eq K2CO3 0.04 eq Pd(dppf)CI2, H2O / IPA 4020 4021 4022 To the solution of Compound 4020 (2.00 g, 4.94 mmol, 1.00 eq) and Compound 4021 15   (1.65 g, 12.3 mmol, 2.50 eq) in IPA (32 mL) and H2O (16 mL) was added K2CO3 (2.05 g, 14.8 mmol, 3.00 eq) and Pd(dppf)C12 (360 mg, 492 umol, 0.10 eq) at 20 °C and the mixture was stirred at 80 °C for 2 hrs under N2. The mixture was poured into the water (30 mL), extracted with EtOAc (30 mL * 2). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1), TLC (Petroleum ether : Ethyl acetate = 5 : 1) showed the spot (Rf = 0.46) was collected. Compound 4022 (1.10 g, 3.60 mmol, 72.9% yield) was obtained as yellow oil which was confirmed by HNMR (EC6159-13-P1A1). LCMS: EC6159-13-P1A1, RT = 0.487 min, M / Z - 100 = 206 ‘HNMR: EC6178-13-P1C1, 400MHz, CDC13-t / 6 3 7.35 (d, 7=8.00 Hz, 2H), 7.09 (d, J= 8.00 Hz, 2H), 6.69 (dd, J= 17.6, 10.8 Hz, 1H), 5.73 (dd, J= 17.6, 0.80 Hz, 1H), 5.16-5.33 (m, 1H), 4.98 (br d, J= 7.60 Hz, 1 H), 4.52-4.67 (m, 1H), 3.72 (s, 3H), 2.93-3.20 (m, 2H), 1.43 (s, 9H). Example 116 Synthesis of methyl (S,E)-2-((tert-butoxycarbonyl)amino)-3-(4-(prop-l-en-l-yl)phenyl)propanoate 4022                                            4024 To the solution of Compound 4022 (500 mg, 1.64 mmol, 1.00 eq) and Compound 4023 (635 mg, 3.27 mmol, 616 uL, 2.00 eq) in dioxane (10 mL) was added Fe(OTf)3 (82 mg, 163 umol, 0.10 eq) at 20 °C and the mixture was stirred at 80 °C for 12 hrs. The mixture was poured into the water (20 mL), extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (water (0.05% HC1)-ACN). Compound 4024 (118 mg, 369 umol, 22.5% yield) was obtained as yellow oil which was confirmed by HNMR (EC6159-19-P1A1). LCMS: EC6159-19-P1A1, RT = 0.466 min, M / Z - 100 = 220 ‘HNMR: EC6178-19-P1A1, 400MHz, CDC13-t / 6 3 7.29 (s, 2H), 7.07 (d, J= 8.00 Hz, 2H), 6.34-6.47 (m, 1H), 6.16-6.31 (m, 1H), 4.98 (br d, J = 8.00 Hz, 1H), 4.51-4.66 (m, 1H), 3.74 (s, 3H), 2.97-3.18 (m, 2H), 1.90 (d, J= 6.40 Hz, 3H), 1.45 (s, 9H). Example 117 Synthesis of (S,E)-2-((tert-butoxycarbonyl)amino)-3-(4-(prop-l-en-l-yl)phenyl)propanoic acid OMe                                 OH NHBoc       . J. „                         NHBoc LiOH«H2O                CX ’p THF / MeOH / H2O 0-20 °C, 2 hrs 4024                                         4025 To the solution of methyl Compound 4024 (118 mg, 369 umol, 1.00 eq) in THF (1.5 mL) and MeOH (0.5 mL) and H2O (0.5 mL) was added LiOH»H2O (31 mg, 738 umol, 2.00 eq) at 0 °C and the mixture was stirred at 0 °C for 1 hr. The mixture was poured into the water (5 mL), adjusted to pH = 5~6 with 2 M HC1, extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly. Cpd 4025 (100 mg, 327 umol, 88.6% yield) was obtained as yellow oil. LCMS: EC6159-20-P1A2, RT = 0.463 min, M / Z - 100 = 206 Example 118 Synthesis of tert-butyl ((S)-l-oxo-3-(4-((E)-prop-l-en-l-yl)phenyl)-l-((R)-2-(pyridin-3- yl)piperidin-l-yl)propan-2-yl)carbamate To the solution of compound 4025 (100 mg, 327 umol, 1.00 eq) and compound 4026 (54 mg, 333 umol, 1.02 eq) in DCM (2 mL) was added DIEA (85 mg, 657 umol, 114 uL, 2.01 eq) at 20 °C and then HATU (149 mg, 392 umol, 1.20 eq) was added at 0 °C. And the mixture was stirred at 20 °C for 2 hrs under N2. The mixture was poured into the water (10 mL), extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly. Compound 4027 (160 mg, crude) was obtained as red oil. LCMS: EC6159-21-P1A1, RT = 0.435 min, M / Z + 1 = 450 Example 119 Synthesis of (S)-2-amino-3-(4-((E)-prop-l-en-l-yl)phenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 4027                                      4028 To the solution of Compound 4027 (160 mg, 355 umol, 1.00 eq) in HCl / EtOAc (4 M, 4 mL, 45.0 eq) at 20 °C and the mixture was stirred at 20 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure. The residue was used for next step directly. Compound 4028 (160 mg, crude, HC1) was obtained as yellow oil. LCMS: EC6159-22-P1A1, RT = 0.301 min, M / Z + 1 = 350 Example 120 Synthesis of N-((S)-l-oxo-3-(4-((E)-prop-l-en-l-yl)phenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 407) 4028                                         Compound 407 To the solution of Compound 4028 (80 mg, 207 umol, 1.00 eq, HC1) in DMF (1.5 mL) was added TEA (109 mg, 1.08 mmol, 150 uL, 5.20 eq) at 20 °C, and Compound 4029 (29 mg, 222 umol, 20 uL, 1.07 eq) was added at 0 °C and the mixture was stirred at 20 °C for 3 hrs. