Serotonin receptor agonists and uses thereof

Abstract

Described herein are compounds of Formulas (I) and (II) and their pharmaceutically acceptable salts, deuterated form, or stereoisomers, as well as their uses (e.g., as serotonin receptor agonists), wherein the R1, R2, R3, R4, R5, R6, A1, A2, A3, B1, B2, B3, B4, B5, B6 and Ring C and X1, X2, X3, R7, R8, R9, R10, R11, R11' R12, R12' R13, R13' R14, R15, R16, R17, and R18 are as defined herein.

Description

SEROTONIN RECEPTOR AGONISTS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present Application claims priority to U.S. Provisional Application No.63 / 690,150 filed September 3, 2024, and which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Rapid and effective treatments for stress-related disorders, such as depression, anxiety and post-traumatic stress disorder, remain a significant unmet medical need. Studies in humans and animals have shown that depression and stress exposure induce structural and functional changes in the brain. Signs of neuronal atrophy have been found in brain regions involved in stress-related behaviors, including prefrontal cortex and hippocampus. In animals, these structural changes have been shown to include loss of neurites, dendritic spines and synaptic contacts, as well as reduced hippocampal neurogenesis. Studies in humans and animals also have shown that depression and stress exposure decrease cerebral cortex and hippocampal levels of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival and synaptic plasticity. Together, these findings are consisent with the hypothesis that reduced BDNF may play a role in stress-related neuronal structural changes. In support of this hypothesis, chronic but not acute administration of typical antidepressant drugs, such as selective serotonin (5-HT) reuptake inhibitors (SSRIs), attenuate the effects of stress on neurogenesis, neuronal structure and BDNF levels in animals and demonstrate antidepressant and anxiolytic effects in humans. In addition, single administration of ketamine attenuates these effects of stress in animals and demonstrates rapid-acting antidepressant effects in humans. Thus, compounds that promote the generation and / or maintenance of neurites, spines, synapses and / or neurons upon single administration may have rapid therapeutic benefit in the treatment of stress-related disorders.

[0003] Tryptamines are a structural class of compounds containing an indolealkylamine backbone with reported psychedelic and non-psychedelic effects. Psychedelic tryptamines include compounds such as psilocybin, its active metabolite psilocin, and N,N- dimethyltryptamine (DMT). Psilocybin and psilocin are found in hundreds of species of hallucinogenic mushrooms and were used in Aztec rituals. DMT is present in ayahuasca, a hallucinogenic brew traditionally used in ceremonial settings in South America. Psilocybin and ayahuasca have been reported to induce rapid and lasting clinical antidepressant efficacyfollowing single administration. Data in rodents and nonhuman primates also suggest the potential for antidepressant-like effects of psilocybin, DMT or ayahuasca. These compounds exert functional activity at a variety of central nervous system receptors, including serotonin receptors, of which partial agonism at 5-HT2A receptors is believed to mediate the psychedelic effects. Psychedelic tryptamines have been reported to exhibit neuronal plasticity-promoting effects, including neuritogenesis, spinogenesis, synaptogenesis, hippocampal cell proliferation and / or hippocampal neurogenesis, which may underlie their therapeutic benefit in the treatment of stress-related disorders, such as depression. Specifically, psilocin and DMT were reported to significantly increase measures of neurite outgrowth in primary embryonic rat cortical neurons. There is published data on the effects of the reference 5-HT2A agonist, DOI, and antagonist, M100907, in NGF-induced neurite outgrowth in rat adrenal medulla pheochromocytoma-derived PC12 cells.

[0004] There is a need for novel pharmaceutical compositions for the treatment of stress- related disorders. Given the reported 5-HT2A receptor agonist activity and ability to promote neurite outgrowth associated with classical psychedelic compounds, novel compounds may provide an improved therapeutic index for treating stress related disorders with reduced side effect profiles. SUMMARY

[0005] In aspects, the present disclosure provides compounds of Formula (I):and pharmaceutically acceptable salts, deuterated forms, or stereoisomers thereof, wherein the groups R1, R2, R3, R4, R5, R6, A1, A2, A3, B1, B2, B3, B4, B5, B6and Ring C are as defined herein.

[0006] In aspects, the present disclosure provides compounds of Formula (II):

[0007] or pharmaceutically acceptable salt, wherein X1, X2, X3, R7, R8, R9, R10, R11, R11’R12, R12’R13, R13’R14, R15, R16, R17, and R18are as defined herein.

[0008] In aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.

[0009] In aspects, the present disclosure provides methods of activating a serotonin receptor in a subject or a biological sample comprising administering the compound disclosed herein or contacting the biological sample with the compound disclosed herein.

[0010] In aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for activating a serotonin receptor in a subject or a biological sample.

[0011] In aspects, the present disclosure provides compounds disclosed herein for use in activating a serotonin receptor in a subject or a biological sample.

[0012] In aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein.

[0013] In aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0014] In aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIGs. 1A-1B show concentration response curves of compound 2 in vitro 5-HT2B agonist activity relative to 5-HT following 15-minute compound incubation (FIG. 1A) andinverse agonism of 5-HT2BR by 1μM of compound 2 persists for at 30-minutes of exposure (FIG. 1B). DETAILED DESCRIPTION

[0016] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0017] Definitions

[0018] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0019] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0020] The term "about" when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as "about 49, about 50, about 55, ... ", "about 50" means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases "less than about" a value or "greater than about" a value should beunderstood in view of the definition of the term "about" provided herein. Similarly, the term "about" when preceding a series of numerical values or a range of values (e.g., "about 10, 20, 30" or "about 10-30") refers, respectively to all values in the series, or the endpoints of the range.

[0021] The terms "administer," "administering" or "administration" as used herein refer to administering a compound or pharmaceutically acceptable salt of the compound or a composition comprising the compound or pharmaceutically acceptable salt of the compound to a patient.

[0022] The term “pharmaceutically acceptable salts” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine dicyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0023] The term "treating" as used herein with regard to a patient, refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

[0024] The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to apatient, is capable of performing the intended result. The "effective amount" will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0025] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.

[0026] The term “carrier” or “vehicle” as used interchangeably herein encompasses carriers, excipients, adjuvants, and diluents or a combination of any of the foregoing, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body. In addition to the adjuvants, excipients and diluents known to one skilled in the art, the carrier includes nanoparticles of organic and inorganic nature.

[0027] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-C6alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0028] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10alkyl, an alkyl comprising up to 6 carbon atoms is a C1-C6alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5alkyl. A C1-C5alkyl includes C5alkyls, C4alkyls, C3alkyls, C2alkyls and C1alkyl (i.e., methyl). A C1-C6alkyl includes all moieties described above for C1-C5alkyls but also includes C6alkyls. A C1-C10alkyl includes all moieties described above for C1-C5alkyls and C1-C6alkyls, but also includes C7, C8, C9and C10alkyls. Similarly, a C1-C12alkyl includes all the foregoing moieties, but also includes C11and C12alkyls. Non-limiting examples of C1-C12alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0029] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12carbon atoms is a C2-C12alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5alkenyl. A C2-C5alkenyl includes C5alkenyls, C4alkenyls, C3alkenyls, and C2alkenyls. A C2-C6alkenyl includes all moieties described above for C2-C5alkenyls but also includes C6alkenyls. A C2-C10alkenyl includes all moieties described above for C2-C5alkenyls and C2-C6alkenyls, but also includes C7, C8, C9and C10alkenyls. Similarly, a C2-C12alkenyl includes all the foregoing moieties, but also includes C11and C12alkenyls. Non-limiting examples of C2-C12alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3- nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2- undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5- dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11- dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0030] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10alkynyl, an alkynyl group comprising up to 6 carbon atoms is a6alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5alkynyl. A C2-C5alkynyl includes C5alkynyls, C4alkynyls, C3alkynyls, and C2alkynyls. A C2-C6alkynyl includes all moieties described above for C2-C5alkynyls but also includes C6alkynyls. A C2-C10alkynyl includes all moieties described above for C2-C5alkynyls and C2-C6alkynyls, but also includes C7, C8, C9and C10alkynyls. Similarly, a C2-C12alkynyl includes all the foregoing moieties, but also includes C11and C12alkynyls. Non-limiting examples of C2-C12alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0031] “Aryl” refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, and which is attached to the rest of the molecule by a single bond. For purposes of this disclosure, the aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryls include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the “aryl” can be optionally substituted.

[0032] “Heteroaryl” refers to a 5- to 20-membered ring system comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, at least one aromatic ring, including compounds with aromatic resonance structures (e.g., 2-pyridone), and which is attached to the rest of the molecule by a single bond. For purposes of this disclosure, the heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2 a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1 oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl, 1 phenyl 1H pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted. “Heteroarylene” refers to a divalent radical derived from “heteroaryl”.

[0033] “Heterocyclyl”, “heterocyclic ring”, or “heterocycle” refers to a stable saturated, unsaturated, or aromatic 3- to 20-membered ring which consists of two to nineteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond. Heterocyclyl orheterocyclic rings include heteroaryls, heterocyclylalkyls, heterocyclylalkenyls, and hetercyclylalkynyls. Unless stated otherwise specifically in the specification, the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl or heterocyclylene group can be optionally substituted. “Heterocyclylene” refers to a divalent radical derived from “heterocyclyl”, “heterocyclic ring”, or “heterocycle”.

[0034] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spirocyclic ring systems, having from three to twenty carbon atoms (e.g., having from three to ten carbon atoms) and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0035] “Haloalkyl” refers to an alkyl, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0036] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon, and which is attached to the rest of the molecule by a single bond. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0037] “Alkoxy” refers to a group of the formula -ORawhere Rais an alkyl, alkenyl or alkynyl as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0038] The term “substituted” used herein means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and / or heteroaryl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and / or heteroarylalkyl group. In embodiments, “substituted” further means any alkyl, cycloalkyl or heterocyclylalkyl in which one or more hydrogen atoms is replaced by an isotope e.g., deuterium. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0039] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. Compounds of the Present Disclosure Formula (I)

[0040] In aspects, the present disclosure provides compounds of Formula (I):and pharmaceutically acceptable salts, deuterated forms, or stereoisomers thereof, wherein: A1is C or N; A2is N or NRA2; A3is N or NRA3; RA2and RA3are independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6carbocyclyl, optionally substituted 3- to 6-membered heterocyclyl, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd; B1and B6are independently C or N; B2is CRB2or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; RB2, RB3, RB4, and RB5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; R1, R2, R3, R4, R5, and R6are independently hydrogen, deuterium, halogen, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl;R1and R2, or R5and R6, together with the carbon atom to which they are attached, form optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; or R1and R2or R5and R6are taken together to form an oxo; R’ is hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-4carbocyclyl, or optionally substituted 3- or 4-membered heterocyclyl; and Ring C is an optionally substituted unsaturated ring, wherein: each Rais independently C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 6-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; and each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0041] In embodiments, I) when A1is C, A3is NRA3, RA3is methyl, R’ is hydrogen, and R1is not -OH or optionally substituted C1-6alkoxy, then Ring C is not:II) when A1is N, R’ is hydrogen or methyl, i) each of R5and R6is hydrogen, or i) R5is methyl, R6is hydrogen, and R1is not -OH or optionally substituted C1-6alkoxy, then 1) Ring C is not unsubstituted phenyl, unsubstituted 2-pyridinyl, unsubstituted 3- pyridinyl, or unsubstituted 4-pyridinyl; and , or, and III) the compound is not .

[0042] In embodiments, the compound is of Formula (I-1) (I-1), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein R1’is hydrogen, deuterium, optionally substituted C1-6alkyl, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd.

[0043] In embodiments, the compound of Formula (I-1) is not:.

[0044] In embodiments, R1’is hydrogen, deuterium, optionally substituted C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), optionally substituted C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or optionally substituted 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S), -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd.

[0045] In embodiments, R1’is hydrogen, deuterium, or C1-6alkyl.

[0046] In embodiments, the compound is of Formula (I-2)and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein C1is CRC1or N; C2is CRC2or N; C3is CRC3or N; C4is CRC4or N; C5is CRC5or N; and RC1, RC3, and RC5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6- membered heterocyclyl; RC2and RC4are independently halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6 carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; orRC1and RC2or RC4and RC5, together with the carbon atoms to which they are attached, form optionally substituted C3-6carbocyclyl, optionally substituted 3- or 6-membered heterocyclyl, optionally substituted C6aryl, or optionally substituted 5- to 6-membered heteroaryl, provided that: i) when A1is C, A3is NRA3, RA3is methyl, R’ is hydrogen, and R1is not -OH or optionally substituted C1-6alkoxy, then Ring C is not: and , and ii) when A1is N, R’ is hydrogen or methyl, i) each of R5and R6is hydrogen, or i) R5is methyl, and R6is hydrogen, and R1is not -OH or optionally substituted C1-6alkoxy, then Ring C is not .

[0047] In embodiments, C1is CRC1or N. In embodiments, C1is CRC1. In embodiments, C1is N.

[0048] In embodiments, C2is CRC2or N. In embodiments, C2is CRC2. In embodiments, C2is N.

[0049] In embodiments, C3is CRC3or N. In embodiments, C3is CRC3. In embodiments, C3is N.

[0050] In embodiments, C4is CRC4or N. In embodiments, C4is CRC4. In embodiments, C4is N.

[0051] In embodiments, C5is CRC5or N. In embodiments, C5is CRC5. In embodiments, C5is N.

[0052] In embodiments, none of C1, C2, C3, C4, and C5is N.

[0053] In embodiments, one of C1, C2, C3, C4, and C5is N.

[0054] In embodiments, C1is N, and none of C2, C3, C4, C5is N. In embodiments, C2is N, and none of C1, C3, C4, and C5is N. In embodiments, C3is N, and none of C1, C2, C4, and C5is N.

[0055] In embodiments, two of C1, C2, C3, C4, and C5are N.

[0056] In embodiments, three of C1, C2, C3, C4, and C5are N.

[0057] In embodiments, four of C1, C2, C3, C4, and C5are N.

[0058] In embodiments, RC1, RC3, and RC5are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), optionally substituted C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), optionally substituted C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), optionally substituted C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or optionally substituted 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S).

[0059] In embodiments, RC2and RC4are independently halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), optionally substituted C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), optionally substituted C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), optionally substituted C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or optionally substituted 3- to 6- membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0060] In embodiments, RC1and RC2or RC4and RC5, together with the carbon atoms to which they are attached, form optionally substituted C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or optionally substituted 3- to 6- membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S), optionally substituted C6 aryl (i.e. phenyl), or optionally substituted 5- to 6-membered heteroaryl (e.g., heteroaryl comprising one 5- or 6- membered ring and 1-4 heteroatoms selected from N, O, and S).

[0061] In embodiments, R1, R2, R3, R4, R5, and R6are independently hydrogen, deuterium, halogen (e.g., -F, -Cl, -Br, or -I), -OH, optionally substituted C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), optionally substituted C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), optionally substituted C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or optionally substituted 3- to 6- membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0062] In embodiments, each of R2, R3, R4, R5, and R6ishydrogen.

[0063] In embodiments, R1is hydrogen.

[0064] In embodiments, R1is -OR1’.

[0065] In embodiments, A1is C or N. A1is N. A1is C.

[0066] In embodiments, A2is N or NRA2. A2is N. A2is NRA2.

[0067] In embodiments, A3is N or NRA3. A3is N. A3is NRA3.

[0068] In embodiments, RA2and RA3are independently hydrogen, optionally substituted C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), optionally substituted C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4),pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), optionally substituted C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), optionally substituted C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or optionally substituted 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S), -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd.

[0069] In embodiments, B1is C or N. In embodiments, B1is C. In embodiments, B1is N.

[0070] In embodiments, B2is CRB2or N. In embodiments, B2is CRB2. In embodiments, B2is N.

[0071] In embodiments, B3is CRB3or N. In embodiments, B3is CRB3. In embodiments, B3is N.

[0072] In embodiments, B4is CRB4or N. In embodiments, B4is CRB4. In embodiments, B4is N.

[0073] In embodiments, B5is CRB5or N. In embodiments, B5is CRB5. In embodiments, B5is N.

[0074] In embodiments, B6is C or N. In embodiments, B6is C. In embodiments, B6is N.

