SMPD1 inhibitors and uses thereof

Abstract

Provided herein are compounds that inhibit sphingomyelin phosphodiesterase 1 (SMPD1), pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in treatment of cancers such as glioblastoma.

Description

[0001] SMPD1 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No.63 / 635,828, filed on April 18, 2024, the disclosure of which is incorporated herein by reference in its entirety. FIELD Provided herein are compounds that inhibit sphingomyelin phosphodiesterase 1 (SMPD1), pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in treatment of cancers such as glioblastoma. BACKGROUND The highly lethal brain tumor glioblastoma (GBM) is one of the most difficult forms of cancer to treat. Despite a relatively advanced catalog of the mutational landscape of GBM, genomic insights have failed to translate into improved survival for many patients, most of whom still die within 2 years, despite aggressive treatment with surgical resection, radiotherapy, and temozolomide (TMZ) (Cloughesy et al. Annu. Rev. Pathol.9:1-25 (2014); Wen et al. Neuro- Oncology 22(8):1073-1113 (2020)). SUMMARY Disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is a 4-, 5-, 6-, or 7-membered heterocyclic ring; m is 0, 1, 2, 3, or 4; each R1is independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C3-C10)cycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (6-10)-membered aryl, (4-10)- membered heteroaryl, -ORa, -CORb, -COORc, and -SOnRd; wherein two R1optionally taken together with the atoms to which they are attached to form a 4-7-membered ring; n is 1 or 2; Ra, Rb, Rc, and Rdare each independently selected from H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C3-C10)cycloalkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; q is 1 or 2; Rxand Ryare each independently selected from hydrogen and (C1-C6)alkyl; R2and R3are each independently selected from H, (C1-C6)alkyl, (6-10)-membered aryl, (C3-C10)cycloalkyl, (4-10)-membered heteroaryl, and (4-10)-membered heterocyclyl; and R4is selected from (C1-C6)alkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; wherein each alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (6-10)-membered aryl, hydroxy, and (C1-C6)alkoxy. In some embodiments: A is a 4-, 5-, 6-, or 7-membered heterocyclic ring; m is 0, 1, 2, 3, or 4; each R1is independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3- C10)cycloalkyl, (6-10)-membered aryl, (4-10)-membered heteroaryl, -ORa, -CORb, -COORc, and - SOnRd; wherein two R1optionally taken together with the atoms to which they are attached to form a 4-7-membered ring; n is 1 or 2; Ra, Rb, Rc, and Rdare each independently selected from H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C10)cycloalkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; R2and R3are each independently selected from H, (C1-C6)alkyl, (6-10)-membered aryl, (C3-C10)cycloalkyl, (4-10)-membered heteroaryl; and R4is selected from (C1-C6)alkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; wherein each alkyl, aryl, cycloalkyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (6-10)-membered aryl, hydroxy, and (C1-C3)alkoxy. In some embodiments, A is selected from piperidine, pyrrolidine, azetidine, morpholine, azepane, piperazine, and 1,4-oxazepane. In some embodiments, A is selected from: , In some embodiments, A is selected from: , . In some embodiments, m is 0. In some embodiments, m is 1 or 2, and each R1is independently selected from halo, (C1- C3)alkyl, (C1-C3)haloalkyl, (C1-C3)hydroxyalkyl, (C1-C3)alkoxy(C1-C3)alkyl, -ORa, -CORb, - COORc, and -SOnRd, wherein Ra, Rb, Rc, and Rdare each independently selected from hydrogen, phenyl, and (C1-C4)alkyl, wherein the phenyl is unsubstituted or substituted with one substituent selected from halo, (C1-C3)alkyl, and (C1-C3)haloalkyl, and n is 2. In some embodiments, each R1is independently selected from fluoro, methyl, hydroxy, -CHF2, -CH2OH, -CH2OCH3, - CH(OH)CH3, -C(CH3)2OH, -C(O)CH3, -S(O)2CH3, -C(O)OCH2CH(CH3)2, and -O-C6H4(4-CF3). In some embodiments, m is 1 or 2, and each R1is independently selected from halo, (C1-C3)alkyl, -ORa, -CORb, -COORc, and -SOnRd, wherein Ra, Rb, Rc, and Rdare each independently selected from hydrogen and (C1-C4)alkyl, and n is 2. In some embodiments, each R1is independently selected from fluoro, methyl, hydroxy, -C(O)CH3, -S(O)2CH3, and -C(O)OCH2CH(CH3)2. In some embodiments, R2is H. In some embodiments, R3is selected from (6-10)-membered aryl, (C3-C10)cycloalkyl, (4- 10)-membered heteroaryl, and (4-10)-membered heterocyclyl. In some embodiments, R3is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cyclobutyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, and tetrahydroisoquinolinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, methyl, phenyl, and methoxy. In some embodiments, R3is selected from: , In some embodiments, R3is selected from (6-10)-membered aryl, (C3-C10)cycloalkyl, and (4-10)-membered heteroaryl. In some embodiments, R3is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, quinolinyl, and benzothiophenyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, methyl, phenyl, and methoxy. In some embodiments, R3is selected from: , In some embodiments, R4is selected from phenyl and naphthyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, (C1-C6)alkyl, (C1-C6)haloalkyl, and (6-10)-membered aryl. In some embodiments, R4is selected from: . In some embodiments, R4is: . In some embodiments, the compound is selected from compounds shown in Table 1 herein, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from compounds shown in Table 2 herein, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from compounds shown in Table 3 herein, and pharmaceutically acceptable salts thereof. In another aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier. In another aspect, disclosed herein is a method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the proliferative disease is cancer associated with an altered lipid environment. In some embodiments, the cancer is selected from glioblastoma, head and neck cancers, breast cancers, lung cancers, esophageal and gastric cancers, pancreatic cancers, colorectal cancers, ovarian cancers, uterine cancers, prostate cancers, renal cancers, skin cancers, leukemias, lymphomas, sarcomas, gliomas, endometrial cancers, cervical cancers, pharyngeal cancers, and liver cancers. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of one or more pharmaceutical agents in combination with the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition. In some embodiments, the pharmaceutical agent is an antiproliferative agent. In some embodiments, the antiproliferative agent is selected from temozolomide, carmustine, nimustine, lomustine, cediranib, fotemustine, erlotinib, galunisertib, bevacizumab, irinotecan, interferon-α2b, sorafenib, O6-benzylguanine, cisplatin, doxorubicin, mitoxantrone, procarbazine, and vincristine. In some embodiments, the method further comprises treating the subject with one or more additional therapies. In some embodiments, the one or more additional therapies are selected from surgery, radiation therapy, immunotherapy, and CAR-T cell therapy, or any combination thereof. In another aspect, disclosed herein is a method of inhibiting cell growth in a biological sample or subject, the method comprising: administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, disclosed herein is a kit comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and instructions for administering to a subject or contacting a biological sample with the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS FIGS.1A-1C show tumor volume growth curves of female C57BL / 6J mice bearing GL261-luc human glioblastoma tumors, treated with IMA-0002400 (FIG.2A), IMA-0002630 (FIG.2B), or IMA-0002684 (FIG.2C). Data points represented as Mean ± SEM FIG.2 shows pharmacodynamic biomarker analysis of GL261-luc human glioblastoma tumors from the IMA-0002400 efficacy study shown in FIG.1A. DETAILED DESCRIPTION Sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, has recently been identified as an actionable drug target in GBM (Bi et al. Cell Rep.37(5):109957 (2021)). SMPD1 catalyzes the conversion of sphingomyelin to ceramide (Hannun et al. Nat. Rev. Mol. Cell. Biol.19(3): 175-191 (2018)). Complete genetic loss of SMPD1, results in elevated sphingomyelin levels, lysosomal stress, and cell death in some contexts (Schuchman et al. Mol. Genet. Metab.120(1-2):27-33 (2017)). The highly brain- penetrant antidepressant fluoxetine was shown to inhibit SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with TMZ, a standard of care for GBM, causes significant increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. Disclosed herein are more potent, selective, and brain penetrant SMPD1 inhibitors that engineer out SERT activity and other fluoxetine liabilities. These compounds may provide a safe, non-toxic, and effective treatment to improve the survival and life quality for patients with glioblastoma, as well as other cancers. Definitions Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular. As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. As used herein, the term “and / or” includes any and all combinations of listed items, including any of the listed items individually. For example, “A, B, and / or C” encompasses A, B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and / or C.” For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition, University Science Books, Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl), 1 to 16 carbon atoms (C1-C16alkyl), 1 to 14 carbon atoms (C1-C14alkyl), 1 to 12 carbon atoms (C1- C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3alkyl), or 1 to 2 carbon atoms (C1-C2alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl. As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C6-C14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl,” i.e., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl,” e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl). As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl. As used herein, the term “cyano” refers to a -CN group. As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I. As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and 3,3,3-trifluoropropyl. As used herein, the term “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. As used herein, the term “heterocyclyl” refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4- membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1- methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5- membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5- bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (1,5)-8- azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl). As used herein, the term “hydroxy” or “hydroxyl” refers to an -OH group. When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof. As used herein, in chemical structures the indication: represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound). For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. When substituent groups are specified by their conventional chemical formulae, written from left to right, such indication also encompass substituent groups resulting from writing the structure from right to left. For example, if a bivalent group is shown as -CH2O-, such indication also encompasses -OCH2-; similarly, -OC(O)NH- also encompasses -NHC(O)O-. When linker moieties are shown, the linkers can be attached to other moieties of the compound in either direction. The terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition. As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably. A “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Compounds Disclosed herein are compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein: A is a 4-, 5-, 6-, or 7-membered heterocyclic ring; m is 0, 1, 2, 3, or 4; each R1is independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C3-C10)cycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (6-10)-membered aryl, (4-10)- membered heteroaryl, -ORa, -CORb, -COORc, and -SOnRd; wherein two R1optionally taken together with the atoms to which they are attached to form a 4-7-membered ring; n is 1 or 2; Ra, Rb, Rc, and Rdare each independently selected from H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C3-C10)cycloalkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; q is 1 or 2; Rxand Ryare each independently selected from hydrogen and (C1-C6)alkyl; R2and R3are each independently selected from H, (C1-C6)alkyl, (6-10)-membered aryl, (C3-C10)cycloalkyl, (4-10)-membered heteroaryl, and (4-10)-membered heterocyclyl; and R4is selected from (C1-C6)alkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; wherein each alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (6-10)-membered aryl, hydroxy, and (C1-C6)alkoxy. In some embodiments: A is a 4-, 5-, 6-, or 7-membered heterocyclic ring; m is 0, 1, 2, 3, or 4; each R1is independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3- C10)cycloalkyl, (6-10)-membered aryl, (4-10)-membered heteroaryl, -ORa, -CORb, -COORc, and - SOnRd; wherein two R1optionally taken together with the atoms to which they are attached to form a 4-7-membered ring; n is 1 or 2; Ra, Rb, Rc, and Rdare each independently selected from H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C3-C10)cycloalkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; R2and R3are each independently selected from H, (C1-C6)alkyl, (6-10)-membered aryl, (C3-C10)cycloalkyl, and (4-10)-membered heteroaryl; and R4is selected from (C1-C6)alkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; wherein each alkyl, aryl, cycloalkyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (6-10)-membered aryl, hydroxy, and (C1-C6)alkoxy. In some embodiments, A is selected from piperidine, pyrrolidine, azetidine, morpholine, azepane, piperazine, and 1,4-oxazepane. In some embodiments, A is piperidine. In some embodiments, A is 1,4-oxazepane. In some embodiments, m is 0. In some embodiments, m is 1 or 2, and each R1is independently selected from halo, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)hydroxyalkyl, (C1- C3)alkoxy(C1-C3)alkyl, -ORa, -CORb, -COORc, and -SOnRd, wherein Ra, Rb, Rc, and Rdare each independently selected from hydrogen, phenyl, and (C1-C4)alkyl, wherein the phenyl is unsubstituted or substituted with one substituent selected from halo, (C1-C3)alkyl, and (C1- C3)haloalkyl, and n is 2. In some embodiments, m is 1 or 2, and each R1is independently selected from halo, (C1-C3)alkyl, -ORa, -CORb, -COORc, and -SOnRd, wherein Ra, Rb, Rc, and Rdare each independently selected from hydrogen and (C1-C4)alkyl, and n is 2. In some embodiments, m is 1 or 2, and each R1is independently selected from fluoro, methyl, hydroxy, -C(O)CH3, -S(O)2CH3, and -C(O)OCH2CH(CH3)2.

[0002] ,

[0003] ,

[0004] , In some embodiments, . In some embodiments, . In some embodiments, R3is selected from (6-10)-membered aryl, (C3-C10)cycloalkyl, (4- 10)-membered heteroaryl, and (4-10)-membered heterocyclyl. In some embodiments, R3is selected from (6-10)-membered aryl, (C3-C10)cycloalkyl, and (4-10)-membered heteroaryl. In some embodiments, R3is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cyclobutyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, and tetrahydroisoquinolinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, methyl, phenyl, and methoxy. In some embodiments, R3is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, quinolinyl, and benzothiophenyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, methyl, phenyl, and methoxy. In some embodiments, R3is selected from , , In some embodiments, R3is selected from , In some embodiments, R4is (6-10)-membered aryl. In some embodiments, R4is selected from phenyl and naphthyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, (C1-C6)alkyl, (C1-C6)haloalkyl, and (6-10)- membered aryl. In some embodiments, R4is selected from phenyl and naphthyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from chloro, trifluoromethyl, and phenyl. In some embodiments, R4is selected from: . . In some embodiments, the compound is selected from compounds shown in Table 1, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from compounds shown in Table 2, and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from compounds shown in Table 3, and pharmaceutically acceptable salts thereof. Table 1. Compounds of the Disclosure