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 41%-71%, 8 min). Compound 407 (22.41 mg, 49.6 umol, 23.9% yield, 98.3% purity) was obtained as white solid which was confirmed by QC of Compound 407. LCMS: EC6159-23-P1A1, RT = 0.394 min, M / Z + 1 = 444 ‘HNMR: EC6159-23-P1C1, 400MHz, CDC13-t / 6 3 8.39-8.53 (m, 2H), 7.39-7.54 (m, 2H), 7.28-7.32 (m, 2H), 7.19-7.26 (m, 3H), 7.12-7.18 (m, 1H), 6.93-7.10 (m, 1H), 6.51 (dd, . / =2.00, 1.69 Hz, 1H), 6.33-6.45 (m, 1H), 6.12-6.29 (m, 1H), 5.57-6.02 (m, 1H), 5.22-5.51 (m, 1H), 3.60-3.85 (m, 1H), 3.05-3.34 (m, 2H), 2.84-2.98 (m, 1H), 2.24-2.48 (m, 1H), 1.89 (br dd, J= 6.40, 1.20 Hz, 3H), 1.63-1.78 (m, 2H), 1.33-1.46 (m, 2H), 0.49-0.79 (m, 1H). LCMS: EC6159-23-P1C2, RT = 0.402 min, m / z + 1 = 444 HPLC: EC6159-23-P1C1, RT = 1.844 min, purity = 98.3% SFC: EC6159-23-PlHl_b2 Example 121 Synthesis of N-((S)-l-oxo-3-(4-((E)-prop-l-en-l-yl)phenyl)-1-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 408) 4028 5.00 eq TEA DMF, 0~25 °C, 2 hrs Compound 408 To the solution of Compound 4028 (80 mg, 207 umol, 1.00 eq, HC1) in DMF (1.5 mL) was added TEA (109 mg, 1.08 mmol, 150 uL, 5.20 eq) at 20 °C, and Compound 4030 (32 mg, 218 umol, 23.3 uL, 1.05 eq) was added at 0 °C and the mixture was stirred at 20 °C for 3 hrs. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 39%-69%, 8 min). Compound 408 (19.27 mg, 41.3 umol, 19.9% yield, 98.7% purity) was obtained as white solid which was confirmed by QC of Compound 408. LCMS: EC6159-24-P1A1, RT = 0.406 min, M / Z + 1 = 460 ’HNMR: EC6159-24-P1C1, 400MHz, CDC13-6 / 6 3 8.48 (br s, 2H), 7.40-7.61 (m, 3H), 7.28-7.33 (m, 2H), 7.19-7.26 (m, 2H), 7.16 (br d, J = 8.00 Hz, 1H), 6.94-7.15 (m, 2H), 6.31-6.46 (m, 1H), 6.22 (dq, J= 16.0, 6.80 Hz, 1H), 5.596.01 (m, 1H), 5.26-5.51 (m, 1H), 3.75 (br d, J= 13.2 Hz, 1H), 3.07-3.32 (m, 2H), 2.84-3.01 (m, 1H), 2.28-2.44 (m, 1H), 1.89 (br dd, J= 6.40, 1.20 Hz, 3H), 1.72 (m, 2H), 1.34-1.49 (m, 2H), 0.60-0.80 (m, 1H). LCMS: EC6159-24-P1C2, RT = 0.418 min, m / z + 1 = 460 HPLC: EC6159-24-P1C1, RT = 1.933 min, purity = 98.9% SFC: EC6159-24-PlHl_b2 Example 122 Synthetic Protocol for Compound 409 and Compound 410 THF / H2O = 1 / 1 1.40 eq (Boc)2O, 2.70 eq NaOH 20°C, 8 hrs 1.10eq 4 M HCI / EtOAc EtO Ac (10 V), 25 °C, 2 hrs 88.5% yield 4031                                         4032 4.97 eq TEA DMF (10 V), 0~25 °C, 2 hrs 4035                                   Compound 409 1.20 eq HATU 2.02 eq DIEA DCM (10 V) 0~25 °C, 2 hrs 53.5% yieid Example 123 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyclopropylphenyl)propanoic acid 1.40 eq (Boc)2O, 2.70 eq NaOH THF / H2O = 1 / 1 20°C, 8 hrs 97.9% yield To a solution of compound 4031 (4.00 g, 16.5 mmol, N / A purity, 1.00 eq, HC1) in THF (20.0 mL) / H2O (20.0 mL) was added (Boc)2O (5.06 g, 23.2 mmol, 5.32 mL, 1.40 eq) and NaOH (1.79 g, 44.6 mmol, 2.70 eq}. The mixture was stirred at 20 °C for 8 hrs. LCMS (EC7606-3-P1A2) showed that compound 4031 was consumed, and the desired MS (m / z (M+l) = 206.1, Rt = 0.528 min) was detected. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate 15.0 mL (5.00 mL x 3). The combined extracts were washed with brine (10.0 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was used to next step without purification. Compound 4032 (5.00 g, 16.2 mmol, 97.9% yield, 99.0% purity) was obtained as yellow oil. LC-MS: EC7606-3-P1A2, Rt = 0.528 min, m / z (M+l) = 206.1. LC-MS: EC7606-3-P1A2, Rt = 0.528 min, m / z (M+l) = 206.1. HPLC: EC7606-3-P1B1, Rt = 1.972 min, 94.1% purity Example 124 Synthesis of tert-butyl ((S)-3-(4-cyclopropylphenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-y I) carbamate 4032                   53.5% yieki                      4034 To a solution of compound 4032 (7.50 g, 24.5 mmol, N / A purity, 1.00 eq} in DCM (75.0 mL) was added HATU (11.2 g, 29.5 mmol, 1.20 eq) and DIEA (6.48 g, 50.2 mmol, 8.74 mL, 2.04 eq) at 0°C then added compound 4033 (4.02 g, 24.8 mmol, N / A purity, 1.01 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS (EC7606-6-P1 Al) showed that compound 4032 was consumed, and the desired MS (m / z (M+l) = 450.2, Rt = 0.476 min) was detected. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was used to next step without purification. Compound 4034 (6.50 g, 13.1 mmol, 53.5% yield, 91.0% purity) was obtained as a white solid. LC-MS: EC7606-6-P1A1, Rt = 0.475 min, m / z (M+l) = 450.2. Example 125 Synthesis of (S)-2-amino-3-(4-cyclopropylphenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 4034                                    4035 To a solution of compound 4034 (3.50 g, 7.78 mmol, N / A purity, 1.00 eq) was added HCl / EtOAc (4 M, 100 mL, 51.3 eq). The mixture was stirred at 25 °C for 2 hrs. LCMS (EC7606-14-P1 Al) showed that compound 4034 was consumed, and the desired MS (m / z (M+l) = 350.2, Rt = 0.337) was detected. The reaction mixture was concentrated under reduced pressure to remove HCl / EtOAc. The residue was used to next step without purification. Compound 4035 (2.60 g, 6.74 mmol, 86.5% yield, HC1) was obtained as a white solid. LC-MS: EC7606-14-P1 Al, Rt = 0.337 min, m / z (M+l) = 350.2. Example 126 Synthesis of N-((5)-3-(4-cyclopropylphenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-yl)furan-2-carboxamide (Compound 409) 4035                                   Compound 409 To a solution of compound 4035 (2.40 g, 6.22 mmol, N / A purity, 1.00 eq, HC1) in DCM (24.0 mL) was added TEA (3.15 g, 31.1 mmol, 4.33 mL, 5.01 eq). Then added compound 4036 (1.32 g, 10.1 mmol, 1.00 mL, N / A purity, 1.03 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS (EC7606-18-P1A1) showed that compound 4035 was consumed, and the desired MS (m / z (M+l) = 444.2, Rt = 0.453 min) was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water (HC1) -ACN]; B%: 20%-50%, 20 min). The crude product was purified by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10 um); mobile phase: [ACN / EtOH (0.1%NH3H2O)]; B%: 40%-40%,A4.8;191min). Compound 409 (1.00 g, 2.16 mmol, 96.0% purity, 1.00 eq) was obtained as a yellow solid. LC-MS: EC7606-18-P1A1, Rt = 0.453 min, m / z (M+l) = 444.2. LCMS: EC8519-1-P1A1, Rt = 0.357 min, m / z (M+l) = 444.3. HPLC: EC8519-1-P1B1, Rt = 1.728 min, 97.9% purity ’H-NMR: EC8519-1-P1N1, 400 MHz, DMSO 6 8.68 (br d, J= 6.8 Hz, 1H), 8.45 - 8.35 (m, 2H), 7.85 (s, 1H), 7.59 (br d, J= 7.8 Hz, 1H), 7.33 (br dd, J= 4.8, 7.6 Hz, 1H), 7.27 - 7.17 (m, 3H), 7.16 - 7.06 (m, 2H), 7.05 - 6.90 (m, 1H), 6.66 - 6.59 (m, 1H), 5.80 - 5.58 (m, 1H), 5.10 (q, J= 7.2 Hz, 1H), 3.86 (br d, J= 13.4 Hz, 1H), 3.06 (br d, J= 7.4 Hz, 2H), 2.82 (brt, J= 12.2 Hz, 1H), 2.31 (br d, J= 13.2 Hz, 1H), 1.62 - 1.23 (m, 6H), 1.17 (br d, J= 7.0 Hz, 1H), 0.87 (brt, J= 7.2 Hz, 3H), 0.67 (br d, J = 12.6 Hz, 1H) SFC: EC8519-1-P1S2 Example 127 Synthesis of N-((S)-3-(4-cyclopropylphenyl)-l-oxo-l-((R)-2fpyridin-3-yl)piperidin-l-yl)propan-2-yl)thiophene-2-carboxamide (Compound 410) 4035 Compound 410 To a solution of compound 4035 (2.40 g, 6.22 mmol, N / A purity, 1.00 eq, HC1) in DCM (24.0 mL) was added TEA (3.16 g, 31.2 mmol, 4.35 mL, 5.02 eq). Then added compound 4037 (1.37 g, 9.35 mmol, 1 mL, N / A purity, 1.00 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS (EC7606-19-P1 Al) showed that compound 4035 was consumed, and the desired MS (m / z (M+l) = 460.3, Rt = 0.461 min) was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water (HC1) -ACN]; B%: 20%-50%, 20 min). The crude product was purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10 um); mobile phase: [ACN / MeOH(0.1%NH3H2O)]; B%: 60%-60%,A4.7;75min). Compound 410 (640 mg, 1.32 mmol, 95.0% purity, 1.00 eq) was obtained as a yellow solid. LC-MS: EC7606-19-P1A1, Rt = 0.461 min, m / z (M+l) = 460.3. LCMS: EC8519-2-P1A1, Rt = 0.357 min, m / z (M+l) = 444.3. HPLC: EC8519-2-P1B1, Rt = 1.826 min, 97.9% purity ’H-NMR: EC8519-2-P1N1, 400 MHz, DMSO 6 8.95 (br d, J= 7.0 Hz, 1H), 8.41 (s, 2H), 7.94 (d, J= 3.0 Hz, 1H), 7.77 (d, J= 4.4 Hz, 1H), 7.59 (br d, J= 8.0 Hz, 1H), 7.32 (br dd, J= 4.8, 7.6 Hz, 1H), 7.24 (br d, J= 7.8 Hz, 2H), 7.13 (br d, J= 8.0 Hz, 3H), 6.98 (br s, 1H), 5.73 (br s, 1H), 5.11 (br d, J= 7.2 Hz, 1H), 3.86 (br d, J = 13.2 Hz, 1H), 3.22 - 2.89 (m, 3H), 2.82 (br t, J= 12.4 Hz, 1H), 2.30 (br d, J= 14.2 Hz, 1H), 1.58 - 1.45 (m, 3H), 1.40- 1.09 (m, 3H), 0.87 (br t, J= 7.2 Hz, 3H), 0.73 -0.55 (m, 1H) SFC: EC8519-1-P1S2 Example 128 Synthesis of tert-butyl ((S)-3-(4-ethynylphenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l- yl)propan-2-yl) carbamate NHBoc 4038                                4040 To a solution of compound 4038 (0.20 g, 691 umol, 1.00 eq) and compound 4039 (113 mg, 696 umol, 1.01 eq) in DCM (3.00 mL) was added DIEA (178 mg, 1.38 mmol, 241 uL, 2.00 eq) and HATU (315 mg, 830 umol, 1.20 eq) at 0 °C. The mixture was stirred at 25°C for 2 hrs. LCMS (EC5892-1-P1 Al) showed that compound 4038 (m / z=289) was consumed completely and the desired MS (Rt =0.451 min, M+l=434.4) was found. The reaction mixture was concentrated under vacuum. No need further purification to give compound 4040 (0.50 g, crude) as yellow oil and used to the next step. Compound 4040 (0.50 g, crude) was obtained as yellow oil, checked by LCMS (EC5892-1-P1A2) and HNMR (EC5892-1-P1A1) LCMS: EC5892-1-P1A1, Ret. Time = 0.451 min, m / z +1 = 434.4 HNMR: EC5892-1-P1A1 (400 MHz, CDCL) 3 = 8.49 - 8.45 (m, 2H), 7.46 (br d, J= 8.0 Hz, 3H), 7.23 (br d, J= 7.9 Hz, 3H), 5.92 (br d, J = 2.8 Hz, 1H), 5.38 (br d, J= 8.6 Hz, 1H), 4.98 - 4.88 (m, 1H), 3.16 (q, J= 7.4 Hz, 3H), 3.08 (s, 1H), 2.91 (dt, J= 2.5, 13.4 Hz, 1H), 1.49 - 1.45 (m, 6H), 1.42 (s, 9H) Example 129 Synthesis of (S)-2-amino-3-(4-ethynylphenyl)-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-l-one 4040                           4041 To a solution of compound 4040 (0.3 g, 692 umol, 1.00 eq) in EtOAc (2.00 mL) was added HClZEtOAc (4 M, 1.50 mL, 8.67 eq). The mixture was stirred at 25°C for 2 hrs. LCMS (EC5892-14-P1A1) showed that compound 4040 (m / z=433) was consumed completely and the desired MS (Rt =0.316 min, M+l=334.3) was found. The reaction mixture was concentrated under vacuum. No need further purification to give compound 4041 (0.58 g, crude, HC1) as white solid and used to the next step. Compound 4041 (0.58 g, crude, HC1) was obtained as white solid, checked by HNMR (EC5892-14-P1A1) LCMS: EC5892-14-P1A1, Ret. Time = 0.316 min, m / z +1 = 334.3 ‘HNMR: EC5892-14-P1A1 (400 MHz, DMSO) 3 = 8.96 (s, 1H), 8.80 - 8.76 (m, 1H), 8.70 (br s, 3H), 8.61 (br d, J= 8.3 Hz, 1H), 7.99 (dd, J = 5.6, 8.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.32 (d, J= 8.1 Hz, 2H), 5.72 (br s, 1H), 4.84 -4.75 (m, 1H), 3.68 (br d, J= 13.5 Hz, 1H), 3.59 (dtd, J= 4.0, 6.6, 13.1 Hz, 1H), 3.21 (br dd, J = 52, 13.1Hz, 1H), 3.11 (dq, . / =4.3, 7.4 Hz, 1H), 3.00 (br dd, J= 9.3, 12.9 Hz, 1H), 2.89 -2.78 (m, 1H), 1.30 (d, J= 6.6 Hz, 4H), 1.28 - 1.26 (m, 4H) Example 130 Synthesis of N-((S)-3-(4-ethynylphenyl)-l-oxo-l-((R)-2-(pyridin-3-yl)piperidin-l-yl)propan-2-y I)furan-2-carboxamide (Compound 411) 4041                            Compound 411 To a solution of compound 4041 (0.29 g, 869 umol, 1.00 eq) and TEA (180 mg, 1.79 mmol, 248 uL, 2.05 eq) in DCM (3.00 mL) was added compound 4042 (114 mg, 879 umol, 87.0 uL, 1.01 eq) at 0°C. The mixture was stirred at 25 °C for 2 hr. LCMS (EC5892-15-P1 Al) showed that compound 4041 (m / z=333) was consumed completely and the desired MS (Rt =0.400 min, M+l=428.3) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%, 9min). Compound 411 (80.0 mg, 182 umol, 20.9% yield, 97.5% purity) was obtained as yellow solid, checked by LCMS(EC5892-15-P1A3), HPLC(EC5892-15-P1A5), HNMR(EC5892-15-P1A1) and Chiral SFC(EC5892-15-P1A6). LCMS: EC5892-15-P1A1, product: Ret. Time = 0.400 min, m / z +1 = 428.3 ‘HNMR: EC5892-15-P1A1 (400 MHz, CDCk) 3 = 8.55 - 8.35 (m, 2H), 7.47 (br d, J= 7.0 Hz, 3H), 7.35 - 7.27 (m, 2H), 7.22 (br d, J= 8.1 Hz, 2H), 7.14 (brd, . / = 3.3 Hz, 1H), 7.11 -6.66 (m, 1H), 6.56 -6.48 (m, 1H), 5.94 (br d, J= 3.1 Hz, 1H), 5.44 (dt, J = 5.5, 8.3 Hz, 1H), 4.00 - 3.88 (m, 1H), 4.60 - 3.63 (m, 1H), 3.28 -3.21 (m, 1H), 3.18-3.11 (m, 1H), 3.09 (s, 1H), 3.01 -2.46 (m, 1H), 2.35 (brd, J= 14.3 Hz, 1H), 2.16 - 1.85 (m, 2H), 1.77 - 1.52 (m, 2H), 1.50 - 1.40 (m, 2H), 0.82 - 0.48 (m, 1H) LCMS: EC5892-15-P1A3, product: Ret. Time = 1.601 min, m / z +1 = 428.3 HPLC: EC5892-15-P1A5, product: Ret. Time = 1.726 min Chiral SFC: EC5892-15-P1A6, ee%=98.4 Example 131 Synthesis of N-((S)-3-(4-ethynylphenyl)-l-oxo-l-((R)-2fpyridin-3-yl)piperidin-l-yl)propan- 2-yl)thiophene-2-carboxamide (Compound 412) 4041                            Compound 412 To a solution of compound 4041 (0.24 g, 720 umol, 1.00 eq) and TEA (150 mg, 1.48 mmol, 205 uL, 2.05 eq) in DCM (3.00 mL) was added compound 4043 (108 mg, 737 umol, 78.8 uL, 1.02 eq) at 0°C. The mixture was stirred at 25 °C for 2 hrs. LCMS (EC5892-7-P1 Al) showed that compound 4041 (m / z=333) was consumed completely and the desired MS (Rt =0.483 min, M+l=444.0) was found. The reaction mixture was concentrated under vacuum. The crude product was purified by prep-HPLC (column: Welch Ultimate AQ-C18 150*30mm*5um; mobile phase: [water (HCl)-ACN]; B%: 19%-49%, lOmin). Compound 412 (30.0 mg, 65.6 umol, 9.11% yield, 