[0075] In embodiments, RB2, RB3, RB4, and RB5are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), optionally substituted C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), optionally substituted C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), optionally substituted C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or optionally substituted 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0076] In embodiments, each Rais independently C1-6alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6),or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0077] In embodiments, each Rbis independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0078] In embodiments, each Rcand each Rdis independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0079] In embodiments, Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6- membered rings and 1-4 heteroatoms selected from N, O, and S).

[0080] In embodiments, Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz.

[0081] In embodiments, Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, orpentylhexylamino), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0082] In embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0083] In embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0084] In embodiments, the compound is selected from the compounds in Table 1. Table 1. Compounds of the Present DisclosureFormula (II)

[0085] The present disclosure provides compounds of formula (II):

[0086] or a pharmaceutically acceptable salt,

[0087] wherein:

[0088] X1, X2, and X3are each independently -C- or -N-;

[0089] R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, -NH(C=O)-alkyl, or absent;

[0090] R10is -H, -alkyl, -haloalkyl, -cycloalkyl, alkyl-OH, or -heterocyclyl;

[0091] R11and R11’are each independently -H, alkyl, -haloalkyl, alkyl-OH, O-alkyl, -OH, -or R11and R11’together with the carbon to which they are attached form oxo;

[0092] R12, R12’R13, and R13’are each independently -H, alkyl, -haloalkyl, alkyl-OH, O-alkyl, or -OH;

[0093] (1) R14, R15, R16, R17, and R18are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -NO2, -alkyl-OH, -CN, -O(C=O)-alkyl, - O-haloalkyl, -O -aryl, -heteroaryl, or -NH(C=O)-alkyl, or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl,

[0094] wherein at least one of R14and R15or R15and R16, together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

[0095] (2) R14, R16, and R18are -H; and R15and R17are not -H; and

[0096] wherein the compound is not:

[0097] The present disclosure provides compounds of Formula (II-A):

[0098] or a pharmaceutically acceptable salt,

[0099] wherein:

[0100] X1, X2, and X3are each independently -C- or -N-;

[0101] R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, -NH(C=O)-alkyl, or absent;

[0102] R10is -H, -alkyl, -haloalkyl, -cycloalkyl, alkyl-OH, or -heterocyclyl;

[0103] R11and R11’are each independently -H, alkyl, -haloalkyl, alkyl-OH, O-alkyl, -OH, -or R11and R11’together with the carbon to which they are attached form oxo;

[0104] R12, R12’R13, and R13’are each independently -H, alkyl, -haloalkyl, alkyl-OH, O-alkyl, or -OH;

[0105] R14, R15, R16, R17, and R18are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, - halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -NO2, -alkyl-OH, -CN, -O(C=O)-alkyl, - O-haloalkyl, -O -aryl, -heteroaryl, or -NH(C=O)-alkyl, or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl,

[0106] wherein at least one of R14and R15or R15and R16, together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl,

[0107] wherein the compound is not:

[0108] The present disclosure provides compounds of Formula (II-B):

[0109] or a pharmaceutically acceptable salt,

[0110] wherein:

[0111] X1, X2, and X3are each independently -C- or -N-;

[0112] R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, -NH(C=O)-alkyl, or absent;

[0113] R10is -H, -alkyl, -haloalkyl, -cycloalkyl, alkyl-OH, or -heterocyclyl;

[0114] R11and R11’are each independently -H, alkyl, -haloalkyl, alkyl-OH, O-alkyl, -OH, -or R11and R11’together with the carbon to which they are attached form oxo;

[0115] R12, R12’R13, and R13’are each independently -H, alkyl, -haloalkyl, alkyl-OH, O-alkyl, or -OH; or

[0116] R14, R16, and R18are -H; and R15and R17are not -H; and

[0117] wherein the compound is not:

[0118] The present disclosure provides compounds of Formula (II-C):

[0119] or pharmaceutically acceptable salt thereof,

[0120] wherein:

[0121] X1, X2, and X3are each independently -C- or -N-;

[0122] R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, or -NH(C=O)-alkyl;

[0123] R10is -H, -alkyl, -haloalkyl, -cycloalkyl, or alkyl-OH;

[0124] R11is -H, -OH, or O-alkyl; or

[0125] R15and R17are each independently -halogen or -alkyl.

[0126] The present disclosure provides compounds of Formula (II-D),

[0127] or pharmaceutically acceptable salt thereof,

[0128] X1, X2, and X3are each independently -C- or -N-;

[0129] R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, or -NH(C=O)-alkyl;

[0130] R10is -H, -alkyl, -haloalkyl, -cycloalkyl, or alkyl-OH;

[0131] R11is -H, -OH, or O-alkyl; and

[0132] In embodiments, X1, X2, and X3are -C-.

[0133] In embodiments, X2is -N- and X1and X3are -C-.

[0134] In embodiments, X3is -N- and X1and X2are -C-.

[0135] In embodiments, X1is -N- and X2and X3are -C-.

[0136] In embodiments, R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, - cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, or -NH(C=O)-alkyl.

[0137] In embodiments, R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, or - cycloalkyl.

[0138] In embodiments, R7, R8, and R9are each independently -H, -S-alkyl, -S(O)2-alkyl, or - SH.

[0139] In embodiments, R7, R8, and R9are each independently -H, -NH-alkyl, -NH2, or -CN.

[0140] In embodiments, R7, R8, and R9are each independently -H, -OH, -O(C=O)-alkyl, or - NH(C=O)-alkyl.

[0141] In embodiments, R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, - cycloalkyl, or -halo.

[0142] In embodiments, R7, R8, and R9are each independently -H, -O-alkyl, or absent.

[0143] In embodiments, R7, R8, and R9are -H. R10

[0144] In embodiments, R10is -H, -alkyl, -haloalkyl, -cycloalkyl, alkyl-OH, or -heterocyclyl.

[0145] In embodiments, R10is -H, -alkyl, -haloalkyl, -cycloalkyl, or alkyl-OH.

[0146] In embodiments, R10is -H, -alkyl, or -haloalkyl.

[0147] In embodiments, R10is -alkyl, -haloalkyl, -cycloalkyl, or alkyl-OH.

[0148] In embodiments, R10is -H, -alkyl, -cycloalkyl, or -haloalkyl.

[0149] In embodiments, R10is -H.

[0150] In embodiments, R10is -alkyl.

[0151] In embodiments, R10is -methyl.

[0152] In embodiments, R11and R11’are each independently -H, alkyl, -haloalkyl, -alkyl-OH, -O-alkyl, -OH, -or R11and R11’together with the carbon to which they are attached form oxo.

[0153] In embodiments, R11and R11’are each independently -H, alkyl, -haloalkyl, -alkyl-OH, -O-alkyl, or -OH.

[0154] In embodiments, R11and R11’together with the carbon to which they are attached form oxo.

[0155] In embodiments, R11and R11’are each independently -H, -O-alkyl, or -OH.

[0156] In embodiments, R11and R11’are each -H or -alkyl.

[0157] In embodiments, R11and R11’are each -H or -haloalkyl.

[0158] In embodiments, R11and R11’are each -H or -alkyl-OH.

[0159] In embodiments, R11and R11’are each -H or -O-alkyl.

[0160] In embodiments, R11and R11’are each -H or -OH.

[0161] In embodiments, R12, R12’R13, and R13’are each independently -H, -alkyl, -haloalkyl, -alkyl-OH, -O-alkyl, or -OH.

[0162] In embodiments, R12, R12’R13, and R13’are each independently -H, -alkyl, or -haloalkyl.

[0163] In embodiments, R12, R12’R13, and R13’are each independently -H or -alkyl-OH.

[0164] In embodiments, R12, R12’R13, and R13’are each independently -H or -haloalkyl.

[0165] In embodiments, R12, R12’R13, and R13’are each independently -H or -alkyl-OH.

[0166] In embodiments, R12, R12’R13, and R13’are each independently -H or -O-alkyl.

[0167] In embodiments, R12, R12’R13, and R13’are each independently -H or -OH.

[0168] In embodiments, R12, R12’R13, and R13’are each independently -H.

[0169] In embodiments, R14, R15, R16, R17, and R18are each independently -H, -alkyl, -O- alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -NO2, -alkyl-OH, - CN, -O(C=O)-alkyl, -O-haloalkyl, -O -aryl, -heteroaryl, or -NH(C=O)-alkyl, or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein at least one of R14and R15or R15and R16, togetherwith the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0170] In embodiments, R14, R15, R16, R17, and R18are each independently -H, -alkyl, -O- alkyl, or -cycloalkyl or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein at least one of R14and R15or R15and R16, together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0171] In embodiments, R14, R15, R16, R17, and R18are each independently -H, -S-alkyl, - S(O)2-alkyl, or -SH, or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein at least one of R14and R15or R15and R16, together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0172] In embodiments, R14, R15, R16, R17, and R18are each independently -H, -NH-alkyl, - NH2, -NO2, -alkyl-OH, or -CN, or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein at least one of R14and R15or R15and R16, together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0173] In embodiments, R14, R15, R16, R17, and R18are each independently -H, -O(C=O)- alkyl, -O-haloalkyl, -O-aryl, -heteroaryl, or -NH(C=O)-alkyl, or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein at least one of R14and R15or R15and R16, together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0174] In embodiments, at least one of R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0175] In embodiments, R16, R17, and R18are -H and R14and R15together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0176] In embodiments, R14, R17, and R18are -H and R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0177] In embodiments, R16, R17, and R18are -H and R14and R15together with the carbon in which they are attached form a heteroaryl.

[0178] In embodiments, R14, R17, and R18are -H and R15and R16together with the carbon in which they are attached form a heteroaryl.

[0179] In embodiments, R16, R17, and R18are -H and R14and R15together with the carbon in which they are attached form a cycloalkyl.

[0180] In embodiments, R14, R17, and R18are -H and R15and R16together with the carbon in which they are attached form a cycloalkyl.

[0181] In embodiments, R16, R17, and R18are -H and R14and R15together with the carbon in which they are attached form an aryl.

[0182] In embodiments, R14, R17, and R18are -H and R15and R16together with the carbon in which they are attached form an aryl.

[0183] In embodiments, R16, R17, and R18are -H and R14and R15together with the carbon in which they are attached form an heterocyclyl.

[0184] In embodiments, R14, R17, and R18are -H and R15and R16together with the carbon in which they are attached form an heterocyclyl.

[0185] In embodiments, R14, R16, and R18are -H; and R15and R17are not -H.

[0186] In embodiments, R14, R15, R16, and R18are -H; and R17is -halo or -alkyl.

[0187] In embodiments, R14, R15, R16, and R18are -H; and R17is -halo or -methyl.

[0188] In embodiments, R14, R15, R16, and R18are -H; and R17is -halo.

[0189] In embodiments, R14, R15, R16, and R18are -H; and R17is -alkyl.

[0190] In embodiments, R14, R15, R16, and R18are -H; and R17is -methyl.

[0191] In embodiments, R14, R16, R17, and R18are -H; and R15is -halo or -alkyl.

[0192] In embodiments, R14, R16, R17, and R18are -H; and R15is -halo or -methyl.

[0193] In embodiments, R14, R16, R17, and R18are -H; and R15is -halo.

[0194] In embodiments, R14, R16, R17, and R18are -H; and R15is -alkyl.

[0195] In embodiments, R14, R16, R17, and R18are -H; and R15is -methyl. Ring D

[0196] In embodiments, Ring D is aryl or heteroaryl.

[0197] In embodiments, Ring D is aryl.

[0198] In embodiments, Ring D is heteroaryl.

[0199] In embodiments, Ring.

[0200] In embodiments, the compound is selected from the compounds in Table 2 and pharmaceutically acceptable salts thereof.

[0201] In embodiments, the compound is selected from the compounds in Table 2.Table 2. Compounds of the Present Disclosure

[0202] In embodiments, the compound is selected from the compounds in Table 3 and pharmaceutically acceptable salts thereof.

[0203] In embodiments, the compound is selected from the compounds in Table 3. Table 3. Compounds of the Present Disclosure

[0204] In embodiments, the compound is selected from the compounds in Table 4 and pharmaceutically acceptable salts thereof.

[0205] Table 4. Compounds of the Present Disclosure

[0206] In embodiments, the compound is selected from the compounds in Table 5 andpharmaceutically acceptable salts thereof.

[0207] Table 5. Compounds of the Present Disclosure

[0208] In embodiments, the compound is selected from the compounds in Table 6 andpharmaceutically acceptable salts thereof.

[0209] Table 6. Compounds of the Present Disclosure

[0210] The compounds of the present disclosure may possess unique or advantageouscharacteristics, as compared to known compounds, such as known H1 receptor (H1R)inhibitors and known platelet-activating factor receptor (PAF-R) inhibitors. For example, thecompounds of the present disclosure may display more potent H1R inhibitation activity and / ormore potent PAF-R inhibitation activity. The compounds of the present disclosure may possessmore favorable characteristics on blood-brain barrier penetration (e.g., less BBBpenetration). The compounds of the present disclosure may further possess H1R and PAF-R dual inhibitation activity, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and / or AUC), and / or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug-drug interaction).These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein. Pharmaceutically acceptable salts

[0211] In embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0212] In embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0213] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0214] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoricacid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0215] In embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4alkyl)4, and the like.

[0216] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0217] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. Pharmaceutical Compositions

[0218] In embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound described herein (e.g., a compound of formula (I), (II), (II- A), (II-B), (II-C), (II-D), or Tables 1-5) or a pharmaceutically acceptable salt, deuterated form, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0219] In embodiments, the compounds described herein herein (e.g., a compound of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5) are administered without apharmaceutically acceptable excipient. In embodiments, the compound described herein is combined with one or more pharmaceutically suitable or acceptable carriers (also referred to herein as one or more pharmaceutically suitable (or acceptable) excipients, physiologically suitable (or acceptable) excipients, or physiologically suitable (or acceptable) carriers) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0220] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0221] In embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In embodiments, the pharmaceutical composition is formulated for oral administration. In embodiments, the pharmaceutical composition is formulated for intravenous injection. In embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In embodiments, the pharmaceutical composition is formulated as a tablet. Methods of Use

[0222] In embodiments, the present disclosure provides methods of activating a serotonin receptor in a subject or a biological sample, comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein.

[0223] In aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for activating a serotonin receptor in a subject or a biological sample.

[0224] In aspects, the present disclosure provides compounds disclosed herein for use in activating a serotonin receptor in a subject or a biological sample.

[0225] In aspects, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject the compound disclosed herein.

[0226] In aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0227] In aspects, the present disclosure provides compounds disclosed herein for use in treating or preventing a disease or disorder in a subject in need thereof.

[0228] In embodiments, the disease or disorder is mediated by a serotonin receptor.

[0229] In embodiments, the present disclosure provides methods of activating a serotonin receptor in a subject or a biological sample, comprising administering at least one compound disclosed herein herein (e.g., a compound of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or a pharmaceutically acceptable salt thereof) to the subject or contacting the biological sample with the compound disclosed herein.

[0230] In embodiments, the present disclosure provides uses of the compound disclosed herein (e.g., a compound of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for activating a serotonin receptor in a subject or a biological sample.

[0231] In embodiments, the present disclosure provides compounds disclosed herein (e.g., compounds of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or a pharmaceutically acceptable salt thereof) for use in activating a serotonin receptor in a subject or a biological sample.

[0232] In embodiments, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject the compound disclosed herein (e.g., a compound of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or a pharmaceutically acceptable salt thereof).

[0233] In embodiments, the present disclosure provides uses of a compound disclosed herein (e.g., a compound of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or apharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0234] In embodiments, the present disclosure provides compounds disclosed herein (e.g., compounds of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or a pharmaceutically acceptable salt thereof) for use in treating or preventing a disease or disorder in a subject in need thereof.

[0235] In embodiments, the disease or disorder is mediated by a serotonin receptor.

[0236] In embodiments, the present disclosure provides methods of treating a mental health disease or disorder, the method comprising administering a compound of the present dislosure (e.g., compounds of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.

[0237] In embodiments, the present disclosure provides methods of treating a mental health disease or disorder, the method comprising administering a pharmaceutical composition comprising a compound of the present dislosure (e.g., compounds of formula (I), (II), (II-A), (II-B), (II-C), (II-D), or Tables 1-5 or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.

