Oxadiazole modulators of TMEM175 for the treatment of neurodegenerative disorders

Abstract

This application provides compounds of formula (I) and formula (II) and pharmaceutically acceptable salts thereof, that are oxadiazole modulators of TMEM175. Also provided herein are pharmaceutical compositions thereof, and methods of treating neurodegenerative disorders using the same.

Description

[0001] OXADIAZOLE MODULATORS OF TMEM175 FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] [1] This application claims the benefit of U.S. Provisional patent application No. 63 / 676,029 filed on July 26, 2024, which is hereby expressly incorporated by reference in its entirety.

[0004] BACKGROUND

[0005] [2] The field of the disclosure relates generally to oxadiazole modulators of TMEM175 for the treatment of neurodegenerative disorders.

[0006] [3] Parkinson's disease (PD), affecting approximately 10 million people worldwide, is characterized by a plethora of debilitating symptoms (Kalia, L. V. & Lang, A. E. (2015). Parkinson's disease. The Lancet, 386(9996), 896-912). Primarily a neurodegenerative disorder, PD results from the progressive loss of dopaminergic neurons in the substantia nigra region of the brain, and the neuronal degeneration in Parkinson’s leads to motor symptoms such as tremors, rigidity, bradykinesia, and postural instability (Poewe, W. et al. (2017). Parkinson disease. Nature Reviews Disease Primers, 3(1), 1-21). Additionally, patients may experience non-motor symptoms including cognitive impairment, depression, and autonomic dysfunction.

[0007] [4] Molecular mechanism studies of the pathogenesis of PD reveal that lysosomal homeostasis is a key pathway for PD. Lysosomal homeostasis is governed by channels and transporters that establish ion gradients across lysosomal membranes (Jung, Y. et al. (2023) The Korean Journal of Physiology & Pharmacology 27.4: 311.). TMEM175 is a lysosomal proton and potassium channel that maintains the lysosomal pH within an optimal range, ensuring the proper activity of lysosomal hydrolases. It was found that TMEM175 gene variants bidirectionally modify the risk of PD. Specifically, the reduced function of TMEM175(M393T) increases the risk of PD, while TMEM175(Q65P) reduces the risk of developing this condition (Hu, M. et al. (2022) Cell 185.13: 2292-2308). Furthermore, it was found that the TMEM175(M393T) variant leads to defects in lysosomal pH regulation and degradation, resulting in reduced autophagy, diminished activity of lysosomal hydrolases, and increased a-Synuclein (aSyn) pathology. Supporting the loss-of-function mechanism associated with TMEM175(M393T), genetic depletion of the TMEM175 protein in cellular and animal models mimics the effects observed with the TMEM175(M393T) variant, leading to impaired lysosomal function and increased aSyn pathology (Cang, C. et al. (2015) Cell 162.5: 1101-1112).

[0008] [5] Despite decades of research, treatment options for PD remain limited, focusing mainly on symptom management rather than disease modification. Thus, there persists a significant unmet medical need in effectively halting or reversing the progression of this challenging indication.

[0009] BRIEF DESCRIPTION

[0010] [6] In one aspect, provided herein are compounds of formula (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

[0011] Xi to X5are independently selected from the group consisting of hydrogen, halogen, C1.5 haloalkyl, and OH;

[0012] Rlaand Rlbare independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy; each Rlcis independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy; or

[0013] Rlaand one Rlctogether with the atoms attached thereto form a 3-6 membered fused cycloalkyl; n is 0 or 1; m is 0 or 1; provided that n + m is 1 or 2; and p is 0, 1, 2, 3, 4, or 5.

[0014] [7] In another aspect, also provided herein are compounds of formula (II):

[0015] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

[0016] Xi to X5 are independently selected from the group consisting of hydrogen, halogen, C1-5 haloalkyl, C1-5 alkyl, and OH;

[0017] Xe is selected from the group consisting of -C-, -O-, -N-, or -S-;

[0018] Rlaand Rlbare independently selected from hydrogen or -F; each Rlcis independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-5 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen; n is 0 or 1; m is 0 or 1; provided that n + m is 1 or 2; p is 0, 1, 2, 3, 4, or 5; and q is 0 or 1; provided that when Xi is halogen or C1-5 haloalkyl, n is 1, m is 1 and q is 0, then Rlaand Rlbare not both -F.

[0019] DETAILED DESCRIPTION

[0020] [8] Provided herein are oxadiazole modulators of TMEM175, e.g., oxadiazole modulators of formula (I) or of formula (II), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Further provided are pharmaceutical compositions thereof, and methods for their use, e.g., for treating TMEM 175 -mediated diseases such as neurodegenerative disorders. Also provided are methods of making the oxadiazole modulators of TMEM 175 described herein, such as oxadiazole modulators of formula (I) or formula (II).

[0021] Definitions

[0022] [9] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. In addition, any method or material similar or equivalent to a method or material described herein can be used. For purposes as described herein, the following terms are defined.

[0023]

[0010] “A,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.

[0024]

[0011] The term “alkyl”, by itself or as part of another substituent, is used in its conventional sense, and refers to a straight or branched chain hydrocarbon radical. The number of carbons may suitably be from 1 to 20, from 1 to 12, from 1 to 8, from 1 to 6, or from 1 to 4. Nonlimiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl. The term “alkenyl” refers to an unsaturated alkyl radical having one or more double bonds. Similarly, the term “alkynyl” refers to an unsaturated alkyl radical having one or more triple bonds. Non-limiting examples of such unsaturated alkyl groups include linear and branched groups including vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.

[0025]

[0012] The terms “alkoxy,” “alkylamino” and “alkylthio”, are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”), an amino group (“amino”) or thio group, and further include mono- and poly-halogenated variants thereof. Additionally, for dialkylamino groups, the alkyl portions can be the same or different.

[0026]

[0013] The terms “halo” or “halogen,” by themselves or as part of another substituent, are used in their conventional sense, and refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl”, for instance Ci-6 haloalkyl and Ci-4 haloalkyl, are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “Ci-4 haloalkyl” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, difluoromethyl, and the like.

[0027]

[0014] The terms “cycloalkyl” and “cycloalkylene” are used in their conventional sense and refer to a saturated or partially saturated carbocyclic moiety having mono- or bicyclic rings and 3 to 10 carbon atoms in the ring. The cycloalkyl moiety can optionally be substituted with one or more substituents. In particular embodiments, cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3- Cs)cycloalkyl). In other particular embodiments cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-Ce)cycloalkyl). Non-limiting examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially saturated (cycloalkenyl) derivatives thereof (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl). In some aspects, bicyclic cycloalkyl rings are limited to fused rings sharing two carbon atoms. In some aspects, bicyclic cycloalkyl rings exclude bridged bicyclic and spiro bicyclic ring structures.

[0028]

[0015] The terms “heterocycle”, “heterocycloalkyl”, “heterocyclyl” and “heterocycloalkylene” are used in their conventional sense and refer to a 3, 4, 5, 6 or 7-membered monocyclic or a 6, 7, 8, 9 and 10-membered bicyclic heterocyclic moiety that is saturated or partially saturated, and has one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from oxygen, nitrogen and sulfur in the ring with the remaining ring atoms being carbon. In some embodiments, bicyclic heterocyclic rings are limited to fused rings sharing two carbon atoms. In some embodiments, bicyclic heterocyclic rings are fused rings sharing one or more heteroatoms selected from oxygen, nitrogen and sulfur. In some embodiments, bicyclic heterocyclic rings exclude bridged bicyclic and spiro bicyclic ring structures. In some embodiments, one ring of a bicyclic heterocyclic ring structure comprises one or more heteroatoms. In some embodiments, both rings of a bicyclic ring structure comprise one or more heteroatoms.

[0029]

[0016] The term “aryl” refers to a cyclic aromatic hydrocarbon moiety having a mono- or bi-cyclic aromatic ring of 5 to 10 carbon ring atoms. Bicyclic aryl ring systems include fused bicyclics having two fused five-membered aryl rings, having a five-membered aryl ring and a fused six-membered aryl ring, and having two fused six-membered aryl rings. The aryl group can be optionally substituted as defined herein.

[0030]

[0017] The term "heteroaryl" is used in its conventional sense and refers to a monovalent aromatic radical of a 5-, 6-, or 7-membered ring and includes fused ring systems (at least one of which is aromatic) of 5-10 atoms containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups may be optionally substituted independently with one or more substituents described herein. 5 or 6 membered heteroaryl can be selected from the group consisting of optionally substituted pyridinyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinone and benzimidazolyl.

[0031]

[0018] The term “fused bicyclic heteroaryl” means a structure having atoms arranged in two rings fused together with at least two atoms common to each ring, and at least one of the rings being a heteroaryl ring. Non limiting examples of bicyclic heteroaryl comprise bicyclic heteroaryl groups comprising 1, 2, 3 or 4 heteroatom(s) independently selected from N, S or O.

[0032]

[0019] The term “heteroatom,” refers to an atom other than hydrogen or carbon. Nonlimiting examples of heteroatoms include N, O, and S.

[0033]

[0020] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers). Racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0034]

[0021] The term “chiral” refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0035]

[0022] The term “chiral purity” refers to the mole% of one chiral compound based on the total moles of chiral compounds.

[0036]

[0023] The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0037]

[0024] The term E / Z refers to the IUPAC isomerism convention where the substituents at each end of a double bond are assigned priority based on their atomic number. If the high-priority substituents are on the same side of the bond it is assigned Z, and if they are on opposite sides of the bond it is assigned E.

[0038]

[0025] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the disclosure. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

[0039]

[0026] The term “spiro” refers to bicyclic molecules for which the two constitutive cyclic moieties have one carbon atom in common.

[0040]

[0027] The term “bridged” refers to bicyclic molecules for which the two constitutive cyclic moieties have two non-adjacent carbon atoms in common.

[0041]

[0028] The term “fused” refers to bicyclic molecules for which the two constitutive cyclic moieties have two adjacent carbon atoms in common.

[0042]

[0029] The term "substituent" denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. The term "substituted" denotes that a specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitution, z.e., replacement of one hydrogen up to replacement of all hydrogens by substituents. Examples of substituents include, but are not limited to, hydroxy, alkyl, alkoxy, halo, haloalkyl, oxo, cyano, nitro, amino, monoalkylamino, dialkylamino, 3-10-membered cycloalkyl, 3- 10-membered heterocycloalkyl, 5-10-membered aryl, and 5-10 membered heteroaryl.

[0043]

[0030] In the description herein, if there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[0044]

[0031] The term “salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases (e.g., those salts that are pharmaceutically acceptable), depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as alginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge, S. M., et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0032] Neutral forms of the compounds of the present disclosure can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0045]

[0033] The term “subject” refers to refers to animals such as mammals, including but not limited to, humans.

[0046]

[0034] The terms “treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

[0047]

[0035] The term "pharmaceutically acceptable" refers to an anion, cation, carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0048]

[0036] The terms “effective dosage”, “effective amount” and “therapeutically effective amount” of a compound or pharmaceutical composition of the present disclosure is an amount sufficient to affect any one or more beneficial or desired, including biochemical, histological and / or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, a “therapeutically effective amount” refers to that amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of a neurodegenerative disorder, a therapeutically effective amount refers to that amount which has the effect of (1) slowing neurodegeneration, (2) slowing neuroinflammation, (3) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the neurodegenerative disease, (4) decreasing the dose of other medications required to treat the neurodegenerative disease, (5) enhancing the effect of another medication, and / or (6) delaying the progression of the disease in a patient.

[0049]

[0037] An effective dosage can be administered in one or more administrations. For the purposes of the present disclosure, an effective dosage of a compound or a pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.

[0050]

[0038] The term "co-administering" refers to either simultaneous administration, or any manner of separate sequential administration, of a compound as described herein or a salt thereof, and a further active pharmaceutical ingredient or ingredients. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g., one compound may be administered topically and another compound may be administered orally.

[0051]

[0039] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound as described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, provided is a single unit dosage form comprising a compound of formula (I) or formula (II), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0052]

[0040] The term “EC50” refers to the concentration of a substance required to achieve half of its maximal effect.

[0053] Compounds of Formula (I)

[0054]

[0041] Some embodiments of the present disclosure are directed to compounds of formula (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0055]

[0042] Each of Xi to X5 is independently selected from: hydrogen, halogen, C1-5 alkyl, C1-5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl, -CH3, -CF3, -CH2F, and -CHF2. In some embodiments, X2 is hydrogen or F. In some embodiments, X2 is hydrogen. In some embodiments, X2 is F. In some embodiments, X3 to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3 and X4 are each independently -F.

[0043] In some embodiments, each of Xi to X5 is independently selected from: hydrogen, halogen, C1-5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl and -CF3. In some embodiments X2 is F. In some embodiments, X3 to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3 and X4 are each -F.

[0056]

[0044] n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, n is i.

[0057]

[0045] m is an integer selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0058]

[0046] In some embodiments, n+m is 1 or 2. In some embodiments n+m is 1. In some embodiments, n+m is 2.

[0059]

[0047] Rlaand Rlbare each independently selected from the group consisting of hydrogen, halogen substituted or unsubstituted C1.5 alkyl, substituted or unsubstituted C1.5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, halogen, C1-3 haloalkyl, unsubstituted C1-3 alkyl, unsubstituted C1-3 alkoxy, C1-3 haloalkoxy, substituted or unsubstituted 3-4 membered cycloalkyl, and substituted or unsubstituted 3-4 membered cycloalkoxy. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, halogen, C1-2 haloalkyl, unsubstituted C1-2 alkyl, unsubstituted C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and cyclopropoxy. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, -F, -Cl, -CF3, -CHF2, -CH2F, -CF2CH3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, -OCF2CH3, -OCH2CHF2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -0CH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2„ cyclopropyl, and cyclopropoxy. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, halogen, C1-2 haloalkyl, and C1-2 haloalkoxy. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, -F, -CF3, -CHF2, -CH2F, -CF2CH3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, -OCF2CH3, and - OCH2CHF2. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, -F, -CF3, -OCF3, and -OCHF2. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, -F, and -OCF3.

