Novel inhibitors of histone demethylases and compositions and methods thereof

Abstract

The invention provides novel compounds that are potent and selective inhibitors of histone demethylases and pharmaceutical compositions and methods thereof for treating various diseases and disorders, such as various types of cancers.

Description

NOVEL INHIBITORS OF HISTONE DEMETHYLASES AND COMPOSITIONS ANDMETHODS THEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 472,833, filed June 14, 2023, the entire content of which is incorporated herein by reference for all purposes.Technical Field of the Invention

[0002] The invention generally relates to pharmaceutical agents and therapeutic uses thereof. More particularly, the invention relates to novel compounds that are potent and selective inhibitors of histone demethylases as well as pharmaceutical compositions and methods thereof for treating various diseases, such as cancer.Background of the Invention

[0003] Cancer is the second leading cause of death worldwide with over 17 million new cases and over 10 million deaths annually. One in every 2-3 people in the U.S. will develop cancer and 1 in every 5-6 patients will die of cancer resulting in enormous health, economic and productivity costs. (Yabroff KR et al. (2011) Cancer Epidemiol Biomarkers Prev 20:2006-2014).

[0004] One of the most efficient processes in biology is the packaging of three billion nucleotides into the nucleus of a cell. This process is achieved by spooling DNA around proteins called histones. Densely wrapping of DNA around histones form nucleosomes which are the basic sub-units of chromatin. Along with its role as a packaging module for DNA, chromatin has been fundamentally shown to be an important regulator of gene expression, a type of gene regulation referred to as epigenetic gene regulation. Epigenetic gene regulation either silences or activates genes. These changes in gene states, which can be heritable, have profound effects on cellular function such as apoptosis, proliferation and differentiation, all occurring without altering gene sequence. (Quina, A S et al. (2006), Biochem. Pharmacol; 1563-1569).

[0005] Highly controlled chromatin chemical alterations occur at the N-terminal tail of histones H3 and H4. These alterations include methylation, ubiquitination, phosphorylation and acetylation. The addition or removal of these groups are mediated by specialized enzymes such as, for example, histone methyl transferases and histone methyl demethylases for methyl groups, and histone acetyltransferases and histone deacetylases for acetyl groups. Dysregulation of these epigeneticenzymes can lead to disease. Aberrant epigenetic activity is likely to play a role in a variety of diseases, including cancer, where dysregulation of these enzymes can alter a cell’s differentiation, proliferation and apoptotic state. Consequently, modulating abnormal activity of epigenetic enzymes may hold great promise for the treatment of human diseases including cancer. (Kelly, T.K. et al (2010), Nat. Biotechnol. 28; 1069-1078; Cloos, P.a.C et al (2008), Genes Dev.22; 1115-1140.)

[0006] Methylation and demethylation of histones as well as non -histone proteins add or remove specific epigenetic methyl marks that define transcriptionally active or inactive chromatin, and consequently effect cell proliferation and cell death.

[0007] The histone demethylase is overexpressed in multiple malignancies, including NSCLC, breast, ovanan, bladder, esophageal, gastric and colorectal cancers. (Wagner KW et al. (2013) JCI 123:5231-5246; Lu DH et al. (2019) Oncol Rep. 41:917-927; 2010; Lu DH et al. (2022) Cell Death & Dis. 13:547:1-11; Wang J et al. (2022) Biochem Biophys Res Com 624:53-58; Wang F et al. (2018) OncoTargets & Ther. 11:6383-6394; Chen JY et al. (2017) Oncogenesis 6:e369: 1-7; Cao LL et al. (2018) Int. J. Biol Markers 33:407-414) Mechanistically it has been shown to repress TET2, promoting tumor proliferation and invasiveness and by upregulating JAG1 promoting sternness, chemoresistance and angiogenesis (Chen JY et al. (2017) Oncogenesis 6:e369:l -7).

[0008] The histone demethylase KDM2B was originally identified as an oncogene that is activated by provirus integration in MoMuLV-induced rodent T cell lymphomas (Pfau PNAS 2008). Subsequent studies in humans provided evidence that KDM2B also plays an important role in the development of human lymphoid, but not myeloid malignancies, including acute and chonic B cell and T cell leukemias, as well as follicular and diffuse B cell lymphomas (Andri covi ch JCI 2015). KDM2B was also linked, to the development of several types of solid human tumors, including bladder carcinomas (Kottakis F et al. (2011) Mol Cell 43:285-298; McNiel et al. (2017) Sig Trans Targ Ther 2:el6045:l-8), basal-like triple negative breast adenocarcinomas (Kottakis et al. (2014) Ca Res 74:3935-3946) and pancreatic adenocarcinomas (Tzatsos A (2013) JCI 123:727).Mechanistically, KDM2B is key to a fundamentally oncogenic pathway, being induced by FGF-2, resulting in repression of miR-101 and the upregulation of the miR-101 target, EZH2.

[0009] The histone demethylase KDM7B is upregulated in gastric, liver, colorectal, prostate, lung, breast, head & neck cancers as well as acute lymphoblastic leukemia (Li S et al (2017) Am J Cancer Res 7:448-461; Ye H et al. (2019) Oncol Res 27:613-621); Zhou W et al. (2018) J Exp Clin Cancer Res 37:215; Fu Y et al. (2018) BBRC 496:981-987; Lv Y et al. (2017) Mol Med Rep 16: 4437-4444; Mama PK et al. (2017) Oncotarget 7:75585-75602; Liu Q et al. (2021) J Pathol 253: 106- 118; Tong D et al. (2016) Oncogenesis 5:e283:l-12; Ma Q et al. (2015) OncoTargets Ther 8: 1979-1988; Bjorkman M et al. (2012) Oncogene 31 :3444-3456; Shao P et al. (2017) Nucleic Acid Res 45: 1687-1702; Wang Q et al. (2016) JCI 126:2205-2220; Zhu G et al. (2015) Epigenomics 7: 143- 153; Shen Y et al. (2014) BBRC 451 : 119-125; Sun X et al. (2013) PLoS ONE 8:e77353: l-9).Additionally, it represses interferon gamma response promoters and may play a key role in mediating cancer immune resistance. (Asensio-Juan E et al. (2017) Nuc Acid Res 45:3800-3811.)

[0010] Numerous biological processes within cancers are dependent on, or regulated by histone demethylases. Three specific histone demethylase enzymes stand out as particularly important for multiple cancers: KDM7b, KDM2b and KDM2a. Despite the fact that these cancer targets have been recognized, they have not yet been adequately addressed in the clinic. Studies have shown that more than half of people diagnosed with cancers where KDM2A, KDM2B and KDM7B are dysregulated eventually die of their cancer. Small molecules targeting these enzymes to date lack appropriate potency, specificity and pharmacological properties.

[0011] There is an urgent unmet need for improved therapeutic agents that addresses the shortcomings of existing therapies. Novel compounds that are potent and selective inhibitors of histone demethylases are highly desired.Summary of the Invention

[0012] The invention is based in part on the unexpected discovery of certain small molecules displaying drug-like characteristics and different enzyme inhibitory characteristics across a spectrum of histone demethylases. The unique chemistry design disclosed herein has provided this opportunity where some inhibitors are relative specific, while others are broader in their inhibitory spectrum. The present invention thus can fundamentally alter the treatment protocol for cancers.

[0013] In one aspect, the invention generally relates to a compound having the structural formula (I):i or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 5- or 6-membered substituted or unsubstituted heterocycle having 1-3 ring heteroatoms with at least one N atom;Ring B is a substituted or unsubstituted, single or fused, carbocyclic or heterocyclic, aromatic or non-aromatic ring system;Z is a single bond or (CH2)i-W-(CH2)j, wherein z and / are independently selected from 0, 1, 2 and 3, and W is selected from the group consisting of a single bond, O, S, NR, NRC(O), C(O)NR, NRS(C>2) and S(C>2)NR, wherein when Z is a single bond Ring A and Ring B are directly bonded covalently; each of R1and R2is independently a C1-5 linear, branched or cyclic hydrocarbon group; and each R is independently H or Ci-6 alkyl group.

[0014] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0015] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition that comprises a compound disclosed herein.

[0016] In yet another aspect, the invention generally relates to a method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0017] In yet another aspect, the invention generally relates to a method for decreasing histone demethylase activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0018] In yet another aspect, the invention generally relates to a method for inhibiting lysine demethylase 2 (KDM2) and / or lysine demethylase 7 (KDM7) comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0019] In yet another aspect, the invention generally relates to a method for enhancing a subject’s native immune system against a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0020] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.Definitions

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0022] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and tra -isomers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0023] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0024] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0025] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0026] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "Ci-6 alkyl" is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0027] As used herein, the terms "alk" or "alkyl" refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, containing no unsaturation. The expression "lower alkyl" refers to alkyl groups of 1 to 4 carbon atoms (inclusive). Whenever it appears herein, a numerical range such as " 1 to 10" refers to each integer in the given range; e.g., " 1to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a Ci-6 alkyl group. In some embodiments, “alkyl” can be a C1.3 alkyl group.

[0028] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0029] As used herein, the term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.

[0030] As used herein, the term "alkylene" refers to a divalent straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., -(CH2)X- , wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.

[0031] As used herein, the term “arylalkyl” refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group.

[0032] As used herein, the terms “cycloalkyl” and "cycloalkenyl" as employed herein includes saturated and partially unsaturated cyclic, respectively, hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons.

[0033] As used herein, the terms “aromatic”, “ar” or “aryl” refer to a radical with 6 to 14 ring atoms (e.g., Ce-i4 aromatic or Ce-i4 aryl) that has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, naphthyl, and anthracene). An aryl group may be, for example, 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems, each with 6 to 14 carbon atoms.

[0034] As used herein, the term “halo” or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

[0035] As used herein, the term "heteroaryl" or, alternatively, "heteroaromatic" refers to a refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic and the like) aromatic ring system (e.g., having 6, 10 or 14 JI electrons shared in a cyclic array) having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-18 membered heteroaryl"). Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms" means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some instances, a heteroaryl canhave 5 to 14 ring atoms. In some embodiments, the heteroaryl has, for example, bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylene. The term “heteroaryl”, for example, may refer to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine and carbazole.

[0036] As used herein, the terms "heterocycle", "heterocyclic"or "heterocyclo" refer to fully saturated or partially unsaturated cyclic groups, for example, 3 to 7 membered monocyclic, 7 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.

[0037] As used herein, the term “heterocyclyl” refers to fully saturated or partially unsaturated cyclic groups, for example, 3- to 7- membered monocyclic, 7- to 12- membered bicyclic, or 10- to 15- membered tricyclic ring systems, which have at least one heteroatom in at least one ring, wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each ring of the heterocyclyl group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. The heterocyclyl group may be attached at any heteroatom or carbon atom of the ring or ring system.

[0038] As used herein, the term “substituents” refers to a group “substituted” on any functional group delineated herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, or heteroaryl group at any atom of that group. Suitable substituents include, without limitation halogen, CN, NO2, OR15, SR15, S(O)2OR13, NR13R16, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, 1 ,2- methylenedioxy, C(O)OR15, C(O)NR15R16, OC(O)NR15R16, NR15C(O)NR15R16, C(NR16)NR15R16, NR15C(NR16)NR15R16, S(O)2NR15R16, R17, C(O)R17, NR15C(O)R17, S(O)R17, S(O)2R17, R16, OXO,C(O)R16, C(O)(CH2)mOH, (CH2)nOR15, (CH2)mC(O)NR15R16, NR15S(O)2R17, where m is independently 0-6 inclusive. Each R15is independently hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl. Each R16is independently hydrogen, alkenyl, alkynyl, Cs-Ce cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl or C1-C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R17is independently C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl or C1-C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl and C1-C4 alkyl in each R15, R16and R17can optionally be substituted with halogen, CN, C1-C4 alkyl, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino, Ci-C2perfluoroalkyl, Ci-C2perfluoroalkoxy, or 1,2-methylenedioxy.

[0039] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0040] The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.

[0041] Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents.

[0042] As used herein, the term "inhibit" refers to any measurable reduction of biological activity. Thus, as used herein, "inhibit" or "inhibition" may be referred to as a percentage of a normal level of activity.

[0043] As used herein, the term “effective amount” of an active agent refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.

[0044] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred.Treatment may be directed at one or more effects or symptoms of a disease and / or the underlying pathology. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0045] As used herein, a "pharmaceutically acceptable form" of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs and isotopically labeled derivatives thereof. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs and isotopically labeled derivatives thereof.

[0046] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchioric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0047] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Tn some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0048] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0049] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). Tn certain cases, a prodrug has improved physical and / or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the bloodfollowing oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0050] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0051] Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc. Of course, other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the presently disclosed compounds. The amino acid residues include the 20 naturally occurring ammo acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3 -methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

[0052] As used herein, the term “pharmaceutically acceptable” excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the otheringredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0053] As used herein, the terms “isolated” or “purified” refer to a material that is substantially or essentially free from components that normally accompany it in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography.

[0054] As used herein, the term “subject” refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.

[0055] As used herein, the term “low dosage” refers to at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition. For example, a low dosage of an agent that is formulated for administration by inhalation will differ from a low dosage of the same agent formulated for oral administration.

[0056] As used herein, the term “high dosage” is meant at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest standard recommended dosage of a particular compound for treatment of any human disease or condition.

[0057] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" or "isotope derivative" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein,in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H, 'H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively.

[0058] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art. Benefits may also be obtained from replacement of normally abundant12C with13C. (See, WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.)

[0059] For example, deuterium (2H) can be incorporated into a compound disclosed herein for the purpose in order to manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate in rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of ki i o = 2-7 are typical. If this rate difference is successfully applied to a compound disclosed herein that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties.

[0060] When discovering and developing therapeutic agents, the person skilled in the art is able to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of those disclosed herein with improved stability through resistance to such oxidativemetabolism. Significant improvements in the pharmacokinetic profiles of compounds disclosed herein are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (t / 2), concen-tra-tion at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and F; and in terms of reduced clearance, dose and materials costs.

[0061] The following is intended to illustrate the above: a compound which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favorable and accurate determination of the extent of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.

[0062] Deuterium-hydrogen exchange in a compound disclosed herein can also be used to achieve a favorable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

[0063] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0064] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0065] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. Therecitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.Detailed Description of the Invention

[0066] The invention provides a unique approach to treatment of cancers where KDM2A, KDM2B and KDM7B are known to be dysregulated. The inhibitory molecules disclosed herein have unique chemical structures and unique enzyme inhibitory profiles.

[0067] Compounds of the invention are orally available and exhibit improved potency and selectivity compared to currently available therapeutic agents. More particularly, compounds and compositions of the invention are useful for the treatment of cancer, including one or more of pancreatic cancer, prostate cancer, breast cancer, bladder cancer, lung cancer, gastric cancer, melanoma and leukemia.

[0068] In one aspect, the invention generally relates to a compound having the structural formula (I):I or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 5- or 6-membered substituted or unsubstituted heterocycle having 1-3 ring heteroatoms with at least one N atom;Ring B is a substituted or unsubstituted, single or fused, carbocyclic or heterocyclic, aromatic or non-aromatic ring system;Z is a single bond or (CH2)i-W-(CH2)j, wherein z and j are independently selected from 0, 1, 2 and 3, and W is selected from the group consisting of a single bond, O, S, NR, NRC(O), C(O)NR, NRS(C>2) and S(Ch)NR, wherein when Z is a single bond Ring A and Ring B are directly bonded covalently; each of R1and R2is independently a C1-5 linear, branched or cyclic hydrocarbon group; and each R is independently H or Ci-6 alkyl group.

[0069] In certain embodiments, Ring A is a 6-membered substituted or unsubstituted C3-5 heteroaryl group.

[0070] In certain embodiments, Ring A is a pyridinyl group.

[0071] In certain embodiments, Ring A is a pyrimidinyl group.

[0072] In certain embodiments, Ring A has the structure of:wherein each of X1and X2is independently selected from CH and N.