[0238] In embodiments, the mental health disease or disorder is selected from the group consisting of major depressive disorder, treatment resistant depression, substance use disorders and eating disorders. In embodiments, eating disorders include illnesses such as anorexia nervosa, bulimia nervosa, and other disorders related to eating (e.g., binge eating).

[0239] In embodiments, the mental health disease or disorder is an eating disorder.

[0240] In embodiments, the mental health disease or disorder is selected from the group consisting of compulsive disorders, anxiety disorders, stress disorders, and rumination.

[0241] In embodiments, the mental health disease or disorder is a mood disorder. In embodiments, mood disorders include e.g., depressive disorders, such as major depressive disorder or treatment resistant depression.

[0242] In embodiments, the mental health disorder is a substance abuse disorder. In embodiments, substance use related disorders are disorders of maladaptive patterns of substance use, and include criteria, such as recurrent substance use related problems, tolerance to a substance, withdrawal upon discontinuing use, an inability to cut down or control use of the substance, and giving up important social, occupational, or recreational activities because of using the substance. See e.g., the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In embodiments, the substance use related disorder is a disorder resulting from the use of: alcohol; caffeine; cannabis; hallucinogens (such as phencyclidine or similarly actingarylcyclohexylamines, and other hallucinogens, such as LSD); inhalants; opioids; sedatives, hypnotics, or anxiolytics; stimulants (including amphetamine-type substances, cocaine, and other stimulants); tobacco; and other substances. Numbered Embodiments

[0243] 1. A compound of Formula (I)

[0244] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

[0245] A1is C or N;

[0246] A2is N or NRA2;

[0247] A3is N or NRA3;

[0248] RA2and RA3are independently hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6carbocyclyl, optionally substituted 3- to 6-membered heterocyclyl, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd;

[0249] B1and B6are independently C or N;

[0250] B2is CRB2or N;

[0251] B3is CRB3or N;

[0252] B4is CRB4or N;

[0253] B5is CRB5or N;

[0254] RB2, RB3, RB4, and RB5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl;

[0255] R1, R2, R3, R4, R5, and R6are independently hydrogen, deuterium, halogen, - OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl;

[0256] R1and R2, or R5and R6, together with the carbon atom to which they are attached, form optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6- membered heterocyclyl; or

[0257] R1and R2or R5and R6are taken together to form an oxo;

[0258] R’ is hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-4carbocyclyl, or optionally substituted 3- or 4-membered heterocyclyl; and

[0259] Ring C is an optionally substituted unsaturated ring,

[0260] wherein:

[0261] each Rais independently C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl;

[0262] each Rbis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; and

[0263] each Rcand Rdis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6- membered heterocyclyl; or

[0264] Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 6- membered heterocyclyl,

[0265] wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; and

[0266] each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl,

[0267] provided that:

[0268] I) when A1is C, A3is NRA3, RA3is methyl, R’ is hydrogen, and R1is not -OH or optionally substituted C1-6alkoxy, then Ring C is not:

[0269] II) when A1is N, R’ is hydrogen or methyl, i) each of R5and R6is hydrogen, or i) R5is methyl, R6is hydrogen, and R1is not -OH or optionally substituted C1-6alkoxy, then

[0270] 1) Ring C is not unsubstituted phenyl, unsubstituted 2-pyridinyl, unsubstituted 3- pyridinyl, or unsubstituted 4-pyridinyl; and.

[0274] 2. The compound of embodiment 1, wherein the compound is of Formula (I-1)

[0275] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

[0276] R1’is hydrogen, deuterium, optionally substituted C1-6alkyl, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl, -

[0277] wherein the compound is not:.

[0278] 3. The compound of embodiment 2, wherein R1’is hydrogen, deuterium, or C1-6alkyl.

[0279] 4. The compound of any one of embodiments 1-3, wherein Ring C is optionally substituted C6-10aryl or optionally substituted 5- to 10-membered heteroaryl.

[0280] 5. The compound of embodiment 1, wherein the compound is of Formula (I-2)

[0281] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

[0282] C1is CRC1or N;

[0283] C2is CRC2or N;

[0284] C3is CRC3or N;

[0285] C4is CRC4or N;

[0286] C5is CRC5or N; and

[0287] RC1, RC3, and RC5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl;

[0288] RC2and RC4are independently halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl; or

[0289] RC1and RC2or RC4and RC5, together with the carbon atoms to which they are attached, form optionally substituted C3-6carbocyclyl, optionally substituted 3- or 6-membered heterocyclyl, optionally substituted C6aryl, or optionally substituted 5- to 6-membered heteroaryl,

[0290] provided that:

[0291] i) when A1is C, A3is NRA3, RA3is methyl, R’ is hydrogen, and R1is not -OH or optionally substituted C1-6alkoxy, then Ring C is not:

[0292] ii) when A1is N, R’ is hydrogen or methyl, i) each of R5and R6is hydrogen, or i) R5is methyl, and R6is hydrogen, and R1is not -OH or optionally substituted C1-6 alkoxy, then Ring C is not.

[0293] 6. The compound of embodiment 5, wherein none of C1, C2, C3, C4, and C5is N or one of C1, C2, C3, C4, and C5is N.

[0294] 7. The compound of embodiment 6, wherein C2is CRC2and C4is CRC4, and RC2and RC4are independently halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl.

[0295] 8. The compound of embodiment 7, wherein RC2and RC4are independently halogen or C1-6alkyl.

[0296] 9. The compound of embodiment 5, wherein RC1and RC2or RC4and RC5, together with the carbon atoms to which they are attached, form optionally substituted C3-6carbocyclyl, optionally substituted 3- or 6-membered heterocyclyl, optionally substituted C6aryl, or optionally substituted 5- to 6-membered heteroaryl.

[0297] 10. The compound of embodiment 9, wherein RC1and RC2or RC4and RC5, together with the carbon atoms to which they are attached, form optionally substituted 3- or 6-membered heterocyclyl or optionally substituted 5- to 6-membered heteroaryl.

[0298] 11. The compound of any one of embodiments 5-10, wherein R1is hydrogen.

[0299] 12. The compound of any one of embodiments 1-11, wherein each of R2, R3, R4, R5, and R6is hydrogen.

[0300] 13. The compound of any one of embodiments 1-12, wherein A2is N, and A3is NRA3, and RA3is hydrogen or alkyl optionally substituted with -OH.

[0301] 14. The compound of any one of embodiments 1-13, wherein none of B1, B2, B3, B4, B5, and B6is N, or one of B1, B2, B3, B4, B5, and B6is N.

[0302] 15. The compound of any one of embodiments 14, wherein RB2, RB3, RB4, and RB5, when available, are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino, optionally substituted C3-6carbocyclyl, or optionally substituted 3- to 6-membered heterocyclyl.

[0303] 16. The compound of embodiment 15, wherein RB2, RB3, RB4, and RB5, when available, are independently hydrogen, halogen, C1-6alkyl, or C1-6alkoxy.

[0304] 17. The compound of any one of embodiments 1-16, wherein R’ is hydrogen.

[0305] 18. A compound selected from the compounds in Table 1, and the pharmaceutically acceptable salts thereof.

[0306] 19. A pharmaceutical composition comprising the compound of any one of embodiments 1-18, and a pharmaceutically acceptable excipient.

[0307] 20. A method of inhibiting a serotonin receptor in a subject or a biological sample, comprising administering the compound of any one of embodiments 1-18 to the subject or contacting the biological sample with the compound of any one of claims 1-18.

[0308] 21. Use of the compound of any one of embodiments 1-18 in the manufacture of a medicament for inhibiting a serotonin receptor in a subject or a biological sample.

[0309] 22. A compound of any one of embodiments 1-18 for use in inhibiting a serotonin receptor in a subject or a biological sample.

[0310] 23. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of embodiments 1-18.

[0311] 24. Use of a compound of any one of embodiments 1-18 in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof.

[0312] 25. A compound of any one of embodiments 1-18 for use in treating or preventing a disease or disorder in a subject in need thereof.

[0313] 26. The method, use, or compound for use of any one of embodiments 23-25, wherein the disease or disorder is mediated by a serotonin receptor.

[0314] 27. The method, use, or compound for use of any one of embodiments 23-25, wherein the disease or disorder is mood / depressive disorder, bipolar disorder, anxiety disorder, psychotic or delirium disorder, schizophrenia, schizoaffective disorder, personality disorder, abuse or neglect disorder, tic disorder, neurocognitive disorder, neurodevelopmental disorder, learning disorder, disruptive mood regulation disorder, intermittent explosive disorder, antisocial personality disorder, conduct disorder, behavioral and psychological symptoms of dementia, depression, anxiety, post-traumatic stress disorder (PTSD), major depressivedisorder (MDD), treatment-resistant depression (TRD), substance use disorder (SUD), compulsive disorders, stress disorders, rumination, eating disorders, or a combination thereof. Examples

[0315] The present disclosure is further illustrated by reference to the following Examples.However, it should be noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the disclosure in any way.

[0316] In embodiments, compounds of the present disclosure can be synthesized using thefollowing methods. General reaction conditions are given, and reaction products can be purified by generally known methods including silica gel chromatography using various organic solvents such as hexane, dichloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.

[0317] In embodiments, enantiomers of the compounds of the present disclosure can beresolved from racemic mixtures via methods well-known in the chemical arts, e.g., via chiral resolution through formation of diastereomeric salts or chiral chromatography with a chiral stationary phase. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0318] Example 1 - Synthesis of Compound 1: N-(3-chloro-5-methylbenzyl)-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine

[0319] Scheme 1

[0320] A mixture of 1-methylindazole-3-carbaldehyde 1.1 (500 mg, 3.12 mmol, 1 equiv.) andammonium acetate (148 mg, 1.56 mmol, 0.5 equiv.) in nitromethane (2.85 mL, 4.68 mmol, 15equiv.) was stirred at 100°C for 3 h under nitrogen atmosphere. The reaction mixture wascooled and concentrated in vacuum to give a residue. The residue was purified by Prep-TLC (PE / EtOAc = 2 / 1) to afford 1.2 (500 mg) as a yellow solid. [M+H]+ (ESI):204.10.

[0321] To a stirred solution of 1.2 (350 mg, 1.72 mmol, 1 equiv.) in THF (7 mL) was addedLiAlH4(261 mg, 6.88 mmol, 4 equiv.) portion-wise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for additional 2 h. The reaction was quenched with water (0.5 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (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 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 2.1 (100 mg) as a colorless oil. [M+H]+ (ESI):176.05

[0322] A solution of 2.1 (40 mg, 0.23 mmol, 1 equiv.) and 3-chloro-5-methylbenzaldehyde (28mg, 0.18 mmol, 0.8 equiv.) in DCM (4 mL) was treated with NaOAc (2 mg, 0.023 mmol, 0.1 equiv.) at room temperature for 5 min under nitrogen atmosphere followed by the addition of NaBH(OAc)3(72 mg, 0.34 mmol, 1.5 equiv.) in portions at 0°C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was diluted with water (5 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The resulting solid was dried in an oven under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH = 20 / 1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: water (0.05% HCl), Mobile Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 5% B to 30% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.9) to afford Compound 1 (5.1 mg) as a white solid. [M+H]+ (ESI):314.05.

[0323] 1H NMR (400 MHz, methanol-d4) δ 7.75 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H),7.48-7.40 (m, 2H), 7.30 (d, J = 7.3 Hz, 2H), 7.18 (dd, J = 8.0, 6.7 Hz, 1H), 4.27 (s, 2H), 4.04 (s, 3H), 3.51 (t, J = 7.0 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 2.38 (s, 3H).

[0324] Example 2 - Synthesis of Compound 2: N-(3-fluoro-5-methylbenzyl)-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine: Compound 2 was synmthesized in one step from previouslyknown fragments (WO 2024 / 192150 Α2)

[0325] Scheme 2

[0326] A solution of 2-(1-methylindazol-3-yl)ethanamine (50 mg, 0.28 mmol, 1 equiv.) and 3-fluoro-5-methylbenzaldehyde (31 mg, 0.23 mmol, 0.8 equiv.) in DCM (4 mL) was treated with NaOAc (2 mg, 0.028 mmol, 0.1 equiv.) at room temperature for 5 min under nitrogen atmosphere followed by the addition of NaBH(OAc)3(91 mg, 0.43 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for additional 2 h. The resulting mixture was diluted with water (5 mL). The aqueous layer was extracted with DCM (3 x 5 mL). The resulting organic phase was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to afford crude N-(3-fluoro-5-methylbenzyl)-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine as a colorless oil. Thecrude product was further purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: water (0.05% HCl), Mobile Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 5% B to 30% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8.9) to afford N-(3-fluoro-5-methylbenzyl)-2-(1-methyl- 1H-indazol-3-yl)ethan-1-amine hydrochloride (5.1 mg) as a white solid.

[0327] [M+H]+ (ESI): 298.15.

[0328] 1H NMR (400 MHz, Methanol-d4) δ 7.74 (dt, J = 8.2, 1.0 Hz, 1H), 7.52 (dt, J = 8.5,1.0 Hz, 1H), 7.46–7.41 (m, 1H), 7.22–7.14 (m, 2H), 7.13-7.09 (m, 1H), 7.07-7.02 (m, 1H), 4.28 (s, 2H), 4.04 (s, 3H), 3.53-3.49 (m, 2H), 3.43–3.35 (m, 2H), 2.40 (s, 3H).

[0329] Example 3 - Synthesis of Compound 3: N-((3-methoxypyridin-2-yl)methyl)-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine

[0330] To a stirred solution of 2.1 (25 mg, 0.14 mmol, 1 equiv.) and 3-methoxypyridine-2-carbaldehyde (19 mg, 0.14 mmol, 1 equiv.) in methanol (0.5 mL) were added acetic acid (0.86 mg, 0.014 mmol, 0.1 equiv.) and sodium cyanoborohydride (13.45 mg, 0.21 mmol, 1.5 equiv.) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of saturated NaHCO3(aq.) (2 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with saturated NaCl (5 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The crude product was purified by Prep-HPLC with the following conditions [Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% FA), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 5% B to 25% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 9.41] to afford in compound 3 (7.6 mg) as an off-white semi-solid. [M+H]+ (ESI):297.15.

[0331] 1H NMR (500 MHz, Methanol-d4) δ 8.58 (s, 1H), 8.17-8.12 (m, 1H), 7.77-7.72 (m,1H), 7.57-7.52 (m, 1H), 7.49-7.43 (m, 2H), 7.41-7.35 (m, 1H), 7.22-7.16 (m, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 3.89 (s, 3H), 3.51-3.44 (m, 2H), 3.42-3.36 (m, 2H).

[0332] Example 4 - Synthesis of Compound 4: 2-(3-(2-((3-chloro-5-methylbenzyl)amino)ethyl)-1H-indazol-1-yl)ethan-1-ol

[0333] Scheme 4

[0334] A mixture of 4.1 (2 g, 13.68 mmol, 1equiv.), (2-bromoethoxy)(tert-butyl)dimethylsilane, 4.2 (3.93 g, 16.42 mmol, 1.2 equiv.), Cs2CO3 (13.38 g, 41.05 mmol, 3 equiv.) and KI (454 mg, 2.74 mmol, 0.2 equiv.) in DMF (20 mL) was stirred at 80°C for 1 h. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 20 mL). The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl (50 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, Acetonitrile in water (0.1% TFA), 60% to 100% gradientin 10 min; detector, UV 220 nm. This resulted in Compound 4.3 (2.8 g) as a brown oil. [M+H]+ (ESI):305.55.

[0335] A mixture of Compound 4.3 (1 g, 3.28 mmol, 1 equiv.) and NH4OAc (0.13 g, 1.64 mmol, 0.5 equiv.) in nitromethane (2.00 g, 32.84 mmol, 10 equiv.) was stirred at 100°C for 30 min. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl (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, C18 silica gel; mobile phase, Acetonitrile in water (0.1% TFA), 80% to 100% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 4.4 (760 mg) as a brown oil. [M+H]+ (ESI):348.05.

[0336] To a stirred mixture of Compound 4.4 (740 mg, 2.13 mmol, 1 equiv.) in THF (10 mL) was added lithium aluminum hydride (2.0 M in THF) (5.3 mL, 10.65 mmol, 5 equiv.) at 0°C. The resulting mixture was stirred at 0°C for 2 h. The reaction was quenched with ice water at 0°C. 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, Acetonitrile in water (10 mmol / L NH4HCO3), 50% to 70% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 4.5 (60 mg) as a yellow oil. MS m / z [M+H]+ (ESI):206.15.