[0060]

[0048] In some embodiments, Rlbis hydrogen and Rlais selected from the group consisting of hydrogen, halogen substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy. In some embodiments, Rlbis hydrogen and Rlais selected from hydrogen, halogen, C1-3 haloalkyl, unsubstituted C1-3 alkyl, unsubstituted C1-3 alkoxy, C1-3 haloalkoxy, substituted or unsubstituted 3-4 membered cycloalkyl, and substituted or unsubstituted 3-4 membered cycloalkoxy. In some embodiments, Rlbis hydrogen and Rlais selected from halogen, Ci-2 haloalkyl, unsubstituted C1-2 alkyl, unsubstituted C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and cyclopropoxy. In some embodiments, Rlbis hydrogen and Rlais selected from -F, -Cl, -CF3, - CHF2, -CH2F, -CF2CH3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, -OCF2CH3, -OCH2CHF2, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, cyclopropyl, and cyclopropoxy. In some embodiments, Rlbis hydrogen and Rlais selected from halogen, C1-2 haloalkyl, and C1-2 haloalkoxy. In some embodiments, Rlbis hydrogen and Rlais selected from -F, -CF3, -CHF2, -CH2F, -CF2CH3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, - OCF2CH3, and -OCH2CHF2. In some embodiments, Rlbis hydrogen and Rlais selected from -F, - CF3, -OCF3, and -OCHF2. In some embodiments, Rlbis hydrogen and Rlais selected from -F, and - OCF3. In some embodiments, Rlbis hydrogen and Rlais -F. In some embodiments, Rlbis hydrogen and Rlais -OCF3.

[0061]

[0049] Each Rlaand Rlbis independently selected from: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, Rlais selected from hydrogen, C1-3 alkoxy, Ci.3haloalkoxy, Ci.3alkyl, 3-4 membered cycloalkyl, halogen, and Ci.3haloalkyl. In some embodiments, Rlbis selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0062]

[0050] Each Rlcis independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy. In some embodiments, each Rlcindependently selected from hydrogen, halogen, C1-3 haloalkyl, unsubstituted C1-3 alkyl, unsubstituted C1-3 alkoxy, C1-3 haloalkoxy, substituted or unsubstituted 3-4 membered cycloalkyl, and substituted or unsubstituted 3-4 membered cycloalkoxy. In some embodiments, each Rlcindependently selected from hydrogen, halogen, C1-2 haloalkyl, unsubstituted C1-2 alkyl, unsubstituted C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and cyclopropoxy. In some embodiments, each Rlcindependently selected from hydrogen, -F, -Cl, - CF3, -CHF2, -CH2F, -CF2CH3, -CH2CHF2, -OCF3, -OCHF2, -OCH2F, -OCF2CH3, -OCH2CHF2, - CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, cyclopropyl, and cyclopropoxy. In some embodiments, each Rlcindependently selected from hydrogen, halogen, C1-2 haloalkyl, unsubstituted C1-2 alkyl, and unsubstituted C1-2 alkoxy. In some embodiments, each Rlcindependently selected from hydrogen, -CF3, -CHF2, -CH2F, -CH3, - CH2CH3, -CH(CH3)2, and cyclopropyl. In some embodiments, each Rlcindependently selected from hydrogen, -CF3, -CH3, -CH(CH3)2, and cyclopropyl. In some embodiments, each Rlcindependently hydrogen, -CF3, or -CH3. In some embodiments, each Rlcis hydrogen. In some embodiments, each Rlcis -CH3. In some embodiments, each Rlcis -CF3.

[0051] Each Rlcis independently selected from: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0063]

[0052] In some embodiments, Rlaand one Rlctogether with the atoms attached thereto form a 3-membered cycloalkyl fused to the ring to which Rlaand Rlcare attached.

[0064]

[0053] p is an integer selected from 0, 1, 2, 3, 4 and 5. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0065]

[0054] In some embodiments, the compound of formula (I) is a compound of formula (la): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0066]

[0055] In some embodiments, the compound of formula (I) is a compound of formula (la).

[0067]

[0056] In some embodiments, Xi to X5 is each independently selected from: hydrogen, halogen, C1.5 alkyl, C1.5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl, -CH3, -CF3, -CH2F, and -CHF2. In some embodiments, X2 is hydrogen or F. In some embodiments, X2 is hydrogen. In some embodiments, X2 is F. In some embodiments, X3to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3and X4 are each independently -F.

[0068]

[0057] In some embodiments, each Xi to X5 is independently selected from: hydrogen, halogen, C1-5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl and -CF3. In some embodiments X2 is F. In some embodiments, X3to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3and X4 are each independently -F.

[0069]

[0058] In some embodiments, X3, X4, and X5 are each hydrogen.

[0070]

[0059] n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, n is i.

[0071]

[0060] m is an integer selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0061] In some embodiments, n+m is 1 or 2. In some embodiments n+m is 1. In some embodiments, n+m is 2.

[0072]

[0062] In some embodiments, each Rlaand Rlbis independently selected from: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, Rlais selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl. In some embodiments, Rlbis selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0073]

[0063] Each Rlcis independently selected from: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from hydrogen, C1-3 alkoxy, C1.3 haloalkoxy, C1.3 alkyl, 3-4 membered cycloalkyl, halogen, and C1.3 haloalkyl.

[0074]

[0064] In some embodiments, each Rlcis independently selected from substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1.5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0075]

[0065] In some embodiments, Rlaand one Rlctogether with the atoms attached thereto form a 3-membered cycloalkyl fused to the ring to which Rlaand Rlcare attached.

[0076]

[0066] p is an integer selected from 0, 1, 2, 3, 4 and 5. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0077]

[0067] In some embodiments, the compound of formula (I) is a compound of formula (lb) or formula (Ic): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0078]

[0068] In some embodiments, the compound of formula (I) is a compound of formula (lb).

[0069] In some embodiments, Xi to X5 is each independently selected from: hydrogen, halogen, C1-5 alkyl, C1-5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl, -CH3, -CF3, -CH2F, and -CHF2. In some embodiments, X2 is hydrogen or F. In some embodiments, X2 is hydrogen. In some embodiments, X2 is F. In some embodiments, X3 to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3 and X4 are each independently -F.

[0079]

[0070] In some embodiments, each of Xi to X5 is independently selected from: hydrogen, halogen, C1-5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl and -CF3. In some embodiments X2 is F. In some embodiments, X3 to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3 and X4 are each independently -F.

[0080]

[0071] n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, n is i.

[0081]

[0072] m is an integer selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0082]

[0073] Each Rlaand Rlbis independently selected from: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, Rlais selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl. In some embodiments, Rlbis selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0083]

[0074] Each Rlcis independent selected from: hydrogen, substituted or unsubstituted C1.5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0084]

[0075] In some embodiments, each Rlcis independently selected from substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0085]

[0076] In some embodiments, Rlaand one Rlctogether with the atoms attached thereto form a 3-membered cycloalkyl fused to the ring to which Rlaand Rlcare attached.

[0086]

[0077] In some embodiments, the compound of formula (I) is a compound of formula (Ic).

[0087]

[0078] In some embodiments, Xi to X5 is each independently selected from: hydrogen, halogen, C1-5 alkyl, C1-5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl, -CH3, -CF3, -CH2F, and -CHF2. In some embodiments, X2 is hydrogen or F. In some embodiments, X2 is hydrogen. In some embodiments, X2 is F. In some embodiments, X3 to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3 and X4 are each independently -F.

[0079] In some embodiments, each of Xi to X5 is independently selected from: hydrogen, halogen, C1-5 haloalkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl and -CF3. In some embodiments X2 is F. In some embodiments, X3 to X5 are each independently selected from hydrogen and halogen. In some embodiments, X3 and X4 are each independently -F.

[0088]

[0080] n is an integer selected from 0 and 1. In some embodiments, n is 0. In some embodiments, n is i.

[0089]

[0081] m is an integer selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0090]

[0082] Each Rlaand Rlbis independently selected from: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, Rlais selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl. In some embodiments, Rlbis selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0091]

[0083] Each Rlcis independent selected from: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from hydrogen, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0092]

[0084] In some embodiments, each Rlcis independently selected from substituted or unsubstituted C1.5 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, 3-4 membered cycloalkyl, halogen, and C1-3 haloalkyl.

[0093]

[0085] In some embodiments, Rlaand one Rlctogether with the atoms attached thereto form a 3-membered cycloalkyl fused to the ring to which Rlaand Rlcare attached.

[0094]

[0086] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0087] In some embodiments, the compound of formula (I) is a compound of formula (le- 1), formula (Ie-2), or formula (Ie-3):

[0095]

[0088] In some embodiments, the compound of formula (I) is a compound of formula (If- 1), formula (If-2), formula (If-3), or formula (If-4):

[0096]

[0097]

[0089] In some embodiments, the compound of formula (I) is a compound of formula (Ig- 1 ), formula (Ig-2), formula (Ig-3), or formula (Ig-4) :

[0098]

[0099]

[0090] In some embodiments, the compound of formula (I) is a compound of formula (Ih):

[0100]

[0091] In some embodiments, the compound of formula (I) is a compound of formula (li):

[0101]

[0092] In some embodiments, the compound of formula (I) is a compound of formula (Ij):

[0102]

[0093] In some embodiments, the compound of formula (I) is a compound of formula (Ik-1), formula (Ik-2), formula (Ik-3), or formula (Ik-4):

[0103]

[0104]

[0094] In some embodiments, the compound of formula (I) is a compound of formula

[0105] (I’): wherein Z1is substituted or unsubstituted 4-5 membered N-heterocycle.

[0106]

[0095] In some embodiments, Z1is a substituted 4-5 membered N-heterocycle. In some embodiments, Z1is a substituted 4-membered N-heterocycle. In some embodiments, Z1is a substituted 5-membered N-heterocycle. In some embodiments, Z1is a 4-5 membered N-heterocycle substituted with one or more substituents each independently selected from selected from the group consisting of hydrogen, halogen substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy. In some embodiments, Z1is a 4-5 membered N-heterocycle substituted with one or more substituents each independently selected from selected from the group consisting of hydrogen, halogen, C1-3 haloalkyl, unsubstituted C1-3 alkyl, unsubstituted C1-3 alkoxy, C1-3 haloalkoxy, substituted or unsubstituted 3-4 membered cycloalkyl, and substituted or unsubstituted 3-4 membered cycloalkoxy.

[0107]

[0096] In some embodiments, Z1is selected from:

[0108]

[0098] In some embodiments, Z1is selected from:

[0099] In some embodiments, Z1is selected from:

[0109]

[0100] In some embodiments, Z1is selected from:

[0110]

[0101] In some embodiments, Z1is selected from: , embodiment,

[0111]

[0103] In some embodiments, the disclosure comprises compounds of formula (I) and pharmaceutically acceptable salts thereof.

[0112]

[0104] In some embodiments, the compound of formula (I) is selected from the compounds listed in Table 1 :

[0113] Table 1

[0114] Compounds of formula (II)

[0115]

[0105] Some embodiments of the present disclosure are directed to compounds of formula or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0116]

[0106] Each Xi to X5 is independently selected from the group consisting of hydrogen, halogen, C1-5 haloalkyl, C1-5 alkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl and - CF3. In some embodiments, X2 is -F. In some embodiments, X3 to X5 are each independently selected from hydrogen, -CH3 and -OH. In some embodiments, X3 and X4 are each independently - CH3. In some embodiments, at least one of X3, X4, or X5 is halogen, OH, or C1-5 haloalkyl.

[0107] Xe is independently selected from -C-, -O-, -N-, or -S-. In some embodiments, Xe is -C-. In some embodiments, Xe is -O-.

[0117]

[0108] Rlaand Rlbare independently selected from hydrogen or -F. In some embodiments, Rlaand Rlbare both hydrogen. In some embodiments, Rlaand Rlbare both -F.

[0118]

[0109] Each Rlcis independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-5 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from hydrogen, C1-3 alkyl, and halogen.

[0119]

[0110] n is an integer selected from 0 or 1. In some embodiments, n is 0. In some embodiments, n is i.

[0120]

[0111] m is an integer selected from 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0121]

[0112] In some embodiments, n + m is 1 or 2. In some embodiments, n+m is 1. In some embodiments, n+m is 2.

[0122]

[0113] p is an integer selected from 0, 1, 2, 3, 4, or 5. In some embodiments p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0123]

[0114] q is an integer selected from 0 to 1. In some embodiments, q is 0. In some embodiments, q is 1.

[0124]

[0115] In some embodiments the compound of formula (II) is a compound of formula (Ila): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0125]

[0116] Each Xi to X5 is independently selected from the group consisting of hydrogen, halogen, C1-5 haloalkyl, C1-5 alkyl, and -OH. In some embodiments, Xi is selected from -F, -Cl and -CF3. In some embodiments, X2 is -F. In some embodiments, X3 to X5 are each independently selected from hydrogen, -CH3 and -OH. In some embodiments, X3 and X4 are each independently -CH3. In some embodiments, at least one of X3, X4, or X5 is halogen, OH, or C1-5 haloalkyl.

[0126]

[0117] Xe is independently selected from -C-, -O-, -N-, or -S-. In some embodiments, Xe is -C-. In some embodiments, Xe is -O-.

[0127]

[0118] Rlaand Rlbare independently selected from hydrogen or -F. In some embodiments, Rlaand Rlbare both hydrogen. In some embodiments, Rlaand Rlbare both -F.

[0128]

[0119] Each Rlcis independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-5 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen. In some embodiments, each Rlcis independently selected from hydrogen, C1-3 alkyl, and halogen.

[0129]

[0120] n is an integer selected from 0 or 1. In some embodiments, n is 0. In some embodiments, n is i.