96.9% purity) was obtained as white solid, checked by LCMS (EC5892-7-P1A7), HPLC (EC5892-7-P1A6) HNMR (EC5892-7-P1A1) and SFC (EC5892-7-P1A7). LCMS: EC5892-7-P1A1, product: Ret. Time = 0.483 min, m / z +1 = 444.0 ‘HNMR: EC5892-7-P1 Al (400 MHz, CDCk) 3 = 8.68 (br s, 1H), 8.55 (br d, J= 1.5 Hz, 1H), 8.21 (br d, J= 6.5 Hz, 1H), 7.86 - 7.77 (m, 1H), 7.69 (d, J= 3.4 Hz, 1H), 7.53 (d, J= 4.9 Hz, 1H), 7.49 (d, J= 7.9 Hz, 2H), 7.30 - 7.27 (m, 1H), 7.27 - 7.17 (m, 2H), 7.14 - 7.07 (m, 2H), 5.95 (br s, 1H), 5.34 - 5.20 (m, 1H), 3.92 -3.72 (m, 1H), 3.30-3.17 (m, 2H), 3.11 (s, 1H), 2.95 - 2.80 (m, 1H), 2.39 - 2.19 (m, 2H), 1.80 - 1.71 (m, 1H), 1.66 - 1.59 (m, 1H), 1.50 (br d, J= 12.5 Hz, 1H), 1.33 - 1.25 (m, 1H), 0.78 -0.62 (m, 1H) LCMS: EC5892-7-P1A7, product: Ret. Time = 1.666 min, m / z +1 = 444.3 HPLC: EC5892-7-P1A6, product: Ret. Time = 1.757 min Chiral SFC: EC5892-7-P1A7, ee%=97.4 Biological Examples Example 1 Determination of inhibition of NF-kB activation induced by TNFa... in vitro assay The ability of a compound disclosed herein to inhibit NFkB activation induced by TNFawas determined using the TNFa Luciferase assay. The HEK293 / NF-kB luciferase cell line was obtained by cotransfection of pNFkB-luc vector with pHyg (Panomics, CA, USA) followed by hygromycin selection. HEK293 / NFkB Luciferase cells were grown in DMEM medium supplemented with 10% fetal bovine serum, lOOU / ml of penicillin, 100 pg / ml of streptomycin / Fungizone, and lOOpg / ml of hygromycin B as the selecting agent. HEK293 NFkB Luciferase cells were grown in T75 flasks (Nunc™ Cell Culture Treated EasYFlasks™) in a cell culture incubator at 37°C and 5%CO2. Confluent T75 cell culture flasks (approximately 8-10 million of cells per flask) were washed with 10 ml of sterile PBS (without calcium and magnesium) under a biosafety cabinet. After aspiration of the PBS with a sterile glass pipette, the layer of cells (for each T75 flask) was covered with 1 ml of TrypLE™ Express without phenol red (Gibco) at room temperature. After one minute of incubation, HEK293 were mechanically resuspended in the TrypLE by tapping the side of the flask. The cells were then resuspended with 10 ml of prewarmed complete culture medium and transferred to a conical tube. Cells were centrifuged for 5 minutes at 4000 rpm (1000g) at room temperature. The cellular pellet was resuspended with 24 ml of pre-warmed cell culture media and 200 ml of cell suspension (approximately 80,000 cells per well) was plated per well in 96-well cell culture plates (Costar #3599, Corning, NY, USA) using a multichannel pipette and reversed pipetting to prevent air bubble formation. After plating, the cells were maintained overnight in the cell culture incubator before being treated. For each 96 well cell culture plate, 8 wells were used as “control wells” (only culture medium added) and to 8 wells only TNFa was added. The NF-kB Luciferase reporter cell line was challenged with 25 ng / ml of TNF-a for four hours in the presence and absence (control conditions) of a dose range of the different compounds to be tested. For each compound, a dose range of concentrations was tested in quadruplicate and used to determine an IC50. Luciferase activity was monitored using the Luc-Screen® Extended-Glow Luciferase Reporter Gene Assay System by chemoluminescence according to the instruction of the manufacturer (Invitrogen) and a BioTek Synergy HT plate reader (BioTek Instruments, VT, USA). The IC50, concentration at which NF-kB activation was reduced by 50%, for a 5 representative number of compounds is provided in Tables 5-8 below. Table 5 Cpd No. (see Cpd Table 1 above) IC50 (pM) Cpd No. (see Cpd Table 1 above) IC50 (pM) Cpd No. (see Cpd Table 1 above) IC50 (pM) 101 0.008667 102 0.001764 103 0.01273 104 0.0031 105 0.0172 106 0.0082 107 0.0073 108 0.0075 109 0.0105 110 0.0065 111 0.0123 112 0.0108 10                                        Table 6 Cpd No. (see Cpd Table 2 above) IC50 (pM) Cpd No. (see Cpd Table 2 above) IC50 (pM) Cpd No. (see Cpd Table 2 above) IC50 (pM) 201 0.0598 204 0.06008 207 0.0548 202 0.06965 205 0.1373 208 0.23 203 0.08975 206 0.2124 209 0.5863 210 0.1833 211 0.1647 212 0.26 213 0.3464 214 0.312 Table 7 Cpd No. (see Cpd Table 3 above) IC50 (pM) Cpd No. (see Cpd Table 3 above) IC50 (pM) Cpd No. (see Cpd Table 3 above) IC50 (pM) 302 0.1896 303 0.6575 304 0.397 305 0.1274 Table 8 Cpd No. (see Cpd Table 4 above) ICso (pM) Cpd No. (see Cpd Table 4 above) IC50 (pM) Cpd No. (see Cpd Table 4 above) IC50 (pM) 401 0.1069 405 0.08535 409 0.01952 402 0.1086 406 0.07393 410 0.02295 403 0.01038 407 0.3008 411 0.2822 404 0.00961 408 0.5666 412 0.5026 Example 2 5                                 Comparative Inhibitory Activity The inventors surprisingly discovered that the R,S enantiomers as disclosed herein are unexpectedly superior to their alternative isomers or mixtures thereof. Exemplary findings are provided in Table 9. 