5-HT2a receptor modulators and methods of use thereof

Abstract

The disclosure provides compounds, e.g., compounds of Formula I, and their use in treating medical diseases or disorders, such as psychiatric and neurological disorders. Pharmaceutical compositions and methods of making various benzisoxazole and benzoisothiazole compounds are provided. The compounds are contemplated to be modulators of the 5-hydroxytryptamine 2A (5-HT2A) receptor.

Description

5-HT2A RECEPTOR MODULATORS AND METHODS OF USE THEREOFCross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 508,570, filed on June 16, 2023; the disclosure of which is incorporated herein by reference.Background

[0002] Modulators of the 5-hydroxytryptamine 2A receptor (5-HT2AR) are sought after as potential pharmaceuticals for a variety of psychiatric and neurological diseases and disorders including, but not limited to, depression, anxiety, post-traumatic stress disorder, obsessive compulsive disorder, substance abuse, eating disorders, migraine headaches, and / or cluster headaches, Alzheimer’s Disease, Parkinson’s Disease, and various somatic illnesses including, but not limited to, various inflammatory, cardiovascular, and / or pain disorders. Although many 5- HT2AR modulators have been developed, few are selective for this receptor over related subtypes, for example, the 5-HT2B receptor, a toxicology anti-target strongly implicated in serious side effects including drug-induced valvular heart disease.

[0003] Thus, there is a need for the development of safe and effective compounds that are 5- HT2A receptor modulators, for example, modulators that demonstrate selective functionality for, and / or binding to, the 5-HT2A receptor over the 5-HT2B receptor.Summary

[0004] The disclosure is directed, in part, to modulators of the 5-hydroxytryptamine 2A (5- HT2A) receptor. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier.

[0005] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein is a single bond, X is CRX, and Y is C(RY)2; or is a double bond, X is C, and Y is C(RY);A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, and phenyl; wherein ring A may be substituted on one or more substituents selected from RA;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;Rxand RYare each independently selected from the group consisting of hydrogen and -C1-C3alkyl; or one Rxand one Ryare joined together to form -CH2-;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 membered heteroaryl); wherein C1-C6alkyl, phenyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4and R5are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O- C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2.C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, - NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy; andRaand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens.

[0006] Also disclosed herein is a compound represented by Formula IIA, Formula IIB, or Formula IIC:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRcis selected from the group consisting of hydrogen and C1-C3alkyl;Rdis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3alkyl, and C1-C3alkoxy; wherein -C1-C3alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, - C(O)-NH2, and -OCH3;Reis selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3alkyl;R1is selected from the group consisting of hydrogen, -CH3,R2and R3are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m is 0, 1, 2, or 3.

[0007] Further disclosed herein is a compound represented by Formula III:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinis a single bond, X is CRX, and Y is C(RY)2; oris a double bond, X is C, and Y is C(R' );Rxand RYare each independently selected from the group consisting of hydrogen and -C1- C3alkyl; or Rxand R' are joined together to form -CH2-;Rwis selected from the group consisting of hydrogen, C1-C6alkyl, and -SO2-phenyl; wherein C1-C6alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C1-C3alkyl, and C1-C3alkoxy;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1.C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C3-C6cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C3- C6cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R5is selected from the group consisting of halogen, hydroxyl, cyano, -NRaRb, -C(O)- NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -CO2H, -C(O)- C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1. C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens; and m is 0, 1, 2, or 3.

[0008] For example, disclosed herein is a compound represented by Formula IVA, IVB, or I VC:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRwis selected from the group consisting of hydrogen and C1-C3alkyl;RYis hydrogen or -CH3;RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3;R1is selected from the group consisting of hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -R2is selected from the group consisting of hydrogen, -CH3, and -CH2OH;R3is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, - CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxy phenyl, p-hydroxyphenyl, and p- aminophenyl; and m is 0, 1, 2, or 3.

[0009] Further disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent that treats, ameliorates, and / or prevents a neurological disease and / or disorder.

[0010] In another embodiment, provided herein are methods of ameliorating, and / or preventing a neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of any of the compounds described herein, or a pharmaceutical composition thereof. In certain embodiments, the neurological disease or disorder is selected from the group consisting of, for example, depression, anxiety, substance abuse, and headache.

[0011] Also disclosed herein are methods of selectively modulating the 5 -hydroxy tryptamine 2A (5-HT2A) receptor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.Detailed Description

[0012] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art

[0013] Definitions

[0014] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0015] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-6alkyl, C1-4 alkyl, and C1-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2- ethyl-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0016] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C1-C5alkenyl, C2-C6alkenyl, and C3-C4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0017] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to hereinas C2-6 alkynyl, and C3-6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0018] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-C5alkoxy, C1-C6alkoxy, and C2-C6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0019] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1-C8alkyl, C1-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8alkoxy, heteroaryl oxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR5XSOR?9NR58SO2R59, COO-alkyl, COO-aryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SO-alkyl, SO2-alkyl, S-aryl, SO-aryl, SO2-aryl; or R56and R57may be joined to form a cyclic ring (saturatedor unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, C1-C8alkyl, C1-C4haloalkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, substituted C6-C10aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0020] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0021] The term “cyano” as used herein refers to the radical -CN.

[0022] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10cycloalkyl, C3-6cycloalkyl or C4-6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

[0023] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0024] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, di chloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br, and I), referred to herein as C1-6haloalkyl, C1.4haloalkyl, and C1-3 haloalkyl, respectively.

[0025] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0026] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole,thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0027] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-lH-4,7-methanoisoindole). “Spiro heterocyclyl,” or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms.

[0028] The terms “hydroxy” and “hydroxyl” as used herein refer to the radical -OH.

[0029] The term “oxo” as used herein refers to the radical =0.

[0030] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0031] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0032] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0033] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and / or partial agonism.

[0034] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0035] The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3 -naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with variouspharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0036] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),”“R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0037] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “£” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0038] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents onthe same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0039] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a preexisting one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0040] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0041] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that 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 of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0042] C6rtain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

[0043] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-s)alkyl, (C2- i2)alkyl carbonyl oxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl - l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy )ethyl having from 4 to 7 carbon atoms, 1-methyl- 1 -(alkoxycarbonyl oxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3 -phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-2)alkylamino(C2- a)alkyl (such as P-dimethylaminoethyl), carbarn oyl-(C1-2)alkyl, N,N-di(C1-2)alkylcarbamoyl-(C1- 2)alkyl and piperidino-, pyrrolidine-, or morpholino(C2-3)alkyl.

[0044] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-6)alkylcarbonyloxymethyl, l-((C1-6)alkylcarbonyloxy)ethyl, l-methyl-l-((C1-6)alkylcarbonyloxy)ethyl (C1-6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxy carbonylaminomethyl, succinoyl, (C1-6)alkylcarbonyl, a-amino(C1-4)alkylcarbonyl, aryl alkyl carbonyl and a- aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a- aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0045] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.

[0046] Compounds

[0047] The disclosure is directed to, in part, to compounds that are modulators of the 5- hydroxytryptamine 2A (5-HT2A) receptor. In some embodiments, the modulators of the disclosure exhibit selective functionality for, and / or binding to, the 5-HT2A receptor over the 5- HT2B and / or 5-HT2C receptor. In certain embodiments, compounds of the disclosure can be used to treat a variety of neurological diseases and disorders including, but not limited to, depression, anxiety, substance abuse, migraine headaches, and / or cluster headaches.

[0048] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein single bond, X is CRX, and Y is C(RY)2; or double bond, X is C, and Y is C(RY);A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, and phenyl; wherein ring A may be substituted on one or more substituents selected from RA;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;Rxand RYare each independently selected from the group consisting of hydrogen and -C1- C3alkyl; or one Rxand one R' are joined together to form -CH2-;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 membered heteroaryl); wherein C1-C6alkyl, phenyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4and R5are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O- C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1.C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1.C6alkyl, C1-C6alkyl, C2.C6aC6alkenyl, C2.C6aC6alkynyl, C1-C6aC6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy; andRaand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens.

[0049] In some embodiments, a compound disclosed herein is represented by

[0050] In some embodiments, R6and R7are hydrogen. In other embodiments, R2and R3are hydrogen. In certain embodiments, a compound disclosed herein is represented byRcis selected from the group consisting of hydrogen and C1-C3alkyl;Rdis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3alkyl, -C1-C3alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein -C1-C3alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and - OCH3;Reis selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3alkyl; and m is 0, 1, 2, or 3.

[0052] In some embodiments, for example, Rcis selected from the group consisting of hydrogen and -CH3; Rdis selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; and Reis selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano.

[0053] In further embodiments, RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3. For example, in certain embodiments RAis independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3.

[0054] In some embodiments, A is selected from the group consisting of, for example,

[0055] In other embodiments, R4and R5are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. In still other embodiments, R4is hydrogen. In further embodiments, R5is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. In certain other embodiments, R3is hydrogen or -CH3. In some embodiments, R1is hydrogen. In additional embodiments, R1is selected from the group consisting of hydrogen, -CH3,and

[0056] Also disclosed herein is a compound represented by Formula IIA, Formula IIB, orFormula IIC:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRcis selected from the group consisting of hydrogen and C1-C3alkyl;Rdis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3alkyl, and C1-C3alkoxy; wherein -C1-C3alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, - C(O)-NH2, and -OCH3;Reis selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3alkyl;R2and R3are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m is 0, 1, 2, or 3.

[0057] In some embodiments, Rdis selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; and Reis selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano. In other embodiments, R4is hydrogen. In further embodiments, R5is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2. In certain embodiments, R5is hydrogen or -CH3. In some embodiments, R1is hydrogen.

[0058] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds.

[0059] Further disclosed herein is a compound represented by Formula III:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein is a single bond, X is CRX, and Y is C(RY)2; oris a double bond, X is C, and Y is C(R' );Rxand RYare each independently selected from the group consisting of hydrogen and -C1- C3alkyl; or Rxand R' are joined together to form -CH2-;Rwis selected from the group consisting of hydrogen, C1-C6alkyl, and -SO2-phenyl; wherein C1-C6alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C1-C3alkyl, and C1-C3alkoxy;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1.C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or moresubstituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C3-C6cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C3- C6cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- C>, alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1. C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R5is selected from the group consisting of halogen, hydroxyl, cyano, -NRaRb, -C(O)- NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -CO2H, -C(O)-C1.C6alkyl, C1.C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1- C& alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens; andm is 0, 1, 2, or 3.

[0060] In some embodiments, a compound disclosed herein is represented by

[0061] In some embodiments, R6and R7are hydrogen. For example, in some embodiments a compound disclosed herein is represented by

[0062] In some embodiments, RYis hydrogen or -CH3. In other embodiments, Rwis selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2. In further embodiments, RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3. For example, in certain embodiments RAis independently selected from each occurrence from the group consisting of fluoro, chloro, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, -CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH, and -OCH2CH3.

[0063] In some embodiments, R2is hydrogen. In other embodiments, R3is selected from the group consisting of hydrogen, -CH3, and -CH2OH. In still other embodiments, R4is hydrogen. In further embodiments, R5is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, p- hydroxyphenyl, andp-aminophenyl.

[0064] In some embodiments, R1is selected from the group consisting of hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CFbCFb-phenyl. cyclopropyl,hydrogen.

[0065] Also disclosed herein is a compound represented by Formula IVA, IVB, or IVC:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRwis selected from the group consisting of hydrogen and C1-C3alkyl;Rvis hydrogen or -CH3;RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3;R1is selected from the group consisting of hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -R2is selected from the group consisting of hydrogen, -CH3, and -CH2OH;R3is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, - CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, p-hydroxyphenyl, and p- aminophenyl; and m is 0, 1, 2, or 3.

[0066] In some embodiments, the compound is a compound identified in Table 2 below or a pharmaceutically acceptable salt thereof.Table 2. Exemplary compounds.

[0067] In some embodiments, the compound is a compound identified in Table 3 below or a pharmaceutically acceptable salt thereof.Table 3. Exemplary compounds.

[0068] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio, or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0069] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0070] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example,diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0071] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0072] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0073] Methods

[0074] Another aspect of the disclosure provides methods of treating patients suffering from a neurological disease or disorder. In particular, in certain embodiments, the disclosure provides a method of treating the below medical indications comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

[0075] For example, provided herein is a method of treating a neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II. Also provided herein is a method of treating a neurological disease or disorder in a patient in needthereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein, e g., a compound of Formula I or Formula II, and a pharmaceutically acceptable excipient.

[0076] Non-limiting examples of a neurological disease or disorder include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods herein include, but are not limited to, migraine headaches and cluster headaches.

[0077] For example, in some embodiments the methods described herein may include treating a depressive disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the depressive disorder may be major depressive disorder. In other embodiments, the depressive disorder may include treatment resistant depressions.

[0078] In certain embodiments, the methods described herein may include treating an anxiety disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the anxiety disorder may be generalized anxiety disorder. In other embodiments, the anxiety disorder may be social anxiety disorder.

[0079] In further embodiments, the methods described herein may include treating a trauma and / or stress disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, such a disorder may be post-traumatic stress disorder. In other embodiments, such a disorder may be an adjustment disorder.

[0080] In certain embodiments, the methods described herein may include treating obsessive compulsive disorder, for example, body dysmorphic disorder, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0081] In other embodiments, the methods described herein may include treating an eating disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the eating disorder may be anorexia. In other embodiments, the eating disorder may be bulimia.

[0082] In still further embodiments, the methods described herein may include treating a sleep-wake disorder, for example, insomnia, in a patient in need thereof, comprising administeringto the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0083] In some embodiments, the methods described herein may include treating a psychotic disorder, for example, insomnia, in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the psychotic disorder may be schizophrenia. In other embodiments, the psychotic disorder may be schizoaffective disorder. In still other embodiments, the psychotic disorder may be schizotypal personality disorder.

[0084] In certain embodiments, the methods described herein may include treating substance-related disorders and / or addictive disorders in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, such a disorder may be alcohol use disorder. In other embodiments, such a disorder may be opioid use disorder. In still other embodiments, such a disorder may be tobacco use disorder. For example, in some embodiments a compound disclosed herein may be useful in facilitating smoking cessation.

[0085] In certain other embodiments, the methods described herein may include treating a neurocognitive disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the neurocognitive disorder may include those due to a primary neurodegenerative disease, for example, Alzheimer’s disease or Parkinson’s disease.

[0086] In some embodiments, the methods described herein may include treating a personality disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In other embodiments, the methods described herein may include treating an autism spectrum disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0087] In further embodiments, the methods described herein may include treating a bipolar disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the bipolar disorder may be bipolar I disorder. In other embodiments, the bipolar disorder may be bipolar II disorder.

[0088] In other embodiments, the methods described herein may include treating a pain disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the pain disorder may be neuropathic pain. In other embodiments, the pain disorder may be migraine. In still other embodiments, the pain disorder may be cluster headache. In further embodiments, the pain disorder may be trigeminal neuralgia. In still further embodiments, the pain disorder may be cancer pain. In certain embodiments, the pain disorder may be regional pain disorder. In yet other embodiments, the pain disorder may be phantom limb pain. In some embodiments, a contemplated pain disorder may be a chronic pain.

[0089] In certain embodiments, a compound disclosed herein, e.g., a compound of Formula I or Formula II, may exhibit anxiolytic, anti-depressive, and anti-drug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions. For example, a contemplated (5-HT2A) receptor modulator of the present disclosure may confer anti-depressant like activities without incurring psychedelic drug-like actions. For example, in some embodiments, a compound disclosed herein may be safe and effective for use in a method described herein, yet lack the hallucinogenic effects of known psychedelics such as, for example, DMT and psilocybin.

[0090] This disclosure also provides a method of selectively modulating the 5- hydroxytryptamine 2A (5-HT2A) receptor. The method includes administering to a patient a compound disclosed herein, e.g., a compound of Formula I or Formula II, a pharmaceutically acceptable salt and / or stereoisomer thereof, wherein the compound selectively modulates the 5- HT2A over the 5-HT2B and / or 5-HT2C receptor. The method of selectively modulating the 5- HT2A receptor can be used to treat, ameliorate, and / or prevent diseases or disorders that are affected by, associated with, or would benefit from selective modulations at the 5-HT2A receptor. In selectively modulating the 5-HT2A receptor over the 5-HT2B and / or 5-HT2C receptor, the method provides, for example, reduced side effects such as, but not limited to, drug-induced valvular heart disease associated with modulating the 5-HT2B receptor.

[0091] In certain embodiments, a method described herein further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder, or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.

[0092] Contemplated patients include not only humans, but other animals such as companion animals (e.g., dogs, cats), domestic animals (e g., cow, swine), and wild animals (e g., monkeys, bats, snakes).

[0093] Compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present within the patient's body at the same time, this need not be so.

[0094] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. Forexample, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y- Y, etc.

[0095] For example, the methods described herein include administering to the patient a therapeutically effective amount of at least one compound of Formula I or Formula II, as described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein, e.g., a compound of Formula I or Formula II, present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that treats a neurological disease or disorder or that treats a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor.

[0096] For example, in some embodiments the methods described herein can include administering to the patient one or more additional therapeutic agents in combination with a compound disclosed herein. In certain embodiments, the one or more additional therapeutics agents that may be administered in combination with a compound disclosed herein may be a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the selective serotonin reuptake inhibitor may be selected from the group consisting of, for example, fluoxetine, paroxetine, sertraline, citalopram and escitalopram. In other embodiments, the one or more additional therapeutics agents may be a serotonin and norepinephrine reuptake inhibitor (SNRI). For example, the serotonin and norepinephrine reuptake inhibitor may be selected from the group consisting of, e.g., duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran. In still other embodiments, the one or more additional therapeutics agents may be selected from the group consisting of, for example, trazodone, mirtazapine, vortioxetine, vilazodone and bupropion. In certain embodiments, the one or more additional therapeutics agents may be a tricyclic antidepressant. For example, in some embodiments the tricyclic antidepressant may be selected from the group consisting of, e.g., imipramine, nortriptyline, amitriptyline, doxepin and desipramine. In further embodiments, the one or more additional therapeutics agents may be a monoamine oxidase inhibitor (MAOI). For example, in some embodiments the monoamine oxidase inhibitor may be selected from the group consisting of, e.g., tranylcypromine, phenelzine and isocarboxazid. In other embodiments, the one or more additional therapeutics agents may be,for example, a lithium compound, e.g., a lithium salt, e.g., lithium carbonate, lithium acetate, lithium sulfate, lithium citrate, lithium orotate, or lithium gluconate. In some embodiments, the one or more additional therapeutics agents may be, for example, ketamine or esketamine. In certain embodiments, the one or more additional therapeutics agents may be, for example, dextromethorphan. In other embodiments, the one or more additional therapeutics agents may be, for example, D-methadone.

[0097] In some embodiments, administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and / or preventing a neurological disease or disorder or in treating, ameliorating, and / or preventing a disease or disorder that is affected by, associated with, or would benefit from selective modulation at the 5-HT2A receptor in the patient. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0098] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I or Formula II.

[0099] Pharmaceutical Compositions and Kits

[0100] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0101] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains oneor more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0102] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0103] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0104] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceuticalformulating art.

[0105] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0106] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0107] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0108] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. Theactive component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0109] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0110] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0111] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens®, Pluronics®, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0112] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0113] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0114] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (ELPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate- methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[0115] The disclosure also provides kits for use by, e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0116] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

[0117] Exemplary Embodiments of the Invention

[0118] El. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein single bond, X is CRX, and Y is C(RY)2; or double bond, X is C, and Y is C(RY);A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, and phenyl; wherein ring A may be substituted on one or more substituents selected from RA;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;Rxand RYare each independently selected from the group consisting of hydrogen and -C1- C3alkyl; or one Rxand one RYare joined together to form -CH2-;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 membered heteroaryl); wherein C1-C6alkyl, phenyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- G, alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4and R?are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O- C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2.C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, - NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy; andRaand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens.

[0119] E2. The compound of El, wherein the compound is represented by

[0120] E3. The compound of El or E2, wherein R6and R7are hydrogen.

[0121] E4. The compound of any one of E1-E3, wherein R2and R3are hydrogen.

[0122] E5. The compound of any one of E1-E4, wherein the compound is represented by

[0123] E6. The compound of any one of E1-E5, wherein A is selected from the group consisting ofRcis selected from the group consisting of hydrogen and C1-C3alkyl;Rdis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3alkyl, C1-C3alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein -C1-C3alkyl may optionally be substituted by one, two, or three substituents eachindependently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and - OCH3;Reis selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3alkyl; and m is 0, 1, 2, or 3.

[0124] E7. The compound of any one of E1-E6, wherein:Rcis selected from the group consisting of hydrogen and -CH3;Rdis selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; andReis selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano.

[0125] E8. The compound of any one of E1-E5, wherein RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, - CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with - CH3.

[0126] E9. The compound of any one of E1-E5 and E7, RAis independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3.

[0127] E10. The compound of any one of E1-E9, wherein A is selected from the group consisting of

[0128] El l. The compound of any one of El -El 0, wherein R4and R5are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)- N(CH2CH3)2

[0129] E12. The compound of any one of El-El 1, wherein R4is hydrogen.

[0130] E13. The compound of any one of E1-E12, wherein R5is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

[0131] E14. The compound of any one of E1-E13, wherein R5is hydrogen or -CH3

[0132] E15. The compound of any one of E1-E14, wherein R1is selected from the group consisting of hydrogen, -CH3,

[0133] E16. The compound of any one of E1-E15, wherein R1is hydrogen.

[0134] E17. A compound represented by Formula IIA, Formula IIB, or Formula IIC:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRcis selected from the group consisting of hydrogen and C1-C3alkyl;Rdis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3alkyl, and C1-C3alkoxy; wherein -C1-C3alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, - C(O)-NH2, and -OCH3;Reis selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3alkyl;R1is selected from the group consisting of hydrogen, -CH3,R2and R3are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m is 0, 1, 2, or 3.

[0135] El 8. The compound of any one of E1-E6, wherein:Rdis selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; andReis selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano.

[0136] E19. The compound of E17 or E18, wherein R4is hydrogen.

[0137] E20. The compound of any one of E17-E19, wherein R5is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

[0138] E21. The compound of any one of E17-E20, wherein R5is hydrogen or -CH3.

[0139] E22. The compound of any one of E17-E21, wherein R1is hydrogen.

[0140] E23. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0141] E24. A compound represented by Formula III:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein is a single bond, X is CRX, and Y is C(RY)2; oris a double bond, X is C, and Y is C(RY);Rxand RYare each independently selected from the group consisting of hydrogen and -C1- C3alkyl; or Rxand RYare joined together to form -CH2-;Rwis selected from the group consisting of hydrogen, C1-C6alkyl, and -SO2-phenyl; wherein C1-C6alkyl and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, C1-C3alkyl, and C1-C3alkoxy;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1.C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -Cs-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2.C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2.C6alkynyl, -C3-C6cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein C1-C6alkyl, C2.C6alkenyl, C2.C6alkynyl, -C3- C6cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1- C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2.C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R5is selected from the group consisting of halogen, hydroxyl, cyano, -NRaRb, -C(O)- NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -CO2H, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens; and m is 0, 1, 2, or 3.

[0142] E25. The compound of E24, wherein the compound is represented by

[0143] E26. The compound of E24 or E25, wherein R6and R7are hydrogen.

[0144] E27. The compound of any one of E24-E26, wherein the compound is represented by

[0145] E28. The compound of any one of E24-E27, wherein RYis hydrogen or -CH3

[0146] E29. The compound of any one of E24-E28, wherein Rwis selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2

[0147] E30. The compound of any one of E24-E29, wherein RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, - CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; whereintetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with - CH3

[0148] E31. The compound of any one of E24-E30, wherein RAis independently selected from each occurrence from the group consisting of fluoro, chloro, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, -CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH, and -OCH2CH3

[0149] E32. The compound of any one of E24-E31, wherein R2is hydrogen.

[0150] E33. The compound of any one of E24-E32, wherein R3is selected from the group consisting of hydrogen, -CH3, and -CH2OH.

[0151] E34. The compound of any one of E24-E33, wherein R4is hydrogen.

[0152] E35. The compound of any one of E24-E34, wherein R?is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)- N(CH2CH3)2, phenyl, m-hy droxypheny 1, p-hydroxy phenyl, and p-aminophenyl.

[0153] E36. The compound of any one of E24-E35, wherein R1is selected from the group consisting of hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2-phenyl. cyclopropyl,or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRwis selected from the group consisting of hydrogen and C1-C3alkyl;R3is hydrogen or -CH3;RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3;R1is selected from the group consisting of hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -R2is selected from the group consisting of hydrogen, -CH3, and -CH2OH;R3is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, - CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, / n-hydroxy phenyl, p-hydroxyphenyl, and p- aminophenyl; and m is 0, 1, 2, or 3.

[0155] E38. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0156] E39. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or stereoisomer thereof.

[0157] E40. A pharmaceutical composition comprising a compound of any one of E1-E39 and a pharmaceutically acceptable excipient.

[0158] E41. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of E1-E39.

[0159] E42. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of E1-E39 and a pharmaceutically acceptable excipient.

[0160] E43. The method of E41 or E42, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.Examples

[0161] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unlessotherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[0162] General Information

[0163] Reagents and solvents were received from commercial sources without further purification unless specified or prepared by literature methods. 'H NMR and13C NMR spectra were recorded on a 300 or 400 MHz Bruker spectrometer, using DMSO-d6, CDCL or CD3OD as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. Chemical shifts were given in δ relative to TMS, the coupling constants / were given in Hz. LCMS analytical method and instruments were generated using one of the following methods. Detection was performed by UV (254 nm) and ELSD for all methods.

[0164] Method A (LCMS 17,41,42, 50,52)

[0165] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Express C18, 2.7pm particle size), elution with solvent A: Water / 0.1%FA; solvent B: Acetonitrile / 0.07%FA:

[0166] Method B (LCMS 17,41,42,47, 50,52)

[0167] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Express C18, 2.7pm particle size), elution with solvent A: Water / 0.1%FA; solvent B: Acetonitrile / 0.07%FA:

[0168] Method C (LCMS25)

[0169] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO C18, 2.6pm particle size), elution with solvent A: Water / (5mmol / L) NH4HCO3; solvent B: Acetonitrile:

[0170] Method D (LCMS25)

[0171] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO Cl 8, 2.6pm particle size), elution with solvent A: Water / (5mmol / L) NH4HCO3; solvent B: Acetonitrile:

[0172] Method E (LCMS40)

[0173] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Express C18, 2.7pm particle size), elution with solvent A: Water / 0.05%TFA; solvent B: Acetonitrile / 0.05%TFA:

[0174] Method F (LCMS45)

[0175] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,2.7pm particle size), elution with solvent A: Water / 0.04%NH4H20; solvent B: Acetonitrile:

[0176] Method G (LCMS45)

[0177] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,2.7pm particle size), elution with solvent A: Water / 0.04%NEUH20; solvent B: Acetonitrile:

[0178] Method H (LCMS46,48)

[0179] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,4.0pm particle size), elution with solvent A: Water / (5mmol / L) NH4HCO3; solvent B: Acetonitrile:

[0180] Method I (LCMS46.48)

[0181] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Poroshell HPH-C18,4.0pm particle size), elution with solvent A: Water / (5mmol / L) NH4HCO3; solvent B: Acetonitrile:

[0182] Method J (LCMS49)

[0183] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 2.0 mm Poroshell 120 EC-C18, 1.9pm particle size), elution with solvent A:Water / 0.1% FA; solvent B: Acetonitrile / 0.07% FA:

[0184] Method K (LCMS49)

[0185] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 2.0 mm Poroshell 120 EC-C18, 1.9pm particle size), elution with solvent A:Water / 0.1% FA; solvent B: Acetonitrile / 0.07% FA:

[0186] Method L (LCMS51,53)

[0187] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO-C18, 2.6pm particle size), elution with solvent A: Water / (5mmol / L) NH4HCO3; solvent B: Acetonitrile / Acetonitrile:

[0188] Method M (LCMS51,53)

[0189] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (50 x 3.0 mm Kinetex® EVO-C18, 2.6pm particle size), elution with solvent A: Water 5mM NH4HCO3; solvent B: Acetonitrile / Acetonitrile:

[0190] Method N (LCMS60)

[0191] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Agilent® EC-C18, 1.9pm particle size), elution with solvent A: Water / 0.1%FA; solvent B: Acetonitrile / 0.07%FA:

[0192] Method O (LCMS61)

[0193] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 2.0 mm Gemini NX-C18, 3.0pm particle size), elution with solvent A: (5mmol / L) NH4HCO3; solvent B: Acetonitrile:

[0194] Method P (LCMS63)

[0195] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Halo C18, 100 A, 2.0 pm particle size), elution with solvent A: Water / 0.05%TFA; solvent B: Acetonitrile / 0.05%TFA:

[0196] Method 0 (LCMS63)

[0197] Experiments were performed on a SHIMADZU® 20A HPLC with a C18-reverse- phase column (30 x 3.0 mm Halo C18, 100 A, 2.0 pm particle size), elution with solvent A: Water / 0.05%TFA; solvent B: Acetonitrile / 0.05%TFA:

[0198] Example 1: Synthesis of 3-[(3R)-piperidin-3-yl]-2,l-benzoxazole and 3-[(3S)- piperidin-3-yl]-2,l-benzoxazole (Compounds 109 and 110)

[0199] Tert-butyl 3-{2-[(tert-butoxycarbonyl)amino]benzoyl}piperidine-l-carboxylate. To a solution of tert-butyl A-(2-bromophenyl)carbamate (8.00 g, 29.4 mmol) in THF (2 mL) was added dropwise CH3Li (1.29 g, 58.8 mmol 1.6 M in Et2O) and n-BuLi (30 mL, 318 mmol 2.5 M in n- hexane) at -78 °C under N2atmosphere. The reaction mixture was stirred at -78 °C for 30 min before a solution of tert-butyl 3-(2-methoxypropanoyl) piperi dine- 1 -carboxylate (11.97 g, 44.1 mmol) in 2 mL THF was added dropwise. After an addition 30 min, the reaction mixture was quenched with NH4CI (aq) and then extracted with EtOAc (5 x 100 ml). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na?SO4, and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with petroleum ether: ethyl acetate (9: 1) to afford the desired product as a yellow solid (1.30 g, 11 % yield). LCMS 53 (Method M) (ESI) C22H32N2O5 calcd 404.23; found [M+H]+: 405.