[0005] Table 2. Compounds of the disclosure

[0006] Table 3. Compounds of the disclosure

[0007] Certain compounds described herein have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers, in mixtures and as pure or partially purified compounds, are included within the scope of this disclosure. The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by methods disclosed herein or appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. Compounds may also possess tautomeric forms, and all tautomers also constitute embodiments of the disclosure. The present disclosure also includes an isotopically labeled compound, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) are11C,13N,15O, and18F. Isotopically- labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent. Compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. a. Methods of Synthesis Compounds disclosed herein can be prepared by a variety of methods, including those illustrated in the Examples. Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE, England. Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Standard experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006). When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution). Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation. The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated. b. Pharmaceutically Acceptable Salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compound with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. Amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like. Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine and N,N’-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Pharmaceutical Compositions The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease or condition, the prophylactically effective amount will be less than the therapeutically effective amount. The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi- solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Thus, the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage. The route by which the disclosed compounds are administered, and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions. Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90% by weight of the composition. Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% by weight of the composition. Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50% by weight of the composition. Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% by weight of the composition. Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1% by weight of the composition. Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s), when used, in a systemic or topical composition is typically about 0.001 to about 1% by weight of the composition. Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5% by weight of the composition. Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5% by weight of the composition. Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% by weight of the composition. Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100% by weight of the composition. Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition. Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed.1975, pp.335-337; and McCutcheon’s Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp.236-239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5% by weight of the composition. Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% by weight of actives and 90% to 99.9% by weight of a carrier including a diluent and a solvent. Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5% by weight, and more particularly from about 25% to about 50% by weight of actives. The oral dosage compositions include about 50% to about 95% by weight of carriers, and more particularly, from about 50% to about 75% by weight. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof. Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type. The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure. Solid compositions may be coated by conventional methods, typically with pH or time- dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac. Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non- effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners. Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants. The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components. The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976). A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols. The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95% by weight of the composition. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95% by weight of the composition. Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95% by weight of the composition. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95% by weight of the composition. The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition. Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95% by weight of the composition. The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1% by weight of the composition. Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. Methods of Use The present disclosure provides methods of using the compounds and compositions described herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds). The methods include methods of treating diseases such as cancer, and methods of inhibiting the proliferation of cancer cells. For example, the methods include methods of treating glioblastoma, head and neck cancers, breast cancers, lung cancers, esophageal and gastric cancers, pancreatic cancers, colorectal cancers, ovarian cancers, uterine cancers, prostate cancers, renal cancers, skin cancers, leukemias, lymphomas, sarcomas, gliomas, endometrial cancers, cervical cancers, pharyngeal cancers, and liver cancers. As discussed above, SPMD1 has recently been identified as an actionable drug target in GBM and may also be a drug target in other cancers having an altered lipid environment, particularly cancers with alterations in sphingolipid biosynthesis pathways. Accordingly, in some embodiments, the disclosure provides a method of treating cancer in a subject in need thereof (e.g., a subject suffering from cancer), comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof). In some embodiments, the cancer is a cancer associated with an altered lipid environment, such as a cancer with alternations in sphingolipid biosynthesis pathways. In some embodiments, the cancer is selected from glioblastoma, head and neck cancers, breast cancers, lung cancers, esophageal and gastric cancers, pancreatic cancers, colorectal cancers, ovarian cancers, uterine cancers, prostate cancers, renal cancers, skin cancers, leukemias, lymphomas, sarcomas, gliomas, endometrial cancers, cervical cancers, pharyngeal cancers, and liver cancers. In some embodiments, the cancer is glioblastoma. In another aspect, disclosed is a method of inhibiting cancer cell proliferation, comprising contacting cancer cells with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof), in an amount effective to inhibit the cancer cell proliferation. In some embodiments, the cancer cells are selected from glioblastoma cells, head and neck cancer cells, breast cancer cells, lung cancer cells, esophageal and gastric cancer cells, pancreatic cancer cells, colorectal cancer cells, ovarian cancer cells, uterine cancer cells, prostate cancer cells, renal cancer cells, skin cancer cells, leukemia cells, and lymphoma cancer cells. In some embodiments, the cancer cells are glioblastoma cells. In some embodiments, the step of contacting the cancer cells with the compound comprises administering the compound to a subject suffering from cancer. In another aspect, disclosed herein is a method of inhibiting cell growth in a biological sample or subject, the method comprising: administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method inhibits growth of cancer cells. In some embodiments, the cancer cells are selected from glioblastoma cells, head and neck cancer cells, breast cancer cells, lung cancer cells, esophageal and gastric cancer cells, pancreatic cancer cells, colorectal cancer cells, ovarian cancer cells, uterine cancer cells, prostate cancer cells, renal cancer cells, skin cancer cells, leukemia cells, and lymphoma cancer cells. In some embodiments, the cancer cells are glioblastoma cells. In another aspect, disclosed is a method of inhibiting SMPD1 in a sample, comprising contacting the sample with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof), in an amount effective to inhibit SMPD1. In some embodiments, the step of contacting the sample with the compound comprises administering the compound to a subject (e.g., a subject) suffering from cancer. Methods of determining the enzymatic activity of SMPD1 are known in the art (see, e.g., van Diggelen et al. J. Inherit. Metab. Dis.2005;28(5):733-41). It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments described herein. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. A compound or composition described herein may be used in combination with other known therapies. Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. A compound or composition described herein and the at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the compound described herein can be administered first, and the additional agent can be administered subsequently, or the order of administration can be reversed. In some embodiments, a compound or composition described herein is administered in combination with at least one of surgery, radiation therapy, hormone therapy, immunotherapy, or CAR-T cell therapy. In some embodiments a compound or composition described herein is administered in combination with two or more of surgery, radiation therapy, hormone therapy, immunotherapy, and CAR-T cell therapy. In some embodiments, a compound or composition described herein is used in combination with surgery. Surgery is a standard treatment for glioblastoma multiforme, though its effectiveness is limited by the difficulty of complete tumor resection, especially in high-risk areas of the brain, and the presence of residual tumor cells. In most cases, a surgeon will perform a craniotomy, in which a section of the skull is removed to access the tumor. A specialized type of craniotomy is an awake craniotomy, in which the patient is awake during part of the procedure and interacts with the surgeon as the location of key areas of the brain are mapped. Another specialized type of surgery is laser interstitial thermal therapy (LITT), in which a neurosurgeon uses an intraoperative MRI go guide a small laser catheter to the tumor site. The laser heats the tumor to kill cancerous cells. In some embodiments, a compound or composition described herein is used in combination with radiation therapy, which uses high doses of radiation to kill cancer cells. External beam radiation therapy uses focused, high-energy beams that are aimed directly at the cancer site to destroy cancer cells. Specific external radiation therapies that can be used, e.g., to treat GBM, include 3D conformal radiation therapy (which uses three-dimensional scans to determine the exact shape and size of the tumor, and a linear accelerator shapes the radiation beams to minimize exposure to healthy tissue), intensity modulated radiation therapy (which focuses multiple beams of radiation with different intensity levels directly on the tumor, to deliver a very high dose of radiation), and proton therapy (which uses proton beams instead of X-ray beams). Another form of radiation therapy is internal radiation therapy, in which a source of radiation is placed inside the body (e.g., brachytherapy, in which a solid radiation source is placed in or near the tumor). In some embodiments, the radiation therapy uses rhenium nanoliposomes (which include186Re as a radiation source). In some embodiments, a compound or composition described herein is used in combination with chemotherapy. For example, a compound or composition described herein can be used in combination with any of the following: actinomycins, alkylating agents, anthracyclines, antifolates, antiestrogen agents, anti-metabolites, anti-androgens, antimicrotubule agents, aromatase inhibitors, bleomycins, bromodomain inhibitors, Ca2+adenosine triphosphate (ATP)ase inhibitors, cytosine analogs, deltoids / retinoids, dihydrofolate reductase inhibitors, deoxyribonucleic acid (DNA) topoisomerase inhibitors, dopaminergic neurotoxins, glucocorticoids, histone deacetylase inhibitors, hormonal therapies, immunotherapeutic agents, inosine monophosphate (IMP) dehydrogenase inhibitors, isoprenylation inhibitors, luteinizing hormone-releasing hormone agonists, mammalian target of rapamycin (mtor) inhibitors, multi- drug resistance (MDR) inhibitors, mitomycins, photodyamic therapies, proteasome inhibitors, platinum containing compounds (e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, satraplatin, or triplatin tetranitrate), receptor tyrosine kinase inhibitors, ribonucleotide reductase inhibitors, thrombospondin mimetics, uracil analogs, vinca alkaloids, vitamin D3 analogs, DOT1L inhibitors, agents targeting epigenetic mechanisms, or an additional chemotherapeutic agent such as N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-NHCH2CH3or a salt thereof, actinomycin D, AG13736, 17-allylamino-17-demethoxygeldanamycin, 9-aminocamptothecin, N-(4-(3-amino- 1H-indazol-4-yl)phenyl}-N′-(2-fluoro-5-methylphenyl)urea or a salt thereof, N-(4-(4- aminothieno[2,3-d]pyrimidin-5-yl)phenyl}-N′-(2-fluoro-5-(trifluoromethyl)phenyl)urea or a salt thereof, temozolomide, procarbazine, altretamine, mitozolomide, anastozole, AP-23573, asparaginase, azacitidine, O6-benzylguanine, bevacizurnab, bicalutamide, bleomycin a2, bleomycin b2, bortezemib, busulfan, campathecins, carmustine (BCNU), CB1093, cediranib, cetuximab, CHOP (C: Cytoxan® (cyclophosphamide); H: Adriamycin® (hydroxydoxorubicin); O: Vincristine (Oncovin®); P: prednisone), chlorambucil, CHIR258, CNF-101, CNF-1001, CNF- 2024, CP547632, crisnatol, cytarabine, cyclophosphamide, cytosine arabinoside, daunorubicin, dacarbazine, dactinomycin, dasatinib, daunorubicin, deferoxamine, demethoxyhypocrellin A, depsipeptide, dexamethasone, 17-dimethylaminoethylamino-17-demethoxygeldanamycin, docetaxel, doxifluridine, doxorubicin, EB 1089, epothilone D, epirubicin, 5-ethynyl-1-13-D- ribofuranosylimidazole-4-carboxamide (EICAR), erlotinib, etoposide, everolimus, 5-fluorouracil (5-FU), floxuridine, fludarabine, flutamide, fotemustine, gefitinib, geldanamycin, gemcitabine, galunisertib, goserelin, N-(2-(4-hydroxyanilino}-3-pyridinyl}-4-methoxybenzenesulfonamide or a salt thereof, hydroxyurea, idarubicin, ifosfamide, imatinab, interferon-α, interferon-γ, IPI-504, irinotecan, KH 1060, lapatanib, leucovorin calcium, LAQ824, leuprolide acetate, letrozole, lomustine (CCNU), lovastatin, megestrol, melphalan, mercaptopurine, methotrexate, 1-methyl-4- phyenylpyridinium, MG132, mitomycin, mitoxantrone, MLN518, MLN4924, MS-275, mycophenolic acid, mitomycin C, nimustine, nitrosoureas, oprelvekin, paclitaxel, PD98059, peplomycin, photosensitizer Pc4, phthalocyanine, pirarubicin, plicamycin, prednisone, procarbazine, PTK787, PU24FC1, PU3, radicicol, raloxifene, rapamycin, raltitrexed, retinoids such as fenretinide, ribavirin, rituximab (Rituxin®), sorafenib, staurosporine, steroids such as dexamethasone and prednisone, suberoylanilide hydroxamic acid, tamoxifen, taxol, temozolomide, teniposide, thapsigargin, thioguanine, thrombospondin-1, tiazofurin, topotecan, trapoxin, trastuzumab, treosulfan, trichostatin A, trimetrexate, trofosfamide, tumor necrosis factor, valproic acid, VER49009, verapamil, vertoporfin, vinblastine, vincristine, vindesine, vinorelbine vitamin D3, VX-680, zactima, ZK-EPO, zorubicin, bevacizumab, enzastaurin, temsirolimus, cilengitide, lapatinib, sunitinib, axitinib, pazopanib, vemurafenib, dabrafenib, JQ1, or combinations thereof. In some embodiments, a compound or composition described herein is administered in combination with one or more of temozolomide, carmustine, nimustine, lomustine, cediranib, fotemustine, erlotinib, galunisertib, bevacizumab, irinotecan, interferon-α2b, sorafenib, O6- benzylguanine, cisplatin, doxorubicin, mitoxantrone, procarbazine, and vincristine. Kits For use in the therapeutic applications described herein, kits and articles of manufacture are also provided, which include a compound or pharmaceutical composition described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical comosition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof ). In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic. The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Patent Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, in some embodiments the container(s) includes a compound of formula (I, or a pharmaceutically acceptable salt thereof, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein. For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non- limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Examples Abbreviations used in the Examples include the following: ACN is acetonitrile; AcOH is acetic acid; CbzCl is benzyl chloroformate; DAST is diethylaminosulfur trifluoride; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DIPEA is N,N-diisopropylethyl amine; DMA is N,N-dimethylacetamide; DMP is Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1- dihydro-1,2-benziodoxol-3-(1H)-one); DMSO is dimethylsulfoxide; EtOAc is ethyl acetate; FA is formic acid; IBX is 2-iodoxybenzoic acid; LAH is lithium aluminum hydride; MeOH is methanol; NMR is nuclear magnetic resonance; PE is petroleum ether; TBAF is tetra-n- butylammonium fluoride; TEA is triethylamine; TEMPO is (2,2,6,6-tetramethylpiperidin-1- yl)oxyl; TIPSCl is triisopropylsilyl chloride; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin layer chromatography; Example 1 Compound Syntheses Synthesis of IMA-0002025 2: To a solution of tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate 1 (500 mg, 2.18 mmol, 1 eq) in DCM (10 mL) was added DMP (1.85 g, 4.36 mmol, 1.35 mL, 2 eq) at 0 °C under N2, then the reaction was stirred at 20 °C for 2 h. The reaction was quenched with saturated aq. sodium carbonate (100 mL), extracted with DCM (50 mL×3), the organic phases were combined, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc=1 / 0 to 4 / 1 to give tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate 2 (373 mg, 1.64 mmol, 75.26% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 9.74 (t, J = 2.4 Hz, 1H), 4.84 (br d, J = 1.2 Hz, 1H), 4.08 - 3.85 (m, 1H), 2.83 - 2.77 (m, 1H), 2.76 - 2.70 (m, 1H), 2.58 - 2.50 (m, 1H), 1.77 - 1.38 (m, 15H). 3: To a solution of tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate 2 (185 mg, 813.91 μmol, 1 eq) in THF (3 mL) was added bromo(phenyl)magnesium (3 M, 406.95 μL, 1.5 eq) at 25 °C under N2 and stirred for 3 h. The reaction mixture was poured into aqueous NH4Cl (10 mL) and extracted with EtOAc (10 mL*2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (PE / EtOAc = 2 / 1) to give tert-butyl 2-(2- hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate 3 (92 mg, 301.23 μmol, 37.01% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.43 - 7.30 (m, 5H), 4.82 - 4.73 (m, 1H), 4.41 (br d, J = 2.4 Hz, 1H), 3.92 (br s, 2H), 2.84 - 2.73 (m, 1H), 2.17 - 2.04 (m, 2H), 1.93 - 1.80 (m, 2H), 1.61 (br s, 6H), 1.47 (s, 9H). 4: To a solution of tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate 3 (30 mg, 98.23 μmol, 1 eq) in DCM (1 mL) was added HCl / dioxane (1 mL) at 0 °C, then the mixture was stirred at 25 °C for 1h. The reaction mixture was concentrated under reduced pressure to give a crude residue used directly in the next step.1-phenyl-2-(2-piperidyl)ethanol 4 (26 mg, crude) was obtained as a white solid. IMA-0002025: To a solution of 1-phenyl-2-(2-piperidyl)ethanol 4 (26 mg, 126.65 μmol, 1 eq) in DMA (3 mL) was added NaH (25.33 mg, 633.23 μmol 60% purity, 5 eq), then the mixture was stirred at 50 °C for 0.5 h under N2.1-fluoro-4-(trifluoromethyl)benzene 5 (31.17 mg, 189.97 μmol, 24.11 μL, 1.5 eq) was added at 25°C and stirred at 50 °C for 0.5 h. The reaction solution was cooled to room temperature, the reaction mixture was quenched by addition of aqueous NH4Cl (15 mL) and extracted with EtOAc (15 mL*2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (FA)-ACN]; gradient: 22%-52% B over 9 min), the purified solution was lyophilized to give IMA-0002025 (11.45 mg, 32.77 μmol, 25.88% yield, 100% purity) as a colorless oil. LCMS: Ret. Time: 0.488 min, M+H+, m / z: 350.2.1H NMR (400 MHz, CDCl3) δ = 8.55 - 8.48 (m, 1H), 7.45 - 7.40 (m, 2H), 7.36 - 7.28 (m, 5H), 6.93 - 6.87 (m, 2H), 5.40 - 5.33 (m, 1H), 3.21 - 3.09 (m, 2H), 2.73 - 2.66 (m, 1H), 2.53 - 2.47 (m, 1H), 2.09 - 1.97 (m, 2H), 1.88 - 1.82 (m, 2H), 1.67 - 1.62 (m, 2H), 1.44 - 1.23 (m, 2H). Synthesis of IMA-0002145 IMA-0002145 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate as the alcohol starting material. IMA-0002145 (13 mg, 38.76 μmol, 17.65% yield, 100% purity) was obtained as a colorless oil. LCMS: Ret. Time: 0.485 min, M+H+, m / z: 336.3.1H NMR (400 MHz, CDCl3) δ = 8.51 - 8.45 (m, 1H), 7.36 - 7.31 (m, 2H), 7.30 - 7.23 (m, 4H), 7.21 - 7.19 (m, 1H), 6.82 (br d, J = 8.4 Hz, 2H), 5.24 (br dd, J = 4.4, 7.6 Hz, 1H), 3.54 - 3.42 (m, 1H), 3.17 - 2.96 (m, 2H), 2.62 - 2.45 (m, 1H), 2.19 - 2.07 (m, 1H), 2.05 - 1.87 (m, 2H), 1.85 - 1.57 (m, 2H). 2: To a solution of the 2-[(2R)-1-tert-butoxycarbonylazetidin-2-yl]acetic acid 1 (200 mg, 929.17 μmol, 1 eq) in the THF (5 mL) was added BH3•THF (1 M, 1.12 mL, 1.2 eq) at 0 °C under N2atmosphere, then the mixture was heated to 70 °C and stirred for 12 h under N2atmosphere. MeOH (10 mL) was added to the mixture slowly. The mixture was extracted with EtOAc (20 x 3 mL) to induce phase separation. The organic layer was isolated, washed with saturated aq. sodium chloride (10 mL) twice, dried over Na2SO4, and condensed under reduced pressure to remove the organic solvent. tert-Butyl (2R)-2-(2-hydroxyethyl)azetidine-1-carboxylate 2 (150 mg, crude) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 4.42 - 4.32 (m, 1H), 3.93 - 3.80 (m, 2H), 3.79 - 3.62 (m, 2H), 2.39 (m, J = 6.0, 8.8, 11.2 Hz, 1H), 1.99 - 1.79 (m, 3H), 1.45 (s, 9H). IMA-0002333 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (2R)-2-(2-hydroxyethyl)azetidine-1-carboxylate 2 as the alcohol starting material. IMA-0002333 (13.12 mg, 34.44 μmol, 20.06% yield, 96.438% purity, FA) was obtained as a yellow oil. LCMS: Ret. Time: 0.471 min, M+H+, m / z: 322.1.1H NMR (400 MHz, CDCl3) δ = 8.54 - 8.51 (m, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.35 - 7.31 (m, 4H), 7.31 - 7.28 (m, 1H), 6.86 (m, J = 8.8 Hz, 2H), 5.39 - 5.30 (m, 1H), 4.68 - 4.58 (m, 1H), 3.87 - 3.78 (m, 1H), 3.73 - 3.65 (m, 1H), 2.61 - 2.43 (m, 2H), 2.43 - 2.29 (m, 2H). IMA-0002334 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (2R)-2-[(2S)-2-hydroxy-2-phenyl-ethyl]azetidine-1-carboxylate as the alcohol starting material. IMA-0002334 (22.04 mg, 56.51 μmol, 29.92% yield, 94.184% purity, FA) was obtained as a yellow oil. LCMS: Ret. Time: 0.474 min, M+H+, m / z: 322.1.1H NMR (400 MHz, CDCl3) δ = 8.58 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.38 - 7.28 (m, 5H), 6.88 (d, J = 8.4 Hz, 2H), 5.29 - 5.21 (m, 1H), 4.58 - 4.46 (m, 1H), 3.94 - 3.82 (m, 1H), 3.80 - 3.69 (m, 1H), 2.76 - 2.63 (m, 1H), 2.48 - 2.30 (m, 3H). Synthesis of IMA-0002335 2: To a solution of 2-[(2S)-1-tert-butoxycarbonylazetidin-2-yl]acetic acid 1 (300 mg, 1.39 mmol, 1 eq) in the THF (7 mL) was added BH3•THF (1 M, 1.67 mL, 1.2 eq) at 0 °C under N2 atmosphere, then the mixture was heated to 70 °C and stirred for 12 h under N2atmosphere. MeOH (10 mL) was added to the mixture slowly. The mixture was extracted with EtOAc (20 x 3 mL) to induce phase separation. The organic layer was isolated, washed with saturated aq. sodium chloride solution (10 mL) twice, dried over Na2SO4, and concentrated under a reduced pressure to obtain tert-butyl (2S)-2-(2-hydroxyethyl)azetidine-1-carboxylate 2 (249 mg, crude) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 4.42 - 4.32 (m, 1H), 3.92 - 3.79 (m, 2H), 3.78 - 3.62 (m, 2H), 2.38 (m, J = 6.0, 8.8, 11.2 Hz, 1H), 1.95 - 1.81 (m, 3H), 1.51 - 1.37 (m, 9H). IMA-0002335 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (2S)-2-(2-hydroxyethyl)azetidine-1-carboxylate 2 as the alcohol starting material. IMA-0002335 (9.67 mg, 25.51 μmol, 18.57% yield, 96.900% purity, FA) was obtained as a yellow oil. LCMS: Ret. Time: 0.473 min, M+H+, m / z: 322.1.1H NMR (400 MHz, CDCl3) δ = 8.52 (s, 1H), 7.43 - 7.37 (m, 2H), 7.36 - 7.27 (m, 4H), 6.90 - 6.82 (m, 2H), 5.39 - 5.31 (m, 1H), 4.71 - 4.58 (m, 1H), 3.90 - 3.78 (m, 1H), 3.76 - 3.65 (m, 1H), 2.52 - 2.45 (m, 1H), 2.45 - 2.27 (m, 3H). 5C: To a mixture of tert-butyl (2S)-2-[(2S)-2-hydroxy-2-phenyl-ethyl]azetidine-1- carboxylate 4C (50 mg, 180.27 μmol, 1 eq) in DCM (2 mL) was added TFA (0.4 mL), then the mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give (1S)-2-[(2S)-azetidin- 2-yl]-1-phenyl-ethanol 5C (40 mg, crude, TFA) as a yellow oil. LCMS: Ret. Time: 0.287 min, M+H+, m / z: 178.1. IMA-0002336: To a solution of (1S)-2-[(2S)-azetidin-2-yl]-1-phenyl-ethanol 5C (40 mg, 137.33 μmol, 1 eq, TFA) in DMA (2 mL) was added NaH (27.46 mg, 686.66 μmol, 60% purity, 5 eq) at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 50 °C for 0.5 h. Then cooled to 25 °C, 1-fluoro-4-(trifluoromethyl)benzene (33.80 mg, 206.00 μmol, 26.14 μL, 1.5 eq) was added and the solution was stirred at 50 °C for 1 h. The mixture was quenched by slow addition of saturated aqueous NH4Cl (5 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18150x25mmx5um; mobile phase: [water (FA)-ACN]; gradient: 13%-43% B over 10 min), the purified solution was lyophilized to give IMA-0002336 (12.01 mg, 31.10 μmol, 22.65% yield, 95.130% purity, FA) as a yellow oil. LCMS: Ret. Time: 0.470 min, M+H+, m / z: 322.1.1H NMR (400 MHz, CDCl3) δ = 8.59 (s, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.37 - 7.28 (m, 5H), 6.88 (d, J = 8.8 Hz, 2H), 5.25 (dd, J = 5.2, 8.0 Hz, 1H), 4.51 (m, J = 7.6 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.80 - 3.69 (m, 1H), 2.76 - 2.65 (m, 1H), 2.47 - 2.31 (m, 3H). Synthesis of IMA-0002367 2: To a mixture of tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate 1 (100.00 mg, 327.43 μmol, 1 eq), 4-phenylphenol (55.73 mg, 327.43 μmol, 1 eq) and PPh3 (94.47 mg, 360.17 μmol, 1.1 eq) in THF (2 mL). The vial was then placed under an atmosphere of nitrogen, cooled to 0 °C, DIAD (72.83 mg, 360.17 μmol, 69.83 μL, 1.1 eq) was added to the mixture, then the mixture was stirred at 25 °C for 12 hr. The mixture was poured into saturated aq. NaHCO3(10 mL) and extracted by DCM (3 x 20 mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc = 5: 1), the purified solution was concentrated to give tert-butyl 2-[2-phenyl-2-(4-phenylphenoxy)ethyl]piperidine-1-carboxylate 2 (60 mg, 131.12 μmol, 40.04% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.50 - 7.45 (m, 2H), 7.42 - 7.30 (m, 8H), 7.29 (br s, 1H), 7.26 - 7.23 (m, 1H), 6.92 - 6.85 (m, 2H), 5.12 - 5.05 (m, 1H), 4.76 - 4.59 (m, 1H), 2.90 - 2.77 (m, 1H), 2.29 - 2.16 (m, 1H), 2.05 - 1.95 (m, 1H), 1.77 - 1.57 (m, 6H), 1.38 - 1.31 (m, 1H), 1.28 - 1.13 (m, 9H). IMA-0002367: A mixture of tert-butyl 2-[2-phenyl-2-(4-phenylphenoxy)ethyl] piperidine-1-carboxylate 2 (60.00 mg, 131.12 μmol, 1 eq) in HCl / dioxane (2 M, 2 mL, 30.51 eq), then the mixture was stirred at 25 °C for 0.5 h. The pH was adjusted to 7 with TEA and the mixture concentrated to give a residue. The residue was purified by prep-HPLC (column: C18 150 × 30mm; mobile phase: [water (FA)-ACN]; gradient: 28%-58% B over 7 min), the purified solution was lyophilized to give IMA-0002367 (27.07 mg, 67.09 μmol, 51.16% yield, 100% purity, FA) as a white solid. LCMS: Ret. Time: 0.512 min, M+H+, m / z: 358.2.1H NMR (400 MHz, CDCl3) δ = 8.57 - 8.53 (m, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.45 - 7.34 (m, 6H), 7.32 - 7.28 (m, 2H), 7.20 (br d, J = 1.2 Hz, 2H), 7.00 - 6.92 (m, 2H), 5.73 - 5.65 (m, 1H), 3.37 - 3.27 (m, 1H), 3.27 - 3.16 (m, 1H), 2.85 - 2.74 (m, 1H), 2.42 - 2.31 (m, 1H), 2.30 - 2.21 (m, 1H), 2.05 - 1.96 (m, 1H), 1.94 - 1.82 (m, 2H), 1.80 - 1.72 (m, 2H), 1.56 - 1.44 (m, 1H). Synthesis of IMA-0002368 2: To a mixture of tert-butyl (2S)-2-(2-hydroxyethyl)piperidine-1-carboxylate 1 (1 g, 4.36 mmol, 1 eq) in DCM (20 mL) was added Dess-Martin (3.70 g, 8.72 mmol, 2.70 mL, 2 eq) at 0 °C under N2atmosphere, then the mixture was stirred at 25 °C for 2 h under N2atmosphere. The reaction was quenched with saturated aq. sodium carbonate (20 mL), extracted with DCM (20 mL × 3), the organic phases were combined, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 5 / 1) to give tert-butyl (2S)-2-(2-oxoethyl)piperidine-1-carboxylate 2 (800 mg, 3.52 mmol, 80.71% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 9.76 - 9.72 (m, 1H), 4.91 - 4.77 (m, 1H), 4.07 - 3.91 (m, 1H), 2.83 - 2.70 (m, 2H), 2.59 - 2.47 (m, 1H), 1.79 - 1.69 (m, 1H), 1.64 (m, 4H), 1.53 - 1.48 (m, 1H), 1.45 (s, 9H). 3: To a solution of the tert-butyl (2S)-2-(2-oxoethyl)piperidine-1-carboxylate 2 (800 mg, 3.52 mmol, 1 eq) in THF (15 mL) was added bromo(phenyl)magnesium (3 M, 1.76 mL, 1.5 eq) at 0°C under N2atmosphere, then the mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into saturated aq. NH4Cl (20 mL) and extracted with dichloromethane (20 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 3 / 1) to give tert-butyl (2S)-2-[(2S)-2-hydroxy-2-phenyl-ethyl]piperidine-1-carboxylate 3 (354 mg, 1.16 mmol, 32.93% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.31 (m, 4H), 7.27 (s, 1H), 4.81 - 4.71 (m, 1H), 4.48 - 4.31 (m, 1H), 4.01 - 3.81 (m, 1H), 2.84 - 2.72 (m, 1H), 2.16 - 2.05 (m, 1H), 1.93 - 1.83 (m, 1H), 1.71 - 1.55 (m, 6H), 1.47 (s, 9H). 4: To a mixture of tert-butyl (2S)-2-[(2S)-2-hydroxy-2-phenyl-ethyl]piperidine-1- carboxylate 3 (350.00 mg, 1.15 mmol, 1 eq) in DCM (15 mL) was added MnO2(1.99 g, 22.92 mmol, 20 eq), then the mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered, the filter cake was washed with DCM (20 mL x 3), the filtrate was concentrated to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 10 / 1) to give tert-butyl (2S)-2-phenacylpiperidine-1-carboxylate 4 (275 mg, 906.41 μmol, 79.09% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ = 8.03 - 7.96 (m, 2H), 7.61 - 7.54 (m, 1H), 7.52 - 7.44 (m, 2H), 4.90 - 4.77 (m, 1H), 4.15 - 3.95 (m, 1H), 3.28 - 3.19 (m, 1H), 3.19 - 3.11 (m, 1H), 2.95 - 2.84 (m, 1H), 1.72 - 1.60 (m, 5H), 1.52 - 1.42 (m, 1H), 1.38 (s, 9H). 5: To a mixture of tert-butyl (2S)-2-phenacylpiperidine-1-carboxylate 4 (100 mg, 329.60 μmol, 1 eq) in THF (5 mL) was added lithium tri-tert-butoxyaluminum hydride (166.95 mg, 659.21 μmol, 184.68 μL, 2 eq) at 0 °C under N2 atmosphere, then the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by addition of water (10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:EtOAc = 3:1), the purified solution was concentrated to give tert-butyl (2S)-2-[(2S)-2-hydroxy-2-phenyl-ethyl]piperidine-1-carboxylate 5 (85 mg, 278.31 μmol, 84.44% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.42 - 7.31 (m, 4H), 7.29 - 7.27 (m, 1H), 4.83 - 4.70 (m, 1H), 4.51 - 4.32 (m, 1H), 4.03 - 3.80 (m, 1H), 2.85 - 2.72 (m, 1H), 2.17 - 2.06 (m, 1H), 1.88 (td, J = 5.1, 14.5 Hz, 1H), 1.66 - 1.58 (m, 6H), 1.47 (s, 9H). 6: A mixture of tert-butyl (2S)-2-[(2S)-2-hydroxy-2-phenyl-ethyl]piperidine-1- carboxylate 5 (85 mg, 278.31 μmol, 1 eq) in HCl / dioxane (2 M, 2 mL, 14.37 eq) , then the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to give (1S)-1- phenyl-2-[(2S)-2-piperidyl]ethanol 6 (80 mg, crude, HCl) as a white solid. LCMS: Ret. Time: 0.331 min, M+H+, m / z: 206.1. IMA-0002368: To a solution of (1S)-1-phenyl-2-[(2S)-2-piperidyl]ethanol 6 (80 mg, 330.91 μmol, 1 eq, HCl) in DMA (3 mL) was added NaH (66.18 mg, 1.65 mmol, 60% purity, 5 eq) at 0 °C under N2 atmosphere, then the reaction mixture was stirred at 50°C for 0.5 h. Then cooled to 25°C, 1-fluoro-4-(trifluoromethyl)benzene (81.45 mg, 496.37 μmol, 63.00 μL, 1.5 eq) was added and the solution was stirred at 50 °C for 1 h. The mixture was quenched by slow addition of saturated aqueous NH4Cl (10 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: C18150 × 30mm; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B over 7 min), the purified solution was lyophilized to give IMA-0002368 (63.86 mg, 160.50 μmol, 48.50% yield, 99.383% purity, FA) as a colorless oil. LCMS: Ret. Time: 0.477 min, M+H+, m / z: 350.1.1H NMR (400 MHz, CDCl3) δ = 8.64 - 8.60 (m, 1H), 7.46 - 7.40 (m, 2H), 7.39 - 7.29 (m, 4H), 7.27 - 7.23 (m, 1H), 6.95 - 6.84 (m, 2H), 5.46 - 5.34 (m, 1H), 3.22 - 3.11 (m, 1H), 3.10 - 2.99 (m, 1H), 2.71 - 2.60 (m, 1H), 2.58 - 2.46 (m, 1H), 2.12 - 2.00 (m, 1H), 1.90 - 1.78 (m, 2H), 1.77 - 1.53 (m, 3H), 1.44 - 1.23 (m, 1H). Synthesis of IMA-0002369 IMA-0002369 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate and 4-chlorophenol as the alcohol starting materials. IMA-0002369 (16.26 mg, 43.84 μmol, 45.59% yield, 97.565% purity, FA) was obtained as a colorless oil. LCMS: Ret. Time: 0.473 min, M+H+, m / z: 316.1.1H NMR (400 MHz, CDCl3) δ = 8.54 - 8.50 (m, 1H), 7.34 - 7.28 (m, 4H), 7.26 - 7.22 (m, 1H), 7.15 - 7.07 (m, 2H), 6.82 - 6.74 (m, 2H), 5.53 - 5.41 (m, 1H), 3.33 - 3.21 (m, 1H), 3.16 - 3.09 (m, 1H), 2.74 (br dd, J = 7.6, 11.6 Hz, 1H), 2.22 - 2.14 (m, 2H), 1.96 - 1.84 (m, 2H), 1.75 - 1.57 (m, 3H), 1.53 - 1.42 (m, 1H). Synthesis of IMA-0002370 2: To a solution of tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate 1 (200 mg, 879.90 μmol, 1 eq) in THF (4 mL) was added bromo(cyclohexyl)magnesium (1 M, 1.32 mL, 1.5 eq) at 0 °C under N2, then the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated aq. NH4Cl (10 mL) and extracted by dichloromethane (10 mL x 3), the combined organic phase was dried and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EtOAc=10:1), the purified solution was concentrated to give tert-butyl 2-(2-cyclohexyl-2-hydroxy-ethyl)piperidine-1-carboxylate 2 (64 mg, 205.49 μmol, 23.35% yield) as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 4.56 - 4.38 (m, 1H), 4.02 - 3.82 (m, 1H), 3.12 - 2.91 (m, 1H), 2.73 - 2.54 (m, 1H), 2.08 - 1.97 (m, 1H), 1.79 - 1.68 (m, 4H), 1.65 - 1.52 (m, 7H), 1.47 (s, 9H), 1.32 - 1.15 (m, 5H), 1.14 - 0.96 (m, 3H). 