[0130]

[0121] m is an integer selected from 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0131]

[0122] In some embodiments, n + m is 1 or 2. In some embodiments, n+m is 1. In some embodiments, n+m is 2.

[0132]

[0123] p is an integer selected from 0, 1, 2, 3, 4, or 5. In some embodiments p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[0133]

[0124] q is an integer selected from 0 to 1. In some embodiments, q is 0. In some embodiments, q is 1.

[0134]

[0125] In some embodiments, the compound of formula (II) is selected from the compounds listed in Table 2:

[0135] Table 2

[0136]

[0126] In some embodiments, the disclosure comprises compounds of formula (II) and pharmaceutically acceptable salts thereof.

[0137] Pharmaceutical Compositions

[0138]

[0127] In some embodiments, pharmaceutical compositions of compound formula (I) and compound formula (II) are provided. In such embodiments, the pharmaceutical compositions comprise (i) compound formula (I) or a pharmaceutically acceptable salt thereof or (ii) compound formula (II) or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

[0128] The pharmaceutical compositions of the present disclosure can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g., binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. In the practice of methods of the present disclosure, a therapeutically effective amount of any one of the compounds of this disclosure or a combination of any of the compounds of this disclosure or a pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art. For instance, compounds or compositions of the present disclosure can be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.

[0139]

[0129] Suitable excipients are known to those skilled in the art and are described in detail in, e.g . (i) Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; (ii) Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and (iii) Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Examples of pharmaceutically acceptable excipients include, without limitation, carriers, diluents, adjuvants, and vehicles. Non-limiting examples include, buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, and flavoring agents.

[0140]

[0130] The compositions comprising compound Formulae (I) or (II) may be formulated as a pharmaceutical composition in accordance with standard pharmaceutical practice. A typical formulation is prepared by mixing a compound of the present disclosure and one or more excipients.

[0141]

[0131] When a pharmaceutical composition according to the present disclosure is prepared as a formulation for oral administration, the carrier and / or diluent to be used may include, for instance and without limitation: cellulose and cellulose derivatives (e.g., microcrystalline cellulose); calcium silicate; com starch; saccharides (e.g., lactose, sucrose, dextrose, mannitol, and combinations thereof); calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agents, emulsifying agents, diluents, and combinations thereof. Formulations for oral administration may also include, for instance and without limitation: polymers (for instance hydrophilic polymers such as polyvinylpyrrolidone); antioxidants; preservatives; wetting agents; lubricating agents; glidants; processing aids; granulating agents; dispersing agents; colorants; and flavoring agents.

[0142]

[0132] Compressed tablets can be prepared in a suitable tableting device by compressing the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with or more of a carrier, binder, lubricant, inert diluent, preservative, surface active, dispersing agent, and an inert liquid diluent. The tablets can optionally be coated or scored. Tablets may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay coating material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0143]

[0133] When the pharmaceutical composition according to the present disclosure is prepared as a formulation for injections, the carrier to be used may include, for instance and without limitation, water, saline, an aqueous glucose solution, an aqueous sugar-like solution, alcohols, glycols (e.g., polyethylene glycol 400), ethers, oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifying agents, and combinations thereof.

[0144]

[0134] The pharmaceutical compositions may further comprise pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.

[0145]

[0135] In some embodiments, pharmaceutical compositions comprising compound formula (I) or compound formula (II), or a pharmaceutically acceptable salt thereof, further comprise an additional therapeutic agent.

[0146] Combination Therapy

[0147]

[0136] The compounds of the present disclosure may be administered in combination with other additional therapeutic agents, such as for instance and without limitation, standard of care agents appropriate for a neurodegenerative disease or disorder.

[0148]

[0137] The compounds as described herein or pharmaceutically acceptable salts thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compound as described herein such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt thereof can be coadministered with one or more additional therapeutic agents used and / or developed to treat a disease or condition mediated, at least in part, by TMEM175. In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agent that are being used and / or developed to treat Parkinson’s Disease (PD). In some embodiments, the one or more additional therapeutic agent may be dopamine-replacement therapies (levodopa / carbidopa), dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine), catechol-O- methyltransferase (COMT) inhibitors (entacapone, levodopa / carbidopa / entacapone, tolcapone, opicapone), monoamine oxidase B (MAO-B) inhibitors (selegiline hydrochloride, rasagiline, safinamide), amantadine, anticholinergic medications (trihexyphenidyl, benztropine mesylate), acetylcholinesterase inhibitors (rivastigmine), serotonin 5-HT2A receptor agonists (pimavanserin), or dopamine transporters for imaging (ioflupane 1-123).

[0149]

[0138] Those additional agents may be administered separately from the compound or pharmaceutically acceptable salt thereof described herein, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound as described herein in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0150]

[0139] The amount of both a compound of the disclosure and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, compositions as described herein are formulated such that a dosage of between about 0.01 - 150 mg / kg body weight / day of a compound of the disclosure can be administered, or a dosage of about 0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg / kg body weight / day, or a dosage of between about 0.01 - 100 mg / kg body weight / day, or a dosage of about 0.05 - 60 mg / kg body weight / day, or any dosage between any of these amounts.

[0151]

[0140] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6thedition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0152] Methods of Treatment

[0153]

[0141] In some embodiments, the compounds of the present disclosure may be administered as single agents. In some embodiments, the compounds of the present disclosure may be administered in combination with at least one additional therapeutic agent.

[0142] In some embodiments, provided herein are methods of treating a disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0154]

[0143] In some embodiments, provided herein are methods of treating a TMEM175 mediated disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0155]

[0144] In some embodiments, provided herein are methods of modulating TMEM175 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0156]

[0145] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a disease, disorder or condition in a subject in need thereof.

[0157]

[0146] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a TMEM 175 -mediated disorder in a subject in need thereof.

[0158]

[0147] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for modulating TMEM 175 in a subject.

[0159]

[0148] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a disease, disorder or condition in a subject in need thereof.

[0160]

[0149] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a TMEM 175 -mediated disorder in a subject in need thereof.

[0161]

[0150] In some embodiments, the disorder is a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder includes, but is not limited to, a central nervous system (CNS) disorder, such as Parkinson’s disease (PD), Parkinsonism, Alzheimer’s disease (AD), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age related memory dysfunction, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer’s disease), argyrophilic grain disease, lysosomal disorders, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms / relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV- associated dementia (HAD). In some embodiments, the treatment is for neurodegenerative and central nervous system (CNS) disorders, such as Parkinson’s disease (PD) and rapid eye movement sleep behavior disorder (RBD).

[0162]

[0151] In certain embodiments, treatment may be administered after one or more symptoms have developed. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0163]

[0152] Administration of the compounds of the disclosure may be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0164]

[0153] The dosage regimen may be adjusted to provide the optimum desired response. For instance, a single dose may be administered, several doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Each unit dose may contain a predetermined quantity of a compound of formula (I) or a compound of formula (II) calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are influenced by (i) the unique characteristics of the particular active compound formula, (ii) and the particular therapeutic or prophylactic effect to be achieved, and (iii) pharmacokinetic factors associated with the drug and associated excipients, and the disease to be treated.

[0165]

[0154] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen may be adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined. Dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient doseescalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0155] The amount of the compound of the disclosure administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 150 mg per kg body weight per day, or about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g / day, or about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, for instance by dividing such larger doses into several small doses for administration throughout the day.

[0166]

[0156] While certain dose and administration regimens are disclosed herein, said disclosure does not limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure.

[0167]

[0157] In some embodiments, a method of modulating TMEM175 in a subject suffering from a neurodegenerative disorder is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a pharmaceutical composition comprising formula (I) or formula (II) as described elsewhere herein.

[0168]

[0158] In some embodiments, a method of treatment in a subject suffering from a neurodegenerative disorder is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a pharmaceutical composition comprising formula (I) or formula (II) as described elsewhere herein.

[0169]

[0159] In some embodiments, a method of treating Parkinson’s Disease is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a pharmaceutical composition comprising formula (I) or formula (II) as described elsewhere herein.

[0170] Examples

[0171]

[0160] Example 1: ( / ?)- l -((2.S'.3.S')-3-cthoxy-2-mcthylazctidin- l -yl)-2-((5-(4-fluorophcnyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0172]

[0161] Step 1 : tert-butyl (2.S'.3.S)-3-cthoxy-2 -methylazetidine- 1 -carboxylate

[0173]

[0162] To a solution of tert-butyl (2.S'.3.S')-3-hydroxy-2-mcthylazctidinc- 1 -carboxylate (500.0 mg, 2.67 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion in mineral oil) (320.4 mg, 8.01 mmol) and the mixture was stirred at 0°C for 10 minutes. Then iodoethane (624.7 mg, 4.01mmol) was slowly added and stirred at 25°C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the title compound (260.0 mg, 1.08 mmol, 40.7% yield) as a colorless oil. LC-MS: (ESI, m / z): 216.3 [M+H]+

[0174]

[0163] Step 2: (2.S'.3.S)-3-cthoxy-2-mcthylazctidinc trifluoroacetate

[0175]

[0164] A solution of tert-butyl (2S, 35) -3 -ethoxy-2-methylazetidine-l -carboxylate (100.0 mg, 0.46 mmol) in trifluoroacetic acid (0.2 mL) and dichloromethane (0.2 mL) was stirred at 25°C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (125 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 116.2 [M+H]+

[0176]

[0165] Step 3: (R)-l-((2S,3S)-3-ethoxy-2-methylazetidin-l-yl)-2-((5-(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0177]

[0166] To a solution of (5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (80.0 mg, 0.32 mmol), (2S,3S)-3 -ethoxy-2 -methylazetidine trifluoroacetate (91.7 mg, crude) and N,N- diisopropylethylamine (205.4 mg, 1.59 mmol) was added propylphosphonic anhydride (241.7 mg, 0.38 mmol, 50% in ethyl acetate) in dichloromethane (2 mL) and the mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 24%B to 40%B inlO min; Wave Length: 254 / 220 nm; RTl(min): 8.97 to afford the title compound (22.6 mg, 0.06 mmol, 20.2% yield) as a white solid. LC-MS: (ESI, m / z): 349.0 [M+H]+

[0178]

[0167] Example 2: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-(l,l- difluoroethyl)azetidin- 1 -yl)propan- 1 -one

[0168] Step 1 : tert-butyl 3 -( 1 , 1 -difluoroethyl)azetidine- 1 -carboxylate

[0179]

[0169] Under nitrogen, a solution of tert-butyl 3 -acetylazetidine -1 -carboxylate (1.00 g, 5.02 mmol) in dichloromethane (10 mb) was slowly added to diethylaminosulfur trifluoride (4.00 g, 25.09 mmol) and stirred at 0 °C for 5 minutes. Then the solution was stirred at 25°C for 1 hour. After completion, the reaction was quenched with saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the title compound (510.0 mg, 2.07 mmol, 41.3% yield) as a yellow oil. LC-MS: (ESI, m / z): 222.2 [M+H]+

[0180]

[0170] Step 2 : 3 -( 1 , 1 -difluoroethyl)azetidine trifluoroacetate

[0181]

[0171] A solution of tert-butyl 3 -(l,l-difluoroethyl)azetidine-l -carboxylate (200.0 mg, 0.9 mmol) in trifluoroacetic acid (1 m , 0.9mmol) and dichloromethane (1 m ) was stirred at 25 °C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (230.0 mg, crude). The crude product was directly used in the next step without purification. EC-MS: (ESI, m / z): 122.1 [M+H]+

[0182]

[0172] Step 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-(l,l- difluoroethyl)azetidin- 1 -yl)propan- 1 -one

[0183]

[0173] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (100.0 mg, 0.37 mmol), 3-(l,l-difluoroethyl)azetidine trifluoroacetate (113.1 mg, crude) and N,N- diisopropylethylamine (240.9 mg, 1.87 mmol) in dichloromethane (2 mb) was added propylphosphonic anhydride (286.2 mg, 0.45 mmol, 50% in ethyl acetate) and the mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (44.3 mg, 0.11 mmol, 30.7% yield) as a white solid. LC-MS: (ESI, m / z): 371.1 [M+H]+

[0184]

[0174] Example 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-(2,2- difluoroethyl)azetidin- 1 -yl)propan- 1 -one

[0185]

[0175] Step 1 : tert-butyl 3 -(2,2-difluoroethyl)azetidine- 1 -carboxylate

[0186]

[0176] A solution of tert-butyl 3 -(2-oxoethyl)azetidine-l -carboxylate (900.0 mg, 4.52 mmol) in dichloromethane (2 mL) was stirred at 0°C for 10 minutes. Then diethylaminosulfur trifluoride (3.60 g, 22.58 mmol) was added and stirred at 25°C for 1 hour. After completion, the reaction was quenched with saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the title compound (600.0 mg, 2.44 mmol, 54.% yield) as a yellow oil. LC-MS: (ESI, m / z): 222.2 [M+H]+

[0187]

[0177] Step 2: 3 -(2, 2-difluoroethyl)azetidine trifluoroacetate

[0188]

[0178] A solution of tert-butyl 3 -(2,2-difluoroethyl)azetidine-l -carboxylate (280.0 mg, 1.27 mmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (3 mL) was stirred at 25°C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (300.0 mg, crude) The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 122.2 [M+H]+

[0179] Step 3: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-(2,2- difluoroethyl)azetidin- 1 -yl)propan- 1 -one

[0189]

[0180] To a solution of 3-(2,2-difluoroethyl)azetidine trifluoroacetate (135.7 mg, crude), (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (100.0 mg, 0.37 mmol) in dichloromethane (2 mL) was added A.A-diisopropylcthylaminc (240.9 mg, 1.87 mmol) and propylphosphonic anhydride (286.2 mg, 0.45 mmol, 50% in ethyl acetate), and the mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (52.9 mg, 0.13 mmol, 37.2% yield) as a white solid. LC-MS: (ESI, m / z): 371.1 [M+H]+

[0190]

[0181] Example 4: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((27?,3S)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0191]

[0182] Step 1: tert-butyl (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidinc- l -carboxylatc