[0200] 2-(piperidine-3-carbonyl)aniline. A solution of tert-butyl 3-{2-[( tert- butoxycarbonyl)amino] -benzoyl } -piperidine- 1 -carboxylate ( 1.30 g, 3.21 mmol) in HCl / di oxane (2 mL) was stirred for 12 h at rt before being concentrated under reduced pressure to afford the desired product as a yellow solid (600 mg, 91 % yield). LCMS 47 (ESI) C12H16N2O calcd 204.13; found [M+H]+: 205. The product was used directly in the next step.

[0201] Tert-butyl 3-(2-aminobenzoyl)piperidine-l-carboxylate. To a stirred solution of 2- (piperidine-3-carbonyl)aniline (600 mg, 2.93 mmol) in di chloromethane (6 mL) was added di-lert- butyl dicarbonate (705 mg, 3.23 mmol) and trimethylamine (892 mg, 8.81 mmol). The reaction mixture was stirred for 0.5 h at rt before being concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with petroleum etherethyl acetate (3:1)to afford the desired product as a yellow solid (600 mg, 67 % yield). LCMS 50 (Method B) (ESI) C17H24N2O3calcd 304.18; found [M+H]+: 305.

[0202] Tert-butyl 3-(2,l-benzoxazol-3-yl)piperidine-l-carboxylate. To a stirred solution of tert-butyl 3-(2-aminobenzoyl)piperidine-l-carboxylate (600 mg, 1.97 mmol) in acetonitrile (15 mL) was added iodosobenzene (2.60 g, 11.8 mmol). The reaction mixture was stirred for 2 h at 40 °C before being concentrated under reduced pressure. The residue was purified by chromatography (SiO2), eluting with petroleum etherethyl acetate (3:1) to afford the desired product as a yellow solid (300 mg, 50 % yield). LCMS 47 (ESI) C17H22N2O3calcd 302.16; found [M+H]+: 303.

[0203] 3-(piperidin-3-yl)-2,l-benzoxazole. To a solution of tert-butyl 3-(2,l-benzoxazol-3- yl)piperidine-l -carboxylate (300 mg, 0.99 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred for 0.5 h at rt before being concentrated under reduced pressure and the residue adjusted to pH 8 with saturated Na2CO3(aq). The residue was purified by chromatography (column, C18; mobile phase, water (NH4HCO30.1%) in acetonitrile, 0% to 20% gradient in 30 min; detector, UV 220 nm) to afford the desired product as a yellow solid (100 mg, 50 % yield). LCMS 40 (ESI) C12H14N2O calcd 202.11; found [M+H]+: 203.

[0204] 3-[(3R)-piperidin-3-yl]-2,l-benzoxazole & 3-[(3S)-piperidin-3-yl]-2,l-benzoxazole. 3-(piperidin-3-yl)-2,l-benzoxazole (100 mg) was separated by Prep-Chiral-HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(10 mM NH3-MeOH), Mobile Phase B: IP A— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; wavelength: 317 / 320 nm; RTl(min): 9; RT2(min): 13; sample Solvent: methanol: dichloromethane = 4: 1; Sample concentration: mg / mL; Injection Volume: 0.2 mL; Number Of Runs: 13) to afford:

[0205] 3-[(3R)-piperidin-3-yl]-2,l-benzoxazole. Yellow solid (16.7 mg, 17 % yield). LCMS 63 (Method P) (ESI) C12H14N2O calcd 202.11; found [M+H]+: 203.05. ‘H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J= 8.8 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.41 - 7.30 (m, 1H), 6.99 (t, J = 7.5 Hz, 1H), 3.47 (s, 1H), 3.19 (d, J = 11.9 Hz, 1H), 3.03 - 2.79 (m, 2H), 2.60 (d, J = 10.8 Hz, 1H), 2.11 (d, J= 12.6 Hz, 1H), 1.96-1.80 (m, J= 12.4 Hz, 1H), 1.69 (s, 1H), 1.54 (d, J= 12.8 Hz, 1H).

[0206] 3-[(3S)-piperidin-3-yl]-2,l-benzoxazo!e. White oil (18.1 mg, 18 % yield). LCMS 51 (Method L) (ESI) C12H14N2O calcd 202.11; found [M+H]+: 202.95. 'HNMR (400 MHz, DMSO- d6)δ 7.78 - 7.73 (m, J= 8.9, 1.1 Hz, 1H), 7.55 - 7.50 (m, J= 9.1, 1.0 Hz, 1H), 7.39 - 7.34 (m, J =9.1, 6.3, 1.0 Hz, 1H), 7.03 - 6.98 (m, J= 8.8, 6.3, 0.7 Hz, 1H), 3.52 - 3.43 (m, J= 14.4, 7.6, 3.8 Hz, 1H), 3.17 (dd, J= 1 1.9, 3.6 Hz, 1H), 2.95 (dd, J= 13.0, 3.4 Hz, 1H), 2.83 (dd, J= 12.1, 10.6 Hz, 1H), 2.58 (dd, J = 12.0, 3.0 Hz, 1H), 2.15 - 2.07 (m, J= 10.9, 3.8, 1.9 Hz, 1H), 1.94 - 1.82 (m, J= 12.2, 3.9 Hz, 1H), 1.74 - 1.67 (m, J = 13.2, 3.4 Hz, 1H), 1.61 - 1.49 (m, J = 15.9, 13.1, 7.9, 4.0 Hz, 1H).

[0207] Example 2: Synthesis of 3-(l,2,5,6-Tetrahydropyridin-3-yl)-2,l-benzoxazole (Compound 111)

[0208] 1-tert-Butyl 3-methyl 5,6-dihydro-2H-pyridine-l,3-dicarboxylate. To a stirred mixture of l-(tert-butoxycarbonyl)-5,6-dihydro-2#-pyridine-3 -carboxylic acid (4.00 g, 17.60 mmol) in DCM (20 mL) and MeOH (20 mL) was added TMSCHN2 (17.6 mL, 35.20 mmol) dropwise at 0 °C under an N2 atmosphere. The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The reaction was quenched with AcOH at room temperature and the resulting mixture was concentrated under vacuum. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0 % to 60 % gradient in 30 min; UV 254 nm to afford the desired product as a yellow liquid (3.60 g, 84.7% yield). LCMS 53 (Method L) (ESI) C12H19NO4 calcd 241.13; Found [M+H]+:242. 'H NMR (400 MHz, DMSCM,) δ 7.01 (d, J= 4.3, 2.0 Hz, 1H), 4.00 (d, J= 2.6 Hz, 2H), 3.69 (s, 3H), 3.39 (d, J= 5.7 Hz, 2H), 2.27 (d, J= 2.9 Hz, 2H), 1.41 (s, 9H).

[0209] tert-Butyl 3-(hydroxymethyl)-5,6-dihydro-2H-pyridine-l-carboxylate. To a stirred mixture of 1-tert-butyl 3-methyl 5,6-dihydro-277-pyridine-l,3-dicarboxylate (3.60 g, 14.92 mmol)in toluene (40 mL) was added DIBAL-H (25.6 mL, 64.00 mmol dropwise at 0 °C under an N2 atmosphere. The resulting mixture was stirred for 30 min at room temperature under an N2 atmosphere. The reaction was quenched with MeOH at 0 °C. The resulting mixture was filtered and the residue was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0 % to 50 % gradient in 30 min; UV 254 nm to afford the desired product as a yellow oil (1.60 g, 50.2% yield). LCMS 53 (Method L) (ESI) C11H19NO3 calcd 213.14; Found [M+H]’:214. 'H NMR (400 MHz, DMSO-d6) δ 5.69 (s, 1H), 4.78 (s, 1H), 3.81 (d, J= 23.0 Hz, 4H), 3.35 (d, J= 5.8 Hz, 2H), 2.10 - 1.95 (m, 2H), 1.41 (s, 9H).

[0210] tert-Butyl 3-formyl-5,6-dihydro-2H-pyridine-l-carboxylate. A solution of tert-Butyl 3-(hydroxymethyl)-5,6-dihydro-277-pyridine-l-carboxylate (1.60 g, 7.50 mmol) and MnCL (9.78 g, 112.60 mmol) in DCM (20 mL) was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, and the residue was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford to afford the desired product as a yellow oil (1.20 g, 75.9% yield). LCMS 48 (Method H) (ESI) C11H17NO3 calcd 211.12; Found [M+H]+:212. 'H NMR (400 MHz, DMSO-d6) δ 9.43 (d, J= 1.2 Hz, 1H), 7.13 (d, J= 2.6 Hz, 1H), 4.00 - 3.89 (m, 2H), 3.44 (d, J= 5.7 Hz, 2H), 2.41 (d, J= 2.9 Hz, 2H), 1.41 (d, J= 1.3 Hz, 9H).

[0211] tert-Butyl 3-[hydroxy(2-nitrophenyl)methyl]-5, 6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of l-iodo-2-nitrobenzene (282.8 mg, 1.13 mmol) in tetrahydrofuran (6 mL) was added phenylmagnesium bromide (514.9 mg, 2.83 mmol) dropwise at -40 °C under an N2 atmosphere and stirred for 5 min at -40 °C under an N2 atmosphere. To the above mixture was added tert-butyl 3-formyl-5,6-dihydro-277-pyridine-l -carboxylate (200.0 mg, 0.94 mmol) dropwise at -40 °C. The resulting mixture was stirred for additional 1 h at -40 °C. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were washed with water (3 x 5 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5: 1) to afford the desired product as a yellow oil (150.0 mg, 47.3% yield). LCMS 52 (Method B) (ESI) C17H22N2O5 calcd 334.15; Found [M+H]+:335. 'H NMR (400 MHz, CDCI3) δ 7.92 (d, J= 8.1 Hz, 1H), 7.86 - 7.81(m, 1H), 7.66 (d, J= 7.7 Hz, 1H), 7.46 (d, J= 7.8 Hz, 1H), 5.77 (s, 1H), 5.73 (s, 1H), 3.84 (d, J =16.7 Hz, 2H), 3.42 (d, J= 5.8 Hz, 2H), 2.12 (d, J = 3.1 Hz, 2H), 1.43 (s, 9H).

[0212] tert-Butyl 3-(2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-l-carboxylate. To a stirred solution of / m-butyl 3-[hydroxy(2-nitrophenyl)methyl]-5,6-dihydro-277-pyridine-l -carboxylate (150.0 mg, 0.44 mmol) in DCM (2 mL) was added MnCh (390.3 mg, 4.48 mmol). The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was filtered, the residue was washed with CH2CI2 (3 x 4 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5: 1) to afford the desired product as a yellow oil (80.0 mg, 53.6% yield). LCMS 49 (Method J) (ESI) C17H20N2O5 calcd 332.14; Found [M+H]+:333. ’H NMR (400 MHz, CDCI3) δ 8.18 (d, J= 1.1 Hz, 1H), 7.74 (d, J = 1.2 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.43 (d, J= 1.5 Hz, 1H), 6.35 (d, J= 2.1 Hz, 1H), 4.34 (d, J = 2.4 Hz, 2H), 3.52 (d, J= 5.7 Hz, 2H), 2.28 (d, J= 4.1 Hz, 2H), 1.51 (s, 9H).

[0213] tert-Butyl 3-(2,l-benzoxazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate. To a stirred solution of tert-butyl 3-(2-nitrobenzoyl)-5,6-dihydro-2H-pyridine- l -carboxylate (80.0 mg, 0.24 mmol) in MeOH (0.5 mL) and EtOAc (0.5 mL) was added SnCh.2H2O (163.0 mg, 0.72 mmol). The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction was quenched with sat. NaHCO.i (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 4 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5: 1) to afford the desired product as a white solid (30.0 mg, 41.5% yield). LCMS 54 (ESI) C17H20N2O3 calcd 300.15; Found [M+H]+:301. 'H NMR (400 MHz, CDCI3) δ 7.64 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 7.29 (d, J= 6.1 Hz, 1H), 7.00 (d, J= 7.6 Hz, 1H), 6.94 - 6.87 (m, 1H), 4.56 (s, 2H), 3.63 (d, J =5.7 Hz, 2H), 2.48 (s, 2H), 1.52 (s, 9H).

[0214] 3-(l,2,5,6-Tetrahydropyridin-3-yl)-2,l-benzoxazole. HC1 (gas) in 1,4-dioxane (1 mL, 4 M) was added to a stirred solution of tert-butyl 3-(2, l-benzoxazol-3-yl)-5,6-dihydro-2 / f- pyridine-1 -carboxylate (45.0 mg, 0.15 mmol) in dioxane (1 mL). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2CC>3 (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10 % to 50 % gradient in 20 min;detector, UV 254 nm to afford the desired product as a white solid (18.1 mg, 60.3% yield). LCMS 51 (Method L) (ESI) C12H12N2O calcd 200.24; Found [M+H]+:201.15. 'H NMR (400 MHz, CDC13) 57.61 (d, J= 1.1 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.33 - 7.27 (m, 1H), 7.01 - 6.94 (m, 1H), 6.88 (d, J= 1.9 Hz, 1H), 3.99 (d, J= 1.8 Hz, 2H), 3.09 (d, J= 5.7 Hz, 2H), 2.46 - 2.33 (m, 2H).

[0215] Example 3: Synthesis of 7-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-2,l- benzoxazole (Compound 112)

[0216] tert-Butyl 3-[(3-fluoro-2-nitrophenyl) (hydroxy) methyl 1-5, 6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of l-fluoro-3-i odo-2 -nitrobenzene (909.9 mg, 3.40 mmol) in THF (10 mL) was added phenylmagnesium chloride (4.2 mb, 2 M in THF) dropwise at -40 °C and stirred for 5 min at -40 °C under an N2 atmosphere. To the above mixture was added tert-butyl 3- formyl-5,6-dihydro-2H-pyridine-l-carboxylate (600.0 mg, 2.84 mmol) dropwise at -40 °C and the resulting mixture was stirred for additional 1 h at -40 °C under an N2 atmosphere. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was extracted with CH2CI2. (3 x 50 mL) The combined organic extracts were washed with water (3 x 10 mL) and dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5 : 1) to afford the desired product as a yellow oil (300 mg, 29.9% yield). LCMS 54 (ESI) C17H21FN2O5 calcd 352. 14; Found [M+H]+: 353. 'H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.64 (m, 1H), 7.60 - 7.42(m, 2H), 6.15 (d, J = 4.8 Hz, 1H), 5.69 (s, 1H), 5.28 (s, 1H), 3.75 (d, J = 17.8 Hz, 1H), 3.60 (s, 1H), 3.30 (s, 2H), 2.12 - 1.95 (m, 2H), 1.35 (s, 9H).

[0217] tert-Butyl 3-(3-fluoro-2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-l-carboxylate. To a stirred solution of tert-butyl 3-[(3-fluoro-2-nitrophenyl)(hydroxy)methyl]-5,6-dihydro-277- pyridine-1 -carboxylate (290.0 mg, 0.82 mmol) in DCM (3 mL) was added MnCh (715.5 mg, 8.23 mmol). The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was filtered, and the residue was washed with CH2CI2(3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow oil (200 mg, 69.3% yield). LCMS 50 (Method B) (ESI) C17H19FN2O5calcd 350.13; Found [M+H]- : 351. 'H NMR (400 MHz, DMSO-d6) δ 7.92 - 7.72 (m, 2H), 7.51 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 4.11 (d, J = 2.3 Hz, 2H), 3.43 (d, J= 5.7 Hz, 2H), 2.33 (d, J= 2.7 Hz, 2H), 1.43 (s, 9H).

[0218] tert-Butyl 3-(7-fhioro-2, 1 -benzoxazol-3-yl)-5, 6-dihydro-2H-pyridine-l-carboxylate. To a stirred solution of tert-butyl 3-(3-fluoro-2-nitrobenzoyl)-5,6-dihydro-2H-pyridine-l- carboxylate (190.0 mg, 0.54 mmol) in MeOH (1 mL) and EtOAc (1 mL) was added SnC12.2H2O (370.3 mg, 1.62 mmol). The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction was quenched with sat. NaHCOi (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 5 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5: 1) to afford the desired product as a white solid (110 mg, 63.7% yield). LCMS 50 (Method B) (ESI) C17H19FN2O3 calcd 318.14; Found [M+H]+:319. 'H NMR (300 MHz, CDCI3) δ 7.47- 7.39 (m, 1H), 6.98 - 6.87 (m, 3H), 4.56 (s, 2H), 3.64 (d, J= 5.7 Hz, 2H), 2.49 (s, 2H), 1.51 (s, 9H).

[0219] 7-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-2,l-benzoxazole. HC1 (gas) in dioxane (1 mL) was added to a stirred solution of tert-butyl 3-(7-fluoro-2,l-benzoxazol-3-yl)-5,6-dihydro- 277-pyridine- l -carboxylate (100.0 mg, 0.31 mmol) in dioxane. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2COs (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10 % to 50 % gradient in 30 min; detector, UV 254 nm to afford the desired product as a white solid (30.4 mg, 44.1% yield). LCMS51 (Method L) (ESI) C12H11FN2O calcd 218.09; Found [M+H]+:219.15. ’H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J= 8.8 Hz, 1H), 7.25 (d, J= 7.3 Hz, 1H), 7.11 - 6.98 (m, 2H), 3.80 (s, 2H), 2.89 (d, J= 5.7 Hz, 2H), 2.33 (s, 2H).

[0220] Example 4: Synthesis of 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzofuran-7- carbonitrile (Compound 121)

[0221] l-(2,2-Diethoxyethoxy)-2-iodobenzene. To a stirred solution of 2-iodophenol (7.00 g, 31.81 mmol) and K2CO3(13.19 g, 95.45 mmol) in DMF (70 mL) was added 2-bromo-l,l- diethoxyethane (12.54 g, 63.63 mmol) at room temperature and stirred for 1 h at 100 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (100 mL). The organic extract was washed with water (3x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow oil (5.4 g, 50.4% yield). LCMS 49 (Method J) (ESI) C12H17IO3 calcd 336.02; Found [M+H]+: 337.

[0222] 7-Iodo-l-benzofuran. A solution of l-(2,2-diethoxyethoxy)-2-iodobenzene (5.40 g, 16.06 mmol) and PPA (3.70 g, 32.12 mmol) in toluene (50 mL) was stirred for 1 h at 100 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (500 mL). The organic extract was washed with water (3 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (3.5 g, 89.2% yield). LCMS 17 (Method B) (ESI) C8H5IO calcd 243.94; Found[M+H]+: 245.

[0223] 2,3-Dibromo-7-iodo-2,3-dihydro-l-benzofuran . A solution of 7-i odo-1 -benzofuran (1 .00 g, 4.09 mmol) and Br2 (0.65 g, 4.09 mmol) in CHCI3 (10 mL) was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was extracted with EtOAc (200 mL). The organic extract was washed with water (3 x 200 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (1 g, 60.4% yield).

[0224] 3-Bromo-7-iodo-l-benzofuran. A solution of 2,3-dibromo-7-iodo-2,3-dihydro-l- benzofuran (1.00 g, 2.47 mmol) and KOH (0.42 g, 7.42 mmol) in EtOH (10 mL) was stirred for 1 h at 80 °C under an N2 atmosphere and concentrated under vacuum. The resulting mixture was extracted with EtOAc (200 mL). The organic extract was washed with water (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a white solid (600 mg, 75.0% yield). *H NMR (300 MHz, CDCI3) δ 7.78 - 7.70 (m, 2H), 7.57 - 7.47 (m, 1H), 7. 14 - 7.04 (m, 1H).

[0225] 3-Bromo-l-benzofuran-7-carbonitrile. To a stirred solution of 3-bromo-7-iodo-l- benzofuran (400.0 mg, 1.23 mmol) and Zn(CN)2(174.5 mg, 1.48 mmol) in DMF (6 mL) was added Pd(PPli3)4 (143.1 mg, 0.12 mmol, 0.1 equiv) at room temperature under an N2 atmosphere. The resulting mixture was stirred for 1 h at 110 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (150 mL). The organic extract was washed with water (3 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to afford the desired product as a yellow oil (140 mg, 51 % yield). 'H NMR (300 MHz, CDCI3) δ 7.84 - 7.78 (m, 2H), 7.72 - 7.66 (m, 1H), 7.47 - 7.39 (m, 1H).

[0226] tert-Butyl 3-(7-cyano-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate.To a stirred solution of 3-bromo-l-benzofuran-7-carbonitrile (130.0 mg, 0.58 mmol), Pd(dppf)Ch (42.8 mg, 0.05 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro- 217-pyri dine- 1 -carboxylate (217.2 mg, 0.70 mmol) in 1,4-dioxane (2 mL) and H2O (1 mL) was added K2CO3(242.7 mg, 1.75 mmol) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (50 mL). The organic extract was washed with water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration,the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3 : 1 ) to afford the desired product as a yellow oil (65 mg, 34.2% yield). LCMS 52 (Method B) (ESI) C19H20N2O3calcd 324.15; Found [M+H]+: 325.

[0227] 3-(l,2,5,6-Tetrahy(lropyridin-3-yl)-l-benzofuran-7-carbonitrile. A solution of tertbutyl 3-(7-cyano-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (65.0 mg, 0.20 mmol) and HC1 (gas) in 1,4-dioxane (2 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 9 with saturated ISfeCCE (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 40% gradient in 20 min; UV 254 nm to afford the desired product as a yellow oil (18.7 mg, 41.6% yield). LCMS 46 (Method I) (ESI) C14H12N2O calcd 224.09; Found [M+H]+: 225.05.1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.18 (m, 3H), 7.86 - 7.75 (m, 1H), 7.51 - 7.36 (m, 1H), 6.55 - 6.40 (m, 1H), 3.72 - 3.69 (m, 2H), 3.09 - 2.97 (m, 2H), 2.40 - 2.29 (m, 2H).

[0228] Example 5: Synthesis of 4-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l- benzofuran-7-carbonitrile (Compound 122)

[0229] 4-Fluoro-l-benzofuran-7-carbonitrile. A solution of 7-bromo-4-fluoro-l-benzofuran (2.00 g, 9.30 mmol), zinc cyanide (1.09 g, 9.30 mmol) and Pd(PPh3)4(1.07 g, 0.93 mmol) in DMF (20.0 mL) was stirred overnight at 100 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water, driedover anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (1.00 g, 66.7 % yield). LCMS 52 (Method A) (ESI) C9H4FNO calcd 161.03; Found [M+H]+: 162. 'H NMR (400 MHz, CDCI3) δ 7.75 (d, J = 2.3 Hz, 1H), 7.64 -7.59 (m, 1H), 7.04 (d, J= 8.6 Hz, 1H), 6.99 - 6.95 (m, 1H).

[0230] 2,3-Dibromo-4-fluoro-2,3-dihydro-l-benzofuran-7-carbonitrile. To a stirred solution of 4-fhioro-l-benzofuran-7-carbonitrile (1.00 g, 6.21 mmol) in CH2CI2 (10.0 mL) was added Br2 (0.1 mb, 18.62 mmol) dropwise at 0 °C under an N2 atmosphere. The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The reaction was quenched with Na2S2Ch(aq). The aqueous layer was extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow solid (700.0 mg, 35.1% yield). ’H NMR (400 MHz, CDCI3) δ 7.68 - 7.63 (m, 1H), 7.00 - 6.89 (m, 2H), 5.79 - 5.75(m, 1H).

[0231] 3-Bromo-4-fluoro-l-benzofuran-7-carbonitrile. A solution of 2,3-dibromo-4-fluoro- 2,3-dihydro-l-benzofuran-7-carbonitrile (700.0 mg, 2.18 mmol) in DCM (10.0 mL) was treated with DBU (498.1 mg, 3.27 mmol), The resulting mixture was stirred for 2 h at 50 °C under an N2 atmosphere. The aqueous layer was extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (6: 1) to afford the desired product as a yellow solid (300.0 mg, 57.3% yield). ’H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.10 - 7.99 (m, 1H), 7.46 - 7.38 (m, 1H).

[0232] 3-(7-Cyano-4-fluoro-l-benzofuran-3-yl)-5, 6-dihydro-2H-pyridine-l-carboxylate. A solution of 3-bromo-4-fluoro-l-benzofuran-7-carbonitrile (300.0 mg, 1.25 mmol), Pd(dppf)C12 (45.7 mg, 0.06 mmol), K2CO3(518.2 mg, 3.75 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydro-tertpyridine-l -carboxylate (579.7 mg, 1.88 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1)to afford the desired product as a yellow solid (400.0 mg, 46.7% yield). LCMS 52 (Method A) (ESI) C19H19FN2O3 calcd 342. 14; Found [M+H]+: 343. 'H NMR (400 MHz, DMSO-d6) 8.43 ( δs, 1H), 8.10 - 7.99 (m, 1H), 7.46 - 7.38 (m, 1H), 6.40 - 6.34 (s, 1H), 4.24 (d, J = 3.2 Hz, 2H), 3.55 (d, J= 5.8 Hz, 2H), 2.34 (d, J= 2.8 Hz, 2H), 1.49 (s, 9H).

[0233] 4-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l-benzofuran-7-carbonitrile. A solution of tert-butyl 3-(7-cyano-4-fluoro-l-benzofuran-3-yl)-5,6-dihydro-277-pyridine-l -carboxylate (100.0 mg, 0.29 mmol) in dioxane (0.5 mL) and HC1 (gas) in 1,4-dioxane (0.5 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 30 min; detector, UV 254 nm to afford the desired product as a white solid (63.3 mg, 89.5% yield). LCMS 51 (Method L) (ESI) C14H11FN2O calcd 242.09; Found [M+H]+: 242.95. 'H NMR (400 MHz, DMSO-t76) δ 8.34 (d, J= 1.9 Hz, 2H), 8.02 - 7.95 (m, 1H), 7.40 - 7.32 (m, 1H), 6.34 - 6.29 (m, 1H), 3.68 - 3.59 (m, 2H), 3.00 - 2.92 (m, 2H), 2.31 - 2.23 (m, 2H).

[0234] Example 6: Synthesis of 3-(6,7-difluoro-l-benzofuran-3-yl)-l, 2,5,6- tetrahydropyridine (Compound 126)

[0235] 2,3-Difluorophenyl acetate. To a stirred solution of 2,3 -difluorophenol (4 g, 30.75 mmol) and TEA (9.33 g, 92.24 mmol) in DCM (20 mL) was added acetyl chloride (2.90 g, 36.90 mmol) dropwise at 0 °C. The resulting mixture was stirred for 30 min at room temperature and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10 / 1) to afford the desired product as an off-white liquid (3.4 g, 64.2% yield).

[0236] l-(3,4-Difluoro-2-hydroxyphenyl)ethanone. To a stirred solution of 2,3- di fluorophenyl acetate (3.4 g, 19.75 mmol) in DCE (20 mL) was added AICI3 (3.95 g, 29.63 mmol) in portions at room temperature and the resulting mixture was stirred overnight at 90 °C under an N2 atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5 / 1) to afford the desired product as a yellow solid (2.3 g, 67.6% yield).JH NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 7.54 (m, 1H), 6.87 (m, 1H), 2.50 (d, J= 1.8 Hz, 3H).

[0237] 2-Chloro-l-(3,4-difluoro-2-hydroxyphenyl)ethanone. To a stirred solution of l-(3,4- difluoro-2-hydroxyphenyl)ethanone (1 g, 5.81 mmol) in DCE (7 mL) and MeOH (3 mL) was added BnMesNCLI (4.04 g, 11.62 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 65 °C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a yellow solid (1.1 g, 91.6% yield).XH NMR (400 MHz, DMSO-d6) 11.7 δ7 (s, 1H), 7.67 (m, 1H), 7.04 (td, J= 9.5, 6.9 Hz, 1H), 5.10 (s, 2H).

[0238] 6, 7-Difluoro-2H-l-benzofuran-3-one. To a stirred solution of 2-chl oro-1 -(3,4- difluoro-2-hydroxyphenyl)ethanone (1.1 g, 5.33 mmol) in MeOH (15 mL) was added AcONa (0.87 g, 10.65 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 65 °C and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a yellow solid (374 mg, 41.2% yield). ’H NMR (400 MHz, DMSO-d6) 7 δ.55 (m, 1H), 7.30 - 7.19 (m, 1H), 4.98 (s, 2H).

[0239] 6, 7-Difluoro-l-benzofuran-3-yl trifluoromethanesulfonate. To a stirred solution of 6,7-difluoro-2Z / -l-benzofuran-3-one (370 mg, 2.18 mmol) and DIEA (843.3 mg, 6.53 mmol) in DCM (15 mL) was added TfzO (920.5 mg, 3.26 mmol) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desired product as a yellow solid (310 mg, 47.1% yield). 'H NMR (300 MHz, DMSO- d&) δ 8.89 (s, 1H), 7.57 (d, J= 4.6 Hz, 1H), 7.56 - 7.52 (m, 1H).