[0073] In certain embodiments, Ring A is:

[0074] In certain embodiments, Ring A is:

[0075] In certain embodiments, Ring A is a 5 -membered substituted or unsubstituted C3-4 heteroaryl group.

[0076] In certain embodiments, Ring A is oxazolyl group.

[0077] In certain embodiments, Ring A has the structure:wherein Y1is N or CH, and Y2is NH, O or S.

[0078] In certain embodiments, Ring A is:

[0079] In certain embodiments, Ring A is:

[0080] In certain embodiments, Ring B is a substituted or unsubstituted, 6-membered aryl or heteroaryl ring.

[0081] In certain embodiments, Ring B is a substituted 6-membered aryl ring.

[0082] In certain embodiments, Ring B is:wherein each R3is independently selected from the group consisting of halo, CN, R, OR, SR and NRR’; each of R and R’ is independently a C1-3 alkyl group; and n is 0, 1, 2 or 3.

[0083] In certain embodiments, Ring B is a substituted 6-membered heteroaryl ring.

[0084] In certain embodiments, Ring B is a substituted pyridinyl group.

[0085] In certain embodiments, Ring B is:wherein each R3is independently selected from the group consisting of halo, CN, R, OR, SR and NRR’; each of R and R’ is independently a C1-3 alkyl group; and n is 0, 1, 2 or 3.

[0086] In certain embodiments, n is 1. In certain embodiments, R3is OCH3 or OCH2CH3.

[0087] In certain embodiments, n is 2. In certain embodiments, one R' is OCH3 or OCH2CH3. In certain embodiments, the other R3is F or Cl. In certain embodiments, the other R3is CH3 or CH2H3.

[0088] In certain embodiments, R1is a C3-5 cycloalkyl. In certain embodiments, R1is cyclobutyl.

[0089] In certain embodiments, R2is a C1-2 alkyl group. In certain embodiments, R2is CH3. In certain embodiments, R2is CH2CH3.

[0090] In certain embodiments, Z is a single bond. In certain embodiments, Z is O. In certain embodiments, Z is CH2.

[0091] In certain embodiments, the compound has a cis- configuration:

[0092] In certain embodiments, the compound has a trans- configuration:

[0093] In certain embodiments, the compound has one or more deuterium atoms in place of one or more hydrogen atoms.

[0094] In certain embodiments, the compound has one deuterium atom in place of one hydrogen atom.

[0095] Exemplary compounds of the invention include those listed in Table 1.Table 1. Exemplary Compounds

[0096] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0097] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0098] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition that comprises a compound disclosed herein.

[0099] In certain embodiments, the unit dosage form is a tablet or a capsule.

[0100] In yet another aspect, the invention generally relates to a method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0101] In certain embodiments, the disease or disorder is mediated by lysine demethylase 2 (KDM2) and / or lysine demethylase 7 (KDM7).

[0102] In certain embodiments, the disease or disorder is cancer, or a related disease or disorder.

[0103] In certain embodiments, the disease or disorder is selected from the group consisting of malignant neoplasm, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, lymphoma, pancreatic cancer, leukemia, ovarian cancer, glioblastoma, diffuse intrinsic pontine glioma, or a related disease or disorder.

[0104] In certain embodiments, the disease or disorder is type 2 diabetes or disorders of gluconeogenesis, or a related disease or disorder.

[0105] In certain embodiments, the subject’s native immune system is enhanced or made more effective against the disease or disorder.

[0106] In yet another aspect, the invention generally relates to a method for decreasing histone demethylase activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0107] In yet another aspect, the invention generally relates to a method for inhibiting lysine demethylase 2 (KDM2) and / or lysine demethylase 7 (KDM7) comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0108] In yet another aspect, the invention generally relates to a method for enhancing a subject’s native immune system against a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0109] In certain embodiments of the methods disclosed herein, administration to a subject is via oral administration.

[0110] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0111] In certain embodiments of the use, the disease or disorder is cancer, or a related disease or disorder.

[0112] In certain embodiments of the use, the disease or disorder is malignant neoplasm, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, lymphoma, pancreatic cancer, leukemia, ovarian cancer, glioblastoma, diffuse intrinsic pontine glioma, or a related disease or disorder.

[0113] In certain embodiments of the use, the disease or disorder is type 2 diabetes or disorders of gluconeogenesis, or a related disease or disorder.

[0114] Compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention include aqueous or oleaginous suspension. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation is also a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that are employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0115] For this purpose, any bland fixed oil employed includes synthetic mono- or di -glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms are also be used for the purposes of formulation.

[0116] Pharmaceutically acceptable compositions of this invention are orally administered in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents are optionally also added.

[0117] Alternatively, pharmaceutically acceptable compositions of this invention are administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0118] Pharmaceutically acceptable compositions of this invention are also administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0119] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically -transdermal patches are also used.

[0120] For topical applications, provided pharmaceutically acceptable compositions are formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Exemplary carriers for topical administration of compounds of this aremineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0121] Pharmaceutically acceptable compositions of this invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0122] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0123] The amount of compounds of the present invention that are optionally combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the hosttreated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0124] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

[0125] The following examples are meant to be illustrative of the practice of the invention, and not limiting in any way.ExamplesCompounds and Synthetic Methods

[0126] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0127] Compounds of the invention, including those specifically disclosed herein above and below, may be prepared as described in the following schemes.Chemical synthesis and analytical data:Abbreviations:DCM DichloromethaneDMAP 4-DimethylaminopyridineDMF Dimethyl FormamideEA Ethyl acetateH NMR Nuclear magnetic resonance spectrometryLC-MS Liquid chromatography-coupled mass spectrometryHPLC High Performance Liquid ChromatographyMeOH Methyl alcoholMTBE Methyl tert-butyl etherN2 NitrogenPE Petroleum etherTEA TriethylamineTHF TetrahydrofuranTLC Thin-layer chromatographyLC-MS or HPLC Method:• Method 1:

[0128] LC-MS instrument type: Agilent 1200\G6110A; column: Kinetex@ 5um EV0 C18 30*2.1mm A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in Acetonitrile (v / v); gradient: 0.01 min 5% B^> 0.80 min 95% B— > 1.2 min 95% B— > 1.21 min 5% B— > 1.5 min 5% B; flow rate: 1.5 mL / min; oven temperature: 50 °C; Detector: DAD (220&254nm).• Method 2:

[0129] MS instrument type: SHIMADZU LCMS-2020; Column: Kinetex EVO Cl 830*2.1mm, 5um, mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in Acetonitrile (v / v), gradient: 0.00 min 5% B^ 0.80 min 95% B^1.20 min 95% B^1.21 min 5% B— >1.55 min 5% B, flow rate: 1.5 mL / min, oven temperature: 50°C; UV detection: 220 nm & 254 nm.Compounds I and IIGeneral procedure for preparation of Compound 2:

[0130] To the mixture of ethyl l-benzyl-3-oxo-piperidine-4-carboxylate (500 g, 1.68 mol, 1 eq, HC1) and t-BuOK (565.25 g, 5.04 mol, 3 eq) in DMF (4500 mL) was added EtI (419.01 g, 2.69 mol, 214.88 mL, 1.6 eq) at 0 °C, then the mixture was stirred for 15 h at 25 °C. LCMS: EW18478-38- P1A showed the desired MS (RT=0.528 mins, MS+1 = 262.1). MTBE (5000 mL) was added.The solution was poured into ice-water (w / w = 1 / 1) (500 mL). The separated aqueous phase was extracted with MTBE (1000 mL). The combined organic phase was washed with brine (1000 mL*3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give ethyl l-benzyl-4- ethyl-3-oxo-piperidine-4-carboxylate (300 g, 1.04 mol, 61.74% yield) as a yellow oil.

[0131] LCMS: (Method 1): RT=0.528 mins, MS+1 = 262.1.General procedure for preparation of Compound 3:

[0132] The solution of ethyl l-benzyl-4-ethyl-3-oxo-piperidine-4-carboxylate (300 g, 1.04 mol, 1 eq) and aq. HCI (12 M, 1.73 L, 20 eq) in EtOH (700 mL) was stirred for 24 h at 80 °C. The reaction was concentrated. The solution was poured into ice-water (w / w = 1 / 1) (1000 mL). The pH was adjusted to 9 using NajCO? solid, extracted with EA (1000 mL x 2). The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=30 / l, 10 / 1) to afford l-benzyl-4-ethyl-piperi din-3 -one (80 g, 368.14 mmol, 36.36% yield) as yellow oil.

[0133] H NMR: 400 MHz CDC13: 7.29-7.35 (m, 5H),7.60 (s, 2H), 3.22 (d, J= 14 Hz, 1H), 2.94-2.97 (m, 1H), 2.82 (d, J= 14 Hz, 1H), 2.48-2.49 (m, 1H), 2.07-2.20 (m, 1H), 1.75-1.95 (m, 1H), 1.51-1.52 (m, 1H), 1.30-1.45 (m, 1H), 0.93 (t, J= 7.6 Hz, 3H).

[0134] To the solution of LiHMDS (1 M, 110.44 mL, 1.2 eq, THF solution) in THF (100 mL) was added a solution of l-benzyl-4-ethyl-piperi din-3 -one (20 g, 92.04 mmol, 1 eq) in THF (50 mL). Then the reaction mixture was stirred at -70 °C for 0.5 h. The solution of [N- (trifluoromethylsulfonyloxy)anilino] trifluoromethanesulfonate (42.99 g, 110.44 mmol, 1.2 eq) in THF (50 mL) was added to the reaction mixture and stirred at 25 °C for 10 hrs. The sat. NaHCCF (60 mL) was added to the reaction mixture and extracted with EA (200 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous ISfeSCL, filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, Petroleum ether / Ethyl acetate= 1 / 0 to 100 / 1) to give (l-benzyl-4-ethyl-3,6-dihydro- 2H-pyridin-5-yl) trifluoromethanesulfonate (14 g, 40.07 mmol, 43.54% yield) was obtained as yellow oil.

[0135] The solution of (l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl) trifluoromethanesulfonate (2.00 g, 5.72 mmol, 1 eq), BPD (1.74 g, 6.87 mmol, 1.2 eq), AcOK (1.69 g, 17.17 mmol, 3 eq) cyclopentyl(diphenyl) phosphane;dichloromethane;dichloropalladium;iron (467.49 mg, 572.46 umol, 0.1 eq) cyclopentyl (diphenyl)phosphane;iron (317.36 mg, 572.46 umol, 0.1 eq) in dioxane (30 mL) was stirred for 3 h at 100 °C. LCMS: EW19589-61-P1 A showed the desired MS (RT=0.699 mins, MS+1 = 328.4). Then 2-chloro-4-(4- methoxyphenyl) pyridine (1.26 g, 5.72 mmol, 1 eq), ISfeCCE (1.82 g, 17.16 mmol, 3 eq), cyclopentyl (diphenyl)phosphane;dichloromethane;dichloropalladium;iron (467.12 mg, 572.00 umol, 0.1 eq) in H2O (10 mL) was added and the solution was stirred for 6 h at 100 °C. LCMS: EW 19589-63 -P1C2 showed the desired MS (RT=0.626mins, MS+1 = 385.2) and the material was consumed. The solution was concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=10 / l, 2 / 1) to afford 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5- yl)-4-(4-methoxyphenyl)pyridine (800 mg, 2.08 mmol, 36.37% yield) as yellow oil.

[0136] LCMS: (method 1): RT=0.626mins, MS+1 = 385.2.

[0137] The mixture of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-4-(4- methoxyphenyl)pyridine (100 mg, 260.07 umol, 1 eq), Pd / C (20 mg, 10% purity, 1.00 eq, 50% wet), Pd(OH)2(20 mg, 142.41 umol, 5.48e-l eq, 50% wet) in MeOH (1 mL) / NH3.H2O (0.1 mL, 28%) was stirred for 12 h at 25°C under H2(0.1 MPa). The mixture was filtered. The filtrate was concentrated to give 2-(4-ethyl-3-piperidyl)-4-(4- methoxyphenyl) pyridine (75 mg, 253.03 umol, 97.29% yield) as a yellow oil.General procedure for preparation of Target 17 (1)1 and Target 18 (II)(I) (II)

[0138] The solution of 2-(4-ethyl-3-piperidyl)-4-(4-methoxyphenyl)pyridine (75.00 mg, 253.03 umol, 1 eq), CH3COOH (75.97 mg, 1.27 mmol, 72.35 uL, 5 eq), cyclobutanone (35.47 mg, 506.06 umol, 37.81 uL, 2 eq), NaBHsCN (23.85 mg, 379.55 umol, 1.5 eq) in THF (1 mL) was stirred for 1 h at 25 °C. LCMS: EW19589-80-P1A showed the desired MS (RT=0.590, 0.670 mins, MS+1 = 351.3). The residue was purified by PREP. HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(0.05%HCl)-ACN];B%: 15%-55%,10min) . 14.15 mg of Target 17 / 18 (I and II) (Pl) and 15.08 mg of Target 17 / 18 (I and II) (P2) were obtained.

[0139] LCMS: (Method 1): RT=0.590, 0.670 mins, MS +1 = 351.3

[0140] Target 17 (I) 'H NMR: 400 MHz CDCh: 12.38 (s, 1 H), 8.62 (d, J= 6.0 Hz, 1H), 7.85- 7.99 (m, 2H), 7.80 (d, J= 7.2 Hz, 2H), 7.12 (d, J= 7.2 Hz, 2H), 3.95-4.09 (m, 1H), 3.98 (s, 3H), 3.46-3.57 (m,3H), 2.91-3.12 (m, 1H), 2.71-2.89 (m, 3H), 1.75-2.31 (m, 7H), 1.19-1.27 (m, 2H), 0.86 (t, J= 6.8 Hz, 3H),

[0141] LCMS: (Method 2): RT=1.692 mins, MS+1 = 351.3.

[0142] Target 17a(II) 'H NMR: 400 MHz CDC13: 12.46 (s, 1 H), 8.66 (d, J= 6.0 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J= 6.0 Hz, 1H), 7.79 (d, J= 7.8 Hz, 2H), 7.12 (d, J= 7.8 Hz, 2H), 3.67-4.68 (m, 1H), 3.95 (s, 3H), 3.68-3.78 (m, 1H), 3.49-3.50 (m, 1H), 3.39-3.41(m, 1H), 2.68-2.85 (m, 4H), 1.75- 2.45 (m, 8H), 1.05-1.19 (m, 1H), 0.82 (t, J = 6.0 Hz, 3H),LCMS: (Method 2): RT=1.822 mins, MS+1 = 351.2.Compounds III and IV:LC-MS or HPLC Method:• Method 1:

[0143] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1.0 mL / min.• Method 2:

[0144] 5-95 AB 4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0145] 5 95 AB 6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0146] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0147] 9 -95 AB-ELSD_2min: LC / MS (The column used for chromatography was a Luna-Cl 82.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0148] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was EEO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2. 1 *50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method ?:

[0149] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was EEO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0150] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min.Mobile phase A was FLO+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (Sum particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.1 2

[0151] To the mixture of 2, 4-di chloropyrimidine 1 (2 g, 13.4 mmol, 1 eq) and (4- methoxyphenyl)boronic acid (2.24 g, 14.8 mmol, 1.1 eq) and K2CO3 (3.71 g, 26.9 mmol, 2 eq) in DMF (20 mL) was added Pd(PPhs)4 (1.55 g, 1.34 mmol, 0.1 eq) under N2. The mixture was heated to 80 °C and stirred for 12 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) showed 1 was consumed and three new spots was detected. Then it was separated between 40 mL of water and 80 mL of ethyl acetate. The organic phase was separated, washed with 60 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-13% Ethylacetate / Petroleum ethergradient @ 80 mL / min) to give compound 2 (1.9 g, 8.61 mmol, 64.1% yield) as a yellow solid.