[0337] A mixture of Compound 4.5 (25 mg, 0.12 mmol, 1 equiv.) ,3-chloro-5- methylbenzaldehyde (18 mg, 0.12 mmol, 1 equiv.), acetic acid (7 mg, 0.12 mmol, 1 equiv.) and sodium cyanoborohydride (15 mg, 0.24 mmol, 2 equiv.) in methanol (1 mL) was stirred at room temperature for 1 h. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% FA), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 9% B to 26% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 10.18). This resulted in Compound 4 (11.0 mg) as a white solid. [M+H]+ (ESI):344.05.

[0338] 1H NMR (300 MHz, Methanol-d4) δ 7.76 – 7.67 (m, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.48 – 7.24 (m, 3H), 7.17 (dd, J = 14.8, 7.5 Hz, 2H), 4.47 (t, J = 5.4 Hz, 2H), 4.15 (s, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.42 (dd, J = 7.8, 4.3 Hz, 2H), 3.36 (d, J = 5.6 Hz, 2H), 2.36 (s, 3H).

[0339] Example 5 - Synthesis of Compound 5: 2-(3-(2-((3-fluoro-5-methylbenzyl)amino)ethyl)-1H-indazol-1-yl)ethan-1-ol

[0340] Scheme 5

[0341] A mixture of Compound 4.5 (25 mg, 0.12 mmol, 1 equiv.), 3-fluoro-5-methylbenzaldehyde 2.2(16 mg, 0.12 mmol, 1 equiv.), acetic acid (7 mg, 0.12 mmol, 1 equiv.) and sodium cyanoborohydride (15 mg, 0.24 mmol, 2 equiv.) in methanol (1 mL) was stirred at room temperature for 1 h. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% FA), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 8% B to 26% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 8.45). This resulted in Compound 5 (12.4 mg) as a white solid. [M+H]+ (ESI):328.10.

[0342] 1H NMR (300 MHz, Methanol-d4) δ 7.72 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H),7.42 (dd, J = 8.0, 6.7 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.06 - 6.85 (m, 2H), 4.47 (t, J = 5.4 Hz, 2H),4.19 (s, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.44 (dd, J = 7.5, 4.9 Hz, 2H), 3.35 (d, J = 6.6 Hz, 2H), 2.38 (s, 3H).

[0343] Example 6 - Synthesis of compound 6: 2,2,2-trifluoro-N-(2-(1-methyl-1H-indazol-3-yl)ethyl)ethan-1-amine

[0344] Scheme 6

[0345] To a stirred solution of Compound 2.1 (50 mg, 0.285 mmol, 1 equiv.) indichloromethane (1 mL) were added Et3N (86.62 mg, 0.855 mmol, 3 equiv.) and trifluoroacetic anhydride (119.86 mg, 0.570 mmol, 2 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. Thereaction was quenched by the addition of sat. sodium hyposulfite (aq.) (1mL) at roomtemperature. The resulting mixture was extracted with ethyl acetate (3 x 10mL). The combinedorganic layers were washed with saturated NaCl (2x10 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, C18 silica gel; mobile phase, Acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 6.1 (40 mg) as a yellow solid.

[0346] To a stirred mixture of Compound 6.1 (30 mg, 0.111 mmol, 1 equiv.) in tetrahydrofuran(0.30 mL) were added borane-tetrahydrofuran complex (1.0 M in THF) (0.55 mL, 0.555 mmol, 5 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of methanol (2 mL) at 0°C. The filtrate was concentrated under reduced pressure. The crudeproduct was purified by Prep- HPLC with the following conditions [Column: Xselect CSHPrep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% FA), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 5% B to 25% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 9.41] to afford in Compound 6 (12.6 mg) as a white solid. [M+H]+ (ESI):258.10.

[0347] 1H NMR (500 MHz, Methanol-d4) δ 7.79-7.75 (m, 1H), 7.57-7.54 (m, 1H), 7.50-7.45(m, 1H), 7.24-7.19 (m, 1H), 4.25-4.16 (m, 2H), 4.06 (s, 3H), 3.71-3.64 (m, 2H), 3.50-3.41 (m, 2H).

[0348] Example 7 - Synthesis of Compound 7: 5-(2-(((2-(1-methyl-1H-indazol-3-yl)ethyl)amino) methyl) phenyl) pyridin-2-ol. Compound synthesized with precursorpreviously described and commercially available aldehyde 7.1 (Cas#11111115-70-8) and intermediate 2.1 in one step.

[0349] Scheme 7

[0350] A solution of compound 2.1 (30 mg, 0.15 mmol, 1 equiv.) in methanol (2 mL) wastreated with Compound 7.1(26 mg, 0.15 mmol, 1 equiv.) at room temperature, followed by the addition of HOAc (27.13 mg, 0.453 mmol, 3 equiv.) at room temperature. To the above mixture was added sodium cyanoborohydride (18.93 mg, 0.302 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at room temperature for additional overnight. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XSelectCSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: water (0.05% HCl), Mobile Phase B: Acetonitrile; Flow rate: 20 mL / min; Gradient: 14% B to 44% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 6.52) to afford Compound 7 (5.2 mg) as a white solid. [M+H]+ (ESI):359.1

[0351] 1H NMR (400 MHz, Methanol-d4) δ 8.21 – 8.06 (m, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.83– 7.74 (m, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.66 – 7.53 (m, 2H), 7.52 – 7.49 (m, 1H), 7.48 – 7.39(m, 2H), 7.21 – 7.12 (m, 1H), 7.08 (d, J = 9.1 Hz, 1H), 4.36 (s, 2H), 4.02 (s, 3H), 3.47 – 3.39(m, 2H), 3.35 – 3.31 (m, 2H).

[0352] Example 8 - Synthesis of compound 8: (EGX-24-06-12-CL-1) N-(3-chloro-5-methylbenzyl)-2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)ethan-1-amine

[0353] Scheme 8

[0354] To a solution of 1H-pyrazolo[4,3-c]pyridine (3.9 g, 33 mmol, 1 equiv.) in DMF (40mL) was added NIS (8.8 g, 39 mmol, 1.2 equiv.) at room temperature. The resulting mixturewas stirred at 80°C for 12 h under nitrogen atmosphere. The reaction was quenched by theaddition of sat. Na2SO3(aq.) (10 mL) and sat. NaHCO3(aq.) (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 40% gradient in 15 min; detector, UV 220 nm. This resulted in 8.2 (3.3 g) as a yellow solid. [M+H]+ (ESI):245.80.

[0355] To a solution of 8.2 (2.15 g, 8.77 mmol, 1 equiv.) in DMF (10 mL) was added NaH(386 mg, 9.65 mmol, 1.1 equiv., 60%) at 0°C. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. To the above mixture was added CH3I (0.6 mL, 9.6 mmol, 1.1 equiv.) at 0°C. The resulting mixture was stirred at room temperature for 1h under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at 0°C. The resulting mixture was extracted with DCM (20 mL x 3). The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 5 min; detector, UV 220 nm. This resulted in 8.3 (1.2 g) as a yellow solid. [M+H]+ (ESI):259.95.

[0356] Into a 100 mL 3-necked round-bottom flask were added 8.3 (900 mg, 3.47 mmol, 1 equiv.), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (813 mg, 4.17 mmol, 1.2 equiv.), Pd(dppf)Cl2 (254 mg, 0.35 mmol, 0.1 equiv.), Cs2CO3 (3.4 g, 10.4 mmol, 3 equiv.) and 1,4- dioxane (23 mL), H2O (4.6 mL) at room temperature. The resulting mixture was stirred at 90°C for 16 h under nitrogen atmosphere. To the above mixture was added H2O (4.6 mL) at 90°C. The resulting mixture was stirred at 110°C for additional 4 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 40% gradient in 15 min; detector, UV 220 nm. The obtained contaminated product (426 mg) was then purified by Prep-TLC (DCM / MeOH = 15 / 1) to afford 8.4 (276 mg, 46% yield, 85% purity) as a light brown solid. [M+H]+ (ESI):173.00.

[0357] Into a 50 mL pressure tank reactor were added 8.4 (270 mg, 1.57 mmol, 1 equiv.) and NH3-MeOH (7 M in MeOH) (10 mL), Raney-Ni (270 mg) at room temperature. The resulting mixture was stirred at 50°C for 16 h under hydrogen (5 atm.) atmosphere. The resulting mixture was filtered through a pad of Celite, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 8.5 (200 mg) as a yellow oil. [M+H]+ (ESI):177.25.

[0358] Into an 8 mL vial were added 8.5 (30 mg, 0.17 mmol, 1 equiv.) and sodium cyanoborohydride (32 mg, 0.51 mmol, 3 equiv.), HOAc (10 uL, 0.17 mmol, 1 equiv.) and methanol (1 mL) and 3-chloro-5-methylbenzaldehyde (22 uL, 0.17 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (0.3 mL) at room temperature. The reaction mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column19*250 mm, 5μm; Mobile Phase A: water (0.05% HCL), Mobile Phase B: MeCN; Flow rate: 20ml / min; Gradient (B%): 3% B to 20% Bin 10 min; Wave Length: 254nm / 220nm; RT1(min): 7.43) to afford Compound 8 (16.3 mg) as a white solid. [M+H]+ (ESI):315.05.

[0359] 1H NMR (400 MHz, methanol-d4) δ 9.64 (s, 1H), 8.52 (d, J = 6.9 Hz, 1H), 8.15 (d, J =6.9 Hz, 1H), 7.48 – 7.38 (m, 1H), 7.34 – 7.31 (m, 2H), 4.30 (s, 2H), 4.22 (s, 3H), 3.64 (s, 4H),2.39 (s, 3H).

[0360] Example 9 - Synthesis of compound 9: N-(3-fluoro-5-methylbenzyl)-2-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)ethan-1-amine

[0361] Scheme 9

[0362] Into an 8 mL vial were added 8.5 (30 mg, 0.17 mmol, 1 equiv.) and sodiumcyanoborohydride (32 mg, 0.51 mmol, 3 equiv.), HOAc (10 uL, 0.17 mmol, 1 equiv.) and methanol (1 mL) and 3-fluoro-5-methylbenzaldehyde (20 uL, 0.17 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (0.3 mL) at room temperature. The mixture was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 24% B to 38% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.42) to afford the freebase. Then 2 M aq.HCl (3 equiv.) was added and lyophilized to afford Compound 9 (14.4 mg) as a white solid. [M+H]+ (ESI):299.10.

[0363] 1H NMR (400 MHz, methanol-d4) δ 9.63 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 8.13 (dd, J= 7.0, 0.8 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J = 9.2 Hz, 1H), 7.04 (d, J = 9.6 Hz, 1H), 4.31 (s, 2H), 4.21 (s, 3H), 3.64 (s, 4H), 2.40 (s, 3H).

[0364] Example 10 - Synthesis of compound 10: N-(3-chloro-5-methylbenzyl)-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)ethan-1-amine

[0365] Scheme 10

[0366] To a solution of 3-iodo-1H-pyrazolo[3,4-c]pyridine 10.1 (2 g, 8.16 mmol, 1 equiv.) inDMF (20 mL) was added NaH (0.5 g, 12.24 mmol, 1.5 equiv., 60%) at 0°C under N2. Then the mixture was stirred at 0°C for 20 min. CH3I (1.7 g, 12.24 mmol, 1.5 equiv.) was added and the mixture was stirred at 25°C for 1 h. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was diluted with DCM (50 mL). The organic phase was separated and the aqueous was extracted with DCM (2 x 20 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 30% to 60% gradient in 10 min; detector, UV 220 nm. to give 10.2 (1.2 g) as a yellow solid. [M+H]+ (ESI):259.98.

[0367] Into a 40 mL vial were added 10.2 (900 mg, 3.47 mmol, 1 equiv.) and 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (813 mg, 4.17 mmol, 1.2 equiv.), Pd(dppf)Cl2 (254 mg, 0.35 mmol, 0.1 equiv.), K2CO3 (1.44 g, 10.4 mmol, 3 equiv.), 1,4-dioxane (10 mL) and H2O (2 mL) at room temperature. The resulting mixture was stirred at 90°C for 24 h under nitrogen atmosphere. Water (1.5 mL) was added and was stirred at 100°C for additional 8 h undernitrogen atmosphere. The resulting mixture was diluted with MeOH (30 mL). The resultingmixture was filtered on a pad of Celite, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 15 min; detector, UV220 nm. Then purified by Prep-TLC (DCM / MeOH = 15 / 1) to afford 10.3 (256 mg) as a brown solid. [M+H]+ (ESI):173.10.

[0368] Into a 50 mL pressure tank reactor were added 10.3 (80 mg, 0.46 mmol, 1 equiv.) andRaney-Ni (80 mg, 1.363 mmol) and NH3-MeOH (7 M in MeOH) (4 mL) at room temperature. The resulting mixture was stirred at 45°C for 16 h under hydrogen atmosphere (5 atm.). The resulting mixture was filtered through a pad of Celite, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 10.4 (60 mg) as a yellow oil. [M+H]+ (ESI):177.10.

[0369] Into an 8 mL vial were added amine 10.4 (30 mg, 0.17 mmol, 1 equiv.) and sodiumcyanoborohydride (32 mg, 0.51 mmol, 3 equiv.), HOAc (10 uL, 0.17 mmol, 1 equiv.) and methanol (1 mL) and 3-chloro-5-methylbenzaldehyde (22 uL, 0.17 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (0.3 mL) at room temperature. The mixture was basified to pH 9 with NH3-H2O. The resulting mixture was extracted with DCM (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3-H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 28% B to 40% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 9.62) to afford the freebase. Then 2 M aq.HCl (3 equiv.) was added and lyophilized to afford Compound 10 (4.8 mg) as a white solid. [M+H]+ (ESI):315.05.

[0370] 1H NMR (300 MHz, methanol-d4) δ 9.65 (s, 1H), 8.50-8.40 (m, 2H), 7.43 (s, 1H), 7.35-7.31 (m, 2H), 4.35-4.30 (m, 5H), 3.61 (s, 4H), 2.39 (s, 3H).

[0371] Example 11 - Synthesis of compound 11: N-(3-fluoro-5-methylbenzyl)-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)ethan-1-amine

[0372] Scheme 11

[0373] Into an 8 mL vial were added amine 2.1 (30 mg, 0.17 mmol, 1 equiv.) and sodiumcyanoborohydride (32 mg, 0.51 mmol, 3 equiv.), HOAc (10 uL, 0.17 mmol, 1 equiv.) and methanol (1 mL) and 3-fluoro-5-methylbenzaldehyde (20 uL, 0.17 mmol, 1 equiv.) at roomtemperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4Cl (aq.) (0.3 mL) at room temperature. The mixture was basified to pH 9 with NH3-H2O. The resulting mixture was extracted with DCM (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crudeproduct was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep C18OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3-H2O), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 25% B to 40% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.58) to afford the freebase. Then 2 M aq.HCl (3 equiv.) was added and lyophilized to Compound 11 (16.7 mg) as a white solid. [M+H]+ (ESI):299.05.

[0374] 1H NMR (300 MHz, methanol-d4) δ 9.64 (s, 1H), 8.49 (d, J = 6.6 Hz, 1H), 8.41 (d, J =6.6 Hz, 1H), 7.23 (s, 1H), 7.21-7.12 (m, 1H), 7.04 (d, J = 9.6 Hz, 1H), 4.36 (s, 3H), 4.31 (s, 2H), 3.61 (s, 4H), 2.40 (s, 3H).

[0375] Example 12 - Synthesis of compound 12: N-(3-chloro-5-methylbenzyl)-2-methoxy-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine

[0376] Scheme 12

[0377] A solution of 1-methylindazole-3-carbaldehyde, 12.1 (500 mg, 3.12 mmol, 1 equiv.)and Ammonium acetate (148.4 mg, 1.56 mmol, 0.5 equiv.) in nitromethane (2.85 ml, 46.80 mmol, 15 equiv.) was stirred at 100°C for 2 h under nitrogen atmosphere. The reaction was quenched with water (10 ml) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with saturated NaCl (5 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by Prep-TLC (hexane / ethyl acetate 2:1) to afford Compound 12.2 (400 mg) as a yellow solid. Used directly for the next steps.