[0240] tert-Butyl 3-(6, 7-difluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of 6,7-difluoro-l-benzofuran-3-yl trifluoromethanesulfonate (310 mg, 1.03 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / 7- pyridine-1 -carboxylate (475.8 mg, 1.54 mmol) in dioxane (2 mL) and H2O (10 mL) were added Pd(dppf)Ch (150.1 mg, 0.21 mmol) and K2CO3(425.4 mg, 3.08 mmol) at room temperature. The resulting mixture was stirred for 30 min at 80 °C under an N2 atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a light-yellow oil (312 mg, 90.6% yield). LCMS 60 (ESI) C18H19F2NO3 calcd 335.13; Found [M+H]+: 336.

[0241] 3-(6, 7-Difluoro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3 -(6, 7-difluoro-l-benzofuran-3-yl)-5,6-dihydro-2 / 7-pyri dine- 1 -carboxylate (150 mg, 0.45 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (2 mL) and stirred for 20 min at room temperature. The resulting mixture was concentrated under vacuum and basified to pH 8 with saturated Na2CO3(aq.). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 26% B in 2 min, 26% to 44% B in 10 min) to afford the desired product as a white solid, 28.6 mg, 27.1% yield. LCMS 40 (ESI) C13H11F2NO calcd 235.08; Found [M+H]+: 236. 'H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.69 (m, 1H), 7.37 (m, 1H), 6.43 (d, J = 5.2 Hz, 1H), 3.50 (s, 2H), 2.85 (s, 2H), 2.21 (s, 2H).

[0242] Example 7: Synthesis of 3-(5,7-Difluoro-l-benzofuran-3-yl)-l, 2,5,6- tetrahydropyridine (Compound 127)

[0243] 3,5-Difluoro-2-[(triniethylsilyl)methoxy]benz(ddehyde. To a solution of 3,5-difluoro- 2-hydroxybenzaldehyde (1.50 g, 9.48 mmol), (chloromethyl) trimethylsilane (1.28 g, 10.43 mmol), Nal (1.56 g, 10.43 mmol) and K2CO3(3.93 g, 28.46 mmol) in DMF (20 mL) was stirred for 1 h at 60 °C under an N2 atmosphere. The resulting mixture was diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a white solid (1.00 g, 43.1% yield).

[0244] 5, 7-Difluoro-2,3-dihydro-l-benzofuran-3-ol. A solution of 3,5-difluoro-2- [(trimethylsilyl)methoxy]benzaldehyde (1.00 g, 4.09 mmol) and CsF (5.60 g, 36.83 mmol, 9.0 equiv) in DMF (20 mL) was stirred overnight at 110 °C under an N2 atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desired product as a colorless oil (600.0 mg, 85.1% yield). 'H NMR (400 MHz, CDCI3) 6. δ98 - 6.91 (m, 1H), 6.88 - 6.78 (m, 1H), 5.54 - 5.32 (m, 1H), 4.72 - 4.60 (m, 1H), 4.59 - 4.49 (m, 1H).

[0245] 5, 7-Difluoro-2H-l-benzofuran-3-one. To a solution of 5,7-difluoro-2,3-dihydro-l- benzofuran-3-ol (800.0 mg, 4.64 mmol) in DCM (20 mL) was added the Dess-Martin reagent (1971.2 mg, 4.64 mmol) in portions at 0 °C and stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid(300.0 mg, 37.9% yield).JH NMR (400 MHz, DMSO-d6) 3 7.87 - 7.78 (m, 1H), 7.42 - 7.37 (m, 1H), 4.96 (s, 2H).

[0246] 5, 7-Difluoro-l-benzofuran-3-yl trifluoromethanesulfonate. To a stirred solution of 5,7-difluoro-2£f-l-benzofuran-3-one (300.0 mg, 1.76 mmol, 1.0 equiv) in DCM (5 mL) was added DIEA (682.38 mg, 5.28 mmol) and TfzO (746.3 mg, 2.64 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature, and diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 5: 1) to afford the desired product as a light-yellow oil (200.0 mg crude, 37.5% yield).

[0247] tert-Butyl 3-(5, 7-difluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a solution of 5,7-difluoro-l-benzofuran-3-yl trifluoromethanesulfonate (210.0 mg, 0.69 mmol, 1.0 equiv), and K2CO3(288.1 mg, 2.08 mmol, 3.0 equiv) in dioxane (3 mL) and H2O (0.6 mL) were added tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro- 2 / / -pyridine- l -carboxylate (322.3 mg, 1.04 mmol, 1.5 equiv), and Pd(dppf)C12 (101.7 mg, 0.13 mmol, 0.2 equiv). It was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (200.0 mg, 85.8% yield). LCMS 54 (ESI) C18H19F2NO3 calcd 335.13; Found [M+H]+: 336. ’H NMR (400 MHz, DMSO-d6) 3 8.32 (s, 1H), 7.67 - 7.52 (m, 1H), 7.45 - 7.31 (m, 1H), 6.55- 6.38 (m, 1H), 4.28 - 4.11 (m, 2H), 3.61 - 3.46 (m, 2H), 2.36 - 2.24 (m, 2H), 1.44 (s, 9H).

[0248] 3-(5, 7-Difluoro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(5,7-difluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (100.0 mg, 0.29 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (3 mL) in portions at room temperature. The mixture was basified to pH 8 with Na2COs (aq ). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 50% gradient in 25 min; UV 254 nm to afford the desired product as a white solid (35.6 mg, 50.4% yield). LCMS 51 (Method M) (ESI) C13H11F2NO calcd 235.08; [M+H]+: 236.10.rH NMR (400 MHz, CD3OD) 7 δ.89 (s, 1H), 7.56 - 7. 19 (m, 1H), 7.12- 6.71 (m, 1H), 6.48 - 6.25 (m, 1H), 3.72 - 3.49 (m, 2H), 3.07 - 2.83 (m, 2H), 2.42 - 2.24 (m, 2H).

[0249] Example 8: Synthesis of 3-(4,7-difluoro-l-benzofuran-3-yl)-l, 2,5,6- tetrahydropyridine (Compound 128)

[0250] 4, 7-Difluoro-2,3-dihydro-l-benzofuran-3-ol. To a solution of trimethylsulfoxonium iodide (5.35 g, 24.35 mmol) in DMSO (30 mL) was added NaO / Bu (2.34 g, 24.35 mmol) and the resulting mixture was stirred for 0.5 h at 0 °C. To the reaction was added 3,6-difluoro-2- hydroxybenzaldehyde (3.50 g, 22.13 mmol) and it was stirred for an additional 2 h at room temperature. The resulting mixture was fdtered, the residue was washed with ethyl acetate (2 x 100 mL). The fdtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow solid, (1.50 g, 39.3% yield).

[0251] 4, 7-Difluoro-2H-l-benzofuran-3-one. To a solution of 4,7-difluoro-2,3-dihydro-l- benzofuran-3-ol (700.0 mg, 4.06 mmol) in dichloromethane (8 mL) was added Dess-Martin reagent (1.72 g, 40.67 mmol) and stirred for 0.5 h at room temperature. The resulting mixture was filtered, the residue was washed with ethyl acetate (2 x 100 ml). The filtrate was concentrated under reduced pressure to afford the desired crude product as a dark yellow oil (250.0 mg, 36.1% yield). The crude product was used in the next step directly without further purification.

[0252] 4, 7-Difluoro-l-benzofuran-3-yl trifluoromethanesulfonate. To a solution of 4,7- difluoro-2 / f-l-benzofuran-3-one (230.0 mg, 1.35 mmol) in dichloromethane (3 mL) was added DIEA (524.2 mg, 4.05 mmol) at room temperature. To the mixture was added TfzO (572.1 mg, 2.02 mmol, 1.5 equiv) dropwise at 0 °C for 1 h. The resulting mixture was filtered, the residue was washed with ethyl acetate (5 x 10 mL). The filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography (SiO2) eluting with 100% PE to afford the desired product as a yellow solid (200.0 mg, 48.9% yield).

[0253] tert-Butyl 3-(4-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate. To a solution of 4,7-difluoro-l-benzofuran-3-yl trifluoromethanesulfonate (350.0 mg, 1.15 mmol) and K2CO3(320.1 mg, 2.31 mmol) in dioxane (4 mL) and H2O (1 mL) were added Pd(dppf)Ch (169.5 mg, 0.23 mmol) and / c77-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydro-2H-pyridine-l -carboxylate (429.7 mg, 1.39 mmol). After stirring for 2 h at 90 °C under an N2 atmosphere the reaction was quenched with ice at room temperature. The resulting mixture was filtered, the residue was washed with ethyl acetate (5 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desired product as a yellow solid (150.0 mg, 38.6 yield). LCMS 49 (Method J) (ESI) C18H19F2NO3 calcd: 335.13 Found [M+H]+:336.

[0254] 3-(4, 7-difluoro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. To a stirred solution of / cvZ-butyl 3-(4,7-difluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (150.0 mg, 0.44 mmol) in dioxane (1 mL) was added HC1 (gas) in dioxane (1 mL). After stirring for 2 h at room temperature the mixture was basified to pH 8 with saturated Na2CO3(aq.). The resulting mixture was concentrated under reduced pressure. The crude product (70.0 mg) was purified by Prep-HPLC with the following conditions, Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 42% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.18 to afford the desired product as a white solid (51.8 mg, 49.2% yield). LCMS 51 (Method M) (ESI) C13H11F2NO calcd 235.08; Found [M+Hp^O.lO.’H NMR (400 MHz, DMSO-t76) 8.1 δ4 (s, 1H), 7.33 - 7.26 (m, J= 9.5, 3.6 Hz, 1H), 7.14 - 7.07 (m, J = 10.4, 8.9, 3.3 Hz, 1H), 6.28 - 6.23 (m, J = 4.2, 2.1 Hz, 1H), 3.49 (d, J = 3.0 Hz, 2H), 2.83 (t, J = 5.6 Hz, 2H), 2.2 - 2.12 (m, J = 5.7, 2.6 Hz, 2H).

[0255] Example 9: Synthesis of 3-(7-Chloro-5-fluoro-l-benzofuran-3-yl)-l, 2,5,6- tetrahydropyridine (Compound 130)

[0256] 7-Chloro-5-fluoro-2,3-dihydro-l-benzofuran-3-ol. A solution of Me?SOI (2.77 g, 12.60 mmol) in DMSO (20.0 mL) was treated with Z-BuONa (1.21 g, 12.60 mmol) for 30 min at 0 °C under an N2 atmosphere followed by the addition of 3-chloro-5-fluoro-2- hydroxybenzaldehyde (2.00 g, 11.46 mmol) at room temperature under an N2 atmosphere and it was stirred for an additional 2 h. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid, 1 .20 g, 55.5% yield.(400 MHz, DMSO-t / fi) 7 δ.35 - 7.26 (m, 1H), 7.23 - 7.17 (m, 1H), 5.86 (d, J = 5.9 Hz, 1H), 5.38 - 5.28 (m, 1H), 4.68 - 4.59 (m, 1H), 4.38 - 4.30 (m, 1H).

[0257] 7-chloro-5-fluoro-2H-l-benzofuran-3-one. To a stirred solution of 7-chloro-5- fluoro-2, 3 -dihydro- l-benzofuran-3-ol (500.0 mg, 2.65 mmol) in DCM (5.0 mL) was added the Dess-Martin reagent (1124.6 mg, 2.65 mmol) in portions at 0 °C and stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (300.0 mg, 60.7% yield).

[0258] 7-Chloro-5-fluoro-l-benzofuran-3-yl trifluoromethanesulfonate. A solution of 7- chloro-5-fluoro-2H-l-benzofuran-3-one (300.0 mg, 1.61 mmol) in DCM (3.0 mL) was treated with DIEA (623.5 mg, 4.83 mmol) followed by the addition of TfzO (680.5 mg, 2.41 mmol) dropwise at 0 °C. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were concentrated under reducedpressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (8: 1) to afford the desired product as a yellow solid, (200.0 mg, 39.0% yield).

[0259] tert-Butyl 3-(7-chloro-5-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 7-chloro-5-fluoro-l-benzofuran-3-yl trifluoromethanesulfonate (200.0 mg, 0.63 mmol), Pd(dppf)C12 (25.8 mg, 0.03 mmol), K2CO3(260.3 mg, 1.88 mmol) and / f / 7-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (291.1 mg, 0.94 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desired product as a yellow solid (100.0 mg, 45.3% yield). 'H NMR (400 MHz, DMSCM,) δ 8.34 (s, 1H), 7.78 - 7.73 (m, 1H), 7.57 - 7.49 (m, 1H), 6.51 (d, J = 20.0 Hz, 1H), 4.20 - 4.15 (m, 1H), 3.85 - 3.80 (m, 1H), 3.53 - 3.47 (m, 1H), 3.39 - 3.34 (m, 1H), 2.35 - 2.28 (m, 1H), 2.16 - 2.09 (m, 1H), 1.42 (d, J = 15.7 Hz, 9H).

[0260] 3-(7-Chloro-5-fluoro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(7-chloro-5-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate (100.0 mg, 0.28 mmol) in dioxane (0.5 mL) was added HCl(gas) (0.5 mL, 4 M in 1,4- dioxane) at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL) and basified to pH 9 with saturated Na2CC>3 (aq ). The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 30% B to 50% B in 30 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.19) to afford the desired product as a yellow solid (27.8 mg, 38.9%) yield. LCMS 48 (Method H) (ESI) C13H11CIFNO calcd 251.05; Found [M+H]+:252.10.rH NMR (400 MHz, DMSO-c / 6) 8.2 δ2 (s, 1H), 7.76 - 7.69 (m, 1H), 7.53 - 7.46 (m, 1H), 6.40 (d, J = 4.4 Hz, 1H), 3.52 - 3.46 (m, 2H), 2.88 - 2.79 (m, 2H), 2.23 - 2.15 (m, 2H).

[0261] Example 10: Synthesis of 3-(7-Chloro-4-fluoro-l-benzofuran-3-yl)-l,2,5,6- tetrahydropyridine (Compound 131)

[0262] l-Chloro-2-(2,2-diethoxyethoxy)-4-fluorobenzene. To a stirred mixture of 2-chloro- 5 -fluorophenol (1.00 g, 6.82 mmol) in DMF (10 mL) was added [bromo(ethoxy)methoxy] ethane (1.87 g, 10.23 mmol) and CS2CO3(6.69 g, 20.47 mmol) and stirred for 1 h at 100 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white liquid (1.50 g, 83.6% yield). ’H NMR (400 MHz, CDCI3) 5 7.32 - 7.27 (m, 1H), 6.74 - 6.66 (m, 1H), 6.66 - 6.58 (m, 1H), 4.87 (d, J= 5.2 Hz, 1H), 4.03 (d, J= 5.2 Hz, 2H), 3.85 - 3.76 (m, 2H), 3.72 - 3.65 (m, 2H), 1.28 - 1.24 (m, 6H).

[0263] 7-Chloro-4-fluoro-l-benzofuran. To a stirred mixture of l-chloro-2-(2,2- diethoxyethoxy)-4-fluorobenzene (1.50 g, 5.71 mmol) in toluene (50 mL) was added PPA (1.68 g, 17.13 mmol) and stirred overnight at 110 °C under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (5 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (12:1) to afford the desired product as a white solid (150.0 mg, 15.4% yield).XH NMR (400 MHz, DMSO-d6) δ 8.20 (d, .7= 2.2 Hz, 1H), 7.51 - 7.42 (m, 1H), 7.21 (d, .7= 2.3 Hz, 1H), 7. 17 (d, J= 9.0 Hz, 1H).

[0264] 2,3-Dibromo- 7-chloro-4-fluoro-2,3-dihydro-l-benzqfuran. To a stirred mixture of 7- chloro-4-fluoro-l -benzofuran (150.0 mg, 0.87 mmol) in DCM (5 mL) was added Br2 (168.6 mg,1.05 mmol) dropwise and stirred overnight at room temperature under an N2 atmosphere. The reaction was quenched with sat. Na2S20s (aq.) and the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow oil (220.0 mg, 75.7% yield).NMR (400 MHz, CD3OD) 7 δ.52 - 7.45 (m, 1H), 7.29 (s, 1H), 6.95 (d, J= 8.6 Hz, 1H), 6.13 (s, 1H).

[0265] 3-Bromo-7-chloro-4-fluoro-l-benzofuran. To a stirred mixture of 2,3-dibromo-7- chloro-4-fhioro-2,3 -dihydro- 1 -benzofuran (220.0 mg, 0.66 mmol) in DCM (5 mL) was added DBU (304.1 mg, 1.99 mmol). The resulting mixture was stirred for 2 h at 50 °C under an N2 atmosphere. The residue was purified by chromatography (SiO2) eluting with PE / EA (12:1) to afford the desired product as a white solid (140.0 mg, 84.2% yield). 'HNMR (400 MHz, DMSO- d6) δ 8.46 (d, J= 1.7 Hz, 1H), 7.67 - 7.44 (m, 1H), 7.34 - 7.09 (m, 1H).

[0266] tert-Butyl 3-(7-chloro-4-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a stirred mixture of 3-bromo-7-chloro-4-fluoro-l-benzofuran (140.0 mg, 0.56 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / 7-pyridine-l- carboxylate (260.3 mg, 0.84 mmol) in dioxane (4 mL) and H2O (2 mL) was added K2CO3(232.7 mg, 1.68 mmol) and Pd(dppf)C12 (41.0 mg, 0.05 mmol). The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (12: 1) to afford the desired product as a white solid (100.0 mg, 50.6% yield). LCMS 54 (ESI) C18H19CIFNO3 calcd 351.10; Found [M+H]+:352. 'H NMR (400 MHz, DMSO-cL) δ 8.27 (s, 1H), 7.56 - 7.48 (m, 1H), 7.25 - 7.13 (m, 1H), 6.29 (s, 1H), 4.18 (d, J= 3.1 Hz, 2H), 3.49 (d, J= 5.7 Hz, 2H), 2.27 (d, J= 5.5 Hz, 2H), 1.44 (s, 9H).

[0267] 3-(7-Chloro-4-fluoro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. tert-Butyl 3- (7-chloro-4-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2ff-pyridine-l-carboxylate (100.0 mg, 0.28 mmol) in HC1 (gas) in 1,4-dioxane (1 mL, 4 M) and dioxane (1 mL) was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum and basified to pH 9 with saturated Na2CO3(aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 0% to 60% gradient in 30 min; UV 254 nm to afford the desiredproduct as a white solid (31.1 mg, 42.9% yield). LCMS 40 (ESI) C13H11CIFNO calcd 251.05; Found [M+H]+:252.05. 'H NMR (400 MHz, DMSO-d6) 8 δ.18 (s, 1H), 7.60 - 7.46 (m, 1H), 7.24- 7.07 (m, 1H), 6.26 (s, 1H), 3.51 (s, 2H), 2.85 (d, J= 5.7 Hz, 2H), 2.27 - 2.15 (m, 2H).

[0268] Example 11: Synthesis of 3-(7-chloro-4,6-difluoro-l-benzofuran-3-yl)-l,2,5,6- tetrahydropyridine (Compound 134)

[0269] 2-Chloro-3,5-difluorophenol. To a stirred solution of 3, 5 -difluorophenol (5.00 g, 38.43 mmol) in TFA (250 mL) and ACN (50 mL) was added NCS (5.13 g, 38.43 mmol) and stirred for 3 days at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desired product as a yellow oil (2.00 g, 31.6% yield).

[0270] 2-Chloro-l-(2,2-diethoxyethoxy)-3,5-difluorobenzene. To a stirred solution of 2- chloro-3,5-difluorophenol (1.70 g, 10.33 mmol) and 2-bromo- 1,1 -di ethoxy ethane (3.05 g, 15.49 mmol) in DMF (20 mL) were added CS2CO3(10.10 g, 30.99 mmol) and stirred overnight at 120 °C under an N2 atmosphere. The resulting mixture was quenched with 10 mL of water and extracted with EtOAc (3 x 10 mL). The combined organic extracts was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a colorless oil (1.80 g, 62.0% yield).

[0271] 7-Chloro-4,6-difluoro-l-benzofuran. To a stirred solution of 2-chl oro-1 -(2,2- diethoxyethoxy)-3,5-difluorobenzene (2.00 g, 7.12 mmol) in toluene (30 mL) was added PPA (2.46 g, 21.37 mmol) and stirred overnight at 110 °C under an N2 atmosphere. The resultingmixture was concentrated under vacuum. The resulting mixture was diluted with 30 mL of water and extracted with EtOAc (3 x 30 mL). The combined organic extracts was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE to afford the desired product as a white solid (450.0 mg, 33.4% yield).1H NMR (300 MHz, DMSO-d6) δ 8.23 (d, J= 2.3 Hz, 1H), 7.49 (dd, J = 10.4, 9.6 Hz, 1H), 7.23 (d, J= 2.2 Hz, 1H).

[0272] 2,3-Dibromo-7-chloro-4,6-difluoro-2,3-dihydro-l-benzofuran. To a stirred solution of 7-chloro-4,6-difluoro-l -benzofuran (430.0 mg, 2.28 mmol) inDCM (5 mL) was added Br2 (0.21 mL, 4.19 mmol, 1.8 equiv). The resulting mixture was stirred for overnight at room temperature under an N2 atmosphere. The resulting mixture was diluted with 50 mL of CH2CI2 and washed with Na2CO3 (aq.) (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow oil (600.0 mg, 75.5% yield).XH NMR (400 MHz, DMSO-d6) 8. δ14 (d, J= 2.1 Hz, 1H), 7.46 - 7.33 (m, 1H), 7.14 (d, J = 2.1 Hz, 1H).

[0273] 3-Bromo-7-chloro-4,6-difluoro-l-benzofuran. To a stirred solution of 2,3-dibromo- 7-chloro-4,6-difluoro-2,3-dihydro-l-benzofuran (400.0 mg, 1.14 mmol) in DCM (5 mL) was added DBU (524.4 mg, 3.44 mmol) and stirred for 1 h at 50 °C under an N2 atmosphere. After concentration, the residue was purified by chromatography (SiO2) eluting with PE to afford the desired product as a white solid (250.0 mg, 81.4% yield). 'H NMR (400 MHz, CDCI3) 7 δ.67 (s, 1H), 6.96 - 6.85 (m, 1H).

[0274] tert-Butyl 3-(7-chloro-4,6-difluoro-l-benzqfuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A mixture of 3-bromo-7-chloro-4,6-difluoro-l-benzofuran (130.0 mg, 0.48 mmol), zc / 7-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2J / -pyridine-l- carboxylate (225.4 mg, 0.72 mmol), K2CO3(201.5 mg, 1.45 mmol) and Pd(dppf)Ch (17.7 mg, 0.02 mmol) in dioxane (2 mL) and H2O (1 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid, (100.0 mg, 55.6% yield). LCMS 60 (ESI) C18H18CIF2NO3 calcd 369.09; Found [M + H]+:370. ^ NMR (400 MHz, CDCI3) 7.61 δ(s, 1H), 6.92 - 6.84 (m, 1H), 6.29 (s, 1H), 4.23 - 4.17 (m, 2H), 3.63 - 3.50 (m, 2H), 2.36 - 2.29 (m, 2H), 1.50 (s, 9H).

[0275] 3-(7-Chloro-4,6-difluoro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(7-chloro-4,6-difluoro-l-benzofuran-3-yl)-5,6-dihydro-2 / 7- pyridine-1 -carboxylate (100 mg, 0.27 mmol) in dioxane (2 mL) was added HC1 (gas) in 1,4- di oxane (2 mL, 4 M) and stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 8 with saturated Na2CC>3 (aq.). The mixture was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3), MobilePhase B: ACN; Flow rate: 60 mL / min; Gradient: 60% B to 87% B in 7 min; Wave Length: 254nm / 220nm; RTl(min): 6.8) to afford the desired product as a white solid (13.9 mg, 19.0% yield). LCMS 63 (ESI) C13H10CIF2NO calcd 269.04; Found [M + H]+:269.95.1HNMR (300 MHz, CD3OD) δ 7.88 (s, 1H), 7.18 - 7.01 (m, 1H), 6.30 (s, 1H), 3.68 - 3.52 (m, 2H), 3.08 - 2.93 (m, 2H), 2.43 - 2.23 (m, 2H).

[0276] Example 12: Synthesis of 3-(4,7-dichloro-5-fluoro-l-benzofuran-3-yl)-l,2,5,6- tetrahydropyridine (Compound 135)

[0277] 2,5-Dichloro-4-fIuorophenol. To a stirred mixture of 3-chloro-4-fluorophenol (6.00 g, 41.09 mmol, 1.0 equiv) and NCS (5.48 g, 41.09 mmol,) in ACN (60 mL) was added TFA (300 mL) at room temperature under an N2 atmosphere. The reaction was stirred for 2 hours. The resulting mixture was concentrated under vacuum to afford the desired crude product as a yellowoil (3.00 g, 67.6% yield). LCMS 50 (Method B) (ESI) C6H3CI2FO calcd 179.95; Found [M+H]+: 181.

[0278] l,4-Dichloro-2-(2,2-diethoxyethoxy)-5-fluorobenzene. To a stirred mixture of 2,5- dichloro-4-fluorophenol (3.00 g, 11.05 mmol) and 2 -bromo- 1,1 -di ethoxy ethane (3.27 g, 16.57 mmol) in DMF (50 mL) was added CS2CO3(10.80 g, 33.15 mmol) and stirred overnight at 120 °C under an N2 atmosphere. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (12: 1) to afford the desired product as a white liquid (3.00 g, 60.7% yield). LCMS 51 (Method L) (ESI) C12H15CI2FO3 calcd 296.04; Found [M+H]+:297. 'H NMR (400 MHz, CDCI3) δ 7.19 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 6.6 Hz, 1H), 4.84 (d, J= 5.2 Hz, 1H), 4.01 (d, J= 5.2 Hz, 2H), 3.86 - 3.73 (m, 2H), 3.71 - 3.62 (m, 2H), 1.25 (d, 7.1Hz, 6H).

[0279] 4, 7-Dichloro-5-fluoro-l-benzofuran. 1,4-di chi oro-2 -(2, 2-di ethoxy ethoxy)-5- fluorobenzene (3.00 g, 10.13 mmol) and PPA (1.16 g, 10.13 mmol) in toluene (30 mL) was stirred for 1 h at 110 °C under an N2 atmosphere and concentrated under vacuum. The residue was diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (12: 1) to afford the desired product as a white solid (600.0 mg, 29.1% yield). 'H NMR (400 MHz, CDCI3) 7. δ75 (d, .7= 2,2 Hz, 1H), 7.18 (d, .7= 9.1 Hz, 1H), 6.93 (d, .7= 2.1 Hz, 1H).

[0280] 2,3-Dibromo-4, 7-dichloro-5-fluoro-2,3-dihydro-l-benzofuran. To a stirred solution of 4,7-dichloro-5-fluoro-l -benzofuran (600.0 mg, 2.92 mmol) in DCM (10 mL) was added Br2 (0.18 mL, 3.51 mmol) dropwise at 0 °C and stirred overnight at room temperature under an N2 atmosphere. The reaction was quenched with sat. Na2SC>3 (aq.) and extracted with CH2CI2 (3 x 15 mL). The combined organic extracts were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow oil (750.0 mg, 70.2% yield).JH NMR (400 MHz, CDCI3) 7 δ.24 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 5.71 (s, 1H).

[0281] 3-bromo-4, 7-dichloro-5-fluoro-l-benzofuran. To a stirred solution of 2,3-dibromo- 4,7-dichloro-5-fluoro-2,3-dihydro-l-benzofuran (750.0 mg, 2.07 mmol) in DCM (10 mL) wasadded DBU (946.7 mg, 6.21 mmol) and stirred for 1 h at 50 °C under an N2 atmosphere. The mixture was purified by chromatography (SiO2) eluting with PE / EA (12:1) to afford the desired product as a white solid (530.0 mg, 90.5% yield). 'H NMR (400 MHz, DMSO-d6) 8 δ.64 - 8.43 (m, 1H), 7.93 - 7.69 (m, 1H).

[0282] tert-Butyl 3-(4, 7-dichloro-5-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A mixture of 3-bromo-4,7-dichloro-5-fluoro-l-benzofuran (300.0 mg, 1.05 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2J7-pyridine-l- carboxylate (490.1 mg, 1.58 mmol), K2CO3(438.1 mg, 3.15 mmol) and Pd(dppf)C12 (77.3 mg, 0.10 mmol) in dioxane (4 mL) and H2O (2 mL) was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over anhydrous ISfeSCE, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (9: 1) to afford the desired product as a white solid (250.0 mg, 61.2% yield). LCMS 49 (Method K) (ESI) C1sHisChFNCh calcd 385.06; Found[M+H]+: 386. ’H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.78 (d, J= 9.6 Hz, 1H), 6.04 - 5.92 (m, 1H), 4.12 (s, 2H), 3.51 (d, J = 5.7 Hz, 2H), 2.31 - 2.14 (m, 2H), 1.42 (s, 9H).

[0283] 3-(4, 7-Dichloro-5-fluoro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(4,7-dichloro-5-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2F / - pyridine-1 -carboxylate (150.0 mg, 0.38 mmol) in dioxane (1 mL) was added HC1 (gas)(l mL, 4 M in 1,4-di oxane) under an N2 atmosphere and stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL) and then it was basified to pH 9 with saturated Na2COs (aq.). The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 70% gradient in 30 min; UV 254 nm to afford the desired product as a white solid (59.1 mg, 52.8% yield). LCMS 48 (Method H) (ESI) C13H10CI2FNO calcd 285.01; Found [M+H]+:286.rH NMR (300 MHz, DMSO-d6) 8 δ.17 (d, J = 1.8 Hz, 1H), 7.81 - 7.64 (m, 1H), 5.92 (d, J= 4.7 Hz, 1H), 3.43 (s, 2H), 2.97 - 2.81 (m, 2H), 2.22 - 2.06 (m, 2H).