[0192]

[0183] A mixture of silver trifluoromethanesulfonate (7.40 g, 28.84 mmol), potassium fluoride (2.50 g, 42.73 mmol), and l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (5.70 g, 16.02 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of tert-butyl (2 / ?.3.S)-3-hydroxy-2-mcthylazctidinc- 1 -carboxylate (2.00 g, 10.68 mmol) in ethyl acetate (20 mL) followed by the dropwise addition of 2-fluoro-pyidine (3.1 g, 32.04 mmol) and (trifluoromethyl)trimethylsilane (4.5 g, 32.04 mmol) and the mixture was stirred at ambient temperature for 2 days. After filtration, the solids were collected and washed by ethyl acetate. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the title compound (1.00 g, 2.25 mmol, 25.5% yield) as a colorless oil. LC- MS: (ESI, m / z): 256.2 [M+H]+

[0193]

[0184] Step 2: (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidinc hydrochloride

[0194]

[0185] A solution of tert-butyl (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidinc- l - carboxylate (1.00 g, 3.92 mmol) in hydrochloric acid / 1.4-dioxane (10 mL, 4 M) was stirred at 25°C for 1 hour. After completion, the reaction solution was concentrated under vacuum to afford the title compound (690.0 mg, crude). The product was directly used in the next step without purification. LC-MS: (ESI, m / z): 156.1 [M+H]+

[0195]

[0186] Step 3: tert-butyl (( / ?)- l -((2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l -yl)- l - oxopropan-2-yl)carbamate

[0196]

[0187] A solution of (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidinc hydrochloride (800.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (650.0 mg, 3.42 mmol), A.A-diisopropylcthylaminc (2.20 g, 17.1 mmol) and A.A. A'.A-tctramcthyl-o-(7-azabcnzotriazol- l -yl)uroniiim hexafluorophosphate (1.90 g, 5.13 mmol) in dichloromethane (10 mL) was stirred at 25°C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse phase chromatography eluting with (acetonitrile / 0. 1% NH4HCO3 in water) to afford the title compound (816.0 mg, 2.49 mmol, 73.6% yield) as a pink solid. LC-MS: (ESI, m / z): 327.3 [M+H]+

[0197]

[0188] Step 4: ( / ?)-2-amino- l -((2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)propan-l-one hydrochloride

[0198]

[0189] A solution of tert-butyl (( / ?)- l -((2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)-l-oxopropan-2-yl)carbamate (400.0 mg, 1.23 mmol) in hydrochloric acid / 1.4-dioxane (5 mL, 4M) was stirred at 25°C for 1 hour. After completion, the reaction solution was concentrated under vacuum to afford the title compound (330.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 227.2 [M+H]+

[0199]

[0190] Step 5: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2J?,35)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0200]

[0191] A solution of (7 )-2 -amino- 1 -((2 / ?.3.S)-2-mcthyl-3 -(trifhioromethoxy)azetidin- 1- yl)propan-l-one hydrochloride (138.0 mg, crude), 5-(4-chlorophcnyl)- l .3.4-oxadiazol-2(3 / / )-onc (60.0 mg, 0.31 mmol), AA'-diisopropylcthylaminc (196.8 mg, 1.53 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (202.4 mg, 0.46 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford the title compound (55.6 mg,0. 14 mmol, 44.9% yield) as a white solid. LC-MS: (ESI, m / z): 405.0 [M+H]+

[0201]

[0192] Example 5: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-3-hydroxy-3- methyl- 1 -(5 -azaspiro [2.4] heptan-5 -yl)butan- 1 -one

[0202]

[0193] Step 1: tert-butyl ( / ?)-(3-hydroxy-3-mcthyl- l -oxo- l -(5-azaspiro|2.4|hcptan-5- yl)butan-2-yl)carbamate

[0203]

[0194] A solution of 5-azaspiro[2.4]heptane hydrochloride (416.5 mg, 3.13 mmol), (R)-2- ((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid (500.0 mg, 2.14 mmol), N,N- diisopropylethylamine (1.30 g, 10.72 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A'.A'- tetramethyluronium hexafluorophosphate (1.20 g, 3.22 mmol) in dichloromethane (5 mL) was stirred at 25°C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (650.0 mg, 1.87 mmol, 87.4% yield) as a pink solid. LC-MS: (ESI, m / z): 313.4 [M+H]+

[0204]

[0195] Step 2: (7?)-2-amino-3-hydroxy-3-methyl-l-(5-azaspiro[2.4]heptan-5-yl)butan-l- one hydrochloride

[0205]

[0196] A solution of tert-butyl ( / ?)-(3-hydroxy-3-mcthyl- l -oxo- l -(5-azaspiro|2.4|hcptan- 5-yl)butan-2-yl)carbamate (200.0 mg, 0.64 mmol) in hydrochloric acid / 1.4-dioxane (3 m , 4M) was stirred at 25 °C for 1 hour. After completion, the reaction solution was concentrated under vacuum to afford the title compound (150.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 213.3 [M+H]+

[0206]

[0197] Step 3: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-3-hydroxy-3- methyl- 1 -(5 -azaspiro [2.4] heptan-5 -yl)butan- 1 -one

[0207]

[0198] A solution of ( / ?)-2-amino-3-hydroxy-3-mcthyl- l -(5-azaspiro|2.4|hcptan-5- yl)butan-l-one hydrochloride (97.1 mg, crude), 5-(4-chlorophcnyl)- l .3.4-oxadiazol-2(3H)-onc (60.0 mg, 0.31 mmol), / V, / V-diisopropylethylamine (196.8 mg, 1.53 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (202.4 mg, 0.46 mmol) in dichloromethane (2 mb) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 29%B to 49%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 10.6 to afford the title compound (59.0 mg, 0.14 mmol, 48.9% yield) as a white solid. LC-MS: (ESI, m / z): 391.0 [M+H]+

[0208]

[0199] Example 6: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2R,35)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0209]

[0210] Synthetic Route

[0211]

[0200] A solution of ( / ?)-2-amino- l -((2 / ?.3.S')-2-mcthyl-3-(trifliioromcthoxy)azctidin- l - yl)propan-l-one hydrochloride(138.0 mg, 0.53 mmol), 5-(4-fluorophenyl)-l,3,4-oxadiazol-2(327)- one (54.9 mg, 0.31 mmol), A'.A'-diisopropylcthylaminc (196.8 mg, 1.53 mmol) and 1H- benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (202.4 mg, 0.46 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30* 150mm, 5um; Mobile Phase A: Water(10mmol NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 43% B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 8.6 to afford the title compound (29.3 mg, 0.07 mmol, 24.3% yield) as a white solid. LC-MS: (ESI, m / z): 389.2 [M+H]+

[0201] Example 7: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -(3-mcthyl-3- (trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0212]

[0202] Step 1: tert-butyl 3 -methyl-3-(trifluoromethoxy)azetidine-l -carboxylate

[0213]

[0203] A mixture of silver trifluoromethanesulfonate (7.40 g, 28.84 mmol), potassium fluoride (2.50 g, 42.73 mmol), and l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (5.60 g, 16.02 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of tert-butyl 3 -hydroxy-3 -methylazetidine- 1 -carboxylate (2.00 g, 10.68 mmol) in ethyl acetate (20 m ) followed by the dropwise addition of 2-fluoro-pyidine (3.10 g, 32.04 mmol) and then (trifluoromethyl)trimethylsilane (4.50 g, 32.04 mmol) stirred at ambient temperature for 2 days. After filtration, the solids were collected and washed by ethyl acetate. The residue was purified by flash chromatography on cl 8 gel eluting with petroleum ether / ethyl acetate (3: 1) to afford tert-butyl 3 -methyl-3-(trifluoromethoxy)azetidine-l -carboxylate (300.0 mg, 1.17 mmol, 11.% yield) as a colorless oil. LC-MS: (ESI, m / z): 256.1 [M+H]+

[0214]

[0204] Step 2: 3-methyl-3-(trifluoromethoxy)azetidine hydrochloride

[0215]

[0205] A solution of tert-butyl 3 -methyl-3-(trifluoromethoxy)azetidine-l -carboxylate (275.0 mg, 1.08 mmol) in hydrochloric acid / 1.4-dioxane (3 mb, 4M) was stirred at 25°C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (226.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 156.1 [M+H]+

[0216]

[0206] Step 3: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-methyl-3- (trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0217]

[0207] To a solution of (5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)-Z)-alanine (80.0 mg, 0.3 mmol) and 3-methyl-3-(trifluoromethoxy)azetidine hydrochloride(69.5 mg, crude) in dichloromethane (0.5 mL) was added A'.A'-diisopropylcthylaminc (192.7 mg, 1.49 mmol) and propylphosphonic anhydride (286.2 mg, 0.45 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH Phenyl Hexy Column, 30*150 mm, 5 pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 28% B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 10.55 to afford the title compound (20. 1 mg, 0.04 mmol, 16.3% yield) as a white solid. LC-MS: (ESI, m / z): 405.2 [M+H]+

[0218]

[0208] Example 8: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((.S)-4.4- difluoro-2-methylpyrrolidin- 1 -yl)propan- 1 -one

[0209] Step 1 : (R)-2 -amino- 1 -((S)-4,4-difluoro-2 -methyl pyrrol idin- 1 -yl)propan- 1 -one hydrochloride

[0219]

[0210] A solution of tert-butyl ((R)- 1 -((.S)-4.4-difluoro-2-mcthy Ipyrrolidin- 1 -yl)- 1 - oxopropan-2-yl)carbamate (120.0 mg, 0.42 mmol) in hydrochloric acid / 1.4-dioxane (3 mb, 4 M) was stirred at 25°C for 2 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (102.5 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 193.2 [M+H]+

[0220]

[0211] Step 2: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-4,4-difluoro- 2-methylpyrrolidin- 1 -yl)propan- 1 -one

[0221]

[0212] A solution of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(327)-one (80.0 mg, 0.30 mmol), AA'-diisopropylcthylaminc (192.7 mg, 1.49mmol), ( / ?)-2-amino- l -((.S)-4.4-difluoro-2- methylpyrrolidin-l-yl)propan-l-one hydrochloride (81.6 mg, crude) and IH-bcnzotriazol- l - yloxytris(dimethylamino)phosphonium hexafluorophosphate (198.9 mg, 0.45 mmol) in dichloromethane (2 m ) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 43% B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 8.87 to afford the title compound (13.7 mg, 0.03 mmol, 10.2% yield) as a white solid. LC-MS: (ESI, m / z): 371.1 [M+H]+

[0222]

[0213] Example 9: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2S'.4 / ?)-4- methoxy-2-methylpyrrolidin- 1 -yl)propan- 1 -one

[0223] Synthetic Route

[0224]

[0214] Step 1: tert-butyl (2.S'.4 / ?)-4-mcthoxy-2-mcthy I pyrrolidine- 1 -carboxylate

[0225]

[0215] Under nitrogen, to a solution of tert-butyl (2.S'.4 / ?)-4-hydroxy-2- methylcyclopentane-1 -carboxylate (500.0 mg, 2.5 mmol) in tetrahydrofuran (5 mL) was added sodium hydride (60% dispersion in mineral oil) (299.5 mg, 7.49 mmol) and the mixture was stirred at 0°C for 5 minutes. Then, iodomethane (531.0 mg, 3.74 mmol) was added and stirred at 25°C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3 : 1) to afford the title compound (450.0 mg, 1.98 mmol, 79.5% yield) as a white solid. LC- MS: (ESI, m / z): 216.3 [M+H]+

[0226]

[0216] Step 2: (2.S'.4 / ?)-4-mcthoxy-2-mcthy I pyrrolidine hydrochloride

[0227]

[0217] A solution of tert-butyl (2.S'.4 / ?)-4-mcthoxy-2-mcthylpyrrolidinc- 1 -carboxylate (280.0 mg, 1.3 mmol) in hydrochloric acid / 1.4-dioxane (5 mL, 4M) was stirred at 25°C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (183.6 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 116.5 [M+H]+

[0228]

[0218] Step 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,4J?)-4- methoxy-2-methylpyrrolidin- 1 -yl)propan- 1 -one

[0229]

[0219] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (80.0 mg, 0.30 mmol), (2.S'.4 / ?)-4-mcthoxy-2-mcthylpyrrolidinc hydrochloride (103.2 mg, crude) in dichloromethane (2 mL) was added A.A-diisopropylcthylaminc (129.5 mg, 1.0 mmol) and propylphosphonic anhydride (228.9 mg, 0.36 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (33.6 mg, 0.09 mmol, 30.4% yield) as a white solid. LC-MS: (ESI, m / z):365.1 [M+H]+

[0220] Example 10a: ( / ?)-4.4-difluoro-2-((5-(4-fliiorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-

[0230] 1 -((25,3 / ?)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 -yl)butan- 1 -one

[0231]

[0221] Example 10b: (5)-4,4-difluoro-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-

[0232] 1 -((25,3 / ?)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 -yl)butan- 1 -one

[0233]

[0222] Step 1: tert-butyl (2S,3R)-2-methyl-3-(trifluoromethoxy)azetidine-l-carboxylate

[0234]

[0223] A mixture of silver trifluoromethanesulfonate (7.40 g, 28.84 mmol), potassium fluoride (2.50 g, 42.73 mmol), and l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (5.60 g, 16.02 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of (25.3 / ?)- 1 ,2-dimcthylazctidin-3-ol (2.00 g, 10.68 mmol) in ethyl acetate (20 mb) followed by the dropwise addition of 2-fluoro-pyridine (3.10 g, 32.04 mmol) and (trifluoromethyl)trimethylsilane (4.50 g, 32.04 mmol) stirred at ambient temperature for 1 day. After filtration, the solids were collected and washed by ethyl acetate. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the title compound (640.0 mg, 2.25 mmol, 21.1% yield) as a colorless oil. LC-MS: (ESI, m / z): 256.2 [M+H]+

[0235]

[0224] Step 2: (25.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidinc hydrochloride