10 Cpd No. Compound* IC50 (pM) 102 o o       2----\ i   <       --Z     $ ---V       I o X IZ \ o _____।           ZI / ° 0.001764 114 0 A>\XX I I           H                   \ 0 ( / ° 0.00896 103 Co> Xi 1 11                    H                               If o                                     0 0 0.01273 115 T II               H                       II ^zk    0                              0 0 0.0504 * An asterisk with a wavy bond indicates a mixture of isomers at the carbon with the asterisk. Example 3 Determination of Anti-inflammatory Activity using Acute LPS Model of Inflammation in Mice... in vivo model The ability of the compounds disclosed herein to reduce inflammation was determined in vivo by using the above mouse model. The impact of the compounds on the production of proinflammatory cytokines induced by LPS can be evaluated in various tissues (e.g., plasma, brain, intestine, spleen, lung, etc). Adult C57B16 / J wild-type mice were used to assess the impact of a compound disclosed herein (“test” compound) on cytokines production induced by an intraperitoneal injection of LPS (lipopolysaccharide) [LPS from Escherichia coli 0111 :B4, Sigma-Aldrich # L4391], Prior to treatment with LPS (Img / Kg (intraperitoneal injection) dissolved in sterile PBS), mice were randomized into a placebo / control group receiving an intraperitoneal (IP) injection of the vehicle used to dissolve the test compound (50% PEG4000 / 50% DMSO) and into a treatment group (receiving 20 mg / Kg of the test compound IP). Mice were injected with the test compound or the vehicle 15 minutes prior to the LPS injection. Mice were then humanely euthanatized four hours after the intraperitoneal injection of LPS. Following euthanasia, blood was collected by an intracardiac puncture using EDTA as an anticoagulant. Blood was immediately centrifuged at 1500g for 4 minutes and the plasma collected and snap frozen in liquid nitrogen. All the other tissues were rapidly dissected out and snap frozen in liquid nitrogen. Samples were stored at -80°C. Tissue homogenates were prepared by sonication in ice-cold M-PER Reagent (Pierce Biotechnology, Rockford, IL, USA) containing ImM phenylmethanesulfonyl fluoride, IX of protease cocktail inhibitor (Roche, Inc., USA) and ImM sodium orthovanadate (Sigma-Aldrich, MO, USA). Cytokines were quantified by electrochemiluminescence using MULTISPOT plates from a V-Plex assay kit Pro-Inflammatory Panel 1 (mouse) kit (Mesoscale discovery, USA). All LPS treated samples were diluted 10X with diluent 41 from the kit and control samples were assayed without dilution. The amount of proinflammatory cytokines interferon-gamma, IL-10, and TNFa produced was less in the treatment group versus the control group. Formulation Examples The following are representative pharmaceutical formulations containing a compound of the present disclosure. Tablet Formulation The following ingredients are mixed intimately and pressed into single scored tablets. Ingredient                           Quantity per tablet mg compound of this disclosure               400 cornstarch                                  50 croscarmellose sodium                     25 lactose                                      120 magnesium stearate                         5 Capsule Formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Ingredient compound of this disclosure lactose spray dried magnesium stearate Quantity per capsule mg 200 148 2 Injectable Formulation Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg / mL Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration. Topical Gel Composition To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration. Ophthalmic Solution Composition To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration. Nasal spray solution To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Claims