[0284] Example 13: Synthesis of 4-ethoxy-3-(l,2,5,6-tetrahydropyridin-3-yl)-l- benzofuran-7-carbonitrile (Compound 140)

[0285] 4-Fluoro-l-benzofuran-7-carbonitrile To a stirred solution of 7-bromo-4-fluoro-l- benzofuran (4.00 g, 18.60 mmol) and zinc cyanide (2.18 g, 18.60 mmol) in DMA (40 mL) was added Pd(PPhs)4 (2.15 g, 1.86 mmol). The resulting mixture was stirred overnight at 100 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (2.00 g, 66.7% yield). LCMS 52 (Method B) (ESI) C9H4FNO calcd 161.03; Found [M+H]+: 162. *H NMR (400 MHz, DMSO-d6) 8 δ.30 (d, J= 2.0 Hz, 1H), 7.96 (d, J= 8.2, 5.0, 2.5 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.30 (d, J= 2.4 Hz, 1H).

[0286] 2,3-Dibromo-4-fluoro-2,3-dihydro-l-benzofuran-7-carbonitrile. Br2 (0.95 mL, 18.61 mmol) was added to a stirred solution of 4-fluoro-l-benzofuran-7-carbonitrile (2.50 g, 15.51 mmol) in DCM (25 mL). The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The reaction was quenched with sat. Na2SOa(aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (3 x 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 50% gradient in 20 min; UV 254 nm to afford the desired product as a white solid (3.00 g, 60.2% yield). LCMS 46 (Method I) (ESI) CyFLBnFNO calcd318.86; Found [M+H]+:320. ^ NMR (400 MHz, CDC13) 5 7.66 (d, J= 8.8, 5.0 Hz, 1H), 7.00 - 6.91 (tn, 2H), 5.76 (s, 1H).

[0287] 3-Bromo-4-ethoxy-l-benzofuran-7-carbonitrile. A solution of 2,3-dibromo-4- fluoro-2,3-dihydro-l-benzofuran-7-carbonitrile (1.00 g, 3.11 mmol) and KOH (349.7 mg, 6.23 mmol) in EtOH (10 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic extracts were washed with water (3 x 3 mL), and dried over anhydrous Na2SO4. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a white solid (550.0 mg, 66.3% yield). LCMS 46 (Method I) (ESI) CnH8BrNO2calcd 264.97; Found [M+H]+: 266. 'H NMR (400 MHz, CDCI3) δ 7.56 (s, 1H), 7.50 (d, J= 8.5 Hz, 1H), 6.64 (d, J= 8.5 Hz, 1H), 4.16 (d, J= 7.0 Hz, 2H), 1.47 (d, J= 7.0 Hz, 3H).

[0288] tert-Butyl 3-(7-cyano-4-ethoxy-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of 3-bromo-4-ethoxy-l-benzofuran-7-carbonitrile (550.0 mg, 2.06 mmol) and Zc' / V-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / 7- pyridine-1 -carboxylate (958.6 mg, 3.10 mmol) in H2O (5 mL) and dioxane (10 mL) were added Pd(dppf)Cl2(75.6 mg, 0.13 mmol) and K2CO3(856.9 mg, 6.20 mmol). The resulting mixture was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with water (3 x 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (4:1) to afford the desired product as a white solid (650.0 mg, 85.3% yield). LCMS 47 (ESI) C2IH24N2O4 calcd 368.17; Found [M+H]+:369. 'HNMR (400 MHz, CDCI3) 5 7.57 - 7.50 (m, 2H), 6.69 (d, J= 8.5 Hz, 1H), 6.10 (d, J= 4.1, 2.0 Hz, 1H), 4.28 - 4.09 (m, 4H), 3.57 (d, J= 5.8 Hz, 2H), 2.33 - 2.23 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.49 (s, 9H).

[0289] 4-Ethoxy-3-(l,2,5,6-tetrahydropyridin-3-yl)-l-benzofuran-7-carbonitrile. HC1 (gas) in 1,4-di oxane (3 mL) was added to a stirred solution of / cvz-butyl 3-(7-cyano-4-ethoxy-l- benzofuran-3-yl)-5,6-dihydro-2 / 7-pyridine-l -carboxylate (100.0 mg, 0.27 mmol) in dioxane (3 mL). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum and the residue was dissolved in MeOH (0.5 mL). Then it was basified to pH 10 with saturated Na2CO3(aq.). The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobilephase, MeCN in water (10 mmol / L NH4HCO3), 0% to 70% gradient in 20 min; UV 254 nm to afford the desired product as a white solid (34.5 mg, 47.3% yield). LCMS 51 (Method L) (ESI) C16H16N2O2 calcd 268.12; Found [M+H]+:269.05. 'H NMR (400 MHz, DMSO-d6) 8.03 δ (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.17 (d, J = 3.9, 1.7 Hz, 1H), 4.25 (d, J = 6.9 Hz, 2H), 3.55 (d, J= 2.3 Hz, 2H), 2.88 (d, J = 5.8 Hz, 2H), 2.16 (d, J= 5.4, 2.6 Hz, 2H), 1.42 (d, J= 6.9 Hz, 3H).

[0290] Example 14: Synthesis of 4-hydroxy-3-(l,2,5,6-tetrahydropyridin-3-yl)-l- benzofuran-7-carbonitrile (Compound 141)

[0291] 3-Bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylate. KOH (0.35 g, 6.23 mmol) was added to a stirred solution of 2,3-dibromo-4-fluoro-2,3-dihydro-l-benzofuran-7- carbonitrile (1.00 g, 3.11 mmol) in MeOH (15 mL). The resulting mixture was stirred for 6 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (550.0 mg, 70.0% yield). LCMS 54 (ESI) C10ILBrNCh calcd 250.96; Found [M+H]+: 252. 'H NMR (400 MHz, CDCh) δ 7.64 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.01 (s, 3H).

[0292] tert-Butyl 3-(7-cyano-4-methoxy-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of 3-bromo-4-methoxy-l-benzofuran-7-carbonitrile (300.0 mg, 1.19 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / f- pyridine-1 -carboxylate (552.0 mg, 1.78 mmol) in H2O (3 mL) and dioxane (6 mL) were added K2CO3(493.4 mg, 3.57 mmol) and Pd(dppf)C12 (43.5 mg, 0.05 mmol). The resulting mixture was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc(3 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL), and dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow oil (380.0 mg, 90.0% yield). LCMS 53 (Method L) (ESI) C20H22N2O4 calcd 354.16; Found [M+H]+: 355. 'H NMR (400 MHz, CDCI3) 7.5 δ8 (d, J= 8.4 Hz, 1H), 7.55 (s, 1H), 6.73 (d, J= 8.5 Hz, 1H), 6.06 (d, J= 4.1, 2.0 Hz, 1H), 4.00 (s, 3H), 3.58 (d, J= 5.8 Hz, 2H), 2.30 (d, J= 5.7, 2.8 Hz, 2H), 2.05 (s, 2H), 1.50 (s, 9H).

[0293] 4-Hydroxy-3-(l ,2,5, 6-tetrahydropyridin-3-yl)-l -benz ofuran-7-carbonitrile. To a stirred solution of tert-butyl 3-(7-cyano-4-methoxy- l-benzofuran-3-yl)-5,6-dihydro-2 / 7-pyridine- 1-carboxylate (200.0 mg, 0.56 mmol) in DCM (1 mL) was added BBr? (2 mL). The resulting mixture was stirred for 48 h at room temperature under an N2 atmosphere. The reaction was quenched with MeOH at 0 °C. The mixture was basified to pH 10 with saturated ISfeCCh (aq.) and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: : column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 60% gradient in 30 min; UV 254 nm to afford the desired product as a white solid (37.5 mg, 27.6% yield). LCMS 63 (Method Q) (ESI) C14H12N2O2 calcd 240.09; Found [M+H]+: 241.10. ’H NMR (400 MHz, DMSO-d6) 7 δ.80 (s, 1H), 7.36 (d, J= 8.5 Hz, 1H), 6.48 - 6.34 (m, 2H), 3.93 (s, 2H), 3.03 (d, J= 5.9 Hz, 2H), 2.28 (s, 2H).

[0294] Example 15: Synthesis of 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzofuran-6- carbonitrile (Compound 143)

[0295] l-Benzofuran-6-carbonitrile. Pd(PPh3)4 was added to a stirred mixture of 6-bromo- 1-benzofuran (2.00 g, 10.15 mmol) and Zn(CN)2(11.92 g, 101.51 mmol) in DMA (30 mL) Theresulting mixture was stirred for 1 h at 100 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL), and dried over anhydrous Na2SO4. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white semi-solid (1.03 g, 68.8% yield). ’H NMR (400 MHz, CDCh) δ 7.85 - 7.77 (m, 2H), 7.71 - 7.66 (m, 1H), 7.54 - 7.48 (m, 1H), 6.90 - 6.84 (m, 1H).

[0296] 2,3-Dibromo-2,3-dihydro-l-benzofuran-6-carbonitrile. Br2 (0.5 mL, 8.63 mmol) was added to a stirred mixture of l-benzofuran-6-carbonitrile (1.03 g, 7.19 mmol) in DCM (10 mL) at room temperature under an N2 atmosphere. The resulting mixture was stirred for 1.5 h at room temperature under an N2 atmosphere. The reaction was quenched with sat. Na2SCh (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired crude product as a yellow oil (1.90 g, 87.9% yield). The crude product was used in the next step directly without further purification. 'H NMR (400 MHz, CDCh) 3 7.62 (d, J= 7.8 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.36 - 7.31 (m, 1H), 6.91 (s, 1H), 5.72 (s, 1H).

[0297] 3-Bromo-l-benzofuran-6-carbonitrile. A mixture of 2,3-dibromo-2,3-dihydro-l- benzofuran-6-carbonitrile (1.90 g, 6.27 mmol) and DBU (2.86 g, 18.81 mmol) in DCM (20 mL). was stirred for 2 h at 50 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 60% gradient in 30 min; UV 254 nm to afford the desired product as a white semi-solid (800.0 mg, 57.4% yield). 'HNMR (300 MHz, DMSO-d6) 8 δ.60 (s, 1H), 8.37 (d, J= 1.1 Hz, 1H), 7.83 - 7.72 (m, 2H).

[0298] tert-Butyl 3-(6-cyano-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l -carboxylate. To a stirred mixture of 3-bromo-l-benzofuran-6-carbonitrile (800.0 mg, 3.15 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (1.46 g, 4.72 mmol) in dioxane (20 mL) and H2O (10 mL) was added K2CO3(1.31 g, 9.45 mmol) and Pd(dppf)Ch (230.6 mg, 0.31 mmol). The resulting mixture was stirred for 1 h at 80 °C under anN2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (12: 1) to afford the desired product as a white solid (300.0 mg, 25.5% yield). ‘HNMR (300 MHz, CDCh) δ 7.90 (d, J= 8.2 Hz, 1H), 7.86 - 7.82 (m, 1H), 7.79 (s, 1H), 7.60 - 7.54 (m, 1H), 6.44 - 6.39 (m, 1H), 4.25 (d, J= 2.4 Hz, 2H), 3.63 (d, J = 5.7 Hz, 2H), 2.41 (d, J= 3.9 Hz, 2H), 1.53 (s, 9H).

[0299] 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzofuran-6-carbonitrile. To a stirred mixture of tert-Butyl 3-(6-cyano-l -benzofuran-3-yl)-5,6-dihydro-2 / 7-pyridine-l -carboxylate (150 mg, 0.46 mmol) in dioxane (1 mL) was added HC1 (gas) in 1,4-dioxane (1 mL). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere and concentrated under vacuum. The mixture was neutralized to pH 7 with saturated Na2CCh (aq.).The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 18 % B to 37 % B in 7 min; Wave Length: 254 nm / 220 nm; RTl(min): 7.07) to afford the desired product as a white solid (66.6 mg, 63.7% yield). LCMS 40 (ESI) C14H12N2O calcd 224.09; Found [M+H]+:225.05. ’HNMR (400 MHz, DMSO-d6) 8.31 δ (s, 1H), 8.24 (s, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.70 (d, J= 8.2 Hz, 1H), 6.45 (d, J= 4.6 Hz, 1H), 3.52 (s, 2H), 2.85 (d, J= 5.7 Hz, 2H), 2.20 (d, J= 5.9 Hz, 2H).

[0300] Example 16: Synthesis of 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzofuran-5- carbonitrile (Compound 144)

[0301] 2,3-Dibromo-2,3-dihydro-l-benzofuran-5-carbonitrile. To a stirred mixture of 1- benzofuran-5-carbonitrile (200.0 mg, 1.397 mmol) in DCM (2 mL) was added Br2 (0.09 mL, 1.676mmol) in portions and stirred for 1.5 h at room temperature under an N2 atmosphere. The reaction was quenched with sat. Na2SC>3 (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired crude product as a white oil (250.0 mg, 59.0% yield). The crude product was used in the next step directly without further purification.!H NMR (400 MHz, CDCI3) 3 7.82 (d, .7 = 1.7 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.19 - 7.14 (m, 1H), 6.92 (s, 1H), 5.72 (s, 1H).

[0302] 3-Bromo-l-benzofuran-5-carbonitrile. A mixture of 2,3 -dibromo-2, 3 -dihydro- 1- benzofuran-5-carbonitrile (250 mg, 0.825 mmol) and DBU (376.8 mg, 2.475 mmol) in DCM (5 mL) was stirred for 2 h at 50 °C under an N2 atmosphere. The resulting mixture was extracted with CH2Q2 (3 x 5 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (150.0 mg, 81.8% yield). 'HNMR (400 MHz, CDCI3) 7 δ.94 - 7.90 (m, 1H), 7.78 (s, 1H), 7.68 - 7.63 (m, 1H), 7.62 - 7.58 (m, 1H).

[0303] tert-Butyl 3-(5-cyano-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate.To a stirred mixture of 3-bromo-l-benzofuran-5-carbonitrile (140.0 mg, 0.631 mmol) and tert- butyl 3-14,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-27 / -pyridine-l -carboxylate (292.4 mg, 0.947 mmol) in dioxane (2 mL) and H2O (2 mL) was added K2CO3(261.4 mg, 1.893 mmol) and Pd(dppf)C12 (23.1 mg, 0.032 mmol). The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a yellow solid (180.0 mg, 88.0% yield). LCMS 54 (ESI) C19H20N2O3 calcd 324.15; Found [M+H]+: 325.XH NMR (400 MHz, CDCI3) 8.1 δ4 (d, J= 1.1 Hz, 1H), 7.71 (s, 1H), 7.62 - 7.56 (m, 2H), 6.42 - 6.37 (m, 1H), 4.22 (s, 2H), 3.61 (d, J= 5.7 Hz, 2H), 2.40 (d, J = 7.0 Hz, 2H), 1.51 (s, 9H).

[0304] 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzofuran-5-carbonitrile. HC1 (gas) in 1,4- dioxane (1 mL) was added to a stirred mixture of tert-butyl 3-(5-cyano-l-benzofuran-3-yl)-5,6-dihydro-27 / -pyridine-l -carboxylate (180.0 mg, 0.555 mmol, 1.0 equiv) in dioxane (2 mL) at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 7 with saturated Na2CCh (aq.). The crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water ( l Ommol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 18% B to 37% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.07) to afford the desired product as a white solid (30.8 mg, 34.6% yield). LCMS 63 (Method P) (ESI) C14H12N2O calcd 224.09; Found [M+H]+: 225.10 'H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 1.4 Hz, 1H), 8.23 (s, 1H), 7.86 - 7.75 (m, 2H), 6.56 - 6.48 (m, 1H), 3.51 (d, J= 2.3 Hz, 2H), 2.85 (d, J= 5.7 Hz, 2H), 2.25 - 2.21 (m, 2H).

[0305] Example 17: Synthesis of tert-butyl 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl)- 5,6-dihydro-2H-pyridine-l-carboxylate (Compound 146)

[0306] tert-butyl (E)-3-(2-ethoxy-2-oxoethylidene)piperidine-l-carboxylate. Under N2 atmosphere, a stirred solution of NaH (2.41 g, 100.37 mmol) in THF (20 mL) was treated with triethyl phosphonoacetate (11.25 g, 50.19 mmol) for 30 min at 0 °C. Then tert-butyl 3- oxopiperidine-1 -carboxylate (5.00 g, 25.1 mmol) was added dropwise while maintaining the temp at 0 °C. The final reaction mixture was stirred overnight at rt before concentrating under reduced pressure. The crude product was purified chromatography (SiO2) eluting with 16% of EtOAc in petroleum ether to afford the desired product as a yellow oil (3.00 g, 44 % yield, (E):(Z)=9:5). LCMS (ESI) C14H23NO4 calcd 269.16; found [M+H]+: 270. (E) 'H NMR (400 MHz, CDCI3) δ 5.74 (s, 1H), 4.19 - 4.11 (m, 2H), 4.00 - 3.90 (m, 2H), 3.54 - 3.44 (m, 2H), 3.00 - 2.87 (m, 2H),1.76 - 1.66 (m, 2H), 1.46 (s, 9H), 1.28 (t, J= 7.1 Hz, 3H). LCMS 50 (Method B) (ESI) C14H23NO4 calcd 269.16; found [M+H]+: 270 (Z) 'H NMR (400 MHz, CDCI3) 5.7 δ0 - 5.64 (m, 1H), 4.62 (d, J= 1.3 Hz, 2H), 4.22 - 4.13 (m, 2H), 3.49 (t, J = 5.9 Hz, 2H), 2.38 - 2.30 (m, 2H), 1.77 - 1.67 (m, 2H), 1.45 (s, 9H), 1.28 (d, J= 7.1 Hz, 3H).

[0307] isopropyl (3Z)-3-(2-hydroxyethylidene)piperidine-l-carboxylate. To a stirred solution of tert-butyl (3Z)-3-(2-ethoxy-2-oxoethylidene)piperidine-l-carboxylate (2.70 g, 10.02 mmol) in ether (10.0 mL) was added DIB AL-H (13.4 mL, 20.06 mmol, 1.5 M in toluene) dropwise at -78 °C under a N2 atmosphere. The final reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of ice water. The reaction mixture was extracted with dichloromethane (3 x 50 mL), the combined organic extracts dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography (Si O2) eluting with 50% of MeOH in dichloromethane to afford the desired product as a yellow liquid (1.70 g, 80 % yield). LCMS 54 (ESI) C12H21NO3 calcd 227.15; found [M+H]+: 228. ’H NMR (400 MHz, CDCI3) 5 δ.55 (s, 1H), 4.17 (d, J = 6.9 Hz, 2H), 3.96 (s, 1H), 3.86 (s, 1H), 3.46 (s, 2H), 2.36 - 2.23 (m, 2H), 2.05 (s, 1H), 1.61 (s, 2H), 1.45 (s, 9H).

[0308] 5-fluoro-2-iodophenol. To a stirred solution of 4-fluoro-l-iodo-2-methoxybenzene (2.80 g, 11.11 mmol) in di chloromethane (30.0 mL) was added boron tribromide (13.92 g, 55.55 mmol) dropwise at 0 °C under a N2 atmosphere. The final reaction mixture was stirred for 30 min at room temperature before being quenched with water at 0 °C. The reaction mixture was extracted with di chloromethane (3 x 100 mL), the combined organic extracts dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by chromatography(SiO2) eluting with 16% of EtOAc in petroleum ether afforded the desired product as a yellow liquid (2.10 g, 79 % yield). 'H NMR (400 MHz, DMSO-t76) 1 δ0.81 (s, 1H), 7.73 - 7.63 (m, 1H), 6.74 - 6.60 (m, 1H), 6.61 - 6.45 (m, 1H).

[0309] tert-butyl (3E)-3-[2-(5-fluoro-2-iodophenoxy)ethylidene]piperidine-l -carboxylate. A solution of tert-butyl (3Z)-3-(2-hydroxyethylidene)piperidine-l-carboxylate (600.0 mg, 2.64 mmol), 5-fluoro-2-iodophenol (628.2 mg, 2.64 mmol) and triphenylphosphine (1.04 g, 3.96 mmol) in THF (10.0 mL) was stirred for 10 min at rt under a N2 atmosphere before the of diisopropyl azodicarboxylate ( 1.60 g, 7.92 mmol) dropwise at rt. The reaction mixture was stirred an additional 30 min at rt before being concentrated under reduced pressure. The residue was purified by prep- TLC (20 x 20 cm 16% of ethyl acetate in petroleum ether) to afford the desired product as a yellowoil (900 mg, 53 % yield). LCMS 50 (Method B) (ESI) C18H23FINO3 calcd 447.07; found [M+H]+: 448. 'H NMR (400 MHz, DMSO-4) δ 7.86 - 7.68 (m, 1H), 7.00 - 6.91 (m, 1H), 6.69 - 6.61 (m, 1H), 5.54 (t, 6.4 Hz, 1H), 4.67 (d, J= 6.4 Hz, 2H), 3.83 (s, 1H), 3.44 - 3.33 (m, 2H), 3.33 (s,1H), 2.38 (t, .7= 6.0 Hz, 1H), 2.34 - 2.24 (m, 1H), 1.56 (d, J= 8.3 Hz, 2H), 1.37 (s, 9H).

[0310] tert-butyl 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. Into a 10 mL schlenk tube were added C0CI2 (29.0 mg, 0.22 mmol) at room temperature, then heat it with a hairdryer for 2 min. To the above tube was added DPPB (57.2 mg, 0.13 mmol, 0.1 equiv) and tetrahydrofuran (5.0 mL). The resulting mixture was stirred for additional 5 min at room temperature. To the above mixture was added [(chloromagnesio)methyl]trimethylsilane (492.9 mg, 3.35 mmol, 3.0 equiv) dropwise at O °C. The resulting mixture was stirred for additional 5 min at 0 °C. To the above mixture was added tert- butyl (3E)-3-[2-(5-fluoro-2-iodophenoxy)ethylidene]piperidine-l -carboxylate (500.0 mg, 1.12 mmol, 1.0 equiv) dropwise at room temperature. The resulting mixture was stirred for an additional 30 min at 80 °C. The reaction was quenched by the addition of sat. NH4CI (aq.) at 0 °C. The aqueous layer was extracted with ethyl acetate (3 X 50 mL). The combined organic layer was dried over Na2SO4and was concentrated. The residue was purified by chromatography (SiO2) eluting with 50 % of MeOH in dichloromethane to afford the desired product as a brown solid (300.0 mg, 84 % yield). LCMS 50 (Method A) (ESI) C18H22FNO3 calcd 319.16; found [M+H]+: 320.

[0311] 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl)-l,2,5,6-tetrahydropyridine. To a stirred solution of tert-butyl 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl)-5,6-dihydro-2 / 7-pyridine-l- carboxylate (300.0 mg, 0.94 mmol) in 1,4-dioxane (1.0 mL) was added HC1 (gas) in 1,4-dioxane (2 mL, 4 M) dropwise at 0 °C. The reaction mixture was stirred at rt for 30 min before being concentrated under reduced pressure. The residue was dissolved in methanol (5.0 mL) and neutralized to pH 7 with saturated ammonia bicarbonate solution before concentrating again under reduced pressure. The crude product was purified by chromatography (column, C 18; mobile phase, acetonitrile in water (0.1% formic acid), 5% to 95% gradient in 10 min; detector, UV 254 nm) to afford the desired product as a light-yellow oil (20.7 mg, 10 % yield). LCMS 40 (ESI) C13H14FNO calcd 219.11; found [M+H]+: 220.10. ’H NMR (400 MHz, DMSO-d6) 8.3 δ3 (s, 1H), 7.17 - 7.08 (m, 1H), 6.78 - 6.66 (m, 2H), 5.64 (d, J = 3.9 Hz, 1H), 4.69 (t, J = 9.3 Hz, 1H), 4.45 - 4.35 (m, 1H), 4.20 - 4.09 (m, 1H), 3.43 (d, J= 16.7 Hz, 1H), 3.15 (d, J= 16.3 Hz, 1H), 2.97 (d, J= 6.1 Hz, 2H), 2.16 (d, J = 6.2 Hz, 2H).

[0312] Example 18: Synthesis of 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl) piperidine(Compound 147)

[0313] 6-fluoro-l-benzofuran-3-yl trifluoroniethanesulfonate. To a stirred solution of 6- fluoro-27 / -l-benzofuran-3-one (1.00 g, 6.60 mmol) and TEA (2.00 g, 19.70 mmol in DCM (15 mL) was added Tf20 (2.80 g, 9.90 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at rt before being diluted with water. The resulting mixture was extracted with CH2CI2 (3 x 50 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow oil (420 mg, 22 % yield). LCMS 50 (Method A) (ESI) C9H4F4O4S calcd 283.98; found [M+H]+: 285.

[0314] tert-butyl 3-(6-fluoro-l -benzofuran-3-yl)-5, 6-dihydro-2H-pyridine-l-carboxylate.To a stirred solution of 6-fluoro-l-benzofuran-3-yl trifluoromethanesulfonate (320.0 mg, 1.13 mmol) and ze / 7-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2L7-pyridine-l- carboxylate (522.3 mg, 1.69 mmol) in H2O (2 mL) and dioxane (10 mL) was added Pd(dppf)Ch (165 mg, 0.23 mmol) and K2CO3(467 mg, 3.40 mmol) in portions at rt. The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere before diluting with water. The resulting mixture extracted with EtOAc (3 X 50 mL) and the combined organic extracts were concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desired product an a yellow oil (210 mg, 59 % yield). LCMS 50 (Method A) (ESI) C18H20FNO3 calcd 317.14; found [M+H]+: 318.

[0315] tert-butyl 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl)piperidine-l-carboxylate. To a stirred solution of tert-butyl 3-(6-fluoro-l-benzofuran-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate (210.0 mg, 0.67 mmol) in MeOH (5 mL) was added PtCh (0.08 g, 0.33 mmol) in portions at rt. The resulting mixture was stirred overnight at rt under a H2atmosphere before themixture was filtered through celite. The filter cake was washed with MeOH and the filtrate concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desire product as a yellow oil (130 mg, 61 % yield). LCMS 54 (ESI) C18H24FNO3 calcd 321.17; found [M+H]+: 322.

[0316] 3-(6-fluoro-2,3-dihydro-l-benzofuran-3-yl) piperidine. A solution of tert-butyl 3-(6- fluoro-2, 3 -dihydro- l-benzofuran-3-yl) piperidine- 1 -carboxylate (150 mg, 0.47 mmol) and TFA (2 mL) in DCM (2 mL) was stirred for 20 min at rt before being concentrated under reduced pressure. The crude product (65 mg) was purified by HPLC (Column: XBridge Prep OBD Cl 8 Column 30*150 mm, 5m; Mobile Phase A: Water (lOmmol / L NH4HC03+0.05%NH3H20), Mobile Phase B: MEOH; Flow rate: 60 mL / min; Gradient: 33% B to 47% B in 9 min; wavelength: 254nm / 220nm nm) to afford the desire product as a white solid (34.9 mg, 33 % yield). LCMS 63 (Method Q) (ESI) C13H16FNO calcd 221.12; found [M+H]+: 222.00. 'HNMR (400 MHz, DMSO-d6) 7.22 δ (t, J= 7.0 Hz, 1H), 6.65 (t, J= 8.6 Hz, 2H), 4.62 - 4.41 (m, 2H),3.90 - 3.67 (m, 1H). 3.29 (d, J= 8.5 Hz, 1H), 2.82 (d, J= 61.8 Hz, 1H), 2.41 (s, 2H), 1.82 - 1.45 (m, 3H), 1.43 - 1.02 (m, 2H).

[0317] Example 19: Synthesis of 3-(l, 2,5, 6-Tetrahydropyridin-3-yl)-l-benzothiophene- 7-carbonitrile (Compound 159)

[0318] l-Benzothiophene-7-carbonitrile. To a stirred solution of 7-bromo-l-benzothiophene (1.00 g, 4.69 mmol) and Zn(CN)2(1.65 g, 14.03 mmol) in DMA (10 mL) was added Pd(PPh3)4 (1.08 g, 0.93 mmol). The resulting mixture was stirred for 3 h at 90 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic extracts were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (400.0 mg, 53.5% yield).

[0319] 3-Bromo-l-benzothiophene-7-carbonitrile. To a stirred solution of 1- benzothiophene-7-carbonitrile (330.0 mg, 2.07 mmol) in DCM (5 mL) was added Bn (0.12 mL, 2.32 mmol). The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was extracted with CEI2CI2 (3 x 10 mL). The combined organic extracts were washed with Na2SOs (aq.) (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 55% gradient in 15 min; UV 254 nm to afford the desired product as a white solid (220.0 mg, 44.5% yield). 'H NMR (400 MHz, CDCI3) 8 δ.05 (d, J= 8.2, 1.1 Hz, 1H), 7.78 (d, J= 7 A, 1.1 Hz, 1H), 7.60 (s, 1H), 7.59 - 7.53 (m, 1H).

[0320] 3-Methyl-l-benzothiophene-7-carbonitrile. To a stirred solution of 3 -bromo- 1- benzothiophene-7-carbonitrile (160.0 mg, 0.67 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3- dioxolan-2-yl)-5,6-dihydro-2 / f-pyridine-l -carboxylate (313.9 mg, 1.01 mmol) in H2O (1.5 mL) and dioxane (3 mL) were added Pd(dppf)C12 (24.5 mg, 0.03 mmol) and K2CO3(278.6 mg, 2.01 mmol). The resulting mixture was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3x10 mL), dried over anhydrous ISfeSCU After fdtration, the filtrate was concentrated under reduced pressure to afford the desired product as a colorless oil (200.0 mg, 87.4% yield). LCMS 52 (Method B) (ESI) C19H20N2O2S calcd 340.12; Found [M+H]+:341.XH NMR (300 MHz, CDCI3) δ 8.13 (d, J = 8.2 Hz, 1H), 7.72 (d, J= 7.3 Hz, 1H), 7.51 - 7.40 (m, 2H), 6.14 (d, J = 33, 2.6 Hz, 1H), 4.23 (s, 2H), 3.63 (d, J= 5.8 Hz, 2H), 2.39 (d, J= 6.2 Hz, 2H), 1.51 (s, 9H).