[0225] A solution of tert-butyl (2S,3J?)-2-methyl-3-(trifluoromethoxy)azetidine-l- carboxylate (600.0 mg, 2.35 mmol) in hydrochloric acid / 1.4-dioxane (5 mL, 4M) was stirred at 25°C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (435. 1 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 156.1 [M+H]+

[0236]

[0226] Step 3: tert-butyl (4.4-difluoro- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- 1 -yl)- 1 -oxobutan-2-yl)carbamate

[0237]

[0227] A solution of 2-((tert-butoxycarbonyl)amino)-4,4-difluorobutanoic acid (1.00 g, 4.19 mmol), (2S,3J?)-2-methyl-3-(trifluoromethoxy)azetidine hydrochloride (435.1 mg, crude), A.A-diisopropylcthylaminc (2.00 g, 16.12 mmol) and propylphosphonic anhydride (3.07 g, 4.83 mmol, 50% in ethyl acetate) in dichloromethane (10 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (500.0 mg, 1.24 mmol, 38.5% yield) as a white oil. LC-MS: (ESI, m / z): 377.1 [M+H]+

[0238]

[0228] Step 4: 2-amino-4.4-difluoro-l -((2.S'.3 / ?)-2-mcth l-3-(trifluoromcthoxy)azctidin- l - yl)butan-l-one hydrochloride

[0239]

[0229] A solution of tert-butyl (4,4-difluoro-l-((2S,3J?)-2-methyl-3- (trifluoromethoxy)azetidin-l-yl)-l-oxobutan-2-yl)carbamate (310.0 mg, 0.86 mmol) in hydrochloric acid / 1.4-dioxane (5 mL, 4M) was stirred at 25°C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the crude product (268.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 277.1 [M+H]+

[0240]

[0230] Step 5: ( / ?)-4.4-difliioro-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l - ((2.S'.3 / ?)-2-nicthyl-3-(trifliioromcthoxy)azctidin- l -yl)butan- l -onc and (.S)-4.4-difluoro-2-((5-(4- fluorophenyl)-l, 3, 4-oxadiazol-2-yl)amino)- l -((2.S'.3 / ?)-2 -methyl -3-(trifluoromethoxy)azetidin- 1- yl)butan-l-one

[0241]

[0231] To a solution of 2-amino-4,4-difluoro-l-((2S,3J?)-2-methyl-3- (trifluoromethoxy)azetidin-l-yl)butan-l-one hydrochloride (268.0 mg, crude) and 5-(4- fluorophenyl)-l,3,4-oxadiazol-2(327)-one (150.0 mg, 0.83 mmol) in dichloromethane (5 mL) was added A.A-diisopropylcthylaminc (488.2 mg, 3.78 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (503.8 mg, 1.14 mmol). The mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the product. Then, the product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RTl(min): 3.91; RT2(min): 27.32; Sample Solvent: EtOH; Injection Volume: 2.0 mL to afford ( / ?)-4.4-difluoro-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)-l- ((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin-l-yl)butan- l-onc (19.3 mg, 0.04 mmol, 5.2% yield) as a white solid and (.S)-4.4-difluoro-2-((5-(4-fliiorophcnyl)-l.3.4-oxadiazol-2-yl)amino)-l- ((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin-l-yl)biitan- l-onc (20.0 mg, 0.04mmol, 5.4% yield) as a yellow solid.

[0242]

[0232] Example 11: ( / ?)-2-((5-(4-chlorophcnyl)-l.3.4-oxadiazol-2-yl)amino)-l-((2S'.4 / ?)-2- methyl -4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0243]

[0233] Step 1: tert-butyl (( / ?)-l-((2.S'.4 / ?)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidin-l-yl)-l- oxopropan-2-yl)carbamate

[0244]

[0234] A solution of (2.S'.4 / ?)-2-mcthyl-4-(trifluoromcthoxy [pyrrolidine hydrochloride (260.1 mg, 1.26 mmol), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (239.0 mg, 1.26 mmol), N, A-diisopropylcthylaminc (489.3 mg, 3.79 mmol) and 2-(7-azabcnzotriazol-l-yl)-W.A".A"- tetramethyluronium hexafluorophosphate (721.2 mg, 1.90 mmol) in dichloromethane (5 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to afford the title compound (390.1 mg, 1.09 mmol, 86.1% yield) as a white oil. LC-MS: (ESI, m / z): 341.2[M+H]+

[0245]

[0235] Step 2: (R)-2 -amino- l -((2.S'.4 / ?)-2 -methyl -4-(trifluoromethoxy )pyrrolidin-l- yl)propan-l-one hydrogen chloride

[0246]

[0236] A solution of tert-butyl (( / ?)- l -((2.S'.4 / ?)-2-mcth l-4-(trifluoromcthoxy)pyrrolidin- l - yl)-l-oxopropan-2-yl)carbamate (200.0 mg, 0.59 mmol) in hydrogen chloride / 1,4-dioxane (2 mL, 4.0 M) was stirred at 25 °C for 2 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (150.6 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1[M+H]+

[0247]

[0237] Step 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,4J?)-2- methyl-4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0248]

[0238] A solution of ( / ?)-2-amino- 1 -((2.S'.4 / ?)-2-mcthy I -4-(trifluoromcthoxy [p rrol idin- 1 - yl)propan-l-one hydrogen chloride (50.1 mg, crude), 5-(4-chlorophcnyl)-3 / / - l .3.4-oxadiazol-2-onc (36.0 mg, 0.18 mmol) A.A-diisopropylcthylaminc (70.2 mg, 0.54 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (80.3 mg, 0.18 mmol) in dichloromethane (3 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (25.6 mg, 0.06 mmol, 32.8% yield) as a white solid. LC-MS: (ESI, m / z): 419.1[M+H]+

[0249]

[0239] Example 12: ( / ?)-2-((5-(3.4-difltiorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l - ((2.SA / ?)-4-fliioro-2-mcthylpyrrolidin- 1 -yl)propan- 1 -one

[0250] Synthetic Route

[0251]

[0240] Step 1 : tert-butyl (( / ?)- ! -((2.S'.4 / ?)-4-fluoro-2-mcthylpyrrolidin- 1 -yl)- 1 -oxopropan- 2-yl)carbamate

[0252]

[0241] A solution of (2S,4J?)-4-fluoro-2-methylpyrrolidine hydrochloride (100.0 mg, 0.72 mmol), (tert-butoxycarbonyl)-D-alanine (220.1 mg, 1.16 mmol), A. A-diisopropylcthylaminc (0.6 mb, 3.88 mmol) and 2-(7-Azabcnzotriazol- l -yl)-A A. A'. ’-tctramcthyluronium hexafluorophosphate (478.9 mg, 1.26 mmol) in dichloromethane (2.0 mb) was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (200.0 mg, 0.72 mmol, 75.2% yield) as a yellow oil. LC- MS: (ESI, m / z): 275.2 [M+H]+

[0253]

[0242] Step 2: ( / ?)-2-amino- l -((2.S'.4 / ?)-4-fluoro-2-mcthylpyrrolidin- l -yl)propan- l -onc hydrochloride

[0254]

[0243] A solution of tert-butyl (( / ?)- 1 -((2.S'.4 / ?)-4-fluoro-2-mcthylpyrrolidin- 1 -yl)- 1 - oxopropan-2-yl)carbamate (150.0 mg, 0.55 mmol) in hydrochloric acid / l,4-dioxane (2.0 mb, 4M) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (158.2 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 175.1 [M+H]+

[0255]

[0244] Step 3: (J?)-2-((5-(3,4-difluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,4J?)-4- fluoro-2-methylpyrrolidin- 1 -yl)propan- 1 -one

[0256]

[0245] A solution of 5-(3.4-difluorophcnyl)-3rt- l .3.4-oxadiazol-2-onc (60.0 mg, 0.30 mmol), (J?)-2 -amino- 1 -((2.S'.4 / ?)-4-fluoro-2-mcthylpyrrol idin- 1 -yl)propan- 1 -one hydrochloride (158.2 mg, crude), A,A-diisopropylethylamine (0.3 mb, 1.82 mmol) and benzotriazol- 1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate (401.5 mg, 0.91 mmol) in dichloromethane (1.0 mb) was stirred at 25°C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 : 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 25%B to 41%B inlO min; Wave Length: 254 / 220 nm; RT 10.05 min to afford the title compound (39.0 mg, 0.10 mmol, 36.2% yield) as a white solid. LC-MS: (ESI, m / z): 355.2 [M+H]+

[0257]

[0246] Example 13: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(5- azaspiro [2.4]heptan-5 -yl)propan- 1 -one

[0258] Synthetic Route

[0259]

[0247] A solution of (2 / ?)-2-amino- l -(5-azaspiro|2.4|hcptan-5-yl)propan- l -onc (70.0 mg, 0.42mmol), 5-(4-fluorophenyl)-3H-l,3,4-oxadiazol-2-one (50.0 mg, 0.28 mmol), IH-benzotriazol- l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (184.1 mg, 0.42 mmol) and N,N- diisopropylethylamine (0.1 m , 0.83 mmol) in A. '-dimcth lformamidc (0.5 m ) was stirred at 25 °C for 2 hours. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the product. The product was further purified by Prep- HPEC with the following conditions: XBridge Prep Shield RP OBD C18 Column, 30* 150 mm, 5 m; Mobile Phase A: water (lOmmol / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 24%B to 48%B in 10 min; Wave Length: 254 / 220 nm; RT1: 8.3 min to afford the title compound (27.1 mg, 0.081 mmol, 29.3% yield) as a white solid. LC-MS: (ESI, m / z): 331.0 [M+H]+

[0260]

[0248] Example 14: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(5- azaspiro [2.4]heptan-5 -yl)propan- 1 -one

[0261]

[0249] Step 1: tert-butyl ( / ?)-( l -oxo- l -(5-azaspiro|2.4|hcptan-5-yl)propan-2-yl)carbamatc

[0262]

[0250] To a solution of 5-azaspiro[2.4]heptane hydrochloride (900.0 mg, 9.26 mmol), 2- (7-Azabcnzotriazol- l -yl)-A.A.A". A-tctramcthyluroniiim hexafluorophosphate (4.2 g, 11.12 mmol) in dichloromethane (10.0 mL) was added N, A-diisopropylethylamine (4.8 m , 27.79 mmol) and (tert-butoxycarbonyl)-D-alanine (1.9 g, 10.19 mmol). The mixture was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (1.80 g, 6.70 mmol, 72.4% yield) as a yellow oil. LC-MS: (ESI, m / z): 269.2 [M+H]+

[0263]

[0251] Step 2: (R)-2 -amino- 1 -(5-azaspiro[2.4]heptan-5-yl)propan- 1 -one hydrochloride

[0264]

[0252] A solution of tert-butyl ( / ?)-( l -oxo- l -(5-azaspiro|2.4|hcptan-5-yl)propan-2- yl)carbamate (1.80 g, 6.71 mmol) in hydrochloric acid / l,4-dioxane (20.0 mL, 4M) was stirred at 25 °C for 1 hour. After completion, the reaction was concentrated to afford the title compound (1.41 g, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 169.1 [M+H]+

[0265]

[0253] Step 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(5- azaspiro [2.4]heptan-5 -yl)propan- 1 -one

[0266]

[0254] A solution of ( / ?)-2-amino- l -(5-azaspiro|2.4|hcptan-5-yl)propan- l -onc hydrochloride (50.0 mg, crude), 5-(4-chlorophcnyl)- l .3.4-oxadiazol-2(3 / / )-onc (64.1 mg, 0.38 mmol), lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (168.7 mg, 0.38 mmol) and N, A-diisopropylcthylaminc (0.1 mL, 0.76 mmol) in N, JV-dimethylformamide (0.5 mL) was stirred at 25 °C for 2 hours. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: XBridge Prep Shield RP OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: water ( 1 Ommol / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 30%B to 55%B in 10 min; Wave Length: 254 / 220 nm; RT1: 8.2 min to afford the title compound (26.6 mg, 0.074 mmol, 29.5% yield) as a white solid. LC-MS: (ESI, m / z): 347.0 [M+H]+

[0267]

[0255] Example 15: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2J?,4S)-2- methyl-4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0268]

[0256] Step 1: tert-butyl (2 / ?.4.S)-2-mcthyl-4-(trifluoromcthoxy [pyrrolidine- 1 -carboxylate

[0257] A mixture of silver trifluoromethanesulfonate (3.40 g, 13.41 mmol), potassium fluoride (1.15 g, 19.87 mmol), and l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (2.60 g, 7.45 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of tert-butyl (2 / ?.4.S)-4-hydroxy-2-mcthylpyrrolidinc- l -carboxylate (1.00 g, 4.97 mmol) in ethyl acetate (20.0 mL) followed by the dropwise addition of 2-fluoro-pyridine (1.45 g, 14.91 mmol) and then trimethyl(trifluoromethyl)silane (2.1 g, 14.91 mmol). The reaction mixture was then stirred at 25 °C for 10 hours. After filtration, the filtrate was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (230.0 mg, 0.85 mmol, 17.2% yield) as a yellow oil. LC-MS: (ESI, m / z): 270.1 [M+H]+

[0269]

[0258] Step 2: (2 / ?.4.S)-2-mcthyl-4-(tri fl uoromcthoxy [pyrrolidine hydrochloride

[0270]

[0259] A solution of tert-butyl (2 / ?.4.S)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidinc- 1- carboxylate (220.0 mg, 0.82 mmol) in hydrochloric acid / l,4-dioxane (2.5 mL, 4M) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (180.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 170.1 [M+H]+

[0271]

[0260] Step 3: tert-butyl (( / ?)- l -((2 / ?.4.S)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidin- l -yl)- l- oxopropan-2-yl)carbamate

[0272]