3: To a solution of tert-butyl 2-(2-cyclohexyl-2-hydroxy-ethyl)piperidine-1-carboxylate 2 (64.00 mg, 205.49 μmol, 1 eq) in HCl / dioxane (2 M, 2 mL, 15.25 eq) was stirred at 25 °C for 45 min. The reaction mixture was concentrated to give the crude product used directly in the next step.1-cyclohexyl-2-(2-piperidyl)ethanol 3 (42 mg, 169.49 μmol, 82.48% yield, HCl) was obtained as a white solid. LCMS: Ret. Time: 0.383 min, M+H+, m / z: 212.1. IMA-0002370: To a solution of 1-cyclohexyl-2-(2-piperidyl)ethanol 3 (42.00 mg, 169.49 μmol, 1 eq, HCl) in DMA (2 mL) was added NaH (33.89 mg, 847.45 μmol, 60% purity, 5 eq) at 0 °C and stirred at 50 °C for 0.5 h under N2.1-fluoro-4-(trifluoromethyl) benzene (41.72 mg, 254.23 μmol, 32.27 μL, 1.5 eq) was added at 25 °C and stirred at 50 °C for 1 h. The reaction solution was cooled to room temperature, the reaction mixture was quenched by addition of aq. NH4Cl (15 mL) and extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified with prep-HPLC (column: C18150×30mm; mobile phase: [water(FA)-ACN];gradient:30%-60% B over 7 min) and lyophilized to give IMA-0002370 (1.39 mg, 3.91 μmol, 2.31% yield, 100% purity) as a colorless gum. LCMS: Ret. Time: 0.539 min, M+H+, m / z: 356.2.1H NMR (400 MHz, CDCl3) δ = 8.62 - 8.59 (m, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.65 - 4.57 (m, 1H), 3.25 - 3.17 (m, 1H), 2.87 - 2.77 (m, 1H), 2.67 - 2.59 (m, 1H), 2.26 - 2.20 (m, 1H), 1.91 (br dd, J = 1.6, 7.2 Hz, 2H), 1.87 - 1.83 (m, 2H), 1.74 (br d, J = 13.2 Hz, 3H), 1.69 - 1.64 (m, 3H), 1.50 - 1.39 (m, 2H), 1.33 - 1.26 (m, 2H), 1.20 - 1.06 (m, 4H). Synthesis of IMA-0002371 IMA-0002371 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and bromo-(4-fluorophenyl) magnesium as the starting materials. IMA-0002371 (19.01 mg, 51.74 μmol, 16.80% yield, 100% purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.483 min, M+H+, m / z: 368.1.1H NMR (400 MHz, CDCl3) δ = 8.55 - 8.47 (m, 1H), 7.37 - 7.27 (m, 4H), 6.95 - 6.87 (m, 2H), 6.84 - 6.77 (m, 2H), 5.51 - 5.43 (m, 1H), 3.16 - 3.06 (m, 1H), 2.97 - 2.88 (m, 1H), 2.63 - 2.49 (m, 2H), 2.08 - 1.97 (m, 1H), 1.79 - 1.45 (m, 5H), 1.33 - 1.16 (m, 1H). Synthesis of IMA-0002381 IMA-0002381 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and bromo(cyclopentyl)magnesium as the starting materials. IMA-0002381 (4.01 mg, 11.75 μmol, 4.73% yield, 100% purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.525 min, M+H+, m / z: 342.2.1H NMR (400 MHz, CDCl3) δ = 8.63 - 8.55 (m, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.14 - 7.09 (m, 2H), 4.81 (br t, J = 6.0 Hz, 1H), 3.36 - 3.27 (m, 1H), 2.98 (br s, 1H), 2.75 - 2.65 (m, 1H), 2.18 (br dd, J = 7.6, 14.6 Hz, 2H), 1.96 - 1.83 (m, 3H), 1.79 - 1.66 (m, 4H), 1.65 (br s, 3H), 1.54 - 1.45 (m, 2H), 1.45 - 1.27 (m, 3H). Synthesis of IMA-0002382 IMA-0002382 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate and naphthalen-1-ol as the alcohol starting materials. IMA-0002382 (5.11 mg, 15.42 μmol, 33.27% yield, 100% purity, FA) was obtained as a yellow solid. LCMS: Ret. Time: 0.518 min, M+H+, m / z: 364.3.1H NMR (400 MHz, CDCl3) δ = 8.60 (s, 1H), 8.43 - 8.38 (m, 1H), 7.81 - 7.77 (m, 1H), 7.55 - 7.48 (m, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.25 - 7.17 (m, 2H), 6.65 (d, J = 7.6 Hz, 1H), 5.63 (dd, J = 3.2, 9.6 Hz, 1H), 3.16 - 3.05 (m, 2H), 2.66 - 2.60 (m, 1H), 2.34 (br d, J = 4.4 Hz, 1H), 2.16 - 2.12 (m, 1H), 1.94 - 1.82 (m, 2H), 1.67 - 1.41 (m, 4H). Synthesis of IMA-0002383 2: The reactant of 1-iodo-4-methyl-benzene (383.70 mg, 1.76 mmol, 2 eq) followed by the addition of THF (2 mL). Next, i-PrMgCl (2 M, 879.90 μL, 2 eq) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 1 hr. After cooling to 0 °C, a solution of tert-butyl 2-(2- oxoethyl)piperidine-1-carboxylate 1 (200 mg, 879.90 μmol, 1 eq) in THF (1 mL) was added. The mixture was stirred under N2 balloon at 25 °C for 1 hr. The reaction mixture was poured into saturated aq. NH4Cl (15 mL) and extracted with DCM (10 mL x 3), the combined organic phase was dried and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EtOAc=5:1), the purified solution was concentrated to give tert-butyl 2-[2- hydroxy-2-(p-tolyl)ethyl]piperidine-1-carboxylate 2 (78 mg, 244.18 μmol, 27.75% yield) as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.31 (br s, 1H), 7.29 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 4.79 - 4.69 (m, 1H), 4.49 - 4.36 (m, 1H), 4.06 - 3.82 (m, 1H), 2.87 - 2.78 (m, 1H), 2.39 - 2.35 (m, 3H), 2.14 - 2.08 (m, 1H), 1.88 (td, J = 5.2, 14.0 Hz, 1H), 1.67 - 1.63 (m, 4H), 1.56 - 1.38 (m, 11H). 3: To a solution of tert-butyl 2-[2-hydroxy-2-(p-tolyl)ethyl]piperidine-1-carboxylate 2 (78.00 mg, 244.18 μmol, 1 eq) in HCl / dioxane (2 M, 2 mL, 16.38 eq) was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated to give the crude product used directly in the next step. 2-(2-piperidyl)-1-(p-tolyl)ethanol 3 (78 mg, crude, HCl) was obtained as a white solid. LCMS: Ret. Time: 0.368 min, M+H+, m / z: 220.0. IMA-0002383: To a solution of 2-(2-piperidyl)-1-(p-tolyl)ethanol 3 (78.00 mg, 304.95 μmol, 1 eq, HCl) in DMA (2 mL) was added NaH (60.98 mg, 1.52 mmol, 60% purity, 5 eq) at 0 °C and stirred at 50 °C for 0.5 h under N2.1-fluoro-4-(trifluoromethyl)benzene (75.06 mg, 457.42 μmol, 58.05 μL, 1.5 eq) was added at 25 °C and stirred at 50 °C for 1.5 h. The reaction solution was cooled to room temperature, the reaction mixture was quenched by addition of aq. NH4Cl (15 mL) and extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified with prep-HPLC (column: C18150×30mm;mobile phase: [water(FA)-ACN];gradient:28%-58% B over 1 min) and lyophilized to give IMA-0002383 (7.4 mg, 20.16 μmol, 6.61% yield, 99% purity) as a colorless gum. LCMS: Ret. Time: 0.508 min, M+H+, m / z: 364.1.1H NMR (400 MHz, CDCl3) δ = 8.64 - 8.59 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.27 - 7.23 (m, 2H), 7.12 (d, J = 7.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.42 (br dd, J = 5.2, 8.2 Hz, 1H), 3.17 (br d, J = 12.0 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.71 - 2.60 (m, 1H), 2.57 - 2.47 (m, 1H), 2.30 (s, 3H), 2.09 - 2.00 (m, 1H), 1.82 (br d, J = 11.6 Hz, 2H), 1.74 - 1.54 (m, 3H), 1.42 - 1.30 (m, 1H). IMA-0002384 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-3-methyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002384 (45.31 mg, 124.68 μmol, 37.08% yield, 100% purity, FA) was obtained as a yellow solid. LCMS: Ret. Time: 0.518 min, M+H+, m / z: 364.3.1H NMR (400 MHz, CDCl3) δ = 8.62 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.23 - 7.14 (m, 3H), 7.06 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 5.34 (dd, J = 4.4, 9.2 Hz, 1H), 3.17 (br d, J = 12.4 Hz, 1H), 3.09 - 3.02 (m, 1H), 2.67 (dt, J = 3.6, 12.4 Hz, 1H), 2.51 (ddd, J = 5.6, 9.2, 14.4 Hz, 1H), 2.32 (s, 3H), 2.05 (ddd, J = 4.8, 7.6, 14.4 Hz, 1H), 1.89 - 1.79 (m, 2H), 1.72 - 1.56 (m, 3H), 1.42 - 1.29 (m, 1H). Synthesis of IMA-0002385 IMA-0002385 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate and 3-phenylphenol as the alcohol starting materials. IMA-0002385 (34.16 mg, 94.60 μmol, 66.60% yield, 99% purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.517 min, M+H+, m / z: 358.1.1H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1H), 7.53 - 7.49 (m, 2H), 7.45 - 7.37 (m, 4H), 7.35 - 7.28 (m, 2H), 7.27 - 7.24 (m, 1H), 7.24 - 7.18 (m, 2H), 7.16 - 7.09 (m, 2H), 6.88 - 6.84 (m, 1H), 5.75 - 5.66 (m, 1H), 3.32 - 3.23 (m, 1H), 3.18 (br dd, J = 3.2, 7.2 Hz, 1H), 2.75 (dt, J = 3.2, 12.0 Hz, 1H), 2.37 - 2.20 (m, 2H), 2.02 - 1.93 (m, 1H), 1.92 - 1.84 (m, 1H), 1.83 - 1.64 (m, 3H), 1.42 (br s, 1H). IMA-0002386 was synthesized following the same general scheme for IMA-0002383 but utilizing 2-iodonaphthalene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002386 (20.39 mg, 45.77 μmol, 16.70% yield, 100% purity, FA) was obtained as a yellow oil. LCMS: Ret. Time: 0.517 min, M+H+, m / z: 400.2.1H NMR (400 MHz, CDCl3) δ = 8.66 - 8.60 (m, 1H), 7.91 - 7.86 (m, 1H), 7.85 - 7.75 (m, 3H), 7.53 - 7.43 (m, 3H), 7.40 (d, J = 8.8 Hz, 2H), 7.01 - 6.90 (m, 2H), 5.69 - 5.61 (m, 1H), 3.20 - 3.10 (m, 1H), 3.06 - 2.95 (m, 1H), 2.70 - 2.58 (m, 2H), 2.23 - 2.11 (m, 1H), 1.88 - 1.75 (m, 2H), 1.73 - 1.56 (m, 2H), 1.56 - 1.47 (m, 1H), 1.37 - 1.22 (m, 1H). Synthesis of IMA-0002387 IMA-0002387 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-2-phenyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002387 (12.01 mg, 25.23 μmol, 10.02% yield, 99.050% purity, FA) was obtained as a yellow gum. LCMS: Ret. Time: 0.531 min, M+H+, m / z: 426.2.1H NMR (400 MHz, CDCl3) δ = 8.72 - 8.65 (m, 1H), 7.56 - 7.48 (m, 3H), 7.48 - 7.42 (m, 1H), 7.40 - 7.34 (m, 4H), 7.33 - 7.28 (m, 2H), 7.26 - 7.20 (m, 1H), 6.74 - 6.63 (m, 2H), 5.27 - 5.14 (m, 1H), 3.17 - 3.07 (m, 1H), 3.06 - 2.97 (m, 1H), 2.64 (dt, J = 4.0, 11.6 Hz, 1H), 2.56 - 2.42 (m, 1H), 2.17 - 2.07 (m, 1H), 1.76 - 1.49 (m, 4H), 1.34 - 1.18 (m, 2H). Synthesis of IMA-0002388 IMA-0002388 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-4-phenyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002388 (34.28 mg, 80.57 μmol, 54.49% yield, 100% purity) was obtained as a white solid. LCMS: Ret. Time: 0.543 min, M+H+, m / z: 426.2.1H NMR (400 MHz, CDCl3) δ = 8.64 (s, 1H), 7.57 - 7.51 (m, 4H), 7.50 - 7.46 (m, 2H), 7.45 - 7.40 (m, 4H), 7.37 - 7.32 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 5.62 - 5.57 (m, 1H), 3.27 - 3.20 (m, 1H), 3.12 - 3.04 (m, 1H), 2.79 - 2.63 (m, 2H), 2.26 - 2.17 (m, 1H), 1.93 - 1.71 (m, 4H), 1.63 - 1.55 (m, 1H), 1.41 - 1.29 (m, 1H). Synthesis of IMA-0002399 IMA-0002399 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (2R)-2-(2-hydroxyethyl) piperidine-1-carboxylate as the alcohol starting material. IMA-0002399 (50.31 mg, 0.14 mmol, 28.97% yield, 98% purity) was obtained as a colorless oil. LCMS: Ret. Time: 0.497 min, M+H+, m / z: 350.1.1H NMR (400 MHz, CDCl3) δ = 1.25 - 1.43 (m, 1 H) 1.57 - 1.77 (m, 3 H) 1.84 (m, J=10.8 Hz, 2 H) 2.04 - 2.14 (m, 1 H) 2.52 - 2.60 (m, 1 H) 2.64 (td, J=12.8, 3.6 Hz, 1 H) 3.02 - 3.11 (m, 1 H) 3.17 (d, J=12.8 Hz, 1 H) 5.42 (dd, J=8.8, 4.8 Hz, 1 H) 6.89 (d, J=8.4 Hz, 2 H) 7.22 - 7.26 (m, 1 H) 7.28 - 7.44 (m, 6 H) 8.60 (s, 1 H). IMA-0002400 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (2R)-2-[(2S)-2-hydroxy-2-phenyl-ethyl] piperidine-1-carboxylate as the starting material. IMA-0002400 (48.86 mg, 0.13 mmol, 27.56% yield, 96% purity) was obtained as a yellow gum. LCMS: Ret. Time: 0.467 min, M+H+, m / z: 350.1.1H NMR (400 MHz, CDCl3) δ = 1.42 - 1.56 (m, 1 H) 1.69 - 1.82 (m, 3 H) 1.86 - 2.03 (m, 2 H) 2.17 - 2.26 (m, 1 H) 2.27 - 2.37 (m, 1 H) 2.77 (td, J=12.0, 4.4 Hz, 1 H) 3.15 - 3.24 (m, 1 H) 3.29 (br d, J=12.4 Hz, 1 H) 5.69 (dd, J=10.4, 2.8 Hz, 1 H) 6.92 (d, J=8.8 Hz, 2 H) 7.19 - 7.26 (m, 3 H) 7.31 - 7.36 (m, 2 H) 7.41 (d, J=8.8 Hz, 2 H) 8.48 (s, 1 H). Synthesis of IMA-0002401 IMA-0002401 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl (2S)-2-(2-oxoethyl)piperidine-1-carboxylate and bromo(phenyl)magnesium as the starting materials. IMA-0002401 (36.11 mg, 103.35 μmol, 31.23% yield, 100% purity) was obtained as a yellow oil. LCMS: Ret. Time: 0.472 min, M+H+, m / z: 350.1.1H NMR (400 MHz, CDCl3) δ = 8.56 - 8.50 (m, 1H), 7.46 - 7.39 (m, 2H), 7.39 - 7.32 (m, 2H), 7.30 - 7.27 (m, 1H), 7.26 - 7.19 (m, 2H), 6.99 - 6.90 (m, 2H), 5.77 - 5.65 (m, 1H), 3.33 - 3.21 (m, 1H), 3.20 - 3.09 (m, 1H), 2.81 - 2.69 (m, 1H), 2.34 - 2.14 (m, 2H), 2.02 - 1.85 (m, 2H), 1.74 (m, 3H), 1.57 - 1.38 (m, 1H). Synthesis of IMA-0002402 IMA-0002402 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-chloro-2-iodo-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002402 (45.97 mg, 119.77 μmol, 41.87% yield, 100% purity) was obtained as a white solid. LCMS: Ret. Time: 0.510 min, M+H+, m / z: 384.1.1H NMR (400 MHz, CDCl3) δ = 8.62 - 8.58 (m, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.24 - 7.13 (m, 2H), 6.88 - 6.81 (m, 2H), 5.70 - 5.61 (m, 1H), 3.34 - 3.18 (m, 2H), 2.80 - 2.68 (m, 1H), 2.52 (ddd, J = 4.0, 10.4, 14.0 Hz, 1H), 2.27 - 2.15 (m, 1H), 2.09 - 1.98 (m, 1H), 1.92 - 1.61 (m, 4H), 1.50 - 1.30 (m, 1H). Synthesis of IMA-0002403 IMA-0002403 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-(2-chlorophenyl)-2-hydroxy-ethyl]piperidine-1-carboxylate as the starting material. IMA-0002403 (45.63 mg, 118.88 μmol, 46.25% yield, 100% purity) was obtained as a white solid. LCMS: Ret. Time: 0.543 min, M+H+, m / z: 426.2.1H NMR (400 MHz, CDCl3) δ = 8.48 - 8.44 (m, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.40 - 7.35 (m, 1H), 7.34 (s, 1H), 7.23 - 7.17 (m, 2H), 6.92 - 6.87 (m, 2H), 5.90 (dd, J = 3.2, 9.2 Hz, 1H), 3.29 (br d, J = 12.8 Hz, 1H), 3.23 - 3.14 (m, 1H), 2.75 (dt, J = 3.6, 12.0 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.23 (ddd, J = 6.0, 9.2, 14.8 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.92 - 1.84 (m, 1H), 1.82 - 1.67 (m, 3H), 1.52 - 1.40 (m, 1H). Synthesis of IMA-0002404 IMA-0002404 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and bromo-(4-chlorophenyl) magnesium as the starting materials. IMA-0002404 (21.43 mg, 55.27 μmol, 23.49% yield, 99% purity) was obtained as a white solid. LCMS: Ret. Time: 0.502, M+H+, m / z: 384.11H NMR (400 MHz, CDCl3) δ = 8.60 - 8.56 (m, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.30 - 7.25 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.55 (dd, J = 5.6, 8.0 Hz, 1H), 3.20 (br d, J = 12.4 Hz, 1H), 3.04 - 2.95 (m, 1H), 2.71 - 2.59 (m, 2H), 2.16 - 2.05 (m, 1H), 1.83 (br d, J = 11.2 Hz, 2H), 1.77 - 1.55 (m, 3H), 1.41 - 1.26 (m, 1H). Synthesis of IMA-0002405 IMA-0002405 was synthesized following the same general scheme for IMA-0002383 but utilizing 2-iodonaphthalene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002405 (57.23 mg, 128.25 μmol, 31.19% yield, 99.825% purity, FA) was obtained as a yellow solid. LCMS: Ret. Time: 0.521 min, M+H+, m / z: 400.2.1H NMR (400 MHz, CDCl3) δ = 8.62 - 8.52 (m, 1H), 7.82 - 7.77 (m, 1H), 7.76 - 7.67 (m, 3H), 7.47 - 7.41 (m, 3H), 7.39 (d, J = 8.8 Hz, 2H), 7.01 - 6.94 (m, 2H), 5.88 - 5.80 (m, 1H), 3.26 (m, J = 12.0 Hz, 1H), 3.16 (br dd, J = 3.2, 7.2 Hz, 1H), 2.74 (dt, J = 3.6, 12.0 Hz, 1H), 2.37 - 2.21 (m, 2H), 2.01 - 1.83 (m, 2H), 1.82 - 1.61 (m, 3H), 1.56 - 1.40 (m, 1H). IMA-0002406 was synthesized following the same general scheme for IMA-0002383 but utilizing 2-iodonaphthalene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002406 (40.42 mg, 90.74 μmol, 30.79% yield, 100% purity, FA) was obtained as a light yellow gum. LCMS: Ret. Time: 0.535 min, M+H+, m / z: 400.3.1H NMR (400 MHz, CDCl3) δ = 8.48 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.62 - 7.50 (m, 3H), 7.40 - 7.35 (m, 3H), 6.86 (d, J = 8.8 Hz, 2H), 6.04 (dd, J = 3.6, 9.6 Hz, 1H), 3.18 (br dd, J = 3.2, 8.0 Hz, 1H), 3.08 (br d, J = 12.4 Hz, 1H), 2.66 - 2.58 (m, 2H), 2.30 (ddd, J = 3.6, 8.0, 14.4 Hz, 1H), 1.99 - 1.93 (m, 1H), 1.82 (br d, J = 13.2 Hz, 1H), 1.74 - 1.59 (m, 2H), 1.55 - 1.48 (m, 1H), 1.41 - 1.30 (m, 1H). Synthesis of IMA-0002407 IMA-0002407 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-hydroxy-2-(1-naphthyl)ethyl]piperidine-1-carboxylate as the starting material. IMA-0002407 (40.34 mg, 90.56 μmol, 35.71% yield, 100% purity, FA) was obtained as a light yellow gum. LCMS: Ret. Time: 0.518 min, M+H+, m / z: 400.2.1H NMR (400 MHz, CDCl3) δ = 8.49 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.48 - 7.43 (m, 1H), 7.34 (d, J = 8.4 Hz, 3H), 6.95 - 6.88 (m, 2H), 6.45 - 6.38 (m, 1H), 3.46 - 3.34 (m, 1H), 3.20 (br d, J = 12.4 Hz, 1H), 2.73 (dt, J = 3.2, 12.4 Hz, 1H), 2.53 (ddd, J = 2.4, 6.4, 15.2 Hz, 1H), 2.41 - 2.28 (m, 1H), 2.06 - 1.99 (m, 1H), 1.87 - 1.73 (m, 3H), 1.66 - 1.57 (m, 1H), 1.53 - 1.42 (m, 1H). Synthesis of IMA-0002408 IMA-0002408 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-2-phenyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002408 (27.39 mg, 58.09 μmol, 26.38% yield, 100% purity, FA) was obtained as a yellow oil. LCMS: Ret. Time: 0.526 min, M+H+, m / z: 426.2.1H NMR (400 MHz, CDCl3) δ = 8.55 - 8.51 (m, 1H), 7.55 - 7.48 (m, 3H), 7.38 (dd, J = 5.6, 7.6 Hz, 5H), 7.34 - 7.28 (m, 2H), 7.25 - 7.19 (m, 1H), 6.74 - 6.65 (m, 2H), 5.38 - 5.29 (m, 1H), 3.14 (m, J = 11.6 Hz, 1H), 2.96 - 2.92 (m, 1H), 2.69 - 2.61 (m, 1H), 2.40 (m, J = 6.0 Hz, 2H), 1.84 - 1.70 (m, 2H), 1.69 - 1.55 (m, 3H), 1.35 - 1.25 (m, 1H). Synthesis of IMA-0002421 IMA-0002421 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate and naphthalen-1-ol as the alcohol starting materials. IMA-0002421 (2.49 mg, 6.60 μmol, 14.23% yield, 100% purity, FA) was obtained as a light yellow gum. LCMS: Ret. Time: 0.502 min, M+H+, m / z: 332.2.1H NMR (400 MHz, CDCl3) δ = 8.69 (s, 1H), 8.46 - 8.42 (m, 1H), 7.81 - 7.75 (m, 1H), 7.56 - 7.48 (m, 2H), 7.41 (d, J = 7.2 Hz, 2H), 7.36 - 7.28 (m, 3H), 7.25 - 7.16 (m, 2H), 6.62 (d, J = 7.6 Hz, 1H), 5.52 (dd, J = 3.6, 9.2 Hz, 1H), 3.12 (br d, J = 12.4 Hz, 1H), 3.03 - 2.94 (m, 1H), 2.64 (dt, J = 3.6, 12.0 Hz, 1H), 2.50 - 2.42 (m, 1H), 2.00 (br d, J = 4.4 Hz, 1H), 1.80 (br d, J = 9.6 Hz, 2H), 1.60 - 1.50 (m, 2H), 1.43 - 1.29 (m, 2H). Synthesis of IMA-0002422 IMA-0002422 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-3-methyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002422 (44.79 mg, 103.92 μmol, 17.37% yield, 95% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.527 min, M+H+, m / z: 364.3.1H NMR (400 MHz, CDCl3) δ = 8.52 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.19 - 7.11 (m, 3H), 7.03 (br d, J = 7.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 5.74 (dd, J = 2.8, 10.0 Hz, 1H), 3.29 (br d, J = 12.4 Hz, 1H), 3.20 (tt, J = 3.6, 7.2 Hz, 1H), 2.78 (dt, J = 3.2, 12.4 Hz, 1H), 2.38 - 2.31 (m, 1H), 2.27 (s, 3H), 2.25 - 2.17 (m, 1H), 2.02 - 1.72 (m, 5H), 1.56 - 1.43 (m, 1H). Synthesis of IMA-0002423 IMA-0002423 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate and 4-phenylphenol as the alcohol starting materials. IMA-0002423 (7.22 mg, 14.24 μmol, 21.72% yield, 93% purity, TFA) was obtained as a light yellow gum. LCMS: Ret. Time: 0.517 min, M+H+, m / z: 358.3.1H NMR (400 MHz, CDCl3) δ = 9.24 (br s, 1H), 7.48 - 7.45 (m, 2H), 7.41 - 7.37 (m, 4H), 7.36 - 7.28 (m, 5H), 7.27 - 7.22 (m, 1H), 6.90 - 6.86 (m, 2H), 5.31 (dd, J = 4.0, 9.6 Hz, 1H), 3.25 (br d, J = 10.8 Hz, 2H), 2.82 - 2.70 (m, 1H), 2.57 - 2.44 (m, 1H), 2.08 - 1.93 (m, 2H), 1.89 - 1.83 (m, 1H), 1.70 - 1.61 (m, 3H), 1.48 - 1.37 (m, 1H). IMA-0002422 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-4-phenyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002424 (33.06 mg, 77.70 μmol, 14.88% yield, 100% purity) was obtained as a white solid. LCMS: Ret. Time: 0.538 min, M+H+, m / z: 426.2.1H NMR (400 MHz, CDCl3) δ = 9.75 - 9.63 (m, 1H), 9.09 - 8.90 (m, 1H), 7.55 - 7.47 (m, 4H), 7.45 - 7.38 (m, 4H), 7.37 - 7.31 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 5.59 - 5.52 (m, 1H), 3.30 (br d, J = 12.4 Hz, 2H), 2.90 - 2.76 (m, 1H), 2.36 - 2.25 (m, 2H), 2.12 - 2.00 (m, 1H), 1.96 - 1.88 (m, 1H), 1.83 - 1.70 (m, 3H), 1.58 - 1.41 (m, 1H). Synthesis of IMA-0002425 IMA-0002425 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-hydroxy-2-(3-phenylphenyl)ethyl]piperidine-1-carboxylate as the starting material. IMA-0002425 (58.15 mg, 123.33 μmol, 35.64% yield, 100% purity, FA) was obtained as a light yellow gum. LCMS: Ret. Time: 0.558 min, M+H+, m / z: 426.2.1H NMR (400 MHz, CDCl3) δ = 8.56 (s, 1H), 7.63 (s, 1H), 7.54 - 7.50 (m, 2H), 7.45 - 7.39 (m, 5H), 7.36 - 7.30 (m, 3H), 7.00 (d, J = 8.4 Hz, 2H), 5.90 (br d, J = 8.4 Hz, 1H), 3.26 - 3.16 (m, 2H), 2.69 (dt, J = 3.2, 12.4 Hz, 1H), 2.34 (ddd, J = 2.4, 7.6, 15.2 Hz, 1H), 2.21 - 2.14 (m, 1H), 1.95 - 1.84 (m, 2H), 1.81 - 1.70 (m, 2H), 1.66 - 1.59 (m, 1H), 1.51 - 1.39 (m, 1H). Synthesis of IMA-0002437 IMA-0002437 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and bromo(cyclopentyl)magnesium as the starting materials. IMA-0002437 (46.44 mg, 133.30 μmol, 45.11% yield, 98% purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.505 min, M+H+, m / z: 342.2.1H NMR (400 MHz, CDCl3) δ = 8.60 - 8.58 (m, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.06 - 6.92 (m, 2H), 4.54 - 4.44 (m, 1H), 3.36 - 3.25 (m, 1H), 3.11 - 2.98 (m, 1H), 2.84 - 2.70 (m, 1H), 2.26 - 2.14 (m, 2H), 1.99 - 1.80 (m, 3H), 1.79 - 1.66 (m, 4H), 1.65 - 1.48 (m, 5H), 1.41 - 1.27 (m, 3H). Synthesis of IMA-0002438 IMA-0002437 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and bromo(cyclohexyl)magnesium as the starting materials. IMA-0002438 (36.07 mg, 97.42 μmol, 12.53% yield, 96% purity) was obtained as a brown gum. LCMS: Ret. Time: 0.522 min, M+H+, m / z: 356.2.1H NMR (400 MHz, CDCl3) δ = 8.65 - 8.52 (m, 1H), 7.61 - 7.50 (m, 2H), 7.02 - 6.91 (m, 2H), 4.38 - 4.29 (m, 1H), 3.38 - 3.28 (m, 1H), 3.14 - 3.03 (m, 1H), 2.86 - 2.73 (m, 1H), 2.21 (ddd, J = 4.0, 9.6, 14.0 Hz, 1H), 1.95 - 1.82 (m, 3H), 1.80 - 1.61 (m, 8H), 1.61 - 1.51 (m, 1H), 1.46 - 1.30 (m, 1H), 1.24 - 0.96 (m, 5H). IMA-0002439 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and bromo-(4-fluorophenyl) magnesium as the starting materials. IMA-0002439 (66.99 mg, 178.70 μmol, 44.21% yield, 98% purity) was obtained as a white solid. LCMS: Ret. Time: 0.500 min, M+H+, m / z: 368.1.1H NMR (400 MHz, CDCl3) δ = 8.58 - 8.47 (m, 1H), 7.46 - 7.36 (m, 4H), 6.97 (d, J = 8.4 Hz, 2H), 6.91 (t, J = 8.4 Hz, 2H), 6.04 - 5.94 (m, 1H), 3.42 - 3.31 (m, 1H), 3.29 - 3.22 (m, 1H), 2.87 - 2.76 (m, 1H), 2.41 (br dd, J = 6.8, 14.4 Hz, 1H), 2.28 - 2.17 (m, 1H), 2.04 - 1.76 (m, 5H), 1.60 - 1.47 (m, 1H). Synthesis of IMA-0002440 IMA-0002440 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-3-phenyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002440 (44.88 mg, 95.18 μmol, 36.90% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.552 min, M+H+, m / z: 426.2.1H NMR (400 MHz, CDCl3) δ = 8.62 (s, 1H), 7.61 (s, 1H), 7.57 - 7.53 (m, 2H), 7.50 (td, J = 1.6, 6.8 Hz, 1H), 7.46 - 7.41 (m, 4H), 7.40 - 7.33 (m, 3H), 6.94 (d, J = 8.8 Hz, 2H), 5.52 (dd, J = 4.8, 8.8 Hz, 1H), 3.18 (br d, J = 12.0 Hz, 1H), 3.07 - 3.01 (m, 1H), 2.69 - 2.60 (m, 2H), 2.18 - 2.11 (m, 1H), 1.88 - 1.78 (m, 2H), 1.72 - 1.53 (m, 3H), 1.40 - 1.27 (m, 1H). Synthesis of IMA-0002444 IMA-0002444 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-2-methyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002444 (29.52 mg, 81.23 μmol, 12.82% yield, 100% purity) was obtained as a light yellow gum. LCMS: Ret. Time: 0.500 min, M+H+, m / z: 364.2.1H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.18 - 7.07 (m, 3H), 6.80 (d, J = 8.4 Hz, 2H), 5.43 (dd, J = 2.4, 10.4 Hz, 1H), 3.16 - 3.11 (m, 2H), 2.68 (dt, J = 3.6, 12.0 Hz, 1H), 2.47 - 2.42 (m, 1H), 2.41 (s, 3H), 2.09 - 2.00 (m, 1H), 1.94 (br dd, J = 2.4, 13.6 Hz, 1H), 1.85 (br d, J = 13.6 Hz, 1H), 1.72 - 1.56 (m, 3H), 1.45 - 1.34 (m, 1H). Synthesis of IMA-0002445 IMA-0002445 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-hydroxy-2-(o-tolyl)ethyl]piperidine-1-carboxylate as the starting material. IMA-0002445 (58.5 mg, 160.97 μmol, 53.47% yield, 100% purity) was obtained as a light yellow gum. LCMS: Ret. Time: 0.508 min, M+H+, m / z: 364.2.1H NMR (400 MHz, CDCl3) δ = 8.46 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.30 - 7.28 (m, 1H), 7.17 - 7.07 (m, 3H), 6.87 (d, J = 8.8 Hz, 2H), 5.79 (dd, J = 2.0, 10.4 Hz, 1H), 3.29 - 3.25 (m, 1H), 3.20 (br d, J = 12.0 Hz, 1H), 2.76 - 2.70 (m, 1H), 2.42 (s, 3H), 2.33 - 2.27 (m, 1H), 2.20 - 2.14 (m, 1H), 2.00 (br dd, J = 3.6, 13.6 Hz, 1H), 1.91 - 1.85 (m, 1H), 1.78 - 1.67 (m, 3H), 1.52 - 1.43 (m, 1H). IMA-0002446 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and bromo-(4-chlorophenyl) magnesium as the starting materials. IMA-0002446 (92.82 mg, 241.82 μmol, 63.61% yield, 100% purity) as a white solid. LCMS: Ret. Time: 0.517, M+H+, m / z: 384.2.1H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.36 - 7.32 (m, 2H), 7.31 - 7.26 (m, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.78 - 5.65 (m, 1H), 3.33 - 3.25 (m, 1H), 3.25 - 3.17 (m, 1H), 2.85 - 2.75 (m, 1H), 2.31 - 2.15 (m, 2H), 2.06 - 1.92 (m, 2H), 1.85 - 1.68 (m, 3H), 1.61 - 1.49 (m, 1H). Synthesis of IMA-0002447 IMA-0002447 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-4-methyl-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002447 (50.9 mg, 133.06 μmol, 34.73% yield, 95% purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.508 min, M+H+, m / z: 364.1.1H NMR (400 MHz, CDCl3) δ = 8.59 - 8.51 (m, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.68 - 5.60 (m, 1H), 3.23 (br d, J = 12.8 Hz, 1H), 3.09 (br dd, J = 2.8, 6.0 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.32 - 2.29 (m, 3H), 2.24 - 2.18 (m, 2H), 1.96 - 1.86 (m, 2H), 1.76 - 1.69 (m, 2H), 1.66 - 1.57 (m, 1H), 1.54 - 1.42 (m, 1H). Synthesis of IMA-0002448 IMA-0002448 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate and 3-phenylphenol as the alcohol starting materials. IMA-0002448 (22.71 mg, 61.62 μmol, 62.66% yield, 97% purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.517 min, M+H+, m / z: 358.2.1H NMR (400 MHz, CDCl3) δ = 9.23 - 9.12 (m, 1H), 7.42 - 7.37 (m, 2H), 7.35 - 7.29 (m, 2H), 7.29 - 7.20 (m, 5H), 7.18 (br s, 2H), 7.03 (d, J = 8.0 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.72 - 6.66 (m, 1H), 5.25 (dd, J = 3.6, 9.6 Hz, 1H), 3.26 - 3.08 (m, 2H), 2.73 - 2.58 (m, 1H), 2.43 (ddd, J = 5.2, 9.6, 14.4 Hz, 1H), 2.00 - 1.94 (m, 1H), 1.89 (br dd, J = 2.4, 13.6 Hz, 1H), 1.81 - 1.73 (m, 1H), 1.65 - 1.54 (m, 3H), 1.40 - 1.25 (m, 1H). Synthesis of IMA-0002449 IMA-0002449 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-chloro-3-iodo-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002449 (13.06 mg, 26.23 μmol, 9.06% yield, 100% purity, TFA) was obtained as a colorless oil. LCMS: Ret. Time: 0.502 min, M+H+, m / z: 384.1.1H NMR (400 MHz, CDCl3) δ = 9.55 - 9.34 (m, 1H), 9.21 - 8.97 (m, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.35 - 7.28 (m, 1H), 7.27 - 7.20 (m, 3H), 6.93 - 6.81 (m, 2H), 5.40 - 5.25 (m, 1H), 3.28 - 3.09 (m, 2H), 2.82 - 2.63 (m, 1H), 2.54 - 2.41 (m, 1H), 2.07 - 1.96 (m, 1H), 1.95 - 1.85 (m, 2H), 1.75 - 1.59 (m, 3H), 1.47 - 1.32 (m, 1H). Synthesis of IMA-0002450 IMA-0002450 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-(3-chlorophenyl)-2-hydroxy-ethyl]piperidine-1-carboxylate as the starting material. IMA-0002450 (37.72 mg, 86.57 μmol, 23.91% yield, 98.652% purity, FA) was obtained as a yellow oil. LCMS: Ret. Time: 0.510 min, M+H+, m / z: 384.2.1H NMR (400 MHz, CDCl3) δ = 8.57 - 8.51 (m, 1H), 7.51 - 7.39 (m, 2H), 7.36 - 7.32 (m, 1H), 7.25 - 7.16 (m, 3H), 6.96 - 6.83 (m, 2H), 5.70 - 5.58 (m, 1H), 3.31 - 3.21 (m, 1H), 3.20 - 3.10 (m, 1H), 2.84 - 2.68 (m, 1H), 2.25 - 2.07 (m, 2H), 2.01 - 1.85 (m, 2H), 1.79 - 1.60 (m, 3H), 1.59 - 1.39 (m, 1H). Synthesis of IMA-0002469 IMA-0002469 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (2R)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate and bromo-(4-fluorophenyl) magnesium as the starting materials. IMA-0002469 (19.77 mg, 47.82 μmol, 27.08% yield, 100% purity, FA) as a colorless oil. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 368.2.1H NMR (400 MHz, CDCl3) δ = 8.81 - 8.58 (m, 1H), 7.51 - 7.29 (m, 4H), 7.20 - 6.81 (m, 4H), 5.51 - 5.28 (m, 1H), 3.36 - 3.00 (m, 3H), 2.92 - 2.78 (m, 1H), 2.74 - 2.58 (m, 1H), 2.46 - 2.18 (m, 1H), 1.79 - 1.69 (m, 1H), 1.69 - 1.49 (m, 2H), 1.37 (br d, J = 3.2 Hz, 2H). Synthesis of IMA-0002470 IMA-0002470 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (2S)-2-(2-hydroxyethyl)piperidine-1-carboxylate and bromo-(4-fluorophenyl) magnesium as the starting materials. IMA-0002470 (35.18 mg, 95.76 μmol, 31.09% yield, 100% purity) was obtained as a white gum. LCMS: Ret. Time: 0.491 min, M+H+, m / z: 368.1.1H NMR (400 MHz, CDCl3) δ = 7.49 - 7.37 (m, 4H), 7.06 - 6.97 (m, 2H), 6.96 - 6.89 (m, 2H), 5.69 - 5.56 (m, 1H), 3.34 - 3.21 (m, 1H), 3.11 - 2.98 (m, 1H), 2.81 - 2.60 (m, 2H), 2.23 - 2.09 (m, 1H), 1.90 - 1.81 (m, 3H), 1.78 - 1.65 (m, 2H), 1.42 - 1.29 (m, 1H). Synthesis of IMA-0002471 IMA-0002471 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (2R)-2-[(2S)-2-(4-fluorophenyl)-2-hydroxy-ethyl]piperidine-1-carboxylate as the starting material. IMA-0002471 (23.29 mg, 63.39 μmol, 21.37% yield, 100% purity) was obtained as a brown oil. LCMS: Ret. Time: 0.502 min, M+H+, m / z: 368.1.1H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 8.8 Hz, 2H), 7.34 - 7.28 (m, 2H), 7.06 - 6.98 (m, 2H), 6.90 (d, J = 8.4 Hz, 2H), 5.39 (dd, J = 3.6, 9.2 Hz, 1H), 3.14 - 3.03 (m, 1H), 2.84 - 2.75 (m, 1H), 2.65 - 2.56 (m, 1H), 2.13 - 2.02 (m, 1H), 1.86 - 1.78 (m, 4H), 1.62 (br d, J = 6.4 Hz, 1H), 1.46 - 1.35 (m, 2H). Synthesis of IMA-0002472 IMA-0002472 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (2S)-2-[(2R)-2-(4-fluorophenyl)-2-hydroxy-ethyl]piperidine-1-carboxylate as the starting material. IMA-0002472 (62.36 mg, 149.76 μmol, 48.62% yield, 99.281% purity, FA) was obtained as a colorless oil. LCMS: Ret. Time: 0.492 min, M+H+, m / z: 368.1.1H NMR (400 MHz, CDCl3) δ = 8.53 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.38 - 7.28 (m, 2H), 6.97 - 6.86 (m, 4H), 5.79 - 5.68 (m, 1H), 3.34 - 3.25 (m, 1H), 3.24 - 3.14 (m, 1H), 2.85 - 2.71 (m, 1H), 2.34 - 2.22 (m, 1H), 2.22 - 2.12 (m, 1H), 2.05 - 1.87 (m, 2H), 1.86 - 1.68 (m, 3H), 1.58 - 1.40 (m, 1H). Synthesis of IMA-0002473 IMA-0002473 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-2-methoxy-benzene and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002473 (5.45 mg, 14.36 μmol, 3.38% yield, 100% purity) was obtained as a light yellow gum. LCMS: Ret. Time: 0.518 min, M+H+, m / z: 380.4.1H NMR (400 MHz, CDCl3) δ = 8.58 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.27 - 7.21 (m, 2H), 6.92 - 6.84 (m, 4H), 5.81 - 5.68 (m, 1H), 3.95 - 3.89 (m, 3H), 3.22 - 3.15 (m, 1H), 2.95 (br d, J = 6.4 Hz, 1H), 2.69 - 2.65 (m, 1H), 2.29 (ddd, J = 5.6, 8.8, 14.4 Hz, 1H), 2.15 - 2.05 (m, 1H), 2.02 - 1.91 (m, 1H), 1.83 (br s, 2H), 1.70 - 1.56 (m, 2H), 1.47 - 1.40 (m, 1H). Synthesis of IMA-0002475 IMA-0002475 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl 3-(2-hydroxyethyl)piperidine-1-carboxylate as the alcohol starting material. IMA-002475 (27.23 mg, 77.94 μmol, 26.92% yield, 100% purity) was obtained as a brown oil. LCMS: Ret. Time: 0.472 min, M+H+, m / z: 350.2.1H NMR (400 MHz, CDCl3) δ = 8.55 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.40 - 7.28 (m, 5H), 6.96 - 6.86 (m, 2H), 5.25 (dd, J = 3.2, 9.2 Hz, 1H), 3.52 - 3.26 (m, 2H), 2.79 - 2.69 (m, 1H), 2.65 - 2.52 (m, 1H), 2.38 - 2.24 (m, 1H), 2.09 - 1.74 (m, 4H), 1.69 (ddd, J = 3.2, 7.2, 14.2 Hz, 1H), 1.36 - 1.15 (m, 1H). sis of IMA-0002476 IMA-0002476 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate and bromo(phenyl)magnesium as the starting materials. IMA-0002476 (93.58 mg, 236.66 μmol, 99.99% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.502 min, M+H+, m / z: 350.1.1H NMR (400 MHz, CDCl3) δ = 8.55 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H), 7.31 - 7.27 (m, 3H), 6.87 (d, J = 8.8 Hz, 2H), 5.20 (dd, J = 3.6, 9.2 Hz, 1H), 3.41 (br d, J = 11.2 Hz, 2H), 2.88 - 2.74 (m, 2H), 2.08 (ddd, J = 4.8, 9.6, 14.0 Hz, 1H), 1.98 - 1.81 (m, 3H), 1.80 - 1.67 (m, 2H). Synthesis of IMA-0002477 IMA-0002477 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate and 4-chlorophenol as the alcohol starting materials. IMA-00002477 (22.95 mg, 71.72 μmol, 27.12% yield, 98.7% purity) was obtained as a light yellow gum. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 316.3.1H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1H), 7.31 (d, J = 4.4 Hz, 4H), 7.26 - 7.21 (m, 1H), 7.12 - 7.08 (m, 2H), 6.76 - 6.72 (m, 2H), 5.24 (dd, J = 4.4, 9.2 Hz, 1H), 3.20 - 3.13 (m, 2H), 2.74 - 2.67 (m, 1H), 2.47 (ddd, J = 5.2, 9.2, 14.4 Hz, 1H), 2.01 (ddd, J = 4.4, 8.0, 14.4 Hz, 1H), 1.93 - 1.83 (m, 2H), 1.71 - 1.62 (m, 3H), 1.46 - 1.34 (m, 1H). Synthesis of IMA-0002486 & IMA-0002487 IMA-0002486 and IMA-0002487 were synthesized following the same general scheme for IMA-0002383 but utilizing 5-iodoisoquinoline and tert-butyl 2-(2-oxoethyl)piperidine-1- carboxylate and as the starting materials. IMA-0002486 (16.38 mg, 36.50 μmol, 8.21% yield, 99.48% purity, FA) was obtained as a brown gum. LCMS: Ret. Time: 0.400 min, M+H+, m / z: 401.1.1H NMR (400 MHz, CDCl3) δ = 9.25 (s, 1H), 8.64 - 8.49 (m, 2H), 8.12 - 8.06 (m, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.70 - 7.70 (m, 1H), 7.55 - 7.47 (m, 1H), 7.43 - 7.36 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.29 (t, J = 6.4 Hz, 1H), 3.31 - 3.23 (m, 1H), 3.22 - 3.15 (m, 1H), 2.77 - 2.65 (m, 1H), 2.25 (br t, J = 6.0 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.92 - 1.84 (m, 1H), 1.70 - 1.43 (m, 4H). IMA-0002487 (22.18 mg, 49.32 μmol, 11.09% yield, 99.27% purity, FA) was obtained as a brown gum. LCMS: Ret. Time: 0.407 min, M+H+, m / z: 401.1.1H NMR (400 MHz, CDCl3) δ = 9.25 (s, 1H), 8.64 - 8.49 (m, 2H), 8.12 - 8.06 (m, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.70 - 7.70 (m, 1H), 7.55 - 7.47 (m, 1H), 7.43 - 7.36 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.29 (t, J = 6.4 Hz, 1H), 3.31 - 3.23 (m, 1H), 3.22 - 3.15 (m, 1H), 2.77 - 2.65 (m, 1H), 2.25 (br t, J = 6.0 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.92 - 1.84 (m, 1H), 1.70 - 1.43 (m, 4H). Synthesis of IMA-0002492 IMA-0002492 was synthesized following the same general scheme for IMA-0002335 but utilizing 2-(4-tert-butoxycarbonylmorpholin-3-yl)acetic acid as the starting material. IMA- 0002492 (144.52 mg, 345.49 μmol, 34.23% yield, 95% purity, FA) was obtained as a brown gum. LCMS: Ret. Time: 0.467 min, M+H+, m / z: 352.2.1H NMR (400 MHz, CDCl3) δ = 8.45 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.38 - 7.31 (m, 4H), 7.29 (dd, J = 2.8, 5.6 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 5.41 (dd, J = 5.2, 8.0 Hz, 1H), 3.88 (dd, J = 3.2, 12.0 Hz, 1H), 3.82 - 3.69 (m, 2H), 3.60 (dd, J = 10.0, 12.0 Hz, 1H), 3.25 (dtd, J = 3.2, 6.4, 9.6 Hz, 1H), 3.08 - 2.92 (m, 2H), 2.42 (ddd, J = 6.4, 8.0, 14.4 Hz, 1H), 2.06 (td, J = 6.0, 14.4 Hz, 1H). IMA-0002493 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 3-(2-hydroxy-2-phenyl-ethyl)morpholine-4-carboxylate as the starting material. IMA-0002493 (188.84 mg, 521.33 μmol, 45.06% yield, 97% purity) was obtained as a yellow solid. LCMS: Ret. Time: 0.475 min, M+H+, m / z: 352.2.1H NMR (400 MHz, CDCl3) δ = 8.41 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.35 - 7.27 (m, 5H), 6.92 (d, J = 8.8 Hz, 2H), 5.55 (dd, J = 3.6, 9.2 Hz, 1H), 4.02 (dd, J = 3.2, 12.0 Hz, 1H), 3.90 - 3.84 (m, 1H), 3.82 - 3.74 (m, 1H), 3.62 (dd, J = 10.0, 12.0 Hz, 1H), 3.44 - 3.36 (m, 1H), 3.09 - 2.97 (m, 2H), 2.22 - 2.08 (m, 2H). Synthesis of IMA-0002496 IMA-0002496 was synthesized following the same general scheme for IMA-0002383 but utilizing 8-iodoisoquinoline and tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002496 (11.48 mg, 28.36 μmol, 16.61% yield, 98.927% purity) was obtained as a brown gum. LCMS: Ret. Time: 0.419 min, M+H+, m / z: 401.2.1H NMR (400 MHz, CDCl3) δ = 9.74 - 9.69 (m, 1H), 8.63 - 8.56 (m, 1H), 8.52 (s, 1H), 7.78 - 7.73 (m, 1H), 7.73 - 7.66 (m, 2H), 7.64 - 7.58 (m, 1H), 7.39 (d, J = 8.8 Hz, 2H), 6.97 - 6.84 (m, 2H), 6.26 - 6.14 (m, 1H), 3.26 - 3.19 (m, 1H), 3.12 - 3.06 (m, 1H), 2.73 - 2.67 (m, 1H), 2.59 - 2.52 (m, 1H), 2.21 (m, J = 3.6, 6.4, 14.4 Hz, 1H), 1.93 - 1.84 (m, 2H), 1.65 - 1.52 (m, 3H), 1.48 - 1.34 (m, 1H). Synthesis of IMA-0002497 IMA-0002497 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-hydroxy-2-(8-isoquinolyl)ethyl]piperidine-1-carboxylate as the starting material. IMA-0002497 (15.75 mg, 38.84 μmol, 45.49% yield, 98.741% purity) was obtained as a brown gum. LCMS: Ret. Time: 0.415 min, M+H+, m / z: 401.3.1H NMR (400 MHz, CDCl3) δ = 9.87 (m, J = 2.4 Hz, 1H), 8.64 - 8.52 (m, 1H), 8.50 - 8.38 (m, 1H), 7.74 - 7.68 (m, 1H), 7.67 - 7.60 (m, 2H), 7.60 - 7.54 (m, 1H), 7.43 - 7.32 (m, 2H), 6.99 - 6.88 (m, 2H), 6.61 - 6.48 (m, 1H), 3.43 - 3.23 (m, 2H), 2.86 - 2.68 (m, 1H), 2.42 - 2.24 (m, 2H), 2.01 - 1.84 (m, 2H), 1.80 - 1.44 (m, 4H). Synthesis of IMA-0002502 IMA-0002502 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-chloro-2-iodo-benzene and tert-butyl (R)-2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002502 (327.06 mg, 760.85 μmol, 58.37% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.499 min, M+H+, m / z: 384.2. SFC of IMA-0002502: Ret. Time: 1.433 min, Area%: 99.718%1H NMR (400 MHz, CDCl3) δ = 8.55 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.23 - 7.15 (m, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.65 (dd, J = 2.4, 10.4 Hz, 1H), 3.37 - 3.18 (m, 2H), 2.82 - 2.68 (m, 1H), 2.50 (ddd, J = 3.6, 10.5, 14.1 Hz, 1H), 2.25 - 2.13 (m, 1H), 2.04 (br dd, J = 3.2, 13.9 Hz, 1H), 1.93 - 1.62 (m, 4H), 1.42 (br d, J = 12.8 Hz, 1H). Synthesis of IMA-0002503 IMA-0002503 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (R)-2-((S)-2-(2-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate as the starting material. IMA-0002503 (373.48 mg, 868.84 μmol, 56.46% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.492 min, M+H+, m / z: 384.2. SFC of IMA- 0002503: Ret. Time: 1.242 min, Area%: 100.000%.1H NMR (400 MHz, CDCl3) δ = 8.37 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.40 - 7.30 (m, 2H), 7.23 - 7.16 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.92 (dd, J = 3.6, 9.2 Hz, 1H), 3.45 - 3.17 (m, 2H), 2.90 - 2.71 (m, 1H), 2.57 - 2.44 (m, 1H), 2.37 - 2.23 (m, 1H), 2.12 - 1.99 (m, 1H), 1.95 - 1.80 (m, 3H), 1.78 - 1.68 (m, 1H), 1.55 - 1.37 (m, 1H). Synthesis of IMA-0002504 IMA-0002504 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-chloro-2-iodo-benzene and tert-butyl (S)-2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002504 (212.86 mg, 495.19 μmol, 60.52% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.495 min, M+H+, m / z: 384.2. SFC of IMA-0002504: Ret. Time: 1.259 min, Area%: 100.000%.1H NMR (400 MHz, CDCl3) δ = 8.43 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.40 - 7.36 (m, 1H), 7.35 - 7.31 (m, 1H), 7.23 - 7.17 (m, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.91 (dd, J = 3.6, 9.2 Hz, 1H), 3.43 - 3.12 (m, 2H), 2.77 (dt, J = 3.2, 12.4 Hz, 1H), 2.45 (ddd, J = 3.6, 6.0, 14.8 Hz, 1H), 2.33 - 2.18 (m, 1H), 2.11 - 1.99 (m, 1H), 1.94 - 1.80 (m, 1H), 1.80 - 1.68 (m, 2H), 1.56 - 1.38 (m, 1H). Synthesis of IMA-0002505 IMA-0002505 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (S)-2-((S)-2-(2-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate as the starting material. IMA-0002505 (212.86 mg, 495.19 μmol, 60.52% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.503 min, M+H+, m / z: 384.2. SFC of IMA- 0002505: Ret. Time: 1.409 min, Area%: 99.645%1H NMR (400 MHz, CDCl3) δ = 8.59 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.40 - 7.34 (m, 2H), 7.24 - 7.15 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.69 - 5.56 (m, 1H), 3.39 - 3.16 (m, 2H), 2.81 - 2.66 (m, 1H), 2.60 - 2.49 (m, 1H), 2.28 - 2.16 (m, 1H), 2.08 - 1.97 (m, 1H), 1.93 - 1.74 (m, 3H), 1.71 - 1.58 (m, 1H), 1.49 - 1.30 (m, 1H). Synthesis of IMA-0002506 IMA-0002506 was synthesized following the same general scheme for IMA-0002383 but utilizing 1-iodo-2-methyl-benzene and tert-butyl (R)-2-(2-oxoethyl)piperidine-1-carboxylate and as the starting materials. IMA-0002506 (36.22 mg, 88.46 μmol, 22.63% yield, 100% purity, FA) was obtained as a brown gum. LCMS: Ret. Time: 0.503 min, M+H+, m / z: 364.2.1H NMR (400 MHz, CDCl3) δ = 8.60 (s, 1H), 7.49 - 7.37 (m, 2H), 7.31 (br d, J = 6.4 Hz, 1H), 7.20 - 7.05 (m, 3H), 6.86 - 6.73 (m, 2H), 5.49 - 5.38 (m, 1H), 3.15 - 2.94 (m, 2H), 2.75 - 2.58 (m, 1H), 2.48 - 2.34 (m, 3H), 2.32 - 2.19 (m, 1H), 1.99 - 1.74 (m, 3H), 1.67 - 1.49 (m, 2H), 1.47 - 1.25 (m, 2H). Synthesis of IMA-0002507 IMA-0002507 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (S)-2-(2-hydroxyethyl)piperidine-1-carboxylate and 1-iodo-2-methyl-benzene as the starting materials. IMA-0002507 (47.04 mg, 126.85 μmol, 30.09% yield, 98% purity) as a colorless solid. LCMS: Ret. Time: 0.520 min, M+H+, m / z: 364.3.1H NMR (400 MHz, CDCl3) δ = 8.59 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 6.8 Hz, 1H), 7.18 - 7.09 (m, 3H), 6.80 (d, J = 8.8 Hz, 2H), 5.43 (dd, J = 2.8, 10.1 Hz, 1H), 3.11 (br d, J = 12.4 Hz, 2H), 2.71 - 2.62 (m, 1H), 2.46 - 2.34 (m, 4H), 2.03 (ddd, J = 2.8, 8.4, 14.4 Hz, 1H), 1.93 (br dd, J = 2.8, 13.6 Hz, 1H), 1.88 - 1.81 (m, 1H), 1.71 - 1.53 (m, 3H), 1.45 - 1.31 (m, 1H). Synthesis of IMA-0002509 & IMA-000213 IMA-0002509 and IMA-000213 were synthesized following the same general scheme for IMA-0002383 but utilizing 4-iodobenzonitrile and tert-butyl 2-(2-oxoethyl)piperidine-1- carboxylate and as the starting materials. IMA-0002513 (20.6 mg, 49.00 μmol, 4.82% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.481 min, M+H+, m / z: 375.1.1H NMR (400 MHz, CDCl3) δ = 8.58 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.47 - 7.41 (m, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.50 (br dd, J = 4.8, 8.4 Hz, 1H), 3.20 - 3.09 (m, 1H), 3.06 - 2.94 (m, 1H), 2.73 - 2.60 (m, 1H), 2.54 - 2.41 (m, 1H), 2.07 - 1.97 (m, 1H), 1.88 - 1.79 (m, 2H), 1.68 - 1.53 (m, 3H), 1.44 - 1.30 (m, 1H). IMA-0002509 (15.27 mg, 36.32 μmol, 3.57% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.480 min, M+H+, m / z: 375.1.1H NMR (400 MHz, CDCl3) δ = 8.51 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 5.6, 8.4 Hz, 4H), 6.87 (d, J = 8.8 Hz, 2H), 5.62 (dd, J = 4.4, 8.8 Hz, 1H), 3.26 - 3.13 (m, 2H), 2.80 - 2.73 (m, 1H), 2.16 - 2.08 (m, 2H), 1.98 - 1.90 (m, 2H), 1.79 - 1.73 (m, 1H), 1.67 - 1.49 (m, 3H). Synthesis of IMA-0002511 IMA-0002511 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (R)-2-((S)-2-cyclopentyl-2-hydroxyethyl)piperidine-1-carboxylate as the starting material. IMA-0002511 (25.85 mg, 72.99 μmol, 9.00% yield, 96.4% purity) was obtained as a light yellow gum. LCMS: Ret. Time: 0.517 min, M+H+, m / z: 342.2.1H NMR (400 MHz, CDCl3) δ = 8.58 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 4.80 - 4.73 (m, 1H), 3.29 (br d, J = 12.4 Hz, 1H), 3.02 - 2.89 (m, 1H), 2.69 (td, J = 8.4, 12.4 Hz, 1H), 2.26 - 2.10 (m, 2H), 1.96 - 1.83 (m, 3H), 1.78 - 1.64 (m, 5H), 1.63 - 1.47 (m, 4H), 1.38 - 1.27 (m, 3H). Synthesis of IMA-0002512 IMA-0002512 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (S)-2-(2-hydroxyethyl)piperidine-1-carboxylate and bromo(cyclopentyl) magnesium as the starting materials. IMA-0002512 (12.57 mg, 36.49 μmol, 5.54% yield, 99.1% purity) was obtained as a brown gum. LCMS: Ret. Time: 0.501 min, M+H+, m / z: 342.2.1H NMR (400 MHz, CDCl3) δ = 8.63 (s, 1H), 7.53 (br d, J = 8.4 Hz, 2H), 7.10 (br d, J = 8.4 Hz, 2H), 4.75 (br s, 1H), 3.24 (br d, J = 12.0 Hz, 1H), 2.88 (br s, 1H), 2.73 - 2.58 (m, 1H), 2.24 - 2.01 (m, 2H), 1.94 - 1.78 (m, 3H), 1.75 - 1.24 (m, 13H). Synthesis of IMA-0002516 2: A solution of amino hydrogen sulfate (968.13 mg, 8.56 mmol, 1.2 eq) in AcOH (6 mL) heated to 70 °C was added 3-allyltetrahydropyran-4-one 1 (1 g, 7.13 mmol, 1 eq), then the mixture was stirred at 75 °C for 12 h. The mixture was poured into water (20 mL) and extracted with EtOAc (3 x 20 mL), the pH was adjusted to 12 with NaOH at combined organic phase, the combined organic phase was washed with brine (20 mL), and dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 22%- 52% B over 9 min) to give 7-allylazepan-2-one 2 (288 mg, 1.86 mmol, 26.01% yield, 98.7% purity) as a white solid. LCMS: Ret. Time: 0.424 min, M+H+, m / z: 154.4.1H NMR (400 MHz, CDCl3) δ = 5.83 - 5.69 (m, 1H), 5.56 (br s, 1H), 5.18 (s, 1H), 5.17 - 5.13 (m, 1H), 3.47 - 3.37 (m, 1H), 2.50 - 2.45 (m, 2H), 2.36 - 2.16 (m, 2H), 2.01 (br dd, J = 4.0, 10.4 Hz, 1H), 1.92 - 1.82 (m, 2H), 1.64 - 1.48 (m, 2H), 1.44 - 1.29 (m, 1H). 3: Ozone was bubbled into a solution of 7-allylazepan-2-one 2 (288 mg, 1.88 mmol, 1 eq)in DCM (2 mL) at -78 °C for 30 minutes. After excess O3was purged by N2, PPh3(591.60 mg, 2.26 mmol, 1.2 eq) was added at -78 °C. The reaction mixture was allowed to warm-up slowly to 25 °C for 12 h. The DCM was removed under reduced pressure. The mixture was dissolved with toluene (20 mL). The KOH (2 M, 20 mL, 21.28 eq) was added until the aqueous layer turned basic (pH=12). The reaction mixture was allowed to warm up slowly to 55 °C for 12 h. The layers were then separated, and the toluene layer was passed through a filter to remove any solids or tarry material. The toluene was removed under reduced pressure. The residue was purified by prep-TLC (SiO2, PE:EtOAc = 1:1, Rf =0.05) to give 2-(7-oxoazepan-2- yl)acetaldehyde 3 (277 mg, 1.23 mmol, 65.52% yield, 69.0% purity) as a yellow solid. LCMS: Ret. Time: 0.291 min, M+H+, m / z: 156.1.1H NMR (400 MHz, CDCl3) δ = 9.76 (s, 1H), 6.68 (br s, 1H), 4.02 - 3.84 (m, 1H), 2.82 - 2.61 (m, 2H), 2.55 - 2.42 (m, 2H), 2.02 - 1.94 (m, 1H), 1.91 - 1.83 (m, 1H), 1.79 (td, J = 3.6, 14.0 Hz, 1H), 1.66 - 1.43 (m, 3H). 4: To a solution of the 2-(7-oxoazepan-2-yl)acetaldehyde 3 (277 mg, 1.78 mmol, 1 eq) in THF (6 mL) was added bromo(phenyl)magnesium (3 M, 892.43 μL, 1.5 eq) at 0 °C under N2, then the mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into saturated aq. NH4Cl (10 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by prep-TLC (PE:EtOAc=0:1, Rf=0.2) to give 7-(2-hydroxy-2-phenyl-ethyl)azepan-2-one 4 (163 mg, 541.46 μmol, 30.34% yield, 77.5% purity) as a yellow oil. LCMS: Ret. Time: 0.457 min, M+H+, m / z: 232.2.1H NMR (400 MHz, CDCl3) δ = 7.39 - 7.30 (m, 5H), 6.60 - 6.42 (m, 1H), 5.01 - 4.78 (m, 1H), 3.57 - 3.47 (m, 2H), 2.46 (dt, J = 2.8, 6.8 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.93 - 1.71 (m, 4H), 1.60 - 1.48 (m, 3H), 1.33 - 1.22 (m, 1H). 5: To a mixture of 7-(2-hydroxy-2-phenyl-ethyl)azepan-2-one 4 (163 mg, 698.66 μmol, 1 eq) in THF (2 mL) was added BH3•THF (1 M, 2.10 mL, 3 eq) at 0 °C under N2 atmosphere, then the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into aq. NH4Cl (4 mL) and extracted with EtOAc (4 mL x 3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Waters Atlantis T3150 x 30 mm x 5 um; mobile phase: [water (FA)-ACN]; gradient: 5%-35% B over 9 min) to give 2-(azepan-2-yl)-1- phenyl-ethanol 5 (84 mg, 375.34 μmol, 53.72% yield, 98% purity) as a yellow oil. LCMS: Ret. Time: 0.362 min, M+H+, m / z: 220.2.1H NMR (400 MHz, CDCl3) δ = 8.34 (br s, 1H), 8.02 (br s, 1H), 7.39 - 7.31 (m, 2H), 4.96 (br t, J = 10.0 Hz, 1H), 3.83 - 3.61 (m, 1H), 3.18 (br s, 1H), 2.97 (s, 3H), 2.89 (s, 3H), 2.37 - 1.43 (m, 6H). IMA-0002516: To a mixture of 2-(azepan-2-yl)-1-phenyl-ethanol 5 (84 mg, 383.00 μmol, 1 eq) in DMA (1 mL) was added NaH (38 mg, 950.09 μmol, 60% purity, 2.48 eq) at 0 °C under N2 atmosphere, then the mixture was stirred at 50 °C for 0.5 h.1-fluoro-4- (trifluoromethyl)benzene (75.42 mg, 459.60 μmol, 58.33 μL, 1.2 eq) was added to the mixture at 25 °C, then the mixture was stirred at 50 °C for 12 h under N2 atmosphere. The reaction mixture was poured into aq. NH4Cl (2 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 22%- 52% B over 18 min) to give IMA-0002516 (38.02 mg, 92.86 μmol, 24.25% yield, 100% purity, FA) as a white solid. LCMS: Ret. Time: 0.503 min, M+H+, m / z: 364.2.1H NMR (400 MHz, CDCl3) δ = 8.56 (s, 1H), 7.46 - 7.39 (m, 2H), 7.37 - 7.33 (m, 2H), 7.33 - 7.27 (m, 2H), 7.27 - 7.22 (m, 1H), 6.96 - 6.87 (m, 2H), 5.73 - 5.65 (m, 1H), 5.44 - 5.34 (m, 1H), 3.45 - 3.29 (m, 1H), 3.19 - 3.04 (m, 1H), 3.01 - 2.91 (m, 1H), 2.55 (ddd, J = 5.6, 9.2, 14.4 Hz, 1H), 2.28 - 1.92 (m, 3H), 1.87 - 1.67 (m, 5H), 1.67 - 1.58 (m, 1H), 1.58 - 1.45 (m, 1H). Synthesis of IMA-0002517 2: To a solution of tert-butyl 2-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate 1 (3 g, 11.61 mmol, 1 eq) in ACN (45 mL) was added benzyl bromide (2.38 g, 13.94 mmol, 1.66 mL, 1.2 eq) and K2CO3(3.21 g, 23.23 mmol, 2 eq), the mixture was stirred at 50 °C for 12 h under N2. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50mL), dried with anhydrous Na2SO4, filtered, and concentrated to give tert-butyl 4-benzyl-2-(2-methoxy-2-oxo-ethyl) piperazine-1-carboxylate 2 (3.95 g, 11.34 mmol, 97.61% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.28 - 7.24 (m, 4H), 7.23 - 7.20 (m, 1H), 4.48 (br s, 1H), 3.90 - 3.76 (m, 1H), 3.57 (s, 3H), 3.51 - 3.46 (m, 1H), 3.42 - 3.36 (m, 1H), 3.10 - 2.97 (m, 1H), 2.86 - 2.56 (m, 4H), 2.12 (dd, J = 3.6, 11.6 Hz, 1H), 2.01 - 1.95 (m, 1H), 1.41 (s, 9H). 3: To a suspension of LiAlH4(2.5 M, 7.54 mL, 1.1 eq) in THF (50 mL) was added dropwise a solution of tert-butyl 4-benzyl-2-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate 2 (5.97 g, 17.13 mmol, 1 eq) in THF (50 mL) at 0 °C under nitrogen atmosphere and stirred at 0 °C for 1 h. To the reaction mixture was added Na2SO4•10H2O and stirred at 0 °C for 10 min. The resulting mixture was filtered. The filtrate was concentrated under vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% EtOAc / PE gradient @ 60mL / min) to collect the product (TLC: PE / EtOAc=1 / 1, Rf=0.70). tert-Butyl 4-benzyl-2-(2-hydroxyethyl) piperazine-1-carboxylate 3 (1.65 g, 5.15 mmol, 30.05% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.36 - 7.31 (m, 3H), 7.31 - 7.24 (m, 2H), 4.36 - 4.22 (m, 1H), 4.04 - 3.95 (m, 1H), 3.91 - 3.79 (m, 1H), 3.66 - 3.56 (m, 1H), 3.49 (br s, 2H), 3.43 - 3.32 (m, 1H), 3.07 - 2.97 (m, 1H), 2.74 - 2.68 (m, 1H), 2.28 - 2.23 (m, 1H), 2.04 - 1.99 (m, 1H), 1.73 - 1.62 (m, 1H), 1.47 (s, 10H). 4: To a solution of (COCl)2 (1.31 g, 10.30 mmol, 901.51 μL, 2 eq) in DCM (15 mL) was added a solution of DMSO (1.41 g, 18.02 mmol, 1.41 mL, 3.5 eq) in DCM (5 mL). The mixture was stirred for 30 min at -78 °C, and a solution of tert-butyl 4-benzyl-2-(2- hydroxyethyl)piperazine-1-carboxylate 3 (1.65 g, 5.15 mmol, 1 eq) in DCM (5 mL) was added to the mixture and stirred at -78 °C for 1 h. The mixture was treated with TEA (4.17 g, 41.20 mmol, 5.73 mL, 8 eq) and allowed to warm to 0 °C, then the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into water (25 mL), and after separation of the phases the organic phase was washed with water (25 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc=4 / 1 to 3 / 1 and product (Plate1-TLC, PE:EtOAc=5:1, Rf=0.50) was collected. tert-Butyl 4-benzyl-2-(2-oxoethyl)piperazine-1-carboxylate 4 (1.1 g, 3.45 mmol, 67.09% yield) was obtained as a light yellow oil.1H NMR (400 MHz, CDCl3) δ = 9.75 (t, J = 2.4 Hz, 1H), 7.34 - 7.28 (m, 4H), 7.26 - 7.23 (m, 1H), 4.63 (br d, J = 1.6 Hz, 1H), 3.99 - 3.78 (m, 1H), 3.57 - 3.39 (m, 2H), 3.15 - 2.98 (m, 1H), 2.89 - 2.74 (m, 3H), 2.69 (br d, J = 11.6 Hz, 1H), 2.22 (br dd, J = 3.2, 11.6 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.45 (s, 9H). 5: To a solution of tert-butyl 4-benzyl-2-(2-oxoethyl)piperazine-1-carboxylate 4 (1.1 g, 3.45 mmol, 1 eq) in THF (15 mL) was added bromo(phenyl)magnesium (3 M, 2.30 mL, 2 eq) at 0°C under N2, then the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into saturated aq. NH4Cl (30 mL) and extracted with dichloromethane (30 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by chromatography on silica gel eluting with PE / EtOAc=19 / 1 to 10 / 1 and product (Plate1-TLC, PE:EtOAc=5:1, Rf=0.60 and 0.40) was collected. tert-Butyl 4-benzyl-2-(2- hydroxy-2-phenyl-ethyl)piperazine-1-carboxylate 5 (571 mg, 1.44 mmol, 41.68% yield) was obtained as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.38 - 7.31 (m, 4H), 7.26 (br s, 1H), 4.51 - 4.37 (m, 2H), 4.06 - 3.83 (m, 3H), 3.17 - 2.97 (m, 2H), 2.91 - 2.78 (m, 1H), 1.58 (br s, 2H), 1.51 (s, 9H), 1.42 (br s, 9H). 6: To tert-butyl 4-benzyl-2-(2-hydroxy-2-phenyl-ethyl)piperazine-1-carboxylate 5 (571 mg, 1.44 mmol, 1 eq) was added HCl (2 M, 3 mL, 4.17 eq) in dioxane (3 mL), then the mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude product used directly in next step.2-(4-Benzylpiperazin-2-yl)-1-phenyl-ethanol 6 (615 mg, crude, HCl) was obtained as a light yellow solid. LCMS: Ret. Time: 0.367 min, M+H+, m / z: 297.2. 7: To a solution of 2-(4-benzylpiperazin-2-yl)-1-phenyl-ethanol 6 (615 mg, 1.85 mmol, 1 eq, HCl) in DMA (5 mL) was added NaH (369.48 mg, 9.24 mmol, 60% purity, 5 eq) at 0 °C and stirred at 50 °C for 0.5 h under N2.1-fluoro-4-(trifluoromethyl)benzene (454.78 mg, 2.77 mmol, 351.73 μL, 1.5 eq) was added at 25 °C and stirred at 50 °C for 1 h. The reaction solution was cooled to room temperature, the reaction mixture was quenched by addition of aq. NH4Cl (15 mL) and extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 50%-80% B over 10 min) to give 1- benzyl-3-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperazine 7 (330 mg, 719.18 μmol, 38.93% yield, 96% purity) as a light yellow solid. LCMS: Ret. Time: 0.500 min, M+H+, m / z: 441.3.1H NMR (400 MHz, CDCl3) δ = 7.43 (d, J = 8.8 Hz, 2H), 7.34 - 7.27 (m, 10H), 6.86 (d, J = 8.8 Hz, 2H), 5.35 (dd, J = 3.2, 9.6 Hz, 1H), 3.56 - 3.45 (m, 2H), 3.11 - 3.04 (m, 1H), 3.01 - 2.94 (m, 1H), 2.93 - 2.83 (m, 2H), 2.77 (br d, J = 11.2 Hz, 1H), 2.12 - 1.99 (m, 2H), 1.85 - 1.75 (m, 2H). 8: To a solution of 1-benzyl-3-[2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl] piperazine 7 (330.00 mg, 749.15 μmol, 1 eq) in DCM (4 mL) was added TEA (151.61 mg, 1.50 mmol, 208.54 μL, 2 eq) and Boc2O (245.25 mg, 1.12 mmol, 258.16 μL, 1.5 eq), then the mixture was stirred at 20 °C for 12 hr. The mixture was poured into water (10 mL) and extracted with DCM (3x10 mL), the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (PE:EtOAc=5:1) and product (Plate1, PE:EtOAc=5:1, Rf=0.40) was collected. tert-Butyl 4-benzyl-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 8 (330 mg, 604.31 μmol, 80.67% yield, 99% purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.542 min, M+H+, m / z: 541.4.1H NMR (400 MHz, CDCl3) δ = 7.33 - 7.18 (m, 12H), 6.71 (br d, J = 8.4 Hz, 2H), 4.99 - 4.90 (m, 1H), 4.31 (br d, J = 2.4 Hz, 1H), 4.06 - 3.97 (m, 1H), 3.46 (d, J = 13.2 Hz, 1H), 3.29 (d, J = 13.2 Hz, 1H), 3.08 - 2.97 (m, 1H), 2.69 (br d, J = 0.8 Hz, 2H), 2.42 - 2.29 (m, 1H), 2.17 - 2.05 (m, 2H), 1.98 (s, 1H), 1.23 - 1.01 (m, 9H). IMA-0002517: To a solution of tert-butyl 4-benzyl-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 8 (180.00 mg, 332.95 μmol, 1 eq) in DCE (18 mL) was added isobutyl carbonochloridate (136.42 mg, 998.86 μmol, 130.67 μL, 3 eq) at 0 °C and the solution was stirred at 90 °C for 12 h. The mixture was concentrated to give a residue. MeOH (18 mL) was added, and the mixture was allowed to stir at 110 °C for 12 hours in microwave. The reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by Prep-HPLC (column: Welch Xtimate C18150 x 25 mm x 5 um; mobile phase: [water (FA)-ACN]; gradient: 20%-50% B over 10 min) to give IMA-0002517 (85 mg, 171.19 μmol, 51.42% yield, 100% purity, FA) as a white solid. LCMS: Ret. Time: 0.525 min, M+H+, m / z: 451.3.1H NMR (400 MHz, CDCl3) δ = 8.29 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.38 - 7.28 (m, 5H), 6.93 (br d, J = 8.4 Hz, 2H), 5.56 (br dd, J = 3.2, 8.4 Hz, 1H), 4.28 - 4.16 (m, 1H), 4.02 (dt, J = 1.6, 4.0 Hz, 1H), 3.24 - 3.15 (m, 2H), 3.13 - 2.98 (m, 2H), 2.83 (br t, J = 10.4 Hz, 1H), 2.20 (br dd, J = 4.8, 9.2 Hz, 2H), 1.91 (br d, J = 3.2 Hz, 1H), 0.92 (br d, J = 5.6 Hz, 6H). Synthesis of IMA-0002524 2: To a mixture of O1-tert-butyl O2-methyl 2-methylpiperidine-1,2-dicarboxylate 1 (5 g, 19.43 mmol, 1 eq) in THF (50 mL) was added LiAlH4 (2.5 M, 8.55 mL, 1.1 eq) at 0 °C under N2 atmosphere, then the mixture was stirred at 0 °C for 1 h under N2 atmosphere. Water (1 mL), 15% aq. NaOH (1 mL) and water (3 mL) were added to the reaction mixture under N2atmosphere at 0 °C, the resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 10 / 1) to give tert-butyl 2-(hydroxymethyl)-2-methyl-piperidine-1-carboxylate 2 (3.3 g, 14.39 mmol, 74.06% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 4.80 - 4.64 (m, 1H), 3.91 - 3.79 (m, 1H), 3.69 - 3.61 (m, 2H), 3.04 - 2.92 (m, 1H), 1.68 - 1.60 (m, 4H), 1.46 - 1.44 (m, 9H), 1.43 - 1.26 (m, 2H), 1.24 (s, 3H). 3: To a mixture of tert-butyl 2-(hydroxymethyl)-2-methyl-piperidine-1-carboxylate 2 (3.3 g, 14.39 mmol, 1 eq) in DCM (70 mL) was added Dess-Martin (7.32 g, 17.27 mmol, 5.35 mL, 1.2 eq) at 0 °C under N2atmosphere, then the mixture was stirred at 25 °C for 2 h under N2atmosphere. The reaction was quenched with saturated aq. NaHCO3 (50 mL), extracted with DCM (50 mL × 3), the organic phases were combined, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 10 / 1) to give tert-butyl 2-formyl-2-methyl-piperidine-1-carboxylate 3 (2.4 g, 10.56 mmol, 73.37% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ = 9.17 (br s, 1H), 3.96 - 3.83 (m, 1H), 2.91 - 2.76 (m, 1H), 1.82 - 1.71 (m, 2H), 1.60 - 1.46 (m, 3H), 1.44 (s, 9H), 1.27 (s, 3H), 1.25 - 1.19 (m, 1H). 4: To a suspension of methyl(triphenyl)phosphonium bromide (5.66 g, 15.84 mmol, 3 eq) in THF (45 mL) was added sodium bis(trimethylsilyl)amide (1 M, 7.92 mL, 1.5 eq) at 0 °C under nitrogen atmosphere and stirred at 0 °C for 1 h. Then tert-butyl 2-formyl-2-methyl-piperidine-1- carboxylate 3 (1.2 g, 5.28 mmol, 1 eq) in THF (15 mL) was added to the reaction mixture at 0 °C and stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was poured into saturated aq. NH4Cl (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 10 / 1) to give tert-butyl 2-methyl-2-vinyl-piperidine-1-carboxylate 4 (1.08 g, 4.79 mmol, 90.79% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 6.06 - 5.94 (m, 1H), 4.95 - 4.91 (m, 1H), 4.90 - 4.86 (m, 1H), 3.68 - 3.58 (m, 1H), 3.32 - 3.19 (m, 1H), 1.67 - 1.58 (m, 2H), 1.57 - 1.47 (m, 4H), 1.46 - 1.41 (m, 12H). 5: tert-Butyl 2-methyl-2-vinyl-piperidine-1-carboxylate 4 (1.7 g, 7.54 mmol, 1 eq) was added to a tetrahydrofuran solution of 9-BBN (0.5 M, 60.36 mL, 4 eq)at 0 °C under N2atmosphere and the reaction solution was stirred at 25 °C for 12 h. H2O (6.71 g, 372.48 mmol, 6.71 mL, 49.37 eq), NaOH (3 M, 35.79 mL, 14.23 eq) and H2O2(26.04 g, 229.66 mmol, 22.07 mL, 30% purity, 30.44 eq) were sequentially added to the reaction solution at 0 °C, and the reaction solution was stirred at 50 °C for 2 h. After the reaction solution was cooled to room temperature, it was quenched with saturated aq. sodium thiosulfate (100 mL), extracted with EtOAc (3 x 50 mL), washed with water (2 x 50 mL) and brine (50 mL), and dried over Na2SO4, and the solvent removed under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 3 / 1) to give tert-butyl 2-(2-hydroxyethyl)-2- methyl-piperidine-1-carboxylate 5 (1.55 g, 6.37 mmol, 84.43% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 3.80 - 3.59 (m, 3H), 3.24 - 3.11 (m, 1H), 2.32 - 2.19 (m, 1H), 2.12 (td, J = 7.2, 14.0 Hz, 1H), 2.01 - 1.91 (m, 1H), 1.78 - 1.66 (m, 1H), 1.60 - 1.56 (m, 5H), 1.49 - 1.44 (m, 12H). 6: To a mixture of tert-butyl 2-(2-hydroxyethyl)-2-methyl-piperidine-1-carboxylate 5 (1.55 g, 6.37 mmol, 1 eq) in DCM (30 mL) was added Dess-Martin (3.24 g, 7.64 mmol, 2.37 mL, 1.2 eq) at 0 °C under N2 atmosphere, then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction was quenched with saturated aq. NaHCO3(50 mL), extracted with DCM (50 mL × 3), the organic phases were combined, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 0 to 5 / 1) to give tert-butyl 2-methyl-2-(2-oxoethyl)piperidine-1-carboxylate 6 (960 mg, 3.98 mmol, 62.45% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 9.81 - 9.74 (m, 1H), 3.66 - 3.51 (m, 1H), 3.37 - 3.29 (m, 1H), 3.26 (dd, J = 2.4, 15.2 Hz, 1H), 2.63 - 2.44 (m, 1H), 1.87 - 1.73 (m, 1H), 1.63 - 1.54 (m, 5H), 1.47 - 1.44 (m, 12H). IMA-0002524 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 2-methyl-2-(2-oxoethyl)piperidine-1-carboxylate and bromo(phenyl) magnesium as the starting materials. IMA-0002524 (79.14 mg, 217.77 μmol, 100.00% yield, 100% purity) was obtained as a light yellow gum. LCMS: Ret. Time: 0.491 min, M+H+, m / z: 364.3.1H NMR (400 MHz, CDCl3) δ = 8.55 - 8.43 (m, 1H), 7.48 - 7.38 (m, 2H), 7.37 - 7.29 (m, 4H), 7.27 - 7.21 (m, 1H), 6.96 - 6.85 (m, 2H), 5.48 (dd, J = 2.0, 10.4 Hz, 1H), 3.15 - 3.05 (m, 1H), 3.05 - 2.95 (m, 1H), 2.67 - 2.55 (m, 1H), 2.17 - 2.05 (m, 1H), 1.90 - 1.80 (m, 1H), 1.79 - 1.70 (m, 3H), 1.69 - 1.60 (m, 2H), 1.54 (s, 3H). Synthesis of IMA-0002525 IMA-0002525 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (S)-2-((S)-2-cyclopentyl-2-hydroxyethyl)piperidine-1-carboxylate as the starting material. IMA-0002525 (16.1 mg, 41.39 μmol, 6.81% yield, 99.6% purity, FA) was obtained as a light-yellow gum. LCMS: Ret. Time: 0.500 min, M+H+, m / z: 342.2.1H NMR (400 MHz, CD3OD) δ = 7.58 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 4.67 (ddd, J = 3.2, 6.4, 9.2 Hz, 1H), 3.35 (br d, J = 12.8 Hz, 1H), 3.22 (br t, J = 10.0 Hz, 1H), 3.02 - 2.92 (m, 1H), 2.36 - 2.22 (m, 1H), 2.17 - 2.02 (m, 2H), 1.99 - 1.89 (m, 1H), 1.88 - 1.70 (m, 4H), 1.69 - 1.53 (m, 5H), 1.51 - 1.27 (m, 4H). Synthesis of IMA-0002526 IMA-0002526 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl (R)-2-(2-oxoethyl)piperidine-1-carboxylate and bromo(cyclopentyl) magnesium as the starting materials. IMA-0002526 (63.75 mg, 162.24 μmol, 24.63% yield, 98.6% purity, FA) was obtained as a yellow gum. LCMS: Ret. Time: 0.502 min, M+H+, m / z: 342.2.1H NMR (400 MHz, CD3OD) δ = 8.56 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 4.67 (ddd, J = 3.2, 6.4, 8.8 Hz, 1H), 3.37 - 3.31 (m, 1H), 3.24 - 3.12 (m, 1H), 2.94 (dt, J = 3.2, 12.8 Hz, 1H), 2.35 - 2.20 (m, 1H), 2.16 - 2.03 (m, 2H), 1.99 - 1.88 (m, 1H), 1.86 - 1.71 (m, 4H), 1.69 - 1.50 (m, 5H), 1.49 - 1.27 (m, 4H). Synthesis of IMA-0002530 IMA-0002530 was synthesized following the same general scheme for IMA-0002025 but utilizing tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate and bromo(phenyl)magnesium as the starting materials. IMA-0002530 (73.78 mg, 206.95 μmol, 41.69% yield, 98% purity, FA) was obtained as a brown gum. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 350.2.1H NMR (400 MHz, CDCl3) δ = 8.56 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.38 - 7.27 (m, 5H), 6.87 (d, J = 8.8 Hz, 2H), 5.21 (dd, J = 3.6, 9.2 Hz, 1H), 3.44 - 3.28 (m, 2H), 2.87 - 2.69 (m, 2H), 2.08 (ddd, J = 4.8, 9.2, 14.0 Hz, 1H), 1.95 - 1.79 (m, 3H), 1.79 - 1.71 (m, 1H), 1.71 - 1.56 (m, 2H). Synthesis of IMA-0002531 IMA-0002531 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 4-[(2S)-2-hydroxy-2-phenyl-ethyl]piperidine-1-carboxylate as the starting material. IMA-0002531 (62.18 mg, 169.07 μmol, 34.06% yield, 95% purity) was obtained as a brown gum. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 350.1.1H NMR (400 MHz, CDCl3) δ = 8.57 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.38 - 7.27 (m, 5H), 6.87 (d, J = 8.8 Hz, 2H), 5.21 (dd, J = 3.6, 9.2 Hz, 1H), 3.44 - 3.20 (m, 2H), 2.88 - 2.64 (m, 2H), 2.08 (ddd, J = 4.8, 9.2, 14.0 Hz, 1H), 1.96 - 1.79 (m, 3H), 1.78 - 1.70 (m, 1H), 1.69 - 1.47 (m, 2H). Synthesis of IMA-0002533 IMA-0002533 was synthesized following the same general scheme for IMA-0002383 but utilizing 3-iodobenzonitrile and tert-butyl 2-(2-oxoethyl) piperidine-1-carboxylate as the starting materials. IMA-0002533 was obtained as an off-white solid. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 375.3.1H NMR (400 MHz, CDCl3) δ = 8.61 (s, 1H), 7.73 - 7.63 (m, 2H), 7.61 - 7.51 (m, 1H), 7.48 - 7.35 (m, 3H), 6.98 - 6.85 (m, 2H), 5.86 - 5.75 (m, 1H), 5.51 (dd, J = 5.2, 8.8 Hz, 1H), 3.25 - 3.10 (m, 1H), 3.07 - 2.96 (m, 1H), 2.78 - 2.60 (m, 1H), 2.50 (ddd, J = 5.6, 8.8, 14.2 Hz, 1H), 2.21 - 1.99 (m, 1H), 1.96 - 1.77 (m, 2H), 1.75 - 1.56 (m, 3H), 1.54 - 1.28 (m, 1H). Synthesis of IMA-0002534 IMA-0002534 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (R)-2-((S)-2-hydroxy-2-(o-tolyl)ethyl)piperidine-1-carboxylate as the starting material. IMA-0002534 (67.08 mg, 184.58 μmol, 83.85% yield, 100% purity) was obtained as a light-yellow gum. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 364.2.1H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.8 Hz, 2H), 7.38 - 7.31 (m, 1H), 7.22 - 7.11 (m, 3H), 6.85 (d, J = 8.8 Hz, 2H), 5.60 (dd, J = 2.8, 9.6 Hz, 1H), 3.17 - 3.03 (m, 1H), 3.00 - 2.83 (m, 1H), 2.63 (dt, J = 2.8, 12.0 Hz, 1H), 2.45 (s, 3H), 2.18 - 1.97 (m, 1H), 1.89 - 1.71 (m, 3H), 1.69 - 1.56 (m, 1H), 1.53 - 1.38 (m, 2H), 1.33 - 1.18 (m, 1H). Synthesis of IMA-0002535 IMA-0002535 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (S)-2-((R)-2-hydroxy-2-(o-tolyl)ethyl)piperidine-1-carboxylate as the starting material. IMA-0002535 (76.12 mg, 208.62 μmol, 94.77% yield, 99.6% purity) was obtained as a light-yellow gum. LCMS: Ret. Time: 0.500 min, M+H+, m / z: 364.2.1H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.8 Hz, 2H), 7.34 (br d, J = 5.2 Hz, 1H), 7.20 - 7.11 (m, 3H), 6.85 (d, J = 8.8 Hz, 2H), 5.58 (dd, J = 2.4, 9.6 Hz, 1H), 3.15 - 3.04 (m, 1H), 3.01 - 2.83 (m, 1H), 2.72 - 2.58 (m, 2H), 2.44 (s, 3H), 2.12 - 1.98 (m, 1H), 1.91 - 1.68 (m, 3H), 1.62 (br d, J = 7.6 Hz, 1H), 1.53 - 1.36 (m, 2H), 1.33 - 1.15 (m, 1H). Synthesis of IMA-0002540 2: To a mixture of tert-butyl 2-(2-methoxy-2-oxo-ethyl)piperazine-1-carboxylate 1 (1 g, 3.87 mmol, 1 eq) in MeOH (15 mL) was added (HCHO)n(174.36 mg, 159.96 μL) and AcOH (278.97 mg, 4.65 mmol, 265.94 μL, 1.2 eq) at 20 °C and stirred for 10 min, then NaBH3CN (291.93 mg, 4.65 mmol, 1.2 eq) was added to the mixture and stirred at 20 °C for 12 h under N2. The mixture was poured into saturated aq. NaHCO3(20 mL) the resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (20mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 5 / 1 to 10 / 1) to give tert-butyl 2-(2-methoxy-2-oxo-ethyl)-4- methyl-piperazine-1-carboxylate 2 (0.52 g, 1.91 mmol, 49.32% yield) as a light-yellow gum.1H NMR (400 MHz, CDCl3) δ = 4.57 - 4.48 (m, 1H), 3.95 - 3.81 (m, 1H), 3.67 (s, 3H), 3.13 - 3.00 (m, 1H), 2.91 - 2.79 (m, 1H), 2.73 (br d, J = 10.4 Hz, 2H), 2.61 (br dd, J = 6.0, 14.8 Hz, 1H), 2.25 (s, 3H), 2.12 (br dd, J = 3.6, 11.6 Hz, 1H), 2.00 - 1.89 (m, 1H), 1.46 (s, 9H). 3: To a mixture of tert-butyl 2-(2-methoxy-2-oxo-ethyl)-4-methyl-piperazine-1- carboxylate 2 (520 mg, 1.91 mmol, 1 eq) in THF (6 mL) was added LiAlH4 (2.5 M, 763.75 μL, 1 eq) at 0 °C under N2 atmosphere, then the mixture was stirred at 0 °C for 1 h under N2 atmosphere. Na2SO4•10H2O (740 mg) was added to the reaction mixture under N2atmosphere at 0 °C, the resulting mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (DCM / MeOH, from 5 / 1 to 10 / 1) to give tert-butyl 2-(2-hydroxyethyl)-4-methyl-piperazine-1-carboxylate 3 (450 mg, 1.84 mmol, 96.46% yield) as a yellow oil. LCMS: Ret. Time: 0.318 min, M+H+, m / z: 245.0.1H NMR (400 MHz, CDCl3) δ = 4.39 - 4.19 (m, 1H), 4.01 - 3.80 (m, 2H), 3.69 - 3.59 (m, 1H), 3.46 - 3.33 (m, 1H), 3.11 - 2.96 (m, 1H), 2.81 - 2.65 (m, 2H), 2.26 (s, 3H), 2.20 (br dd, J = 4.0, 11.2 Hz, 1H), 2.14 - 1.92 (m, 2H), 1.85 - 1.66 (m, 1H), 1.47 (s, 9H). 4: To a solution of (COCl)2(311.69 mg, 2.46 mmol, 214.96 μL, 2 eq) in DCM (10 mL) at -65 °C was added a solution of DMSO (191.87 mg, 2.46 mmol, 191.87 μL, 2 eq) in DCM (10 mL). The mixture was stirred for 30 min at -65 °C, and a solution of tert-butyl 2-(2- hydroxyethyl)-4-methyl-piperazine-1-carboxylate 3 (300 mg, 1.23 mmol, 1 eq) was added to the mixture and stirred at -65 °C for 1 h. The mixture was treated with TEA (745.47 mg, 7.37 mmol, 1.03 mL, 6 eq) and allowed to warm to 0 °C, then the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product used directly in next step. tert- Butyl 4-methyl-2-(2-oxoethyl)piperazine-1-carboxylate 4 (230 mg, 949.18 μmol, 77.30% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.99 (s, 1H), 3.91 - 3.76 (m, 1H), 3.16 - 2.99 (m, 1H), 2.01 - 1.86 (m, 4H), 1.45 (s, 3H), 1.40 - 1.31 (m, 2H), 0.66 (s, 9H). IMA-0002540 was synthesized following the same general scheme for IMA-0002370 but utilizing tert-butyl 4-methyl-2-(2-oxoethyl)piperazine-1-carboxylate and bromo(phenyl) magnesium as the starting materials. IMA-0002540 was obtained as a brown gum. LCMS: Ret. Time: 0.434 min, M+H+, m / z: 365.3.1H NMR (400 MHz, CDCl3) δ = 8.41 (s, 1H), 7.43 (br d, J = 8.8 Hz, 2H), 7.35 - 7.27 (m, 5H), 6.90 (d, J = 8.8 Hz, 2H), 5.49 - 5.36 (m, 1H), 3.38 - 3.24 (m, 1H), 3.11 - 2.87 (m, 4H), 2.43 - 2.38 (m, 3H), 2.36 - 2.26 (m, 1H), 2.25 - 2.08 (m, 2H), 1.92 (br s, 1H). Synthesis of IMA-0002542 IMA-0002542 was synthesized following the same general scheme for IMA-0002383 but utilizing 8-iodoisoquinoline and tert-butyl (R)-2-(2-oxoethyl)piperidine-1-carboxylate as the starting materials. IMA-0002542 (20.65 mg, 46.25 μmol, 15.05% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.427 min, M+H+, m / z: 401.2.1H NMR (400 MHz, CDCl3) δ = 9.70 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.50 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.63 - 7.55 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.19 (dd, J = 3.6, 9.6 Hz, 1H), 3.23 (br d, J = 11.6 Hz, 2H), 2.75 - 2.62 (m, 2H), 2.31 (ddd, J = 3.6, 7.6, 14.4 Hz, 1H), 1.99 (br dd, J = 2.8, 13.6 Hz, 1H), 1.88 (br d, J = 13.6 Hz, 1H), 1.79 - 1.61 (m, 3H), 1.48 - 1.33 (m, 1H). Synthesis of IMA-0002543 IMA-0002543 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (R)-2-((S)-2-hydroxy-2-(isoquinolin-8-yl)ethyl)piperidine-1-carboxylate as the starting material. IMA-0002543 (16.33 mg, 36.58 μmol, 5.64% yield, 100% purity, FA) was obtained as a white solid. LCMS: Ret. Time: 0.435 min, M+H+, m / z: 401.2.1H NMR (400 MHz, CDCl3) δ = 9.88 (s, 1H), 8.52 (br s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.67 (dd, J = 7.6, 13.2 Hz, 2H), 7.60 - 7.53 (m, 2H), 7.36 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.66 (br d, J = 9.6 Hz, 1H), 3.51 - 3.45 (m, 2H), 2.87 (br dd, J = 6.8, 10.0 Hz, 1H), 2.51 (br dd, J = 8.0, 14.0 Hz, 1H), 2.41 - 2.33 (m, 1H), 2.04 - 1.92 (m, 2H), 1.81 - 1.72 (m, 3H), 1.63 - 1.53 (m, 1H). IMA-0002544 was synthesized following the same general scheme for IMA-0002383 but utilizing 8-iodoisoquinoline and tert-butyl (S)-2-(2-oxoethyl)piperidine-1-carboxylate as the starting materials. IMA-0002544 (14.04 mg, 34.36 μmol, 8.38% yield, 98% purity, FA) was obtained as an off-white solid. LCMS: Ret. Time: 0.426 min, M+H+, m / z: 401.2.1H NMR (400 MHz, CDCl3) δ = 9.86 (s, 1H), 8.52 (br s, 1H), 8.38 (d, J= 5.6 Hz, 1H), 7.66 (dd, J = 7.6, 16.0 Hz, 2H), 7.59 - 7.52 (m, 2H), 7.35 (d, J= 8.4 Hz, 2H), 6.93 (d, J= 8.4 Hz, 2H), 6.64 (br d, J = 10.0 Hz, 1H), 3.55 - 3.42 (m, 2H), 2.91 - 2.82 (m, 1H), 2.57 - 2.47 (m, 1H), 2.41 - 2.31 (m, 1H), 2.03 (br dd, J = 3.2, 14.0 Hz, 1H), 1.97 - 1.90 (m, 1H), 1.83 - 1.72 (m, 3H), 1.63 - 1.50 (m, 1H). Synthesis of IMA-0002545 IMA-0002545 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl (S)-2-((S)-2-hydroxy-2-(isoquinolin-8-yl)ethyl)piperidine-1-carboxylate as the starting material. IMA-0002545 (99.08 mg, 247.43 μmol, 45.28% yield, 100% purity) was obtained as a white solid. LCMS: Ret. Time: 0.418 min, M+H+, m / z: 401.2.1H NMR (400 MHz, CDCl3) δ = 9.70 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.50 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 5.6 Hz, 2H), 7.61 - 7.55 (m, 1H), 7.37 (d, J= 8.4 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 6.19 (dd, J = 3.2, 9.6 Hz, 1H), 3.31 - 3.16 (m, 2H), 3.02 (s, 1H), 2.94 (s, 1H), 2.76 - 2.63 (m, 2H), 2.32 (ddd, J = 3.6, 8.0, 14.4 Hz, 1H), 2.09 (s, 1H), 2.03 - 1.96 (m, 1H), 1.87 (br d, J = 13.2 Hz, 1H), 1.81 - 1.57 (m, 3H), 1.49 - 1.33 (m, 1H). Synthesis of IMA-0002548 2: To a solution of LDA (2 M, 100.21 mL, 3 eq) in anhydrous THF (223 mL) was cooled to -78 °C for 1 h, and then tert-butyl acetate (23.28 g, 200.42 mmol, 26.88 mL, 3 eq) was added dropwise with stirring over 20 min. After an additional 40 minutes maintained at -78 °C, a solution of ethyl (R)-4-cyano-3-hydroxybutanoate 1 (10.5 g, 66.81mmol, 1 eq) was added dropwise. The mixture was allowed to stir at -40 °C for 4 h. The mixture was quenched by slow addition of saturated aq. NH4Cl (300 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (500 mL x 3). The combined organic layers were washed with 0.5M aq. HCl (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. tert-butyl (R)-6-cyano-5-hydroxy-3-oxohexanoate 2 (15.1 g, crude) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 4.45 - 4.37 (m, 1H), 4.18 - 4.07 (m, 1H), 3.45 - 3.39 (m, 2H), 2.94 - 2.87 (m, 2H), 2.63 - 2.61 (m, 2H), 1.49 (s, 9H). 3: To a mixture of tert-butyl (R)-6-cyano-5-hydroxy-3-oxohexanoate 2 (10 g, 44.00 mmol, 1 eq) in AcOH (100 mL) was added PtO2(1.00 g, 4.40 mmol, 0.1 eq), then the mixture was stirred at 25 °C for 12 h under H2 atmosphere (50 Psi). After the reaction was finished, wash the tubing with MeOH 200 mL, collected all the reaction solution was concentrated to give tert- butyl 2-((2S,4R)-4-hydroxypiperidin-2-yl)acetate (8 g, crude) as a light yellow gum. tert-butyl 2- ((2S,4R)-4-hydroxypiperidin-2-yl)acetate (8 g, 37.16 mmol, 1 eq) was dissolved in THF (10 mL) and aq. NaHCO3 (1 M, 120 mL, 3.23 eq). To the mixture was added Boc2O (12.16 g, 55.74 mmol, 12.81 mL, 1.5 eq) and stirred at 30 °C for 12 h. The reaction mixture was extracted with DCM (200 mL x 3) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 1 / 1), the purified solution was concentrated under reduced pressure to give tert-butyl (2S,4R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-hydroxypiperidine- 1-carboxylate 3 (6.78 g, 21.50 mmol, 57.85% yield) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ = 4.53 (br d, J = 5.6 Hz, 1H), 4.19 - 4.14 (m, 1H), 3.84 (br d, J = 13.2 Hz, 1H), 3.27 - 3.15 (m, 1H), 2.87 (dd, J = 9.6, 13.2 Hz, 1H), 2.62 (dd, J = 6.8, 13.2 Hz, 1H), 2.37 - 2.16 (m, 1H), 1.82 - 1.75 (m, 2H), 1.70 - 1.63 (m, 2H), 1.44 (d, J = 5.2 Hz, 18H). 