[0321] 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzothiophene-7-carbonitrile. To a stirred solution of / cvZ-butyl 3-(7-cyano-l-benzothiophen-3-yl)-5,6-dihydro-277-pyridine-l-carboxylate (100.0 mg, 0.29 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred for 30 min at room temperature under an N2 atmosphere. The mixture was basified to pH 8 with saturated Na2COs (aq.). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 21% B in 9 min; waveLength: 254 nm / 220 nm. to afford thedesired product as a white solid (55.4 mg, 78.4% yield). LCMS 63 (Method Q) (ESI) C14H12N2S calcd 240.17; Found [M+H+ACN]+: 282.05.XH NMR (400 MHz, DMSO-d6) 8. δ30 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 7.3 Hz, 1H), 7.90 (d, J = 3.6 Hz, 1H), 7.63 (t, J= 7.8 Hz, 1H), 6.22 (s, 1H), 3.73 (s, 2H), 3.06 (s, 2H), 2.35 (s, 2H).

[0322] Example 20: Synthesis of 5-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l- benzothiophene-7-carbonitrile (Compound 168)

[0323] Ethyl [(2-bromo-4-fluorophenyl)sulfanyl]methanethioate. To a stirred solution of 2- bromo-4-fluoroaniline (3 g, 15.79 mmol) and NaNCh (1.20 g, 17.37 mmol) in HC1 (10 mL) and H2O (10 mL) was added potassium ethyl xanthate (3.04 g, 18.95 mmol) dropwise at 0 °C and stirred for 2 h at room temperature. The resulting mixture was extracted with EtOAc (5 x 100 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as an off-white oil (1.6 g, 34.3% yield). 'H NMR (400 MHz, CDCh) 5 7.60 (s, 1H), 7.47 (s, 1H), 7.10 (s, 1H), 4.65 - 4.57 (m, 2H), 1.37 - 1.31 (m, 3H).

[0324] 2-Bromo-l-[(2,2-dimethoxyethyl)sulfanyl]-4-fluorobenzene. To a stirred solution of ethyl [(2-bromo-4-fluorophenyl)sulfanyl]methanethioate (1.6 g, 5.42 mmol) and ethane, 2-bromo- 1,1 -dimethoxy- (1.10 g, 6.50 mmol) in EtOH (15 mL) was added KOH (0.91 g, 16.26 mmol) at room temperature and stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure and diluted with H2O (20 mL), it was extracted with EtOAc (3 x 20 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desiredproduct as an off-white oil (1.2 g, 75.0% yield). 'HNMR (400 MHz, CDCI3) 7 δ.43 (s, 1H), 7.34 (s, 1H), 7.01 (s, 1H), 4.58 - 4.50 (m, 1H), 3.36 (s, 6H), 3.08 (d, J= 5.6 Hz, 2H).

[0325] 7-Bromo-5-fluoro-l-benzothiophene. To a stirred solution of 2-bromo-l-[(2,2- dimethoxyethyl)sulfanyl]-4-fluorobenzene (1.2 g, 4.07 mmol) in chlorobenzene (20 mL) was added PPA (1.40 g, 12.20 mmol) at room temperature and stirred for 2 h at 110 °C under an N2 atmosphere. The resulting mixture was diluted with water and extracted with EtOAc (3 x 50 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as an off-white oil (385 mg, 40.9% yield). 'H NMR (400 MHz, CDCI3) 7. δ59 (d, J = 5.4 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J= 5.4 Hz, 1H), 7.32 (s, 1H).

[0326] 5-Fluoro-l-benzothiophene-7-carbonitrile. A mixture of 7-bromo-5 -fluoro- 1- benzothiophene (350 mg, 1.52 mmol), Pd(PPh3)4 (350.1 mg, 0.30 mmol) and Zn(CN)2(533.5 mg, 4.55 mmol) in DMA (10 mL) was stirred for 2 h at 100 °C under an N2 atmosphere. The resulting mixture was diluted with water, quenched with FeSCU aqueous solution and extracted with EtOAc (3 x 20 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desired product as a white solid (175 mg, 65.2% yield). 'H NMR (400 MHz, CDCI3) δ 7.69 - 7.57 (m, 2H), 7.40 (s, 1H), 7.32 (d, J= 5.5 Hz, 1H).

[0327] 5-Fluoro-l-benzothiophene-7-carbonitrile. To a stirred solution of 7-bromo-5- fluoro-1 -benzothiophene (170 mg, 0.736 mmol) in DCM (5 mL) was added B12 (176.4 mg, 1.10 mmol) dropwise at 0 °C and stirred for 2 days at room temperature. The reaction was quenched with 10 mL of Na2S2Ch at 0 °C and extracted with EtOAc (3 x 10 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (60 mg, 46.0% yield). ’H NMR (400 MHz, DMSO-d6) 8. δ36 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H).

[0328] tert-Butyl 3-(7-cyano-5-fluoro-l-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A mixture of 3-bromo-5-fluoro-l-benzothiophene-7-carbonitrile (60 mg, 0.20 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / 7-pyridine-l- carboxylate (90.6 mg, 0.29 mmol), Pd(dppf)C12 (28.6 mg, 0.04 mmol) and K2CO3(81.0 mg, 0.59 mmol) in dioxane (2.5 mL) and H2O (0.5 mL) was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was diluted with 20 mL of water and extracted with EtOAc (3 x 20 mL) andthe combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a white solid (52 mg, 74.3% yield). LCMS 60 (ESI) C19H19FN2O2S calcd 358. 12; Found [M + H]+:359.

[0329] 5-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l-benzothiophene-7-carbonitrile. To a stirred solution of tert-Butyl 3-(7-cyano-5-fluoro-l-benzothiophen-3-yl)-5,6-dihydro-2H- pyridine- 1 -carboxylate (52 mg, 0.17 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature and stirred for 15 min at room temperature. The mixture was concentrated under reduced pressure and the residue was basified to pH 8 with saturated Na2CCh (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 37% B in 2 min, 37% to 55% B in 10 min) to afford the desired product as a white solid (22.8 mg, 59.4% yield). LCMS 52 (ESI) C14H11FN2S calcd 258.06; Found [M + H]+:258.90.JH NMR (400 MHz, CD3OD) 5 8.00 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 6.26 - 6.20 (m, 1H), 3.85 - 3.78 (m, 2H), 3.23 (s, 2H), 2.55 - 2.46 (m, 2H).

[0330] Example 21: Synthesis of 4-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-l- benzothiophene-7-carbonitrile (Compound 169)

[0331] 4-Fluoro-l-benzothiophene-7-carbonitrile. To a solution of 7-bromo-4-fluoro-l- benzothiophene (700 mg, 3.029 mmol), zinc cyanide (1067.1 mg, 9.087 mmol) and Pd(PPh3)4 (700.1 mg, 0.606 mmol) in DMA (10 mL) was stirred for 1 h at 110 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (320 mg, 59.6% yield). 'H NMR (400 MHz, DMSO-d6) 5 7.42 - 7.39 (m, 2H), 7.31 - 7.13 (m, 2H).

[0332] 3-Bromo-4-fluoro-l-benzothiophene-7-carbonitrile. To a stirred mixture of 4-fluoro- l-benzothiophene-7-carbonitrile (300 mg, 1.693 mmol) in DCM (5 mL) was added Br2 (1352.8 mg, 8.465 mmol) in portions at 0 °C and stirred overnight at room temperature. The reaction was quenched by the addition of Na2S2C>3 at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol ZL NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm to afford the desired product as a white solid (70 mg, 16.1% yield). ’HNMR (400 MHz, DMSO-d6) δ 8.24 - 8.17 (m, 1H), 8.12 (m, 1H), 7.51 (m, 1H).

[0333] tert-Butyl 3-(7-cyano-4-fluoro-l-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A mixture of 3-bromo-4-fluoro-l-benzothiophene-7-carbonitrile (20 mg, 0.078 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2J7-pyridine-l- carboxylate (36.2 mg, 0.117 mmol ), Pd(dppf)C12 (5.7 mg, 0.008 mmol) and K2CO3(32.4 mg, 0.234 mmol) in dioxane (2 mL) and H2O (0.4 mL) was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 5 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (15 mg, 53.5% yield). LCMS 51 (Method L) (ESI) C19H19FN2O2S calcd 358.12; Found [M+H]+:359.

[0334] 4-Fluoro-3-(l ,2,5, 6-tetrahydropyridin-3-yl)-l -benzothiophene- 7-carbonitrile. A solution of tert-butyl 3-(7-cyano-4-fluoro-l-benzothiophen-3-yl)-5,6-dihydro-2rt-pyridine-l- carboxylate (20 mg, 0.056 mmol) and TFA (2 mL) in DCM (2 mL) was stirred for 10 min at room temperature. After concentrated under reduced pressure, the residue was diluted with MeOH (0.5 mL) and basified to pH δ with saturated Na2COs (aq.). The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm to afford the desired product as a white solid (11.9 mg, 82.5% yield). LCMS 63 (Method P) (ESI) C14H11FN2S calcd 258.06; Found [M+H]+: 259.10. 'H NMR (400 MHz, CD3OD) 7.84 ( δdd, J= 8.3, 4.3 Hz, 1H), 7.58 (s, 1H), 7.27 (dd, J= 11.2, 8.3 Hz, 1H), 5.99 (m, 1H), 3.59 (m, 2H), 3.03 (t, J= 5.9 Hz, 2H), 2.40 - 2.22 (m, 2H).

[0335] Example 22: Synthesis of 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzothiophene- 6-carbonitrile (Compound 176)

[0336] l-Benzothiophene-6-carbonitrile. A solution of 6-bromo-l -benzothiophene (1.00 g, 4.69 mmol), Pd(PPh3)4 (0.54 g, 0.47 mmol) and Zn(CN)2(0.55 g, 4.69 mmol) in DMA (10.0 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a white solid (600.0 mg, 80.3% yield). 'H NMR (400 MHz, DMSCM,) δ 8.69 - 8.63 (m, 1H), 8.14 (d, J = 5.4 Hz, 1H), 8.08 (d, J= 8.3 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.63 (d, J= 5.4 Hz, 1H).

[0337] 3-Bromo-l-benzothiophene-6-carbonitrile. To a stirred solution of 1- benzothiophene-6-carbonitrile (600.0 mg, 3.77 mmol) in DCM (6.0 mL) was added Br2 (0.5 mL) dropwise at room temperature under an N2 atmosphere and stirred for 2 h at room temperature under an N2 atmosphere. The reaction was quenched by the addition of NazSzOs. The aqueous layer was extracted with EtOAc (3 x 30 mL) The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a white solid (300.0 mg, 33.4% yield 'H NMR (400 MHz, CD3OD) 8 δ.46 - 8.42 (m, 1H), 8.03 (s, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.80 - 7.75 (m, 1H).

[0338] tert-Butyl 3-(6-cyano-l-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A mixture of 3-bromo-l-benzothiophene-6-carbonitrile (300.0 mg, 1.26 mmol), Pd(dppf)Ch (44.2 mg, 0.06 mmol), K2CO3(522.4 mg, 3.78 mmol) and tert-butyl 3-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)-5,6-dihydro-27 / -pyridine- l -carboxylate (584.4 mg, 1.89 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (200.0 mg, 46.6% yield).!H NMR (400 MHz, CDC13) 8 δ.19 (d, J = 1.4 Hz, 1H), 8.00 (d, J= 8.5 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.53 (s, 1H), 6.17 - 6.12 (m, 1H), 4.23 (s, 2H), 3.646 - 3.60 (m, 2H), 2.43 - 2.35 (m, 2H), 1.51 (s, 9H).

[0339] 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzothiophene-6-carbonitrile. A solution of ze / 7-butyl 3-(6-cyano-l-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-l -carboxylate (100.0 mg, 0.29 mmol) in HC1 (2.0 mb, 4 M in 1,4-dioxane) was stirred for 1 h at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (1 mL) and basified to pH 9 with saturated NazCCE (aq.). The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 2% B to 2% B in 5 min, 2% B to 20% B in 20 min, 20% B to 41% B in 30 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.9) to afford the desired product as a yellow solid (25.0 mg, 35.4% yield). LCMS 51 (Method L) (ESI) C14H12N2S calcd 240.07; Found [M+H]+:241.15. *H NMR (400 MHz, CD3OD) 8. δ38 - 8.27(m, 1H), 8.09 - 8.00 (m, 1H), 7.75 - 7.67 (m, 1H), 7.66 - 7.57 (m, 1H), 6.17 - 6.08 (m, 1H), 3.67 - 3.56 (m, 2H), 3.09 - 2.98 (m, 2H), 2.41 - 2.28 (m, 2H).

[0340] Example 23: Synthesis of 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzothiophene- 5-carbonitrile (Compound 177)

[0341] l-Benzothiophene-5-carbonitrile. To a stirred solution of 5-bromo-l-benzothiophene (2.00 g, 9.38 mmol) and Zn(CN)2(1.32 g, 11.26 mmol) in DMA (15 mL) was added Pd(PPh3)4 (1.08 g, 0.93 mmol) at room temperature under an N2 atmosphere. The resulting mixture wasstirred for 1 h at 100 °C under an N2 atmosphere and diluted with H2O (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (1 g, 66.9% yield). LCMS 49 (Method K) (ESI) C9H5NS calcd 159.01[M+H]+: 160. 'H NMR (400 MHz, DMSO-ds) δ 8.44 (d, J= 1.6 Hz, 1H), 8.29 - 8.24 (m, 1H), 8.00 (d, J= 5.4 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.61 - 7.56 (m, 1H).

[0342] 3-Bromo-l-benzothiophene-5-carbonitrile. To a stirred solution of 1- benzothiophene-5-carbonitrile (1.00 g, 6.28 mmol) in DCM (10 mL) was added Br2 (1.00 g, 6.28 mmol) at 0 °C under an N2 atmosphere. The resulting mixture was stirred for 1 h at 0 °C under an N2 atmosphere. The resulting mixture was diluted with EtOAc (100 mL) and washed with saturated sodium thiosulfate (3x100 mL), the combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (800 mg, 53.4% yield). LCMS 49 (Method K) (ESI) C9H4BrNS calcd 236.92; Found [M+H]+:238.

[0343] tert-Butyl 3-(5-cyano-l-benzothiophen-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 3-bromo-l-benzothiophene-5-carbonitrile (200.0 mg, 0.84 mmol), tert- butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-277-pyridine-l-carboxylate (311.6 mg, 1.00 mmol), K2CO3(348.2 mg, 2.52 mmol) and Pd(dppf)C12 (61.4 mg, 0.08 mmol) in 1,4-di oxane (4 mL) and H2O (2 mL) was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3: 1) to afford the desired product as a yellow oil (130 mg, 45.6% yield). LCMS 49 (Method K) (ESI) C19H20N2O2S calcd 340.12; Found [M+H]+:341.

[0344] 3-(l,2,5,6-Tetrahydropyridin-3-yl)-l-benzothiophene-5-carbonitrile. To a stirred solution of Zc / 'Z-butyl 3-(5-cyano-l-benzothiophen-3-yl)-5,6-dihydro-277-pyridine-l-carboxylate (100.0 mg, 0.29 mmol) in 1,4-dioxane (0.5 mL) was added HC1 (gas) (0.5 mL, 4 M in 1,4-dioxane). The resulting mixture was stirred for 3 h at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (1 mL) and basified to pH 9 with saturated Na2COs (aq.). The mixture was purified by Prep-HPLC with thefollowing conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 47% B in 9 min; Wavelength: 254 nm / 220 nm nm; RTl(min): 9.3) to afford the desired product as a white solid (49.6 mg, 70.1% yield). LCMS 41 (Method B) (ESI) C14H12N2S calcd: 240.07; Found [M+H]+:241. 'H NMR (300 MHz, CD3OD) δ 8.35 - 8.30 (m, 1H), 8.13 - 8.05 (m, 1H), 7.67 - 7.59 (m, 2H), 6.22 - 6.11 (m, 1H), 3.74 - 3.63 (m, 2H), 3.16 - 3.06 (m, 2H), 2.49 - 2.34 (m, 2H).

[0345] Example 24: Synthesis of {l-[(3R)-piperidin-3-yl]imidazo[4,5-b]pyridin-5- yl}methanol (Compound 193)

[0346] 6-bromo-3-methoxy-2-nitropyridine. A solution of 6-bromo-2-nitropyridin-3-ol (6.00 g, 27.5 mmol), iodomethane (11.72 g, 82.6 mmol) and cesium carbonate (26.9 g, 82.6 mmol) in acetone (50 mL) was stirred overnight at 60 °C under a N2 atmosphere. The reaction mixture was filtered through celite, the filter cake was washed with di chloromethane (4 x 20 mL), and the filtrate concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with 40% of EtOAc in di chloromethane to afford the desired product as a lightyellow solid (5.3 g, 83 % yield). LCMS 54 (ESI) C6HsBrlShCh calcd 231.95; found [M+H]+: 233.

[0347] methyl 5-methoxy-6-nitropyridine-2-carboxylate. A mixture of 6-bromo-3-m ethoxy - 2-nitropyridine (2.50 g, 10.73 mmol), [l,l’-Bis (diphenylphosphino) ferrocene] di-chloropalladium(II) (2.36 g, 3.22 mmol) and triethylamine (4.4 mL, 32.2 mmol) in MeOH (30 mL) and DMSO (90 mL) was stirred for 4 h at 100 °C under a CO atmosphere. The resulting mixture was filtered through celite and the filter cake was washed with methanol (5 x 10 mL). The resulting mixture was diluted with brine (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with 50% of EtOAc in petroleum ether to afford the desired product as a light brown solid (1.5 g, 66 % yield). LCMS 49 (Method J) (ESI) C8HsNiOs calcd 212.04; found [M+H]+: 213. 'H NMR (300 MHz, CDC13) 8 8.37 (d, J= 8.6 Hz, 1H), 7.60 (d, J= 8.6 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H).

[0348] methyl 5-{[(3R)-l-(tert-butoxycarbonyl)piperidin-3-yl]andno}-6-nitropyridine-2- carboxylate. A solution of methyl 5-methoxy-6-nitropyridine-2-carboxylate (1.00 g, 4.71 mmol) and tert-butyl (37?)-3-aminopiperidine-l-carboxylate (1.04 g, 5.18 mmol) in DMF (5 mL) was stirred for 20 hours at 70 °C before being concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluted with 40% of EtOAc in petroleum ether to afford the desired product as a yellow solid (700 mg, 39 % yield). LCMS 49 (Method J) (ESI) C17H24N4O6 calcd 380.17; found [M+H]+: 381

[0349] methyl 6-anuno-5-{[(3R)-l-(tert-butoxycarbonyl)piperidin-3-yl]amino}pyridine-2- carboxylate. A mixture of methyl 5-{[(37?)-l-(tert-butoxycarbonyl) piperi din-3 -yl] amino}-6- nitropyridine-2-carboxylate (700 mg, 1.84 mmol) and Pd / C (140 mg, 1.32 mmol) in MeOH (10 mL) was stirred for 15 minutes at room temperature under a H2atmosphere. The resulting mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with 3% MeOH in di chloromethane to afford the desired product as a yellow solid (400 mg, 62 % yield). LCMS 47 (ESI) C17H26N4O4 calcd 350.20; found [M+H]+: 351

[0350] tert-butyl (3R)-3-[5-(methoxycarbonyl)imidazo[4, 5-b]pyridin-l-yl]piperidine-l- carboxylate. A solution of methyl 6-amino-5-{ [(3A)-l-(terZ-butoxycarbonyl) piperidin-3-yl] amino} pyridine-2-carboxylate (400 mg, 1.14 mmol) and AcOH (0.05 mL, 0.873 mmol) in triethyl orthoformate (5 mL) was stirred overnight at 110 °C before being concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with 5% of MeOH in di chloromethane to afford the desired product as a yellow solid (300 mg, 73 % yield). LCMS 45 (Method F) (ESI) C18H24N4O4 calcd 360.18; found [M+H]+: 361

[0351] tert-butyl (3R)-3-[5-(hydroxymethyl) imidazo [4,5-b] pyridin-l-yl] piperidine-1- carboxylate. To a stirred solution of tert-butyl (37?)-3-[5-(methoxycarbonyl) imidazo[4,5- Z>]pyridin- 1 -yl] piperidine- 1 -carboxylate (300 mg, 0.83 mmol) in THF (10 mL) was added lithium aluminum hydride (158 mg, 4.16 mmol) at it. The reaction mixture was stirred for 30 min at rt before being quenched with methanol (5 mL). The resulting mixture was filtered through celite, the filter cake washed with MeOH (5 x 10 mL) and the filtrate concentrated under reduced pressure to afford the desired product as an orange solid (200 mg, 72 % yield). LCMS 49 (Method K) (ESI) C17H24N4O3 calcd 332.18; found [M+H]+: 333. Used directly in the next step.

[0352] {l-[(3R)-piperidin-3-yl]imidazo[4,5-b]pyridin-5-yl}methanol. To a stirred solution of / ert-butyl (37?)-3-[5-(hydroxymethyl)imidazo[4,5-6]pyridin-l-yl]piperidine-l -carboxylate (200 mg, 0.60 mmol) in 10 mL dichloromethane was added 5 mL TFA dropwise at rt. The resulting mixture was stirred for 30 minutes before adjusting to pH 8 with ammonium bicarbonate (aq) and concentrating under reduced pressure. The residue was purified by chromatography (column, Cl 8; mobile phase, acetonitrile in water (10 mmol / L ammonium bicarbonate), 1% to 20% gradient in 10 min) to afford the desired product as a yellow solid (54.8 mg, 39 % yield). LCMS 49 (Method K) (ESI) C12H16N4O calcd 232.13; found [M+H]+: 233.05. *H NMR (400 MHz, DMSO-cL) 8.55 δ (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 5.40 (s, 1H), 4.66 - 4.55 (m, 3H), 3.49 - 3.41 (m, 1H), 3.26 - 3.18 (m, 2H), 2.86 - 2.84 (m, 1H), 2.17 - 2.15 (m, 2H), 1.95 - 1.93 (m, 1H), 1.79 (d, .7= 20.2 Hz, 1H).

[0353] Example 25: Synthesis of l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridine(Compound 195)

[0354] tert-butyl 3-((2-nitropyridin-3-yl)amino)piperidine-l-carboxylate. To a stirred solution of / e / v-biityl 3-aminopiperidine-l-carboxylate (1.00 g, 4.99 mmol), 3-fluoro-2- nitropyridine (1.06 g, 7.49 mmol) and DIEA (1.94 g, 14.97 mmol) in 10 mL of DMF under N2 was stirred for 2 h at 90 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL), the combinedextracts dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with 20% of ethyl acetate in petroleum ether to afford the desired product as a white solid (1.10 g, 68 % yield). LCMS 61 (ESI) C15H22N4O4calcd 322.16; found [M+H]+: 323.

[0355] Tert-butyl 3-((2-aminopyridin-3-yl)anuno)piperidine-l-carboxylate. To a stirred solution of tert-Butyl 3-[(2-nitropyridin-3-yl)amino]piperidine-l-carboxylate (1.10 g, 3.41 mmol) in 15 mL of MeOH under N2atmosphere was added Zn (1.12 g, 17.06 mmol), NH4CI (0.55 g,10.23 mmol, 3.0 equiv). After 2 h at rt, the reaction mixture was extracted with EtOAc (3 x 50 mL), the combined organic extracts dried over anhydrous Na2SCU, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by chromatography (SiO2) eluting with 30% of ethyl acetate in petroleum ether to afford the desired product as a purple solid (400 mg, 40 % yield). LCMS 60 (ESI) C15H24N4O2calcd 292. 19; found [M+H]+: 293.

[0356] tert-butyl 3-(lH-imidazo[4,5-b]pyridin-l-yl)piperidine-l-carboxylate. A solution of tert-butyl 3-[(2-aminopyridin-3-yl)amino]piperidine-l-carboxylate (430.0 mg, 1.47 mmol) in 10 mL of tri ethyl orthoformate was stirred at 110 °C under N2atmosphere. After 2 hr, the reaction mixture was extracted with EtOAc (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude produce was purified by chromatography (SiO2) eluting with 50% of ethyl acetate in petroleum ether to afford the desired product as a brown solid (180 mg, 40 % yield). LCMS 61 (ESI) C16H22N4O2calcd 302.17; found [M+H]+: 303.

[0357] l-(piperidin-3-yl)-lH-imidazo[4,5-b]pyridine. A solution of / c' / 7-butyl 3- {imidazo[4,5-b]pyridin-l-yl}piperidine-l-carboxylate (180.0 mg, 0.59 mmol) in 2 mL ofHCl / 1,4- dioxane under N2atmosphere was stirred for 1 h at room temperature before being concentrated under reduced pressure. The crude product (75 mg) was purified by Prep-HPLC (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: 10 mmol / L NH4HC03+0.05% NELEbO, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 1% B to 15% B in 8 min; waveLength: 254 nm / 220 nm) to afford the desire product as a light yellow solid (37.5 mg, 31 % yield). LCMS 48 (Method H) (ESI) C11H14N4 calcd 202.12; found [M+H]+: 203. 'H NMR (300 MHz, CDCI3) 8 δ.60 (dd, J = 4.7, 1.5 Hz, 1H), 8.38 (s, 1H), 7.82 (dd, J= 8.1, 1.5 Hz, 1H), 7.27 -7.23 (m, 1H), 4.43 (ddd, J = 14.3, 10.0, 3.9 Hz, 1H), 3.55 - 3.39 (m, 1H), 3.16 (dd, J = 12.1, 4.0 Hz, 1H), 3.04 (dd, J = 11.6, 9.8 Hz, 1H), 2.80 (td, J= 11.4, 3.0 Hz, 1H), 2.30 (dd, J= 12.5, 4.5 Hz, 1H), 2.16 - 1.93 (m, 2H), 1.86 - 1.67 (m, 1H).

[0358] Example 26: Synthesis of synthesis of 5-(2,5-dimethoxy-4-methylphenyl)-l, 2,3,6- tetrahydropyridine (Compound 250)

[0359] tert-butyl 3-(2,5-dimethoxy-4-methylphenyl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of l-bromo-2,5-dimethoxy-4-methylbenzene (300.0 mg, 1.29 mmol), tert- butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-277-pyridine-l-carboxylate (602.1 mg, 1.94 mmol), Pd(dppf)Ch (94.9 mg, 0.13 mmol), K2CO3(538.2 mg, 3.89 mmol) and H2O (3 mL) in dioxane (6 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The mixture was diluted with H2O (100 mL) and it was extracted with ethyl acetate (4 x 100 mL). The combined organic phase was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (6: 1) to afford the desired product as a white solid, 150.0 mg, 34.6% yield. LCMS 53 (Method M) (ESI) [M+H]+: 218.1HNMR (400 MHz, DMSO-Je) δ 6.83 (s, 1H), 6.67 (s, 1H), 5.83 (s, 1H), 4.11 (s, 1H), 3.71 (d, J= 12.5 Hz, 5H), 3.45 (t, J= 5.8 Hz, 2H), 2.21 - 2.08 (m, 2H), 2.14 (s, 3H), 1.41 (d, J= 5.4 Hz, 9H), 1.21 (s, 2H).

[0360] 3-(2,5-dimethoxy-4-methylphenyl)-l,2,5,6-tetrahydropyridine. A solution of tert- butyl 3-(2,5-dimethoxy-4-methylphenyl)-5,6-dihydro-2Z7-pyridine-l -carboxylate (150.0 mg, 0.45 mmol, 1.0 equiv) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure; the residue was dissolved with MeOH (2 mL) and basified to pH 8 with saturated ISfeCCL (aq.). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, acetonitrile in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. to afford the desired product as a white solid, 52.7 mg, 50.2% yield. LCMS 40 (ESI) [M+H]+: 234. 'H NMR (400 MHz, DMSO-d6) 6 δ.78 (s, 1H), 6.62 (s, 1H), 5.88 - 5.66 (m, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 3.42 (s, 2H), 2.80 - 2.67 (m, 2H), 2.12 (s, 3H), 2.10 - 1.98 (m, 2H).

[0361] Example 27: Synthesis of 7-(5-methyl-l,3,4-oxadiazol-2-yl)-3-(l,2,5,6- tetrahydropyridin-3-yl)-lH-indazole (Compound 305)

[0362] 3-Bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylate. To a stirred solution of methyl 3-bromo-177-indazole-7-carboxylate (2.00 g, 7.84 mmol) and NaH (0.30 g, 12.54 mmol) in dimethylformamide (20 mL) was added SEM-C1 (3.90 g, 23.52 mmol) at 0 °C. The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The reaction was quenched by the addition of NH4CI (aq.) (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a colorless oil (2.60 g, 86.0% yield). LCMS 52 (Method A) (ESI) C1sLEiBrlSbOaSi calcd 384.05; Found [M+H]+:385. 'H NMR (400 MHz, CDCI3) δ 8.11 (d, J = 7.4, 1.2 Hz, 1H), 7.94 (d, J= 8.0, 1.2 Hz, 1H), 7.40 (d, J= 7.7 Hz, 1H), 6.15 (s, 2H), 4.11 (s, 3H), 3.48 - 3.37 (m, 2H), 0.93 - 0.82 (m, 2H), 0.06 (s, 9H).