[0152] To a solution of 2-chloro-4-(4-methoxyphenyl)pyrimidine 2 (70.1 mg, 318 pmol, 1.3 eq), l-benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (80 mg, 244 pmol, 1 eq) and K2CO3 (67.6 mg, 489 pmol, 2 eq) in dioxane (1.5 mL) and H2O (0.3 mL) was added Pd(dppf)C12 (17.9 mg, 24.4 pmol, 0. 1 eq). The mixture was stirred at 110 °C for 12 hours. LC-MS (ET31767-35-P1L1) showed 2 was consumed completely and desired mass was detected. Then it was separated between 5 mL of water and 10 mL of ethyl acetate. The organic phase was separated, washed with 7 mL of brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (S1O2, petroleum ether: ethyl acetate = 1 : 1) to give compound 3 (60 mg, 156 pmol, 63.7% yield) as a yellow oil.

[0153] LCMS: (Method 1 ): RT=1.009 mins, MS+1 = 386.2.

[0154] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-4-(4- methoxyphenyl)pyrimidine 3 (50 mg, 130 pmol, 1 eq) and (Boc)2O (84.9 mg, 389 pmol, 3 eq) in MeOH (8 mL) was added Pd / C ( 15 mg, 10% purity) and Pd(OH)2 (50 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 35 °C for 2 hours. LC-MS (ET31767-46-P1L2) showed 3 was consumed completely and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 1 : 1) to give compound 4 (20 mg, 50.3 pmol, 38.8% yield) as a yellow oil and compound 4a (10 mg, 25.2 pmol, 19.4% yield) as a yellow oil.

[0155] LCMS: (Method 1): RT=1.326, 1.386 mins, MS+1 = 398.2.General procedure for preparation of compound 5

[0156] A mixture of tert-butyl 4-ethyl-3-[4-(4-methoxyphenyl)pyrimidin-2-yl]piperidine-l- carboxylate 4 (20.0 mg, 50.3 pmol, 1 eq) in EtOAc / HCl (2 M, 2.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 12 hours under N2 atmosphere. LC-MS (ET31767-55-P1L1) showed 4 was consumed completely and desired mass was detected. The reaction mixture was concentrated in vacuum to give a crude compound 5 (20 mg, crude, HC1 salt) as a yellow solid.

[0157] LCMS: (method 1): RT=0.923 mins, MS+1 = 298.1.

[0158] To a solution of 2-(4-ethyl-3-piperidyl)-4-(4-methoxyphenyl) pyrimidine 5 (17.8 mg, 59.9 pmol, 1 eq, HC1 salt) in MeOH (1 mL) was added TEA (7.27 mg, 71.9 pmol, 1.2 eq). The mixture was stirred at 20 °C for 10 min. Then the cyclobutanone (12.6 mg, 180 pmol, 3 eq) and AcOH (360 pg, 5.99 pmol, 0.1 eq) was added in above mixture and the mixture was stirred at 20 °C for 20 min. After addition the NaBHiCN (11.3 mg, 180 pmol, 3 eq) was added and the resulting mixture was stirred at 20 °C for 3.5 hours. LC-MS (ET31767-57-P1L1) showed 5 was consumed completely and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 80*40mm*3 um; mobile phase: [water (0.04%HCl)-ACN]; B%: 20%-50%, 7min) to give Target 11 (III) (6.6 mg, 17.0 pmol, 28.4% yield, 100% purity, HC1 salt) as a yellow solid.

[0159] LCMS: (method 1): RT=0.963 mins, MS+1 = 352.2.

[0160] 1H NMR (400 MHz, CHLOROFORM-7) 5 ppm 8.64 (br d, 7=4.82 Hz, 1H), 8.11 (br d,7=8.33 Hz, 2H), 7.61 (br d, 7=4.39 Hz, 1H), 7.00 - 7.07 (m, 2H), 4.37 (br d, 7=11.40 Hz, 1H), 3.93 (s, 1H), 3.91 (s, 3H), 3.83 (br d, 7=10.96 Hz, 1H), 3.41 (br d, 7=10.96 Hz, 1H), 3.27 (br d, 7=10.52Hz, 1H), 2.90 (br s, 2H), 2.55 - 2.80 (m, 3H), 2.23 - 2.38 (m, 2H), 1.97 - 2.08 (m, 2H), 1.79 (br d, 7=8.33 Hz, 1H), 1.32 - 1.46 (m, 1H), 0.94 (br s, 1H), 0.76 (br t, 7=6.80 Hz, 3H).

[0161] A mixture of tert-butyl 4-ethyl-3-[4-(4-methoxyphenyl)pyrimidin-2-yl]piperidine-l- carboxylate 4a (10 mg, 25.2 pmol, 1 eq) in EtOAc / HCl (2 M, 1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hour under N2 atmosphere. LC-MS (ET31767-51-P1L2) showed 4a was consumed completely and desired mass was detected. The reaction mixture was concentrated in vacuum to give a crude compound 5a (13 mg, crude, HC1 salt) as a yellow solid.

[0162] LCMS: (method 1): RT=0.908 mins, MS+1 = 298.1.General procedure for preparation of Target 11 (IV)

[0163] To a solution of 2-(4-ethyl-3-piperidyl)-4-(4-methoxyphenyl) pyrimidine 5a (13 mg, 38.9 pmol, 1 eq, HC1 salt) in MeOH (1 mL) was added TEA (4.73 mg, 46.7 pmol, 1.2 eq). The mixture was stirred at 20 °C for 10 min. Then the cyclobutanone (8.19 mg, 117 pmol, 3 eq) and AcOH (234 pg, 3.89 pmol, 0.1 eq) was added in above mixture and the mixture was stirrd at 20 °C for 20 min. After addition the NaBHA’N (7.34 mg, 117 pmol, 3 eq) was added and the resulting mixture was stirred at 20 °C for 11.5 hours. LC-MS (ET31767-54-P1L1) showed 5a was consumed completely and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate Cl 8 150*25mm*5um; mobile phase: [water (0.04%HCl)-ACN]; B%: 15%-40%, 8min) to give Target 11 (IV) (3.3 mg, 8.51 pmol, 21.9% yield, 100% purity, HC1 salt) as a white solid.

[0164] LCMS: (method 1): RT=0.989 mins, MS+1 = 352.1.

[0165] H NMR (400 MHz, CHLOROFORM-^ ) 5 ppm 8.66 (br s, 1H), 8.23 (br s, 2H), 7.74 (br s, 1H), 7.06 (br s, 2H), 3.99 (br s, 1H), 3.94 (s, 3H) 3.39 - 3.67 (m, 4H), 2.89 (br s, 3H), 2.13 - 2.39 (m, 4H), 1.93 - 2.12 (m, 2H), 1.77 (br s, 1H), 1.26 (br s, 2H), 0.79 - 0.89 (m, 3H).Compounds V and VILC-MS or HPLC Method:• Method 1:

[0166] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1.0 rnL / min.• Method 2:

[0167] 5 -95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0168] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 mm, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0169] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40 min and 5-95% B at 0.4-3.0min, hold on 95% B for 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 850*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0170] 9 -95AB-ELSD 2min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0171] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was ELO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2.1 *50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 7:

[0172] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0173] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (Sum particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.Experimental procedure for the largest scale run:General procedure for preparation of compound 2

[0174] To the mixture of 5-bromo-2-chloro-pyridine 1 (1 g, 5.20 mmol, 1 eq) and (4- methoxyphenyl) boronic acid (869 mg, 5.72 mmol, 1.1 eq) and K2CO3 (1.44 g, 10.4 mmol, 2 eq) in DMF (20 mL) was added Pd(PPhs)4 (600 mg, 520 pmol, 0. 1 eq) under N2. The mixture was heated to 80 °C and stirred for 12 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) showed 1 was consumed and three new spots was detected. Then it was separated between 40 mL of water and 80 mL of ethyl acetate. The organic phase was separated, washed with 60 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give compound 2 (1.1 g, 5.01 mmol, 96.4% yield) as a white solid.

[0175] To a solution of 2-chloro-5-(4-methoxyphenyl)pyridine 2 (80.6 mg, 367 pmol, 1.2 eq), 1- benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (100 mg, 306 pmol, 1 eq) and K2CO3 (127 mg, 917 pmol, 3 eq) in dioxane (0.5 mL) and H2O (0. 1 mL) was added 4-ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropalladium (21.6 mg, 30.6 pmol, 0. 1 eq). The mixture was stirred at 100 °C for 3 hours. LC-MS (ET31767-45-P1L1) showed 2 was consumed completely and desired mass was detected. Then it was separated between 5 mL of water and 10 mL of ethyl acetate. The organic phase was separated, washed with 7 mL of brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ethergradient @ 60 mL / min) to give compound 3 (40 mg, 104 pmol, 34.0% yield) as a yellow oil, which was confirmed by LCMS.

[0176] LCMS: (Method 1): RT 0.998, MS+1 = 385.2.

[0177] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-5-(4- methoxyphenyl)pyridine 3 (50 mg, 130 pmol, 1 eq) and (Boc)2O (85.1 mg, 390 umol, 3 eq) in MeOH (8 mL) was added Pd / C (15 mg, 10% purity) and Pd(OH)2 (50.0 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (20 Psi) at 45 °C for 2 hours. LC-MS (ET31767-48-P1B1) showed 3 was consumed completely and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give compound 4 (70 mg, crude) as a yellow oil.

[0178] LCMS: (method 1): RT=1.130mins, MS+1 = 397.2.

[0179] A mixture of tert-butyl 4-ethyl-3-[5-(4-methoxyphenyl)-2-pyridyl]piperidine-l- carboxylate 4 (50 mg, 126 pmol, 1 eq) in MeOH / HCl (4 M, 1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 0.5 hour under N2 atmosphere. LC-MS (ET31767-62-P1L1) showed 4 was consumed completely and desired mass was detected. The reaction mixture was concentrated in vacuum to give crude compound 5 (40 mg, crude, HC1 salt) as a yellow oil.

[0180] LCMS: (method 1): RT=0.881, 0.948 mins, MS+1 = 297.1.(V) (VI)

[0181] To a solution of 2-(4-ethyl-3-piperidyl)-5-(4-methoxyphenyl) pyridine 5 (40 mg, 120 pmol, 1 eq, HC1 salt) in MeOH (1 mL) was added TEA (4.59 mg, 44.2 pmol, 0.2 eq). The mixture was stirred at 20 °C for 10 mins. Then the cyclobutanone (25.3 mg, 360 pmol, 3 eq) and AcOH (722 ug, 12.0 pmol, 0.1 eq) were added in above mixture and the mixture was stirred at 20 °C for 20 mins. After addition, the NaBJECN (22.7 mg, 361 pmol, 3 eq) was added and the resulting mixture was stirred at 20 °C for 11.5 hours. LC-MS (ET31767-63-P1L1) showed 5 was consumed completely and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 80*40mm*3 um; mobile phase: [water (0.04%HCl)-ACN]; B%: 25%-49%, 7min) to give Target 14 (V) (12 mg, 34.2 pmol, 28.5% yield, 100% purity, HC1 salt) as a yellow solid and Target 14a (VI) (3.7 mg, 10.5 pmol, 8.71% yield, 99.2% purity, HC1 salt) as a white solid.

[0182] LCMS: (method 1): RT=0.942, 1.014 mins, MS+1 = 351.2.

[0183] Target 14a (VI): 'H NMR (400 MHz, METHANOL-74) 8 ppm 9.03 (s, 1H) 8.72 (br d, 7=8.25 Hz, 1H), 8.04 (d, 7=8.38 Hz, 1H), 7.77 (d, 7=8.63 Hz, 2H), 7.13 (d, 7=8.63 Hz, 2H), 3.88 (s, 3H) 3.71 - 3.79 (m, 1H), 3.62 - 3.71 (m, 2H), 3.35 - 3.41 (m, 1H), 3.19 - 3.28 (m, 1H), 3.00 (br t, 7=11.82 Hz, 1H), 2.35 - 2.44 (m, 3H), 2.31 (br dd, 7=14.88, 2.88 Hz, 2H), 2.03 - 2.15 (m, 1H), 1.82 - 1.96 (m, 2H), 1.65 - 1.78 (m, 1H), 1.22 - 1.32 (m, 1H), 1.12 - 1.22 (m, 1H), 0.88 (t, 7=7.38 Hz, 3H).

[0184] Target 14 (V): ’H NMR (400 MHz, METHANOL-74) 8 ppm 9.10 (d, 7=1.75 Hz, 1H),8.85 (dd, 7=8.44, 1.69 Hz, 1H), 7.93 (d, 7=8.50 Hz, 1H), 7.81 (d, 7=8.75 Hz, 2H), 7.14 (d, 7=8.75 Hz, 2 H), 4.05 (br d, 7=12.63 Hz, 1H), 3.86 - 3.92 (m, 4H), 3.68 - 3.76 (m, 1H), 3.58 - 3.67 (m, 1H), 3.44 (br d, 7=12.38 Hz, 1H), 3.01 (td, 7=12.44, 3.50 Hz, 1H), 2.37 - 2.49 (m, 4H), 2.20 - 2.33 (m, 3H),1.85 - 1.98 (m, 2H), 1.60 - 1.72 (m, 1H), 0.99 (br t, 7=6.82 Hz, 1H), 0.79 - 0.88 (m, 3H).Compounds VII and VIIILC-MS or HPLC Method:• Method 1:

[0185] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1 .0 mL / min.• Method 2:

[0186] 5 -95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0187] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0188] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0189] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was aLuna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0190] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. The columnused for chromatography was Xbridge Shield RP18 2.1 *50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 7 :

[0191] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was FLO+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (Sum particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0192] 5 95CD 6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min.Mobile phase A was FLO+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2. l*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.1 2

[0193] A solution of 3 -methoxyphenol (419 mg, 3.38 mmol, 1 eq) in DMA (5 mL) at 20 °C was stirred under N2. Then t-BuOK (417 mg, 3.72 mmol, 1.1 eq) was added. The solution was stirred at 20 °C for 0.5 hour. Then 2, 4-di chloropyridine 1 (500 mg, 3.38 mmol, 1 eq) was added and heated to 80 °C and stirred at 80 °C for 3.5 hours. The reaction mixture was diluted with H2O 10 mL and extracted with ethyl acetate 30 mL. The combined organic layers were washed with Saturated NaCl solution 100 mL, dried over anhydrous Na2SCU, filtered and concentrated under reduced pressure to give a crude compound 2 (790 mg, crude) as a yellow oil.

[0194] To the mixture of 2-chloro-4-(3-methoxyphenoxy)pyridine 2 (39.6 mg, 168 pmol, 1.1 eq) and l-benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (50 mg, 153 pmol, 1 eq and Na2CCh (63.3 mg, 598 pmol, 3.91 eq) in dioxane (0.5 mL) and EfcO (0.1 mL) was added 4-ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropalladium (10.8 mg, 15.3 pmol, 0.1 eq) under N2. The mixture was purged with N23 times and heated to 100 °C and stirred for 8 hours. LCMS (ET31620-48-P1C) showed 2 remained and desired mass was detected. The mixture was fdtered and the filtrate was concentrated under reduced pressure to get crude product. The residue was punfied by prep-TLC (SiC>2, petroleum ether: ethyl acetate = 0: 1) to give compound 3 (60 mg, 150 pmol, 32.7% yield) as a yellow oil.LCMS: (method 1): RT=0.620 mins, MS+1 = 401.2.3 4

[0195] The mixture of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-4-(3- methoxyphenoxy)pyridine 3 (60 mg, 150 pmol, 1 eq), Pd / C (40 mg, 10% purity), Pd(OH)2 (40 mg) and BOC2O (98.1 mg, 449 pmol, 3 eq) in MeOH (3 mL) was stirred for 12 hours at 40 °C under H2 (15 psi). LCMS (ET31620-55-P1C1) showed 3 was consumed and the desired ms was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure to get crude product. The crude product was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 3: 1) to give compound 4 (30 mg, 72.7 pmol, 48.5% yield) as a colourless oil.

[0196] LCMS: (Method 1): RT=0.763, 0.776 mins, MS+1 = 413.3.