1. A compound of Formula (I), Formula (II), Formula (III) or Formula (IV):(I)5 wherein:the dashed line is an optional bond; R1 is C3-C5 alkyl;OH , or O; and10          R2 is H or C3-C7 alkyl;(II)wherein:Y is O or S; andR3 is -H, -F, or -CX3, wherein each X is independently -H or -F;(III)5 wherein:Y is O or S; andR4 is -CX3, wherein each X is independently -H or -F;(IV)10 wherein:Y is O or S; andR5 is C2-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, or C3-C4 cycloalkyl; or a pharmaceutically acceptable salt thereof.15   2. The compound of claim 1, wherein the compound is of Formula (I) or apharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein the compound is of Formula (IA):

4. The compound of any one of claims 1-3, wherein the compound is of Formula (IB):(IB) or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-4 wherein L is a bond.

6. The compound of any one of claims 1-5 wherein R2 is H.15   7.     The compound of any one of claims 1-4, wherein the compound isor a pharmaceutically acceptable salt thereof.

8. The compound acceding to claim 7, wherein the compound is5 or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is of Formula (II) or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 or claim 9, wherein the compound is of Formula (IIA)(IIA)5 or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1 and 9-10, wherein R3 is -CH2F, -CHF2, or -CF3.10   12. The compound of any one of claims 1 and 9-11, wherein R3 is -CHF2.