[0261] A solution of (2 / ?.4.S)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidinc hydrochloride (180.0 mg, 0.88 mmol), (tert-butoxycarbonyl)-D-alanine (221.4 mg, 1.17 mmol), N,N- diisopropylethylamine (0.56 mL, 3.19 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A'.A'- tetramethyluronium hexafluorophosphate (525.6 mg, 1.38 mmol) in dichloromethane (2.0 mL) was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (250.0 mg, 0.73 mmol, 0.83% yield) LC-MS: (ESI, m / z): 341.2 [M+H]+

[0273]

[0262] Step 4: ( / ?)-2-amino- l -((2 / ?.4.S)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidin- l - yl)propan-l-one hydrochloride

[0274]

[0263] A solution of tert-butyl (( / ?)- l -((2 / ?.4.S)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidin- l - yl)-l-oxopropan-2-yl)carbamate (250.0 mg, 0.73 mmol) in hydrochloric acid / l,4-dioxane (2.5 mL, 4M) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (220.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1 [M+H]+

[0275]

[0264] Step 5: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2R,45)-2- methyl-4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0276]

[0265] A solution of (R)-2 -amino- \ -((2RAS)-2 -methyl -4-(trifluoromethoxy)pyrrolidin- 1- yl)propan-l-one hydrochloride (131.9 mg, crude), 5-(4-chlorophenyl)-3H-l,3,4-oxadiazol-2-one (60.0 mg, 0.31 mmol), X '-diisopropylcthylaminc (0.21 mL, 1.22 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (404.9 mg, 0.92 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 : 1) to afford the crude product. The crude product was further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 33%B to 53%B inl0.5 min; Wave Length: 254 / 220 nm; RT1: 12.42 min to afford the title compound (39.1 mg, 0.093 mmol, 30.5% yield) as a white solid. LC-MS: (ESI, m / z): 419.1 [M+H]+

[0277]

[0266] Example 16: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3- (trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0278] Synthetic Route

[0279]

[0280]

[0267] A solution of 5-(4-chlorophcn l)-3 / / -l.3.4-oxadiazol-2-onc hydrochloride (55.5 mg, 0.22 mmol), (2 / ?)-2-amino-l-|3-(trifluoromcthoxy)azctidin- l- l |propan-l-onc (100.0 mg, 0.40 mmol), A.A-diisopropylcthylaminc (0.3 mL, 1.80 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (312.4 mg, 0.71 mmol) in A.A- dimethylformamide (1.0 mL) was stirred at 25°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (19.7 mg, 0.05 mmol, 10.7% yield) as a white solid. LC-MS: (ESI, z): 391.0 [M+H]+

[0281]

[0268] Example 17: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((27?,3^)_2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0269] Step 1: tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc- 1 -carboxylate

[0282]

[0270] A solution of silver trifluoromethanesulfonate (2.76 g, 10.70 mmol), Selectfluoro (2.12 g, 5.90 mmol) and potassium fluoride (938.0 mg, 15.9 mmol) in ethyl acetate (10 mL) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of tert-butyl (2 / ?.3 / ?)-3-hydroxy-2-mcthyl- pyrrolidine-1 -carboxylate (800.0 mg, 3.9 mmol) in ethyl acetate (10 mL) followed by the dropwise addition of 2-fluoro-pyridine (1.17 g, 11.90 mmol) and (trifhroromethyl)trimethylsilane (1.71 g,

[0283] 11.90 mmol). The mixture was stirred at ambient temperature for 10 h. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. After filtration, the solids were collected and washed by ethyl acetate. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the title compound (150.0 mg, 0.50 mmol, 14.0% yield) as a yellow solid. LC-MS: (ESI, m / z): 270. 1 [M+H]+

[0284]

[0271] Step 2: (2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc hydrochloride

[0285]

[0272] A solution of tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc- l - carboxylate (120.0 mg, 0.4 mmol) in hydrochloric acid / l,4-dioxane (1.5 mL, 4M) was stirred at 25° C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (98.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 170.1 [M+H]+

[0286]

[0273] Step 3: tert-butyl (( / ?)- l -((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l -yl)- l- oxopropan-2-yl)carbamate

[0287]

[0274] A solution of (27?)-2-(tert-butoxycarbonylamino)propanoic acid (109.6 mg, 0.50 mmol), (2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc hydrochloride (98.0 mg, crude), A, N- diisopropylethylamine (296.7 mg, 2.3 mmol) and 2-(7-azabcnzotriazol-l -yl)-A'. A'. A". A"- tetramethyluronium hexafluorophosphate (660.8 mg, 1.7 mmol) in dichloromethane (2 mL) was stirred at 25° C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the title compound (150.0 mg, 0.4 mmol, 76.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 341.2 [M+H]+

[0288]

[0275] Step 4: ( / ?)-2-amino- l -((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)propan-l-one hydrochloride

[0289]

[0276] A solution of tert-butyl (( / ?)- l -((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)-l-oxopropan-2-yl)carbamate (100.0 mg, 0.2 mmol) in hydrochloric acid / l,4-dioxane (1.5 mL, 4M) was stirred at 25° C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (60.0 mg, crude). LC-MS: (ESI, m / z): 241.2 [M+H]+

[0277] Step 5: ( / ?)-2-((5-(4-fluorophcnyl)-l.3.4-oxadiazol-2-yl)amino)-l-((2 / ?.3 / ?)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0290]

[0278] A solution of ( / ?)-2-amino-l-((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin-l- yl)propan-l-one hydrochloride (60.0 mg, crude), 5-(4-fluorophenyl)-3H-l,3,4-oxadiazol-2-one (44.9 mg, 0.20 mmol), '-diisopropylcthylaminc (0.1 mL, 0.7 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (441.5 mg, 1.0 mmol) in dichloromethane (2 mL) was stirred at 25° C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30%B to 53%B in 9min; Wave Length: 254 / 220 nm to afford the title compound (30.3 mg, 0.07 mmol, 30.2% yield) as a white solid. LC-MS: (ESI, m / z . 403.1 [M+H]+

[0291]

[0279] Example 18: ( / ?)-l-(3-(trifluoromcthoxy)azctidin-l-yl)-2-((5-(4- (trifluoromethyl)phenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0292] Synthetic Route

[0280] A solution of (2 / ?)-2-amino-l-|3-(trifluoromcthoxy)azctidin-l-yl |propan-l-onc hydrochloride (100.0 mg, 0.40 mmol), lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (833.2 mg, 1.80 mmol), A.A-diisopropylcthylaminc (0.2 mL, 1.40 mmol) and 5-[4-(trifluoromethyl)phenyl]-3H-l,3,4-oxadiazol-2-one (75.9 mg, 0.30 mmol) in dichloromethane (2 mL) was stirred at 25° C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min mL / min; Gradient: 30% B to 50% B in 10 min; Wave Length: 254nm / 220nm to afford the title compound (28.5 mg, 0.06 mmol, 14.3% yield) as a white solid. LC-MS: (ESI, z): 425.0 [M+H]+

[0293]

[0281] Example 19: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-3- fluoro-3-methylpyrrolidin- 1 -yl)propan- 1 -one (

[0294] Synthetic Route

[0295]

[0282] To a solution of (2 / ?)-2-||5-(4-chlorophcnyl)-l.3.4-oxadiazol-2-yl ]amino]propanoic acid (60.0 mg, 0.20 mmol), (3S)-3-fluoro-3-methyl-pyrrolidine hydrochloride (23.1 mg, 0.16 mmol) in dichloromethane (1 mL) was added A'.A'-diisopropylcthylaminc (0.2 mL, 1.3 mmol) and propylphosphonic anhydride (127.2 mg, 0.2 mmol, 50% in ethyl acetate). The mixture was stirred at 25°C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the product. The product was further purified by Prep- HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25%B to 45%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 8.97 to afford the title compound (38.5 mg, 0.1 mmol, 48.7% yield) as a white solid. LC-MS: (ESI, m / z . 353.0 [M+H]+

[0296]

[0283] Example 20: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(l,l- difluoro-5 -azaspiro [2.3]hexan-5-yl)propan- 1 -one

[0297] Synthetic Route

[0298]

[0284] To a solution of (2 / ?)-2-| |5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl |amino|propanoic acid (50.0 mg, 0.19 mmol), 2,2-difluoro-5-azaspiro[2.3]hexane hydrochloride (35.2 mg, 0.23 mmol) and A'.A'-diisopropylcthylaminc (120.3 mg, 0.93 mmol) in dichloromethane (2 mb) was added propanephosphonic acid cyclic anhydride (120.8 mg, 0.19 mmol, 50% in ethyl acetate) and the mixture was stirred at 25 °C for 2 hours. After completion, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (21.7 mg, 0.06 mmol, 31.1% yield) as a white solid. LC-MS: (ESI, m / z): 369.1 [M+H]+

[0299]

[0285] Example 21: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-(2,2,2- trifluoroethoxy)azetidin- 1 -yl)propan- 1 -one

[0300] Synthetic Route

[0301]

[0286] To a solution of (2 / ?)-2-| |5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl ]amino]propanoic acid (100.0 mg, 0.37 mmol), 3-(2,2,2-trifluoroethoxy)azetidine hydrochloride (143.3 mg, 0.75 mmol) and A.A-diisopropylcthylaminc (24.1 mg, 1.87 mmol) in dichloromethane (1 mL) was added propanephosphonic acid cyclic anhydride (356.2 mg, 0.56 mmol, 50% in ethyl acetate), and the mixture was stirred at 25° C for 2 hours. After completion, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (33.2 mg, 0.08 mmol, 21.1% yield) as a white solid. LC-MS: (ESI, m / z): 405.0 [M+H]+

[0302]

[0287] Example 22: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -(4- azaspiro [2.3]hexan-4-yl)propan- 1 -one

[0303]

[0288] Step 1: tert-butyl ( / ?)-( l -oxo- l -(4-azaspiro|2.3 |hcxan-4-yl)propan-2-yl)carbamatc

[0304]

[0289] A solution of 4-azaspiro[2.3]hexane oxalic acid(2: 1) (100.0 mg, 0.78 mmol), (27?)- 2-(tert-butoxycarbonylamino)propanoic acid (74.2 mg, 0.39 mmol), 2-(7-azabenzotriazol-l-yl)- N, N, N', A'-tctramcthyluronium hexafluorophosphate (223.3 mg, 0.59 mmol) and A.A- diisopropylethylamine (151.2 mg, 1.17 mmol) in dichloromethane (3 mL) was stirred at 25° C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to afford the title compound (95.1 mg, 0.43 mmol, 95.7% yield) as a white solid. LC-MS: (ESI, m / z): 255.2 [M+H]+

[0305]

[0290] Step 2: (7?)-2-amino- l -(4-azaspiro|2.3 |hcxan-4-yl)propan- l -onc trifluoroacetate

[0306]

[0291] A solution of tert-butyl ( / ?)-( l -oxo- l -(4-azaspiro|2.3 |hcxan-4-yl)propan-2- yl)carbamate (90.2 mg, 0.35 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (1 mL) was stirred at 25° C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (80.5 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 154.1 [M+H]+

[0307]

[0292] Step 3: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(4- azaspiro [2.3]hexan-4-yl)propan- 1 -one

[0308]

[0293] To a solution of (2R)-2 -amino- l-(4-azaspiro[2.3]hexan-4-yl)propan-l -one trifluoroacetate (80.5 mg, crude), 5-(4-chlorophenyl)-377-l,3,4-oxadiazol-2-one (50.2 mg, 0.25 mmol) and A.A-diisopropylcthylaminc (164.2 mg, 1.27 mmol) in AA'-dimcthylfonnamidc (2 mL) was added 177-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (169.2 mg, 0.38 mmol) and the mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (24.3 mg, 0.07 mmol, 28.4% yield) as a white solid. LC-MS: (ESI, m / z): 333.0 [M+H]+

[0309]

[0294] Example 23: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -(( / ?)-2- methylazetidin- 1 -yl)propan- 1 -one

[0310] Synthetic Route

[0311]

[0295] To a solution of (2 / ?)-2-| |5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl ]amino]propanoic acid (100.0 mg, 0.37mmol), (2 / ?)-2-mcthylazctidinc hydrochloride (61.0 mg, 0.56 mmol) and N,N- diisopropylethylamine (145.3 mg, 1.12 mmol) in dichloromethane (2 mb) was added propanephosphonic acid cyclic anhydride (356.2 mg, 0.56 mmol, 50% in ethyl acetate). The mixture was stirred at 25° C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to afford the title compound (60.5 mg, 0.18 mmol, 48.6% yield) as a white solid. LC-MS: (ESI, m / z): 321.0[M+H]+

[0312]

[0296] Example 24: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((.S)-2- methylazetidin- 1 -yl)propan- 1 -one

[0313] Synthetic Route

[0314]

[0297] To a solution of (2 / ?)-2-| |5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl ]amino]propanoic acid (100.0 mg, 0.37 mmol), (2.S)-2-mcthylazctidinc hydrochloride (61.2 mg, 0.57 mmol) and N.N- diisopropylethylamine (145.3 mg, 1.12 mmol) in dichloromethane (1 mL) was added propanephosphonic acid cyclic anhydride (356.2 mg, 0.56 mmol, 50% in ethyl acetate) and the mixture was stirred at 25° C for 2 hours. After completion, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:2) to afford the title compound (30.2 mg, 0.09 mmol, 25.1% yield) as a white solid. LC-MS: (ESI, m / z): 321.0[M+H]+

[0315]

[0298] Example 25: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((J?)-3- (2,2,2-trifluoroethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0316]

[0317]

[0299] Step 1: tert-butyl ( / ?)-3-(2.2.2-trifluorocthox [pyrrolidine- 1 -carbox late

[0318]

[0300] Under nitrogen, to a solution of tert-butyl ( / ?)-3-hydroxypyrrolidinc- 1 -carboxylate (2.00 g, 10.68 mmol) in tetrahydrofuran (20 mb) was added sodium hydride (1.28 g, 32.04 mmol, 60% in mineral oil) and the mixture was stirred at 0 °C for 10 minutes. Then to the mixture was added a solution of 2,2,2-trifluoroethyltrifluoromethanesulfonate (3.72 g, 16.02 mmol) in tetrahydrofuran (20 mb) and the mixture was stirred at 60° C for 2 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to afford the title compound (500.0 mg, 1.86 mmol, 17.4% yield) as a white oil. LC-MS: (ESI, m / z): 269.3 [M+H]+.