[0197] A mixture of tert-butyl 4-ethyl-3-[4-(3-methoxyphenoxy)-2-pyridyl] piperidine-1- carboxylate 4 (30 mg, 72.7 pmol, 1 eq) and HCl / MeOH (4 M, 1 mL) was stirred for 0.5 hour at 20 °C. LCMS (ET31620-60-P1A1) showed 4 was consumed and the desired mass was detected. The mixture was concentrated by N2 to give compound 5 (25 mg, crude, HC1 salt) as a colorless oil.

[0198] LCMS: (Method 1): RT=0.637, 0.688 mins, MS+1 =313.2.VII VIII

[0199] To a solution of 2-(4-ethyl-3-piperidyl)-4-(3 -methoxyphenoxy) pyridine 5 (25 mg, 71.7 pmol, 1 eq, HC1 salt) in MeOH (1 mL) was added TEA (8.70 mg, 86.0 pmol, 1.2 eq). The mixture was stirred at 20 °C for 10 min. Then the cyclobutanone (15.1 mg, 215 pmol, 3 eq) and AcOH (4.30 mg, 71.7 pmol, 1 eq) was added in above mixture and the mixture was stirred at 20 °C for 20 min. After addition the NaBEECN (13.5 mg, 215 pmol, 3 eq) was added and the resulting mixture was stirred at 20 °C for 12.5 hours. LCMS (ET31620-61 -Pl A2) showed 5 was almost consumed and the desired mass was detected. The reaction mixture was diluted with 5 mL of H2O and extracted with 15 mL of EA. The combined organic layers were washed with 10 mL of saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex luna C18 80*40mm*3 um; mobile phase: [water(0.04%HCl)-ACN]; B%: 25%-42%, 7min) to give of Target 13 (VII) (11.5 mg, 27.9 pmol, 38.9% yield, 97.6% purity, HC1 salt) as a yellow solid and Target 13a (VIII) (4.8 mg, 1 1.4 pmol, 15.9% yield, 95.4% purity, HC1 salt) as a white solid.

[0200] LCMS: (method 1): RT=0.666, 0.719 mins, MS+1 =367.2.

[0201] Target 13 (VII): ’H NMR (400 MHz, METHANOL-74) 6 ppm 8.64 (d, 7=7.00 Hz, 1H),7.47 (t, 7=8.25 Hz, 1H), 7.37 (d, 7=2.50 Hz, 1H), 7.26 (dd, 7=7.00, 2.50 Hz, 1H), 7.01 (br d, 7=0.63 Hz, 1H), 6.81 - 6.88 (m, 2H), 3.92 - 4.00 (m, 1H), 3.83 (s, 4 H), 3.64 (br dd, 7=11.88, 2.13 Hz, 1H),3.48 (s, 1H) 3.36 - 3.44 (m, 1H), 2.95 (td, 7=12.51, 4.13 Hz, 1H), 2.34 - 2.47 (m, 4H), 2.22 (br d, 7=12.26 Hz, 3H), 1.82 - 1.95 (m, 2H), 1.54 - 1.66 (m, 1H), 1.03 (tq, 7=10.62, 3.51 Hz, 1H), 0.80 - 0.88 (m, 3H).

[0202] Target 13a (VIII): 'H NMR (400 MHz, METHANOL-74) 8 ppm 8.63 (d, 7=6.88 Hz, 1H), 7.59 (d, 7=2.25 Hz, 1H), 7.47 (t, 7=8.25 Hz, 1H), 7.33 (dd, 7=6.82, 2.19 Hz, 1H), 7.01 (dd, 7=8.38, 2.00 Hz, 1H), 6.79 - 6.89 (m, 2H) 3.83 (s, 3H), 3.56 - 3.76 (m, 3H), 3.33 - 3.41 (m, 1H), 3.14 - 3.23 (m, 1H), 2.90 - 3.00 (m, 1H), 2.33 - 2.47 (m, 3H), 2.26 (br d, 7=12.88 Hz, 2 H), 1.97 - 2.07 (m, 1H), 1.79 - 1.95 (m, 2H), 1.71 (br d, 7=13.26 Hz, 1 H), 1.28 (ddd, 7=13.70, 7.50, 3.19 Hz, 1H), 1.09 - 1.22 (m, 1H), 0.87 (t, 7=7.38 Hz, 3H).Compounds IX and XLC-MS or HPLC Method:• Method 1:

[0203] 5-95 AB 2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min .5% B in 0.01 mm, 5-95% B (0.01-1.00 mm), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1.0 mL / min.• Method 2:

[0204] 5-95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min .5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0205] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min , hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 4:

[0206] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0207] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min) ,95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0208] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 7:

[0209] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 8:

[0210] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.

[0211] To a solution of l-(bromomethyl)-3-methoxy-benzene 1 (1 g, 4.97 mmol, 1 eq) and (2- chloro-4-pyridyl)boronic acid (783 mg, 4.97 mmol, 1 eq) and Na2CCh (1.05 g, 9.95 mmol, 2 eq) intoluene (10 mL) and EtOH (2.5 mL) and H2O (2 mL) was added Pd(PPh?)4 (287 mg, 248.68 pmol, 0.05 eq) under N2. The mixture was heated to 80 °C and stirred for 12 hours. LC-MS (ET31541-33- P1A) showed 1 was consumed completely and desired mass was detected. The mixture was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 2 (820 mg, 3.51 mmol, 70.6% yield) as a colorless oil.

[0212] LCMS: (Method 1): RT=1.224 mins, MS+1 = 234.0.

[0213] To a mixture of 2-chloro-4-[(3-methoxyphenyl)methyl]pyridine 2 (150 mg, 642 prnol, 1 eq) and l-benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (420 mg, 1.28 mmol, 2 eq) and Na2COs (272 mg, 2.57 mmol, 4 eq) in dioxane (5 mL) and Water (1 mL) was added 4-ditert-butylphosphanyl-N,N-dimethyl-anilme; dichloropalladium (45.5 mg, 64.2 pmol, 0.1 eq) under N2. The mixture was heated to 100 °C and stirred for 12 hours. LCMS (ET31541-65-pla2) showed 2 was consumed completely and desired mass was detected. The mixture was filtered and concentrated under reduced pressure to get a crude product as a black gum. The crude product was purified by reversed-phase HPLC (column: C18 20-35um 100A 80g; mobile phase: [water-ACN]; B%: 0%-50% @ 80mL / min) to give compound 3 (120 mg, 301 pmol, 46.9% yield) as a green oil, which was confirmed by LCMS (ET31541-68-P1A1).

[0214] LCMS: ET31541-65-pla2 (Method 1): RT=0.944 mins, MS+1 = 399.2.

[0215] LCMS: ET31541-68-P1A1 (Method 1): RT=0.928mins, MS+1 = 399.2.

[0216] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-4-[(3- methoxyphenyl)methyl]pyridine 3 (120 mg, 301 pmol, 1 eq) and (Boc)2O (329 mg, 1.51 mmol, 5 eq) in MeOH (10 mL) was added Pd / C (20 mg, 10% purity) and Pd(OH)2 (20 mg, 142 pmol) under N2atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15Psi) at 35 °C for 12 hours. LC-MS (ET31767-74-P1L1) showed 3 was consumed completely and desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude compound 4 (150 mg, crude) as a yellow oil.

[0217] LCMS: ET31767-74-P1L1 (Method 1): RT=1.064, 1.096 mins, MS+1 = 41 1.2.4 5

[0218] A mixture of tert-butyl 4-ethyl-3-[4-[(3-methoxyphenyl)methyl]-2-pyridyl]piperidine-l- carboxylate 4 (150 mg, 365 pmol, 1 eq) in MeOH / HCl (4 M, 3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hour under N2 atmosphere. LC-MS (ET31767-75-P1L1) showed 4 was consumed completely and desired mass was detected. The reaction mixture was concentrated in vacuum to give a crude compound 5 (160 mg, crude, HC1 salt) as a yellow oil.

[0219] LCMS: ET31767-75-P1L1 (Method 1): RT=0.857, 0.946 mins, MS+1 = 311.1.General procedure for preparation of Target 12 (IX) and Target 12a (X)IX X

[0220] To a solution of 2-(4-ethyl-3-piperidyl)-4-[(3-methoxyphenyl) methyl] pyridine 5 (160 mg, 515 pmol, 1 eq, HC1) in MeOH (2 mL) was added TEA (10.4 mg, 103 pmol, 1.2 eq). The mixture was stirred at 20 °C for 10 min. Then the cyclobutanone (108 mg, 1.55 mmol, 3 eq) and AcOH (31.0 mg, 55.4 pmol, 1 eq was added in above mixture and the mixture was stirred at 20 °C for 20 min. After addition, the NaBHsCN (97.2 mg, 1.55 mmol, 3 eq) was added and the resulting mixture was stirred at 20 °C for 11.5 hours. LC-MS (ET31767-78-P1L1) showed 5 was consumed completely and desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 80*40mm*3 um; mobile phase: [water (0.04%HCl)-ACN]; B%: 27%-47%,7min) to give Target 12 (IX) (40 mg, 99.6 pmol, 19.3% yield, 99.9% purity, HC1 salt) as a yellow solid and Target 12a (X) (15.4 mg, 37.2 pmol, 7.22% yield, 96.9% purity, HC1 salt) as a white solid.

[0221] LCMS: (method 1): RT=0.921, 1.018 mins, MS+1 = 365.2.

[0222] Target 12 (IX): 'H NMR (400 MHz, DMSO-76) 5 ppm 8.60 (d, 7=5.63 Hz, 1H) 7.63 (s, 1H), 7.54 (br d, 7=5.50 Hz, 1H), 7.19 - 7.27 (m, 1H), 6.79 - 6.87 (m, 3H), 4.10 (s, 2H), 3.87 (br d, . / -12,76 Hz. 1 H), 3.73 - 3.80 (m, 1H) 3.72 (s, 3H), 3.39 (br d, . / I 2.63 Hz, 1H), 3.17 - 3.25 (m, 1H), 2.77 - 2.90 (m, 1H), 2.38 (br d, 7=8.51 Hz, 2H), 2.12 - 2.24 (m, 4H), 1.89 - 2.00 (m, 1H), 1.69 - 1.79 (m, 2H), 1.43 (ddd, 7=13.60, 10.66, 7.13 Hz, 1H), 0.80 - 0.86 (m, 1 H), 0.66 - 0.78 (m, 1H), 0.57 - 0.65 (m, 3H).

[0223] Target 12a (X): ‘H NMR (400MHz, METHANOL-74) § = 8.68 (br d, 7=5.9 Hz, 1H), 8.11 (br s, 1H), 7.85 (br d, 7=5.7 Hz, 1H), 7.28 (t, 7=7.8 Hz, 1H), 6.94 - 6.82 (m, 3H), 4.30 (s, 2H), 3.80 - 3.77 (m, 3H), 3.76 - 3.57 (m, 3H), 3.40 (br d, 7=9.4 Hz, 1H), 3.27 (br s, 1H), 3.02 (br t, 7=11.7 Hz, 1H), 2.48 - 2.34 (m, 3H), 2.28 (br d, 7=12.8 Hz, 2H), 2.17 - 2.04 (m, 1H), 1.94 - 1.80 (m, 2H), 1.78 - 1.67 (m, 1H), 1.20 - 1.09 (m, 2H), 0.82 (br t, 7=7.3 Hz, 3H).Compound XILC-MS or HPLC Method:• Method 1:

[0224] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182. l*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 mm. The flow rate was 1.0 mL / min.• Method 2:

[0225] 5 -95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0226] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0227] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0228] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was aLuna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0229] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was FLO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 7 :

[0230] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was FLO+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used forchromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0231] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min.Mobile phase A was EEO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (Sum particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.General procedure for preparation of compound B

[0232] To a mixture of ethyl l-benzyl-3-oxo-piperidine-4-carboxylate A (40 g, 153 mmol, 1 eq) in DMF (250 mL) was added t-BuOK (34.4 g, 306 mmol, 2 eq) in 5 portions during 10°C ~15 °C under N2. The mixture was stirred for 0.5 hour and then EtI (47.8 g, 306 mmol, 24.5 mL, 2 eq was added dropwise during 15 °C and 20 °C. After the addition, the mixture was heated to 40 °C and stirred for other 12 hours under N2. And then iodoethane (47.8 g, 306 mmol, 24.5 mL, 2 eq) was added. The mixture was stirred for other 72 hours under N2. LC-MS (ET31541-176-P1F) showed desired mass was detected. The mixture was quenched with 2 L of saturated solution of NH4CI and extracted with 2 L of ethyl acetate. The organic layer was washed with 2 L of brine, separated and dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give a crude compound A (78 g, crude) as a light-yellow oil.

[0233] LCMS: (Method 1): RT=0.838 mins, MS+1 = 290.1.General procedure for preparation of compound CB C

[0234] The solution of ethyl l-benzyl-4-ethyl-3-oxo-piperidine-4-carboxylate B (78 g, 270 mmol, 1 eq) in HCI / H2O (12 M, 260 mL, 11.6 eq) and EtOH (260 mL) was heated to 80 °C and stirred for 12 hours. TLC (petroleum ether / ethyl acetate = 5 / 1) showed B was consumed and two new spots was detected. The mixture was concentrated under reduced pressure to remove ethanol. The aqueous layer was diluted with 50 mL of water and basified with solid of NaiCO.- to pH 9. The mixture was extracted with 200 mL of ethyl acetate for 2 times. Then the organic layers were combined, washed with 50 mL of brine, dried over anhydrous I feSCL, filtered and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (S1O2, Petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound C (38 g, 175 mmol, 64.9% yield) as a yellow oil.C D

[0235] LiHMDS (1 M, 189.82 mL, 1.1 eq) was added dropwise to a solution of l-benzyl-4- ethyl-piperi din-3 -one C (37.5 g, 173 mmol, 1 eq) in THF (400 mL) at -60 °C under N2. The mixture was stirred for 0.5 hour and a solution of [N-(trifluoromethylsulfonyloxy)anilino] trifluoromethanesulfonate (80.6 g, 207 mmol, 1.2 eq) in THF (200 mL) was added dropwise at -60 °C. After the addition, the mixture was warmed to 20 °C and stirred for 2.5 hours. LC-MS (ET33008-80-P1A) showed C was consumed completely and desired mass was detected. Then it was partitioned between 1 .0 L of sat. NH4CI and 500 mL of ethyl acetate. The organic phase was separated, washed with 500 mL of brine, dried over N^SCfi, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (Si O2, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1 ) to give compound D (22 g, 63.0 mmol, 36.5% yield) as a brown oil.

[0236] LCMS: (Method 1): RT=0.895 mins, MS+1 = 350.1.General procedure for preparation of compound Int.6

[0237] To solution of (l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl) trifluoromethanesulfonate D (11 g, 31.5 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (8.79 g, 34.6 mmol, 1.1 eq) and AcOK (9.27 g, 94.5 mmol, 3 eq) in dioxane (220 mL) was added Pd(dppf)C12 (1.15 g, 1.57 mmol, 0.05 eq) and purged with N2 for 3 times. The mixture was stirred at 100 °C for 4 hours under N2 atmosphere. LC-MS (ET33008-87-P1 A) showed D was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (Si O2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1). The purified product was re-purified by reversed-phase HPLC (column: Cl 8 20-35um 100A 120g; mobile phase: [water (0.1% TFA)-ACN]; B%: 0%-35% @ lOOmL / min) to give compound Int.6 (5.5 g, 16.8 mmol, 12.9% yield) as a brown oil.

[0238] LCMS: (Method 1): RT=0.885 mins, MS+1 = 328.2.

[0239] To a mixture of oxazole (5 g, 72.4 mmol, 4.63 mL, 1.5 eq) and 1 -bromo-4-methoxy- benzene 1 (9.03 g, 48.3 mmol, 6.06 mL, 1 eq) and KOAc (9.47 g, 96.5 mmol, 2 eq) in DMA (60 mL) was added Pd(OAc)2 (217 mg, 965 pmol, 0.02 eq) under N2. The mixture was heated to 120 °C and stirred for 12 hours. LC-MS (ET31541-78-P1A) showed 1 was consumed completely and desired mass was detected. The mixture was cooled to 15 °C and diluted with 100 mL of water and 100 mL of ethyl acetate. The organic layer was separated and washed with 100 mL of brine, separated and concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 2 (2.2 g, 12.6 mmol, 26.0% yield) as a yellow solid, which was detected by LC-MS (ET31541-78-P1C).