4: To a stirred solution of tert-butyl (2S,4R)-2-(2-(tert-butoxy)-2-oxoethyl)-4- hydroxypiperidine-1-carboxylate 3 (6.78 g, 21.50 mmol, 1 eq) in DMF (70 mL) was added imidazole (3.32 g, 48.80 mmol, 2.27 eq) and tert-butyl(chloro)diphenylsilane (6.50 g, 23.65 mmol, 6.05 mL, 1.1 eq) and the reaction stirred at 25 °C for 16 h. The reaction mixture was poured into aq. NH4Cl (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=5% EtOAc), the purified solution was concentrated under reduced pressure to give tert-butyl (2S,4R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-((tert-butyldiphenylsilyl)oxy) piperidine-1-carboxylate 4 (11.1 g, crude) as a colorless oil. LCMS: Ret. Time: 0.777 min, M+H+, m / z: 554.4.1H NMR (400 MHz, CDCl3) δ = 7.73 (br d, J = 6.8 Hz, 2H), 7.69 - 7.62 (m, 4H), 7.43 (br d, J = 7.2 Hz, 4H), 4.67 - 4.55 (m, 1H), 4.11 (br d, J = 2.8 Hz, 1H), 3.82 (br d, J = 13.2 Hz, 1H), 3.38 - 3.11 (m, 2H), 2.72 (br dd, J = 3.2, 14.4 Hz, 1H), 1.95 (br d, J = 14.4 Hz, 1H), 1.72 - 1.60 (m, 1H), 1.45 (d, J = 1.6 Hz, 18H), 1.35 (br s, 2H), 1.12 (s, 9H). 5: To a mixture of tert-butyl (2S,4R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-((tert- butyldiphenylsilyl)oxy)piperidine-1-carboxylate 4 (11.1 g, 20.04 mmol, 1 eq) in THF (110 mL) was added LiAlH4(2.5 M, 10.00 mL, 1.25 eq) at 0 °C under N2atmosphere, then the mixture was stirred at 0 °C for 1 h under N2 atmosphere. To the reaction mixture was added THF (100 mL) at 0 °C under N2. Na2SO4•10H2O (10 g) and H2O (1 mL) were added to the reaction mixture under N2atmosphere at 0 °C slowly and stirred at 0 °C for 0.5 h, the resulting mixture was filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0to 1 / 1), the purified solution was concentrated under reduced pressure to give tert-butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2- hydroxyethyl)piperidine-1-carboxylate 5 (7.6 g, 15.71 mmol, 78.39% yield) as a colorless oil. LCMS: Ret. Time: 0.699 min, M+Na+, m / z: 506.2.1H NMR (400 MHz, CDCl3) δ = 7.65 (t, J = 6.4 Hz, 4H), 7.49 - 7.34 (m, 6H), 4.40 (br s, 1H), 4.22 - 4.08 (m, 1H), 3.84 (br d, J = 12.4 Hz, 1H), 3.64 (td, J = 3.6, 11.2 Hz, 1H), 3.45 (br t, J = 11.2 Hz, 1H), 3.25 (dt, J = 3.2, 12.8 Hz, 1H), 2.62 - 2.46 (m, 1H), 1.85 - 1.61 (m, 3H), 1.47 (s, 11H), 1.08 (s, 9H). 6: To a mixture of tert-butyl (2R,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2- hydroxyethyl)piperidine-1-carboxylate 5 (7.4 g, 15.30 mmol, 1 eq) in DCM (160 mL) was added Dess-Martin (8.41 g, 19.83 mmol, 6.14 mL, 1.30 eq) at 0 °C under N2atmosphere, then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction was dissolved in DCM (500 mL), washed with aq. NaHCO3(100 mL x 3) and aq. Na2SO3(100 mL x 3), combined the organic phase and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=10% EtOAc), the purified solution was concentrated under reduced pressure to give tert-butyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2- oxoethyl)piperidine-1-carboxylate 6 (6.3 g, 13.08 mmol, 85.49% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 9.75 (t, J = 2.4 Hz, 1H), 7.68 - 7.59 (m, 4H), 7.48 - 7.42 (m, 2H), 7.41 - 7.36 (m, 4H), 4.74 (br d, J = 4.8 Hz, 1H), 4.15 (br d, J = 1.6 Hz, 1H), 3.87 (br d, J = 12.0 Hz, 1H), 3.32 (dt, J = 2.8, 13.2 Hz, 1H), 3.16 - 3.01 (m, 2H), 1.81 - 1.65 (m, 2H), 1.52 - 1.35 (m, 11H), 1.09 (s, 9H). 7A, 7B: To a solution of tert-butyl (2S,4R)-4-((tert-butyldiphenylsilyl)oxy)-2-(2- oxoethyl)piperidine-1-carboxylate 6 (6.1 g, 12.66 mmol, 1 eq) in THF (120 mL) was added PhMgBr (3 M, 7.00 mL, 1.66 eq) at 0 °C under N2, then the mixture was stirred at 25 °C for 2 h under N2. The reaction mixture was poured into saturated aq. NH4Cl (100 mL) and extracted with dichloromethane (100 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=17% EtOAc), the purified solution was concentrated to give tert-butyl (2R,4R)-4- [tert-butyl(diphenyl)silyl]oxy-2-[(2R)-2-hydroxy-2-phenyl-ethyl]piperidine-1-carboxylate 7B (4.38 g, 7.82 mmol, 61.78% yield) as a light yellow oil. tert-Butyl (2R,4R)-4-[tert- butyl(diphenyl)silyl]oxy-2-[(2S)-2-hydroxy-2-phenyl-ethyl]piperidine-1-carboxylate 7A (2.27 g, 4.05 mmol, 32.02% yield) was obtained as a light yellow oil. LCMS of 7A and 7B: Ret. Time: 0.769 min, M+H-C4H8-18+, m / z: 486.3.1H NMR of 7B: (400 MHz, CDCl3) δ = 7.64 - 7.56 (m, 4H), 7.45 - 7.40 (m, 5H), 7.37 - 7.32 (m, 6H), 4.53 (br d, J = 10.4 Hz, 2H), 4.20 - 4.16 (m, 1H), 4.03 - 3.85 (m, 1H), 3.47 - 3.30 (m, 1H), 3.07 - 2.88 (m, 1H), 1.81 - 1.72 (m, 1H), 1.67 (br d, J = 14.8 Hz, 2H), 1.55 - 1.40 (m, 11H), 0.99 (s, 9H).1H NMR of 7A: (400 MHz, CDCl3) δ = 7.66 - 7.60 (m, 4H), 7.46 - 7.40 (m, 2H), 7.39 - 7.29 (m, 8H), 7.26 - 7.21 (m, 1H), 4.79 (dd, J = 4.0, 8.4 Hz, 1H), 4.39 (br d, J = 5.4 Hz, 1H), 4.19 - 4.16 (m, 1H), 3.73 (br d, J = 11.2 Hz, 1H), 3.41 - 3.23 (m, 1H), 2.61 - 2.48 (m, 1H), 2.29 (td, J = 4.8, 14.5 Hz, 1H), 1.80 - 1.73 (m, 1H), 1.71 - 1.63 (m, 1H), 1.50 - 1.38 (m, 11H), 1.04 (s, 9H). 8: To a solution of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2R)-2-hydroxy- 2-phenyl-ethyl]piperidine-1-carboxylate 7B (2 g, 3.57 mmol, 1 eq) in toluene (20 mL) was added 4-(trifluoromethyl)phenol (869 mg, 5.36 mmol, 1.5 eq), (NE)-N-(piperidine-1- carbonylimino)piperidine-1-carboxamide (1.35 g, 5.36 mmol, 1.5 eq) and tributylphosphine (1.08 g, 5.36 mmol, 1.32 mL, 1.5 eq) at 20 °C. The mixture was degassed and purged with N23 times and warmed to 110 °C and stirred at 110 °C for 12 h. The reaction mixture was cooled to 20 °C, poured into brine (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2,PE / EtOAc=7% EtOAc), the purified solution was concentrated under reduced pressure to give tert-butyl (2R,4R)-4-[tert- butyl(diphenyl)silyl]oxy-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1- carboxylate 8 (1.4 g, 1.99 mmol, 55.67% yield) as a light yellow gum. LCMS: Ret. Time: 0.858 min, M+Na+, m / z: 726.3.1H NMR (400 MHz, CDCl3) δ = 7.65 (dd, J = 1.2, 8.0 Hz, 4H), 7.49 - 7.27 (m, 13H), 6.86 (d, J = 8.4 Hz, 2H), 5.21 (br dd, J = 4.8, 7.2 Hz, 1H), 4.50 (br s, 1H), 4.25 - 4.17 (m, 1H), 3.95 - 3.82 (m, 1H), 3.54 - 3.40 (m, 1H), 3.02 - 2.85 (m, 1H), 2.30 - 2.14 (m, 1H), 1.72 - 1.61 (m, 2H), 1.50 - 1.42 (m, 2H), 1.35 (s, 9H), 1.09 (s, 9H). 9: A mixture of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2S)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 8 (1.2 g, 1.70 mmol, 1 eq) in TBAF (1 M, 20 mL, 11.73 eq) was stirred at 30 °C for 2 h. The mixture was dissolved in DCM (100 mL) and washed with water (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 1 / 1), the purified solution was concentrated under reduced pressure to give tert-butyl (2S,4R)-4-hydroxy-2-[(2S)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 9 (660 mg, 1.42 mmol, 83.17% yield) as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.41 (d, J = 8.8 Hz, 2H), 7.39 - 7.36 (m, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.25 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 5.31 (dd, J = 4.4, 8.2 Hz, 1H), 4.50 (br s, 1H), 4.20 (br s, 1H), 3.94 - 3.85 (m, 1H), 3.34 (br t, J = 12.0 Hz, 1H), 2.69 - 2.49 (m, 1H), 2.37 - 2.24 (m, 1H), 1.81 - 1.70 (m, 3H), 1.67 (br s, 1H), 1.65 - 1.60 (m, 1H), 1.39 (s, 9H). IMA-0002548: A mixture of tert-butyl (2S,4R)-4-hydroxy-2-[(2S)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 9 (60 mg, 128.89 μmol, 1 eq) in HCl / dioxane (2 M, 4 mL, 62.07 eq) was stirred at 25 °C for 30 min. The mixture was concentrated (20 °C) to give a residue. The residue was purified by prep-HPLC (column: YMC- Actus Triart C18150 x 30 mm x 7 um; mobile phase: [water(FA)-ACN]; gradient:20%-50% B over 10 min), the purified solution was lyophilized to give IMA-0002548 (13.91 mg, 33.57 μmol, 26.05% yield, 99.3% purity, FA) as a yellow solid. LCMS: Ret. Time: 0.460 min, M+H+, m / z: 366.2.1H NMR (400 MHz, CDCl3) δ = 8.41 (s, 1H), 7.44 (br d, J = 8.8 Hz, 2H), 7.36 - 7.28 (m, 5H), 6.90 (br d, J = 8.8 Hz, 2H), 5.37 (br dd, J = 3.2, 8.8 Hz, 1H), 3.76 - 3.63 (m, 1H), 3.33 - 3.17 (m, 2H), 2.76 - 2.63 (m, 1H), 2.54 - 2.39 (m, 1H), 2.14 (br d, J = 13.2 Hz, 1H), 2.09 - 1.94 (m, 2H), 1.74 - 1.47 (m, 2H). Synthesis of IMA-0002549 2: To a solution of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2S)-2-hydroxy- 2-phenyl-ethyl]piperidine-1-carboxylate 1 (1 g, 1.79 mmol, 1 eq) in toluene (10 mL) was added 4-(trifluoromethyl)phenol (435.00 mg, 2.68 mmol, 1.5 eq), (NE)-N-(piperidine-1- carbonylimino)piperidine-1-carboxamide (676.00 mg, 2.68 mmol, 1.5 eq) and tributylphosphine (542.00 mg, 2.68 mmol, 660.98 μL, 1.5 eq) at 20 °C. The mixture was degassed and purged with N23 times and warmed to 110 °C and stirred at 110 °C for 12 h. The reaction mixture was cooled to 20 °C, the reaction mixture poured into brine (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=7% EtOAc), the purified solution was concentrated under reduced pressure to give tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2R)-2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 2 (1 g, 1.42 mmol, 79.53% yield) as a light yellow gum. LCMS: Ret. Time: 0.833 min, M+Na+, m / z: 726.3.1H NMR (400 MHz, CDCl3) δ = 7.62 - 7.54 (m, 4H), 7.46 - 7.29 (m, 13H), 6.88 (d, J = 8.8 Hz, 2H), 5.10 (dd, J = 2.4, 10.0 Hz, 1H), 4.57 (br d, J = 2.0 Hz, 1H), 4.20 - 4.16 (m, 1H), 4.09 - 3.87 (m, 1H), 3.41 - 3.23 (m, 1H), 2.86 (ddd, J = 2.4, 10.8, 15.2 Hz, 1H), 2.31 - 2.19 (m, 1H), 1.71 (br s, 2H), 1.53 - 1.41 (m, 2H), 1.25 - 1.07 (m, 9H), 0.92 (s, 9H). 3: A mixture of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2R)-2-phenyl-2- [4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (0.8 g, 1.14 mmol, 1 eq) in TBAF (1 M, 10 mL, 8.80 eq) was stirred at 30 °C for 2 h. The mixture was dissolved in DCM (100 mL) and washed with water (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 1 / 1), the purified solution was concentrated under reduced pressure to give tert-butyl (2S,4R)-4-hydroxy-2-[(2R)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 3 (520 mg, 1.12 mmol, 98.29% yield) as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 8.8 Hz, 2H), 7.35 - 7.28 (m, 4H), 7.27 - 7.22 (m, 1H), 6.90 (d, J = 8.8 Hz, 2H), 5.10 (br d, J = 10.0 Hz, 1H), 4.61 (br d, J = 4.8 Hz, 1H), 4.22 (br d, J = 2.0 Hz, 1H), 4.08 - 3.90 (m, 1H), 3.34 - 3.20 (m, 1H), 2.67 - 2.52 (m, 1H), 2.31 - 2.15 (m, 1H), 1.96 - 1.87 (m, 1H), 1.81 - 1.64 (m, 3H), 1.29 - 1.16 (m, 10H). IMA-0002549: A mixture of tert-butyl (2S,4R)-4-hydroxy-2-[(2R)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 3 (60.00 mg, 128.89 μmol, 1 eq) in HCl / dioxane (2 M, 2.00 mL, 31.03 eq) was stirred at 25 °C for 30 min. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18150 x 30 mm x 7 um; mobile phase: [water(FA)-ACN]; gradient:20%-50% B over 10 min), the purified solution was lyophilized to give IMA-0002549 (25.56 mg, 62.13 μmol, 48.20% yield, 100% purity, FA) as a yellow solid. LCMS: Ret. Time: 0.452 min, M+H+, m / z: 366.1.1H NMR (400 MHz, CDCl3) δ = 8.38 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.37 - 7.27 (m, 5H), 6.92 (br d, J = 8.8 Hz, 2H), 5.71 - 5.52 (m, 1H), 3.83 - 3.77 (m, 1H), 3.32 (br d, J = 13.6 Hz, 1H), 3.26 - 3.15 (m, 1H), 2.86 - 2.69 (m, 1H), 2.34 - 2.17 (m, 3H), 2.05 (br d, J = 12.8 Hz, 1H), 1.86 - 1.60 (m, 2H). Synthesis of IMA-0002550 2: To a solution of benzyl 5-[tert-butyl(dimethyl)silyl]oxy-2-(2-hydroxy-2-phenyl- ethyl)piperidine-1-carboxylate 1 (400.00 mg, 851.63 μmol, 1 eq) in MeOH (10 mL) was added Pd / C (90.63 mg, 85.16 μmol, 10% purity, 0.1 eq) under N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (40 Psi) at 20 °C for 12 h. The mixture was filtered through filter cake and the filtrate was concentrated and the crude product used directly in next step.2-[5-[tert-butyl(dimethyl)silyl]oxy-2-piperidyl]-1-phenyl- ethanol 2 (229 mg, 682.45 μmol, 80.13% yield, N / A purity) was obtained as a gray solid. LCMS: Ret. Time: 0.516 min, M+H+, m / z: 366.1. 3: To a solution of 2-[5-[tert-butyl(dimethyl)silyl]oxy-2-piperidyl]-1-phenyl-ethanol 2 (229.00 mg, 682.45 μmol, 1 eq) in DMA (4 mL) was added NaH (68.24 mg, 1.71 mmol, 60% purity, 2.5 eq) at 0 °C under and stirred at 20 °C for 0.5 h. Then 1-fluoro-4-(trifluoromethyl) benzene (167.99 mg, 1.02 mmol, 129.92 μL, 1.5 eq) was added and stirred at 20 °C for 2 h. The reaction solution was cooled to room temperature, the reaction mixture was quenched by addition of aq. NH4Cl (15 mL) and extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna (C18150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 35%-65% B over 9 min), the purified solution was lyophilized to give tert-butyl-dimethyl-[[6-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]-3-piperidyl]oxy]silane 3 (115 mg, 218.77 μmol, 32.06% yield, FA) as a light yellow solid. LCMS: Ret. Time: 0.585 min, M+H+, m / z: 480.3.1H NMR 400 MHz, CDCl3) δ = 7.45 - 7.35 (m, 4H), 7.33 - 7.29 (m, 2H), 7.27 - 7.22 (m, 1H), 7.01 - 6.96 (m, 2H), 5.83 - 5.69 (m, 1H), 4.09 - 4.00 (m, 1H), 3.21 - 3.12 (m, 1H), 3.08 - 3.00 (m, 1H), 2.63 - 2.50 (m, 1H), 2.18 - 1.98 (m, 2H), 1.70 (br s, 4H), 0.84 - 0.75 (m, 9H), 0.08 - -0.01 (m, 6H). IMA-0002550: To a solution of tert-butyl-dimethyl-[[6-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl] -3-piperidyl]oxy]silane 3 (115 mg, 218.77 μmol, 1 eq, FA) in dioxane (2 mL) was added HCl / dioxane (2 M, 2 mL, 18.28 eq) and stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenexluna (C18150 x 25mm x 10um; mobile phase: [water (HCl)- ACN]; gradient: 18%-48% B over 10 min), the purified solution was lyophilized to give IMA- 0002550 (43.75 mg, 108.44 μmol, 49.57% yield, 99.6% purity, HCl) as a white solid. LCMS: Ret. Time: 0.477 min, M+H+, m / z: 366.0.1H NMR (400 MHz, CDCl3) δ = 10.03 - 9.88 (m, 1H), 8.54 - 8.40 (m, 1H), 7.41 - 7.35 (m, 4H), 7.24 (br d, J = 4.8 Hz, 3H), 6.99 (br d, J = 8.4 Hz, 2H), 5.97 - 5.83 (m, 1H), 4.17 (br s, 1H), 3.69 (br d, J = 12.4 Hz, 1H), 3.30 (br d, J = 2.4 Hz, 1H), 2.96 (br t, J = 11.2 Hz, 1H), 2.56 (br dd, J = 6.8, 14.4 Hz, 1H), 2.36 - 2.21 (m, 1H), 2.13 (br d, J = 13.2 Hz, 1H), 1.95 (br d, J = 14.0 Hz, 1H), 1.81 (br d, J = 12.4 Hz, 1H), 1.68 - 1.54 (m, 1H). Synthesis of IMA-0002551 2: To a mixture of 6-methylpyridin-3-ol 1 (20 g, 183.28 mmol, 1 eq) in DMF (200 mL) was added imidazole (24.95 g, 366.55 mmol, 2 eq). The reaction mixture was stirred under nitrogen atmosphere. To this solution was added tert-butyldimethylsilyl chloride (37.29 g, 247.42 mmol, 30.44 mL, 1.35 eq), the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with aq. NH4Cl (1 L). The solution was extracted with EtOAc (3 x 500 mL), washed with brine (3 x 500 mL), and dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 10 / 1) to give tert-butyl-dimethyl-[(6-methyl-3-pyridyl)oxy] silane 2 (34.8 g, 155.78 mmol, 85.00% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 8.09 (d, J = 2.4 Hz, 1H), 7.05 - 7.01 (m, 1H), 7.01 - 6.97 (m, 1H), 2.46 (s, 3H), 0.97 (s, 9H), 0.21 - 0.15 (m, 6H). 3: To a solution of tert-butyl-dimethyl-[(6-methyl-3-pyridyl)oxy]silane 2 (34.8 g, 155.78 mmol, 1 eq) in THF (700 mL)at -70 °C was added slowly LDA (2 M, 156.00 mL, 2 eq) under N2atmosphere. The reaction mixture was stirred at -70 °C for further 10 minutes. Then a solution of dimethyl carbonate (28.07 g, 311.57 mmol, 26.25 mL, 2 eq) was added to the mixture at -70 °C. The reaction mixture was stirred at -70 °C for 1 h under N2atmosphere. The reaction mixture was quenched with saturated aq. ammonium chloride (1L). The solution was extracted with EtOAc (3 x 1L), washed with brine (3 x 500 mL), and dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EtOAc=20% / EtOAc) to give methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-2-pyridyl]acetate 3 (20 g, 71.07 mmol, 45.62% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.15 (d, J = 2.8 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.08 (m, 1H), 3.78 (s, 2H), 3.71 (s, 3H), 0.98 (s, 8H), 0.21 (s, 6H). 4: A solution of methyl 2-[5-[tert-butyl (dimethyl) silyl] oxy-2-pyridyl] acetate 3 (10.00 g, 35.53 mmol, 1 eq) in IPA (250 mL) was stirred at 25 °C until becoming clear solution. Adjust the H2 back pressure regulator to 2.5 MPa, the flow rate of H2 to 90 mL / min, heated the fixed bed (10% Ru / SiO2, 12 g) to 100 °C. Then the solution was pumped into the reactor at a flow rate of 1 mL / min. After the reaction was finished, wash the tubing with IPA 200 mL, collected all the reaction solution for analysis. The mixture was concentrated under reduced pressure to give the crude product used directly in the next step. Methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-2- piperidyl]acetate 4 (9.77 g, 33.99 mmol, 95.64% yield) was obtained as a colorless oil. LCMS: Ret. Time: 0.460 min, M+H+, m / z: 288.2.1H NMR (400 MHz, CDCl3) δ = 3.60 (br d, J = 5.6 Hz, 1H), 3.54 (br s, 3H), 2.91 - 2.81 (m, 1H), 2.77 - 2.70 (m, 1H), 2.66 - 2.59 (m, 1H), 2.29 - 2.26 (m, 1H), 1.66 - 1.58 (m, 1H), 1.57 - 1.31 (m, 4H), 1.15 - 1.08 (m, 1H), 0.78 (s, 9H), -0.07 - -0.09 (m, 6H). 5: To a solution of methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-2-piperidyl]acetate 4 (8.00 g, 27.83 mmol, 1 eq) in DCM (80 mL) was added DIPEA (10.76 g, 83.25 mmol, 14.5 mL, 2.99 eq), then CbzCl (7.12 g, 41.74 mmol, 5.96 mL, 1.5 eq) was added and stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of saturated aq. NH4Cl (100 mL), and then extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~10% EtOAc / PE gradient @ 80 mL / min). Benzyl 5-[tert- butyl(dimethyl)silyl]oxy-2-(2-methoxy-2-oxo-ethyl)piperidine-1-carboxylate 5 (6.17 g, 14.63 mmol, 52.59% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.37 - 7.24 (m, 5H), 5.16 - 5.02 (m, 2H), 4.75 - 4.58 (m, 1H), 4.18 - 3.99 (m, 1H), 3.62 - 3.47 (m, 4H), 2.66 - 2.47 (m, 3H), 1.82 - 1.72 (m, 1H), 1.67 - 1.57 (m, 2H), 1.55 - 1.41 (m, 1H), 0.84 (br s, 9H), 0.02 (br d, J = 14.4 Hz, 6H). 6: Benzyl 5-[tert-butyl(dimethyl)silyl]oxy-2-(2-methoxy-2-oxo-ethyl)piperidine-1- carboxylate 5 (6.17 g, 14.63 mmol, 1 eq) was dissolved in EtOH (80 mL), H2O (20 mL) and CaCl2(4.43 g, 39.92 mmol, 2.73 eq) was added. NaBH4(3.02 g, 79.83 mmol, 5.45 eq) was added in portions at 25 °C. The reaction mixture was stirred for 12 h under N2. The mixture was added into aq. NH4Cl (100 mL, 20 °C) slowly and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc / PE gradient @ 90 mL / min). Benzyl 5-[tert-butyl(dimethyl)silyl] oxy-2-(2-hydroxyethyl)piperidine-1- carboxylate 6 (3.5 g, 8.89 mmol, 60.76% yield, N / A purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.658 min, M+H+, m / z: 394.3.1H NMR (400 MHz, CDCl3) δ = 7.42 - 7.30 (m, 5H), 5.25 - 5.05 (m, 2H), 4.48 - 4.35 (m, 1H), 4.12 - 4.03 (m, 1H), 3.62 (br s, 2H), 3.43 - 3.32 (m, 1H), 2.62 - 2.50 (m, 1H), 2.01 - 1.89 (m, 1H), 1.86 - 1.74 (m, 2H), 1.66 - 1.46 (m, 3H), 0.93 - 0.85 (m, 9H), 0.14 - 0.04 (m, 6H). 7: To a solution of (COCl)2 (2.32 g, 18.28 mmol, 1.6 mL, 2.06 eq) in DCM (50 mL) at - 65 °C was added a solution of DMSO (1.40 g, 17.92 mmol, 1.4 mL, 2.01 eq) in DCM (1.6 mL). The mixture was stirred for 30 min at -65 °C, and a solution of benzyl 5-[tert-butyl(dimethyl) silyl]oxy-2-(2-hydroxyethyl)piperidine-1-carboxylate 6 (3.50 g, 8.89 mmol, 1 eq) in DCM (30 mL) was added to the mixture and stirred at -65 °C for 1 h. The mixture was treated with TEA (5.38 g, 53.17 mmol, 7.4 mL, 5.98 eq) and allowed to warm to 0 °C, then the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into water (100 mL), and after separation of the phases the organic phase was washed with water (100 mL). The organic phase was dried over sodium Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in next step. Benzyl 5-[tert-butyl(dimethyl)silyl]oxy-2-(2-oxoethyl) piperidine-1- carboxylate 7 (3.48 g, 8.89 mmol, 100.00% yield) was obtained as a light yellow oil.1H NMR (400 MHz, CDCl3) δ = 9.75 - 9.56 (m, 1H), 7.38 - 7.24 (m, 5H), 5.16 - 4.99 (m, 2H), 4.90 - 4.69 (m, 1H), 4.19 - 3.92 (m, 1H), 3.60 - 3.41 (m, 1H), 2.79 - 2.64 (m, 1H), 2.62 - 2.49 (m, 2H), 1.85 (br s, 2H), 1.62 - 1.42 (m, 2H), 0.92 - 0.75 (m, 9H), 0.10 - 0.09 (m, 6H). 8A, 8B: To a solution of benzyl 5-[tert-butyl(dimethyl)silyl]oxy-2-(2-oxoethyl) piperidine-1-carboxylate 7 (3.48 g, 8.89 mmol, 1 eq) in THF (50 mL) was added PhMgBr (3 M, 4.5 mL, 1.52 eq) at 0 °C under N2, the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into aq. NH4Cl (50 mL) and extracted with dichloromethane (50 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~7% EtOAc / PE gradient @ 60 mL / min). Benzyl 5-[tert-butyl(dimethyl)silyl]oxy-2-(2- hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate 8A (1.55 g, 3.30 mmol, 37.13% yield) was obtained as a colorless gum. Benzyl 5-[tert-butyl(dimethyl)silyl]oxy-2-(2-hydroxy-2-phenyl- ethyl)piperidine-1-carboxylate 8B (1.65 g, 3.51 mmol, 39.53% yield) was obtained as a colorless gum. LCMS of 8A and 8B: Ret. Time: 0.700 min, M+H+, m / z: 452.3 and Ret. Time: 0.717 min, M+H+, m / z: 452.3.1H NMR of 8A: (400 MHz, CDCl3) δ = 7.43 - 7.28 (m, 9H), 7.25 (br s, 1H), 5.28 (br s, 2H), 4.64 - 4.55 (m, 1H), 4.49 - 4.37 (m, 1H), 3.67 - 3.51 (m, 1H), 2.71 - 2.58 (m, 1H), 2.30 - 2.18 (m, 1H), 1.87 - 1.76 (m, 2H), 1.72 - 1.41 (m, 4H), 0.89 (s, 9H), 0.13 - 0.05 (m, 6H).1H NMR of 8B: (400 MHz, CDCl3) δ = 7.40 - 7.29 (m, 8H), 7.27 - 7.22 (m, 2H), 5.21 - 5.03 (m, 2H), 4.82 - 4.58 (m, 1H), 4.49 - 4.30 (m, 1H), 3.62 - 3.46 (m, 1H), 2.73 - 2.56 (m, 1H), 2.27 - 2.12 (m, 1H), 1.92 - 1.74 (m, 3H), 1.71 - 1.48 (m, 3H), 0.96 - 0.80 (m, 9H), 0.15 - -0.03 (m, 6H). 9: To a solution of benzyl 5-[tert-butyl(dimethyl)silyl]oxy-2-(2-hydroxy-2-phenyl- ethyl)piperidine-1-carboxylate 8B (1.65 g, 3.51 mmol, 1 eq) in MeOH (200 mL) was added Pd / C (373.85 mg, 351.30 μmol, 10% purity, 0.1 eq) under N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(40 psi) at 25 °C for 12 h. The reaction mixture was filtered and Pd / C (1.12 g, 1.05 mmol, 10% purity, 0.3 eq) was added and stirred at 25 °C for 2 h under H2 (40 Psi). The mixture was filtered through Celatom® and the filtrate was concentrated. The crude product was used directly in the next step.2-[5-[tert- butyl(dimethyl)silyl]oxy-2-piperidyl]-1-phenyl-ethanol 9 (1.1 g, 3.28 mmol, 93.32% yield) was obtained as a gray gum. LCMS: Ret. Time: 0.492 min, M+H+, m / z: 336.2.1H NMR (400 MHz, CDCl3) δ = 7.45 - 7.31 (m, 4H), 7.26 - 7.17 (m, 1H), 5.04 - 4.90 (m, 1H), 3.80 (br s, 1H), 2.92 (br s, 2H), 2.81 - 2.71 (m, 1H), 1.86 - 1.64 (m, 3H), 1.61 - 1.48 (m, 2H), 1.46 - 1.39 (m, 1H), 0.92 (s, 9H), 0.11 - 0.00 (m, 6H). 10: To a solution of 2-[5-[tert-butyl(dimethyl)silyl]oxy-2-piperidyl]-1-phenyl-ethanol 9 (1.10 g, 3.28 mmol, 1 eq) in DMA (15 mL) was added NaH (327.78 mg, 8.20 mmol, 60% purity, 2.5 eq) at 0 °C under and stirred at 20 °C for 0.5 h.1-Fluoro-4-(trifluoromethyl) benzene (806.92 mg, 4.92 mmol, 624.07 μL, 1.5 eq) was added and stirred at 20 °C for 2 h. The reaction mixture was poured into aq. NH4Cl (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 x 3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl-dimethyl-[[6-[2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl]-3-piperidyl]oxy]silane 10 (1.5 g, 3.13 mmol, 95.40% yield) as a yellow oil. LCMS: Ret. Time: 0.580 min, M+H+, m / z: 480.3. IMA-0002551: To a solution of tert-butyl-dimethyl-[[6-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]-3-piperidyl]oxy]silane 10 (100 mg, 208.49 μmol, 1 eq) in HCl / dioxane (2 M, 4 mL, 38.37 eq) was stirred at 20 °C for 12 h. The reaction mixture was concentrated to give the crude. The crude product was purified with prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (HCl)-ACN]; gradient:18%-48% B over 10 min) and lyophilized to give IMA-0002551 (7.45 mg, 18.34 μmol, 8.79% yield, 98.9% purity, HCl) as a white solid. LCMS: Ret. Time: 0.477 min, M+H+, m / z: 366.0.1H NMR (400 MHz, CDCl3) δ = 9.76 - 9.49 (m, 1H), 8.65 - 8.47 (m, 1H), 7.41 (br d, J = 8.4 Hz, 4H), 7.33 - 7.28 (m, 2H), 7.26 - 7.23 (m, 1H), 6.93 (br d, J = 8.4 Hz, 2H), 5.53 (br dd, J = 5.2, 8.4 Hz, 1H), 4.11 - 3.96 (m, 1H), 3.60 (br d, J = 12.8 Hz, 1H), 3.21 - 3.05 (m, 1H), 2.89 - 2.75 (m, 2H), 2.27 - 2.20 (m, 1H), 2.11 - 1.98 (m, 1H), 1.86 (br d, J = 13.6 Hz, 1H), 1.64 (br d, J = 13.2 Hz, 1H), 1.49 - 1.39 (m, 1H). Synthesis of IMA-0002552 2: To a solution of tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate 1 (4.1 g, 17.80 mmol, 1 eq) and NaHCO3 (7.48 g, 89.01 mmol, 3.46 mL, 5 eq) in THF (40 mL) and H2O (20 mL) was added CbzCl (6.07 g, 35.61 mmol, 5.08 mL, 2 eq ) at 0 °C, then the mixture was stirred at 25 °C for 12 hr. The mixture was poured into H2O (20 mL) the resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 5 / 1).1-Benzyl 4-(tert-butyl) 2-(2-hydroxyethyl)piperazine- 1,4-dicarboxylate 2 (4.5 g, 12.35 mmol, 69.36% yield) was obtained as a light-yellow oil. LCMS: Ret. Time: 0.510 min, M+H+, m / z: 387.1.1H NMR (400 MHz, CDCl3) δ = 7.40 - 7.30 (m, 5H), 5.16 (br d, J = 2.4 Hz, 2H), 4.45 - 4.29 (m, 1H), 4.08 - 3.85 (m, 3H), 3.66 - 3.58 (m, 1H), 3.44 - 3.29 (m, 1H), 3.17 - 3.04 (m, 1H), 3.02 - 2.73 (m, 3H), 1.91 - 1.78 (m, 1H), 1.77 - 1.62 (m, 1H), 1.51 - 1.40 (m, 9H). 3: To a solution of (COCl)2(2.79 g, 21.95 mmol, 1.92 mL, 2 eq) in DCM (50 mL) at -65 °C was added a solution of DMSO (1.72 g, 21.95 mmol, 1.72 mL, 2 eq) in DCM (50 mL). The mixture was stirred for 30 min at -65 °C, and a solution of 1-benzyl 4-(tert-butyl) 2-(2- hydroxyethyl)piperazine-1,4-dicarboxylate 2 (4 g, 10.98 mmol, 1 eq) in DCM (50 mL) was added to the mixture and stirred at -65 °C for 1 h. The mixture was treated with TEA (6.66 g, 65.86 mmol, 9.17 mL, 6 eq) and allowed to warm to 0 °C, then the mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4(s), filtered, and concentrated to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 3 / 1).1-Benzyl 4-(tert-butyl) 2-(2-oxoethyl)piperazine-1,4- dicarboxylate 3 (2.6 g, 7.17 mmol, 65.36% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 9.74 (br s, 1H), 7.42 - 7.29 (m, 5H), 5.14 (s, 2H), 4.86 - 4.60 (m, 1H), 4.10 - 3.82 (m, 3H), 3.16 - 2.91 (m, 2H), 2.90 - 2.68 (m, 2H), 2.65 - 2.50 (m, 1H), 1.45 (s, 9H). 4A, 4B: To a solution of 1-benzyl 4-(tert-butyl) 2-(2-oxoethyl)piperazine-1,4- dicarboxylate 3 (2.6 g, 7.17 mmol, 1 eq) in THF (40 mL) was added bromo(phenyl)magnesium (3 M, 3.59 mL, 1.5 eq) at -20 °C under N2atmosphere, then the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated aq. NH4Cl (80 mL) and extracted with dichloromethane (50 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 3 / 1).1-Benzyl 4-(tert-butyl) 2-(2-hydroxy-2-phenylethyl)piperazine-1,4- dicarboxylate 4B (980 mg, 2.22 mmol, 31.01% yield, N / A purity) was obtained as a colorless gum. LCMS of 4B: Ret. Time: 0.565 min, M+H+, m / z: 463.2.1H NMR of 4B: (400 MHz, DMSO-d6) δ = 7.43 - 7.20 (m, 10H), 5.23 (br s, 1H), 5.06 (br s, 2H), 4.46 (br s, 1H), 4.31 - 4.09 (m, 1H), 3.96 - 3.72 (m, 3H), 3.08 - 2.88 (m, 2H), 2.83 - 2.67 (m, 1H), 1.92 - 1.66 (m, 2H), 1.38 (s, 9H). LCMS of 4A: Ret. Time: 0.565 min, M+H+, m / z: 463.2.1H NMR of 4A: (400 MHz, DMSO-d6) δ = 7.41 - 7.17 (m, 10H), 5.44 - 5.30 (m, 1H), 5.09 (s, 2H), 4.69 - 4.53 (m, 1H), 4.47 - 4.31 (m, 1H), 4.21 - 4.06 (m, 1H), 3.93 - 3.70 (m, 2H), 3.04 - 2.64 (m, 3H), 1.93 - 1.70 (m, 1H), 1.64 - 1.51 (m, 1H), 1.46 - 1.33 (m, 9H). 5: To a solution of 1-benzyl 4-(tert-butyl) 2-(2-hydroxy-2-phenylethyl)piperazine-1,4- dicarboxylate 4B (300.00 mg, 681.00 μmol, 1 eq) in MeOH (4 mL) was added Pd / C (72.47 mg, 68.10 μmol, 10% purity, 0.1 eq) under N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (20 psi) at 25 °C for 2 h. The mixture was filtered through Celite, and the filtrate was concentrated. The crude product was used directly in next step. tert-Butyl 3-(2-hydroxy-2-phenyl-ethyl)piperazine-1-carboxylate 5 (200 mg, 652.74 μmol, 95.85% yield) was obtained as a brown gum.1H NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 4.4 Hz, 4H), 7.28 (br d, J = 4.4 Hz, 1H), 5.02 (dd, J = 4.0, 7.6 Hz, 1H), 4.03 - 3.77 (m, 2H), 3.10 - 2.66 (m, 7H), 1.94 - 1.76 (m, 2H), 1.52 - 1.42 (m, 9H). 6: To a solution of tert-butyl 3-(2-hydroxy-2-phenyl-ethyl)piperazine-1-carboxylate 5 (200.00 mg, 652.74 μmol, 1 eq) in DMA (4 mL), was added NaH (65.27 mg, 1.63 mmol, 60% purity, 2.5 eq) at 0 °C under N2 atmosphere and stirred at 50 °C for 0.5 h under N2. Then 1- fluoro-4-(trifluoromethyl) benzene (160.67 mg, 979.12 μmol, 124.26 μL, 1.5 eq) was added at 25 °C and stirred at 25 °C for 12 h. The reaction mixture was quenched by addition of aq. NH4Cl (15 mL) and extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product used directly in next step. tert-Butyl 3-[2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl] piperazine-1-carboxylate 6 (290 mg, crude) was obtained as a yellow oil. LCMS: Ret. Time: 0.524 min, M+H+, m / z: 451.1. 7: To a solution NaHCO3(108.16 mg, 1.29 mmol, 50.10 μL, 2 eq) and tert-butyl 3-[2- phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 6 (290 mg, 643.74 μmol, 1 eq) in dioxane (3 mL) and H2O (1 mL), then was added FMOC-OSU (217.15 mg, 643.74 μmol, 1 eq), the mixture was stirred at 25 °C for 12 h. After stirring at room temperature for 16 h, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4(s), filtered, and concentrated to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 1 / 1).1-((9H-fluoren-9-yl)methyl) 4-(tert-butyl) 2-(2-phenyl-2-(4- (trifluoromethyl)phenoxy)ethyl)piperazine-1,4-dicarboxylate 7 (197 mg, 292.84 μmol, 45.49% yield) was obtained as a yellow oil. LCMS: Ret. Time: 0.693 min, M+H+-100, m / z: 573.2. 8: To 1-((9H-fluoren-9-yl)methyl) 4-(tert-butyl) 2-(2-phenyl-2-(4-(trifluoromethyl) phenoxy)ethyl)piperazine-1,4-dicarboxylate 7 (170.00 mg, 252.70 μmol, 1 eq) was added in HCl / dioxane (3 mL), then the mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give the crude product used directly in next step.9H-fluoren-9- ylmethyl 2-[2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 8 (153 mg, 251.20 μmol, 99.41% yield, HCl) was obtained as a yellow solid. LCMS: Ret. Time: 0.602 min, M+H+, m / z: 573.3. 9: To a solution of 9H-fluoren-9-ylmethyl 2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperazine-1-carboxylate 8 (153.00 mg, 251.20 μmol, 1 eq, HCl) in DCM (3 mL), was added TEA (50.84 mg, 502.40 μmol, 69.93 μL, 2 eq) and acetyl acetate (30.77 mg, 301.44 μmol, 28.31 μL, 1.2 eq), the mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure to give the crude product used directly in next step.9H-fluoren-9- ylmethyl 4-acetyl-2-[2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 9 (154 mg, 250.55 μmol, 99.74% yield) was obtained as a yellow solid. LCMS: Ret. Time: 0.657 min, M+H++Na+, m / z: 637.2. IMA-0002552: To a solution of 9H-fluoren-9-ylmethyl 4-acetyl-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 9 (154 mg, 250.55 μmol, 1 eq) in MeOH (3 mL), was added piperidine (32.00 mg, 375.82 μmol, 37.11 μL, 1.5 eq), the mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna (C18150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 15%-45% B over 9 min) and lyophilized to give IMA-0002552 (5.74 mg, 12.19 μmol, 4.87% yield, 93.14% purity, FA) as a brown gum. LCMS: Ret. Time: 0.473 min, M+H++Na+, m / z: 393.2.1H NMR (400 MHz, CDCl3) δ = 8.20 (s, 1H), 7.54 (br d, J = 8.4 Hz, 2H), 7.43 - 7.33 (m, 4H), 7.30 - 7.23 (m, 1H), 7.09 (br d, J = 8.4 Hz, 2H), 5.64 (br d, J = 2.4 Hz, 1H), 4.34 - 3.97 (m, 1H), 3.76 - 3.55 (m, 1H), 3.13 - 2.95 (m, 1H), 2.88 (br d, J = 10.8 Hz, 1H), 2.78 - 2.56 (m, 2H), 2.47 - 2.36 (m, 1H), 2.02 (br s, 1H), 1.95 (s, 3H), 1.79 (br d, J = 1.2 Hz, 1H). Synthesis of IMA-0002556 2: To a solution of tert-butyl-dimethyl-[[6-[2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl]-3-piperidyl]oxy]silane 1 (856.00 mg, 1.78 mmol, 1 eq) in TEA (361.17 mg, 3.57 mmol, 496.80 μL, 2 eq) and DCM (15 mL) was added Boc2O (584.25 mg, 2.68 mmol, 615.00 μL, 1.5 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into aq. NaHCO3(50 ml) slowly and extracted with DCM (100 mL x 3). The combined organic layers were washed, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% EtOAc / PE gradient @ 60 mL / min). tert-Butyl 5-[tert-butyl(dimethyl)silyl]oxy-2- [2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (691 mg, 1.19 mmol, 66.78% yield, N / A purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.709 min, M+H+, m / z: 602.3.1H NMR (400 MHz, CDCl3) δ = 7.35 - 7.29 (m, 2H), 7.28 - 7.20 (m, 4H), 7.18 - 7.14 (m, 1H), 6.79 (br d, J = 8.4 Hz, 2H), 5.00 - 4.89 (m, 1H), 4.47 (br s, 1H), 3.89 (br d, J = 12.4 Hz, 1H), 3.94 - 3.83 (m, 1H), 3.50 - 3.36 (m, 1H), 2.54 - 2.44 (m, 1H), 2.21 - 2.07 (m, 1H), 1.95 - 1.79 (m, 1H), 1.76 - 1.56 (m, 3H), 1.45 (s, 9H), 0.85 - 0.78 (m, 9H), 0.04 - -0.02 (m, 6H). 3: To a solution of tert-butyl 5-[tert-butyl(dimethyl)silyl]oxy-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (691 mg, 1.19 mmol, 1 eq) in TBAF (1 M, 10 mL, 8.39 eq) was stirred at 20 °C for 12 h. The mixture was dissolved in DCM (50mL) and washed with water (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc / PE gradient @ 50 mL / min). tert-Butyl 5-hydroxy-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 3 (288 mg, 618.68 μmol, 51.91% yield) was obtained as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.47 - 7.38 (m, 2H), 7.38 - 7.27 (m, 5H), 6.91 - 6.85 (m, 2H), 5.12 - 5.01 (m, 1H), 4.71 - 4.56 (m, 1H), 4.41 - 4.22 (m, 1H), 3.53 (s, 1H), 2.56 (s, 1H), 2.32 - 2.15 (m, 1H), 2.01 - 1.86 (m, 2H), 1.82 - 1.62 (m, 3H), 1.54 - 1.45 (m, 1H), 1.29 - 1.07 (m, 9H). 4: To a mixture of tert-butyl 5-hydroxy-2-[2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl]piperidine-1-carboxylate 3 (70 mg, 150.37 μmol, 1 eq) in DCM (3 mL) was added DAST (41.21 mg, 255.64 μmol, 33.78 μL, 1.7 eq) at -65 °C under N2 atmosphere, then the mixture was stirred at -65 °C for 1 h, then the mixture was stirred at 20 °C for 1 h. The mixture was quenched by slow addition of saturated aq. NaHCO3(5 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step. tert- Butyl 5-fluoro-2-[2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 4 (86 mg, crude, HCl) was obtained as an off-white solid. LCMS: Ret. Time: 0.700 min, M+H+-100, m / z: 368.2. IMA-0002556: To a solution of tert-butyl 5-fluoro-2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 4 (86 mg, 183.96 μmol, 1 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 1 mL, 21.74 eq) at 20 °C and stirred at 20 °C for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (column: Phenomenex Luna (C18150 x 25mm x 10um; mobile phase: [water (HCl)-ACN]; gradient: 20%-50% B over 10 min) and lyophilized to give IMA-0002556 (35.47 mg, 85.20 μmol, 46.31% yield, 97% purity, HCl) as a white solid. LCMS: Ret. Time: 0.485 min, M+H+, m / z: 368.0.1H NMR (400 MHz, CD3OD) δ = 7.49 (d, J = 8.4 Hz, 2H), 7.46 - 7.35 (m, 4H), 7.34 - 7.25 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 5.60 (dd, J = 4.0, 8.8 Hz, 1H), 5.11 - 4.93 (m, 1H), 3.69 - 3.55 (m, 1H), 3.40 (s, 2H), 2.36 (ddd, J = 6.4, 8.8, 14.8 Hz, 1H), 2.25 - 2.13 (m, 2H), 2.11 - 2.01 (m, 1H), 1.97 - 1.72 (m, 2H). Synthesis of IMA-0002557 2: To a solution of tert-butyl-dimethyl-[[6-[2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl] -3-piperidyl]oxy]silane 1 (1.40 g, 2.92 mmol, 1 eq) in TEA (590.70 mg, 5.84 mmol, 812.52 μL, 2 eq) and DCM (25 mL) was added Boc2O (955.54 mg, 4.38 mmol, 1.01 mL, 1.5 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into aq. NaHCO3 (50 ml) slowly and extracted with DCM (100 mL x 3). The combined organic layers were washed, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% EtOAc / PE gradient @ 60 mL / min). tert-Butyl 5-[tert-butyl(dimethyl)silyl]oxy-2- [2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl]piperidine-1-carboxylate 2 (877 mg, 1.51 mmol, 51.83% yield) was obtained as a colorless gum. LCMS: Ret. Time: 0.708 min, M+H+, m / z: 602.3.1H NMR (400 MHz, CDCl3) δ = 7.30 (br s, 6H), 7.26 - 7.24 (m, 1H), 6.91 - 6.79 (m, 2H), 5.26 - 5.11 (m, 1H), 4.61 - 4.31 (m, 1H), 4.20 - 3.94 (m, 1H), 3.63 - 3.45 (m, 1H), 2.95 - 2.60 (m, 1H), 2.57 - 2.27 (m, 1H), 2.10 - 1.74 (m, 2H), 1.70 - 1.58 (m, 2H), 1.54 (s, 9H), 0.92 (br s, 9H), 0.17 - 0.01 (m, 6H). 