[0378] Into a 20 mL round-bottom flask were added MeONa (358.92 mg, 6.64 mmol, 1.5equiv.) and Methanol (10 mL, 246.99 mmol, 55.76 equiv.) at 0°C. To the above mixture was added 12.2 (900 mg, 4.429 mmol, 1 equiv.) dropwise / in portions at 0°C. The resulting mixture was stirred at 0°C for additional 15min. The resulting mixture was extracted with EtOAc (2 x 20mL). The combined organic layers were washed with saturated NaCl (2x20 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, Acetonitrile in water (10 mmol / L NH4HCO3), 10% to 100% gradient in 25 min; detector, UV 220 nm to afford 12.3 (450 mg) as a yellow oil.

[0379] A mixture of 12.3 (450 mg, 1.913 mmol, 1 equiv.) and Raney-Ni (450 mg, 7.667 mmol,4.01 equiv.) in NH3 in Methanol (9 mL) was stirred at 50°C for 5 h under hydrogen(5atm) atmosphere. The resulting mixture was filtered, and the filter cake was washed with Methanol (3 x 10 mL). 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, Acetonitrile in water (10 mmol / L NH4HCO3), 10% to 100% gradient in 25 min; detector, UV 220 nm. This resulted in 12.4 (40 mg) as a yellow oil.

[0380] Example 13 and 14 - Synthesis of compound 13 and 14: N-(3-chloro-5-methylbenzyl)-2-methoxy-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine (R or S) and N-(3- chloro-5-methylbenzyl)-2-methoxy-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine (R or S)

[0381] Scheme 13 and 14

[0382] The 12 (20 mg) was purified by Prep-Chiral HPLC following the conditions (Column:CHIRALPAK IM, 2*25 cm, 5 μm; Mobile Phase A: HEX (0.5% 2 M NH3-Methanol)--HPLC, Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient (B%): isocratic 15; Wave Length: 220 / 254 nm; RT1(min): 6.769; RT2(min): 10.058; Sample Solvent: EtOH--HPLC; Injection Volume: 0.5 mL; Number of Runs: 12) to give 13 (enantiomer 1) withouth knowing R or Sconfiguration but enantiomeric pure (4.3 mg) and 14 (enantiomer 2) withouth knowing R or S configuration but enantiomeric pure (4.5 mg, 22% yield, 97% purity) as a white solid.

[0383] Example 15 - Synthesis of compound 15: N-(3-fluoro-5-methylbenzyl)-2-methoxy-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine

[0384] Scheme 15

[0385] A solution of 12.4 (800 mg, 4.183 mmol, 1 equiv.), HOAc (251.22 mg, 4.183 mmol, 1equiv.) and 3-chloro-5-methylbenzaldehyde (485.03 mg, 3.138 mmol, 1 equiv.) in methanol (10 mL) was stirred at room temperature for overnight. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 10 min; detector, UV 254 nm to afford 15 (400 mg, 30% yield, 99% purity) as a yellow solid.

[0386] Synthesis 16 and 17: N-(3-fluoro-5-methylbenzyl)-2-methoxy-2-(1-methyl-1H-indazol-3-yl)ethan-1-amine Enantiomer 1 and N-(3-fluoro-5-methylbenzyl)-2-methoxy-2-(1- methyl-1H-indazol-3-yl)ethan-1-amine Enantiomer 2.

[0387] Scheme 16 and 17

[0388] The 12 (80 mg) was purified by Prep-HPLC with the following conditions (Column:YMC-Actus Triart C18 ExRS 30*1 50mm, 5μm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 49% B to 65% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.13) to afford 16, Enantiomer 1 (23.7 mg) as a colorless semi-solid and 17, Enantiomer 2 (25.8 mg) as a colorless semi-solid. [M+H]+ (ESI):328.10.

[0389] 1H NMR (400 MHz, Methanol-d4) δ 7.85 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H),7.46 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 9.1 Hz, 1H), 7.05 (d, J = 9.5 Hz, 1H), 5.07 (d, J = 9.3 Hz, 1H), 4.31 (s, 2H), 4.07 (s, 3H), 3.67 (t, J = 11.0 Hz, 1H), 3.34 (s, 4H),2.40 (s, 3H).

[0390] [M+H]+ (ESI):328.10.

[0391] 1H NMR (400 MHz, Methanol-d4) δ 7.85 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H),7.46 (t, J = 7.6 Hz, 1H), 7.26 – 7.17 (m, 2H), 7.13 (d, J = 9.1 Hz, 1H), 7.05 (d, J = 9.6 Hz, 1H),5.14 – 5.05 (m, 1H), 4.31 (s, 2H), 4.07 (s, 3H), 3.67 (t, J = 11.2 Hz, 1H), 3.38 (s, 4H), 2.40 (s,

[0392] Example 16 - Synthesis of Compound 18: 2-((3-chloro-5-methylbenzyl)amino)-1-(1-methyl-1H-indazol-3-yl)ethan-1-ol

[0393] Scheme 18

[0394] To a solution of 1-methylindazole-3-carbaldehyde (1 g, 6.24 mmol, 1 equiv.) andTMSCN (929 mg, 9.36 mmol, 1.5 equiv.) in CHCl3 (1 mL) was added ZnI2 (199 mg, 0.62 mmol, 0.1 equiv.) at 25°C. Then the mixture was heated to 80°C and stirred for 12 h. The reaction mixture was quenched with sat.NaHCO3solution (20 mL) and then extracted with DCM (20 mL x 2). The combined organic phase was concentrated in vacuum to giveIntermediate 18.1 (700 mg crude) as a brown oil. [M+H]+ (ESI):260.10.

[0395] To a solution of Intermediate 18.1 (500 mg, 6.94 mmol, 1 equiv.) in THF (20 mL) wasadded 1 M lithium aluminum hydride (10.4 mL, 20.83 mmol, 3 equiv.) at 0°C. Then the mixture was stirred at 25°C for 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford Compound 18.2(1.2 g) as a yellow solid. [M+H]+ (ESI):192.20.

[0396] A solution of Compound 18.2 (20 mg, 0.11 mmol, 1 equiv.) and 3-chloro-5-methylbenzaldehyde (16 mg, 0.11 mmol, 1.0 equiv.) and NaBH3CN (13 mg, 0.210 mmol, 2.0 equiv.) and AcOH (19 mg, 0.32 mmol, 3.0 equiv.) in methanol (0.4 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The mixture was basified to pH 10 with NH3-H2O. The residue was purified by reversed-phase flash chromatography with the followingconditions: column, C18 column; mobile phase, acetonitrile in water (0.1% NH3.H2O+10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted inCompound 18 (10.5 mg) as a white solid. [M+H]+ (ESI):330.00.

[0397] 1H NMR (300 MHz, methanol-d4) δ 7.90 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H),7.47-7.35 (m, 2H), 7.35-7.25 (m, 2H), 7.25-7.15 (m, 1H), 5.43-5.39 (m, 1H), 4.35-4.25 (m, 2H), 4.04 (s, 3H), 3.62-3.39 (m, 2H), 2.41 (s, 3H).

[0398] Example 17 - Synthesis of Compound 19: 5-(((2-(1-methyl-1H-indazol-3-yl)ethyl)amino)methyl)quinolin-4(1H)-one

[0399] Scheme 19

[0400] Into a 100 mL vial were added 5-bromo-1H-quinolin-4-one (1.4 g, 6.25 mmol, 1equiv.), potassium ethenyltrifluoroboranuide (2.51 g, 18.7 mmol, 3 equiv.), Pd(dppf)Cl2-DCM (255 mg, 0.31 mmol, 0.05 equiv.) and K2CO3 (2.59 g, 18.7 mmol, 3 equiv.) and dioxane (15 mL), DMF (15 mL) H2O (3.5 mL) at room temperature. The resulting mixture was stirred at 100°C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with 1,4-dioxane (30 mL). The resulting mixture was filtered through a pad of Celite, the filter cake was washed with dioxane (2 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column,C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in10 min; detector, UV 220 nm. This resulted in 19.1 (734 mg) as a white solid. [M+H]+ (ESI):172.10.

[0401] Into a 50 mL round-bottom flask were added 19.1 (734 mg, 4.28 mmol, 1 equiv.) andpotassium osmate(VI) dihydrate (79 mg, 0.21 mmol, 0.05 equiv.), NaIO4(3.67 g, 17.15 mmol, 4 equiv.) and THF (16 mL), H2O (4 mL) at room temperature. The resulting mixture was stirred at 0°C for 30 min, then for 4 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with THF (30 mL). The resulting mixture was filtered through a pad ofCelite, the filter cake was washed with THF (2 x 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted again with THF (50 mL). Some salts precipitated. Then DMSO (8 mL) was added. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 19.2 (534 mg, 71% yield, 98% purity) as a yellow solid. [M+H]+ (ESI):174.00.

[0402] Into an 8 mL vial were added 19.2 (30 mg, 0.17 mmol, 1 equiv.), 2.1 (30 mg, 0.17mmol, 1 equiv.) and sodium cyanoborohydride (33 mg, 0.52 mmol, 3 equiv.), HOAc (10 uL, 0.17 mmol, 1 equiv.) and methanol (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched bythe addition of sat. NH4Cl (aq.) (0.3 mL) at room temperature. The mixture was basified to pH= 9 with NH3·H2O. The resulting mixture was extracted with DCM (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase flash with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient (B%): 12% B to 27% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 6.47) to afford the freebase. Then 2 M aq.HCl (3 equiv.) was added and then dried via lyophilization to afford Compound 19 (26.9 mg) as a white solid. [M+H]+ (ESI): 333.10.

[0403] 1H NMR (400 MHz, methanol-d4) δ 8.37 (d, J = 7.0 Hz, 1H), 7.95 – 7.84 (m, 2H), 7.69(dd, J = 5.5, 2.9 Hz, 1H), 7.67 – 7.62 (m, 1H), 7.51 – 7.44 (m, 1H), 7.44 – 7.36 (m, 1H), 7.17– 7.05 (m, 1H), 6.79 (d, J = 7.0 Hz, 1H), 4.80 (s, 2H), 3.98 (s, 3H), 3.62 (t, J = 6.8 Hz, 2H),3.41 (t, J = 6.8 Hz, 2H).

[0404] Example 18 - Synthesis of Compound 20: 8-(((2-(1-methyl-1H-indazol-3-yl)ethyl)amino)methyl) iso quinolin-1(2H)-one

[0405] Scheme 20

[0406] Into an 8 mL vial were added 2.1 (25 mg, 0.14 mmol, 1 equiv.), 20.1 (32 mg, 0.14mmol, 1 equiv, 80%) and sodium cyanoborohydride (27 mg, 0.43 mmol, 3 equiv.), HOAc (8 uL, 0.14 mmol, 1 equiv.) and methanol (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 21% B to 32% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 9.02) to afford the freebase. Then 3 eq. of 2 M HCl (a.q.) was added and lyophilized to afford Compound 20 (20.3 mg) as a white solid. [M+H]+ (ESI):333.10.

[0407] 1H NMR (300 MHz, Methanol-d4) δ 7.83 – 7.68 (m, 2H), 7.68 – 7.52 (m, 2H), 7.48(dt, J = 8.5, 1.0 Hz, 1H), 7.43 – 7.35 (m, 1H), 7.24 (d, J = 7.0 Hz, 1H), 7.15 – 7.04 (m, 1H),6.72 (d, J = 7.1 Hz, 1H), 4.68 (s, 2H), 3.99 (s, 3H), 3.57 (t, J = 6.6 Hz, 2H), 3.38 (t, J = 6.6 Hz, 2H).

[0408] Example 19 - Synthesis of Compound 21: 2-((3-fluoro-5-methylbenzyl)amino)-1-(1-methyl-1H-indazol-3-yl)ethan-1-ol

[0409] Scheme 21

[0410] A solution of Compound 18.2 (100 mg, 0.52 mmol, 1 equiv.), 3-fluoro-5-methylbenzaldehyde (72.24 mg, 0.52 mmol, 1 equiv.) in methanol (0.5 mL) was treated with HOAc (31 mg, 0.52 mmol, 1 equiv.) at room temperature for 3 min under nitrogen atmospherefollowed by the addition of sodium cyanoborohydride (66 mg, 1.04 mmol, 2 equiv.) at roomtemperature. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Column: ER; Mobile Phase A: water (10 mmol / L NH4CO3+0.05% NH3.H2O), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: isocratic 13-30; wave length: 254nm / 220nm;RT1(min): 8.32 / 9.76) to afford 21 (5.6 mg) as an off-white solid. [M+H]+ (ESI):314.10

[0411] 1H NMR (300 MHz, methanol-d4) δ 7.93-7.87 (m, 1H), 7.53-7.44 (m, 2H), 7.24-6.95(m, 4H), 5.43-5.35 (m, 1H), 4.40-4.24 (m, 2H), 4.04 (s, 3H), 3.70-3.51 (m, 1H), 3.43-3.35 (m, 1H), 2.40 (d, J = 0.7 Hz, 3H).

[0412] Examples 19 and 20 - Synthesis of Compound 22 and 23:

[0413] Scheme 22 and 23

[0414] The Compound 21 (50 mg) was purified by Prep-HPLC with the following conditions(Column: CHIRALPAK IM, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-methanol)- -HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 25; Wave Length: 220 / 271 nm; RT1(min): 12.203; RT2(min): 15.542; Sample Solvent: EtOH-- HPLC; Injection Volume: 0.6 mL; Number of Runs: 5) to afford Compound 22, Enantiomer 1(6.1 mg, 12% yield, 97.9% purity) as a white solid and Compound 22, Enantiomer 2 (6.8 mg,13% yield, 96.5% purity) as a white solid. [M+H]+ (ESI):314.10.

[0415] The MS and 1H-NMR data of the two enantiomers are the same.

[0416] 1H NMR (300 MHz, methanol-d4) δ 7.93-7.87 (m, 1H), 7.53-7.44 (m, 2H), 7.24- 6.95(m, 4H), 5.43-5.35 (m, 1H), 4.40-4.24 (m, 2H), 4.04 (s, 3H), 3.70-3.51 (m, 1H), 3.43-3.35 (m, 1H), 2.40 (d, J = 0.7 Hz, 3H).

[0417] Example 21 - Synthesis of Compound 25: N-(3-fluoro-5-methylbenzyl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)ethan-1-amine

[0418] Scheme 25

[0419] To a solution of 5-methoxy-1H-indazole-3-carbaldehyde 25.1 (1.9 g, 10.785 mmol, 1 equiv.) in Acetonitrile (50 mL) was added K2CO3 (4.47 g, 32.355 mmol, 3 equiv.) followed by CH3I (3.06 g, 21.570 mmol, 2 equiv.) at 25°C. Then the mixture was stirred at 25°C for 12 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuum to give a crude product. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 10 min; detector, UV 220 nm. to give 25.2(750 mg) as a yellow solid.

[0420] To a solution of 25.2 (650 mg, 3.417 mmol, 1 equiv.) in nitromethane (2.75 mL, 51.255 mmol, 15 equiv.) was added NH4OAc (100.93 mg, 1.708 mmol, 0.5 equiv.) at 25°C. Then the mixture was heated to 100°C and stirred for 0.5 h. The reaction mixture was cooled and concentrated in vacuum to give a residue. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in water (10 mmol / L NH4HCO3), 40% to 70% gradient in 10 min; detector, UV 220 nm. to give 25.3 (650 mg) as a yellow solid.

[0421] To a solution of 25.3 (100 mg, 0.429 mmol, 1 equiv.) in THF (1 mL) was added drop- wise lithium aluminum hydride (1.0 M in THF) (2.14 mL, 2.145 mmol, 5 equiv.) at 0°C. Then the mixture was heated to 60°C and stirred for 2 h. The reaction mixture was cooled to 0-5°C and quenched with water (0.1 mL) followed by 15% NaOH solution (0.1 mL). The resulting mixture was filtered through a pad of celite and the filter cake was washed with THF (1 mL x 3). The filtrate was concentrated in vacuum to give a residue. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. to give 25.4 (30 mg) as a colorless oil.