[0363] 3-Bromo-l-{[2-(trimethylsilyl)ethoxy Jmethyl}indazoIe-7-carbohydrazide. A solution of methyl 3-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7-carboxylate (2.60 g, 6.74 mmol) in hydrazine hydrate (30 mL) and ethyl alcohol (30 mL). was stirred overnight at 100 °C under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 61% gradient in 20 min; UV 254 nm to afford the desired product as a white solid (2.00 g, 76.9% yield). LCMS 53 (Method M) (ESI) C14H2iBrN4O2Si calcd384.06[M+H]+:385. 'H NMR (400 MHz, CDCh) δ 7.83 (d, J= 8.1, 1.1 Hz, 1H), 7.64 (d, J= 7.2, 1.1 Hz, 1H), 7.34 (d, J= 6.6, 1.5 Hz, 1H), 5.90 (s, 2H), 3.53 - 3.47 (m, 2H), 0.91 - 0.83 (m, 2H), 0.06 (s, 9H).

[0364] 3-Bromo-7-(5-methyl-l ,3,4-oxadiazol-2-yl)-l -{[2-(trimethylsilyI)ethoxy] methyl}indazole. A solution of 3-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}indazole-7- carbohydrazide (1.00 g, 2.59 mmol) and 4-m ethylbenzene- 1 -sulfonic acid hydrate (197.4 mg, 1.03 mmol) in triethyl orthoacetate (10 mL) was stirred overnight at 120 °C under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 75% gradient in 30 min; UV 254 nm to afford the desired product as a white solid (300.0 mg, 28.2% yield). LCMS 53 (Method M) (ESI) C1eftiBr^ChSi calcd 408.06; Found [M+H]+:409.

[0365] tert-Butyl 3-[7-(5-methyl-l,3,4-oxadiazol-2-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}indazol-3-yl]-5, 6-dihydro-2H-pyridine-l-carboxylate. To a stirred solution of 3-bromo-7-(5-methyl-l,3,4-oxadiazol-2-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl [indazole (300.0 mg, 0.73 mmol) and / c / v-butyl 3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-27 / -pyridine-l-carboxylate (339.9 mg, 1.09 mmol) in dioxane (5 mL) and H2O (5 mL) was added K2CO3(303.8 mg, 2.19 mmol) and Pd(dppf)Ch (26.8 mg, 0.03 mmol). The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic extractss were washed with water (3x3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 4: 1) to afford the desired product as a colorless oil (350.0 mg, 93.3% yield). LCMS 52 (Method A) (ESI) C26H37NsO4Si calcd 511.26; Found [M+H]+:512. 'H NMR (400 MHz, CDCh) 8.29 δ (d, J = 8.2, 1.0 Hz, 1H), 7.99 (d, J= 7.3, 1.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 6.79 (d, J= 4.2, 1.9 Hz, 1H), 6.27 (s, 2H), 4.67 (s, 2H), 3.82 (d, J= 5.7 Hz, 2H), 3.40 (d, J= 8.1 Hz, 2H), 2.82 (s, 3H), 2.65 - 2.56 (m, 2H), 1.69 (s, 9H), 0.81 (d, J= 8.0 Hz, 2H), 0.06 (s, 9H).

[0366] 7-(5-Methyl-l,3, 4-oxadiazol-2-yl)-3-(l,2, 5, 6-tetrahydropyridin-3-yl)-lH-indazole.To a stirred solution of tert-butyl 3-[7-(5-methyl-l,3,4-oxadiazol-2-yl)-l-{[2- (trimethylsilyl)ethoxy]methyl }indazol-3-yl]-5,6-dihydro-2H-pyridine-l-carboxylate (200.0 mg, 0.39 mmol) in dioxane (5 mL) was added HC1 (gas) in 1,4-dioxane (5 mL, 4 M) dropwise. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The mixturewas concentrated under reduced pressure and diluted with DCM (5 mL). Then it was basified to pH 10 with saturated Na2COs (aq ). After concentration, the residue was purified by reversed- phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 60% gradient in 30 min; UV 254 nm to afford the desired product as a yellow solid (37.3 mg, 33.9% yield). LCMS 63 (Method P) (ESI) C15H15N5O calcd 281.13; Found [M+H]+: 282.10.1NMR (300 MHz, DMSO-c / 6) δ 13.17 (s, 1H), 8.2 δ4 (d, J = 8.3, 1.0 Hz, 1H), 7.97 (dd, J= 7.3, 0.9 Hz, 1H), 7.34 (d, J= 8.2, 7.3 Hz, 1H), 6.68 (s, 1H), 3.75 (d, J= 2.9 Hz, 2H), 2.90 (t, J= 5.7 Hz, 2H), 2.65 (s, 3H), 2.26 (s, 2H).

[0367] Example 28: Synthesis of 7-(l-methyl-l,2,3-triazol-4-yl)-3-(l,2,5,6- tetrahydropyridin-3-yl)-lH-indazole; formic acid (Compound 309)

[0368] l-{[2-(Trimethylsilyl)ethoxy]methyl}-7-[2-(trimethylsilyl)ethynyl]indazole. To a stirred solution of 7-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}indazole (2.00 g, 5.343 mmol), Pd(PPh3)2Ch (375.1 mg, 0.534 mmol) and trimethylsilylacetylene (787.2 mg, 8.015 mmol) in TEA (20 mL) was added Cui (203.5 mg, 1.068 mmol). The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was fdtered, the residue was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford the crude product as a yellow oil (2.37 g, 94.4% yield). The crude product was used in the next step directly without further purification. LCMS 54 (ESI) C1sH2sN2OSi2 calcd 344. 17; Found [M+H]+:345.

[0369] 7-Ethynyl-l-{[2-(trimethylsilyl)ethoxy]methyl}indazole. A solution of l-{[2- (trimethylsilyl)ethoxy]methyl}-7-[2-(trimethylsilyl)ethynyl]indazole (2.37 g, 6.877 mmol) and K2CO3(1.91 g, 13.754 mmol) in MeOH and DCM (10 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum and extracted with CH2CI2 (3 x 30 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous ISfeSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1). to afford the desired product as a yellow oil (650.0 mg, 34.6% yield). LCMS 61 (ESI) C1sFLo^OSi calcd 272.13; Found [M+H]+:273.JH NMR (400 MHz, CDCI3) 5 8.25 (s, 1H), 7.96 - 7.94 (m, 1H), 7.81 - 7.77 (m, 1H), 7.37 - 7.31 (m, 1H), 6.31 (s, 2H), 3.89 - 3.74 (m, 2H), 3.66 (s, 1H), 1.15 - 1.00 (m, 2H), 0.11 (s, 9H).

[0370] l-{[2-(trimethylsilyl)ethoxy]methyl}-7-{l-[(trimethylsilyl) methyl]-!, 2, 3-triazol-4- yl}indazole. A solution of CuBr (349.1 mg, 2.434 mmol) in DMF (2 mL) was treated with (2-{[2- (dimethylamino)ethyl](methyl)amino}ethyl)dimethylamine (454.8 mg, 2.625 mmol) for 20 min at room temperature under an N2 atmosphere followed by the addition of 7-ethynyl-l-{[2- (trimethylsilyl)ethoxy]methyl} indazole (650.0 mg, 2.386 mmol) in DMF (5 mL) in portions at room temperature. The resulting mixture was stirred for 5 min at room temperature under an N2 atmosphere. To the above mixture was added (azidomethyl) trimethylsilane (259.0 mg, 2.004 mmol) in DMF (3 mL). The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow oil (750.0 mg, 78.2% yield). LCMS 54 (ESI) C19H3iNsOSi2 calcd 401.21; Found [M+H]+:402. 'll NMR (400 MHz, CDCI3) 5 8.38 (s, 1H), 8.19 (s, 1H), 8.08 (d, J= 8.0, 1.2 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.53 (d, J= 7.6 Hz, 1H), 5.79 (s, 2H), 4.33 (s, 2H), 3.76 - 3.68 (m, 2H), 1.05 - 0.94 (m, 2H), 0.51 (s, 9H), 0.20 (s, 9H).

[0371] 7-(l-((trimethylsilyl)methyl)-lH-l,2,3-triazol-4-yl)-lH-indazole. A solution of 1- { [2-(trimethylsilyl)ethoxy]methyl}-7-{l-[(trimethylsilyl)methyl]-l, 2, 3-triazol-4-yl (indazole (750.0 mg, 1.867 mmol) in HC1 (5 mL) and dioxane (5 mL) was stirred for 1 h at 60 °C under an N2 atmosphere. The resulting mixture was concentrated under vacuum to afford the crude productas a yellow oil (476.7 mg, 94.1% yield). The crude product was used in the next step directly without further purification LCMS 52 (Method B) (ESI) CnHivNsSi calcd 271.13; Found [M+H]+:272.

[0372] 7-(l-methyl-l,2,3-triazol-4-yl)-lH-indazole. To a stirred mixture of 7-(l- ((trimethylsilyl)methyl)-l / / -l,2,3-triazol-4-yl)-l / / -indazole (476.7 mg, 1.867 mmol) in THF (10 mL) was added TBAF (3.73 mL, 3.734 mmol) in portions at 0 °C. The resulting mixture was stirred for 30 min at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (0. 1% FA), 0% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a yellow oil (300.0 mg, 85.7% yield). LCMS 50 (Method B) (ESI) C10H9N5 calcd 199.09; Found [M+H]+: 200. *H NMR (400 MHz, CDCI3) δ 11.76 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.55 (d, J = 7.1 Hz, 1H), 7.20 (d, J= 7.6 Hz, 1H), 4.21 (s, 3H).

[0373] 3-iodo-7-(l-tnethyl-l,2,3-triazol-4-yl)-lH-indazole. To a stirred mixture of 7-(l- methyl-l,2,3-triazol-4-yl)-l / / -indazole (300.0 mg, 1.506 mmol) and NIS (406.5 mg, 1.807 mmol) in THF (5 mL) was added K2CO3(208.1 mg, 1.506 mmol). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was extracted with CH2Q2 (3 x 5 mL). The combined organic extracts were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a yellow solid (280.0 mg, 57.1% yield). LCMS 54 (ESI) C10H8IN5calcd 324.98; Found [M+H]+:326. ’H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 8.77 (s, 1H), 7.89 (d, J= 7.2 Hz, 1H), 7.44 (d, J= 8.1 Hz, 1H), 7.31 (d, .7= 7.6 Hz, 1H), 4.17 (s, 3H).

[0374] tert-Butyl 3-[7-(l-methyl-l,2,3-triazol-4-yl)-lH-indazol-3-yl]-5,6-dihydro-2H- pyridine-l-carboxylate. A mixture of 3-iodo-7-(l-methyl-l,2,3-triazol-4-yl)-177-indazole (200.0 mg, 0.615 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / 7- pyridine-1 -carboxylate (190.2 mg, 0.615 mmol), Pd(dppf)C12 (45.7 mg, 0.06 mmol) and K2CO3(255.1 mg, 1.845 mmol) in dioxane (1.2 mL) and H2O (0.6 mL) was stirred for 1 h at 80 °C under an N2 atmosphere. The residue was purified by reversed-phase flash chromatography with thefollowing conditions: column, C1s silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 60% gradient in 30 min; UV 254 nm to afford the desired product as a yellow solid (100.0 mg, 42.7% yield). LCMS 50 (Method B) (ESI) C20H24N6O2 calcd 380.20; Found [M+H]+:381. 'H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.75 (s, 1H), 7.99 (d, J= 8.2 Hz, 1H), 7.82 (d, J= 7.2 Hz, 1H), 7.26 (d, J= 7.7 Hz, 1H), 6.73 (s, 1H), 4.44 (s, 2H), 4.17 (s, 3H), 3.56 (d, J= 5.8 Hz, 2H), 2.38 (d, J = 6.1 Hz, 2H), 1.45 (s, 9H).

[0375] 7-(l-Methyl-l,2,3-triazol-4-yl)-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole; formic acid To a stirred mixture of tert-butyl 3-[7-(l -methyl-l ,2,3-triazol-4-yl)- l / / -indazol-3-yl]- 5,6-dihydro-2 / f-pyridine-l-carboxylate (120.0 mg, 0.315 mmol) in dioxane (1 mL) was added HC1 (gas) in 1,4-dioxane (1 mL). The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column 30*150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60mL / min mL / min; Gradient: 2% B to 15% B in 9 min; Wave Length: 254 nm / 220 nm; RTl(min): 8.68 / 9.42) to afford the desired product as a white solid (14.8 mg, 14.3% yield). LCMS 51 (Method L) (ESI) C1sHieNe calcd 280.14; Found [M+H]+: 281.20. 'H NMR (400 MHz, DMSO-<A) 8. δ74 (s, 1H), 7.96 (d, J= 8.2 Hz, 1H), 7.81 (d, J= 7.1 Hz, 1H), 7.23 (d, J= 7.7 Hz, 1H), 6.65 (d, J= 4.0 Hz, 1H), 4.17 (s, 3H), 3.76 (d, J = 2.3 Hz, 2H), 2.90 (d, J= 5.6 Hz, 2H), 2.30 - 2.24 (m, 2H).

[0376] Example 29: Synthesis of 7-cyclopropyl-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indazole (Com

[0377] 7-Cyclopropyl-l-{[2-(trimethylsilyl)ethoxy]methyl}indazole. A solution of 7-bromo- l-{[2-(trimethylsilyl)ethoxy]methyl (indazole (3.00 g, 9.16 mmol), cyclopropyltrifluoro-lambda4- borane potassium (1.63 g, 10.99 mmol), Pd(dppf)C12 (670.6 mg, 0.91 mmol) and K2CO3(3.80 g,27.49 mmol) in 1,4-dioxane (60 mL) and H2O (30 mL) was stirred for 3 h at 100 °C under an N2 atmosphere. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3:1) to afford the desired product as a yellow oil (600 mg, 22.6% yield). LCMS 42 (Method A) (ESI) C16H24N2OSi calcd 288. 17; Found [M+H]+:289.

[0378] 7-Cydopropyl-lH-indazole. To a stirred solution of 7-cyclopropyl-l-{[2- (trimethylsilyl)ethoxy]methyl}indazole (600.0 mg, 2.08 mmol) in 1,4-dioxane (6 mL) was added HC1 (6 mL, 4 M in 1,4-dioxane) at room temperature. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure, dissolved in MeOH (2 mL) and basified to pH 9 with saturated Na2COi (aq.). The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (lOmmol / L NH4HCO3), 0% to 50% gradient in 20 min; UV 254 nm to afford the desired product as a yellow oil (200 mg, 60.7% yield). LCMS 42 (Method A) (ESI) C10H10N2 calcd 158.08; Found [M+H]+: 159.

[0379] 7-cydopropyl-3-iodo-lH-indazole. To a stirred solution of 7-cycl opropyl -1 H- indazole (200.0 mg, 1.26 mmol) in DMF (3 mL) was added NIS (341.3 mg, 1.51 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere and extracted with EtOAc (20 mL). The combined organic extracts were washed with water (3x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3: 1) to afford the desired product as a yellow oil (160 mg, 44.5% yield). LCMS 42 (Method A) (ESI) C10H9IN2 calcd 283.98; Found [M+H]+:285.

[0380] tert-Butyl 3-(7-cydopropyl-lH-indazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 7-cyclopropyl-3-iodo-l / / -indazole (150.0 mg, 0.52 mmol), tert-Butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l -carboxylate (195.9 mg, 0.63 mmol), Pd(dppf)Ch (38.6 mg, 0.05 mmol) and K2CO3(218.9 mg, 1.58 mmol) in 1,4- dioxane (4 mL) and H2O (2 mL) was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA(3: 1) to afford the desired product as a yellow oil (140 mg, 78.1% yield). LCMS 49 (Method J) (ESI) C20H25N3O2 calcd 339.19; Found [M+H]+:340.

[0381] 7-Cyclopropyl-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole. To a stirred solution of tert-butyl 3-(7-cyclopropyl-177-indazol-3-yl)-5,6-dihydro-277-pyridine-l-carboxylate (100.0 mg, 0.29 mmol) in 1,4-di oxane (0.5 mL) was added HC1 (0.5 mL, 4 M in 1,4-di oxane) at room temperature under an N2 atmosphere and stirred for 1 h at room temperature under an N2 atmosphere. The mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1 mL) and it was basified to pH 9 with saturated Na2CCh (aq.). The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 3% B in 1 min, 3% B to 20% B in 2 min, 20% to 38% B in 10 min; Wave Length: 254 nm / 220 nm nm; RTl(min): 8.52) to afford the desired product as a white solid (43.4 mg, 61.5% yield). LCMS 41 (Method B) (ESI) C15H17N3 calcd 239.14; Found [M+H]+:240. ’H NMR (300 MHz, CD3OD) 5 7.81 - 7.71 (m, 1H), 7.15 - 7.04 (m, 1H), 7.03 - 6.92 (m, 1H), 6.73 - 6.62 (m, 1H), 4.04 - 3.93 (m, 2H), 3.18 - 3.07 (m, 2H), 2.53 - 2.40 (m, 2H), 2.28 - 2. 14 (m, 1H), 1.12 - 0.99 (m, 2H), 0.85 - 0.70 (m, 2H).

[0382] Example 30: Synthesis of 7-chloro-6-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-IH-indazole (Compound 513)

[0383] (E)-[(3-Chloro-2,4-difluorophenyl) methylidene] hydrazine . To a stirred solution of 3-chloro-2,4-difluorobenzaldehyde (2 g, 11.33 mmol) in EtOH (10 mL) were added hydrazine hydrate (5.67 g, 113.28 mmol) in portions and stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography(SiO2) eluting with PE / EA (1 : 1) to afford the desired product as a white solid (1.3 g, 60.2% yield). LCMS 60 (ESI) C7H5CIF2N2 calcd 190.01; Found [M+H]+: 191.

[0384] 7-Bromo-6-fluoro-lH-indazole. A solution of (£)-[(3-chloro-2,4-difluorophenyl) methylidene] hydrazine (1.3 g, 6.82 mmol) in ethylene glycol (10 mL) was stirred for 2 h at 120 °C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1:1) to afford the desired product as a white solid (800 mg, 54.5% yield). LCMS 60 (ESI) C7H4CIFN2 calcd 170; Found[M+H]+:171. 'HNMR (400 MHz, DMSO-d6) δ 13.74 (s, 1H), 8.27 - 8.16 (m, 1H), 7.81 (dd, J= 8.8, 4.6 Hz, 1H), 7.25 - 7.13 (m, 1H).

[0385] 7-Chloro-6-fluoro-3-iodo- 1 H-indazole. To a stirred solution of 7-chloro-6-fluoro- l / / -indazole (800 mg, 4.69 mmol) and KOH (526.3 mg, 9.38 mmol) in DMF (10 mL) was added I2 (1428.5 mg, 5.63 mmol) in portions at 0 °C. The resulting mixture was stirred for 20 min at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desired product as a white solid (550 mg, 39.5% yield).1HNMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 7.47 (dd, J = 8.8, 4.5 Hz, 1H), 7.33 - 7.21 (m, 1H).

[0386] tert-Butyl 3-(7-chloro-6-fluoro-lH-indazol-3-yl)-5, 6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of 7-chloro-6-fluoro-3-iodo-l / 7-indazole (550 mg, 1.86 mmol), tot-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / 7-pyridine-l- carboxylate (860.5 mg, 2.78 mmol) in H2O (2 mL) and dioxane (10 mL) were added K2CO3(769.2 mg, 5.57 mmol) and Pd(dppf)C12 (271.5 mg, 0.37 mmol) at room temperature. The resulting mixture was stirred for 1 h at 80 °C. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL), the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desired product as a white solid (380 mg, 58.2% yield). LCMS 60 (ESI) C17H19CIFN3O2 calcd 351.11; Found [M+H]+:352.

[0387] 7-Chloro-6-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole. To a stirred solution of tert-Butyl 3-(7-chloro-6-fluoro-l / 7-indazol-3-yl)-5,6-dihydro-2 / 7-pyridine-l- carboxylate (360 mg, 1.02 mmol) in DCM (2 mL) were added TFA (2 mL) in portions and stirred for 20 min at room temperature. The resulting mixture was concentrated under reduced pressure.The crude product (180 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 20% B in 2 min, 20% to 38% B in 10 min) to afford the desired product as a white solid (156.7 mg, 48.6% yield). LCMS 63 (Method Q) (ESI) C12H11CIFN3 calcd 251.06; Found [M+H]+:251.95.1HNMR (400 MHz, DMSO-t76+D2O) δ 8.10 - 8.02 (m, 1H), 7.31 - 7.23 (m, 1H), 6.88 - 6.81 (m, IH), 4.17 - 4.10 (m, 2H), 3.38 - 3.27 (m, 2H), 2.65 - 2.55 (m, 2H).

[0388] Example 31: Synthesis of 6-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indazole-7-carbonitrile (Compound 514)

[0389] (E)-[(3-Bromo-2, 4-difluorophenyl)methylidene]hydrazine. To a stirred solution of 3 - bromo-2,4-difluorobenzaldehyde (1.5 g, 6.79 mmol) in EtOH (20 mL) was added hydrazine hydrate (3.4 g, 67.87 mmol) in portions at room temperature. The resulting mixture was stirred overnight at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desired product as a white solid (1.2 g, 75.2% yield). LCMS 60 (ESI) C7H5BrF2N2 calcd 233.96; Found[M+H]+:235.

[0390] 7-Bromo-6-fluoro-lH-indazole. A solution of (£)-[(3-bromo-2,4- difluorophenyl)methylidene]hydrazine (1.2 g, 5.11 mmol) in ethylene glycol dimethyl ether (20 mL) was stirred overnight at 120 °C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desired product as a white solid (800 mg, 72.8% yield). LCMS 60 (ESI) C7H4BrFN2calcd 213.95; Found [M+H]+:215.

[0391] 6-Fluoro-lH-indazole-7-carbonitrile. To a stirred solution of 7-bromo-6-fluoro-l / 7- indazole (800 mg, 3.72 mmol) in DMF (10 mL) were added Zn(CN)? (0.87 g, 7.44 mmol) and Pd(PPha)4 (0.86 g, 0.74 mmol) at room temperature. The resulting mixture was stirred for 1 h at 60 °C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (Si O2) eluting with PE / EA (1 : 1) to afford the desired product as a white solid (350 mg, 58.3% yield). LCMS 60 (ESI) C8TUFNa calcd 161.04; Found [M+H]+: 162.

[0392] 6-Fluoro-3-iodo-lH-indazole-7-carbonitrile. To a stirred solution of 6-fluoro-l / T- indazole-7-carbonitrile (350 mg, 2.17 mmol) in DMF (10 mL) were added KOH (365.6 mg, 6.52 mmol) and I2 (826.9 mg, 3.26 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature, diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL), the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (L I) to afford the desired product as a white solid (300 mg, 48.1% yield). LCMS 60 (ESI) C8H3FIN3calcd 286.94; Found [M+H]+:288.

[0393] tert-Butyl 3-(7-cyano-6-fluoro-lH-indazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of 6-fluoro-3-iodo-l / 7-indazole-7-carbonitrile (290 mg, 1.01 mmol), Ze / 7-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2 / Z-pyridine-l- carboxylate (468.6 mg, 1.52 mmol) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (148 mg, 0.20 mmol) and K2CO3(419 mg, 3.03 mmol) at room temperature. The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (1 : 1) to afford the desired product as a white solid (190 mg, 54.9% yield). LCMS 53 (Method L) (ESI) C18H19FN4O2 calcd 342.15; Found [M+H]L343.

[0394] 6-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole- 7-carbonitrile; formic acid. To a stirred solution of tert-butyl 3-(7-cyano-6-fluoro-l / f-indazol-3-yl)-5,6-dihydro-2 / f- pyridine-1 -carboxylate (100 mg, 0.29 mmol) in DCM (2 mL) was added TFA (2 mL) in portions at room temperature. The resulting mixture was stirred for 30 min at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions (Column: C1s silica gel; mobile phase, ACN in water (0.1% FA), 5% to 100% gradient in 30 min) to afford the desired product as a white solid (39.3 mg, 46.6% yield). LCMS 40 (ESI) C13H11FN4 calcd 242.10;Found [M+H]+:243.25. 'H NMR (400 MHz, DMSO-i / 6) 10 δ.86 - 10.22(m, 1H), 8.05 (dd, J= 8.1, 4.4 Hz, 1H), 7.16 (dd, J = 11.3, 8.1 Hz, 1H), 6.68 (m, 1H), 4.03 (d, J= 2.5 Hz, 2H), 3.20 (d, J = 12.0 Hz, 2H), 2.47 (d, J= 6.4 Hz, 2H).

[0395] Example 32: Synthesis of 6,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indazole (Compound 517)

[0396] 6, 7-Dif!uoro-3-iodo-lH-indazole. To a stirred solution of 6,7-difluoro- IH-indazole (870.9 mg, 5.65 mmol) and KOH (317.0 mg, 5.65 mmol) in N, / V-dimcthylformamidc (2 mL) were added h (1.72 g, 6.78 mmol). After stirring for 30 min at room temperature, the resulting mixture was quenched with sat. Na2S20s (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (4 x 10 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with 20% of ethyl acetate in petroleum ether to afford the desired product as a white solid (213.0 mg, 13.4% yield). LCMS 54 (ESI) C7H3F2IN2 calcd 279.93; Found [M+H]+:280.

[0397] tert-liuty! 5-(6, 7-difluoro-lH-indazol-3-yl)-3,6-dihydropyridine-2H-pyridine-l- carboxylate. To a solution of 6,7-difluoro-3-iodo-l / / -indazole (208.0 mg, 0.74 mmol) and K2CO3(205.3 mg, 1.47 mmol) in H2O (1 mL) and 1,4-dioxane (4 mL) were added tert-butyl 5-(4,4,5- tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)-3,6-dihydro-2rt-pyridine- l -carboxylate (367.5 mg, 1.19 mmol) and Pd(dppf)C12 (163.1 mg, 0.22 mmol). After stirring for 30 min at 85 °C under an N2 atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, acetonitrile in water (0.1% FA), 1% to 99% gradient in 20 min; detector, UV 254 nm to afford the desired product as a brown solid (230.0 mg, 92.3% yield). LCMS 54 (ESI) C17H19F2N3O2 calcd 335.14; Found [M+H]+:336.

[0398] 6, 7-Difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole. To a stirred solid of tert-butyl 5-(6,7-difluoro-l / / -indazol-3-yl)-3,6-dihydropyridine-2rt-pyri dine- 1 -carboxylate(220.0 mg, 0.66 mmol) was added HC1 (gas) in 1,4-dioxane (13 mL, 4 M). After stirring for 15 min at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 10 with saturated ISfeCCL (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, acetonitrile in water (0.1% FA), 1% to 50% gradient in 25 min; detector, UV220 nm. to afford the desired product as a white solid (58.9 mg, 38.1% yield). LCMS 40 (ESI) C12H11F2N3 calcd 235.09; Found [M+H]+: 236. 'H NMR (400 MHz, DMSO-c / 6) δ 8.35 (s, 1H), 7.84-7.82 (m, 1H), 7.23-7.21 (m, 1H), 6.75 (d, J= 4.1 Hz, 1H), 4.01 - 3.90 (m, 2H), 3.14-3.12 (m, 2H), 2.46-2.44 (m, 2H).

[0399] Example 33: Synthesis of 5,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indazole (Compound 518)

[0400] 5,7-difluoro-lH-indazol-3-amine. To a stirred solution of 2,3,5-trifluorobenzonitrile (1.00 g, 6.36 mmol, 1.0 equiv) in 1-Butanol (15 mL) were added hydrazine hydrate (5 mL, 102.87 mmol, 16.1 equiv) at room temperature. The resulting mixture was stirred for 4 hours at 150 °C under N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with saturated NaCl (aq.) (3 x 20 mL), After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with DCM / MeOH (10: 1). Yellow solid, 750.0 mg, 69.6% yield. LCMS 49 (Method J) (ESI) [M+H]+: 170.

[0401] 5,7-difluoro-3-iodo-lH-indazole. To a stirred solution of 5,7-difluoro- lF / -indazol-3- amine (300.0 mg, 1.77 mmol, 1.0 equiv) in THF (4 mL) was added BFs.Et2O (0.5 mL, 3.94 mmol, 2.2 equiv) and 3-methylbutyl nitrite (0.4 mL) in THF (4 mL) in portions and dropwise at -10 °Cunder N2 atmosphere. The resulting mixture was stirred for 30 min at room temperature. The residue was purified by trituration with ethyl ether (20 mL) to get a black brown solid. The solid then dissolved in propan-2-one (4 mL) with Nal (120.0 mg, 0.80 mmol, 0.5 equiv) was added under an ice-bathed condition. The resulting mixture was stirred for 10 min at room temperature under N2 atmosphere. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with saturated NaCl (aq.) (3 x 10 mL). After filtration, the filtrate was concentrated under reduced pressure. Black solid, 280.0 mg, 56.3% yield. LCMS 49 (Method J) (ESI) [M+H]+:281.

[0402] tert-butyl3-(5, 7-difluoro-lH-indazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate.A mixture of 5,7-difluoro-3-iodo-lrt-indazole (200.0 mg, 0.71 mmol, 1.0 equiv), terLbutyl3- (4, 4, 5,5-tetramethyl- l .3, 2-dioxaborolan-2-yl)-5.6-dihydro-27 / -pyridine- l -carboxylate (450.0 mg, 1.45 mmol, 2.0 equiv), Pd(dppf)Ch (55.0 mg, 0.07 mmol, 0.1 equiv) and K2CO3(300.0 mg, 2.17 mmol, 3.0 equiv) in dioxane (5 mL) and H2O (1 mL) was stirred for 1 hour at 80 °C under N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1). Light yellow solid, 180.0 mg, 75.1% yield. LCMS 49 (Method J) (ESI) [M+H]+:336.