3: To a solution of tert-butyl 5-[tert-butyl(dimethyl)silyl]oxy-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (877 mg, 1.51 mmol, 1 eq) in TBAF (1 M, 15 mL, 9.92 eq) was stirred at 20 °C for 12 h. The mixture was dissolved in DCM (50mL) and washed with water (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30 % EtOAc / PE gradient @ 50 mL / min). tert-Butyl 5-hydroxy-2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 3 (230 mg, 494.09 μmol, 32.66% yield) was obtained as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.29 (br s, 7H), 6.91 - 6.82 (m, 2H), 5.30 - 5.13 (m, 1H), 4.65 - 4.39 (m, 1H), 4.25 - 4.12 (m, 1H), 3.71 - 3.53 (m, 1H), 2.88 - 2.70 (m, 1H), 2.58 - 2.40 (m, 1H), 1.99 - 1.86 (m, 2H), 1.76 - 1.58 (m, 4H), 1.40 - 1.28 (m, 9H). 4: To a mixture of tert-butyl 5-hydroxy-2-[2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl]piperidine-1-carboxylate 3 (120 mg, 257.79 μmol, 1 eq) in DCM (5 mL) was added DAST (70.64 mg, 438.23 μmol, 57.90 μL, 1.7 eq) at -65 °C under N2 atmosphere, then the mixture was stirred at -65 °C for 1 h, then the mixture was stirred at 20 °C for 1 h. The mixture was quenched by slow addition of H2O (5 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step. tert-Butyl 5-fluoro-2-[2- phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 4 (159 mg, crude, HCl) was obtained as an off-white solid. LCMS: Ret. Time: 0.667 min, M+H+-100, m / z: 368.1. IMA-0002557: To a solution of tert-butyl 5-fluoro-2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl] piperidine-1-carboxylate 4 (156 mg, 333.69 μmol, 1 eq) in dioxane (2 mL) was added HCl / dioxane (4 M, 2 mL, 23.97 eq) at 20 °C and stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to give the crude. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(HCl)-ACN]; gradient:20%-50% B over 10 min) and lyophilized to give IMA-0002557 (19.38 mg, 47.99 μmol, 14.38% yield, 100% purity, HCl) as a white solid. LCMS: Ret. Time: 0.477 min, M+H+, m / z: 368.1.1H NMR (400 MHz, CD3OD) δ = 7.49 (d, J = 8.4 Hz, 2H), 7.45 - 7.35 (m, 4H), 7.30 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H), 5.66 - 5.52 (m, 1H), 5.12 - 4.94 (m, 1H), 3.60 (br s, 2H), 3.47 - 3.34 (m, 1H), 2.40 (ddd, J = 4.8, 10.4, 14.4 Hz, 1H), 2.20 (dt, J = 2.8, 10.8 Hz, 1H), 2.13 - 2.03 (m, 2H), 1.89 (br s, 2H). Synthesis of IMA-0002558 2: To a solution of 9H-fluoren-9-ylmethyl 2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperazine-1-carboxylate 1 (200 mg, 349.27 μmol, 1 eq) in DCM (5 mL) was added TEA (70.69 mg, 698.55 μmol, 97.23 μL, 2 eq) and methylsulfonyl methanesulfonate (73.01 mg, 419.13 μmol, 1.2 eq), the mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure to give the crude product used directly in next step.9H- Fluoren-9-ylmethyl 4-methylsulfonyl-2-[2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl] piperazine-1-carboxylate 2 (217 mg, 333.48 μmol, 95.48% yield) was obtained as a yellow solid. LCMS: Ret. Time: 0.662 min, M+H++Na+, m / z: 673.3. IMA-0002558: To a solution of 9H-fluoren-9-ylmethyl 4-methylsulfonyl-2-[2-phenyl-2- [4-(trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 2 (150 mg, 230.52 μmol, 1 eq) in MeOH (3 mL) was added piperidine (58.88 mg, 691.56 μmol, 68.30 μL, 3 eq), the mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna (C18150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 15%-45% B over 9 min) and lyophilized to give IMA-0002558 (15.32 mg, 34.22 μmol, 14.84% yield, 95.7% purity) as a white solid. LCMS: Ret. Time: 0.478 min, M+H+, m / z: 429.2.1H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 8.8 Hz, 2H), 7.39 - 7.29 (m, 5H), 6.90 (d, J = 8.8 Hz, 2H), 5.38 (dd, J = 4.0, 8.4 Hz, 1H), 3.61 (br t, J = 12.0 Hz, 2H), 3.17 - 3.06 (m, 2H), 2.98 - 2.82 (m, 3H), 2.77 (s, 3H), 2.64 (br t, J = 10.4 Hz, 1H), 2.19 (td, J = 7.6, 15.2 Hz, 1H), 1.97 (td, J = 4.4, 14.8 Hz, 1H). Synthesis of IMA-0002559 2: To a solution of 9H-fluoren-9-ylmethyl 2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperazine-1-carboxylate 1 (200 mg, 349.27 μmol, 1 eq) in DCM (3 mL) was added TEA (106.03 mg, 1.05 mmol, 145.84 μL, 3 eq) and methylsulfonyl methanesulfonate (91.26 mg, 523.91 μmol, 1.5 eq), the mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure to give a residue. The crude product was used directly in next step.9H-Fluoren-9-ylmethyl 4-methylsulfonyl-2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperazine-1-carboxylate 2 (227 mg, 348.85 μmol, 99.88% yield) was obtained as a yellow solid. LCMS: Ret. Time: 0.657 min, M+H++Na+, m / z: 673.3. IMA-0002559: To a solution of 9H-fluoren-9-ylmethyl 4-methylsulfonyl-2-[2-phenyl-2- [4-(trifluoromethyl)phenoxy]ethyl]piperazine-1-carboxylate 2 (200 mg, 307.36 μmol, 1 eq) in MeOH (3 mL) was added piperidine (78.51 mg, 922.08 μmol, 91.06 μL, 3 eq), the mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna (C18150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient: 20%-50% B over 18 min) and lyophilized to give IMA-0002559 (26.59 mg, 62.06 μmol, 20.19% yield, 100% purity) as a white solid. LCMS: Ret. Time: 0.474 min, M+H+, m / z: 429.2.1H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 8.8 Hz, 2H), 7.39 - 7.29 (m, 5H), 6.92 (d, J = 8.8 Hz, 2H), 5.42 (dd, J = 3.2, 8.8 Hz, 1H), 3.78 - 3.71 (m, 1H), 3.63 (br d, J = 10.4 Hz, 1H), 3.23 - 3.13 (m, 2H), 2.98 - 2.84 (m, 2H), 2.80 (s, 3H), 2.69 - 2.55 (m, 2H), 2.20 - 2.09 (m, 1H), 1.99 (ddd, J = 3.2, 8.4, 14.4 Hz, 1H). Synthesis of IMA-0002560 2: To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 1 (150 mg, 322.23 μmol, 1 eq) in DCM (5 mL) was added DAST (88.30 mg, 547.79 μmol, 72.38 μL, 1.7 eq) at -70 °C under N2 atmosphere, then the mixture was stirred at -70 °C for 1 h, then the mixture was stirred at 20 °C for 1 h. The mixture was quenched by slow addition of saturated aq. NaHCO3 (5 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step. tert-Butyl (2R,4S)-4-fluoro-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl] piperidine-1-carboxylate 2 (110 mg, crude) was obtained as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.50 - 7.27 (m, 7H), 6.97 - 6.75 (m, 2H), 5.93 - 5.59 (m, 1H), 5.35 - 5.13 (m, 1H), 4.87 - 4.58 (m, 1H), 4.31 - 3.99 (m, 1H), 3.10 - 2.93 (m, 1H), 2.48 - 2.07 (m, 2H), 2.00 - 1.58 (m, 3H), 1.49 - 1.24 (m, 9H), 1.06 (br t, J = 7.2 Hz, 1H). IMA-0002560: To tert-butyl (2R,4S)-4-fluoro-2-[(2S)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (110 mg, 235.30 μmol, 1 eq) was added HCl (2 M, 1 mL, 8.50 eq) in dioxane (1 mL), then the mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (HCl)-ACN]; gradient: 20%-50% B over 10 min). The residue was further purified by Prep-HPLC (column: Waters Xbridge 150 x 25 mm x 5 um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 48%-78% B over 10 min) to give IMA-0002560 (4.4 mg, 11.84 μmol, 5.03% yield, 98.9% purity) as a brown gum. LCMS: Ret. Time: 0.467 min, M+H+, m / z: 368.3.1H NMR (400 MHz, CDCl3) δ = 7.37 (d, J = 8.8 Hz, 2H), 7.31 - 7.27 (m, 2H), 7.26 - 7.17 (m, 3H), 6.84 (d, J = 8.8 Hz, 2H), 5.29 (dd, J = 4.4, 8.8 Hz, 1H), 4.96 - 4.78 (m, 1H), 3.10 (dq, J = 4.0, 7.2 Hz, 1H), 3.00 - 2.91 (m, 1H), 2.89 - 2.81 (m, 1H), 2.09 (td, J = 8.4, 14.8 Hz, 1H), 1.90 - 1.85 (m, 1H), 1.76 (td, J = 4.4, 14.4 Hz, 2H), 1.68 - 1.51 (m, 1H), 1.50 - 1.30 (m, 1H). Synthesis of IMA-0002563 2: A solution of ethyl 2-(6-methyl-2-pyridyl)acetate 1 (5 g, 27.90 mmol, 1 eq) in IPA (120 mL) was stirred at 25 °C until becoming clear solution. Adjust the H2 back pressure regulator to 2.5 MPa, the flow rate of H2to 30 mL / min, heated the fixed bed (10%Ru / SiO2, 3 g) to 100 °C. Then the solution was pumped into the reactor at a flow rate of 0.3 mL / min. After the reaction was finished, wash the tubing with MeOH 100 mL, collected all the reaction solution for analysis. The mixture was concentrated under reduced pressure to give the crude product used directly in next step. Ethyl 2-(6-methyl-2-piperidyl)acetate 2 (4.5 g, 24.29 mmol, 87.06% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 4.12 (q, J = 7.2 Hz, 2H), 2.95 (dddd, J = 2.4, 5.6, 8.0, 10.8 Hz, 1H), 2.73 - 2.60 (m, 1H), 2.40 - 2.34 (m, 2H), 1.75 (quind, J = 3.2, 13.2 Hz, 1H), 1.61 - 1.54 (m, 2H), 1.43 - 1.29 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.14 - 1.06 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H), 1.03 - 0.95 (m, 1H). 3: To a solution of ethyl 2-(6-methyl-2-piperidyl)acetate 2 (2.00 g, 10.80 mmol, 1 eq) in DCM (40 mL) was added DIPEA (4.19 g, 32.39 mmol, 5.64 mL, 3 eq) and CbzCl (2.76 g, 16.19 mmol, 2.31 mL, 1.5 eq), then the mixture was stirred at 20 °C for 12 h. DIPEA (2.09 g, 16.19 mmol, 2.82 mL, 1.5 eq) and CbzCl (920.82 mg, 5.40 mmol, 770.56 μL, 0.5 eq) was added to the mixture and stirred at 20 °C for 12 h. The reaction mixture was poured into aq. NH4Cl (40 mL) and the solution was extracted with EtOAc (2 x 40 mL), washed with brine (40 mL), and dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc=10 / 1 to 5 / 1. Benzyl 2-(2-ethoxy-2- oxo-ethyl)-6-methyl-piperidine-1-carboxylate 3 (1.4 g, 4.38 mmol, 40.60% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.49 - 7.32 (m, 5H), 5.24 - 5.06 (m, 2H), 4.79 - 4.60 (m, 1H), 4.48 - 4.31 (m, 1H), 4.20 - 4.01 (m, 2H), 2.73 - 2.45 (m, 2H), 1.70 - 1.55 (m, 6H), 1.32 - 1.13 (m, 6H). 4: To a solution of benzyl 2-(2-ethoxy-2-oxo-ethyl)-6-methyl-piperidine-1-carboxylate 3 (1.40 g, 4.38 mmol, 1 eq) in THF (15 mL) was added LiAlH4(2.5 M, 2.19 mL, 1.25 eq) at 0 °C under N2atmosphere, then the mixture was stirred at 0 °C for 1 h under N2atmosphere. The reaction mixture was added THF (15 mL) at 0 °C under N2. Na2SO4•10H2O (2.2 g) and H2O (0.2 mL) were added to the reaction mixture under N2atmosphere at 0 °C slowly and stirred at 0 °C for 0.5 h, the resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 3 / 1 to 1 / 1. Benzyl 2-(2-hydroxyethyl)-6-methyl-piperidine-1-carboxylate 4 (600 mg, 2.16 mmol, 49.35% yield) was obtained as a colorless gum. LCMS: Ret. Time: 0.517 min, M+H+, m / z: 278.2.1H NMR (400 MHz, DMSO-d6) δ = 7.40 - 7.34 (m, 4H), 7.34 - 7.28 (m, 1H), 5.12 - 4.99 (m, 2H), 4.37 (t, J = 5.2 Hz, 1H), 4.32 - 4.23 (m, 1H), 4.20 - 4.11 (m, 1H), 3.36 (br dd, J = 6.4, 12.8 Hz, 2H), 1.82 - 1.60 (m, 4H), 1.58 - 1.34 (m, 4H), 1.13 (d, J = 7.2 Hz, 3H). 5: To a solution of (COCl)2 (411.88 mg, 3.24 mmol, 284.05 μL, 2 eq) in DCM (5 mL) was added DMSO (253.52 mg, 3.24 mmol, 253.52 μL, 2 eq) in DCM (3 mL) at -70 °C under N2. The mixture was stirred for 30 min at -70 °C, and a solution of benzyl 2-(2-hydroxyethyl)-6- methyl-piperidine-1-carboxylate 4 (450.00 mg, 1.62 mmol, 1 eq) in DCM (3 mL) was added to the mixture and stirred at -70 °C for 1 h. The mixture was treated with TEA (985.06 mg, 9.73 mmol, 1.35 mL, 6 eq) and allowed to warm to 0 °C, then the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into water (20 mL), and after separation of the phases the organic phase was washed with water (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE:EtOAc=3:1). Benzyl 2-methyl-6-(2-oxoethyl)piperidine-1-carboxylate 5 (300 mg, 1.09 mmol, 67.15% yield) was obtained as a light yellow oil.1H NMR (400 MHz, CDCl3) δ = 9.71 (t, J = 2.0 Hz, 1H), 7.40 - 7.30 (m, 5H), 5.14 (s, 2H), 4.89 - 4.77 (m, 1H), 4.51 - 4.38 (m, 1H), 2.69 (dd, J = 1.6, 7.2 Hz, 2H), 1.70 - 1.51 (m, 6H), 1.20 (d, J = 7.2 Hz, 3H). 6: To a solution of benzyl 2-methyl-6-(2-oxoethyl)piperidine-1-carboxylate 5 (160 mg, 581.10 μmol, 1 eq) in THF (4 mL) was added bromo(phenyl)magnesium (3 M, 387.40 μL, 2 eq) at 0 °C under N2, then the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into saturated aq. NH4Cl (10 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give the crude product used directly in the next step. Benzyl 2-(2-hydroxy-2-phenyl-ethyl)-6-methyl-piperidine-1-carboxylate 6 (260 mg, crude) was obtained as a light-yellow gum. 7: To a solution of benzyl 2-(2-hydroxy-2-phenyl-ethyl)-6-methyl-piperidine-1- carboxylate 6 (260.00 mg, 735.60 μmol, 1 eq) in MeOH (10 mL) was added Pd / C (234.85 mg, 220.68 μmol, 10% purity, 0.3 eq) under N2atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (20 Psi) at 25 °C for 2 h. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was poured into water (10 mL) and adjusted pH to 3 with 1 M HCl and then extracted with PE (10 mL). The aqueous phase was then adjusted pH to 10 with NaHCO3 solution and extracted with EtOAc (10 mL x 3). The combined organic phase was concentrated under reduced pressure to give the crude product used directly in next step.2-(6-Methyl-2-piperidyl)-1-phenyl-ethanol 7 (110 mg, 501.55 μmol, 68.18% yield) was obtained as a light-yellow gum. LCMS: Ret. Time: 0.325 min, M+H+, m / z: 220.2. IMA-0002563: To a solution of 2-(6-methyl-2-piperidyl)-1-phenyl-ethanol 7 (110.00 mg, 501.55 μmol, 1 eq) in DMA (2 mL) was added NaH (50.15 mg, 1.25 mmol, 60% purity, 2.5 eq) at 0 °C and stirred at 50 °C for 0.5 h under N2.1-fluoro-4-(trifluoromethyl)benzene (123.46 mg, 752.32 μmol, 95.48 μL, 1.5 eq) was added at 25 °C and stirred at 50 °C for 1 h. The reaction solution was cooled to room temperature, the reaction mixture was quenched by addition of aq. NH4Cl (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; gradient:22%-52% B over 9 min) to give IMA- 0002563 (37.9 mg, 90.44 μmol, 18.03% yield, 97.7% purity, FA) as an off-white solid. LCMS: Ret. Time: 0.257 min, M+H+, m / z: 364.3.1H NMR (400 MHz, CDCl3) δ = 8.60 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.36 - 7.27 (m, 4H), 7.25 - 7.20 (m, 1H), 6.92 - 6.84 (m, 2H), 5.49 (dd, J = 4.0, 9.2 Hz, 1H), 5.31 (dd, J = 4.0, 9.6 Hz, 1H), 3.17 - 2.98 (m, 1H), 2.96 - 2.80 (m, 1H), 2.67 - 2.04 (m, 2H), 1.98 - 1.77 (m, 2H), 1.73 - 1.37 (m, 4H), 1.11 (d, J = 6.4 Hz, 3H). Synthesis of IMA-0002564 2: To a 100 mL three neck flask was added 3-azidopropan-1-ol 1 (2 g, 19.78 mmol, 1 eq) and dissolved with THF (25 mL). Then the mixture reaction was displaced with nitrogen, cooled to 0 °C with ice bath. NaH (949.40 mg, 23.74 mmol, 60% purity, 1.2 eq) was added in portions (5 min) at 0 °C, and the reaction was stirred at 0 °C for 0.5 h under N2, then ethyl 4-chloro-3-oxo- butanoate (3.58 g, 21.76 mmol, 1.1 eq) in THF (5 mL) was added via syringe dropwise over 3 min under a nitrogen atmosphere at 0 °C, and stirred at 20 °C for 12 h under N2. The mixture was added into stirring aq. NH4Cl (100 mL, 20 °C) slowly and extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10 EtOAc / PE gradient @ 60 mL / min). Ethyl 4-(3-azidopropoxy)-3-oxo-butanoate 2 (828 mg, 3.61 mmol, 18.26% yield) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 4.26 - 4.17 (m, 2H), 4.14 (s, 2H), 3.59 (t, J = 6.0 Hz, 2H), 3.51 (s, 2H), 3.47 - 3.39 (m, 2H), 1.92 - 1.84 (m, 2H), 1.31 - 1.26 (m, 3H). 3: To a solution of ethyl 4-(3-azidopropoxy)-3-oxo-butanoate 2 (828 mg, 3.61 mmol, 1 eq) in EtOH (100 mL) was added Pd / C (384.39 mg, 361.21 μmol, 10% purity, 0.1 eq) under N2atmosphere. The suspension was degassed and purged with N23 times and H23 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 16 h. Pd / C (384.39 mg, 361.21 μmol, 10% purity, 0.1 eq) was added and stirred under H2(45 Psi) at 50 °C for 16 h. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOH (100mL x 3). The combined filtrates were concentrated, and the crude product used directly in next step. Ethyl 2- (1,4-oxazepan-3-yl)acetate 3 (588 mg, 3.14 mmol, 86.94% yield, N / A purity) was obtained as a yellow gum.1H NMR (400 MHz, CDCl3) δ = 4.19 - 4.09 (m, 2H), 3.94 - 3.80 (m, 2H), 3.74 (td, J = 6.0, 12.0 Hz, 1H), 3.59 - 3.43 (m, 1H), 3.34 - 3.24 (m, 1H), 3.08 (td, J = 4.8, 13.6 Hz, 1H), 2.89 (ddd, J = 4.4, 8.8, 13.6 Hz, 1H), 2.34 (br d, J = 6.4 Hz, 1H), 2.17 - 1.73 (m, 4H), 1.31 - 1.25 (m, 3H). 4: To a solution of ethyl 2-(1,4-oxazepan-3-yl)acetate 3 (588 mg, 3.14 mmol, 1 eq) in THF (6 mL) was added NaHCO3(527.63 mg, 6.28 mmol, 2 eq) and Boc2O (1.37 g, 6.28 mmol, 1.44 mL, 2 eq), the mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into stirring NaHCO3(20 mL) slowly and extracted with DCM (30 mL x 3). The combined organic layers were washed, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% EtOAc / PE gradient @ 50 mL / min). tert-Butyl 3-(2-ethoxy-2-oxo- ethyl)-1,4-oxazepane-4-carboxylate 4 (487 mg, 1.69 mmol, 53.97% yield) was obtained as a light-yellow oil. LCMS: Ret. Time: 0.500 min, M+H+-100, m / z: 188.2.1H NMR (400 MHz, CDCl3) δ = 4.48 (br s, 1H), 4.14 - 4.10 (m, 2H), 4.00 - 3.76 (m, 3H), 3.61 - 3.51 (m, 2H), 3.16 (ddd, J = 1.6, 10.8, 14.4 Hz, 1H), 2.55 - 2.46 (m, 2H), 1.97 - 1.79 (m, 1H), 1.70 (br d, J = 14.0 Hz, 1H), 1.47 (s, 9H), 1.28 - 1.24 (m, 3H). 5: To a solution of tert-butyl 3-(2-ethoxy-2-oxo-ethyl)-1,4-oxazepane-4-carboxylate 4 (487 mg, 1.69 mmol, 1 eq) in THF (10 mL) was added LiAlH4 (2.5 M, 0.8 mL, 1.18 eq) at 0 °C under N2, and stirred at 20 °C for 1 h. The reaction mixture was added THF (50 mL) at 0 °C under N2. Na2SO4•10H2O (0.8 g) and H2O (0.08 mL) were added to the reaction mixture under N2atmosphere at 0 °C slowly and stirred at 0 °C for 0.5 h, the resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% EtOAc / PE gradient @ 50 mL / min). tert-Butyl 3-(2-hydroxyethyl)-1,4-oxazepane-4-carboxylate 5 (363 mg, 1.48 mmol, 87.31% yield) was obtained as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 4.52 - 4.37 (m, 1H), 4.15 - 4.03 (m, 2H), 3.87 - 3.75 (m, 1H), 3.66 - 3.58 (m, 1H), 3.54 - 3.46 (m, 1H), 3.44 - 3.35 (m, 1H), 3.30 - 3.20 (m, 1H), 2.98 - 2.87 (m, 1H), 1.99 - 1.86 (m, 1H), 1.72 - 1.53 (m, 3H), 1.51 - 1.48 (m, 9H), 1.31 - 1.22 (m, 1H). 6: To a solution of (COCl)2 (290.00 mg, 2.28 mmol, 0.2 mL, 1.93 eq) in DCM (6 mL) at - 65 °C was added a solution of DMSO (190.00 mg, 2.43 mmol, 0.19 mL, 2.05 eq) in DCM (2 mL). The mixture was stirred for 30 min at -65 °C, and a solution of tert-butyl 3-(2- hydroxyethyl)-1,4-oxazepane-4-carboxylate 5 (291 mg, 1.19 mmol, 1 eq) in DCM (9 mL) was added to the mixture and stirred at -65 °C for 1 h. The reaction mixture was poured into water (20 mL), and after separation of the phases the organic phase was washed with water (20 mL). The organic phase was dried over sodium sulphate, filtered, and concentrated under reduced pressure. The obtained residue was purified by prep-TLC with PE / EtOAc. tert-Butyl 3-(2-oxoethyl)-1,4- oxazepane-4-carboxylate 6 (231 mg, 949.45 μmol, 80.04% yield) was obtained as a light-yellow gum.1H NMR (400 MHz, CDCl3) δ = 9.81 - 9.70 (m, 1H), 4.83 - 4.45 (m, 1H), 4.02 - 3.94 (m, 2H), 3.50 (s, 2H), 3.19 - 3.03 (m, 1H), 2.53 (br d, J = 6.0 Hz, 2H), 2.02 - 1.81 (m, 1H), 1.73 (br s, 1H), 1.59 (br s, 1H), 1.47 (s, 9H). 7: To a solution of tert-butyl 3-(2-oxoethyl)-1,4-oxazepane-4-carboxylate 6 (231 mg, 949.45 μmol, 1 eq) in THF (5 mL) was added PhMgBr (3 M, 0.5 mL, 1.58 eq) at 0 °C under N2, the mixture was stirred at 20 °C for 12 h. PhMgBr (3 M, 316.48 μL, 1 eq) was added at 10 °C under N2and stirred at 20 °C for 2 h. The reaction mixture was poured into saturated aq. NH4Cl (30 mL) and extracted with dichloromethane (20 mL x 3), the combined organic phase was dried and concentrated under vacuum to give the crude product used directly in next step. tert-Butyl 3- (2-hydroxy-2-phenyl-ethyl)-1,4-oxazepane-4-carboxylate 7 (368 mg, crude) was obtained as light-yellow gum. 8: To a solution of tert-butyl 3-(2-hydroxy-2-phenyl-ethyl)-1,4-oxazepane-4-carboxylate 7 (368 mg, 1.14 mmol, 1 eq) in HCl / dioxane (2 M, 8 mL, 13.97 eq) was stirred at 20 °C for 1 h. The crude product was grinded with PE (10 ml x 5), filtered and the filter cake was concentrated to give 2-(1,4-oxazepan-3-yl)-1-phenyl-ethanol 8 (268 mg, crude) as a light yellow solid. LCMS: Ret. Time: 0.318 min, M+H+, m / z: 222.1. IMA-0002564: To a solution of 2-(1,4-oxazepan-3-yl)-1-phenyl-ethanol 8 (293 mg, 1.32 mmol, 1 eq) in DMA (5 mL) was added NaH (264.78 mg, 6.62 mmol, 60% purity, 5 eq) at 0 °C under N2 atmosphere and stirred at 50 °C for 0.5 h, then 1-fluoro-4-(trifluoromethyl)benzene (325.91 mg, 1.99 mmol, 252.06 μL, 1.5 eq) was added and stirred at 20 °C for 1 h. The reaction solution was quenched by addition of aq. NH4Cl (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (column: Phenomenex luna C18150 x 40 mm x 15 um; mobile phase: [water (FA)-ACN]; gradient: 15%-45% B over 15 min) and lyophilized to give IMA-0002564 (62.95 mg, 149.95 μmol, 11.33% yield, 98% purity, FA) as a colorless gum. LCMS: Ret. Time: 0.477 min, M+H+, m / z: 366.0.1H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.8 Hz, 2H), 7.38 - 7.31 (m, 4H), 7.27 (s, 1H), 6.92 (dd, J = 5.2, 8.4 Hz, 2H), 5.50 (dd, J = 3.2, 9.6 Hz, 1H), 5.40 (dd, J = 6.0, 7.2 Hz, 1H), 3.98 - 3.79 (m, 2H), 3.76 - 3.66 (m, 1H), 3.36 (ddd, J = 2.8, 9.2, 12.4 Hz, 1H), 3.27 - 2.93 (m, 2H), 2.86 (br s, 1H), 2.12 - 1.68 (m, 4H). Synthesis of IMA-0002565 2: To a solution of 1-bromo-2-iodo-benzene (2.49 g, 8.80 mmol, 1.13 mL, 2 eq) in THF (40 mL) was added i-PrMgCl (2 M, 4.40 mL, 2 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h, then tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate 1 (1 g, 4.40 mmol, 1 eq) was added into the reaction mixture, the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into saturated aq. NH4Cl (20 mL) and extracted with dichloromethane (50 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 3 / 1). tert-Butyl 2-[2- (2-bromophenyl)-2-hydroxy-ethyl]piperidine-1-carboxylate 2 (1.3 g, 3.38 mmol, 76.89% yield, N / A purity) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.63 - 7.56 (m, 1H), 7.53 (dd, J = 0.8, 8.0 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.17 (dt, J = 1.6, 7.6 Hz, 1H), 5.28 (br s, 1H), 4.77 (br d, J = 6.0 Hz, 1H), 4.53 (br s, 1H), 4.32 - 4.07 (m, 1H), 3.96 - 3.75 (m, 1H), 3.01 - 2.77 (m, 1H), 2.12 - 1.89 (m, 1H), 1.88 - 1.68 (m, 1H), 1.58 - 1.52 (m, 4H), 1.41 (s, 9H). 3: To a solution of tert-butyl 2-[2-(2-bromophenyl)-2-hydroxy-ethyl] piperidine-1- carboxylate 2 (1.3 g, 3.38 mmol, 1 eq) in DCM (12 mL) and TFA (3 mL), the mixture was stirred at 25 °C for 2 hr. The mixture was concentrated under reduced pressure to give the crude product used directly in next step.1-(2-Bromophenyl)-2-(2-piperidyl) ethanol 3 (1.2 g, 3.01 mmol, 89.08% yield, TFA) was obtained as a yellow gum. LCMS: Ret. Time: 0.395 min, M+H+, m / z: 286.0. 4: To a solution of 1-(2-bromophenyl)-2-(2-piperidyl)ethanol 3 (1 g, 2.51 mmol, 1 eq, TFA) in DMA (10 mL) was added NaH (502.19 mg, 12.56 mmol, 60% purity, 5 eq) at 0 °C under N2 atmosphere and stirred at 50 °C for 0.5 h under N2,.1-Fluoro-4-(trifluoromethyl) benzene (618.13 mg, 3.77 mmol, 478.06 μL, 1.5 eq) was added at 25 °C and stirred at 25 °C for 2 h. The reaction mixture was quenched by addition of aq. NH4Cl (45 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product used directly in next step.2-[2-(2-Bromophenyl)-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine 4 (900 mg, crude) was obtained as a yellow oil.. LCMS: Ret. Time: 0.497 min, M+H+, m / z: 451.2. 5: A mixture of 2-[2-(2-bromophenyl)-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine 4 (900 mg, 2.10 mmol, 1 eq) in TEA (425.28 mg, 4.20 mmol, 584.98 μL, 2 eq) and DCM (20 mL) was added tert-butoxycarbonyl tert-butyl carbonate (687.95 mg, 3.15 mmol, 724.15 μL, 1.5 eq) at 20 °C, the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into saturated aq. Na2CO3 (50 mL) and extracted with dichloromethane (50 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 5 / 1). tert-Butyl 2-[2-(2- bromophenyl)-2-[4-(trifluoromethyl)phenoxy] ethyl]piperidine-1-carboxylate 5 (480 mg, 908.40 μmol, 43.23% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.62 - 7.54 (m, 1H), 7.47 - 7.35 (m, 3H), 7.27 - 7.23 (m, 1H), 7.18 - 7.09 (m, 1H), 6.82 (br t, J = 9.2 Hz, 2H), 5.60 - 5.45 (m, 1H), 4.88 - 4.58 (m, 1H), 4.09 - 3.88 (m, 1H), 3.12 - 2.84 (m, 1H), 2.20 - 2.07 (m, 1H), 1.74 - 1.53 (m, 7H), 1.52 - 1.30 (m, 9H). 6: Anhydrous DMA (3 mL) was sparged with a gentle stream of N2 for 30 min prior to use. A 50 mM solution of sulfuric acid was prepared with DMA (3 mL) and 26.8 μL conc. H2SO4(8.54 mg, 87.06 μmol, 4.64 μL, 1 eq) and sparged with N2 for 10 min. To an 8 mL vial equipped with a magnetic stir bar and septum cap was added Pd(OAc)2 (1.95 mg, 8.71 μmol, 0.1 eq), RuPhos (8.12 mg, 17.41 μmol, 0.2 eq). The vial was evacuated and filled with N2three times, purged with a gentle stream of N2 for 10 min, H2SO4 (2 mL), 50 mM in DMA) was added, and the catalyst mixture was stirred in an oil bath at 80 °C for 30 min to give a homogeneous coffee- brown solution. To a 100 mL two-neck round-bottom flask was added Zn (5.69 mg, 87.06 μmol, 1 eq), Zn (CN)2 (10.22 mg, 87.06 μmol, 5.53 μL, 1 eq), and tert-butyl 2-[2-(2-bromophenyl)-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 5 (46 mg, 87.06 μmol, 1 eq). The flask was equipped with a magnetic stir bar, septum, and gas inlet, evacuated, and filled with N2three times, and purged with N2 for 10 min. DMA (20 mL) and catalyst solution (1.0 mL, 50 μmol Pd, 1% loading) were added and the flask was stirred in an oil bath at 120 °C for 1 hr. The mixture was filtered through Celite, and the filtrate was concentrated. The filtration was dissolved in H2O (20 mL) and then extracted with EtOAc (20 mL x 2), the combined organics were washed with brine (20 mL) and dried (Na2SO4). The crude product was used directly in next step. tert-Butyl 2- [2-(2-cyanophenyl)-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 6 (100 mg, crude) was obtained as a yellow solid. LCMS: Ret. Time: 0.642 min, M+H+, m / z: 475.2. IMA-0002565: To a solution of tert-butyl 2-[2-(2-cyanophenyl)-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 6 (100 mg, 210.74 μmol, 1 eq) in TFA (0.5 mL) and DCM (2 mL), the mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column:Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (TFA)-ACN]; gradient: 20%-50% B over 12 min) and lyophilized to give IMA-0002565 (22.35 mg, 44.30 μmol, 21.02% yield, 96.81% purity, TFA) as a white solid. LCMS: Ret. Time: 0.482 min, M+H+, m / z: 375.1.1H NMR (400 MHz, CDCl3) δ = 8.94 - 8.81 (m, 1H), 7.70 - 7.64 (m, 1H), 7.60 - 7.51 (m, 2H), 7.49 - 7.38 (m, 3H), 6.98 - 6.89 (m, 2H), 6.06 - 5.98 (m, 1H), 5.76 - 5.70 (m, 1H), 3.55 - 3.34 (m, 2H), 2.97 - 2.80 (m, 1H), 2.64 - 2.50 (m, 1H), 2.21 - 1.91 (m, 3H), 1.88 - 1.75 (m, 3H), 1.62 - 1.47 (m, 1H). Synthesis of IMA-0002569 2: To a solution of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2R)-2-hydroxy- 2-phenyl-ethyl]piperidine-1-carboxylate 1 (1.9 g, 3.39 mmol, 1 eq) in toluene (20 mL) was added 4-(trifluoromethyl)phenol (825.30 mg, 5.09 mmol, 1.5 eq), (NE)-N-(piperidine-1- carbonylimino)piperidine-1-carboxamide (1.28 g, 5.09 mmol, 1.5 eq) and tributylphosphine (1.03 g, 5.09 mmol, 1.26 mL, 1.5 eq) at 20 °C. The mixture was degassed and purged with N23 times and warmed to 110 °C and stirred at 110 °C for 12 h. The reaction mixture was cooled to 20 °C and then poured into stirring brine (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 2 / 1 to 1 / 1. tert-Butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2S)- 2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (1.1 g, 1.56 mmol, 46.04% yield) was obtained as light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.69 - 7.59 (m, 4H), 7.48 - 7.28 (m, 13H), 6.86 (d, J = 8.4 Hz, 2H), 5.21 (br dd, J = 4.8, 7.2 Hz, 1H), 4.50 (br d, J = 3.2 Hz, 1H), 4.20 (br d, J = 2.8 Hz, 1H), 3.96 - 3.81 (m, 1H), 3.53 - 3.39 (m, 1H), 2.99 - 2.81 (m, 1H), 2.27 - 2.13 (m, 1H), 1.69 - 1.61 (m, 2H), 1.51 - 1.41 (m, 2H), 1.35 (s, 9H), 1.09 (s, 9H). 3: A mixture of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2S)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (1.1 g, 1.56 mmol, 1 eq) in TBAF (1 M, 13.75 mL, 8.80 eq) was stirred at 30 °C for 2 h. The mixture was dissolved in DCM (100 mL) and washed with water (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 2 / 1 to 1 / 1. tert-Butyl (2S,4R)-4- hydroxy-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 3 (637 mg, 1.37 mmol, 87.57% yield) was obtained as colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.44 - 7.30 (m, 6H), 7.26 - 7.22 (m, 1H), 6.88 (d, J = 8.4 Hz, 2H), 5.30 (dd, J = 4.0, 8.4 Hz, 1H), 4.50 (br s, 1H), 4.21 (t, J = 3.2 Hz, 1H), 3.90 (br d, J = 11.6 Hz, 1H), 3.34 (br t, J = 12.0 Hz, 1H), 2.66 - 2.53 (m, 1H), 2.36 - 2.25 (m, 1H), 1.83 - 1.70 (m, 3H), 1.69 - 1.63 (m, 1H), 1.55 (br s, 1H), 1.40 (s, 9H). 4: To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 3 (1.07 g, 2.30 mmol, 1 eq) in THF (20 mL) was added K2HPO4(1 M, 3.45 mL, 1.5 eq) at 20 °C, then TEMPO (36.15 mg, 229.86 μmol, 0.1 eq) and NaClO (5.48 g, 3.68 mmol, 4.54 mL, 5% purity, 1.6 eq) was added to the mixture at 0 °C under N2, the mixture was stirred at 20 °C for 12 h. TEMPO (36.15 mg, 229.86 μmol, 0.1 eq) and NaClO (273.78 mg, 3.68 mmol, 227.01 μL, 1.6 eq) was added to the mixture at 0 °C under N2, the mixture was stirred at 0 °C for 1 h. The mixture was quenched by slow addition of saturated aq. Na2SO3(30 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (2R)-4-oxo-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl] piperidine-1-carboxylate 4 (982 mg, 2.12 mmol, 92.17% yield) as a light yellow gum. 5: To a solution of tert-butyl (2R)-4-oxo-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 4 (982.00 mg, 2.12 mmol, 1 eq) in MeOH (10 mL) was added NaBH4 (160.30 mg, 4.24 mmol, 2 eq) at 0 °C under N2, then the mixture was stirred at 0 °C for 1 h under N2. The mixture was added into stirring aq. NH4Cl (5 mL, 20 °C) slowly and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 2 / 1 to 1 / 1. tert-Butyl (2S,4S)-4-hydroxy-2-[(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1- carboxylate 5 (111 mg, 238.45 μmol, 11.25% yield) was obtained as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.41 (br d, J = 8.8 Hz, 2H), 7.38 - 7.29 (m, 4H), 6.86 (d, J = 8.8 Hz, 2H), 5.31 - 5.15 (m, 1H), 4.83 - 4.53 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.04 - 3.91 (m, 1H), 3.12 - 2.94 (m, 1H), 2.44 - 2.33 (m, 1H), 1.98 - 1.88 (m, 3H), 1.58 - 1.47 (m, 3H), 1.36 (br s, 9H). IMA-00002569: To a solution of tert-butyl (2S,4S)-4-hydroxy-2-[(2S)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 5 (100 mg, 214.82 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 62.67 eq), the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give the crude. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18150 x 25 mm x10 um; mobile phase: [water (TFA)- ACN]; gradient: 20%-50% B over 11 min) to give IMA-00002569 (46.05 mg, 94.13 μmol, 43.82% yield, 98% purity, TFA) as a yellow gum. LCMS: Ret. Time: 0.460 min, M+H+, m / z: 366.1.1H NMR (400 MHz, CDCl3) δ = 9.39 - 9.12 (m, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.35 - 7.29 (m, 4H), 7.27 - 7.24 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 5.34 (dd, J = 4.4, 9.2 Hz, 1H), 4.20 (br s, 1H), 3.80 - 3.62 (m, 1H), 3.28 - 3.15 (m, 1H), 3.00 (br d, J = 12.4 Hz, 1H), 2.50 (ddd, J = 6.0, 9.2, 14.4 Hz, 1H), 2.07 - 2.01 (m, 1H), 1.98 - 1.85 (m, 3H), 1.67 (br d, J = 14.4 Hz, 1H). Synthesis of IMA-0002570 2: To a solution of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2S)-2-hydroxy- 2-phenyl-ethyl]piperidine-1-carboxylate 1 (830 mg, 1.48 mmol, 1 eq) in toluene (10 mL) was added 4-(trifluoromethyl)phenol (360.53 mg, 2.22 mmol, 1.5 eq), (NE)-N-(piperidine-1- carbonylimino)piperidine-1-carboxamide (561.13 mg, 2.22 mmol, 1.5 eq) and tributylphosphane (449.95 mg, 2.22 mmol, 548.72 μL, 1.5 eq) at 20 °C. The mixture was degassed and purged with N2 for 3 times and warmed to 110 °C and stirred for 12 h. The reaction mixture was cooled to 20 °C and poured into stirring brine (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 2 / 1 to 1 / 1. tert-Butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl] oxy-2-[(2R)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (628 mg, 892.17 μmol, 60.17% yield) was obtained as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.50 (br t, J = 6.0 Hz, 4H), 7.37 - 7.19 (m, 13H), 6.80 (d, J = 8.4 Hz, 2H), 5.02 (dd, J = 2.0, 10.0 Hz, 1H), 4.49 (br d, J = 3.2 Hz, 1H), 4.10 (br s, 1H), 3.99 - 3.75 (m, 1H), 3.30 - 3.15 (m, 1H), 2.83 - 2.73 (m, 1H), 2.24 - 2.11 (m, 1H), 1.63 (br s, 2H), 1.39 (br d, J = 5.2 Hz, 2H), 1.16 - 0.99 (m, 9H), 0.84 (s, 9H). 3: A mixture of tert-butyl (2R,4R)-4-[tert-butyl(diphenyl)silyl]oxy-2-[(2R)-2-phenyl-2- [4-(trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 2 (628 mg, 892.17 μmol, 1 eq) in TBAF (1 M, 10 mL, 11.21 eq) was stirred at 30 °C for 2 h. The mixture was dissolved in DCM (100 mL) and washed with water (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 2 / 1 to 1 / 1. tert-Butyl (2S,4R)-4-hydroxy-2-[(2R)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine-1- carboxylate 3 (376 mg, 807.73 μmol, 90.54% yield) was obtained as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 8.8 Hz, 2H), 7.36 - 7.28 (m, 4H), 7.26 - 7.22 (m, 1H), 6.90 (d, J = 8.8 Hz, 2H), 5.11 (dd, J = 2.0, 10.0 Hz, 1H), 4.67 - 4.52 (m, 1H), 4.22 (t, J = 2.8 Hz, 1H), 4.07 - 3.90 (m, 1H), 3.32 - 3.21 (m, 1H), 2.64 - 2.49 (m, 1H), 2.30 - 2.15 (m, 1H), 1.96 - 1.85 (m, 1H), 1.81 - 1.63 (m, 3H), 1.29 - 1.14 (m, 9H). 4: To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[(2R)-2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 3 (769 mg, 1.65 mmol, 1 eq) in THF (15 mL) was added K2HPO4(1 M, 2.48 mL, 1.5 eq) at 20 °C, then TEMPO (25.98 mg, 165.20 μmol, 0.1 eq) and NaClO (3.94 g, 2.64 mmol, 3.26 mL, 5% purity, 1.6 eq) was added to the mixture at 0 °C under N2, the mixture was stirred at 20 °C for 12 h. The mixture was quenched by slow addition of saturated aq. Na2SO3(20 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (2R)-4-oxo-2-[(2R)-2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl]piperidine-1-carboxylate 4 (808 mg, crude) as a yellow gum. 5: To a solution of tert-butyl (2R)-4-oxo-2-[(2R)-2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 4 (808 mg, 1.74 mmol, 1 eq) in MeOH (10 mL) was added NaBH4 (131.90 mg, 3.49 mmol, 2 eq) at 0 °C under N2, then the mixture was stirred at 0 °C for 1 h under N2. The mixture was added into stirring aq. NH4Cl (5 mL, 20 °C) slowly and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 2 / 1 to 1 / 1. tert-Butyl (2S,4S)-4-hydroxy-2-[(2R)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl]piperidine- 1-carboxylate 5 (108 mg, 232.01 μmol, 13.31% yield) was obtained as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.42 (br d, J = 8.8 Hz, 2H), 7.37 - 7.28 (m, 5H), 6.88 (d, J = 8.8 Hz, 2H), 5.14 - 5.01 (m, 1H), 4.90 - 4.64 (m, 1H), 4.43 - 4.22 (m, 1H), 4.01 - 3.82 (m, 1H), 2.84 (dt, J = 2.4, 13.6 Hz, 1H), 2.12 - 2.06 (m, 1H), 1.97 (br d, J = 8.4 Hz, 2H), 1.57 (br dd, J = 5.6, 12.0 Hz, 4H), 1.33 - 1.12 (m, 9H). IMA-00002570: To a solution of tert-butyl (2S,4S)-4-hydroxy-2-[(2R)-2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 5 (50 mg, 107.41 μmol, 1 eq) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL, 125.33 eq), the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give the crude. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18150 x 25 mm x 10 um; mobile phase: [water (TFA)-ACN]; gradient: 22%-52% B over 11 min) to give IMA-00002570 (24.95 mg, 51.00 μmol, 47.48% yield, 98% purity, TFA) as a white solid. LCMS: Ret. Time: 0.467 min, M+H+, m / z: 366.2.1H NMR (400 MHz, CDCl3) δ = 9.65 - 9.47 (m, 1H), 9.19 - 9.00 (m, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.31 - 7.27 (m, 5H), 6.89 (d, J = 8.8 Hz, 2H), 5.51 (dd, J = 3.2, 9.2 Hz, 1H), 4.27 (br s, 1H), 3.79 (br dd, J = 6.0, 9.2 Hz, 1H), 3.39 - 3.27 (m, 1H), 3.12 (br d, J = 12.0 Hz, 1H), 2.24 - 2.15 (m, 2H), 2.10 - 1.93 (m, 3H), 1.78 (br d, J = 14.4 Hz, 1H). Synthesis of IMA-0002571 & IMA-0002572 2: A mixture of tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3-oxo- piperidine-1-carboxylate 1 (600 mg, 1.38 mmol, 1 eq) in DCM (6 mL) was added DAST (670.00 mg, 4.16 mmol, 549.18 μL, 3 eq) at -70 °C and stirred at -70 °C for 0.5 h. The mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into aq. NaHCO3 (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EtOAc= 5:1), the purified solution was concentrated under reduced pressure to give tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3,3-difluoro-piperidine-1- carboxylate 2 (330 mg, 724.24 μmol, 52.34% yield) as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.88 - 7.73 (m, 5H), 5.42 - 4.70 (m, 2H), 4.64 - 4.21 (m, 1H), 3.38 - 2.98 (m, 1H), 2.68 - 2.07 (m, 6H), 2.04 - 1.84 (m, 9H), 1.33 (s, 9H), 0.60 - 0.14 (m, 6H). 3: A mixture of tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3,3- difluoro-piperidine-1-carboxylate 2 (280 mg, 614.50 μmol, 1 eq) in DCM (1 mL) was added TFA (3.07 g, 26.92 mmol, 2.00 mL, 43.81 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give a residue. The residue was dissolved in TFA (3.07 g, 26.92 mmol, 2 mL, 43.81 eq) and stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give 2-(3,3-difluoro-2-piperidyl)-1-phenyl-ethanol 3 (220 mg, crude, TFA) as a brown gum. The reaction mixture was used into next step without further purification. LCMS: Ret. Time: 0.375 min, M+H+, m / z: 242.3. IMA-0002571 & IMA-0002572: To a solution of 2-(3,3-difluoro-2-piperidyl)-1-phenyl- ethanol 3 (220 mg, 619.20 μmol, 1 eq, TFA) in DMA (3 mL) was added NaH (124.00 mg, 3.10 mmol, 60% purity, 5.01 eq) at 0 °C under N2atmosphere, then the reaction mixture was stirred at 0 °C for 0.5 h under N2atmosphere.1-fluoro-4-(trifluoromethyl)benzene (153.00 mg, 932.36 μmol, 118.33 μL, 1.51 eq) was added and the solution was stirred at 20 °C for 2 h under N2 atmosphere. The mixture was warmed to 30 °C and stirred at 30 °C for 1.5 h under N2atmosphere. The mixture was quenched by slow addition of saturated aq. NH4Cl (60 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue were purified by prep-HPLC (column: Phenomenex luna C18150 x 40 mm x 15 um; mobile phase: [water (FA)-ACN]; gradient: 22%-52% B over 15 min), the purified solution was lyophilized to give IMA-0002571 (35.4 mg, 90.48 μmol, 14.61% yield, 98.5% purity) as a light yellow gum. LCMS: Ret. Time: 0.490 min, M+H+, m / z: 386.1.1H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.8 Hz, 2H), 7.42 - 7.38 (m, 2H), 7.37 (s, 2H), 7.30 (br d, J = 7.2 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 5.46 (t, J = 7.2 Hz, 1H), 3.07 (br d, J = 11.2 Hz, 1H), 2.86 - 2.74 (m, 1H), 2.65 - 2.54 (m, 1H), 2.37 - 2.27 (m, 1H), 2.18 (br d, J = 10.8 Hz, 1H), 2.16 - 2.08 (m, 1H), 1.74 - 1.61 (m, 3H). IMA-0002572 (12.65 mg, 32.83 μmol, 5.30% yield, 100% purity) was obtained as a light yellow solid. LCMS: Ret. Time: 0.507 min, M+H+, m / z: 386.1.1H NMR (400 MHz, CDCl3) δ = 7.41 (br d, J = 8.4 Hz, 2H), 7.37 - 7.28 (m, 5H), 6.91 (d, J = 8.4 Hz, 2H), 5.68 (br d, J = 10.8 Hz, 1H), 3.56 - 3.43 (m, 1H), 3.42 - 3.33 (m, 1H), 2.94 - 2.85 (m, 1H), 2.67 - 2.57 (m, 1H), 2.41 - 2.32 (m, 1H), 2.16 - 1.96 (m, 4H). Synthesis of IMA-0002573 2: To a solution of 7-bromo-1,3-benzothiazole 1 (2 g, 9.34 mmol, 1 eq) in THF (20 mL) was added LDA (2 M, 9.34 mL, 2 eq) under -70 °C under N2atmosphere, the mixture was stirred at -70 °C for 1 h, then TIPSCl (1.98 g, 10.28 mmol, 2.20 mL, 1.1 eq) was added into the reaction mixture, the combined mixture was stirred at -70 °C for 1 h. The reaction mixture was poured into H2O (50 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EtOAc, from 5 / 1). (7-bromo-1,3-benzothiazol-2-yl)-triisopropyl-silane 2 (2.1 g, 5.67 mmol, 60.68% yield) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ = 8.16 - 8.10 (m, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 1.54 (td, J = 7.6, 15.2 Hz, 3H), 1.20 (d, J = 7.6 Hz, 18H). 3A, 3B: To a solution of (7-bromo-1,3-benzothiazol-2-yl)-triisopropyl-silane 2 (1.96 g, 5.28 mmol, 2 eq) in THF (20 mL) was added n-BuLi (2.5 M, 2.11 mL, 2 eq) at -70 °C under N2 atmosphere, the mixture was stirred at -70 °C for 1 h, then tert-butyl 2-(2-oxoethyl)piperidine-1- carboxylate 3 (600 mg, 2.64 mmol, 1 eq) was added into the reaction mixture, the combined mixture was stirred at -70 °C for 1 h. The reaction mixture was poured into aq. NH4Cl (50 mL) and extracted with dichloromethane (50 mL x 3), the combined organic phase was dried and concentrated under vacuum to give tert-butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3- benzothiazol-7-yl)ethyl]piperidine-1-carboxylate 3B (140 mg, 269.84 μmol, 10.22% yield) as a yellow solid. tert-Butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3-benzothiazol-7- yl)ethyl]piperidine-1-carboxylate 3A (160 mg, 308.39 μmol, 11.68% yield) was obtained as a yellow solid.1H NMR of 3A: (400 MHz, CDCl3) δ = 8.13 (br d, J = 5.6 Hz, 1H), 7.47 (br d, J = 7.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 5.05 (br dd, J = 3.2, 8.0 Hz, 1H), 4.47 (br s, 1H), 4.05 - 3.82 (m, 1H), 2.88 - 2.67 (m, 1H), 2.23 - 2.02 (m, 3H), 1.64 - 1.52 (m, 9H), 1.48 (s, 9H), 1.20 (d, J = 7.6 Hz, 18H).1H NMR of 3B: (400 MHz, CDCl3) δ = 8.11 (br d, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.45 - 7.41 (m, 1H), 5.11 - 4.93 (m, 1H), 4.87 - 4.42 (m, 2H), 4.34 - 3.86 (m, 2H), 2.97 - 2.84 (m, 1H), 2.48 - 2.30 (m, 1H), 1.65 - 1.50 (m, 18H), 1.20 (dd, J = 2.0, 7.2 Hz, 18H). 4: To a solution of tert-butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3-benzothiazol-7- yl)ethyl]piperidine-1-carboxylate 3B (100 mg, 192.74 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL), the mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated under reduced pressure to give the crude product used directly in the next step.1-(1,3-benzothiazol-7- yl)-2-(2-piperidyl)ethanol 4 (70 mg, 185.98 μmol, 96.49% yield, TFA) was obtained as a yellow solid. LCMS: Ret. Time: 0.326 min, M+H+, m / z: 263.3. IMA-0002573: To a solution of 1-(1,3-benzothiazol-7-yl)-2-(2-piperidyl)ethanol 4 (70 mg, 185.98 μmol, 1 eq, TFA) in DMA (2 mL), was added NaH (37.19 mg, 929.88 μmol, 60% purity, 5 eq) at 0 °C under N2atmosphere and stirred at 0 °C for 0.5 h under N2. Then 1-fluoro-4- (trifluoromethyl)benzene (33.57 mg, 204.57 μmol, 25.96 μL, 1.1 eq) was added at 0 °C and stirred at 0 °C for 2 h. The reaction mixture was poured into aq. NH4Cl (10 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water(TFA)-ACN]; gradient:18%-48% B over 10 min) and lyophilized to give IMA-0002573 (16.28 mg, 31.28 μmol, 16.82% yield, 100% purity, TFA) as a white solid. LCMS: Ret. Time: 0.469 min, M+H+, m / z: 407.1.1H NMR (400 MHz, CDCl3) δ = 9.79 - 9.68 (m, 1H), 8.98 (s, 2H), 8.05 (dd, J = 1.6, 6.8 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.39 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.91 (br d, J = 8.8 Hz, 1H), 3.40 - 3.29 (m, 2H), 2.89 - 2.76 (m, 1H), 2.50 - 2.36 (m, 2H), 2.13 - 2.04 (m, 1H), 1.99 - 1.91 (m, 1H), 1.83 - 1.74 (m, 3H), 1.62 - 1.45 (m, 1H). Synthesis of IMA-0002574 IMA-0002574 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3-benzothiazol-7-yl)ethyl]piperidine-1- carboxylate as the starting material. IMA-0002574 (16.49 mg, 31.68 μmol, 17.04% yield, 100% purity, TFA) was obtained as a white solid. LCMS: Ret. Time: 0.459 min, M+H+, m / z: 407.1.1H NMR (400 MHz, CDCl3) δ = 9.46 - 9.32 (m, 1H), 9.18 - 9.07 (m, 1H), 9.02 (s, 1H), 8.09 (dd, J = 2.8, 6.4 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.70 (br dd, J = 4.4, 9.2 Hz, 1H), 3.27 - 3.15 (m, 1H), 3.12 - 3.04 (m, 1H), 2.74 - 2.62 (m, 2H), 2.19 - 2.09 (m, 1H), 1.93 - 1.82 (m, 2H), 1.76 - 1.66 (m, 1H), 1.62 - 1.53 (m, 2H), 1.47 - 1.30 (m, 1H). Synthesis of IMA-0002575 2: To a solution of 4-bromo-1,3-benzothiazole 1 (3 g, 14.01 mmol, 1 eq) in THF (30 mL), was added LDA (2 M, 14 mL, 2 eq) under -70 °C under N2 atmosphere, the mixture was stirred at -70 °C for 0.5 h, then TIPSCl (2.97 g, 15.41 mmol, 3.30 mL, 1.1 eq) was added into the reaction mixture, the mixture was stirred at -70 °C for 1 h under N2atmosphere. The reaction mixture was poured into aq. NH4Cl (50 mL) and extracted with dichloromethane (50 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE / EtOAc, from 5 / 1) and product collected (Rf= 0.70). (4- bromo-1,3-benzothiazol-2-yl)-triisopropyl-silane 2 (4.3 g, 11.61 mmol, 82.84% yield) was obtained as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 7.91 (dd, J = 0.8, 8.0 Hz, 1H), 7.69 (dd, J = 0.8, 7.6 Hz, 1H), 7.32 - 7.20 (m, 1H), 1.54 (quin, J = 7.6 Hz, 3H), 1.24 (d, J = 7.6 Hz, 18H). 3A, 3B: To a solution of (4-bromo-1,3-benzothiazol-2-yl)-triisopropyl-silane 2 (3.24 g, 8.75 mmol, 1.99 eq) in THF (40 mL), was added n-BuLi (2.5 M, 3.5 mL, 1.99 eq) under -70 °C under N2 atmosphere, the mixture was stirred at -70 °C for 0.5 h under N2 atmosphere, then tert- butyl 2-(2-oxoethyl)piperidine-1-carboxylate 2 (1 g, 4.40 mmol, 1 eq) was added into the reaction mixture, the combined mixture was stirred at -70 °C for 1 h under N2 atmosphere. The reaction mixture was poured into aq. NH4Cl (50 mL) and extracted with dichloromethane (50 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by silica gel column chromatography (PE / EtOAc, from 5 / 1) and product collected (Rf= 0.3 and Rf=0.10). tert-Butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3-benzothiazol- 4-yl)ethyl]piperidine-1-carboxylate 3B (120 mg, 231.29 μmol, 5.26% yield) was obtained as yellow oil. tert-Butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3-benzothiazol-4-yl)ethyl]piperidine- 1-carboxylate 3A (160 mg, 308.39 μmol, 7.01% yield) was obtained as a yellow oil1H NMR of 3A: (400 MHz, CDCl3) δ = 7.89 (d, J = 8.4 Hz, 1H), 7.51 - 7.37 (m, 2H), 5.27 - 5.16 (m, 1H), 4.54 - 4.45 (m, 1H), 4.05 - 3.89 (m, 1H), 2.90 - 2.75 (m, 1H), 2.35 - 2.16 (m, 2H), 1.61 - 1.46 (m, 18H), 1.19 (d, J = 7.6 Hz, 18H).1H NMR of 3B: (400 MHz, CDCl3) δ = 7.87 (d, J = 8.0 Hz, 1H), 7.77 - 7.65 (m, 1H), 7.46 - 7.40 (m, 1H), 5.46 - 5.36 (m, 1H), 5.09 - 4.94 (m, 1H), 4.79 - 4.64 (m, 1H), 4.11 - 4.01 (m, 1H), 3.31 - 3.10 (m, 1H), 2.80 - 2.65 (m, 1H), 1.84 - 1.70 (m, 1H), 1.56 (s, 9H), 1.48 (s, 9H), 1.19 (dd, J = 7.6, 15.2 Hz, 18H). 4: To a solution of tert-butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3-benzothiazol-4- yl)ethyl]piperidine-1-carboxylate 3B (120 mg, 231.29 μmol, 1 eq) in DCM (1.5 mL) was added TFA (0.5 mL), the mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated under reduced pressure to give the crude product used directly in the next step.1-(1,3-benzothiazol-4- yl)-2-(2-piperidyl)ethanol 4 (87 mg, 231.14 μmol, 99.93% yield, TFA) was obtained as a yellow solid. LCMS: Ret. Time: 0.391 min, M+H+, m / z: 263.3. IMA-0002575: To a solution of 1-(1,3-benzothiazol-4-yl)-2-(2-piperidyl)ethanol 4 (70 mg, 185.98 μmol, 1 eq, TFA) in DMA (2 mL), was added NaH (38 mg, 950.09 μmol, 60% purity, 5.11 eq) at 0 °C under N2 atmosphere and stirred at 0 °C for 0.5 h under N2. Then 1-fluoro-4- (trifluoromethyl)benzene (33.57 mg, 204.57 μmol, 25.96 μL, 1.1 eq) was added at 0 °C and stirred at 0 °C for 2 h. The reaction mixture was poured into aq. NH4Cl (10 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (TFA)-ACN]; gradient:20%-50% B over 10 min) and lyophilized to give IMA-0002575 (22.68 mg, 43.14 μmol, 23.20% yield, 99% purity, TFA) as an off-white solid. LCMS: Ret. Time: 0.480 min, M+H+, m / z: 407.1.1H NMR (400 MHz, CDCl3) δ = 9.56 - 9.38 (m, 1H), 9.22 - 9.02 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.43 - 7.34 (m, 3H), 6.90 (d, J = 8.4 Hz, 2H), 6.35 (br dd, J = 3.6, 7.6 Hz, 1H), 4.62 - 4.36 (m, 2H), 3.46 (br d, J = 12.0 Hz, 1H), 3.27 - 3.12 (m, 1H), 2.89 - 2.73 (m, 1H), 2.61 (ddd, J = 4.0, 6.8, 14.4 Hz, 1H), 2.48 - 2.36 (m, 1H), 2.10 - 2.02 (m, 1H), 1.93 - 1.79 (m, 2H), 1.51 - 1.35 (m, 1H). Synthesis of IMA-0002576 IMA-0002576 was synthesized following the same general scheme for IMA-0002336 but utilizing tert-butyl 2-[2-hydroxy-2-(2-triisopropylsilyl-1,3-benzothiazol-4-yl)ethyl]piperidine-1- carboxylate as the starting material. IMA-0002576 (16.26 mg, 30.93 μmol, 16.63% yield, 99% purity, TFA) was obtained as an off-white solid. LCMS: Ret. Time: 0.487 min, M+H+, m / z: 407.1.1H NMR (400 MHz, CDCl3) δ = 10.03 - 9.87 (m, 1H), 9.13 (s, 1H), 8.84 - 8.73 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.45 - 7.36 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 6.37 (t, J = 7.2 Hz, 1H), 3.47 (br dd, J = 2.0, 10.4 Hz, 1H), 3.11 - 3.01 (m, 1H), 2.79 - 2.66 (m, 3H), 2.30 - 2.19 (m, 1H), 1.98 (br d, J = 12.8 Hz, 1H), 1.94 - 1.71 (m, 4H). Synthesis of IMA-0002577 2A, 2B: To a solution of 1,3-benzothiazole (594.75 mg, 4.40 mmol, 477.33 μL, 2 eq) in THF (10 mL) wad added LDA (2 M, 2.20 mL, 2 eq) at -65 °C under N2 and stirred at -65 °C for 0.5 h. Then tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate 1 (500 mg, 2.20 mmol, 1 eq) was added and stirred at -65 °C for 5 h. The reaction mixture was poured into saturated aq. NH4Cl (30 mL) and extracted with dichloromethane (30 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~8% EtOAc / PE gradient @ 60 mL / min) to collect the product (TLC: PE / EtOAc=5 / 1, Rf = 0.40 and 0.20). tert- Butyl 2-[2-(1,3-benzothiazol-2-yl)-2-hydroxy-ethyl]piperidine-1-carboxylate 2A (201 mg, 554.51 μmol, 25.21% yield) was obtained as a yellow solid. tert-Butyl 2-[2-(1,3-benzothiazol-2-yl)-2- hydroxy-ethyl]piperidine-1-carboxylate 2B (203 mg, 560.02 μmol, 25.46% yield, N / A purity) was obtained as a yellow gum1H NMR of 2A: (400 MHz, CDCl3) δ = 8.07 - 7.98 (m, 1H), 7.95 - 7.86 (m, 1H), 7.53 - 7.44 (m, 1H), 7.43 - 7.35 (m, 1H), 5.53 (br s, 1H), 4.85 (br d, J = 11.6 Hz, 1H), 4.73 - 4.52 (m, 1H), 4.14 - 3.88 (m, 1H), 3.09 - 2.93 (m, 1H), 2.85 - 2.67 (m, 1H), 1.85 - 1.55 (m, 6H), 1.54 - 1.42 (m, 9H)1H NMR of 2B: (400 MHz, CDCl3) δ =7.97 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.41 - 7.32 (m, 1H), 5.19 (br t, J = 5.2 Hz, 1H), 4.53 (br dd, J = 4.0, 8.4 Hz, 1H), 3.73 - 3.58 (m, 1H), 2.86 (br t, J = 12.8 Hz, 1H), 2.65 (br s, 1H), 2.21 (br d, J = 14.0 Hz, 1H), 1.79 - 1.55 (m, 6H), 1.43 - 1.29 (m, 9H). IMA-0002577 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-[2-(1,3-benzothiazol-2-yl)-2-hydroxy-ethyl]piperidine-1-carboxylate and 4- (trifluoromethyl)phenol as the alcohol starting materials. IMA-0002577 (143.04 mg, 274.82 μmol, 66.61% yield, 100% purity, TFA) was obtained as a white solid. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 407.1.1H NMR (400 MHz, CDCl3) δ = 9.90 (br dd, J = 2.8, 4.0 Hz, 1H), 9.44 - 9.11 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.52 - 7.40 (m, 3H), 7.40 - 7.29 (m, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.05 (dd, J = 4.4, 8.8 Hz, 1H), 3.54 (br d, J = 12.4 Hz, 1H), 3.35 (br s, 1H), 2.91 (br s, 2H), 2.65 (ddd, J = 4.4, 7.2, 14.8 Hz, 1H), 2.49 (ddd, J = 5.2, 9.2, 14.8 Hz, 1H), 2.09 (br dd, J = 2.8, 14.0 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.90 - 1.82 (m, 2H), 1.63 - 1.43 (m, 1H). Synthesis of IMA-0002578 IMA-0002578 was synthesized following the same general scheme for IMA-0002367 but utilizing tert-butyl 2-[2-(1,3-benzothiazol-2-yl)-2-hydroxy-ethyl]piperidine-1-carboxylate and 4- (trifluoromethyl)phenol as the alcohol starting materials. IMA-0002578 (74.16 mg, 142.48 μmol, 49.44% yield, 100% purity, TFA) was obtained as a white solid. LCMS: Ret. Time: 0.502 min, M+H+, m / z: 407.0.1H NMR (400 MHz, CDCl3) δ = 9.90 (br dd, J = 2.8, 4.0 Hz, 1H), 9.44 - 9.11 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.52 - 7.40 (m, 3H), 7.40 - 7.29 (m, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.05 (dd, J = 4.4, 8.8 Hz, 1H), 3.54 (br d, J = 12.4 Hz, 1H), 3.35 (br s, 1H), 2.91 (br s, 2H), 2.65 (ddd, J = 4.4, 7.2, 14.8 Hz, 1H), 2.49 (ddd, J = 5.2, 9.2, 14.8 Hz, 1H), 2.09 (br dd, J = 2.8, 14.0 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.90 - 1.82 (m, 2H), 1.63 - 1.43 (m, 1H). Synthesis of IMA-0002579 & IMA-0002580 2: To a mixture of tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3-oxo- piperidine-1-carboxylate 1 (500 mg, 1.15 mmol, 1 eq) in THF (5 mL) was added LAH (2.5 M, 500.00 μL, 1.08 eq) at 0 °C under N2atmosphere, then the mixture was stirred at 0 °C for 1 h under N2. To the reaction mixture was added THF (50 mL) at 0 °C under N2. Na2SO4•10H2O (50 mg) was added to the reaction mixture under N2atmosphere at 0 °C slowly and stirred at 20 °C for 0.5 h, the resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=15% EtOAc), the purified solution was concentrated under reduced pressure to give tert-butyl 2-[2-[tert- butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3-hydroxy-piperidine-1-carboxylate 2 (400 mg, 918.13 μmol, 79.63% yield) as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.45 - 7.15 (m, 5H), 4.87 - 4.40 (m, 1H), 4.02 - 3.80 (m, 1H), 3.75 - 3.48 (m, 1H), 2.81 - 2.58 (m, 1H), 2.56 - 2.18 (m, 2H), 2.00 - 1.89 (m, 1H), 1.79 - 1.28 (m, 13H), 0.98 - 0.76 (m, 9H), 0.13 - -0.32 (m, 6H). 3: A mixture of tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3-hydroxy- piperidine-1-carboxylate 2 (300 mg, 688.59 μmol, 1 eq) in DCM (3 mL) was added DAST (188.00 mg, 1.17 mmol, 154.10 μL, 1.69 eq) at -70 °C and stirred at -70 °C for 0.5 h. The reaction mixture was poured into aq. NaHCO3 (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=10% EtOAc), the purified solution was concentrated under reduced pressure to give tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3-fluoro-piperidine-1-carboxylate 3 (220 mg, 502.67 μmol, 73.00% yield) as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.50 - 7.17 (m, 5H), 5.06 - 4.66 (m, 1H), 4.61 - 4.38 (m, 1H), 4.03 - 3.25 (m, 1H), 2.88 - 2.57 (m, 1H), 2.24 - 2.08 (m, 2H), 2.02 - 1.66 (m, 4H), 1.60 - 1.38 (m, 10H), 0.92 - 0.87 (m, 9H), 0.19 - -0.26 (m, 6H). 4: A mixture of tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3-fluoro- piperidine-1-carboxylate 3 (200 mg, 456.97 μmol, 1 eq) in DCM (10 mL) was added TFA (153.50 mg, 1.35 mmol, 0.1 mL, 2.95 eq) at 25 °C and stirred at 25 °C for 0.5 h. The mixture was concentrated to give a yellow gum. The yellow gum was dissolved in TFA (3.07 g, 26.92 mmol, 2 mL, 58.92 eq) and stirred at 25 °C for 12 h. The mixture was concentrated to give 2-(3-fluoro- 2-piperidyl)-1-phenyl-ethanol 4 (160 mg, crude, TFA) as a light-yellow gum. The crude product was used in the next step without further purification. LCMS: Ret. Time: 0.327 min, M+H+, m / z: 224.2. IMA-0002579 & IMA-0002580: To a solution of 2-(3-fluoro-2-piperidyl)-1-phenyl- ethanol 4 (160 mg, 474.34 μmol, 1 eq, TFA) in DMA (2 mL) was added NaH (95.00 mg, 2.38 mmol, 60% purity, 5.01 eq) at 0 °C under N2atmosphere, then the reaction mixture was stirred at 0 °C for 0.5 h under N2 atmosphere.1-fluoro-4-(trifluoromethyl)benzene 5 (117.00 mg, 712.98 μmol, 90.49 μL, 1.5 eq) was added and the solution was stirred at 20 °C for 2 h under N2 atmosphere. The mixture was quenched by slow addition of saturated aq. NH4Cl (60 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (TFA)-ACN]; gradient:18%-48% B over 10 min), the purified solution was lyophilized to give IMA-0002579 (11.95 mg, 32.53 μmol, 6.86% yield, 100% purity) as a light yellow solid. LCMS: Ret. Time: 0.478 min, M+H+, m / z: 386.1.1H NMR (400 MHz, CDCl3) δ = 7.43 (d, J = 8.8 Hz, 2H), 7.37 - 7.28 (m, 5H), 6.88 (d, J = 8.8 Hz, 2H), 5.38 (dd, J = 4.0, 9.6 Hz, 1H), 4.92 - 4.70 (m, 1H), 3.58 - 3.32 (m, 1H), 3.19 (br d, J = 12.0 Hz, 1H), 2.90 - 2.74 (m, 1H), 2.47 (ddd, J = 5.2, 9.2, 14.0 Hz, 1H), 2.38 - 2.16 (m, 2H), 2.10 - 1.97 (m, 1H), 1.69 - 1.55 (m, 2H). IMA-0002580 (14.71 mg, 40.04 μmol, 8.44% yield, 100% purity) was obtained as a light yellow solid. LCMS: Ret. Time: 0.484 min, M+H+, m / z: 386.1.1H NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 8.4 Hz, 2H), 7.37 - 7.27 (m, 5H), 6.87 (d, J = 8.8 Hz, 2H), 5.59 - 5.49 (m, 1H), 5.09 - 4.87 (m, 1H), 3.60 - 3.39 (m, 1H), 3.37 - 3.21 (m, 1H), 2.92 (br t, J = 12.4 Hz, 1H), 2.49 (ddd, J = 5.6, 10.0, 15.2 Hz, 1H), 2.37 - 2.24 (m, 1H), 2.23 - 2.15 (m, 1H), 2.14 - 2.04 (m, 1H), 1.78 - 1.67 (m, 2H). Synthesis of IMA-0002581 2: A mixture of tert-butyl 3-oxopiperidine-1-carboxylate 1 (27 g, 135.51 mmol, 1 eq) and pyrrolidine (10.60 g, 149.06 mmol, 12.44 mL, 1.1 eq) in toluene (110 mL) was degassed and purged with N2for 3 times, then heated to130 °C for 12 h and remove water by Dean-Stark trap. The reaction mixture was used into next step without further work-up. tert-Butyl 5-pyrrolidin-1- yl-3,4-dihydro-2H-pyridine-1-carboxylate 2 (34.2 g, crude) was obtained as an orange oil. 3: To a solution of tert-butyl 5-pyrrolidin-1-yl-3,4-dihydro-2H-pyridine-1-carboxylate 2 (34.2 g, 135.53 mmol, 1 eq) in toluene (340 mL) was added 2-bromo-1-phenyl-ethanone (29.67 g, 149.08 mmol, 1.1 eq) at 0 °C and stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ACN (340 mL) at 0 °C and added TBAI (10.01 g, 27.11 mmol, 0.2 eq). The mixture was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 3 h under N2atmosphere. The reaction mixture was poured into stirring water (1L) and extracted with EtOAc (1L x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=30% EtOAc), the purified solution was concentrated under reduced pressure to give tert-butyl 3-oxo-2- phenacyl-piperidine-1-carboxylate 3 (18.7 g, 58.92 mmol, 43.48% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 7.6 Hz, 2H), 7.63 - 7.53 (m, 1H), 7.51 - 7.43 (m, 2H), 4.81 (br s, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.75 - 3.23 (m, 3H), 2.85 - 2.65 (m, 1H), 2.64 - 2.51 (m, 1H), 2.15 - 2.03 (m, 2H), 1.38 (br s, 9H). 4: 2-(2-Hydroxyethylamino)ethanol (66.37 g, 631.26 mmol, 61.00 mL, 40.07 eq) dissolved in HCOOH (30.33 g, 631.26 mmol, 40.07 eq) and MeOH (50 mL) at 25-50°C for 5 min (reaction temperature rises quickly, pay attention to temperature control). A mixture of tert-butyl 3-oxo-2-phenacyl-piperidine-1-carboxylate 3 (5 g, 15.75 mmol, 1 eq) and dichloropalladium (559 mg, 3.15 mmol, 0.2 eq) was added to the mixture quickly and stirred at 25 °C for 2 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)-3-oxo-piperidine-1-carboxylate 4 (4 g, crude) as a yellow oil. The crude product was used into next step without further purification. LCMS: Ret. Time: 0.521 min, M+Na+, m / z: 342.1. 5: To a stirred solution of tert-butyl 2-(2-hydroxy-2-phenyl-ethyl)-3-oxo-piperidine-1- carboxylate 4 (4 g, 12.52 mmol, 1 eq) in DMF (40 mL) was added tert-butyl-chloro-dimethyl- silane (2.27 g, 15.03 mmol, 1.85 mL, 1.2 eq) and imidazole (1.28 g, 18.79 mmol, 1.5 eq) and the reaction stirred at 25 °C for 12 h. The reaction mixture was poured into aq. NH4Cl (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=20% EtOAc) and concentrated under reduced pressure to give tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2- phenyl-ethyl]-3-oxo-piperidine-1-carboxylate 5 (0.9 g, 2.08 mmol, 16.57% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.31 (br d, J = 4.4 Hz, 4H), 7.26 - 7.21 (m, 1H), 4.68 - 4.62 (m, 2H), 4.10 (s, 1H), 3.16 - 2.99 (m, 1H), 2.54 - 2.36 (m, 2H), 2.10 - 2.04 (m, 3H), 2.00 - 1.91 (m, 2H), 1.46 (s, 8H), 0.88 - 0.83 (m, 9H), 0.10 - -0.23 (m, 6H). 6: To a mixture of tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3-oxo- piperidine-1-carboxylate 5 (400 mg, 922.39 μmol, 1 eq) in THF (4 mL) was added LiAlH4(2.5 M, 400.00 μL, 1.08 eq) at 0 °C under N2 atmosphere, then the mixture was stirred at 0 °C for 1 h under N2. To the reaction mixture was added THF (50 mL) at 0 °C under N2. Na2SO4•10H2O (50 mg) was added to the reaction mixture under N2atmosphere at 0 °C slowly and stirred at 20 °C for 0.5 h, the resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=15% EtOAc) and concentrated under reduced pressure to give tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2- phenyl-ethyl]-3-hydroxy-piperidine-1-carboxylate 6 (400 mg, 918.13 μmol, 99.54% yield) as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.28 (m, 4H), 7.25 (br d, J = 7.2 Hz, 1H), 4.90 - 4.74 (m, 1H), 3.98 - 3.70 (m, 1H), 3.65 - 3.52 (m, 1H), 2.83 - 2.65 (m, 1H), 2.27 (br dd, J = 6.4, 13.2 Hz, 1H), 2.00 (ddd, J = 4.0, 7.6, 14.4 Hz, 1H), 1.90 - 1.31 (m, 14H), 0.89 (s, 9H), 0.17-0.28 (m, 6H) 7: To a solution of tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]-3- hydroxy-piperidine-1-carboxylate 6 (400 mg, 918.13 μmol, 1 eq) in DCM (4 mL) was added N,N-dimethylpyridin-4-amine (12.00 mg, 98.23 μmol, 1.07e-1 eq), TEA (186.00 mg, 1.84 mmol, 255.85 μL, 2 eq) and acetyl acetate (104.00 mg, 1.02 mmol, 95.68 μL, 1.11 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into aq. NH4Cl (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EtOAc=5:1) and concentrated under reduced pressure to give tert-butyl 3- acetoxy-2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl-ethyl]piperidine-1-carboxylate 7 (430 mg, 900.13 μmol, 98.04% yield) as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.56 - 7.36 (m, 5H), 4.94 - 4.69 (m, 2H), 4.36 (br s, 1H), 4.12 (br d, J = 11.2 Hz, 1H), 3.11 - 2.73 (m, 1H), 2.37 - 2.26 (m, 1H), 2.18 - 2.08 (m, 1H), 2.02 - 1.54 (m, 16H), 1.01 (s, 9H), 0.30 - -0.14 (m, 6H). 8: A mixture of tert-butyl 3-acetoxy-2-[2-[tert-butyl(dimethyl)silyl]oxy-2-phenyl- ethyl]piperidine-1-carboxylate 7 (400 mg, 837.33 μmol, 1 eq) in TBAF (1 M, 4.00 mL, 4.78 eq) at 25 °C and stirred at 25 °C for 1 h. The mixture was dissolved in DCM (50 mL) and washed with brine (30 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE:EtOAc=1:1) and concentrated under reduced pressure to give tert-butyl 3-acetoxy-2- (2-hydroxy-2-phenyl-ethyl)piperidine-1-carboxylate 8 (300 mg, 825.43 μmol, 98.58% yield) as a light yellow gum.1H NMR (400 MHz, CDCl3) δ = 7.52 - 7.29 (m, 5H), 5.89 - 5.56 (m, 1H), 5.04 - 4.37 (m, 2H), 4.09 - 3.63 (m, 2H), 2.95 - 2.57 (m, 1H), 2.21 (br t, J = 7.2 Hz, 2H), 1.98 - 1.35 (m, 16H). 9: To a solution of tert-butyl 3-acetoxy-2-(2-hydroxy-2-phenyl-ethyl)piperidine-1- carboxylate 8 (300 mg, 825.43 μmol, 1 eq), 4-(trifluoromethyl)phenol (201.00 mg, 1.24 mmol, 1.5 eq) and PPh3 (325.00 mg, 1.24 mmol, 1.5 eq) in THF (10 mL) was added DIAD (250.00 mg, 1.24 mmol, 239.69 μL, 1.5 eq) at 0 °C under N2, then the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, PE / EtOAc=5 / 1) and concentrated under reduced pressure to give tert-butyl 3-acetoxy-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 9 (400 mg, 788.11 μmol, 95.48% yield) as a light yellow gum. 10: A mixture of tert-butyl 3-acetoxy-2-[2-phenyl-2-[4-(trifluoromethyl)phenoxy] ethyl]piperidine-1-carboxylate 9 (400 mg, 788.11 μmol, 1 eq) in MeOH (4 mL)was added KOH (222.00 mg, 3.96 mmol, 5.02 eq) at 25 °C and stirred at 25 °C for 12 h. The reaction mixture was poured into aq. NH4Cl (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=35% EtOAc) and concentrated under reduced pressure to give tert-butyl 3-hydroxy-2-[2-phenyl-2-[4- (trifluoromethyl)phenoxy]ethyl]piperidine-1-carboxylate 10 (200 mg, 429.64 μmol, 54.52% yield) as a colorless gum. LCMS: Ret. Time: 0.585 min, M+Na+, m / z: 488.3. IMA-0002581: A mixture of tert-butyl 3-hydroxy-2-[2-phenyl-2-[4-(trifluoromethyl) phenoxy]ethyl]piperidine-1-carboxylate 10 (200 mg, 429.64 μmol, 1 eq) in DCM (3 mL)was added TFA (1.54 g, 13.46 mmol, 1 mL, 31.33 eq) at 25 °C and stirred at 25 °C for 0.5 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 x 40 mm x 15 um; mobile phase: [water (TFA)-ACN]; gradient: 22%- 52% B over 22 min), the purified solution was lyophilized to give IMA-0002581 (55.26 mg, 115.27 μmol, 26.83% yield, 100% purity, TFA) as a white solid. LCMS: Ret. Time: 0.474 min, M+H+, m / z: 366.2.1H NMR (400 MHz, CDCl3) δ = 10.54 - 9.67 (m, 1H), 9.57 - 7.81 (m, 1H), 7.61 - 7.39 (m, 2H), 7.28 (s, 3H), 7.25 (br s, 2H), 7.09 - 6.85 (m, 2H), 5.57 - 4.64 (m, 1H), 4.19 - 3.63 (m, 1H), 3.44 - 3.24 (m, 2H), 3.05 - 2.77 (m, 1H), 2.52 - 2.17 (m, 2H), 2.13 - 1.91 (m, 2H), 1.77 - 1.54 (m, 2H). Synthesis of IMA-0002582 & IMA-0002583 2: To a solution of benzyl 5-hydroxy-2-(2-methoxy-2-oxo-ethyl)piperidine-1-carboxylate 1 (2.96 g, 9.63 mmol, 1 eq) in DCM (60 mL) was added DMP (6.13 g, 14.45 mmol, 4.48 mL, 1.5 eq) at 0 °C and stirred at 20 °C for 12 h. DMP (4.08 g, 9.63 mmol, 2.98 mL, 1 eq) was added and stirred at 20 °C for 2 h. The reaction mixture was diluted with DCM (40 mL) and washed with saturated aq. NaHCO3 (50 mL × 3) and saturated aq. Na2SO3 (50 mL × 3) dried over anhydrous Na2SO4and concentrated in vacuo to give a crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc / PE gradient @ 60 mL / min). Benzyl 2-(2-methoxy-2-oxo-ethyl)-5-oxo-piperidine-1- carboxylate 2 (1.8 g, 5.90 mmol, 61.21% yield) was obtained as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.44 - 7.31 (m, 5H), 5.18 (br s, 2H), 4.70 - 4.38 (m, 2H), 3.87 - 3.61 (m, 4H), 2.73 (br s, 2H), 2.50 - 2.40 (m, 2H), 2.39 - 2.27 (m, 1H), 1.95 - 1.81 (m, 1H). 3: To a solution of benzyl 2-(2-methoxy-2-oxo-ethyl)-5-oxo-piperidine-1-carboxylate 2 (1.80 g, 5.90 mmol, 1 eq) in DCM (36 mL) was added DAST (2.85 g, 17.69 mmol, 2.34 mL, 3 eq) at -65 °C under N2 atmosphere and stirred at -65 °C for 0.5 h. Then the mixture was stirred at -40 °C for 0.5 h and stirred at 0 °C for 0.5 h. The mixture was quenched by slow addition of saturated aq. NaHCO3 (30 mL). The resulting mixture was transferred to a separatory funnel, and the aqueous layer extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% EtOAc / PE gradient @ 60 mL / min). Benzyl 5,5-difluoro-2-(2-methoxy-2-oxo-ethyl)piperidine-1-carboxylate 3 (1224 mg, 3.74 mmol, 63.43% yield) was obtained as a colorless gum1H NMR (400 MHz, CDCl3) δ = 7.46 - 7.31 (m, 5H), 5.16 (s, 2H), 4.84 (br s, 1H), 4.52 - 4.23 (m, 1H), 3.62 (br s, 3H), 3.26 - 3.00 (m, 1H), 2.71 - 2.47 (m, 2H), 2.16 - 1.87 (m, 3H), 1.79 - 1.65 (m, 1H). 4: To a solution of benzyl 5,5-difluoro-2-(2-methoxy-2-oxo-ethyl)piperidine-1- carboxylate 3 (1.35 g, 4.12 mmol, 1 eq) in THF (27 mL) was added lithium tri-tert- butoxyaluminum hydride (9.40 g, 37.12 mmol, 10.40 mL, 9 eq) at 0 °C under N2 and stirred at 20 °C for 12 h. The reaction mixture was poured into THF (50 mL) and quenched by addition of Na2SO4.10H2O (9.4 g) and H2O (0.94 mL). The reaction mixture was filtered and concentrated to give the crude. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~35% EtOAc / PE gradient @ 60 mL / min). Benzyl 5,5-difluoro-2-(2-hydroxyethyl)piperidine-1-carboxylate 4 (0.66 g, 2.21 mmol, 53.46% yield) was obtained as a colorless gum.1H NMR (400 MHz, CDCl3) δ = 7.39 - 7.19 (m, 5H), 5.10 (br d, J = 9.6 Hz, 2H), 4.50 (br s, 1H), 4.35 - 4.14 (m, 1H), 3.55 (br s, 1H), 3.36 (br d, J = 9.6 Hz, 1H), 3.01 - 2.80 (m, 1H), 2.05 - 1.79 (m, 4H), 1.66 - 1.49 (m, 2H). 5: To a solution of (COCl)2 (174.00 mg, 1.37 mmol, 120.00 μL, 2.05 eq) in DCM (2 mL) at -65 °C was added a solution of DMSO (100.00 mg, 1.28 mmol, 0.1 mL, 1.92 eq) in DCM (1 mL). The mixture was stirred for 30 min at -65 °C, and a solution of benzyl 5,5-difluoro-2-(2- hydroxyethyl)piperidine-1-carboxylate 4 (200.00 mg, 668.20 μmol, 1 eq) in DCM (2 mL) was added to the mixture and stirred at -65 °C for 1 h. The mixture was treated with TEA (407.12 mg, 4.02 mmol, 560.00 μL, 6.02 eq) and allowed to warm to 0 °C, then the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was poured into water (10 mL), and after separation of the phases the organic phase was washed with water (5 mL). The organic phase was dried over sodium sulphate, filtered, and concentrated under reduced pressure. The obtained residue was purified by prep-TLC with PE / EtOAc = 1 / 1. Benzyl 5,5-difluoro-2-(2-oxoethyl)piperidine-1-carboxylate 5 (138 mg, 464.18 μmol, 69.47% yield) was obtained as a colorless gum. 6: To a solution of benzyl 5,5-difluoro-2-(2-oxoethyl)piperidine-1-carboxylate 5 (138.00 mg, 464.18 μmol, 1 eq) in THF (3 mL) was added PhMgBr (3 M, 0.23 mL, 1.49 eq) at 0 °C under N2, the mixture was stirred at 20 °C for 12 h under N2. The reaction mixture was poured into saturated aq. NH4Cl (10 mL) and extracted with dichloromethane (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The obtained residue was purified by prep-TLC with PE / EtOAc=2 / 1. Benzyl 5,5-difluoro-2-(2-hydroxy-2-phenyl- ethyl)piperidine-1-carboxylate 6 (100 mg, 266.38 μmol, 57.39% yield, N / A purity) was obtained as a colorless gum. LCMS: Ret. Time: 0.550 min, M+23+, m / z: 398.1.1H NMR (400 MHz, CDCl3) δ = 7.42 - 7.30 (m, 5H), 5.25 - 5.05 (m, 2H), 4.48 - 4.35 (m, 1H), 4.12 - 4.03 (m, 1H), 3.62 (br s, 2H), 3.43 - 3.32 (m, 1H), 2.62 - 2.50 (m, 1H), 2.01 - 1.89 (m, 1H), 1.86 - 1.74 (m, 2H), 1.66 - 1.46 (m, 3H), 0.93 - 0.85 (m, 9H), 0.14 - 0.04 (m, 6H). 7: To a solution of benzyl 5,5-difluoro-2-(2-hydroxy-2-phenyl-ethyl)piperidine-1- carboxylate 6 (100.00 mg, 266.38 μmol, 1 eq) in THF (4 mL) was added Pd / C (85.04 mg, 79.91 μmol, 10% purity, 0.3 eq) under N2atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (30Psi) at 25 °C for 12 h. The mixture was filtered through Celite and concentrated to give the crude product used directly in the next step.2-(5,5- difluoro-2-piperidyl)-1-phenyl-ethanol 7 (70 mg, crude) was obtained as a white solid. LCMS: Ret. Time: 0.333 min, M+H+, m / z: 242.1. IMA-0002582 & IMA-0002583: To a solution of 2-(5,5-difluoro-2-piperidyl)-1-phenyl- ethanol 7 (70 mg, 290.12 μmol, 1 eq) in DMA (1.5 mL) was added NaH (35 mg, 875.08 μmol, 60% purity, 3.02 eq) at 0 °C under N2 atmosphere and stirred at 0 °C for 0.5 h under N2. Then 1- fluoro-4-(trifluoromethyl)benzene (64.65 mg, 393.97 μmol, 0.05 mL, 1.36 eq) was added at 0 °C and stirred at 20 °C for 2 h. The reaction mixture was poured into saturated aq. NH4Cl (10 mL) and extracted with DCM (10 mL x 3), the combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150 x 25 mm x 10 um; mobile phase: [water (TFA)-ACN]; gradient: 22%- 52% B over 18 min) and lyophilized to give IMA-0002582 (11.96 mg, 23.95 μmol, 8.25% yield, 100% purity, TFA) as a white solid. LCMS: Ret. Time: 0.493 min, M+H+, m / z: 386.0.1H NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 8.4 Hz, 2H), 7.38 - 7.27 (m, 5H), 6.87 (d, J = 8.4 Hz, 2H), 5.32 (dd, J = 4.0, 9.6 Hz, 1H), 3.39 (dt, J = 3.2, 9.6 Hz, 2H), 3.14 - 2.97 (m, 1H), 2.56 (ddd, J = 5.2, 9.2, 14.4 Hz, 1H), 2.32 (dt, J = 3.2, 6.4 Hz, 1H), 2.24 - 1.79 (m, 4H). IMA-0002583 (14.5 mg, 29.04 μmol, 10.01% yield, 100% purity, TFA) was obtained as a white solid. LCMS: Ret. Time: 0.485 min, M+H+, m / z: 386.0.1H NMR (400 MHz, CDCl3) δ = 7.42 (d, J = 8.4 Hz, 2H), 7.37 - 7.27 (m, 5H), 6.88 (d, J = 8.4 Hz, 2H), 5.50 (dd, J = 5.2, 8.0 Hz, 1H), 3.56 - 3.33 (m, 2H), 3.25 - 3.01 (m, 1H), 2.45 - 2.28 (m, 3H), 2.23 - 1.91 (m, 3H). Synthesis of IMA-0002584 2: To a solution of 1,4-oxazepan-5-one 1 (25 g, 217.15 mmol, 1 eq) in DCM (500 mL) was added triethyloxonium tetrafluoroborate (41.25 g, 217.15 mmol, 31.07 mL, 1 eq) in several portions, then the mixture was stirred at 25 °C for 12 h. The reaction was shaken vigorously with saturated aq. NaHCO3 (1 L) until the effervescence subsided. The organic layer was washed with brine (500 mL) and dried over anhydrous granular Na2SO4 then filtered and evaporated. The crude product was used directly in the next step. The 5-ethoxy-2,3,6,7-tetrahydro-1,4-oxazepine 2 (25.2 g, 176.00 mmol, 81.05% yield) was obtained as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 3.99 (q, J = 7.2 Hz, 2H), 3.70 - 3.67 (m, 2H), 3.66 - 3.62 (m, 2H), 3.57 - 3.51 (m, 2H), 2.69 - 2.59 (m, 2H), 1.29 - 1.22 (m, 3H). 3: To a solution of 5-ethoxy-2,3,6,7-tetrahydro-1,4-oxazepine 2 (25.2 g, 176.00 mmol, 1 eq) in toluene (250 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (25.37 g, 176.00 mmol, 1 eq) and TEA (3.56 g, 35.20 mmol, 4.90 mL, 0.2 eq), then mixture was stirred 120 °C for 12 hr. The mixture was concentrated under reduced pressure to give the crude product used directly in next step.2,2-Dim...