[0422] A solution of 25.4 (20 mg, 0.097 mmol, 1 equiv.) in Methanol (0.5 mL) was added 3- fluoro-5-methylbenzaldehyde (13.46 mg, 0.097 mmol, 1 equiv.) and AcOH (17.55 mg, 0.291 mmol, 3.0 equiv.) at 0oC then NaBH3CN (12.25 mg, 0.194 mmol, 2.0 equiv.) was added slowly. The mixture was stirred at room temperature for 2 h under nitrogen atmosphere. the mixture was quenched with aq. NH4Cl and purified by Prep-HPLC. This resulted in Compound 25 (12.4 mg) as a white solid. [M+H]+ (ESI):328.05.

[0423] 1H NMR (300 MHz, Methanol-d4) δ 7.46 – 7.41 (m, 1H), 7.15 (s, 1H), 7.13 – 7.02 (m, 4H), 4.27 (s, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 3.49 (t, J = 7.1 Hz, 2H), 3.35 (d, J = 6.9 Hz, 2H), 2.40 (s, 3H).

[0424] Example 22 - Synthesis of Compound 26: N-(3-fluoro-5-methylbenzyl)-2-(6-methoxy-1-methyl-1H-indazol-3-yl)ethan-1-amine

[0425] Scheme 26

[0426] Into a 50 mL round-bottom flask were added 3-iodo-6-methoxy-1H-indazole (2.0 g, 7.3mmol, 1 equiv.) and Cs2CO3 (4.76 g, 14.6 mmol, 2 equiv.) and DMF (10 mL) at room temperature. To the above mixture was added CH3I (0.55 mL, 8.8 mmol, 1.2 equiv.) dropwise at 0°C. The resulting mixture was stirred at 0°C for 15 min, then 2 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with DCM (50 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). 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, Acetonitrile in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 15 min; detector, UV 220 nm. This resulted in 26.2 (1.65 g) as a white solid. [M+H]+ (ESI):289.05.

[0427] Into a 100 mL 3-necked round-bottom flask were added 26.2 (1.50 g, 5.207 mmol, 1equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (1.22 g, 6.25 mmol, 1.2 equiv.), Pd(dppf)Cl2-DCM (425 mg, 0.521 mmol, 0.1 equiv.), Cs2CO3 (5.09 g, 15.6 mmol, 3 equiv.) and 1,4-dioxane (38 mL), H2O (8 mL) at room temperature. The resulting mixture was stirred at 105°C for 4 h under nitrogen atmosphere. To the above mixture was added H2O (8 mL) at 105°C. The resulting mixture was stirred at 105°C for additional 12 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 mL). The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 20 mL). 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, Acetonitrile in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 15 min; detector, UV 220 nm. This resulted in 26.3 (623 mg) as a brown solid. [M+H]+ (ESI):202.05.

[0428] Into a 50 mL pressure tank reactor were added 26.4 (200 mg, 0.994 mmol, 1 equiv.) and Raney-Ni (200 mg) and NH3 in Methanol (7 M in Methanol) (38 mL) at room temperature. The resulting mixture was stirred at 45°C for 16 h under hydrogen atmosphere (5 atm.). The resulting mixture was filtered through a pad of celite, the filter cake was washed with Methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in crude 26.5 (207 mg) as a grey oil. [M+H]+ (ESI):206.15.

[0429] Into an 8 mL vial were added 26.5 (50 mg, 0.244 mmol, 1 equiv.) and sodium cyanoborohydride (45.92 mg, 0.732 mmol, 3 equiv.), HOAc (14.34 uL, 0.244 mmol, 1 equiv.) and methanol (1 mL) and 3-fluoro-5-methylbenzaldehyde (29.62 uL, 0.244 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of saturated NH4Cl (aq.) (0.3 mL) at room temperature. The mixture was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 42% B to 57% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 6.67) to afford the freebase. Then 3 eq of 2 M HCl (a.q.) was added and lyophilized to afford Compound 26 (23.7 mg) as a white solid. [M+H]+ (ESI): 328.10.

[0430] 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 8.9 Hz, 1H), 7.19 (s, 1H), 7.16 – 7.10 (m, 1H), 7.07 – 6.98 (m, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.80 (dd, J = 8.8, 2.1 Hz, 1H), 4.28 (s, 2H), 3.99 (s, 3H), 3.89 (s, 3H), 3.48 (t, J = 7.2 Hz, 2H), 3.35 (t, J = 6.9 Hz, 2H), 2.39 (s, 3H).

[0431] Example 23 - Synthesis of Compound 27: N-(3-fluoro-5-methylbenzyl)-2-(6-methoxy-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)ethan-1-amine

[0432] Scheme 27

[0433] Into a 50 mL round-bottom flask were added 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2.50 g, 8.95 mmol, 1 equiv.) and K2CO3 (2.47 g, 17.9 mmol, 2 equiv.), DMF (12 mL), MeI (0.61 mL, 9.84 mmol, 1.1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 24 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (40 mL). The resulting mixture was filtered, and the filter cake was washedwith DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue waspurified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Acetonitrile in water (10 mmol / L NH4HCO3), 40% to 80% gradient in 15 min; detector, UV 220 nm. This resulted in 27.2 (1.92 g) as a yellowish solid. [M+H]+ (ESI):293.80.

[0434] Into a 100 mL 3-necked round-bottom flask were added 27.2 (1.60 g, 5.45 mmol, 1equiv.) and t-BuOK (1.84 g, 16.4 mmol, 3 equiv.), DMF (10 mL), methanol (0.66 mL, 16.4 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The reaction was quenched by the addition of formic acid (0.6 mL, 3 eq) at 0 °C. The resulting mixture was diluted with DCM (40 mL). The resultingmixture was filtered through a pad of celite, the filter cake was washed with DCM (3 x 10 mL).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, Acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 27.3 (560 mg) as a yellow solid. [M+H]+ (ESI):289.95.

[0435] Into a 40 mL vial were added 27.3 (500 mg, 1.73 mmol, 1 equiv.) and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (405 mg, 2.08 mmol, 1.2 equiv.), Pd(dppf)Cl2-DCM (141 mg, 0.173 mmol, 0.1 equiv.) and Cs2CO3 (1.69 g, 5.19 mmol, 3 equiv.), dioxane (10 mL) and H2O (2.5 mL) at room temperature. The resulting mixture was stirred at 105°C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (40 mL). The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / DCM / THF (3:1:0~3:1:2) to afford 27.4 (210 mg) as a white solid. [M+H]+ (ESI):203.00.

[0436] Into a 50 mL pressure tank reactor were added 27.4 (210 mg, 1.038 mmol, 1 equiv.) and NH3 in Methanol (7M in Methanol) (10 mL), DMF (10 mL), Raney-Ni (200 mg, 3.408 mmol, 3.28 equiv.) at room temperature. The resulting mixture was stirred at 50°C for 16 h under hydrogen atmosphere (5 atm). The resulting mixture was filtered through a pad of celite, the filter cake was washed with Methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 27.5 (182 mg) as a yellow oil. [M+H]+ (ESI):207.10.

[0437] Into an 8 mL vial were added 27.5 (50 mg, 0.242 mmol, 1 equiv.) and sodium cyanoborohydride (46 mg, 0.73 mmol, 3 equiv.), methanol (1 mL), HOAc (14 uL, 0.24 mmol, 1 equiv.) and 3-fluoro-5-methylbenzaldehyde (29 uL, 0.24 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The residue / crude product was purified by reversed phase flash with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 31% B to 45% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.03) to afford the freebase. Then 3 eq. of 2 M HCl (a.q.) was added and lyophilized to afford Compound 27 (21.1 mg, 23% yield, 99.6% purity) as a white solid. [M+H]+ (ESI): 329.05.

[0438] 1H NMR (300 MHz, Methanol-d4) δ 9.23 (s, 1H), 7.49 (s, 1H), 7.27 – 7.12 (m, 2H), 7.04 (d, J = 9.8 Hz, 1H), 4.30 (s, 2H), 4.22 (s, 3H), 4.11 (s, 3H), 3.66 – 3.48 (m, 4H), 2.40 (s, 3H).

[0439] Example 24 - Synthesis of Compound 28: N-(3-fluoro-5-methylbenzyl)-2-(5-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)ethan-1-amine

[0440] Scheme 28

[0441] Into a 40 mL vial were added 5-methoxy-1H-pyrazolo[3,4-c]pyridine (1.25 g, 8.38mmol, 1 equiv.) and NIS (2.07 g, 9.22 mmol, 1.1 equiv.) and DMF (10 mL) at room temperature. The resulting mixture was stirred at 80°C for 16 h under nitrogen atmosphere. The resulting mixture was diluted with acetonitrile (50 mL). The resulting mixture was filtered through a pad of celite, the filter cake was washed with acetonitrile (2 x 10 mL). 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, Acetonitrile in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 15 min; detector, UV 220 nm. This resulted in 28.2 (1.65 g) as a yellow solid. [M+H]+ (ESI):275.85.

[0442] Into a 50 mL round-bottom flask were added 28.2 (1.60 g, 5.82 mmol, 1 equiv.) andK2CO3 (2.97 g, 21.5 mmol, 3.69 equiv.) and DMF (16 mL) at room temperature. To the above mixture was added MeI (0.43 mL, 6.98 mmol, 1.2 equiv.) at 0°C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with DCM (40 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 28.3 (1.07 g) as a yellow solid. [M+H]+ (ESI):289.90.

[0443] Into a 100 mL 3-necked round-bottom flask were added 28.3 (1 g, 3.46 mmol, 1 equiv.)and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (809 mg, 4.15 mmol, 1.2 equiv.), Pd(dppf)Cl2-DCM (282 mg, 0.35 mmol, 0.1 equiv.) and Cs2CO3 (3.38 g, 10.4 mmol, 3 equiv.), dioxane (20 mL) and H2O (5 mL) at room temperature. The resulting mixture was stirred at 105°C for 16 h under nitrogen atmosphere. The resulting mixture was concentratedunder reduced pressure. The resulting mixture was diluted with DCM (80 mL). The resultingmixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography,eluted with PE / DCM / THF (3:1:0 ~ 3:1:2) to afford 28.4 (332 mg) as a white solid. [M+H]+(ESI):203.05.

[0444] Into a 50 mL pressure tank reactor were added 28.4 (160 mg, 0.79 mmol, 1 equiv.) andNH3 in methanol (10 mL), Raney-Ni (160 mg) at room temperature. The resulting mixture was stirred at 50°C for 16 h under hydrogen atmosphere (5 atm.). The resulting mixture was filtered through a pad of celite, the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in Compound 28.5 (140 mg, 87% yield) as a yellow oil. [M+H]+ (ESI):207.15.

[0445] Into an 8 mL vial were added 28.5 (50 mg, 0.24 mmol, 1 equiv.) and sodiumcyanoborohydride (62 mg, 0.72 mmol, 3 equiv.), methanol (1 mL), HOAc (14 uL, 0.24 mmol, 1 equiv.) and 3-fluoro-5-methylbenzaldehyde (29 uL, 0.24 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The crude product was purified by reversed phase flash with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150 mm, 5um; Mobile Phase A: water (0.1% HCl), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 5% B to 20% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 9.87) to afford the freebase. Then 3 eq. of 2 M HCl (a.q.) was added and lyophilized to afford Compound 28 (30.2 mg, 34% yield, 99.6% purity) as a white solid. [M+H]+ (ESI): 329.05.

[0446] Example 25 - Synthesis of Compound 29 and 30: 2-((3-chloro-5-methylbenzyl)amino)-1-(1-methyl-1H-indazol-3-yl)ethan-1-ol Enantiomer 1(29) and Enantiomer 2 (30).

[0447] Scheme 29 and 30

[0448] The Compound 18 (60 mg) was purified by Prep-Chrial-HPLC with the followingconditions (Column: CHIRALPAK IM, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3- methanol)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 25; Wave Length: 220 / 254 nm; RT1(min): 12.018; RT2(min): 15.347; Sample Solvent: EtOH--HPLC; Injection Volume: 1.2 mL; Number of Runs: 6) to afford Enantiomer1, Compound 29, (20.3 mg) as a white solid and Enantiomer 2, Compound 30 (20.6 mg) as awhite solid. [M+H]+ (ESI):330.00.

[0449] The MS and 1H-NMR data of the two enantiomers are the same.

[0450] 1H NMR (300 MHz, methanol-d4) δ 7.90 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H),7.47-7.35 (m, 2H), 7.35-7.25 (m, 2H), 7.25-7.15 (m, 1H), 5.43-5.39 (m, 1H), 4.35-4.25 (m, 2H), 4.04 (s, 3H), 3.62-3.39 (m, 2H), 2.41 (s, 3H).

[0451] Example 26 and 27 - Synthesis of Compound 31 and 32: N-(3-chloro-5-methylbenzyl)-2-(1H-indazol-3-yl)-2-methoxyethan-1-amine, Enantiomer 1 (31) and N- (3-chloro-5-methylbenzyl)-2-(1H-indazol-3-yl)-2-methoxyethan-1-amine, Enantiomer 2 (32).

[0452] Scheme 31 and 32

[0453] A mixture of 1H-indazole-3-carbaldehyde (5 g, 34.21 mmol, 1 equiv.) and NaH (1.5 g, 37.63 mmol, 1.1 equiv., 60%) in THF (100 mL) was stirred at 0oC for 30 min under nitrogen atmosphere. To the above mixture was added SEM-Cl (6.84 g, 41.05 mmol, 1.2 equiv.) dropwise at 0oC. The resulting mixture was stirred at 0oC for additional overnight. The residue was purified by column chromatography, eluted with PE / EtOAc = 5 / 1 to afford 31.2 (6 g) as a light yellow oil. [M+H]+ (ESI):277.10.

[0454] A solution of 31.2 (5 g, 18.09 mmol, 1 equiv.) was treated with nitromethane (14.7 mL, 271.33 mmol, 15 equiv.), ammonium acetate (860 mg, 9.04 mmol, 0.5 equiv.) at 100oC for 30 min under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated NaCl (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 column; mobile phase, acetonitrile in water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford Intermediate 31.3 (2.4 g) as a yellow solid. [M+H]+ (ESI):320.10.

[0455] Into a 20mL round-bottom flask were added MeONa (20.9 mL, 112.79 mmol, 15 equiv.) and methanol (50 mL) at 0oC. To the above mixture was added 31.3 (2.4 g, 7.51 mmol, 1 equiv.) dropwise / in portions at 0oC. The resulting mixture was stirred at 0oC for additional 15 min. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl (2 x 100 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 column; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 100% gradient in 25 min; detector, UV 220 nm to afford 31.4 (970 mg) as a yellow oil. [M+H]+ (ESI):352.15.

[0456] A solution of 31.4 (970 mg, 2.76 mmol, 1 equiv.) in THF (14 mL) was treated with 1 M lithium aluminum hydride (6.9 mL, 13.80 mmol, 5 equiv.) at 0oC for 5 min. The resulting mixture was stirred at 70oC overnight under nitrogen atmosphere. The reaction was quenched by the addition of NaOH (15% aq.) (10 mL) at 0oC. The resulting mixture was filtered and the filter cake was washed with THF (3 x 40 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (0.1% NH3.H2O), 30% to100% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to afford 31.5 (350 mg) as a yellow oil. [M+H]+ (ESI):322.20.

[0457] A solution of Compound 31.5 (150 mg, 0.47 mmol, 1 equiv.), sodium cyanoborohydride (59 mg, 0.93 mmol, 2 equiv.) and 3-chloro-5-methylbenzaldehyde (48 mg, 0.31 mmol, 1 equiv.) in methanol (2 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 31.6 (70 mg) as a colorless oil. [M+H]+ (ESI):460.15.

[0458] The enantiomeric mixture of Compound 31.6 (70 mg) was purified by CHIRAL-HPLC with the following conditions (Column: CHIRALPAK IK 2*25 cm, 5 μm; Mobile Phase A: HEX (0.1% DEtOAc), Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient (B%): isocratic 2; Wave Length: 220 / 254 nm; RT1(min): 6.064; RT2(min): 7.851; Sample Solvent: EtOH; Injection Volume: 0.5 mL; Number of Runs: 6) to afford two enantiomer as Peak 2 and peak2. [M+H]+ (ESI):460.15.

[0459] A mixture of Enantiomer 1 and 2 (30 mg, 0.065 mmol, 1 equiv.) and HCl (7 mL) in 1,4-dioxane (1 mL) was stirred at room temperature for overnight. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% HCl), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 15% B to 29% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 9.16) to afford Enantiomer 1 (7.6 mg) and Enantiomer 2 (5 mg).