[0240] LCMS: ET31541-78-P1A (Method 1): RT=1.067 mins, MS+1 = 176.1.

[0241] LCMS: ET31541-78-P1C (Method 1): RT=1.066 mins, MS+1 = 176.0. General procedure for preparation of Compound 3

[0242] To a solution of 5-(4-methoxyphenyl)oxazole 2 (500 mg, 2.85 mmol, 1 eq) in DMF (5 mL) was added t-BuOLi (685.46 mg, 8.56 mmol, 3 eq) and l,2-dibromo-l,l,2,2-tetrafluoro-ethane (1.48 g, 5.71 mmol, 2 eq). The mixture was stirred at 60 °C for 3 hours under N2. TLC (petroleum ether / ethyl acetate = 3 / 1) showed 2 was consumed and one new spot was detected. The reaction mixture was quenched by addition sat of NH4CI aq 5 mL, and extracted with 10 mL of ethyl acetate. The combined organic layers were washed with brine lOmL, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate=l / O to 10 / 1) to give compound 3 (474 mg, 1.87 mmol, 65.36% yield) as a yellow oil.

[0243] To a mixture of 2-bromo-5-(4-methoxyphenyl)oxazole 3 (460 mg, 1.81 mmol, 1 eq), 1- benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (888 mg, 2.72 mmol, 1.5 eq) and Na2COs (384 mg, 3.62 mmol, 2 eq) in dioxane (0.5 mL) and water (0.1 mL) was added 4-ditert-butylphosphanyl-N,N-dimethyl-aniline;dichloropalladium (128 mg, 181 pmol, 0.1 eq) under N2. The mixture was heated to 100 °C and stirred for 12 hours. LC-MS (ET31541-97-P1 A2) showed 3 was consumed and the desired mass was detected. The mixture was filtered and concentrated under reduced pressure to get a crude product. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 4 (500 mg, 1.34 mmol, 73.8% yield) as a yellow solid.

[0244] LCMS: ET31541-97-P1A2 (method 1): RT=0.713mins, MS+1 = 375.2General procedure for preparation of Compound 6

[0245] A solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-5-(4- methoxyphenyl)oxazole 4 (450 mg, 1.20 mmol, 1 eq), Pd / C (200 mg, 10% purity), Pd(OH)2 (200 mg) and BOC2O (787 mg, 3.61 mmol, 3 eq) in MeOH (10 mL) was stirred for 12 hours at 40 °C under H2 ( 15psi). LC-MS (ET32485-44-P1A) showed the desired mass was detected. The reaction mixture was fdtered and the filter was concentrated to give a crude compound 5 (460 mg, 1.19 mmol, 99.1% yield) as a yellow oil.

[0246] LCMS: ET32485-44-P1A (Method 1): RT=0.937 mins, MS+1 = 387.3.

[0247] A mixture of tert-butyl 4-ethyl-3-[5-(4-methoxyphenyl)oxazol-2-yl]piperidine-l- carboxylate 5 (120 mg, 310 pmol, 1 eq) in HCl / MeOH (2 M, 2 mL) was stirred for 12 hours at 20 °C. LC-MS (ET31541-101-P1A2) showed 5 was consumed and the desired mass was detected. The reaction was concentrated under reduced pressure to get a crude compound 6 (100 mg, crude, HC1 salt) as a yellow oil.

[0248] LCMS: ET31541-101-P1A2 (method 1): RT=0.917 mins, MS+1 = 287.2.General procedure for preparation of Target 16 (XI)

[0249] To a solution of 2-(4-ethyl-3-piperidyl)-5-(4-methoxyphenyl)oxazole 6 (100 mg, 349 pmol, 1 eq) in MeOH (2 mL) was added TEA (3.53 mg, 35.0 pmol, 0.2 eq). The mixture was stirred at 20 °C for 10 min. Then the cyclobutanone (73.4 mg, 1.05 mmol, 3 eq) and AcOH (2.10 mg, 34.9pmol, 0.1 eq) were added and the mixture was stirred at 20 °C for 20 min. After the NaBHsCN (65.83 mg, 1.05 mmol, 3 eq) was added and the resulting mixture was stirred at 20 °C for 1.5 hours. LC-MS (ET31541-102-P1A1) showed 6 was consumed and the desired mass was detected. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 80*40mm*3 urn; mobile phase: [water (0.04%HCl)- ACN]; B%: 16%-46%, 7min) to give Target 16 (50 mg, 133 pmol, 38.0% yield, 100% purity, HC1 salt) as an off-white solid.

[0250] LCMS: ET31541-102.P1A1 (method 2): RT=L487 mins, MS+1 = 341.3.

[0251] 'H NMR (400MHz, METHANOL-t / 4) 5 = 7.62 (d, J=8.8 Hz, 2H), 7.40 (s, 1H), 7.29 (s, 1H), 7.06 - 6.93 (m, 3H), 3.88 - 3.75 (m, 1H), 3.75 - 3.65 (m, 2H), 3.61 - 3.53 (m, 1H), 3.43 - 3.33 (m, 1H), 3.29 - 3.21 (m, 1H), 3.03 - 2.88 (m, 1H), 2.54 (quin, J=10.2 Hz, 1H), 2.46 - 2.22 (m, 5H), 2.20 - 1.78 (m, 6H), 1.68 - 1.51 (m, 1H), 1.50 - 1.38 (m, 1H), 1.37 - 1.24 (m, 1H), 1.15 - 1.06 (m, 3H), 0.83 (t, 7=7.3 Hz, 1H).Compounds XII and XIIILC-MS or HPLC Method:• Method 1 :

[0252] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182. l*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1.0 mL / min.• Method 2:

[0253] 5 -95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0254] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min.Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0255] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0mm, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 5:

[0256] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was aLuna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0257] 5 95CD 6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was ELO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2. l*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 7 :

[0258] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0259] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min.Mobile phase A was ELO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.General procedure for preparation of compound 2

[0260] To a solution of 5-bromo-lH-imidazole 1 (10 g, 68.0 mmol, 1 eq) in THF (100 mL) wasd added NaH (4.08 g, 102 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then SEM-C1 (12.5 g, 74.8 mmol, 13.3 mL, 1.1 eq) was added to the mixture at 0 °C. After the addition, the mixture was warmed to 20 °C and stirred for 12 hours. LCMS (ET32485-29-P1A) showed 1 was consumed completely and desired mass was detected. Then it was partitioned between 100 mL of saturated solution of NH4CI and 300 mL of ethyl acetate. The organic phase was separated, washed with 200 mL of brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 2 (8 g, 28.9 mmol, 42.4% yield) as a yellow oil and compound 2a (8 g, 28.9 mmol, 42.4% yield) as a yellow oil.

[0261] LCMS: (Method 1): RT=0.735, 0.827 mins, MS = 277.1.

[0262] To a solution of 2-[(4-bromoimidazol-l-yl) methoxy] ethyl-trimethyl-silane 2 (4.6 g, 16.6 mmol, 1 eq), (4-methoxyphenyl) boromc acid (3.03 g, 19.9 mmol, 1.2 eq) and K2CO3 (4.59 g, 33.2 mmol, 2 eq) in dioxane (40 mL) and H2O (4 mL) was added Pd(dppf)C12 (1.21 g, 1.66 mmol, 0.1 eq) under N2. The mixture was stirred at 100 °C for 12 hours. LCMS (ET32485-32-P1A) showed 2 was consumed completely and desired mass was detected. Then it was partitioned between 50 mL of water and 75 mL of ethyl acetate. The organic phase was separated, washed with 50 mL of brine,dried over Na2SC>4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (S1O2, Petroleum ether / Ethyl acetate = 3 / 1 to 1 / 1) to give compound 3 (3.7 g, 9.65 mmol, 58.2% yield) as a yellow oil.

[0263] LCMS: (Method 1): RT=0.724 mins, MS = 305.2.General procedure for preparation of compound 4-70-0°C, 1.5 h34

[0264] To a solution of 2-[[4-(4-methoxyphenyl) imidazol-l-yl] methoxy] ethyl-trimethyl-silane 3 (3.70 g, 12.1 mmol, 1 eq) in THF (50 mL) was added dropwise n-BuLi (2.5 M, 14.6 mL, 3 eq) under N2. The mixture was stirred at -70 °C for 0.5 hour. Then NBS (2.60 g, 14.6 mmol, 1.2 eq) was added. After the addition, the mixture was warmed to 0 °C and stirred for 1 hour. LCMS (ET32485-35-P1A) showed desired mass was detected. Then it was partitioned between 100 mL of saturated solution of NH4CI and 150 mL of ethyl acetate. The organic phase was separated, washed with 150 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiCf, petroleum ether / ethyl acetate = 1:0 to 3: 1) to give compound 4 (450 mg, 1.17 mmol, 9.66% yield) as a yellow oil, which was confirmed by HNMR (ET32485-35-P1F) and NOE (ET32485-35-PlFl_NOE).

[0265] LCMS: (Method 1): RT=0.932 mins, MS+1 = 383.1.

[0266] To a solution of 2-[[2-bromo-4-(4-methoxyphenyl)imidazol-l-yl]methoxy]ethyl- trimethyl-silane 4 (400 mg, 1.04 mmol, 1 eq), l-benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine Int.6 (410 mg, 1.25 mmol, 1.2 eq) and Na2COs (332 mg, 3.13 mmol, 3 eq) in dioxane (4 mL) and H2O (0.4 mL) was added 4-ditert-butylphosphanyl-N,N- dimethyl-aniline;dichloropalladium (73.9 mg, 104 pmol, 0.1 eq) under N2. The mixture was stirred at 100 °C for 2.5 hours. LC-MS (ET32485-38-P1 A) showed the desired mass was detected. Then it was partitioned between 5 mL of water and 15 mL of ethyl acetate. The organic phase wasseparated, washed with 5 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by prep-TLC (SiCh, petroleum ether / ethyl acetate = 0 / 1) to give a crude. The crude was re-purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (lOmM NH4HCOs)-ACN]; B%: 60%- 90%, lOmin) to give compound 5 (100 mg, 199 pmol, 19.0% yield) as ayellow oil.

[0267] LCMS: (Method 1): RT 0.763 mins, MS+1 = 504.4.

[0268] To a solution of 2-[[2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-4-(4- methoxyphenyl)imidazol-l-yl]methoxy]ethyl-trimethyl-silane 5 (100 mg, 199 pmol, 1 eq) in MeOH (2 mL) was added Pd / C (10 mg, 10% purity), Pd(OH)2 (10 mg) and BOC2O (43.3 mg, 199 pmol, 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15psi) at 40 °C for 24 hours. LC-MS (ET33008-2-P1J) showed 5 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give a crude compound 7 (70 mg, crude) as a colorless oil.

[0269] LCMS: (Method 1): RT=0.889 mins, MS+1 = 516.4.

[0270] To solution of tert-butyl 4-ethyl-3-[4-(4-methoxyphenyl)-l-(2- trimethylsilylethoxymethyl) imidazol-2-yl]piperidine-l -carboxylate 6 (70 mg, 136 pmol, 1 eq) in HCl / MeOH (4M, 1 mL) at 15 °C. Then the mixture was stirred at 15 °C for 0.5 hour. LC-MS (ET33008-11-P1A1) showed 5 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give compound 7 (56 mg, crude, HC1 salt) as a yellow oil.

[0271] LCMS: (Method 1): RT=0.737, 0.812 mins, MS+1 = 416.3.General procedure for preparation of compound 7

[0272] To a solution of 2-[[2-(4-ethyl-3-piperidyl)-4-(4-methoxyphenyl)imidazol-l- yl]methoxy]ethyl-trimethyl-silane 6 (56 mg, 124 pmol, 1 eq, HC1 salt) in MeOH (0.6 mL) was added TEA (125 pg, 1.24 pmol, 0.01 eq). The mixture was stirred at 15 °C for 0.1 hour. Cyclobutanone (9.55 mg, 136 pmol, 1.1 eq) and AcOH (74.4 pg, 1.24 pmol, 0.01 eq) were added to the mixture. The mixture was stirred for 0.5 hour. NaBITCN (38.9 mg, 619 pmol, 5 eq) was added and the mixture was stirred at 15 °C for other 12 hours. LC-MS (ET33008-12-P1A) showed 7 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give compound 8 (60 mg, crude) as a white gum.

[0273] LCMS: (Method 1): RT=1.045, 1.153 mins, MS+1 = 470.3.General procedure for preparation of Target 15 (XII) and Target 15a (XIII)

[0274] The solution of 2-[[2-(l-cyclobutyl-4-ethyl-3-piperidyl)-4-(4-methoxyphenyl)imidazol-l- yl]methoxy]ethyl-trimethyl-silane 8 (60 mg, 128 pmol, 1 eq) in TFA (2 mL) was stirred at 30 °C for 0.1 hour. LC-MS (ET33008-13-P1A) showed 8 was consumed completely and desired mass was detected. The mixture was filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100*25mm*5um; mobile phase: [water (lOmM NH4HCCh)-ACN]; B%: 35%-70%, lOmin) to give Target 15 (12 mg, 34.3 pmol, 26.8% yield, 97.0% purity) as a white solid and Target 15a (3.4 mg, 9.55 pmol, 7.48% yield, 95.4% purity) as a white solid.

[0275] LCMS: (Method 1): RT=0.846, 0.882 mins, MS+1 = 340.2.

[0276] Target 15 (XII): 'H NMR (400 MHz, METHANOL-r / 4) 5 ppm 0.84 (t, .7=7.44 Hz, 3H),1.16 (dquin, J=14.56, 7.43, 7.43, 7.43, 7.43 Hz, 1H), 1.26 - 1.39 (m, 1H), 1.48 - 1.64 (m, 1H), 1.78 - 2.00 (m, 3H), 2.16 - 2.40 (m, 5H), 2.81 - 2.93 (m, 1H), 3.01 - 3.17 (m, 2H), 3.55 (br d, J=9.88 Hz,2H), 3.69 (quin, J=8.04 Hz, 1H), 3.81 (s, 3H) 6.96 (d, J=8.76 Hz, 2H), 7.34 (s, 1H), 7.57 - 7.63 (m, 2H).

[0277] Target 15a (XIII): ’H NMR (400 MHz, METHANOL-c / 4) § ppm 1.00 (br d, J=6.50 Hz, 3H), 1.10 (br s, 1H), 1.38 (br s, 1H), 1.46 - 1.63 (m, 1H), 1.65 - 2.03 (m, 6H), 2.04 - 2.30 (m, 4H), 2.41 (br s, 1H), 2.87 - 2.97 (m, 1H), 3.02 (br s, 1H), 3.31 (br d, J=2.88 Hz, 1H), 3.90 (s, 3H), 7.03 (d, J-8.76 Hz, 2H), 7.28 (s, 1H), 7.66 (br d, J 8.25 Hz, 2H).Compounds XIV and XV:LC-MS or HPLC Method:• Method 1:

[0278] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182. l*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5%o B for 0.40 min. The flow rate was 1.0 mL / min.• Method 2:

[0279] 5 -95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0280] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0281] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min.Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0282] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was aLuna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O rnL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0283] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was FLO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 7 :

[0284] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0285] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was FLO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.General procedure for preparation of compound 2

[0286] To a mixture of oxazole (5.15 g, 74.6 mmol, 4.77 mL, 1.5 eq), 4-bromo-l-methoxy-2- methyl-benzene 1 (10 g, 49.7 mmol, 1 eq) and KO Ac (9.76 g, 99.5 mmol, 2 eq) in DMA (200 mL) was added Pd(OAc)2 (223 mg, 995 pmol, 0.02 eq) under N2. The mixture was heated to 120 °C and stirred for 12 hours. LC-MS (ET31541-188-P1A) showed 1 was consumed completely and desired mass was detected. The mixture was cooled to 15 °C and diluted with 300 mL of water and 1.0 L of ethyl acetate. The organic layer was separated and washed with 500 mL of brine, separated and concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 2 (1 g, 5.29 mmol, 10.6% yield) as a yellow solid.