13. The compound of any one of claims 1 and 9-10, wherein the compound isor a pharmaceutically acceptable salt thereof.

14. The compound according to claim 13, wherein the compound isor a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is of Formula (III) or a 5 pharmaceutically acceptable salt thereof.

16. The compound of claim 1 or claim 15, wherein the compound is of Formula (IIIA)(IIIA)10 or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1 and 15-16, wherein R4 is -CHF2.

18. The compound of any one of claims 1 and 15-16, wherein the compound isor a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is of Formula (IV) or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 or claim 19, wherein the compound is of Formula (IVA)(IVA)or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1 and 19-20, wherein R5 is C2-C3 alkyl.

22. The compound of any one of claims 1 and 19-20, wherein R5 is C2-C3 alkenyl.

23. The compound of any one of claims 1 and 19-20, wherein R5 is C2-C3 alkynyl.

24. The compound of any one of claims 1 and 19-20, wherein R5 is C3-C4 cycloalkyl.

25. The compound of any one of claims 1 and 19-21, wherein R5 is propyl.

26. The compound of any one of claims 1, 19-20, and 22, wherein R5 is C2-C3 propenyl or ethynyl.

27. The compound of any one of claims 1, 19-20, and 24, wherein R5 is cyclopropanyl.

28. The compound of any one of claims 1 and 19-20, wherein the compound isor a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound of any one of claims 1-28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

530. A method of treating a disease treatable by inhibiting NF-kB activation comprising administering to a patient in need thereof, the pharmaceutical composition of claim 29.

31. The method of claim 30 wherein the disease is an inflammatory disease.1032. The method of claim 31 wherein the disease is selected from the goup consisting of autoimmune disease, pain, allergies, asthma, chronic obstructive pulmonary disease and sepsis.15   33. The method of claim 30 wherein the disease is selected from the group consisting ofrheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, asthma, inflammatorybowel disease, diabetes, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, osteoporosis, systemic lupus erythematosus, chronic obstructive pulmonary disease, cystic fibrosis, stroke, acute kidney injury, glomerulonephritis, psoriasis, atopic dermatitis, Behcet’s disease, tuberculosis, Crohn’s disease, colitis, Pagett’s disease, pancreatitis,5 periodonitis, inflammatory lung disease, and lupus nephritis.