[0460] Both have same mass and H-NMR

[0461] [M+H]+ (ESI):330.10

[0462] 1H NMR (300 MHz, methanol-d4) δ 7.89-7.80 (m, 1H), 7.61-7.50 (m, 1H), 7.49-7.37 (m, 2H), 7.34-7.25 (m, 2H), 7.23-7.12 (m, 1H), 5.13-5.01 (m, 1H), 4.28 (s, 2H), 3.74-3.60 (m, 1H), 3.43-3.41 (m, 1H), 3.31(s, 3H), 2.36 (s, 3H).

[0463] Example 28 and 29 - Synthesis of Compound 33 and 34: v, Enantiomer 1 and N-(3-fluoro-5-methylbenzyl)-2-(1H-indazol-3-yl)-2-methoxyethan-1-amine, Enantiomer 2.

[0464] Scheme 33 and 34

[0465] A mixture of Compound 31.5 (150 mg, 0.47 mmol, 1 equiv.), sodium cyanoborohydride(58 mg, 0.93 mmol, 2 equiv.), HOAc (28 mg, 0.47 mmol, 1 equiv.) and 3-fluoro-5-methylbenzaldehyde (64 mg, 0.47 mmol, 1 equiv.) in methanol (2 mL) was stirred at roomtemperature for overnight under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (0.1% NH4HCO3), 20% to 50% gradient in 20 min; detector, UV220 nm to afford 33.1 (85 mg) as an off-white solid. [M+H]+ (ESI):444.20

[0466] The 33.1 (70 mg) was purified by CHIRAL-HPLC with the following conditions(Column: CHIRALPAK IK 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-methanol)-- HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 1;Wave Length: 220 / 254 nm; RT1(min): 6.887; RT2(min): 9.915; Sample Solvent: EtOH-- HPLC; Injection Volume: 0.8 mL; Number of Runs: 8) to afford Enantiomer 1, 33.2 andEnantiomer 2, 33.3 (32 mg each) [M+H]+ (ESI):444.20.

[0467] A solution of 33.2 (30 mg, 0.068 mmol, 1 equiv.) and HCl (7 mL) in 1,4-dioxane (1mL) was stirred at room temperature for overnight. The reaction mixture was concentrated invacuum to give a residue. The crude product was purified by Prep-HPLC with the followingconditions (Column: XBridge Shield RP18 OBD Column19*250 mm, 5μm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: acetonitrile; Flow rate: 20 mL / min; Gradient (B%): 36% B to 50% B in 14 min; Wave Length: 254nm / 220nm; RT1(min): 13.27) to afford 33 Enantiomer 1, (7.3 mg) as a white solid.

[0468] Second Enantiomer were prepared via same method and both have mass [M+H]+(ESI):314.10 and H-NMR

[0469] 1H-NMR (300 MHz, methanol-d4) δ 7.86 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H),7.46-7.37 (m, 1H), 7.23-7.19 (m, 2H), 7.17-7.09 (m, 1H), 7.07-6.99 (m, 1H), 5.12-5.07 (m, 1H), 4.30 (s, 2H), 3.72-3.64 (m, 1H), 3.42-3.35 (m, 1H), 3.33 (s, 3H), 2.40 (s, 3H).

[0470] Example 30 - Synthesis of Compound 35: N-(3-fluoro-5-methylbenzyl)-2-(5-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethan-1-amine

[0471] Scheme 35

[0472] Into a 40 mL vial were added 5-methoxy-1H-pyrazolo[4,3-b]pyridine (1.00 g, 6.71mmol, 1 equiv.) and NIS (1.66 g, 7.38 mmol, 1.1 equiv.), DMF (10 mL) at room temperature. The resulting mixture was stirred at 80°C for 16 h under nitrogen atmosphere. Afterconcentration, the resulting mixture was purified by reversed-phase flash chromatography withthe following conditions: column, C18 column; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 15 min; detector, UV 220 nm. This resulted in 35.2 (1.84g) as a yellow solid. [M+H]+ (ESI): 275.90.

[0473] Into a 100 mL round-bottom flask were added 35.2 (1.84 g, 6.7 mmol, 1 equiv.) andK2CO3 (1.85 g, 13.4 mmol, 2 equiv.), DMF (12 mL) at room temperature. To the above mixture was added CH3I (0.50 mL, 8.0 mmol, 1.2 equiv.) at 0°C. The resulting mixture wasstirred at room temperature for 3 h. The resulting mixture was diluted with DCM (200 mL), washed with water (5 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluted with DCM / EtOAc (from 50 / 1 to 20 / 1) to afford 35.3 (1.24 g) as a white solid. [M+H]+ (ESI):289.95.

[0474] Into a 40 mL vial were added 35.3 (600 mg, 2.08 mmol, 1 equiv.) and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (486 mg, 2.49 mmol, 1.2 equiv.), Pd(dppf)Cl2-DCM (51 mg, 0.062 mmol, 0.03 equiv.) and Cs2CO3(2.03 g, 6.23 mmol, 3 equiv.), dioxane (12 mL) and H2O (3 mL) at room temperature. The resulting mixture was stirred at 105°C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (80 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 15 min; detector, UV 220 nm. Then the obtained crude product was purified again by Prep-TLC (PE / DCM / THF = 9 / 3 / 4) to afford 35.4 (129 mg) as a white solid. [M+H]+ (ESI):203.00.

[0475] Into a 50 mL pressure tank reactor were added 35.4 (129 mg, 0.64 mmol, 1 equiv.) and Raney-Ni (130 mg) and ammonia (7.0 M in methanol) (12 mL) at room temperature. The resulting mixture was stirred at 45°C for 16 h under hydrogen atmosphere (5 atm.). The resulting mixture was filtered through a pad of celite, the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 35.5 (138 mg, crude) as a yellow oil. [M+H]+ (ESI):207.10.

[0476] Into an 8 mL vial were added crude material 35.5 (40 mg, 0.19 mmol, 1 equiv.), sodium cyanoborohydride (37 mg, 0.58 mmol, 3 equiv.) and HOAc (11 uL, 0.19 mmol, 1 equiv.), methanol (1 mL) and 3-fluoro-5-methylbenzaldehyde (24 uL, 0.19 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The residue was purified by reversed phase flash with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 37% B to 53% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.3) to afford the freebase. Then 2 M HCl (3 equiv.) was added and lyophilized to afford Compound 35 (22.8 mg) as a white solid. [M+H]+ (ESI): 329.10.

[0477] 1H NMR (300 MHz, methanol-d4) δ 7.93 (d, J = 9.0 Hz, 1H), 7.20-6.98 (m, 3H), 6.89(d, J = 9.0 Hz, 1H), 4.30 (s, 2H), 4.02 (s, 3H), 3.86 (s, 3H), 3.56 (t, J = 7.2 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H).

[0478] Example 31 - Synthesis of Compound 36: N-(3-chloro-5-methylbenzyl)-2-(5-methoxy-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethan-1-amine

[0479] Scheme 36

[0480] Into an 8 mL vial were added 35.5 (40 mg, 0.19 mmol, 1 equiv.), sodiumcyanoborohydride (37 mg, 0.58 mmol, 3 equiv.) and HOAc (11 uL, 0.19 mmol, 1 equiv.), methanol (1 mL) and 3-chloro-5-methylbenzaldehyde (25 uL, 0.19 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase flash with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150mm, 5μm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 50% B to 67% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.5) to afford the freebase. Then 2 M HCl (3 equiv.) was added and lyophilized toafford Compound 36 (24.0 mg) as a white solid. [M+H]+ (ESI):345.05.

[0481] 1H NMR (300 MHz, methanol-d4) δ 7.98 (d, J = 9.0 Hz, 1H), 7.47-7.14 (m, 3H), 6.93(d, J = 9.0 Hz, 1H), 4.29 (s, 2H), 4.04 (s, 3H), 3.89 (s, 3H), 3.56 (t, J = 7.0 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 2.37 (s, 3H).

[0482] Example 32 - Synthesis of Compound 37: N-(3-fluoro-5-methylbenzyl)-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethan-1-amine

[0483] Scheme 37

[0484] Into a 40 mL vial were added 1H-pyrazolo[4,3-b]pyridine (1.4 g, 11.8 mmol, 1 equiv.)and NIS (2.9 g, 12.9 mmol, 1.1 equiv.), DMF (14 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 30% to 70% gradient in 15 min; detector, UV 220 nm. This resulted in 37.2 (2.71 g) as a yellow solid. [M+H]+ (ESI):245.95.

[0485] Into a 100 mL round-bottom flask were added 37.2 (2.7 g, 11.1 mmol, 1 equiv.) andK2CO3 (3.06 g, 22.1 mmol, 2 equiv.), DMF (15 mL) at room temperature. To the above mixture was added CH3I (0.83 mL, 13.3 mmol, 1.2 equiv.) at 0°C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with DCM (40 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV220 nm. This resulted in 37.3 (1.60 g) as a white solid. [M+H]+ (ESI):259.90.

[0486] Into a 100 mL 3-necked round-bottom flask were added 37.3 (1 g, 3.86 mmol, 1 equiv.)and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (903 mg, 4.63 mmol, 1.2 equiv.), Pd(dppf)Cl2-DCM (315 mg, 0.386 mmol, 0.1 equiv.) and Cs2CO3 (3.77 g, 11.6 mmol, 3 equiv.), dioxane (20 mL) and H2O (5 mL) at room temperature. The resulting mixture wasstirred at 105°C for 16 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (80 mL). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluted with PE / DCM / THF (from 3 / 1 / 0 to 3 / 1 / 2) to afford 37.4 (413 mg, 62% yield, 95%purity) as an off-white solid. [M+H]+ (ESI):173.15.

[0487] Into a 50 mL pressure tank reactor were added 37.4 (413 mg, 2.40 mmol, 1 equiv.) andRaney-Ni (400 mg) and ammonia (7.0in methanol) (10 mL) at room temperature. The resulting mixture was stirred at 45°C for 16 h under hydrogen atmosphere (5 atm.). The resulting mixture was filtered through a pad of celite, the filter cake was washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 37.5 (364mg, crude) as a yellow oil. [M+H]+ (ESI):177.15.

[0488] Into an 8 mL vial were added 37.5 (50 mg, 0.28 mmol, 1 equiv.), sodiumcyanoborohydride (53 mg, 0.85 mmol, 3 equiv.) and HOAc (17 uL, 0.28 mmol, 1 equiv.), methanol (1 mL) and 3-fluoro-5-methylbenzaldehyde (34 uL, 0.28 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. After concentration, the residue was purified by reversed phase flash with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 28% B to 43% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 6.95) to afford the freebase. Then 2 M HCl (3 equiv.) was added and lyophilized to affordCompound 37 (27.2 mg) as a white solid. [M+H]+ (ESI): 299.05.

[0489] 1H NMR (400 MHz, methanol-d4) δ 8.82 (dd, J = 5.2, 1.1 Hz, 1H), 8.77 (dd, J = 8.7,1.1 Hz, 1H), 7.90 (dd, J = 8.7, 5.2 Hz, 1H), 7.23 (s, 1H), 7.19-7.12 (m, 1H), 7.08-7.01 (m, 1H), 4.32 (s, 2H), 4.24 (s, 3H), 3.68-3.56 (m, 4H), 2.41 (s, 3H).

[0490] Example 33 - Synthesis of Compound 38: N-(3-chloro-5-methylbenzyl)-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)ethan-1-amine

[0491] Scheme 38

[0492] Into an 8 mL vial were added 37.5 (50 mg, 0.28 mmol, 1 equiv.), sodiumcyanoborohydride (53 mg, 0.85 mmol, 3 equiv.) and HOAc (17 uL, 0.28 mmol, 1 equiv.), methanol (1 mL) and 3-chloro-5-methylbenzaldehyde (44 mg, 0.28 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase flash with the following conditions (Column: XBridge Shield RP18 OBD Column19*250 mm, 5μm; Mobile Phase A: water (0.05% HCl), Mobile Phase B: acetonitrile; Flow rate: 20 mL / min; Gradient (B%): 21% B to 37% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 9.67) to affordCompound 38 ( 30.7 mg, 30% yield, 93.3% purity) as a white solid. [M+H]+ (ESI): 315.05.

[0493] 1H NMR (300 MHz, methanol-d4) δ 8.76-8.64 (m, 1H), 8.57-8.47 (m, 1H), 7.75 (dd, J= 8.7, 4.9 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J = 1.7 Hz, 2H), 4.31 (s, 2H), 4.18 (s, 3H), 3.69-3.47 (m, 4H), 2.39 (s, 3H).

[0494] Example 34 - Synthesis of Compound 39: N-(3-fluoro-5-methylbenzyl)-2-(1H-indazol-3-yl)ethan-1-amine Compound 39 was synthesized in 3 steps from commercially available Iodo intermediate 39.1

[0495] Scheme 39

[0496] A solution of 3-iodo-1H-indazole (8 g, 32.73 mmol, 1 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (12.8 g, 64.10 mmol, 2 equiv.), K3PO4 (19.2 g, 97.61 mmol, 3 equiv.) and bis(4-(di-tert-butylphosphanyl)-N,N-dimethylaniline); dichloropalladium (2.3 mg, 3.28 mmol, 0.1 equiv.) in dioxane (80 mL) and water (16 mL) was stirred at 90°C for 16 h under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with acetonitrile (100 mL x 2). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the followingconditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 39.2 (3.2 g) as a black oil. [M+H]+ (ESI):158.15.

[0497] A solution of 39.2 (3.2 g, 20.36 mmol, 1 equiv.), Raney Nickel (1 g) in 7 M NH3 in methanol (100 mL) was stirred at 50°C for 12 h under hydrogen atmosphere (5 atm). The resulting mixture was filtered, and the filter cake was washed with methanol (100 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 39.3 (1.3 g) as a yellow oil. [M+H]+ (ESI):162.10.

[0498] A solution of Compound 39.3 (1.3 g, 8.06 mmol, 1 equiv.), 3-fluoro-5- methylbenzaldehyde (1.11 g, 8.06 mmol, 1 equiv.), sodium cyanoborohydride (1 g, 16.13 mmol, 2 equiv.) and HOAc (0.48 g, 8.06 mmol, 1 equiv.) in methanol (10 mL) was stirred at 25°C for 2 h under nitrogen atmosphere. After concentration, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 39 (0.8 g, 35% yield) as a white solid. [M+H]+ (ESI):284.10.

[0499] 1H NMR (300 MHz, methanol-d4) δ 7.75 (d, J = 8.2 Hz, 1H), 7.54-7.51 (m, 1H), 7.45- 7.38 (m, 1H), 7.20-7.02 (m, 4H), 4.27 (s, 2H), 3.53 (t, J = 6.9 Hz, 2H), 3.40 (d, J = 6.9 Hz, 2H), 2.40 (s, 3H).

[0500] Example 35 - Synthesis of Compound 40: N-(3-fluoro-5-methylbenzyl)-2-(1- (trifluoromethyl)-1H-indazol-3-yl)ethan-1-amine.

[0501] Compound 40 was synthesized from previously prepared intermediate compound 39 and amination reaction with trifluro iodide after boc preotection and deprotection.

[0502] Scheme 40

[0503] A solution of compound 39 (800 mg, 2.82 mmol, 1 equiv.), Boc2O (924 mg, 4.23 mmol,1.5 equiv.) and Na2CO3 (598 mg, 5.64 mmol, 2 equiv.) in THF (10 mL) and water (10 mL) was stirred at 25°C for 2 h under nitrogen atmosphere. The reaction mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was concentrated in vacuum to give a residue. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 40.1(750 mg) as a white solid. [M+H]+ (ESI):384.10.

[0504] A solution of 40.1 (300 mg, 0.78 mmol, 1 equiv.) in DMF (0.4 mL) was treated withCs2CO3 (637.2 mg, 1.95 mmol, 2.5 equiv.) at 0°C for 2 h under nitrogen atmosphere followed by the addition of trifluoro(iodo)methane (919.6 mg, 1.17 mmol, 1.5 equiv., 25%) dropwise at 25°C. After filtration, the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, (10 mmol / L NH4HCO3) inacetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 40.2 (50mg) as a white oil. [M+H]+ (ESI):452.05.