[0287] LCMS: (Method 1): RT=1.021 mins, MS+1 = 190.1.

[0288] A mixture of 5-(4-methoxy-3-methyl-phenyl)oxazole 2 (0.5 g, 2.64 mmol, 1 eq), 1,2- dibromo-l ,l ,2,2-tetrafluoro-ethane (1.37 g, 5.29 mmol, 2 eq) and t-BuOLi (635 mg, 7.93 mmol, 3 eq) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 hours under N2 atmosphere. LC-MS (ET33008-81-P1A) showed 2 was consumed completely and desired mass was detected. The reaction mixture was partitioned between 10 mL of water and 30 mL of ethyl acetate. The organic phase was separated, washed with 10 mL of brine, dried with anhydrous Na2SC>4, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 3 (400 mg, 1.49 mmol, 56.5% yield) as a white solid.

[0289] LCMS: (Method 1): RT=1.165 mins, MS+1 = 267.9.General procedure for preparation of Compound 4

[0290] To solution of 2-bromo-5-(4-methoxy-3-methyl-phenyl)oxazole 3 (150 mg, 559 pmol, 1 eq), l-benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (366 mg, 1.12 mmol, 2 eq) and K3PO4 (238 mg, 1.12 mmol, 2 eq) in EtOH (0.8 mL) and H2O (0.2 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl-phosphane (37.4 mg, 55.9 pmol, 0.1 eq) and purged with N2 for 3 times. Then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. LC-MS (ET33008-111-P1 A) showed 3 was consumed completely and desired mass was detected. The reaction mixture was partitioned between 5 mL of water and 15 mL of ethyl acetate. The organic phase was separated, washed with 5 mL of brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um); mobile phase: [water (0.05%NH3H20+10mM NH4HCO3)-ACN]; B%: 65%-95%, lOmin) to give compound 4 (120 mg, 309 pmol, 55.2% yield) as a yellow oil.

[0291] LCMS: (Method 1): RT=0.944 mins, MS+1 = 389.2.

[0292] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-5-(4-methoxy-3- methyl-phenyl)oxazole 4 (120 mg, 309 pmol, 1 eq) and BOC2O (202 mg, 927 pmol, 3 eq) in MeOH (24 mL) was added Pd / C (12 mg, 10% purity) and Pd(OH)2 (12 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (30 Psi) at 40 °C for 36 hours. LC-MS (ET33008-120-P1C) showed 4 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiCh, petroleum ether: ethyl acetate = 3 / 1) to give compound 5 (85 mg, 212 pmol, 68.7% yield) as a colorless oil.

[0293] LCMS: (Method 1): RT=1.291 mins, MS+1 = 401.2.General procedure for preparation of compound 6

[0294] The solution of tert-butyl 4-ethyl-3-[5-(4-methoxy-3-methyl-phenyl)oxazol-2- yl]piperidine-l -carboxylate 5 (85 mg, 212 pmol, 1 eq) in HCl / MeOH (4 M, 0.8 mL) was stirred at 15 °C for 0.5 hour. LC-MS (ET33008-136-P1A1) showed 5 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give a crude compound 6 (70 mg, crude, HC1 salt) as a colorless oil.

[0295] LCMS: (Method 1): RT=0.670, 0.713 mins, MS+1 = 301.3.General procedure for preparation of Target 22 (XIV) and Target 22a (XV)XIV XV

[0296] To a solution of 2-(4-ethyl-3-piperidyl)-5-(4-methoxy-3-methyl-phenyl)oxazole 6 (70 mg, 208 pmol, 1 eq, HC1 salt) and cyclobutanone (29.1 mg, 416 pmol, 2 eq) in MeOH (0.7 mL) was added TEA (2.10 mg, 20.8 pmol, 0.1 eq). It was stirred for 0.5 hour. AcOH (1.25 mg, 20.8 pmol, 0.1 eq) was added and the mixture was stirred for 1.5 hours. Then NaBHsCN (65.3 mg, 1.04 mmol, 5 eq) was added in one portion and the mixture was stirred at 15 °C for 10 hours. LC-MS (ET33008- 142-P1A1) showed 6 was consumed completely and desired mass was detected. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Xtimate C18 100*30mm*3um; mobile phase: [water (0.04%HCl)-ACN]; B%: 20%- 40%, 5min) to give Target 22 (17.9 mg, 45.8 pmol, 22.0% yield, 100% purity, HC1 salt) as a white solid and Target 22a (4.6 mg, 11.8 pmol, 5.66% yield, 100% purity, HC1 salt) as a white solid.

[0297] LCMS: (Method 1): RT=0.891 mins, MS+1 = 355.2.

[0298] Target 22 (XIV) : 'H NMR (400 MHz, METHANOL-74) 8 ppm 0.83 (t, J=7.32 Hz, 1H),1.12 (t, 7=7.32 Hz, 2H), 1.27 - 1.49 (m, 2H), 1.50 - 1.68 (m, 1H), 1.82 - 1.99 (m, 3H), 2.00 - 2.17 (m, 1H), 2.23 (s, 3H), 2.25 - 2.47 (m, 4H), 2.54 (quin, 7=10.13 Hz, 1H), 2.89 - 3.01 (m, 1H), 3.25 (br d, 7=13.38 Hz, 1H), 3.57 (br d, 7=11.26 Hz, 1H), 3.65 - 3.73 (m, 1H), 3.76 - 3.85 (m, 1H), 3.86 - 3.89 (m, 3H), 6.95 - 7.02 (m, 1H), 7.26 - 7.40 (m, 1H), 7.46 (s, 1H), 7.49 (br d, 7=8.50 Hz, 1H).

[0299] Target 22a (XV): 'H NMR (400 MHz, METHANOL-d4) 5 ppm 0.88 (t, 7=7.50 Hz, 3H), 1.19 - 1.31 (m, 1H), 1.38 - 1.50 (m, 1H), 1.51 - 1.64 (m, 1H), 1.82 - 1.99 (m, 3H), 2.23 (s, 4H), 2.25 - 2.32 (m, 2H), 2.33 - 2.44 (m, 2H), 2.95 (td, 7=12.91, 2.56 Hz, 1H), 3.10 - 3.17 (m, 2H), 3.56 - 3.68 (m, 2H), 3.68 - 3.79 (m, 1H), 3.87 (s, 3H), 6.98 (d, 7=8.50 Hz, 1H), 7.33 (s, 1H) 7.47 (s, 1H), 7.51 (dd, 7=8.44, 2.06 Hz, 1H).Compounds XVI and XVIILC-MS or HPLC Method:• Method 1:

[0300] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1.0 mL / min.• Method 2:

[0301] 5 -95 AB_4.5min: LC / MS (The column used for chromatography was a Luna-Cl 82.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0302] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0303] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018%Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0304] 9 -95AB-ELSD_2min: LC7MS (The column used for chromatography was a Luna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TEA in water, and mobile phase B was 0.018% TFA in ELPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0305] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was EEO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method ?:

[0306] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was EBO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0307] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40mm and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was ELO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.General procedure for preparation of compound 2

[0308] To a mixture of oxazole (5.05 g, 73.2 mmol, 4.68 mL, 1.5 eq) and 4-bromo-2-fluoro-l- methoxy-benzene 1 (10 g, 48.8 mmol, 1 eq) and KOAc (9.57 g, 97.6 mmol, 2 eq) in DMA (200 mL) was added Pd(0Ac)2 (219. mg, 976 pmol, 0.02 eq) under N2. The mixture was heated to 120 °C and stirred for 12 hours. LC-MS (ET31541-189-P1A) showed 1 was consumed completely and desired mass was detected. The mixture was cooled to 15 °C and diluted with 250 mL of water and 750 mL of ethyl acetate. The organic phase was separated, washed with 50 mL of brine, dried with anhydrous Na^STh, concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 2 (2.3 g, 11.9 mmol, 24.4% yield) as a white solid.

[0309] LCMS: (Method 1): RT=0.947 mins, MS+1 = 194.0.

[0310] A mixture of 1,2-dibromo- 1,1,2, 2-tetrafluoro-ethane (2.96 g, 11.4 mmol, 2 eq), 5-(3- fhroro-4-methoxy-phenyl)oxazole 2 (1.10 g, 5.69 mmol, 1 eq) and t-BuOLi (1.37 g, 17.08 mmol, 1.54 mL, 3 eq) in DMF (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 hours under N2 atmosphere. LC-MS (ET33008-82-P1 A) showed 2 was consumed completely and desired mass was detected. The reaction mixture was partitioned between 30 mL of water and 100 mL of ethyl acetate. The organic phase was separated, washed with 50 mL of brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 3 (700 mg, 2.57 mmol, 45.2% yield) as a white solid.

[0311] LCMS: (Method 1): RT=1.093 mins, MS+1 = 273.9.General procedure for preparation of compound 4

[0312] To solution of 2-bromo-5-(3-fluoro-4-methoxy-phenyl)oxazole 3 (200 mg, 735 iimol, 1 eq), l-benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (481 mg, 1.47 mmol, 2 eq) and K3PO4 (312 mg, 1.47 mmol, 2 eq) in H2O (0.2 rnL) and EtOH (0.8 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl-phosphane (49.2 mg, 73.5 pmol, 0. 1 eq) and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. LC-MS (ET33008-1 12-P1 A) showed 3 was consumed completely and desired mass was detected. The reaction mixture was partitioned between 5 mL of water and 15 mL of ethyl acetate. The organic phase was separated, washed with 5 mL of brine, dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um); mobile phase: [water (0.05% NH3H2O+10mM NH4HCO3)-ACN]; B%: 65%-90%, 10mm) to give compound 4 (170 mg, 433 pmol, 58.9% yield) as a yellow oil.

[0313] LCMS: (Method 1): RT=0.904 mins, MS+1 = 393.2.

[0314] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-5-(3-fluoro-4- methoxy-phenyl)oxazole (170 mg, 433 pmol, 1 eq) and Boc2O (284 mg, 1.30 mmol, 3 eq) in MeOH (34 inL) was added Pd / C (17 mg, 10% purity) and Pd(OH)2 (17 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (30 Psi) at 40 °C for 36 hours. LC-MS (ET33008-121-P1D) showed 4 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (SiO2, petroleum ether: ethyl acetate = 3: 1) to give compound 5 (140 mg, 346 pmol, 79.9% yield) as a colorless oil.

[0315] LCMS: (Method 1): RT=1.237 mins, MS+1 = 405.2.5 6

[0316] To a solution of tert-butyl 4-ethyl-3-[5-(3-fluoro-4-methoxy-phenyl)oxazol-2- yl]piperidine-l -carboxylate 5 (140 mg, 346 pmol, 1 eq) in HCl / MeOH (4 M, 1.4 mL). The mixture was stirred at 15 °C for 0.5 hour. LC-MS (ET33008-137-P1A) showed 5 was consumed completely and desired mass was detected. The mixture was filtered and concentrated under reduced pressure to give a residue to give compound 6 (115 mg, crude, HC1 salt) as a colorless oil.

[0317] LCMS: (Method 1): RT=0.718 mins, MS+1 = 305.2.General procedure for preparation of Target 23 (XVI) and Target 23a (XVII)XVI XVII

[0318] To a solution of 2-(4-ethyl-3-piperidyl)-5-(3-fluoro-4-methoxy-phenyl)oxazole (115 mg, 337 pmol, 1 eq, HCI salt) and cyclobutanone (47.3 mg, 675 pmol, 2 eq) in MeOH (1.1 mL) was added TEA (3.41 mg, 33.7 pmol, 0.1 eq), and the mixture was stirred for 0.5 hour. Then it was added AcOH (2.03 mg, 33.7 pmol, 0.1 eq) and stirred for 1.5 hours. To the mixture was added NaBEfcCN (106 mg, 1.69 mmol, 5 eq) and the mixture was stirred at 15 °C for 10 hours. LC-MS (ET33008-143-P1 Al) showed 6 was consumed completely and desired mass was detected. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 100*30mm*3um; mobile phase: [water (0.04%HCl)- ACN]; B%: 20%-40%, 5min) to give Target 23 (32 mg, 81.0 pmol, 24.0% yield, 100% purity, HCI salt) as a yellow solid and Target 23a (9.5 mg, 24.1 pmol, 7.13% yield, 100% purity, HCI salt) as a white solid.

[0319] LCMS: (Method 2): RT=1.283 mins, MS+1 = 359.2.

[0320] Target 23 (XVI): 'H NMR (400 MHz, METHANOL-74) 5 ppm 0.86 (t, 7=7.32 Hz, 1H), 1.14 (t, 7=7.32 Hz, 2H), 1.30 - 1.52 (m, 1H), 1.53 - 1.72 (m, 1H), 1.86 - 2.03 (m, 3H), 2.04 - 2.24 (m, 1H), 2.25 - 2.50 (m, 4H), 2.58 (quin, 7=10.16 Hz, 1H), 2.94 - 3.07 (m, 1H), 3.35 (br s, 1H), 3.61 (brd, 7=12.01 Hz, 1H), 3.69 - 3.78 (m, 1H), 3.78 - 3.93 (m, 2H), 3.93 - 3.97 (m, 1H), 3.95 (s, 2H), 7.18 - 7.26 (m, 1H), 7.38 - 7.47 (m, 1H), 7.49 (br d, 7=7.13 Hz, 2H).

[0321] Target 23a (XVII): *HNMR (400 MHz, METHANOL-74) 6 ppm 0.79 - 0.91 (m, 1H), 1.11 (t, 7=7.34 Hz, 2H), 1.27 - 1.47 (m, 1H), 1.49 - 1.72 (m, 1H), 1.81 - 1.98 (m, 3H), 1.99 - 2.19 (m, 1H), 2.23 - 2.47 (m, 4H), 2.54 (quin, 7=10.14 Hz, 1H), 2.89 - 3.02 (m, 1H), 3.21 - 3.30 (m, 1H), 3.57 (br d, 7=11.84 Hz, 1H), 3.61 - 3.89 (m, 3H), 3.89 - 3.95 (m, 3H), 7.15 - 7.24 (m, 1H), 7.34 - 7.44 (m, 1H), 7.44 - 7.50 (m, 2H).Compounds XVIIILC-MS or HPLC Method:• Method 1:

[0322] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1 .0 mL / min.• Method 2:

[0323] 5 -95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 mm. The flow rate was 1.0 mL / min.• Method 3:

[0324] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0325] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0326] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0327] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was FLO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2.1 *50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method ?:

[0328] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was FLO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0329] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was ELO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.

[0330] NaH (9.82 g, 245.57 mmol, 60% purity, 1.2 eq) was added to a solution of 2-ethylphenol 1 (25 g, 205 mmol, 24.0 mL, 1 eq in THF (250 mL) at 0 °C under N2. The mixture was stirred for 0.5 hour and then Mel (34.9 g, 246 mmol, 15.3 mL, 1.2 eq) was added dropwise at 0 °C. Then the mixture was warmed to 20 °C and stirred for 11 hours. TLC (petroleum ether / ethyl acetate = 3 / 1) showed 1 was consumed and one new spot was detected. The mixture was poured in 500 mL of water and extracted with 500 mL of ethyl acetate. The organic layer was separated, dried over Na2SC>4, filtered and concentrated under reduced pressure to give a crude compound 2 (27 g, crude) as a light-yellow oil.General procedure for preparation of compound 3

[0331] To a solution of 1 -ethyl-2-methoxy -benzene 2 (27 g, 198 mmol, 1 eq) in MeCN (200 mL) was added NBS (40.6 g, 228 mmol, 1.15 eq). The mixture was stirred at 20 °C for 12 hours. The mixture was filtered and diluted with 500 mL of water and 500 mL of ethyl acetate. The organic layer was separated and washed with 200 mL of sat. Na2SCh, separated, dried over NajSCh, filtered and concentrated under reduced pressure to give a crude compound 3 (40 g, crude) as a light-yellow oil.