[0319]

[0301] Step 2: ( / ?)-3-(2.2.2-trifluorocthoxy)pyrrolidinc hydrogen chloride

[0320]

[0302] A solution of tert-butyl ( / ?)-3-(2.2.2-trifluorocthoxy)pyrrolidinc- 1 -carboxylate (300.0 mg, 1.11 mmol) in hydrogen chloride / 1,4-dioxane (5.0 mb, 4.0 M) was stirred at 25°C for 1 hour. After completion, the reaction solution was concentrated under vacuum to afford the title compound (235.3 mg, crude). LC-MS: (ESI, m / z): 205.6 [M+H]+.

[0303] Step 3: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((7?)-3-(2,2,2- trifluoroethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0321]

[0304] To a solution of ( / ?)-3-(2.2.2-trifluorocthoxy)pyrrolidinc hydrogen chloride (115.3 mg, crude), (27?)-2-[[5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl]amino]propanoic acid (100.0 mg, 0.37 mmol), A.A-diisopropylcthylaminc (241.2 mg, 1.87 mmol) in dichloromethane (3 mL) was added propanephosphonic acid cyclic anhydride (357.3 mg, 0.56 mmol, 50% in ethyl acetate) and the mixture was stirred at 25° C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford the title compound (20.3 mg, 0.048 mmol, 12.8% yield) as a white solid. LC-MS: (ESI, m / z): 419.1 [M+H]+.

[0322]

[0305] Example 26: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,47?)-2- methyl -4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0323]

[0306] Step 1: tert-butyl (2S,47?)-2-methyl-4-(trifluoromethoxy)pyrrolidine-l -carboxylate

[0324]

[0307] Under nitrogen, to a solution of silver trifluoromethanesulfonate (4.54 g, 17.68 mmol), potassium fluoride (1.55 g, 26.19 mmol) and selectfluoro (3.49 g, 9.82 mmol) in ethyl acetate (20 mL) was added tert-butyl (2,S'.4 / ?)-4-hydroxy-2-mcthyl-pyrrolidinc- 1 -carboxylate (2.00 g, 6.55 mmol) at 0 °C. Then 2-fluoro-pyridine (1.92 g, 19.64 mmol) and (trifluoromethyl)trimethylsilane (2.81 g, 19.64 mmol) was added and the mixture was stirred at 25 °C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to afford the title compound (778.2 mg, 2.89 mmol, 44.1% yield) as a white oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0325]

[0308] Step 2: (2.S'.4 / ?)-2-mcthyl-4-(tri fl uoromcthoxy (pyrrolidine hydrogen chloride

[0326]

[0309] A solution of tert-butyl (2S, 47?)-2 -methyl -4-(trifluoromethoxy)pyrrolidine-l- carboxylate (200.0 mg, 0.74 mmol) in hydrogen chloride / 1,4-dioxane (2 m , 4 M) was stirred at 25° C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (163.0 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 205.6 [M+H]+.

[0327]

[0310] Step 3: (J?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,4J?)-2- methyl-4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0328]

[0311] A solution of (2J?)-2-[[5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl]amino]propanoic acid (100.0 mg, 0.40 mmol), (2.S'.4 / ?)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidinc hydrochloride (98.4 mg, crude), A.A-diisopropylcthylaminc (257.2 mg, 1.99 mmol) in dichloromethane (2 mb) was made. Then propanephosphonic acid cyclic anhydride (305.3 mg, 0.48 mmol, 50% in ethyl acetate) was added and the mixture was stirred at 25° C for 1 hour. The resulting solution was extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (43.3 mg, 0.11 mmol, 26.4% yield) as a white solid. LC-MS: (ESI, m / z): 403.1 [M+H]+.

[0329]

[0312] Example 27: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2.S'.4.S)-4- fluoro-2-methylpyrrolidin- 1 -yl)propan- 1 -one

[0330] Synthetic Route

[0331]

[0313] To a solution of (2.S'.4.S')-4-fluoro-2-mcthyl-pyrrolidinc hydrochloride (78.0 mg, 0.56 mmol), '. '-diisopropylcthylaminc (241.2 mg, 1.87 mmol) and (27?)-2-[[5-(4-chlorophenyl)- l,3,4-oxadiazol-2-yl]amino]propanoic acid (100.0 mg, 0.37 mmol) in dichloromethane (1 mL) was added propanephosphonic acid cyclic anhydride (356.2 mg, 0.56 mmol, 50% in ethyl acetate). The mixture was stirred at 25° C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30* 150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 34% B in 7 min; Wave Length: 254 / 220 nm; RTl(min): 6.25 to afford the title compound (33.2 mg, 0.09 mmol, 24.8% yield) as a white solid. LC-MS: (ESI, m / z): 353.1[M+H]+.

[0332]

[0314] Example 28: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,4R)-4- fluoro-2-methylpyrrolidin- 1 -yl)propan- 1 -one

[0333] Synthetic Route

[0334]

[0315] To a solution of (2.S'.4 / ?)-4-fluoro-2-mcthyl-pyrrolidinc hydrochloride (78.3 mg, 0.56 mmol), A.A-diisopropylcthylaminc (241.2 mg, 1.87 mmol) and (27?)-2-[[5-(4-chlorophenyl)- l,3,4-oxadiazol-2-yl]amino]propanoic acid (100.0 mg, 0.37 mmol) in dichloromethane (1 mL) was added propanephosphonic acid cyclic anhydride (356.2 mg, 0.56 mmol, 50% in ethyl acetate). The mixture was stirred at 25° C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (52.0 mg, 0.14 mmol, 38.3% yield)) as a white solid. LC-MS: (ESI, m / z): 353.0 [M+H]+.

[0335]

[0316] Example 29: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((7?)-2- (trifluoromethyl)azetidin- 1 -yl)propan- 1 -one

[0336] Synthetic Route

[0317] To a solution of (2 / ?)-2-| |5-(4-chlorophcnyl)- 1 ,3,4-oxadiazol-2-yl ]amino]propanoic acid (100.0 mg, 0.37 mmol), '. '-diisopropylcthylaminc (241.2 mg, 1.87 mmol) and (7?)-2- (trifluoromethyl)azetidine 4-methylbenzenesulfonic acid (133.3 mg, 0.45 mmol) in dichloromethane (2 mL) was added propanephosphonic acid cyclic anhydride (286.2 mg, 0.45 mmol, 50% in ethyl acetate) and the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH Phenyl Hexy Column, 30* 150 mm, 5 pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 29% B to 48% B in 7 min; Wave Length: 254 / 220 nm; RTl(min): 7 to afford the title compound (29.6 mg, 0.08 mmol, 21. 1% yield) as a white solid. LC-MS: (ESI, m / z): 375.1 [M+H]+.

[0337]

[0318] Example 30: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2R,35)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0338]

[0319] Step 1: tert-butyl (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc- l -carboxylatc

[0339]

[0320] A mixture of silver trifluoromethanesulfonate (5.10 g, 20.12 mmol), potassium fluoride (1.73 g, 29.81 mmol) and l-(chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4- diium tetrafluoroborate) (3.90 g, 11.18 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of tert-butyl (2 / ?.3.S)-3-hydroxy-2-mcthyl-pyrrolidinc- 1 -carboxylate (750.0 mg, 3.73 mmol) in ethyl acetate (10.0 mb) followed by the dropwise addition of 2-fluoro-pyridine (2.17 g, 22.36 mmol) and trimethyl(trifluoromethyl)silane (3.20 g, 22.36 mmol) and the mixture was stirred at ambient temperature for 12 hours. After completion, the reaction was diluted with ethyl acetate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (180.0 mg, 0.66 mmol, 17.9% yield) as a yellow oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0340]

[0321] Step 2: (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy (pyrrolidine hydrochloride

[0341]

[0322] A solution of tert-butyl (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc- 1- carboxylate (160.0 mg, 0.59 mmol) in hydrochloric acid / l,4-dioxane (3.0 m , 4M) was stirred at 25° C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (135.2 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 170.1 [M+H]+.

[0342]

[0323] Step 3: tert-butyl ((J?)-l-((2J?,3S)-2-methyl-3-(trifluoromethoxy)pyrrolidin-l-yl)-l- oxopropan-2-yl)carbamate

[0343]

[0324] A solution of (2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc hydrochloride (100.0 mg, crude), A. A-diisopropylcthylaminc (0.3 mb, 1.77 mmol), (tert-butoxycarbonyl)-D- alanine (89.4 mg, 0.47 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A. A" A'-tctramcthyluronium hexafluorophosphate (292.0 mg, 0.77 mmol) in dichloromethane (1.5 mb) was stirred at 25° C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (150.0 mg, 0.44 mmol, 74.6% yield) as a yellow oil. LC- MS: (ESI, m / z): 341.1 [M+H]+.

[0344]

[0325] Step 4: ( / ?)-2-amino- l -((2 / ?.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)propan-l-one hydrochloride

[0345]

[0326] A solution of tert-butyl (( / ?)- 1 -((27?, 3S)-2-methyl-3-(trifluoromethoxy)pyrrohdin-l- yl)-l-oxopropan-2-yl)carbamate (130.0 mg, 0.38 mmol) in hydrochloric acid / l,4-dioxane (1.5 mb, 4M) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (115.3 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1 [M+H]+.

[0346]

[0327] Step 5: (J?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2J?,3lS)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0347]

[0328] A solution of ( / ?)-2 -amino- 1 -((2 / ?.3.S)-2-mcthyl-3 -(trifhioromethoxy)pyrrolidin- 1- yl)propan-l-one hydrochloride (80.0 mg, crude), A'. A'-diisopropylcthylaminc (0.2 mb, 1.33 mmol), 5-(4-fluorophenyl)-3H-l,3,4-oxadiazol-2-one (83.9 mg, 0.47 mmol) and benzotriazol- 1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate (441.8 mg, 1.00 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 : 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 31%B to 57%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.68 to afford the title compound (53.4 mg, 0.13 mmol, 39.7% yield) as a white solid. LC-MS: (ESI, m / z): 403.1 [M+H]+.

[0348]

[0329] Example 31: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3R)-2- methyl-3 -(2,2,2-trifluoroethoxy)azetidin- 1 -yl)propan- 1 -one

[0349]

[0330] Step 1: tert-butyl (2.S'.3 / ?)-2-mcthyl-3-(2.2, 2-trifluoroethoxy)azetidine-l- carboxylate

[0331] Sodium hydride (320.4 mg, 8.01 mmol, 60% dispersion in paraffin liquid) was added into the solution of tert-butyl(2S,3R)-3-hydroxy-2-methyl-azetidine-l-carboxylate (500.0 mg, 2.67 mmol) in '.A'-dimcthylfonnamidc (5.0 mb) and stirred at 0 °C for 30 minutes. Then 2,2,2-trifluoroethyl trifluoromethane sulfonate (743.7 mg, 3.20 mmol) was added and stirred at 25 °C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (220.0 mg, 0.81 mmol, 30.6% yield) as a yellow oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0350]

[0332] Step 2: (2.S'.3 / ?)-2-mcthyl-3-(2.2.2-trifluorocthoxy)azctidinc trifluoroacetate

[0351]

[0333] A solution of tert-butyl (2.S'.3 / ?)-2-mcthyl-3-(2.2.2-trifluorocthoxy)azctidinc- l - carboxylate (220.0 mg, 0.82 mmol) in dichloromethane (3.0 m ) and trifluoroacetic acid (1.0 m ) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (280.3 mg, crude). The crude product was directly used in the next step without purification. EC-MS: (ESI, m / z): 170.1 [M+H]+.

[0352]

[0334] Step 3: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3R)-2- methyl-3 -(2,2,2-trifluoroethoxy)azetidin- 1 -yl)propan- 1 -one

[0353]

[0335] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (50.0 mg, 0.19 mmol), (2.S'.3 / ?)-2-mcthyl-3-(2.2.2-trifluorocthoxy)azctidinc trifluoroacetate (94.7 mg, crude) and A. A-diisopropylcthylaminc (0.1 mb, 0.75 mmol) in dichloromethane (0.5 mb) was added propyl phosphate tricyclic anhydride solution (152.6 mg, 0.24 mmol, 50% in ethyl acetate), and the mixture was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the product. The product was further purified by Prep-HPEC with the following conditions: XBridge Prep OBD C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: water (10 mmol / E NH4HCO3), Mobile Phase B: acetonitrile; Plow rate: 60 mb / min; Gradient: 35%B to 51%B inlO min; Wave Eength: 254 / 220 nm; RTl(min): 10.97 to afford the title compound (24.3 mg, 0.057 mmol, 30.8% yield) as a white solid. EC-MS: (ESI, m / z): 419.1 [M+H]+.

[0354]

[0336] Example 32: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3R)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0355] Synthetic Route

[0356]

[0337] To a solution of 5-(4-chlorophenyl)-3H-l,3,4-oxadiazol-2-one (40.0 mg, 0.20 mmol), (R)-2 -amino- 1 -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- 1 -yl)propan- 1 -one hydrochloride (68.4 mg, crude) and '. A'-diisopropylcthylaminc (0.1 mL, 0.81 mmol) in dichloromethane (0.5 mL) was added lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (269.8 mg, 0.61 mmol) and the mixture was stirred at 25° C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: XBridge BEH Shield RP18 Column, 30* 150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 28%B to53%B in8min; Wave Length: 254 / 220 nm to afford the title compound (22.5 mg, 0.053 mmol, 26.4% yield) as a white solid. LC-MS: (ESI, m / z): 419.0 [M+H]+.