[0505] A solution of 40.2 (50 mg, 0.11 mmol, 1 equiv.) and HCl in 1,4-dioxane (4.0 M) (0.5mL) in methanol (0.5 mL) was stirred at 25°C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% HCl), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min;Gradient (B%): 12% B to 28% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.36) to afford Compound 40 (16.0 mg) as a white solid. [M+H]+ (ESI):352.05.

[0506] 1H NMR (300 MHz, methanol-d4) δ 8.35-8.27 (m, 1H), 7.87-7.72 (m, 3H), 7.07-6.93(m, 3H), 4.02 (s, 2H), 3.25-3.16 (m, 1H), 2.85-2.74 (m, 1H), 2.60-2.38 (m, 2H), 2.36 (s, 3H).

[0507] Example 36 - Synthesis of Compound 41: N-(3-fluoro-5-methylbenzyl)-2-(1-isopropyl-1H-indazol-3-yl)ethan-1-amine

[0508] Compound 41 was synthesized from previously prepared intermediate compound 40.1and amination reaction with isopropyl iodide after boc preotection and deprotection.

[0509] Scheme 41

[0510] A solution of Compound 40.1 (55 mg, 0.14 mmol, 1 equiv.) in DMF (0.4 mL) wastreated with 2-iodopropane (36 mg, 0.214 mmol, 1.5 equiv.) and Cs2CO3 (70 mg, 0.21 mmol, 1.5 equiv.) at 25°C for 2 h under nitrogen atmosphere. The reaction was quenched with water (5 mL) at 0°C. The resulting mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with NaCl (5 mL) and 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, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 41.2 (50 mg) as a white oil. [M+H]+ (ESI):426.15.

[0511] A solution of Compound 40.2 (50 mg, 0.12 mmol, 1 equiv.) and HCl in 1,4-dioxane(4.0 M) (0.5 mL) in methanol (0.5 mL) was stirred at 25°C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% HCl), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 12% B to 28% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.36) to afford 41 (24.2 mg) as a white solid. [M+H]+ (ESI):326.15.

[0512] 1H NMR (300 MHz, methanol-d4) δ 7.73 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H),7.46-7.38 (m, 1H), 7.20-7.03 (m, 4H), 5.00-4.90 (m, 1H), 4.29 (s, 2H), 3.55 (t, J = 7.0 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 2.38 (m, 3H), 1.53 (d, J = 6.7 Hz, 6H).

[0513] Example 37 - Synthesis of Compound 42: 2-(1-(difluoromethyl)-1H-indazol-3-yl)-N-(3-fluoro-5-methyl benzyl)ethan-1-amine.

[0514] Compound 42 was synthesized from previously prepared intermediate compound 40.1and amination reaction with difluoro bromo intermediate after boc preotection and deprotection.

[0515] Scheme 42

[0516] A solution of 40.1equiv.), diethyl(bromodifluoromethyl)phosphonate (35 mg, 0.13 mmol, 1 equiv.) and KF (15 mg, 0.26 mmol, 2 equiv.) in acetonitrile (1 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified using C18 flash chromatography with the following conditions (Mobile Phase A: water, Mobile Phase B: acetonitrile; Flow rate: 80 mL / min; Gradient: 0% B to 100% B in 30 min; 254 / 220 nm This resulted in 42.1 (40 mg) as a white solid. [M+H]+ (ESI):434.15.

[0517] A solution of 42.1 (40 mg, 0.092 mmol, 1 equiv.) and HCl in 1,4-dioxane (4.0 M) (1mL) in methanol (2 mL) was stirred at room temperature for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water / 0.1%HCl, Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 7% B to 25% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 10.48). This resulted in Compound 42 (18.6 mg) as a white solid. [M+H]+ (ESI):334.15.

[0518] 1H NMR (400 MHz, methanol-d4) δ 8.10-7.72 (m, 2H), 7.70-7.66 (m, 1H), 7.46-7.38(m, 1H), 7.24-7.18 (m, 2H), 7.14-7.02 (m, 2H), 4.26 (s, 2H), 3.82-3.66 (m, 2H), 3.50-3.40 (m, 2H), 2.38 (s, 3H).

[0519] Example 38 - Synthesis of Compound 43: 2-(1-cyclopropyl-1H-indazol-3-yl)-N-(3-fluoro-5-methylbenzyl)ethan-1-amine

[0520] Compound 43 was synthesized from previously prepared intermediate compound 40.1and amination reaction with cylopropyl boric acid via copper catalyed reaction and then boc deprotection.

[0521] Scheme 43

[0522] A solution of compound 40.1 (55 mg, 0.14 mmol, 1 equiv.), cyclopropylboronic acid(37 mg, 0.43 mmol, 3 equiv.), Et3N (72 mg, 0.71 mmol, 5 equiv.), pyridine (79 mg, 1.00 mmol, 7 equiv.) and Cu(OAc)2 (52 mg, 0.28 mmol, 2 equiv.) in THF (2.2 mL) and toluene (1.1 mL) was stirred at 80°C for 16 h under oxygen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 mL x 2). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 50% to 100% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 42.1 (50 mg) as a white oil. [M+H]+ (ESI):424.20.

[0523] A solution of compound 42.1 (50 mg, 0.12 mmol, 1 equiv.) and HCl in 1,4-dioxane (4.0M) (0.5 mL) in methanol (0.5 mL) was stirred at 25°C for 2 h under nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% HCl), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 12% B to 28% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.36) to afford compound 43 (20.9 mg) as a white solid. [M+H]+ (ESI):324.20.

[0524] 1H NMR (300 MHz, methanol-d4) δ 7.80-7.65 (m, 2H), 7.52-7.45 (m, 1H), 7.23-6.95(m, 4H), 4.28 (s, 2H), 3.66-3.60 (m, 1H), 3.52 (t, J = 7.2 Hz, 2H), 3.37 (t, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.31-1.14 (m, 4H).

[0525] Example 39 - Synthesis of Compound 44: 2-(1-ethyl-1H-indazol-3-yl)-N-(3-fluoro-5-methylbenzyl)ethan-1-amine

[0526] Compound 44 was synthesized from previously prepared intermediate compound 40.1and amination reaction with ethyl iodide after boc deprotection.

[0527] Scheme 44

[0528] A solution of compound 40.1 (55 mg, 0.14 mmol, 1 equiv.) in DMF (0.4 mL) wastreated with NaH (9 mg, 0.21 mmol, 1.5 equiv., 60%) at 0°C for 2 h under nitrogen atmosphere followed by the addition of iodoethane (33.55 mg, 0.214 mmol, 1.5 equiv.) dropwise at 25°C. The reaction was quenched with water (2 mL) at 0°C. The resulting mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with NaCl (3 mL) and 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, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 44.1 (50 mg) as a white oil. [M+H]+ (ESI):412.10.

[0529] A solution of compound 44.1 (50 mg, 0.12 mmol, 1 equiv.) and HCl in 1,4-dioxane (4.0M) (0.5 mL) in methanol (0.5 mL) was stirred at 25°C for 2 h under nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: water (0.1% HCl), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient (B%): 12% B to 28% B in 8 min; Wave Length: 254nm / 220nm; RT1(min): 7.36) to afford Compound 44 (26.0 mg) as a white solid. [M+H]+ (ESI):312.10.

[0530] 1H NMR (300 MHz, methanol-d4) δ 7.72 (d, J = 8.2 Hz, 1H), 7.57-7.54 (m, 1H), 7.46-7.41 (m, 1H), 7.21-7.03 (m, 4H), 4.44 (q, J = 7.2 Hz, 2H), 4.28 (s, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 2.39 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H).

[0531] Example 40 - Synthesis of Compound 45: N-(3-fluoro-5-methylbenzyl)-2-(1-(methyl-d3)-1H-indazol-3-yl)ethan-1-amine

[0532] Compound 45 was synthesized from previously prepared intermediate compound 40.1and amination reaction with trideurerated iodide after boc deprotection.

[0533] Scheme 45

[0534] A solution of Compound 40.1 (55 mg, 0.14 mmol, 1 equiv.) in DMF (0.4 mL) wastreated with NaH (9 mg, 0.21mmol, 1.5 equiv., 60%) at 0°C for 2 h under nitrogen atmosphere followed by the addition of CD3I (31 mg, 0.21 mmol, 1.5 equiv.) dropwise at 25°C. The reaction was quenched with water (2 mL) at 0°C. The resulting mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with NaCl (3 mL) and 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, C18 column; mobile phase, water (10 mmol / L NH4HCO3) in acetonitrile, 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in Compound 45.1 (50 mg) as a white oil. [M+H]+ (ESI):401.15.

[0535] A solution of Compound 45.1 (50 mg, 0.12 mmol, 1 equiv.) and HCl in 1,4-dioxane(4.0 M) (0.5 mL) in methanol (0.5 mL) was stirred at 25°C for 2 h under nitrogen atmosphere.The resulting mixture was concentrated under reduced pressure. The reaction mixture waspurified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column19*250 mm, 5μm; Mobile Phase A: water (0.05% HCl), Mobile Phase B: acetonitrile; Flow rate: 20ml / min; Gradient (B%): 3% B to 20% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 7.43) to afford Compound 45 (14.0 mg) as a white solid. [M+H]+ (ESI):301.15.

[0536] 1H NMR (400 MHz, methanol-d4) δ 7.73 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H),7.47-7.42 (m, 1H), 7.20-7.15 (m, 2H), 7.12-7.05 (m, 2H), 4.28 (s, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.38 (t, J = 7.2 Hz, 2H), 2.40 (s, 3H).

[0537] Example 41 – Biolumiescence Resonance Energy Transfer (BRET) Assays

[0538] Methods: Bioluminescence Resonance Energy Transfer (BRET) assays were conductedby Domain Therapeutics North America Inc. using their proprietary bioSens-All® sensor platform. Human 5-HT2B receptors were cloned and transiently transfected into HEK293 cells containing the bioSens-All® sensors.

[0539] Compound activity was assessed by measuring changes in BRET signal relative to vehicle control (0.1% DMSO). For fixed-endpoint experiments, cells were incubated with the test compound for 15 minutes, after which a single BRET signal measurement was recorded. Concentration–response curves were generated using GraphPad Prism 10, comparing compound activity to that of 5-HT.

[0540] For time-course experiments, BRET signal was continuously monitored over a 30- minute period. Data were plotted as the change in BRET signal normalized to vehicle control.

[0541] Results: Compound 2 exhibits concentration-dependent inverse agonism at the human 5-HT2B receptor. (FIG. 1A) Concentration response curve of compound 2 in vitro 5-HT2B agonist activity relative to 5-HT following 15-minute compound incubation. (FIG.1B) Inverse agonism of 5-HT2BR by 1μM of compound 2 persists for at 30-minutes of exposure.

[0542] Example 42 – Activity Data

[0543] Activity data for select compounds of the present disclosure is provided below.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of formula (II):or a pharmaceutically acceptable salt, wherein: X1, X2, and X3are each independently -C- or -N-; R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, -NH(C=O)-alkyl, or absent; R10is -H, -alkyl, -haloalkyl, -cycloalkyl, -alkyl-OH, or -heterocyclyl; R11and R11’are each independently -H, -alkyl, -haloalkyl, -alkyl-OH, O-alkyl, -OH, - or R11and R11’together with the carbon to which they are attached form oxo; R12, R12’R13, and R13’are each independently -H, alkyl, -haloalkyl, -alkyl-OH, -O-alkyl, or -OH; (1) R14, R15, R16, R17, and R18 are each independently -H, -alkyl, -O-alkyl, -cycloalkyl,-halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -NO2, -alkyl-OH, -CN, -O(C=O)-alkyl, - O-haloalkyl, -O-aryl, -heteroaryl, or -NH(C=O)-alkyl, or R14and R15or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein at least one of R14and R15or R15and R16, together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (2) R14, R16, and R18 are -H; and R15 and R17 are not -H; andwherein the compound is not:

2. The compound of claim 1, wherein X1, X2, and X3 are -C-.

3. The compound of claim 1, wherein X2 is -N- and X1 and X3 are -C-.

4. The compound of claim 1, wherein X3 is -N- and X1 and X2 are -C-.

5. The compound of claim 1, wherein X1 is -N- and X2 and X3 are -C-.

6. The compound of any one of claims 1-5, wherein R7, R8, and R9 are each independently-H, -O-alkyl, or absent.

7. The compound of any one of claims 1-5, wherein R7, R8, and R9 are -H.

8. The compound of any one of claims 1-6, wherein R10 is -H, -alkyl, -haloalkyl, -cycloalkyl, or -alkyl-OH.

9. The compound of any one of claims 1-7, wherein R10 is -H.

10. The compound of any one of claims 1-7, wherein R10 is -methyl.

11. The compound of any one of claims 1-10, wherein R11 and R11’ are each independently-H, -O-alkyl, or -OH.

12. The compound of any one of claims 1-11, wherein R11 and R11’ are -H.

13. The compound of any one of claims 1-12, wherein R12, R12’ R13, and R13’ are -H.

14. The compound of any one of claims 1-13, wherein at least one of R14 and R15 or R15and R16together with the carbon in which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

15. The compound of any one of claims 1-13, wherein R14, R16, and R18 are -H; and R15and R17are not -H.

16. The compound of any one of claims 1-13 or 15, wherein the compound is a compoundof Formula (II-C),wherein: X1, X2, and X3are each independently -C- or -N-; R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, or -NH(C=O)-alkyl; R10is -H, -alkyl, -haloalkyl, -cycloalkyl, or alkyl-OH; R11is -H, -OH, or -O-alkyl; or R15and R17are each independently -halogen or -alkyl.

17. The compound of claim 16, wherein X1, X2, and X3 are -C-.

18. The compound of claim 16, wherein X2 is N and X1 and X3 -C-.

19. The compound of claim 16, wherein X3 is N and X1 and X2 -C-.

20. The compound of claim 16, wherein X1 is N and X2 and X3 -C-.

21. The compound of claim 16, wherein R7, R8, and R9 are each independently -H, -O-alkyl, or absent.

22. The compound of any one of claims 16-21, wherein R10 are -H, -alkyl, -cycloalkyl, or-haloalkyl.

23. The compound of any one of claims 16-22, wherein R10 is -H, -O-alkyl, or -OH.

24. The compound of any one of claims 16-23, wherein one of R15 and R17 is -halogen.

25. The compound of any one of claims 16-24, wherein one of R15 and R17 is -alkyl.

26. The compound of any one of claims 16-24, wherein one of R15 and R17 is -halogen andone of R15and R17is -alkyl.

27. The compound of any one of claims 16-24, wherein one of R15 and R17 is -halogen andone of R15and R17is -methyl.

28. The compound of claim 1, wherein the compound is a compound of formula (II-D),X1, X2, and X3are each independently -C- or -N-; R7, R8, and R9are each independently -H, -alkyl, -O-alkyl, -cycloalkyl, -halo, -S-alkyl, -S(O)2-alkyl, -SH, -NH-alkyl, -NH2, -CN, -OH, -O(C=O)-alkyl, or -NH(C=O)-alkyl; R10is -H, -alkyl, -haloalkyl, -cycloalkyl, or -alkyl-OH; R11is -H, -OH, or O-alkyl; and Ring D is aryl or heteroaryl.

29. The compound of claim 28, wherein X1, X2, and X3 are -C-.

30. The compound of claim 28 or 29, wherein R7, R8, and R9 are -H.

31. The compound of any one of claims 28-30, wherein R10 is -H.

32. The compound of any one of claims 28-31, wherein R10 is -H.

33. The compound of any one of claims 28-32, wherein Ring D is aryl.

34. The compound of any one of claims 28-32, wherein Ring D is heteroaryl.

35. The compound of claim 34, wherein the heteroaryl is:.

36. The compound of any one of claims 1-35, wherein the compound is:

37. The compound of any one of claims 1-35, wherein the compound is:

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

39. The compounds of claim 39, wherein the compound ipharmaceutically acceptable salt thereof.

40. A compound selected from the group consisting of:

41. A pharmaceutical composition comprising the compound of any one of claims 1-40 and apharmaceutically acceptable excipient.

42. A method of treating a mental health disease or disorder, the method comprisingadministering a therapeutically effective amount of a compound of any one of claims 1-40 orthe pharmaceutical composition of claim 41.

43. A pharmaceutical composition comprising the compound of any one of claims 1-40 and apharmaceutically acceptable prodrugs and deuterated analogs.

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