[0332] A mixture of oxazole (6.42 g, 93.0 mmol, 5.95 mL, 2 eq), 4-bromo-2-ethyl-l -methoxy- benzene 3 (10 g, 46.5 mmol, 1 eq), Pd(OAc)2 (209 mg, 930 pmol, 0.02 eq), KO Ac (9.13 g, 93.0 mmol, 2 eq) in DMA (200 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 4 hours under N2 atmosphere. LC-MS (ET33008-73-P1 A) showed 3 was consumed completely and desired mass was detected. The reaction mixture was partitioned between200 mL of water and 600 mL of ethyl acetate. The organic phase was separated, washed with 500 mL of brine, dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 4 (0.9 g, 4.43 mmol, 9.52% yield) as a yellow oil.

[0333] LCMS: (Method 1): RT=1.081 mins, MS+1 = 204.1

[0334] A mixture of 5-(3-ethyl-4-methoxy-phenyl)oxazole 4 (0.45 g, 2.21 mmol, 1 eq), 1,2- dibromo-l,l,2,2-tetrafluoro-ethane (1.15 g, 4.43 mmol, 2 eq and t-BuOLi (532 mg, 6.64 mmol, 3 eq) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 hours under N2 atmosphere. LC-MS (ET33008-90-P1B) showed desired compound was detected. The reaction mixture was partitioned between 10 mL of water and 30 mL of ethyl acetate. The organic phase was separated, washed with 10 mL of brine, dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1 / 0 to 10 / 1) to give compound 5 (310 mg, 1.10 mmol, 49.6% yield) as a yellow oil.

[0335] LCMS: (Method 1): RT=L206 mins, MS+1 = 284.0.

[0336] To solution of 2-bromo-5-(3-ethyl-4-methoxy-phenyl)oxazole 5 (100 mg, 354 pmol, 1 eq), l-benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (232 mg, 709 prnol, 2 eq) and K3PO4 (150 mg, 709 pmol, 2 eq) in H2O (0.2 mL) and EtOH (0.8 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl-phosphane (23.7 mg, 35.4 pmol, 0.1 eq) and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. LC-MS (ET33008-113-P1 A) showed 5 was consumed completely and desired compound was detected. The reaction mixture was partitioned between 5 mL of water and1515 mL of ethyl acetate. The organic phase was separated, washed with 5 mL of brine, dried with anhydrous IN^SCL, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um); mobile phase: [water (0.05%NH3H20+10mM NH4HCC>3)-ACN]; B%: 75%-95%, lOmin) to give compound 6 (95 mg, 236 pmol, 66.6% yield) as a yellow oil.

[0337] LCMS: (Method 1): RT 0.975 mins, MS+1 = 403.2.

[0338] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-5-(3-ethyl-4-methoxy- phenyl)oxazole 6 (95 mg, 236 pmol, 1 eq) and BOC2O (155 mg, 708 pmol, 3 eq) in MeOH (20 mL) was added Pd / C (9 mg, 10% purity) and Pd(OH)2 (9 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (30 Psi) at 40 °C for 36 hours. LC-MS (ET33008-122-P1D) showed 6 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum. The residue was purified by prep- TLC (SiO2, petroleum ether: ethyl acetate = 3: 1) to give compound 7 (50 mg, 121 pmol, 51.1% yield) as a colorless oil.

[0339] LCMS: (Method 1): RT=1.334 mins, MS+1 = 415.3.

[0340] The solution of tert-butyl 4-ethyl-3-[5-(3-ethyl-4-methoxy-phenyl)oxazol-2- yl]piperidine-l -carboxylate 7 (50 mg, 121 pmol, 1 eq) in HCl / MeOH (4 M, 0.5 mL) was stirred at 15 °C for 0.5 hours. LC-MS (ET33008-138-P1A) showed 7 was consumed completely and desired mass was detected. The mixture was concentrated under reduced pressure to give a crude compound 8 (40 mg, crude, HC1 salt) as a colorless oil.

[0341] LCMS: (Method 1): RT=0.783, 0.807 mins, MS+1 = 315.2.General procedure for preparation of Target 24 (XVIII)XVIII

[0342] To a solution of 5-(3-ethyl-4-methoxy-phenyl)-2-(4-ethyl-3-piperidyl)oxazole 8 (40 mg, 114 pmol, 1 eq, HC1 salt) and cyclobutanone (16.0 mg, 228 pmol, 2 eq) in MeOH (0.4 mL) was added TEA (1.15 mg, 11.4 pmol, 0.1 eq). It was stirred for 0.5 hour. Then it was added AcOH (685 pg, 11.4 pmol, 0.1 eq) and stirred for 1.5 hours. To the mixture was added NaBHsCN (35.8 mg, 570 pmol, 5 eq) and the mixture was stirred at 15 °C for 10 hours. LC-MS (ET33008-144-P1A1) showed 8 was consumed completely and desired mass was detected. The reaction was 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 (0.04%HCl)-ACN]; B%: 10%- 30%, 8min) to give Target 24 (13.9 mg, 34.3 pmol, 30.1% yield, 100% purity, HC1 salt) as a white solid.

[0343] LCMS: ET33008-144-P1A1 (Method 2): RT=1.517, 1.549 mins, MS+1 = 369.2.

[0344] Target 24 (XVIII): 'H NMR (400 MHz, METHANOL-74) 5 ppm 0.73 (t, 7=7.32 Hz, 1H), 0.98 - 1.05 (m, 2H), 1.10 (t, 7=7.50 Hz, 3H), 1.19 - 1.36 (m, 1H), 1.37 - 1.60 (m, 1H), 1.72 - 2.07 (m, 4H), 2.14 - 2.36 (m, 4H), 2.43 (quin, 7=9.97 Hz, 1H), 2.57 (q, 7=7.50 Hz, 2H), 2.86 (br t, 7=11.69 Hz, 1H), 3.15 (br d, 7=13.51 Hz, 1H), 3.44 - 3.76 (m, 4H), 3.77 (s, 3H), 6.86 - 6.98 (m, 1H), 7.16 - 7.30 (m, 1H), 7.32 - 7.47 (m, 2H).Compounds XIX and XX:• Method 1:

[0345] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1 .0 mL / min.• Method 2:

[0346] 5 -95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0347] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0348] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0349] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was aLuna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0350] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. The columnused for chromatography was Xbridge Shield RP18 2.1 *50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 7 :

[0351] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min.Mobile phase A was LEO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (Sum particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0352] 5 95CD 6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min.Mobile phase A was H2O+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2. l*50mm column (Sum particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.General procedure for preparation of compound 2

[0353] To a mixture of oxazole (7.35 g, 106.37 mmol, 6.80 mL, 2 eq) and 5-bromo-2-methoxy- pyridine 1 (10 g, 53.2 mmol, 6.90 mL, 1 eq) and KOAc (10.4 g, 106 mmol, 2 eq) in DMA (200 mL) was added Pd(OAc)2 (239 mg, 1.06 mmol, 0.02 eq) under N2. The mixture was heated to 120 °C and stirred for 6 hours. LC-MS (ET31541-190-P1A) showed 1 was consumed completely and desired mass was detected. The mixture was cooled to 15 °C and diluted with 300 mL of water and 1000 mL of ethyl acetate. The organic layer was separated and washed with 500 mL of brine, separated and concentrated under reduced pressure to get a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 2 (5.2 g, 29.5 mmol, 55.5% yield) as a white solid.

[0354] LCMS: (Method 1): RT=0.845 mins, MS+1 = 177.1.General procedure for preparation of Compound 32 3

[0355] A mixture of 1,2-dibromo- 1,1,2, 2-tetrafluoro-ethane (7.37 g, 28.4 mmol, 2 eq), 5-(6- methoxy-3-pyridyl)oxazole 2 (2.50 g, 14.2 mmol, 1 eq) and t-BuOLi (3.41 g, 42.6 mmol, 3.84 mL, 3 eq in DMF (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 hours under N2 atmosphere. LC-MS (ET33008-84-P1 A) showed 2 was consumed completely and desired mass was detected. The reaction mixture was partitioned between 50 mL of water and 150 mL of ethyl acetate. The organic phase was separated, washed with 100 mL of brine, dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 3 (1.9 g, 7.45 mmol, 52.50% yield) as a white solid.

[0356] LCMS: (Method 1): RT=1.006 mins, MS+1 = 257.0.

[0357] H NMR (400 MHz, METHANOL-c / 4) 8 ppm 3.94 (s, 3H) 6.87 (d, .7=8.76 Hz, 1H) 7.46 (s, 1H) 7.92 (dd, .7=8.69, 2.44 Hz, 1H) 8.44 (d, .7=2.13 Hz, 1H).

[0358] To solution of 2-bromo-5-(6-methoxy-3-pyridyl)oxazole 3 (400 mg, 1.57 mmol, 1 eq), 1- benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (1.03 g, 3.14 mmol, 2 eq) and KsPCL (666 mg, 3.14 mmol, 2 eq) H1 H2O (0.2 mL) and EtOH (0.8 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl-phosphane (104.85 mg, 156.82 pmol, 0.1 eq) and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 12 hours under N2 atmosphere. LC-MS (ET33008-110-P1B3) showed 3 was consumed compeletely and desired mass was detected. The reaction mixture was partitioned between 5 mL of water and 15 mL of ethyl acetate. The organic phase was separated, washed with 5 mL of brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um); mobile phase: [water (0.05%NH3H20+10mMNH4HC0S)-ACN]; B%: 65%-95%, lOmin) to give compound 4 (300 mg, 799 pmol, 51.0 % yield) as a yellow oil.

[0359] LCMS: (Method 1): RT=0.857 mins, MS+1 = 376.2.

[0360] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-5-(6-methoxy-3- pyridyl)oxazole 4 (300 mg, 799 pmol, 1 eq) and BOC2O (523 mg, 2.40 mmol, 3 eq in MeOH (60 mL) was added Pd / C (30 mg, 10% purity) and Pd(OH)2 (30 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (30 Psi) at 40 °C for 36 hours. LC-MS (ET33008-126-P1C) showed 4 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give a crude compound 5 (300 mg, crude) as a yellow oil.

[0361] LCMS: (Method 1): RT=1.187 mins, MS+1 = 388.2.

[0362] The solution of tert-butyl 4-ethyl-3-[5-(6-methoxy-3-pyridyl)oxazol-2-yl]piperidine-l- carboxylate 5 (100 mg, 258.08 mol, 1 eq) in HCl / MeOH (4 M, 0.5 mL) was stirred at 15°C for 0.3 hour. LC-MS (ET33008-140-P1 A) showed 5 was consumed completely and desired mass was detected. The mixture was filtered and concentrated under reduced pressure to give compound 6 (80 mg, crude, HC1 salt) as a colorless oil.

[0363] LCMS: ET33008-140-P1A (Method 1): RT=0.654 mins, MS+1 = 288.2.General procedure for preparation of Target 25 (XIX) and Target 25a (XX)XIX XX

[0364] To a solution of 2-(4-ethyl-3-piperidyl)-5-(6-methoxy-3-pyridyl)oxazole (80 mg, 247 pmol, 1 eq, HC1 salt) and cyclobutanone (52.0 mg, 741 pmol, 3 eq) in MeOH (0.5 mL) was added TEA (2.50 mg, 24.7 pmol, 0.1 eq). The mixture was stirred at 15 °C for 0.5 hour. Then it was added AcOH (1.48 mg, 24.71 pmol, 0.1 eq) and stirred for 1.5 hours. To the mixture was added NaBEECN (77.63 mg, 1.24 mmol, 5 eq) and the mixture was stirred at 15 °C for 10 hours. LC-MS (ET33008- 146-P1A1) showed 6 was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate Cl 8 150*25mm*5um; mobile phase: [water (0.04%HCl)-ACN]; B%: 5%-20%, 8min) to give Target 25 (38 mg, 101 pmol, 40.7% yield, 100% purity, HC1 salt) as a white solid and Target 25a (14 mg, 37.1 pmol, 15.0% yield, 100% purity, HC1 salt) as a white solid.

[0365] LCMS: (Method 2): RT=0.945, 1.067 mins, MS+1 = 342.2.

[0366] Target 25 (XIX): 'H NMR (400 MHz, METHANOL-74) 5 ppm 0.83 (t, 7=7.32 Hz, 1H), 1.06 - 1.13 (m, 2H), 1.26 - 1.51 (m, 1H), 1.51 - 1.73 (m, 1H), 1.80 - 1.99 (m, 3H), 2.02 - 2.21 (m, 1H), 2.24 - 2.48 (m, 4H), 2.49 - 2.65 (m, 1H), 2.91 - 3.11 (m, 1H), 3.32 - 3.42 (m, 1H), 3.55 - 3.79 (m, 2H), 3.80 - 3.93 (m, 2H), 4.12 (d, 7=7.63 Hz, 3H), 7.30 (dd, 7=16.95, 8.94 Hz, 1H), 7.50 - 7.75 (m, 1H), 8.29 - 8.47 (m, 1H), 8.61 (dd, 7=10.76, 1.63 Hz, 1H).

[0367] Target 25a (XX): H NMR (400 MHz, METHANOL-74) 5 ppm 0.80 - 0.86 (m, 1H), 1.06 - 1.13 (m, 2H), 1.28 - 1.52 (m, 1H), 1.53 - 1.73 (m, 1H), 1.80 - 1.99 (m, 3H), 2.05 (dt, 7=7.89, 3.95 Hz, 1H), 2.14 - 2.63 (m, 5H), 2.91 - 3.03 (m, 1H), 3.33 - 3.42 (m, 1H), 3.54 - 3.77 (m, 2H), 3.78 - 3.92 (m, 2H), 4.09 - 4.18 (m, 3H), 7.29 - 7.42 (m, 1H), 7.56 - 7.71 (m, 1H), 8.35 - 8.49 (m, 1H), 8.59 - 8.68 (m, 1H).Compounds XXI and XXII:LC-MS or HPLC Method:• Method 1:

[0368] 5-95AB_2min: LC / MS (The column used for chromatography was a HALO AQ-C182.1*30mm, (2.7 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80min), 5%B in 1.81min, with a hold at 5% B for 0.40 min. The flow rate was 1.0 mL / min.• Method 2:

[0369] 5-95AB_4.5min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, (3 um particles). Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min) with a hold at 95% B for 0.50 min, 95-5% B (3.50 -3.51 min), with a hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min.• Method 3:

[0370] 5_95AB_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B in2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex Cl 8 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 4:

[0371] 5_95AB_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.4-3.0min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml / min. Mobile phase A was 0.037% Trifluoroacetic Acid in water, mobile phase B was 0.018% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C 18 50*2.1mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization.MS range was 100-1000.• Method 5:

[0372] 9 -95AB-ELSD_2min: LC / MS (The column used for chromatography was a Luna-C182.0*30mm, 3 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 50-1500. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC gradeacetonitrile. The gradient was 5-95% B in 2.30 min .5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95%-100%B(1.00-1.80min), 100-5% B (1.80-1.81 min) with a hold at 5% B for 0.39min. The flow rate wasl.O mL / min (0.01-1.80 min) and 1.2 mL / min (1.81 - 2.30 min).• Method 6:

[0373] 5_95CD_6min-220-254: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was LLO+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was Xbridge Shield RP18 2.1 *50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method ?:

[0374] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H O+lOmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.• Method 8:

[0375] 5_95CD_6min-220: LC / MS (The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.40 min, hold on 95% B for 0.45min, and then 95-5%B in O.Olmin, the flow rate was 0.8 ml / min. Mobile phase A was H2O+I OmM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge Shield RP18 2.1*50mm column (5um particles). Detection methods are diode array (DAD) as well as positive electrospray ionization. MS range was 100-1000.

[0376] To a mixture of oxazole (6.87 g, 99.5 mmol, 6.36 mL, 2 eq) and 1 -bromo-4-ethoxy- benzene 1 (10 g, 49.7 mmol, 7.09 mL, 1 eq) and KOAc (9.76 g, 99.5 mmol, 2 eq) in DMA (200 mL) was added Pd(OAc)2 (223 mg, 995 pmol, 0.02 eq) under N2. The mixture was heated to 120 °C and stirred for 6 hours. LC-MS (ET31541-191-P1A) showed 1 was consumed completely and desired mass was detected. The mixture was cooled to 15 °C and diluted with 200 mL of water and 600 mL of ethyl acetate. The organic layer was separated and washed with 300 mL of brine, separated, concentrated under reduced pressure to get a residue. The residue was purified by columnchromatography (S1O2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 2 (2.5 g, 13.21 mmol, 26.57% yield) as a pink solid.