[0403] 5, 7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole. To a stirred solution of tert-butyl 3-(5,7-difluoro-lrt-indazol-3-yl)-5,6-dihydro-2f / -pyridine- l -carboxylate (100.0 mg, 0.29 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature. The resulting mixture was stirred for 10 min at room temperature. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 8 with saturated Na2COa (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, water (0.1% NH4HCO3) in ACN, 0% to 50% gradient in 30 min; UV 254 nm. White solid, 35.5 mg, 50.4% yield. LCMS 40 (ESI) [M+H]+:236.10. ‘H NMR (400 MHz, CD3OD) δ 7.47 (d, J= 9.1 Hz, 1H), 7.06 (d, J= 11.0 Hz, 1H), 6.60 (d, J= 4.1 Hz, 1H), 3.89 (d, J = 2.3 Hz, 2H), 3.07 (d, J= 5.9 Hz, 2H), 2.43 (d, J= 8.5 Hz, 2H).

[0404] Example 34: Synthesis of 4,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indazole (Compound 519)

[0405] 4, 7-difluoro-lH-indazole. To a stirred solution of 2,3,6-trifhiorobenzaldehyde (1.00 g, 6.24 mmol, 1.0 equiv) in DME (5 mL) was added DIEA (2.42 g, 18.73 mmol, 3.0 equiv) and hydrazine hydrate (0.63 g, 12.49 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 2 hours at 80 °C under N2 atmosphere. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1). Light yellow oil, 500.0 mg, 51.9% yield. LCMS 52 (Method B) (ESI) [M+H]+: 155.

[0406] 4, 7-difluoro-3-iodo-lH-indazole. To a stirred mixture of 4, 7-di fl uoro-1 / / -indazole (400.0 mg, 2.59 mmol, 1.0 equiv) and KOH (500.0 mg, 8.91 mmol, 3.4 equiv) in DMF (10 mL) was added I2 (700.0 mg, 2.75 mmol, 1.0 equiv) slowly at room temperature. The resulting mixture was stirred for 2 hours at room temperature under N2 atmosphere. The reaction was quenched by the addition of saturated Na2S2O3 water solution (10 mL) at ice-bathed condition. The aqueous layer was extracted with EA (3 x 10 mL). The resulting mixture was concentrated under reduced pressure. Light yellow oil, 400.0 mg, 55.0% yield. LCMS 49 (Method K) (ESI) [M+H] ' :281.

[0407] tert-butyl3-(4, 7-difluoro-lH-indazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate.To a stirred solution of 4,7-difluoro-3-iodo-l / / -indazole (300.0 mg, 1.07 mmol, 1.0 equiv) and tert-butyl3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyri dine- 1 -carboxylate (662.5 mg, 2.14 mmol, 2.0 equiv) in dioxane (5 mL) was added Pd(dppf)C12 (100.0 mg, 0.14 mmol, 0.1 equiv), K2CO3(450.0 mg, 3.25 mmol, 3.0 equiv) and H2O (1 mL) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred for 2 hours at 80 °C under N2atmosphere. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1). White solid, 320.0 mg, 89.0% yield. LCMS 49 (Method K) (ESI) [M+H]+:336.

[0408] 4,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole. To a stirred solution of tert-butyl 3-(4,7-difluoro-lZ / -indazol-3-yl)-5,6-dihydro-2f / -pyridine-l-carboxylate (150.0 mg, 0.44 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL) dropwise at room temperature. The resulting mixture was stirred for 10 min at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with saturated Na2COs water solution. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8; mobile phase, (0.1% NH4HCO3) water in ACN, 0% to 50% gradient in 30 min; UV 254 nm. White solid, 30.2 mg, 28.5% yield. LCMS 40 (ESI) [M+H]+:236.10.XH NMR (300 MHz, CDCI3) 7.0 δ0 (s, 1H), 6.71 (s, 2H), 3.97 - 3.90 (m, 2H), 3.11 (s, 2H), 2.37 (s, 2H).

[0409] Example 35: Synthesis of 5-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indazole-7-carbonitrile (Compound 520)

[0410] 5-fluoro-lH-indazole-7-carbonitrile. A solution of 7-bromo-5-fluoro- l / / -indazole (500.0 mg, 2.33 mmol, 1.0 equiv) and Zn(CN)2(273.0 mg, 2.33 mmol, 1.0 equiv) in DMA (5.0 mL) was stirred for 2 h at 120 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desiredproduct as a yellow solid (300.0 mg, 80.1% yield). LCMS 60 (ESI) C8EUFNs calcd 161.04; Found [M+H]+: 162. 'H NMR (400 MHz, DMSO-r / 6) 14 δ.15 (s, 1H), 8.32 (s, 1H), 8.08 - 7.98 (m, 2H).

[0411] 5-fluoro-3-iodo-lH-indazole-7-carbonitrile. A solution of 5-fluoro-17 / -indazolc-7- carbonitrile (400.0 mg, 2.48 mmol) and NIS (558.5 mg, 2.48 mmol) in DMF (5.0 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 10 mL), and dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (300.0 mg, 42.1% yield). LCMS 60 (ESI) C8H3FIN3 calcd 286.94; Found [M+H]+:288. 'H NMR (400 MHz, DMSO-d6) 1 δ4.58 (s, 1H), 8.17 - 8.13 (m, 1H), 7.74 - 7.69 (m, 1H).

[0412] tert-Butyl 3-(7-cyano-5-fluoro-lH-indazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. To a stirred solution of 5-fluoro-3-iodo-177-indazole-7-carbonitrile (300.0 mg, 1.05 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l- carboxylate (484.8 mg, 1.57 mmol) in dioxane (4.0 mL) was added Pd(dppf)Ch.CH2C12 (42.6 mg, 0.05 mmol), K2CO3(433.3 mg, 3.14 mmol) at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (200.0 mg, 55.9% yield). LCMS 60 (ESI) C18H19FN4O2 calcd; Found 342.15 [M-H]’: 341.XH NMR (400 MHz, DMSO-d6) 14.06 δ (s, 1H), 8.27 - 8.18 (m, 1H), 8.03 (m, 1H), 6.79 - 6.73 (s, 1H), 4.40 - 4.35 (m, 2H), 3.54 (d, J= 5.8 Hz, 2H), 2.42 - 2.28 (m, 2H), 1.48 - 1.42 (m, 9H).

[0413] 5-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole-7-carbonitrile. A solution of Zcrt-butyl 3-(7-cyano-5-fluoro-l / / -indazol-3-yl)-5,6-dihydro-2 / 7-pyridine-l-carboxylate (100.0 mg, 0.29 mmol, 1.0 equiv) in dioxane (0.5 mL) and HCl(gas) in 1,4-dioxane (0.5 mL) was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 10 with saturated Na2CCh (aq ). The crude product (100.0 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep Cl 8 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water(0.1% NH4HCO3), Mobile Phase B: ACN; Flow rate: 60.0 mL / min mL / min; Gradient: 5% B to 22% B in 30 min; WaveLength: 254nm / 220nm nm; RTl(min): 9.68) to afford the desired product as a yellow solid (23.2 mg, 32.8% yield). LCMS 48 (Method I) (ESI) C13H11FN4 calcd 242.10; Found [M - H]‘: 241.20.NMR (400 MHz, DMSO-d6) 8 δ.20 (d, J= 9.2 Hz, 1H), 8.05 - 7.98 (m, 1H), 6.65 (s, 1H), 3.71 (s, 2H), 2.93 - 2.84 (m, 2H), 2.24 (s, 2H).

[0414] Example 36: Synthesis of 7-chloro-l-isopropyl-3-(l,2,5,6-tetrahydropyridin-3- yl) indole (Compound 525)

[0415] 7-Chloro-l-isopropylindole. To a stirred solution of sodium hydride (1.90 g, 79.16 mmol) in N, A-dimethylformamide (15 mL) was added indole-7-chloro (3.00 g, 19.79 mmol) in N, A-dimethylform amide (10 mL) dropwise at 0 °C under an N2 atmosphere. The resulting mixture was stirred for 30 min. To the above mixture was added 2-bromopropane (3.65 g, 29.68 mmol) dropwise. The resulting mixture was stirred for an additional 2 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL). The reaction was quenched by the addition of 1 M hydrochloric acid at 0 °C. The organic layer was washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with petroleum ether / ethyl acetate (17:3) to afford the desired product as a colorless liquid (1.05 g, 27.4% yield). LCMS 54 (ESI) C11H12CIN calcd 193.07; Found [M+H]+: 194. 'H NMR (300 MHz, CDCh) 7.4 δ7 - 7.40 (m, 1H), 7.26 - 7.20 (m, 1H), 7.10 - 7.03 (m, 1H), 6.95 - 6.85 (m, 1H), 6.46 (d, J= 3.3 Hz, 1H), 5.71 - 5.55 (m, 1H), 1.45 (d, J= 6.7 Hz, 6H).

[0416] 3-Bromo-7-chloro-l-isopropylindole. A solution of 7-chloro-l-isopropylindole (1.05 g, 5.42 mmol) in dioxane (10 mL) was treated with l,3-dibromo-5,5-dimethylhydantoin (1.01 g,3.524 mmol) for 25 min at 0 °C under an N2 atmosphere. The resulting mixture was diluted with EtOAc (20 mL). The reaction was quenched by the addition of sat. sodium thiosulfate (aq.) at 0 °C. The organic layer was washed with water (3 x 10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (Si O2) eluting with 3% of ethyl acetate in petroleum ether to afford the desired product as a colorless liquid (1.02 g, 69.0% yield). LCMS 54 (ESI) C1iHiiBrCIN calcd 270.98; Found [M+H]+:272. ' H NMR (400 MHz, CDCI3) δ 7.48 - 7.43 (m, 1H), 7.32 - 7.28 (s, 1H), 7.23 - 7.17 (m, 1H), 7.11 - 7.03 (m, 1H), 5.76 - 5.64 (m, 1H), 1.51 (d, J= 6.7 Hz, 6H).

[0417] tert-Butyl 3-(7-chloro-l-isopropylindol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 3-bromo-7-chloro-l-isopropylindole (1.00 g, 3.67 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-277-pyridine-l-carboxylate (1.70 g, 5.50 mmol) in water (1.5 mL) and dioxane (7.5 mL) was treated with [l,l’-Bis (diphenylphosphino) ferrocene] dichloropalladium(II) (0.54 g, 0.73 mmol) and potassium carbonate (1.01 g, 7.34 mmol) for 3 h at 90 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, acetonitrile in water (0.1% fomic acid), 10% to 95% gradient in 10 min; detector, UV 254 nm to afford the desired product as a brown oil (750.0 mg, 54.5% yield). LCMS 54 (ESI) C21H27CIN2O2 calcd 374.18; Found [M+H]+:375.

[0418] 7-Chloro-l-isopropyl-3-(l,2,5,6-tetrahydropyridin-3-yl) indole. To a stirred solution of / c’ / 'Z-butyl 3-(7-chloro-l-isopropylindol-3-yl)-5,6-dihydro-277-pyridine-l-carboxylate (130.0 mg, 0.34 mmol) in di chloromethane (10 mL) was added hydrochloric acid (gas) in 1,4-dioxane (0.43 mL, 1.74 mmol) dropwise at room temperature. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column: Sunfire prep Cl 8 column 30 * 150 mm, 5 m; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 10% B to 30% B in 9 min; Wave Length: 254 nm / 220 nm to afford the desired product as a white solid (66.0 mg, 59.3% yield). LCMS 40 (ESI) C16H19CIN2 calcd 274.12; Found [M+H]+:275.10. 'H NMR (400 MHz, CD3OD) 5 8.49 (s, 1H), 7.75 - 7.73 (m, 1H), 7.57 (s, 1H), 7.19 - 7.17 (m, 1H), 7.06 - 7.04 (m, 1H), 6.33 - 6.31 (m, 1H),5.76 - 7.54 (m, 1H), 4.06 - 4.04 (m, 2H), 3.41 - 3.39(m, 2H), 2.64 - 2.62 (m, 2H), 1.53 (d, J= 6.7 Hz, 6H).

[0419] Example 37: Synthesis3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indol-4-ol (Compound 527)

[0420] 3-(l,2,5,6-Tetrahydropyridin-3-yl)-lH-indol-4-ol. To a solution of tert-butyl 3-[l- (tert-butoxycarbonyl)-5,6-dihydro-277-pyridin-3-yl]-4-methoxyindole-l-carboxylate (150.0 mg, 0.35 mmol) in di chloromethane (5.0 mL) was added BBr.3 (263.1 mg, 1.05 mmol). The mixture was stirred for 30 min at room temperature. The reaction was quenched with water. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 5% to 95% gradient in 20 min; detector, UV 254 nm to afford the desired product as a black solid (32.3 mg, 41.2% yield). LCMS 41 (Method B) (ESI) C13H14N2O calcd 214.11; Found [M+H]+:215.10. 'll NMR (400 MHz, DMSO-d6) 10.8 δ9 (s, 1H), 7.06 (s, 1H), 6.92 - 6.68 (m, 2H), 6.36 (d, J= 13 Hz, 1H), 5.99 (s, 1H), 4.29 (s, 1H), 3.60 (s, 1H), 3.46 (s, 1H), 2.83 (s, 1H), 2.12 (d, J= 35.5 Hz, 2H).

[0421] Example 38: Synthesis of 7-chloro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indol- 5-ol (Compound 529)

[0422] 7-Chloro-5-methoxy-lH-indole. To a stirred solution of 2-chloro-4-methoxy-l- nitrobenzene (2.00 g, 10.662 mmol) in THF (20 mL) was added bromo(ethenyl)magnesium (37.4 mL, 1 M in THF) dropwise at -40 °C and the resulting mixture was stirred for 0.5 h at -40 °C under an N2 atmosphere. The reaction was quenched with sat. NH4CI (aq.) at -40 °C. The resulting mixture was extracted with CH2C12(3 x 50 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow oil (678 mg, 35.0% yield). LCMS 52 (Method A) (ESI) C9H8C1NO calcd 181.03; Found [M-H]':180. ’H NMR (400 MHz, CDCI3) 8. δ21 (s, 1H), 7.17 (m, 1H), 7.01 (d, J= 2.2 Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 6.49 (m, 1H), 3.82 (s, 3H).

[0423] 7-Chloro-3-iodo-5-methoxy-lH-indole. To a stirred solution of 7-chloro-5-methoxy- 17 / -indole (660.0 mg, 3.634 mmol) in DMF (7 mL) was added NIS (817.5 mg, 3.634 mmol) in portions at 0 °C and stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford to afford the desired product as a yellow solid (760 mg, 68.0% yield). LCMS 60 (ESI) C9H7CIINO calcd 306.93; Found [M+H]+:308.

[0424] tert-Butyl 7-chloro-3-iodo-5-methoxyindole-l-carboxylate. To a stirred solution of 7-chloro-3-iodo-5-methoxy-l / 7-indole (750.0 mg, 2.439 mmol), TEA (740.3 mg, 7.317 mmol) and DMAP (29.8 mg, 0.244 mmol) in DCM (8 mL) was added BOC2O (1.60 g, 7.317 mmol) at 0 °C. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The resulting mixture was extracted with CH2CI2 (3 x 20 mL). The combined organic extracts were washed with water (3 x 4 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow solid (367 mg, 36.9% yield). LCMS 54 (ESI) C14HISC1INO3 calcd 406.98; Found [M+H]+:408. ’H NMR (400 MHz, CDCI3) δ 7.65 (s, 1H), 7.03 (d, J= 2.4 Hz, 1H), 6.78 (d, J= 2.4 Hz, 1H), 3.88 (d, J= 1.0 Hz, 3H), 1.64 (s, 9H).

[0425] tert-Butyl 3-[l-(tert-butoxycarbonyl)-5, 6-dihydro-2H-pyridin-3-yl]~ 7-chloro-5- methoxyindole-l-carboxylate. To a stirred solution of tert-butyl 7-chloro-3-iodo-5- methoxyindole-1 -carboxylate (350.0 mg, 0.859 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l -carboxylate (398.2 mg, 1.288 mmol) and K2CO3(356.0 mg, 2.577 mmol) in dioxane (4 mL) and H2O (2 mL) was added Pd(dppf)Ch (62.8 mg, 0.086 mmol). The resulting mixture was stirred for 2 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow oil (200 mg, 50.3% yield). LCMS 49 (Method J) (ESI) C24H31CIN2O5 calcd 462.19; Found [M+H]+:463. 'H NMR (400 MHz, DMSO-de) 7 δ.65 (s, 1H), 7.23 (s, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.30 (s, 1H), 4.17 (d, J = 2.6 Hz, 2H), 3.82 (s, 3H), 3.51 (d, J = 5.7 Hz, 2H), 2.35 - 2.26 (m, 2H), 1.60 (s, 9H), 1.44 (s,9H).

[0426] Example 39: Synthesis of 6,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indole (Compound 533)

[0427] 2, 3 -difluor 0-6- [2-(trimethylsilyl)ethynyl] aniline. To a stirred mixture of 2,3-difluoro- 6-iodoaniline (1.5 g, 5.882 mmol) and trimethylsilylacetylene (808.8 mg, 8.235 mmol) in TEA (15 mL) was added Cui (224.1 mg, 1.176 mmol) and Pd(PPh3)2C12 (412.9 mg, 0.588 mmol). The resulting mixture was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (Si O2) eluting with PE / EA (9: 1) to afford the desired product as a yellow oil (920.0 mg, 69.4% yield). LCMS 54 (ESI) CnHi3F2NSi calcd 225.08; Found [M+H]+:226. 'H NMR. (400 MHz, DMSO-< / 6) 6.8 δ8 (m, 1H), 6.36 (m, 1H), 5.48 (s, 2H) 0.10 (s, 9H).

[0428] 6, 7-difluoro-lH-indole. To a stirred mixture of 2,3-difluoro-6-[2- (trimethylsilyl)ethynyl]aniline (920.0 mg, 4.083 mmol) in DMF (20 mL) was added Cui (1.56 g, 8.166 mmol). The resulting mixture was stirred for 5 h at 100 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5: 1) to afford the desired product as a yellow oil (550.0 mg, 87.9% yield).JH NMR (400 MHz, DMSO-de) 1 δ 1.75 (s, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.34 (d, J= 8.7, 4.3 Hz, 1H), 7.01 (m, 1H), 6.52 (d, J= 2.8 Hz, 1H).

[0429] 6, 7-difluoro-3-iodo-lH-indole. To a stirred mixture of 6,7-difluoro- l / / -indole (540.0 mg, 3.526 mmol) in DMF (10 mL) was added NIS (1.19 g, 5.289 mmol). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere. The reaction was quenched with sat. Na2SOa (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 50% gradient in 30 min; UV 254 nm to afford the desired product as a yellow oil (610.0 mg, 66.9% yield). LCMS 60 (ESI) C8H4F2IN calcd 278.94; Found [M+H]+:280. 'H NMR (400 MHz, DMSO-d6) 12 δ.24 (s, 1H), 7.65 (d, J= 2.5 Hz, 1H), 7.22 - 7.06 (m, 2H).

[0430] tert-butyl 3-(6, 7-difluoro-lH-indol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate.To a stirred mixture of 6,7-difluoro-3-iodo-l / / -indole (600.0 mg, 2.150 mmol) and / c77-butyl 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-277-pyridine-l-carboxylate (997.3 mg, 3.225 mmol) in dioxane (6 mL) and H2O (3 mL) was added K2CO3(891.5 mg, 6.450 mmol) and Pd(dppf)C12 (157.3 mg, 0.215 mmol). The resulting mixture was stirred for 1 h at 80 °C under an N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (9: 1) to afford the desired product as a yellow solid (400.0 mg, 55.6% yield). LCMS 54 (ESI) C18H20F2N2O2 calcd 334.15; Found [M+H]+:335. ’HNMR (400 MHz, CD3OD) δ 7.50 (d, J= 9.0, 4.1 Hz, 1H), 7.29 (s, 1H), 6.94 - 6.90 (m, 1H), 6.25 - 6.23 (m, 1H), 4.24 (s, 2H), 3.59 (d, J= 6.0 Hz, 2H), 2.39 - 2.26 (m, 2H), 1.50 (s, 9H).

[0431] 6,7-Difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indole. HC1 (gas) in 1,4-dioxane (2 mL) was added to a stirred solution of tert-butyl 3-(6,7-difluoro-l / 7-indol-3-yl)-5,6-dihydro- 2 / / -pyridine-l -carboxylate (200.0 mg, 0.598 mmol) in dioxane (2 mL). The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere and concentrated under vacuum. The mixture was dissolved in methanol and the PH was adjusted to 8 with saturated Na2COs (aq.). After concentrated under reduced pressure, the residue was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 2% B in 1.5 min, 2% B to 19% B in 2 min, 19% B to 38% B in 9 min; Wave Length: 254nm / 220nm; RTl(min): 8.94) to afford the desired product as a white solid (68.4 mg, 48.4% yield). LCMS 40 (ESI) C13H12F2N2 calcd 234.14; Found [M+H]+:235.05. 'H NMR (400 MHz, CD3OD) δ 7.53 - 7.48 (m, 1H), 7.28 (s, 1H), 6.98 - 6.90 (m, 1H), 6.26 - 6.23 (m, 1H), 3.71 (d, J = 2.3 Hz, 2H), 3.06 (d, J= 5.9 Hz, 2H), 2.42 - 2.35 (m, 2H).

[0432] Example 40: Synthesis of 5,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indole (

[0433] 5, 7-difluoro-3-iodo-lH-indole. A solution of 5, 7-difluoro-l / / -indole (500.0 mg, 3.27 mmol) and NTS (734.6 mg, 3.27 mmol) in DMF (5.0 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3 : 1) to afford the desired product as a yellow solid (800.0 mg, 87.8% yield). LCMS 42 (Method B) (ESI) C8H4F2IN calcd 278.94; Found [M - H]’:278. 'H NMR (400MHz, DMSO-i / e) δ 12.21 (s, 1H), 7.72 (d, J= 2.6 Hz, 1H), 7.14 - 7.04 (m, 1H), 6.96 - 6.86 (m, 1H).

[0434] tert-butyl 3-(5, 7-difluoro-lH-indol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate. A solution of 5,7-difluoro-3-iodo-U7-indole (800.0 mg, 2.87 mmol), Pd(dppf)C12.CH2C12(l 16.8 mg, 0.14 mmol), K2CO3(1188.7 mg, 8.60 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine- l -carboxylate (1329.8 mg, 4.30 mmol) in dioxane (8.0 mL) and H2O (4.0 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (10 mL), dried over anhydrous ISfeSCU. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (200.0 mg, 20.9% yield). LCMS 41 (Method B) (ESI) C18H20F2N2O2 calcd 334.15; Found [M - H]':333. 'H NMR (400 MHz, DMSO-d6) 11.8 δ3 (s, 1H), 7.56 (s, 1H), 7.45 - 7.38 (m, 1H), 7.09 - 7.00 (m, 1H), 6.25 - 6.18 (m, 1H), 4.24 - 4.15 (m, 2H), 3.55 - 3.46 (m, 2H), 2.32 - 2.24 (m, 2H), 1.44 (s, 9H).

[0435] 5, 7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indole. A solution of tert-butyl 3-(5,7-difluoro-l / / -indol-3-yl)-5,6-dihydro-2Z / -pyridine-l-carboxylate (200.0 mg, 0.60 mmol) in dioxane (0.5 mL) and HCl(gas) in 1,4-dioxane (1.0 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 10 with saturated ISfeCCL (aq.). The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 0% to 50% gradient in 30 min; detector, UV 254 nm to afford the desired product as a yellow solid (78.9 mg, 56.3% yield). LCMS 52 (Method B) (ESI) C13H12F2N2 calcd 234.10; Found [M+H]+:234.95.JH NMR (400 MHz, DMSO-cL) 11.72 δ (s, 1H), 7.49 (s, 1H), 7.39 - 7.35 (m, 1H), 7.03 - 6.97 (m, 1H), 6.15 (d, J = 4.2 Hz, 1H), 3.53 (s, 2H), 2.89 - 2.79 (m, 2H), 2.25 - 2.12 (m, 2H).

[0436] Example 41: Synthesis of 7-chloro-4,6-difluoro-3-( 1,2,5, 6-tetrahydropyridin-3- yl)-lH-indazole (Compound 521)

[0437] 3-Chloro-2,4,6-trifluorobenzaldehyde. To a stirred solution of 2-chloro-l,3,5- trifluorobenzene (2.50 g, 15.01 mmol) in THF (10 mL) was added LDA (2.4 mL, 18.01 mmol) dropwise at -78 °C and stirred for 15 min at -78 °C under an N2 atmosphere. Then DMF (13.9 mL, 180.14 mmol) was added at -78 °C and stirred for 15 min at -78 °C under an N2 atmosphere followed by the addition of H2SO4 (5 mL) at -78 °C. The resulting mixture was stirred for 30 min at -50 °C under an N2 atmosphere. The reaction was quenched with 60 mL of water at room temperature. The aqueous layer was extracted with EtOAc (5 x 60 mL). The organic extracts were concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desired product as a white solid (1.70 g, 58.2% yield). 'H NMR (300 MHz, CDCI3) δ 10.41 - 10.16 (m, 1H), 7.00 - 6.86 (m, 1H).

[0438] 7-Chloro-4,6-difluoro-lH-indazole. A solution of 3 -chi oro-2, 4, 6- trifluorobenzaldehyde (1.00 g, 5.14 mmol) and N2H4.H2O (385.5 mg, 7.71 mmol) in EtOH (10 mL) was stirred for 3 h at 80 °C under an N2 atmosphere. The resulting mixture was concentrated under vacuum and diluted with H2O (70 mL). The aqueous layer was extracted with EtOAc (5 x 70 mL). The organic extracts were concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (400.0 mg, 41.2% yield). LCMS 60 (ESI) C7H3C1F2N2 calcd 188.56; Found [M + H]+:189. 'H NMR (300 MHz, CDCI3) 8 δ.19 (s, 1H), 6.90 - 6.72 (m, 1H).

[0439] 7-Chloro-4,6-difluoro-3-iodo-lH-indazole. A solution of 7-chloro-4,6-difluoro- l 77- in dazole (200.0 mg, 1.06 mmol) and NIS (357.9 mg, 1.59 mmol) in DMF (3 mL) was stirred for 1 h at 50 °C under an N2 atmosphere. The reaction was quenched with 40 mL of Na2S2C>3 (aq.) atroom temperature. The aqueous layer was extracted with EtOAc (5 x 40 mL). The organic extract was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (6:1) to afford the desired product as a white solid (300.0 mg, 89.9% yield). LCMS 60 (ESI) C7H2CIF2IN2 calcd 313.89; Found [M + H]+:315. 'H NMR (300 MHz, CDCI3) 10 δ.44 (s, 1H), 6.90 - 6.69 (m, 1H).

[0440] tert-Butyl 3-(7-chloro-4,6-difluoro-lH-indazol-3-yl)-5,6-dihydro-2H-pyridine-l- carboxylate. A solution of 7-chloro-4,6-difIuoro-3-iodo-l / f-indazole (200.0 mg, 0.63 mmol), tertbutyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2Z7-pyridine-l -carboxylate (295 mg, 0.95 mmol), Pd(dppf)C12 (46.5 mg, 0.06 mmol), K2CO3(263.7 mg, 1.90 mmol) in H2O (2 mL) and dioxane (4 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with PE / EA (6: 1) to afford the desired product as a white solid (200 mg, 85.0% yield). LCMS 52 (ESI) C17H18CIF2N3O2 calcd 369.11; Found [M + H]+:370. 'H NMR (300 MHz, CDCI3) δ 6.83 - 6.64 (m, 2H), 4.51 (s, 2H), 3.70 - 3.54 (m, 2H), 2.50 - 2.35 (m, 2H), 1.54 (s, 9H).

[0441] 7- Chloro-4,6-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indazole. To a stirred solution of tert-butyl 3-(7-chloro-4,6-difluoro-177-indazol-3-yl)-5,6-dihydro-27 / -pyridine-l- carboxylate (100.0 mg, 0.27 mmol) in dioxane (2 mL) was added HC1 (gas) in 1,4-dioxane (2 mL, 4 M) dropwise at room temperature under an N2 atmosphere and stirred for 3 h. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 8 with saturated Na2CCE (aq.). The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: 10 mmol / L NH4HC03+0.05%NH3H20, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 47% B in 2 min, 47% to 60% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 8.48) to afford the desired product as a white solid (38.6 mg, 51.8% yield). LCMS 52 (ESI) C12H10CIF2N3 calcd 269.05; Found [M + H]+:270.15.XH NMR (400 MHz, DMSO-<A) 87.20 (d, J= 3.3 Hz, 1H), 6.57 - 6.40 (m, 1H), 3.77 - 3.61 (m, 2H), 2.86 (d, J= 5.7 Hz, 2H), 2.29 - 2.14 (m, 2H).

[0442] Example 42: Synthesis of 4,7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indole (Compound 535)

[0443] 4, 7-Difluoro-3-iodo-lH-indole. A solution of 4,7-difluoro- I / / -indole (250.0 mg, 1.63 mmol) and NIS (551.0 mg, 2.45 mmol) in DMF (3.0 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (3 : 1) to afford the desired product as a yellow solid (400.0 mg, 87.8% yield). LCMS 41 (Method B) (ESI) C8H4F2IN calcd 278.94; Found [M - H]’ :278. 'H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 7.62 (d, ,7 = 2.6 Hz, 1H), 6.99 - 6.90 (m, 1H), 6.81 - 6.72 (m, 1H).