Claims

1. CLAIMS 1. A compound of formula or a pharmaceutically acceptable salt thereof, wherein: A is a 4-, 5-, 6-, or 7-membered heterocyclic ring that is substituted with m R1groups; m is 0, 1, 2, 3, or 4; each R1is independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C3-C10)cycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (6-10)-membered aryl, (4-10)- membered heteroaryl, -ORa, -CORb, -COORc, and -SOnRd; wherein two R1optionally taken together with the atoms to which they are attached to form a 4-7-membered ring; n is 1 or 2; Ra, Rb, Rc, and Rdare each independently selected from H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C3-C10)cycloalkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; q is 1 or 2; Rxand Ryare each independently selected from hydrogen and (C1-C6)alkyl; R2and R3are each independently selected from H, (C1-C6)alkyl, (6-10)-membered aryl, (C3-C10)cycloalkyl, (4-10)-membered heteroaryl, and (4-10)-membered heterocyclyl; and R4is selected from (C1-C6)alkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; wherein each alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (6-10)-membered aryl, hydroxy, and (C1-C6)alkoxy.

2. The compound of claim 1, wherein wherein: A is a 4-, 5-, 6-, or 7-membered heterocyclic ring; m is 0, 1, 2, 3, or 4; each R1is independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3- C10)cycloalkyl, (6-10)-membered aryl, (4-10)-membered heteroaryl, -ORa, -CORb, -COORc, and - SOnRd; wherein two R1optionally taken together with the atoms to which they are attached to form a 4-7-membered ring; n is 1 or 2; Ra, Rb, Rc, and Rdare each independently selected from H, (C1-C6)alkyl, (C1- C6)haloalkyl, (C3-C10)cycloalkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; R2and R3are each independently selected from H, (C1-C6)alkyl, (6-10)-membered aryl, (C3-C10)cycloalkyl, and (4-10)-membered heteroaryl; and R4is selected from (C1-C6)alkyl, (6-10)-membered aryl, and (4-10)-membered heteroaryl; wherein each alkyl, aryl, cycloalkyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (6-10)-membered aryl, hydroxy, and (C1-C6)alkoxy.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from piperidine, pyrrolidine, azetidine, morpholine, azepane, piperazine, and 1,4- oxazepane.

4. The compound of claim 1 or claim 3, or a pharmaceutically acceptable salt thereof, wherein A is selected from: , 5. The compound of any one of claims -14, or a pharmaceutically acceptable salt thereof, wherein A is selected from: , 6. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein A is:.

7. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein m is 0.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2, and each R1is independently selected from halo, (C1-C3)alkyl, (C1- C3)haloalkyl, (C1-C3)hydroxyalkyl, (C1-C3)alkoxy(C1-C3)alkyl, -ORa, -CORb, -COORc, and - SOnRd, wherein Ra, Rb, Rc, and Rdare each independently selected from hydrogen, phenyl, and (C1-C4)alkyl, wherein the phenyl is unsubstituted or substituted with one substituent selected from halo, (C1-C3)alkyl, and (C1-C3)haloalkyl, and n is 2.

9. The compound of claim 8, wherein each R1is independently selected from fluoro, methyl, hydroxy, -CHF2, -CH2OH, -CH2OCH3, -CH(OH)CH3, -C(CH3)2OH, -C(O)CH3, -S(O)2CH3, - C(O)OCH2CH(CH3)2, and -O-C6H4(4-CF3).

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2, and each R1is independently selected from halo, (C1-C3)alkyl, -ORa, -CORb, -COORc, and -SOnRd, wherein Ra, Rb, Rc, and Rdare each independently selected from hydrogen and (C1-C4)alkyl, and n is 2.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from fluoro, methyl, hydroxy, -C(O)CH3, -S(O)2CH3, and - C(O)OCH2CH(CH3)2.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R2is H.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (6-10)-membered aryl, (C3-C10)cycloalkyl, (4-10)-membered heteroaryl, and (4-10)-membered heterocyclyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R3is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, cyclobutyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, and tetrahydroisoquinolinyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, methyl, phenyl, and methoxy.

15. The compound of claim 13 or claim 14, or a pharmaceutically acceptable salt thereof, wherein R3is selected from: ,,16. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R3is selected from (6-10)-membered aryl, (C3-C10)cycloalkyl, and (4-10)-membered heteroaryl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R3is selected from phenyl, naphthyl, cyclopentyl, cyclohexyl, quinolinyl, and benzothiophenyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, cyano, methyl, phenyl, and methoxy.

18. The compound of claim 16 or claim 17, or a pharmaceutically acceptable salt thereof, wherein R3is selected from: ,19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4is selected from phenyl and naphthyl, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from halo, (C1-C6)alkyl, (C1- C6)haloalkyl, and (6-10)-membered aryl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R4is selected from:.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R4is:.

22. The compound of claim 1, wherein the compound is selected from:and pharmaceutically acceptable salts thereof.

23. The compound of claim 1, wherein the compound is selected from:and pharmaceutically acceptable salts thereof.

24. The compound of claim 1, wherein the compound is selected from:and pharmaceutically acceptable salts thereof.

25. A pharmaceutical composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A method of treating a proliferative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25.

27. The method of claim 26, wherein the subject is a mammal.

28. The method of claim 26, wherein the subject is a human.

29. The method of any one of claims 26-28, wherein the proliferative disease is cancer associated with an altered lipid environment.

30. The method of claim 29, wherein the cancer is selected from glioblastoma, head and neck cancers, breast cancers, lung cancers, esophageal and gastric cancers, pancreatic cancers, colorectal cancers, ovarian cancers, uterine cancers, prostate cancers, renal cancers, skin cancers, leukemias, lymphomas, sarcomas, gliomas, endometrial cancers, cervical cancers, pharyngeal cancers, and liver cancers.

31. The method of any one of claims 26-30, further comprising administering to the subject a therapeutically effective amount of one or more pharmaceutical agents in combination with the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

32. The method of claim 31, wherein the pharmaceutical agent is an antiproliferative agent.

33. The method of claim 32, wherein the antiproliferative agent is selected from temozolomide, carmustine, nimustine, lomustine, cediranib, fotemustine, erlotinib, galunisertib, bevacizumab, irinotecan, interferon-α2b, sorafenib, O6-benzylguanine, cisplatin, doxorubicin, mitoxantrone, procarbazine, and vincristine.

34. The method of any one of claims 26-33, further comprising treating the subject with one or more additional therapies.

35. The method of claim 34, wherein the one or more additional therapies are selected from surgery, radiation therapy, immunotherapy, and CAR-T cell therapy, or any combination thereof.

36. A method of inhibiting cell growth in a biological sample or subject, the method comprising: administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25.

37. A kit comprising: a compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25; and instructions for administering to a subject or contacting a biological sample with the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

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