[0377] LCMS: (Method 1): RT=1.014 mins, MS+1 = 190.1.General procedure for preparation of Compound 3

[0378] A mixture of l,2-dibromo-l,l,2,2-tetrafluoro-ethane (3.29 g, 12.7 mmol, 2 eq), 5-(4- ethoxyphenyl)oxazole 2 (1.2 g, 6.34 mmol, 1 eq) and t-BuOLi (1.52 g, 19.0 mmol, 1.72 mL, 3 eq) in DMF (24 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 hours under N2 atmosphere. LC-MS (ET33008-85-P1 A) showed 2 was consumed completely and desired mass was detected. The reaction mixture was partitioned between 50 mL of water and 150 mL of ethyl acetate. The organic phase was separated, washed with 100 mL of brine, dried with anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give compound 3 (950 mg, 3.54 mmol, 55.9% yield) as a white solid.

[0379] LCMS: (Method 1): RT=1.152 mins, MS+1 = 270.0.

[0380] To solution of 2-bromo-5-(4-ethoxyphenyl)oxazole 3 (200 mg, 746 pmol, 1 eq), 1- benzyl-4-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine Int.6 (488 mg, 1.49 mmol, 2 eq) and K3PO4 (317 mg, 1.49 mmol, 2 eq) in EtOH (0.8 mL) and H2O (0.2 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl-phosphane (49.9 mg, 74.6 pmol, 0. 1 eq) and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. LC-MS (ET33008-114-P1 A) showed 3 was consumed completely and desired mass was detected. The reaction mixture was partitioned between 5 mL of water and 15 mL of ethyl acetate. The organic phase was separated, washed with 5 mL of brine, dried with anhydrous ISfeSCL, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column:Kromasil C18 (250*50mm*10 um); mobile phase: [water (0.05%NH3H20+10mM NH4HCO3)- ACN]; B%: 65%-95%, lOmin) to give compound 4 (140 mg, 360 pmol, 48.3% yield) as a yellow oil.

[0381] LCMS: (Method 1): RT=0.931 mins, MS+1 = 389.2.

[0382] To a solution of 2-(l-benzyl-4-ethyl-3,6-dihydro-2H-pyridin-5-yl)-5-(4- ethoxyphenyl)oxazole 4 (140 mg, 360 pmol, 1 eq) and BOC2O (236 mg, 1.08 mmol, 3 eq) in MeOH (28 mL) was added Pd / C (14 mg, 10% purity) and Pd(OH)2 (14 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (30 Psi) at 40 °C for 36 hours. LC-MS (ET33008-123-P1C) showed 4 was consumed completely and desired mass was detected. The mixture was filtered and concentrated in vacuum to give compound 5 (140 mg, crude) as a yellow oil.

[0383] LCMS: (Method 1): RT=1.277 mins, MS+1 = 401.3.5 6

[0384] The solution of tert-butyl 3-[5-(4-ethoxyphenyl)oxazol-2-yl]-4-ethyl-piperidine-l- carboxylate (110 mg, 275 pmol, 1 eq) in HCl / MeOH (4 M, 0.3 mL) was stirred at 15 °C for 0.3 hours. LC-MS (ET33008-139-P1A) showed 5 was consumed completely and desired mass was detected. The mixture was concentrated under reduced pressure to give a crude compound 6 (90 mg, crude, HC1 salt) as a yellow oil.

[0385] LCMS: (Method 1): RT=0.746 mins, MS+1 = 301.2.6 Target 26 Target 26a

[0386] To a solution of 5-(4-ethoxyphenyl)-2-(4-ethyl-3-piperidyl)oxazole 6 (90 mg, 267 pmol, 1 eq, HC1 salt) and cyclobutanone (56.2 mg, 802 pmol, 3 eq) in MeOH (0.9 mL) was added TEA (2.70 mg, 26.7 pmol, 0.1 eq). The mixture was stirred at 15 °C for 0.5 hour. Then it was added AcOH (1.60 mg, 26.7 pmol, 0.1 eq and stirred for 1.5 hours. To the mixture was added NaBHjCN (83.9 mg, 1.34 mmol, 5 eq) and the mixture was stirred for 10 hours. LC-MS (ET33008-146-P1A1) showed 6 was consumed completely and desired mass was detected. The reaction was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate Cl 8 100*30mm*3um;mobile phase: [water (0.04%HCl)-ACN]; B%: 20%-40%, 5min) to give Target 26 (20 mg, 51.2 pmol, 19.2% yield, 100% purity, HC1 salt) as a white solid and Target 26a (5 mg, 12.8 pmol, 4.79% yield, 100% purity, HC1 salt) as a white solid.

[0387] LCMS: (Method 2): RT=1.376 mins, MS+1 = 355.2.

[0388] Target 26 (XXI): ’H NMR (400 MHz, METHANOL-74) 5 ppm 0.83 (t, 7=7.38 Hz, 1H), 1.07 - 1.15 (m, 2H), 1.26 - 1.36 (m, 1H), 1.38 - 1.43 (m, 3H), 1.45 - 1.68 (m, 1H), 1.81 - 2.16 (m, 4H), 2.21 - 2.46 (m, 4H), 2.54 (quin, 7=10.16 Hz, 1H), 2.95 (td, 7=12.69, 3.25 Hz, 1H), 3.25 (dd, 7=12.69, 3.31 Hz, 1H), 3.51 - 3.61 (m, 1H), 3.63 - 3.73 (m, 1H), 3.75 - 3.91 (m, 2H), 4.01 - 4.18 (m, 2H), 6.95 - 7.04 (m, 2H), 7.26 - 7.43 (m, 1H), 7.57 - 7.65 (m, 2H).

[0389] Target 26a (XXII): H NMR (400 MHz, METHANOL-74) 5 ppm 0.88 (t, 7=7.50 Hz, 3H), 1.18 - 1.32 (m, 1H), 1.40 (t, 7=7.00 Hz, 3H), 1.44 - 1.50 (m, 1H), 1.53 - 1.68 (m, 1H), 1.78 - 2.03 (m, 3H), 2.16 - 2.44 (m, 5H), 2.95 (br t, 7=11.63 Hz, 1H), 3.07 - 3.20 (m, 2H), 3.54 - 3.80 (m, 3H), 4.08 (q, 7=6.96 Hz, 2H), 6.99 (d, 7=8.75 Hz, 2H), 7.34 (s, 1H), 7.61 (d, 7=8.76 Hz, 2H).Bioactivity Testing

[0390] Inhibition of histone demethylation was evaluated using the BPS Bioscience (San Diego, CA) AlphaLlSA Assay Kits for KDM2A (catalog #50611-1), KDM2B (catalog #50610-1), KDM 7B (catalog #50515-1).Assay Protocol.

[0391] All samples and controls are tested in duplicate. Preincubating the enzyme with inhibitor is preferred while it is acceptable to add the substrate mixture and inhibitor followed by diluted FBXL11 (KDM2A), FBXL10 (KDM2B) or PHF8 (KDM7B) without the preincubation step.Step 1:

[0392] Step 1 procedure:1) Re-suspend lyophilized Biotinylated histone H3 peptide substrate in 940 pl of distilled water.2) Prepare serial dilutions of the test inhibitors in lx HDM Assay Buffer 5 (Scheme 2). Add 6 pl of inhibitor solution to each well designated “Test Sample”. For the wells designated “Blank” and "Positive Control" add 6 pl of the same solution without inhibitor (typically lx HDM Assay Buffer 5 with respective concentration of DMSO).3) Thaw FBXL11 on ice. Upon first thaw, briefly spin tube containing enzyme to recover full content of the tube. Aliquot FBXL11 enzyme into single use aliquots. Store remaining undiluted enzyme in aliquots at -80°C immediately. Note: FBXL11 is very sensitive to freeze / thaw cycles. Do not re-use thawed aliquots or diluted enzyme.4) Dilute FBXL11, FBXL10 or PHF8 in lx HDM Assay Buffer 5 at 5 ng / pl (30 ng / 6 pl). Keep diluted enzyme on ice until use. Discard any unused diluted enzyme after use.5) Preincubate 6 pl of diluted FBXL11, FBXL10 or PHF8 with 6 pl of diluted inhibitor(s) for up to 30 minutes at room temperature, with slow shaking. For the wells designated as "Blank", add 6 pl lx HDM Assay Buffer 5.6) Prepare master mix: N wells x (5 pl 4x HDM Assay Buffer 5 + 3 pl Biotinylated substrate).7) Initiate reaction by adding 8 pl of master mix prepared as described above. Incubate at room temperature for one hour. Note: All incubations are done with slow shaking on a rotator platform.Scheme 2 The serial dilution of the compounds was first performed in 100% DMSO with the highest concentration at (X) mM. Each intermediate compound dilution (in 100% DMSO) will then get directly diluted 30x fold into lx HDM Assay Buffer 5 for 3.3x concentration (DMSO). From this intermediate step, 6 pl of compound is added to 6 pl of demethylase enzyme dilution is incubated for 30 minutes at room temperature. After this incubation, 8 pl of peptide substrate is added. The final DMSO concentration is 1% for all wells.Step 2:

[0393] Step 2 procedure:

[0394] Note: Protect your samples from direct exposure to light!1) Dilute anti-Rabbit Acceptor beads (PerkinElmer #AL104C) (1:500) and Primary antibody 16-2 (1.200) with lx Detection buffer in one step. Add 10 pl of acceptor beads / antibody mixture per well. Incubate 30 min at room temperature.Step 3:

[0395] Step 3 procedure:1) Dilute Streptavidin-conjugated donor beads (PE 6760002S) 125-fold with lx Detection buffer. Shake on a rotator platform for 30 minutes at room temperature.2) Read Alpha-counts.

[0396] Exemplary bioactivity date is provided in Table 2.Table 2. Bioactivity Data

[0397] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0398] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and / or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[0399] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.Incorporation by Reference

[0400] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, manuscripts, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.Equivalents

[0401] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

What is claimed:CLAIMS1. A compound having the structural formula (I):I or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 5- or 6-membered substituted or unsubstituted heterocycle having 1-3 ring heteroatoms with at least one N atom;Ring B is a substituted or unsubstituted, single or fused, carbocyclic or heterocyclic, aromatic or non-aromatic ring system;Z is a single bond or (CH2)i-W-(CH2)j, wherein i and j are independently selected from 0, 1, 2 and 3, and W is selected from the group consisting of a single bond, O, S, NR, NRC(O), C(O)NR, NRS(O2) and S(C>2)NR, wherein when Z is a single bond Ring A and Ring B are directly bonded covalently; each of R1and R2is independently a C1-5 linear, branched or cyclic hydrocarbon group; and each R is independently H or C1-6 alkyl group.

2. The compound of claim 1, wherein Ring A is a 6-membered substituted or unsubstituted C3-5 heteroaryl group.

3. The compound of claim 2, wherein Ring A is a pyridinyl group.

4. The compound of claim 2, wherein Ring A is a pyrimidinyl group.

5. The compound of any one of claims 1-4, wherein Ring A has the structure of:wherein each of X1and X2is independently selected from CH and N.

7. The compound of claim 6, wherein Ring A is:

8. The compound of claim 6, wherein Ring A is:

9. The compound of claim 1, wherein Ring A is a 5-membered substituted or unsubstituted C3-4 heteroaryl group.

10. The compound of claim 9, wherein Ring A is imidazolyl group.

11. The compound of claim 9, wherein Ring A is oxazolyl group.

12. The compound of any one of claims 1 and 9-11, wherein Ring A has the structure:wherein Y1is N or CH, and Y2is NH, O or S.

13. The compound of claim 12, wherein Ring A is:

14. The compound of claim 12, wherein Ring A is:

15. The compound of any one of claims 1-15, wherein Ring B is a substituted or unsubstituted, 6-membered aryl or heteroaryl ring.

16. The compound of claim 15, wherein Ring B is a substituted 6-membered aryl ring.

17. The compound of claim 16, wherein Ring B is:whereineach R3is independently selected from the group consisting of halo, CN, R, OR, SR and NRR’; each of R and R’ is independently a C1-3 alkyl group; and n is 0, 1, 2 or 3.

18. The compound of claim 15, wherein Ring B is a substituted 6-membered heteroaryl ring.

19. The compound of claim 17, wherein Ring B is a substituted pyridinyl group.

20. The compound of claim 19, wherein Ring B is:wherein each R3is independently selected from the group consisting of halo, CN, R, OR, SR and NRR’; each of R and R’ is independently a C1-3 alkyl group; and n is 0, 1, 2 or 3.

21. The compound of claim 17 or 20, wherein n is 1.

22. The compound of claim 21, wherein R3is OCH3 or OCH2CH3.

23. The compound of claim 17 or 20, wherein n is 2.

24. The compound of claim 23, wherein one R3is OCH3 or OCH2CH3.

25. The compound of claim 24, wherein the other R3is F or Cl.

26. The compound of claim 24, wherein the other R3is CH3 or CH2H3.

27. The compound of any one of claims 1-26, wherein R1is a C3-5 cycloalkyl.

28. The compound of claim 27, wherein R1is cyclobutyl.

29. The compound of any one of claims 1-28, wherein R2is a C1-2 alkyl group.

30. The compound of claim 29, wherein R2is CH3.

31. The compound of claim 29, wherein R2is CH2CH3.

32. The compound of any one of claims 1-31, wherein Z is a single bond.

33. The compound of any one of claims 1-31, wherein Z is O.

34. The compound of any one of claims 1-31, wherein Z is CH2.

35. The compound of any one of claims 1-34, having a cis- configuration:

36. The compound of any one of claims 1-34, having a trans- configuration:

37. The compound of any one of claims 1-26, having one or more deuterium atoms in place of one or more hydrogen atoms.

38. The compound of claim 37, having one deuterium atom in place of one hydrogen atom.

39. A pharmaceutical composition comprising a compound according to any of claims 1-38, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

40. The pharmaceutical composition of claim 39, suitable for oral administration.

41. A unit dosage form comprising a pharmaceutical composition according to claim 39 or 40.

42. The unit dosage form of claim 41, being a tablet or a capsule.

43. A method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-38.

44. The method of claim 43, wherein the disease or disorder is mediated by lysine demethylase 2 (KDM2) and / or lysine demethylase 7 (KDM7).

45. The method of claim 43 or 44, wherein the disease or disorder is cancer, or a related disease or disorder.

46. The method of claim 45, wherein the disease or disorder is selected from the group consisting of malignant neoplasm, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, lymphoma, pancreatic cancer, leukemia, ovarian cancer, glioblastoma, diffuse intrinsic pontine glioma, or a related disease or disorder.

47. The method of claim 43, wherein the disease or disorder is type 2 diabetes or disorders of gluconeogenesis, or a related disease or disorder.

48. The method of claim 46 or 47, wherein the subject’s native immune system is enhanced or made more effective against the disease or disorder.

49. A method for decreasing histone demethylase activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-38.

50. A method for inhibiting lysine demethylase 2 (KDM2) and / or lysine demethylase 7 (KDM7) comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-38.

51. A method for enhancing a subject’s native immune system against a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-38.

52. The method of any one of claims 43-51, wherein administration is via oral administration.

53. Use of a compound of any of claims 1-38, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

54. The use of claim 53, wherein the disease or disorder is cancer, or a related disease or disorder.

55. The use of claim 53, wherein the disease or disorder is malignant neoplasm, breast cancer, lung cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, lymphoma, pancreatic cancer, leukemia, ovarian cancer, glioblastoma, diffuse intrinsic pontine glioma, or a related disease or disorder.

56. The use of claim 53, wherein the disease or disorder is type 2 diabetes or disorders of gluconeogenesis, or a related disease or disorder.

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