[0444] tert-Butyl 3-(4,7-difluoro-lH-indol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate. A solution of 4,7-difluoro-3-iodo-177-indole (400.0 mg, 1.43 mmol), Pd(dppf)C12.CH2C12 (58.4 mg, 0.07 mmol), K2CO3(594.4 mg, 4.30 mmol) and / c77-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydro-277-pyridine-l -carboxylate (664.9 mg, 2.15 mmol) in dioxane (4.0 mL) and H2O (2.0 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (5:1) to afford the desired product as a yellow solid (100.0 mg, 20.9% yield). LCMS 42 (Method B) (ESI) C18H20F2N2O2 calcd 334.15; Found [M - H]’:333. 'H NMR (400 MHz, DMSO-t / ,) 11.9 δ9 (s, 1H), 7.45 (s, 1H), 6.97 - 6.89 (m, 1H), 6.79 - 6.71 (m, 1H), 6.05 (s, 1H), 4.19 (s, 2H), 3.52 - 3.44 (m, 2H), 2.27 - 3.20 (m, 2H), 1.43 (s, 9H).

[0445] 4, 7-difluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indole. A solution of tert-butyl 3-(4,7-difluoro-177-indol-3-yl)-5,6-dihydro-27 / -pyridine-l-carboxylate (100.0 mg, 0.30 mmol) in dioxane (0.5 mL) and HCl(gas) in 1,4-dioxane (0.5 mL) was stirred for 2 h at room temperatureunder an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 10 with saturated Na2COs (aq.). The crude product (100.0 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 17% B in 15 min, 17% to 32% B in 30 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.03) to afford the desired product as a yellow solid (27.1 mg, 38.7% yield). LCMS 52 (Method B) (ESI) C13H12F2N2 calcd 234.10; Found [M+H]+:234.95.XH NMR (400 MHz, DMSO<76) 5 11.87 (s, 1H), 7.38 (s, 1H), 6.94 - 6.86 (m, 1H), 6.74 - 6.66 (m, 1H), 6.01 (d, J= 5.0 Hz, 1H), 3.51 (d, J= 2.6 Hz, 2H), 2.85 - 2.79 (m, 2H), 2.16 - 2.09 (m, 2H).

[0446] 7-Chloro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indol-5-ol. To a stirred solution of terLbutyl 3-[l-(terz-butoxycarbonyl)-5,6-dihydro-277-pyridin-3-yl]-7-chloro-5-methoxyindole-l- carboxylate (200.0 mg, 0.432 mmol) in DCM (5 mL) was added BBri (324.6 mg, 1.296 mmol) under an N2 atmosphere. The resulting mixture was stirred for 1 h at room temperature under an N2 atmosphere and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18Column 30*150 mm, 5 m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10 % B to 30 % B in 20 min; Wave Length: 254 nm / 220 nm; RTl(min): 21) to afford the desired product as a white solid (15.8 mg, 14.7% yield). LCMS 63 (Method Q) (ESI) C13H13CIN2O calcd 248.07; Found [M+H]+:249.0. ’H NMR (400 MHz, DMSO-J6) δ 11.12 (s, 1H), 9.07 (s, 1H), 7.29 (d, .7= 2.6 Hz, 1H), 7.10 (d, ,7 = 2.1 Hz, 1H), 6.71 (d, .7= 2.0 Hz, 1H), 6.07 (d, J= 4.0 Hz, 1H), 3.53 (d, J= 2.2 Hz, 2H), 2.86 (d, J= 5.7 Hz, 2H), 2.26 - 2.11 (m, 2H).

[0447] Example 43: Synthesis of 2-{[(3 / ?)-3-(lH-Indazol-3-yl)piperidin-l- yl]methyl}phenol and 2-{[(35)-3-(lH-indazol-3-yl)piperidin-l-yl]methyl}phenol (Compounds 523 and 524)

[0448] tert-Butyl 3-(lH-indazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate. A solution of 3 -i odo-1 / / -indazole (1.00 g, 4.09 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (1.90 g, 6.14 mmol), Pd(dppf)Ch (0.30 g, 0.41 mmol), K2CO3(1.70 g, 12.29 mmol) and H2O (3 mL) in dioxane (6 mL) was stirred for 2 h at 80 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3 x 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by chromatography (SiO2) eluting with petroleum ether / ethyl acetate (5: 1) to afford the desired product as a yellow solid (800.0 mg, 65.2% yield). LCMS 50 (Method B) (ESI) C17H21N3O2 calcd 299.16; Found [M+H]+: 300. 'HNMR (400 MHz, DMSO-t76) 13 δ.01 (s, 1H), 7.98 (d, J= 8.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 4.40 (s, 2H), 3.59 - 3.45 (m, 2H), 2.35 (d, J= 4.5 Hz, 2H), 1.44 (s, 9H).

[0449] tert-Butyl 3-(lH-indazol-3-yl)piperidine-l-carboxylate. A solution of terz-butyl 3- (l / / -indazol-3-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (800.0 mg, 2.67 mmol) and Pd / C (142.1 mg, 1.33 mmol, 0.5 equiv) in MeOH (10 mL) was hydrogenated for 5 h at room temperature under hydrogen atmosphere. After filtration, the filtrate was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 10% to 50% gradient in 30 min; detector, UV 254 nm. The resulting mixture was concentrated under vacuum to afford the desired product as a white solid (600.0 mg, 74.5% yield). LCMS 54 (ESI) C17H23N3O2 calcd 301.18; Found [M+H]+: 302. 'H NMR (400 MHz, DMSO-c / 6) 12 δ.74 (s, 1H), 7.79 (d, J= 8.1 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.36 - 7.22 (m, 2H), 7.20 - 7.03 (m, 2H), 3.96 (d, J= 13.0 Hz, 1H),3.12 (d, J = 12.5 Hz, 1H), 2.96 - 2.77 (m, 1H), 2.09 (s, 1H), 1.81 (s, 2H), 1.62 - 1.47 (m, 1H), 1.45 - 1.27 (m, 9H).

[0450] 3-(Piperidin-3-yl)-lH-indazole. To a stirred solution of Zc’ / V-butyl 3-( l / / -indazol-3- yl)piperidine-l-carboxylate (400.0 mg, 1.32 mmol) in dioxane (3 mL) was added HC1 (gas) in 1,4- di oxane (3 mL, 4 M) dropwise and stirred for 2 h at room temperature under an N2 atmosphere. The resulting mixture was concentrated under vacuum and purified by reversed-phase flash chromatography with the following conditions: column, , C18 silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 10% to 50% gradient in 30 min; detector, UV 254 nm to afford the desired product as a white solid, 150.0 mg, 56.1% yield. LCMS 50 (Method B) (ESI) C12H15N3 calcd 201.13; Found [M+H]+: 202. 'H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.45 (d, J= 8.3 Hz, 1H), 7.36 - 7.21 (m, 1H), 7.12 - 6.94 (m, 1H), 3.20 - 3.03 (m, 3H), 2.96 (d, J = 11.9 Hz, 1H), 2.80 - 2.70 (m, 1H), 2.60 - 2.53 (m, 1H), 2.05 (d, J = 13.0 Hz, 1H), 1.89 - 1.74 (m, 1H), 1.72 - 1.62 (m, 1H), 1.60 - 1.47 (m, 1H).

[0451] 2-{[3-(lH-Indazol-3-yl)piperidin-l-yl]methyl}phenol. A solution of 3-(piperidin-3- yl)-U7-indazole (150.0 mg, 0.74 mmol), salicylaldehyde (109.2 mg, 0.89 mmol) and NaBHiCN (140.5 mg, 2.23 mmol) in MeOH (2 mL) was stirred for 2 h at room temperature under an N2 atmosphere. The mixture was purified by Prep-HPLC with the following conditions (Column: CHIRAL ART C6llulose-SC, 3*25 cm, 5 pm; Mobile Phase A: Hex(10 mM NHi-MeOH), Mobile Phase B: EtOH— HPLC; Flow rate: 40 mL / min; Gradient: isocratic 5; Wave Length: 216 / 284 nm; RTl(min): 8.8; RT2(min): 10.34; Sample Solvent: EtOH--HPLC; Injection Volume: 0.35 mL; Number Of Runs: 6) to afford the desired product as a white solid, 120.0 mg, 52.3% yield. LCMS 46 (Method I) (ESI) C19H21N3O calcd 307. 17; Found [M+H]+: 308.

[0452] 2-{[(3R)-3-(lH-Indazol-3-yl)piperidin-l-ylJmethyl}phenol and 2-{[(3S)-3-(lH- indazol-3-yl)piperidin-l-yl]methyl}phenol. 2- { [3 -( 1 H-indazol-3yl)piperidin- 1 -y I ]methyl } phenol (120.0 mg, 0.39 mmol) was purified by chiral HPLC with the following conditions (Column: CHIRALPAK IC-3, 4.6*50 mm, 3 urn; Mobile Phase A: Hex(0.1%DEA): EtOH=95: 5; Flow rate: 1.67ml / min; Gradient: isocratic ; Injection Volume: 3 mL) to afford the tile compounds. 2-{[(3J?)- 3-(lH-Indazol-3-yl)piperidin-l-yl]methyl}phenol White solid (38.7 mg, 25.0% yield). LCMS 63 (Method Q) (ESI) C19H21N3O calcd 307.17; Found [M+H]+: 308. ’H NMR (400 MHz, DMSO-d6) 5 12.69 (s, 1H), 10.76 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.34 - 7.24 (m, 1H), 7.13 - 7.00 (m, 3H), 6.77 - 6.67 (m, 2H), 3.81 - 3.62 (m, 2H), 3.28 (d, J = 11.2 Hz, 1H), 3.18- 3.05 (m, 1H), 2.95 (d, J = 11.3 Hz, 1H), 2.49 - 2.37 (m, 1H), 2.23 - 2.13 (m, 1H), 2.06 (d, J = 9.1 Hz, 1H), 1.89 - 1.78 (m, 1H), 1.75 - 1.59 (m, 2H). 2-{[(35)-3-(lH-indazol-3-yl)piperidin-l- yl]methyl] phenol White solid (34.8 mg, 22.8% yield). LCMS 63 (Method Q) (ESI) C19H21N3O calcd 307.17; Found [M+H]+:308.rH NMR (400 MHz, DMSO-d6) 12 δ.69 (s, 1H), 10.78 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.36 - 7.24 (m, 1H), 7.07 (p, J = 7.4, 7.0 Hz, 3H), 6.80 - 6.64 (m, 2H), 3.79 - 3.60 (m, 2H), 3.30 - 3.25 (m, 1H), 3. 16 - 3.07 (m, 1H), 2.95 (d, J = 11.2 Hz, 1H), 2.44 (t, J = 11.1 Hz, 1H), 2.24 - 2.11 (m, 1H), 2.08 - 1.96 (m, 1H), 1.89 - 1.80 (m, 1H), 1.75 - 1.52 (m, 2H).

[0453] Example 44: Synthesis of 7-chloro-6-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)- IH-indole (Compound 536)

[0454] 7-Chloro-6-fluoro-3-iodo-lH-indole. To a stirred mixture of 7-chloro-6-fluoro- l / 7- indole (300.0 mg, 1.77 mmol) and potassium hydroxide (300.0 mg, 5.35 mmol) in N, N- dimethylformamide (2 mL) was added iodine (450.0 mg, 1.77 mmol) in N, A-dimethylformamide (1 mL) dropwise over 5 minutes at 0 °C. After the addition, the reaction was quenched with sat. sodium hyposulfite (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, acetonitrile in water (10 mmol / L ammonium bicarbonate), 50% to 82% gradient in 5 min to afford the desired product as a pink solid (470.0 mg, 89.9% yield). LCMS 25 (Method C) (ESI) C8H4C1FIN calcd 294.91; Found [M+H]+:296. 'H NMR (400 MHz, DMSO-64,) δ 12.10 (s, 1H), 7.64 (s, 1H), 7.30 - 7.23 (m, 1H), 7.21 - 7.13 (m, 1H).

[0455] tert-Butyl 7-chloro-6-fluoro-3-iodoindole-l-carboxylate. To a stirred mixture of 7- chloro-6-fluoro-3-iodo-l / / -indole (300.0 mg, 1 .02 mmol) and di -tert-butyl di carbonate (332.0 mg,1.52 mmol) in dichloromethane (10 mL) was added N, A-diisopropylethylamine (0.53 mL, 3.04 mmol) and 4-(dimethylamino) pyridine (13.0 mg, 0.106 mmol). The resulting mixture was stirred for 15 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with 10% of ethyl acetate in petroleum ether to afford the desired product as a white solid (380.0 mg, 94.6% yield). LCMS 49 (Method K) (ESI) C13H12CIFINO2 calcd 394.96; Found [M+H]+:396.

[0456] tert-Butyl 3-[l-(tert-butoxycarbonyl)-5, 6-dihydro-2H-pyridin-3-yl]~ 7-chloro-6- fluoroindole-l-carboxylate. A mixture of tert-butyl 7-chloro-6-fluoro-3-iodoindole-l-carboxylate (300.0 mg, 0.76 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro- 2H-pyridine-l-carboxylate (352.0 mg, 1.14 mmol), [l,l'-Bis(diphenylphosphino) ferrocene] dichloropalladium(II) (111.0 mg, 0.15 mmol) and potassium carbonate (210.0 mg, 1.52 mmol) in water (0.5 mL) and dioxane (2.5 mL) was stirred for 2 h at 90 °C under an N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, acetonitrile in water (0.1% formic acid), 83% to 86% gradient in 5 min; detector, UV 230 nm to afford the desired product as a white semi-solid (200.0 mg, 58.4% yield). LCMS 49 (Method K) (ESI) C23H28CIFN2O4 calcd 450.17; Found [M+H]+:451.

[0457] 7-Chloro-6-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indole; formate. To a stirred solution of terLbutyl 3-[l-( / e7T-butoxycarbonyl)-5,6-dihydro-2Z / -pyridin-3-yl]-7-chloro-6- fluoroindole-1 -carboxylate (180.0 mg, 0.40 mmol) in dichloromethane (2 mL) was added trifluoro-acetic acid (2 mL) dropwise at room temperature. The resulting mixture was stirred for 30 min. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 10 with saturated Na2CCh (aq.). The residue was purified by reversed-phase flash chromatography with the following conditions: Column: XBridge Shield RP18 OBD Column 30 * 150 mm, 5 m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 10% B to 29% B in 7 min; Wavelength: 254nm / 220nm to afford the desired product as a white solid (20.4 mg, 17.2% yield). LCMS 17 (Method A) (ESI) C13H12CIFN2 calcd 250.07; Found [M+H] L250.95. ’H NMR (400 MHz, DMSO-J6) 5 11.73 (s, 1H), 8.26 (s, 1H), 7.78 - 7.76 (m, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.27 (d, J = 4.2 Hz, 1H), 3.75 (d, J = 2.6 Hz, 2H), 3.06 - 3.04 (m, 2H), 2.35 (s, 2H).

[0458] Example 45: Synthesis of 6-Fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH- indole-7-carbonitrile (Compound 537)

[0459] 7-Bromo-6-fluoro-lH-indole. In a 50-mL round bottom flask to a solution of 2- bromo- l-fluoro-3 -nitrobenzene (3.00 g, 13.63 mmol) in THF (30 mL) was added dropwise bromo(ethenyl)magnesium (5.37 g, 40.91 mmol) at -50 °C under an N2 atmosphere. The reaction mixture was stirred at -50 °C for 2 h. The reaction was quenched with NH4Cl(aq.) (30 mL) at -40 °C. Then the mixture was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C1s silica gel; mobile phase, Water (0.1% formic acid) in acetonitrile, 10% to 50% gradient in 30 min; detector, UV 254 nm to afford the desired product as a yellow oil (700.0 mg, 23.9% yield). LCMS 45 (Method G) (ESI) C8H5BrFN calcd 212.96; [M - H] :212.

[0460] 6-Fluoro-lH-indole-7-carbonitrile. To a solution of 7-bromo-6-fluoro-l / / -indole (700.0 mg, 4.67 mmol) and zinc cyanide (3.80 g, 32.70 mmol) in DMA (10 mL) was added Pd(PPh3)4 (1.12 g, 1.40 mmol). After stirring for 2 h at 100 °C under an N2 atmosphere the reaction was quenched with ice at room temperature. The resulting mixture was filtered, the residue was washed with EtOAc (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10:1) to afford the desired product as a white solid (300.0 mg, 66.8% yield). LCMS 45 (Method G) (ESI) C9H5FN2 calcd 160.04 Found [M - H]':159.

[0461] 6-Fluoro-3-iodo-lH-indole-7-carbonitrile. To a stirred solution of 6-fhioro-l / / - indole-7-carbonitrile (300.0 mg, 0.87 mmol) in A,A-dimethylformamide (2 mL) was added NIS(843.0 mg, 3.74 mmol) at room temperature. The resulting mixture was stirred for 30 min. The resulting mixture was filtered, the residue was washed with EtOAc (5 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a yellow solid (200.0 mg, 35.9% yield). LCMS 45 (Method G) (ESI) C9H4FIN2 calcd 285.94 [M - H]':285.

[0462] tert-Butyl 3-(7-cyano-6-fluoro-lE / -indol-3-yl)-5,6-dihydro-2ZT-pyridine-l- carboxylate. To a solution of 6-fluoro-3-iodo-lJ / -indole-7-carbonitrile (200.0 mg, 0.69 mmol) and K2CO3(193.2 mg, 1.39 mmol) in dioxane (1.6 mL) and H2O (0.4 mL) were added terZ-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-l-carboxylate (259.4 mg, 0.83 mmol) and Pd(dppf)C12 (102.3 mg, 0.14 mmol). After stirring for 2 h at 90 °C under an N2 atmosphere. The reaction was quenched with ice at room temperature. The resulting mixture was filtered, the residue was washed with EtOAc (5 x 10 mL). The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a yellow solid (87.0 mg, 36.4% yield). LCMS 45 (Method F) (ESI) C19H20FN3O2 calcd 341.15; Found [M - H]’ :340.

[0463] 6-Fluoro-3-(l,2,5,6-tetrakydropyridin-3-yl)-lH-indole-7-carbonitrile. To a stirred solution of tert-butyl 3-(7-cyano-6-fluoro-17 / -indol-3-yl)-5,6-dihydro-277-pyridine-l-carboxylate (87.0 mg, 0.25 mmol) in 1,4-dioxane (1 mL) was added HC1 (gas) in 1,4-dioxane (1 mL). After stirring for 2 h at room temperature the mixture was basified to pH 8 with saturated Na2CO? (aq.). The resulting mixture was concentrated under reduced pressure. The crude product (24.0 mg) was purified by Prep-HPLC with the following conditions, Column: XB ridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 11% B to 27% B in 8 min; Wave Length: 254 / 220 nm; RTl(min): 9.48 / 10.57 to afford to afford the desired product as a white solid (6.7 mg, 10.9% yield). LCMS 63 (Method Q) (ESI) C14H12FN3 calcd 241.10 Found; [M+H]+:242.10.1H NMR (400 MHz, CD3OD) δ 8.08 (dd, J = 8.9, 5.2 Hz, 1H), 7.35 (s, 1H) 7.02 (dd, J= 10.0, 8.8 Hz, 1H), 6.26 (s, 1H), 3.66 (s, 2H), 3.02 (t, J= 5.9 Hz, 2H), 2.36 (s, 2H).

[0464] Example 46: Synthesis of 5-fluoro-3-(l,2,5,6-tetrahydropyridin-3-yl)-lH-indole- 7-carbonitrile (Compound 538)

[0465] 5-Fluoro-lH-indole-7-carbonitrile. A solution of 7 -bromo-5 -fluoro- 1 / 7-indole (800 mg, 3.738 mmol), zinc cyanide (1316.6 mg, 11.214 mmol) and Pd(PPh3)4 (863.8 mg, 0.748 mmol) in A, A-di methyl form ami de (40 mL) was stirred for 2 h at 105 °C under an N2 atmosphere. The aqueous layer was extracted with EtOAc (3x100 mL). The organic extracts were washed with 3x50 mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (500 mg, 83.5% yield). LCMS 54 (ESI) C9H5FN2 calcd 160.04; Found [M+H]+:161

[0466] 5-Fluoro-3-iodo-lH-indole-7-carbonitrile. To a stirred solution of 5-fluoro-l / / - indole-7-carbonitrile (500 mg, 3.122 mmol) in A / A-dimethylformamide (40 mL) was added NIS (1053.6 mg, 4.683 mmol) in portions at 0 °C. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched with sodium thiosulfate pentahydrate at 0 °C. The aqueous layer was extracted with EtOAc (3x100 mL). The organic extracts were washed with 3x50 mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (501 mg, 56.0% yield). LCMS 54 (ESI) C9ILFIN2 Calcd 285.94; Found [M+H]+:287

[0467] tert-Butyl 7-cyano-5-fluoro-3-iodoindole-l-carboxylate. A solution of 5-fluoro-3- iodo-l / f-indole-7-carbonitrile (500 mg, 1.747 mmol), di -tert-butyl dicarbonate (762.9 mg, 3.495 mmol), triethylamine (530.6 mg, 5.2425 mmol) and 4-dimethylaminopyridine (21.3 mg, 0.175 mmol) in dichloromethane (50 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2) eluting with PE / EA (10: 1) to afford the desired product as a white solid (543 mg, 80.4% yield). LCMS 47 ...

Claims

The claimed invention is:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein is a single bond, X is CRX, and Y is C(RY)2; or is a double bond, X is C, and Y is C(RY);A is selected from the group consisting of 8-10 membered fused bicyclic heteroaryl, 12-14 membered fused tricyclic heteroaryl, 8-10 membered fused bicyclic heterocyclyl, and phenyl; wherein ring A may be substituted on one or more substituents selected from RA;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2.C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;Rxand RYare each independently selected from the group consisting of hydrogen and -C1- C3alkyl; or one Rxand one R' are joined together to form -CH2-;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -CH2-phenyl, -CH2CH2-phenyl, and -CH2-(4-6 membered heteroaryl); wherein C1-C6alkyl, phenyl, and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4and R5are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rh, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O- C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2. C6alkynyl, C1-C6alkoxy, -C3C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, - NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy; andRaand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens.

2. The compound of claim 1, wherein the compound is represented by3. The compound of claim 1 or 2, wherein R6and R7are hydrogen.

4. The compound of claim 1 or 2, wherein R2and R3are hydrogen.

5. The compound of claim 1 or 2, wherein the compound is represented by6. The compound of claim 1 or 2, wherein A is selected from the group consisting ofĹ£ZRcis selected from the group consisting of hydrogen and C1-C3alkyl;Rdis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3alkyl, C1-C3alkoxy, -C3-C4 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl; wherein -C1-C3alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and - OCH3;Reis selected from the group consisting of hydrogen, halogen, cyano, and -C1.C3alkyl; and m is 0, 1, 2, or 3.

7. The compound of claim 1 or 2, wherein:Rcis selected from the group consisting of hydrogen and -CH3;Rdis selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; andReis selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano.

8. The compound of claim 1 or 2, wherein RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, - 0CF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3.

9. The compound of claim 1 or 2, RAis independently selected from each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3.

10. The compound of claim 1 or 2, wherein A is selected from the group consisting of11. The compound of claim 1 or 2, wherein R4and R~ are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

12. The compound of claim 1 or 2, wherein R4is hydrogen.

13. The compound of claim 1 or 2, wherein R5is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

14. The compound of claim 1 or 2, wherein R5is hydrogen or -CH3.

15. The compound of claim 1 or 2, wherein R1is selected from the group consisting of hydrogen,16. The compound of claim 1 or 2, wherein R1is hydrogen.

17. A compound represented by Formula IIA, Formula IIB, or Formula IIC:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRcis selected from the group consisting of hydrogen and C1-C3alkyl;Rdis selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -C1-C3alkyl, and C1-C3alkoxy; wherein -C1-C3alkyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NH2, -C(O)-NH2, and -OCH3;Reis selected from the group consisting of hydrogen, halogen, cyano, and -C1-C3alkyl;R1is selected from the group consisting of hydrogen, -CH3R2and R3are each independently selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2; and m is 0, 1, 2, or 3.

18. The compound of claim 1, wherein:Rdis selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -OCH3, -CH2C(O)NH2, and -OCH2CH3; andReis selected from the group consisting of hydrogen, fluoro, chloro, -CH3, and cyano.

19. The compound of claim 17 or 18, wherein R4is hydrogen.

20. The compound of claim 17 or 18, wherein R5is selected from the group consisting of hydrogen, hydroxyl, -CH3, -CH2OH, -NH2, and -NH-C(O)-N(CH2CH3)2.

21. The compound of claim 17 or 18, wherein R5is hydrogen or -CH3.

22. The compound of claim 17 or 18, wherein R1is hydrogen.

23. A compound selected from the group consisting ofor a pharmaceutically acceptable salt and / or stereoisomer thereof.

24. A compound represented by Formula III:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein is a single bond, X is CRX, and Y is C(RY)2; oris a double bond, X is C, and Y is C(RY);Rxand RYare each independently selected from the group consisting of hydrogen and -C1- C3alkyl; or Rxand RYare joined together to form -CH2-;Rwis selected from the group consisting of hydrogen, C1-C6alkyl, and -SO2-phenyl; wherein C1-C6alkyl and phenyl may optionally be substituted by one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl, C1-C3alkyl, and C1-C3alkoxy;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, -C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)- ORb, -O-C(O)-NRaRb, -O-(CO)-C1.C6alkyl, -C(O)-C1-C6alkyl, C1C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, 4-7 membered heterocyclyl, and 5-6 membered heteroaryl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, phenyl, heterocyclyl and heteroaryl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, C1-C3alkyl, and C1-C3alkoxy;R1is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C3-C6cycloalkyl, -CH2-phenyl, -CH2-CH2-phenyl, -CH2-(5-10 membered heteroaryl), and -CH2-(5-10 membered heterocyclyl); wherein C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C3- C6cycloalkyl, phenyl, heteroaryl, and heterocyclyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, and C1-C3alkoxy;R2and R3are each independently selected from the group consisting of hydrogen and C1- Q alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;R4is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1. C6alkyl, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3C6cycloalkyl, and phenyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R5is selected from the group consisting of halogen, hydroxyl, cyano, -NRaRb, -C(O)- NRaRb, -NRa-C(O)-Rb, -NRa-C(O)-NRaRb, -NRa-(CO)-ORb, -O-C(O)-NRaRb, -O-(CO)-C1-C6alkyl, -CO2H, -C(O)-C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl; wherein C1-C6alkyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, -C3-C6cycloalkyl, and phenyl may optionally be substituted by one or more substituentseach independently selected from the group consisting of halogen, hydroxyl, -NRaRb, and C1-C3alkoxy;R6and R7are each independently selected from the group consisting of hydrogen and C1- C6alkyl; wherein C1-C6alkyl may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C3alkyl; wherein C1-C3alkyl may optionally be substituted by one or more halogens; and m is 0, 1, 2, or 3.

25. The compound of claim 24, wherein the compound is represented by26. The compound of claim 24 or 25, wherein R6and R7are hydrogen.

27. The compound of claim 24 or 25, wherein the compound is represented by28. The compound of claim 24 or 25, wherein RYis hydrogen or -CH3.

29. The compound of claim 24 or 25, wherein Rwis selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2.

30. The compound of claim 24 or 25, wherein RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, -CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3.

31. The compound of claim 24 or 25, wherein RAis independently selected from each occurrence from the group consisting of fluoro, chloro, hydroxyl, cyano, phenyl, -CH3, -CHF2, -CH2OH, - CH2CH3, -OCH3, -CH2C(O)NH2, -CH2CH2OH, and -OCH2CH3.

32. The compound of claim 24 or 25, wherein R2is hydrogen.

33. The compound of claim 24 or 25, wherein R3is selected from the group consisting of hydrogen, -CH3, and -CH2OH.

34. The compound of claim 24 or 25, wherein R4is hydrogen.

35. The compound of claim 24 or 25, wherein R5is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, -CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, / M-hydroxyphenyl, p-hydroxyphenyl, and p-aminophenyl.

36. The compound of claim 24 or 25, wherein R1is selected from the group consisting of hydrogen,37. A compound represented by Formula IVA, IVB, or IVC:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, whereinA is selected from the group consisting ofRwis selected from the group consisting of hydrogen and C1-C3alkyl;RYis hydrogen or -CH3;RAis independently selected for each occurrence from the group consisting of fluoro, chloro, bromo, iodo, hydroxyl, cyano, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CHF2, -OCF3, -OCHF2, -CH2OH, -CH2NH2, - CH2C(O)NH2, -CH2CH2OH, -CH2CH2NH2, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxiranyl, azetidinyl, phenyl, triazolyl, and oxadiazolyl; wherein tetrahydropyrrolyl, piperidinyl, piperazinyl, and azetidinyl may optionally be substituted with -CH3;R1is selected from the group consisting of hydrogen, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -R2is selected from the group consisting of hydrogen, -CH3, and -CH2OH;R3is selected from the group consisting of hydrogen, hydroxyl, -NH2, -CH3, -CH2OH, - CH2NH2, -CO2H, -NH-C(O)-N(CH2CH3)2, phenyl, m-hydroxyphenyl, / >-hydroxyphenyl, and p- aminophenyl; and m is 0, 1, 2, or 3.

38. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or stereoisomer thereof.

39. A compound selected from the group consisting ofor a pharmaceutically acceptable salt and / or stereoisomer thereof.

40. A pharmaceutical composition comprising a compound of any one of claims 1, 17, 23, 24, 37, 38, and 39 and a pharmaceutically acceptable excipient.

41. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1, 17, 23, 24, 37, 38, and 39.

42. A method of treating a psychiatric or neurological disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of claims 1, 17, 23, 24, 37, 38, and 39 and a pharmaceutically acceptable excipient.

43. The method of claim 41, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.

44. The method of claim 42, wherein the psychiatric or neurological disease or disorder is selected from the group consisting of depression, anxiety, substance abuse, and headache.

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