[0357]

[0338] Example 33a: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,35)- 3-methoxy-2,3-dimethylazetidin- 1 -yl)propan- 1 -one

[0339] Example 33b: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,37?)- 3-methoxy-2,3-dimethylazetidin- 1 -yl)propan- 1 -one

[0358]

[0340] Step 1: tert-butyl (2S)-3 -hydroxy-2,3 -dimethylazetidine- 1 -carboxylate

[0359]

[0341] Under nitrogen, methylmagnesium bromide (16.2 m , 16.20 mmol, IM) was added into the solution of tert-butyl (.S)-2-mcth l-3-oxoazctidinc- l -carboxylate (1.00 g, 5.40 mmol) in tetrahydrofuran (10.0 mb) and stirred at 0 °C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 : 1) to afford the title compound (500.0 mg, 2.48 mmol, 46% yield) as a yellow oil. EC-MS: (ESI, m / z): 202.1 [M+H]+.

[0360]

[0342] Step 2: tert-butyl (2S)-3-methoxy-2,3-dimethylazetidine- 1 -carboxylate

[0361]

[0343] Sodium hydride (298. 1 mg, 7.45 mmol, 60% dispersion in paraffin liquid) was added into the solution of tert-butyl (2.S)-3-hydroxy-2.3-dimcthylazctidinc- 1 -carboxylate (500.0 mg, 2.48 mmol) in tetrahydrofuran (5.0 m ) and the mixture stirred at 0°C for 10 minutes. Then iodomethane (740.4 mg, 5.22 mmol) was added and stirred at 25°C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (600.0 mg, 2.36 mmol, 95.4% yield) as a yellow oil. LC-MS: (ESI, m / z): 216.2 [M+H]+.

[0362]

[0344] Step 3: (2.S)-3-mcthoxy-2.3-dimcthylazctidinc trifluoroacctatc

[0363]

[0345] A solution of tert-butyl (2.S)-3-mcthoxy-2.3-dimcthylazctidinc- 1 -carboxylate (580.0 mg, 2.69 mmol) in trifluoroacetic acid (1.0 m ) and dichloromethane (3.0 m ) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (673.2 mg, crude). The crude product was directly used in the next step without purification. EC-MS: (ESI, m / z): 116.1 [M+H]+.

[0364]

[0346] Step 4: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-3- methoxy-2,3-dimethylazetidin-l-yl)propan-l-one & ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2- yl)amino)- 1 -((2.S'.3 / ?)-3 -methoxy -2, 3 -dimethylazetidin- 1 -yl)propan- 1 -one

[0365]

[0347] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (200.0 mg, 0.75 mmol), W-diisopropylcthylaminc (0.6 mb, 3.74 mmol), (2S)-3-methoxy-2,3- dimethylazetidine trifluoroacetate ( 172.1 mg, crude) in dichloromethane (2.0 mb) was added propyl phosphate tricyclic anhydride solution (617.7 mg, 0.97 mmol, 50% in ethyl acetate) and the mixture was stirred at 25° C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the product. The product was further purified by Prep- HPEC with the following conditions: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: acetonitrile; Plow rate: 60 mb / min; Gradient: 24%B to 44%B in 9min; Wave Eength: 254 / 220 nm; RT1: 8.68 min to afford the product. The product was separated by Prep-CHIRAE-HPEC with the following conditions: CHIRAEPAK IP 2*25 cm, 5 pm; Mobile Phase A: hexane (0.5% 2M NHs-methanol), Mobile Phase B: ethanol; Flow rate: 20 mb / min; Gradient: isocratic 50; Wave Eength: 220 / 254 nm; Sample Solvent: methanol; Injection Volume: 1.2 mb; Number of Runs: 3. RTi: 7.591 min to afford (R)-2- ((5 -(4-chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2S,3S)-3 -methoxy-2, 3 -dimethylazetidin- 1 - yl)propan-l-one (35.9 mg, 0.096 mmol, 12.9% yield) as a white solid and (R)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3 / ?)-3 -methoxy-2, 3 -dimethylazetidin- 1 - yl)propan-l-one (3.4 mg, 0.0092 mmol, 1.2% yield) as a white solid.

[0366]

[0348] Example 34a: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((R)-6- methyl-5 -azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0367]

[0349] Example 34b: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-6- methyl-5 -azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0368]

[0350] Step 1: tert-butyl 2-methyl-4-methylenepyrrolidine-l -carboxylate

[0369]

[0351] Under nitrogen, potassium tert-butoxide (78.29 mb, 78.29 mmol, 1.0 M in tetrahydrofuran) was added to a solution of methyltriphenylphosphonium bromide (25.82 g, 72.27 mmol) in diethyl ether (150 mb) at 0 °C. The temperature was then increased to 25 °C and stirred for 2 hours. Then a solution of tert-butyl 2 -methyl -4-oxopyrrolidine-l -carboxylate (12.00 g, 60.23 mmol) in diethyl ether (150 mb) was slowly dropped into the reaction mixture at 0 °C for 45 min. Then the temperature was increased to 25 °C and the mixture was stirred at 25 °C for 2 hours. After completion, the reaction was filtered. The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (20: 1) to afford tert-butyl 2 -methyl -4- methylenepyrrolidine-1 -carboxylate (10.10 g, 46.08 mmol, 76.5% yield) as a colorless oil. LC-MS: (ESI, m / z): 198.1 [M+H]+.

[0370]

[0352] Step 2: tert-butyl 6-methyl-5-azaspiro[2.4]heptane-5-carboxylate

[0371]

[0353] Under nitrogen, diethylzinc (77.56 mb, 77.56 mmol, 1.0 M in hexanes) was dissolved in anhydrous dichloromethane (30 mb). The solution was cooled to 0 °C and then a solution of dichloroacetic acid (9.41 g, 73.00 mmol) in dichloromethane (30 mb) was added dropwise over 10 minutes. The solution was stirred at 0 °C for an additional 30 minutes. A solution of diiodomethane (19.55 g, 73.00 mmol) in anhydrous dichloromethane (30 mb) was added dropwise quickly, and the resulting solution was stirred at 0 °C for 30 minutes. After that, a solution of tert-butyl 2-methyl-4-methylenepyrrolidine-l -carboxylate (5.00 g, 22.81 mmol) in anhydrous dichloromethane (30 mL) was added to the reaction mixture. The reaction mixture was stirred in a thawing ice-bath for 90 hours, then quenched with saturated aqueous ammonium chloride solution, dried over magnesium sulfate, concentrated under vacuum to provide the crude product as a yellow oil. The oil was dissolved in ethyl acetate (100 mL), di-tert-butyl dicarbonate (7.47 g, 34.22 mmol) and triethylamine (11.54 g, 114.06 mmol) were sequentially added, and then the reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (20: 1) to afford tert-butyl 6-methyl-5-azaspiro[2.4]heptane-5- carboxylate (2.21 g, 6.77 mmol, 29.7% yield) as a colorless oil. LC-MS: (ESI, z):212.2 [M+H]+.

[0372]

[0354] Step 3: 6-methyl-5-azaspiro[2.4]heptane hydrochloride

[0373]

[0355] A solution of tert-butyl 6-methyl-5-azaspiro[2.4]heptane-5-carboxylate (800.0 mg, 3.79 mmol) in 4 M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to afford 6-methyl-5- azaspiro[2.4]heptane hydrochloride (550.6 mg, crude) as a white solid. The crude product was directly used in the next step without purification.LC-MS: (ESI, mlz)-. 112. 1 [M+H]+.

[0374]

[0356] Step 4: tert-butyl ((2 / ?)- l -(6-mcthyl-5-azaspiro|2.4|hcptan-5-yl)- l -oxopropan-2- yl)carbamate

[0375]

[0357] A solution of A.A-diisopropylcthylaminc (1.20 g, 9.32 mmol), 6-methyl-5- azaspiro[2.4]heptane hydrochloride (540.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (646.5 mg, 3.42 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A'.A'-tctramcthyluroniiim hexafluorophosphate (1.42 g, 3.73 mmol) in A.A-dimcthylformamidc (6 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (2:3) to afford tert-butyl ((2 / ?)- l -(6-mcthyl-5- azaspiro[2.4]heptan-5-yl)-l-oxopropan-2-yl)carbamate (900.3 mg, 2.73 mmol, 88.% yield) as a light yellow solid. LC-MS: (ESI, z):283.2 [M+H]+.

[0376]

[0358] Step 5: (2J?)-2-amino-l-(6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-l-one hydrochloride

[0377]

[0359] A solution of tert-butyl ((2 / ?)- l -(6-mcthyl-5-azaspiro|2.4|hcptan-5-yl)- l - oxopropan-2-yl)carbamate (400.0 mg, 1.42 mmol) in 4 M hydrochloric acid in 1,4-dioxane (6 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to afford (2 / ?)-2-amino- l -(6-mcthyl-5-azaspiro|2.4|hcptan-5-yl)propan- l -onc hydrochloride (300.2 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, z): 183.1 [M+H]+.

[0378]

[0360] Step 6: ( / ?)-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)- l -(( / ?)-6-mcthyl-5- azaspiro [2 ,4]heptan-5 -yl)propan- 1 -one & (R)-2-((5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((.S')-6-mcthy I -5 -azaspiro [2 ,4]heptan-5 -yl)propan- 1 -one

[0379]

[0361] A solution of A.A-diisopropylcthylaminc (443.2 mg, 3.43 mmol), (2R)-2 -amino- 1- (6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-l-one hydrochloride (150.0 mg, crude), 5-(4- fluorophenyl)-l,3,4-oxadiazol-2(327)-one (80.3 mg, 0.45 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (910.1 mg, 2.06 mmol) in W- dimethylformamide (2 mL) was stirred at 25° C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse-phase column eluting with (acetonitrile / 0.1% NH4HCO3 in water) to afford the diastereoisomer. The diastereoisomer was isolated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RTl(min): 10.811; RT2(min): 21.388; Sample Solvent: EtOH; Injection Volume: 1.0 mL to afford ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4- oxadiazol-2-yl)amino)-I-((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-l-one (23.5 mg, 0.07 mmol, 9.9% yield) and (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((5)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-l-one (30.4 mg, 0.09 mmol, 12.9% yield) as a white solid. LC- MS: (ESI, m / z): 345.0 [M+H]+.

[0380]

[0362] Example 35a: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2R,3R)- 2-methyl-3 -(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one

[0381]

[0363] Example 35b: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2R,3S)- 2-methyl-3 -(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one

[0382]

[0364] Example 35c: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,35)- 2-methyl-3 -(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one

[0383]

[0365] Example 35d: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3R)- 2-methyl-3 -(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one

[0384]

[0366] Step 1: tert-butyl ((2 / ?)- l -(2-mcthyl-3-(trifluoromcthyl)pyrrolidin- l -yl)- l - oxopropan-2-yl)carbamate

[0385]

[0367] A solution of A.A-diisopropylcthylaminc (275.8 mg, 2.13 mmol), 2-methyl-3- (trifluoromethyl)pyrrolidine hydrochloride (145.0 mg, 0.71 mmol), (tert-butoxycarbonyl)-D-alanine (148.0 mg, 0.78 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A'.A'-tctramcthyliironiiim hexafluorophosphate (324.5 mg, 0.85 mmol) in A.A-dimcthylfonnamidc (1 mb) was stirred at 25° C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:4) to afford tert-butyl ((2 / ?)- l -(2-mcthyl-3-(trifluoromcthyl)pyrrolidin- l -yl)-l -oxopropan-2-yl)carbamatc (220.3 mg, 0.58 mmol, 81.1% yield) as a light yellow solid. LC-MS: (ESI, m / z)-. 325.2 [M+H]+.

[0386]

[0368] Step 2: (2 / ?)-2-amino- l -(2-mcthyl-3-(trifluoromcthyl)pyrrolidin- l -yl)propan- l -onc hydrochloride

[0369] A solution of tert-butyl ((2 / ?)- 1 -(2-mcthyl -3 -(triflnoromcthyl jpyrrolidin- 1 -yl )- 1 - oxopropan-2-yl)carbamate (200.0 mg, 0.52 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3 mb) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to afford (2 / ?)-2-ammo- l -(2-mcthyl-3-(trifluoromcthyl)pyrrolidin- l -yl)propan- l -onc hydrochloride (150.5 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC -MS: (ESI, z):225.1 [M+H]+.

[0387]

[0370] Step 3: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2R,3R)-2- methyl-3 -(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one & ( / ?)-2-((5 -(4-fl uorophcnyl )- 1 ,3,4- oxadiazol-2-yl)amino)- 1 -((2 / ?.3.S')-2-mcth l-3-(trifluoromcth l jpyrrolidin- 1 -yl)propan- 1 -one & (R)- 2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-2-methyl-3- (trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one & (R)-2-((5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2- yl)amino)- 1 -((2.S'.3 / ?)-2-mcthy I -3 -(trifl uoromcthy I [pyrrol idin- 1 -yl)propan- 1 -one

[0388]

[0371] A solution of A.A-diisopropylcthylaminc (304.9 mg, 2.36 mmol), (2R)-2 -amino- 1- (2-methyl-3-(trifluoromethyl)pyrrolidin-l-yl)propan-l-one hydrochloride (150.0 mg, crude), 5-(4- fluorophenyl)-l,3,4-oxadiazol-2(327)-one (55.3 mg, 0.31 mmol) and IH-bcnzotriazol- l - yloxytris(dimethylamino)phosphonium hexafluorophosphate (626.0 mg, 1.42 mmol) in dichloromethane (3 m ) was stirred at 25° C for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 27% B to 47% B in 10 min; Wave Length: 254nm / 220nm nm to afford two diastereoisomers. The diastereoisomer (faster peak) was isolated by Prep-Chiral - HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 15; Wave Length: 220 / 254 nm; RTl(min): 15.102; RT2(min): 22.58; Sample Solvent: EtOH— HPLC; Injection Volume: 1.5 mL to afford (R)-2-((5-(4-fluorophenyl)-l,3,4- oxadiazol-2-yl)amino)- 1 -((2 / ?.3 / ?)-2-mcth l-3-(trifluoromcth l jpyrrolidin- 1 -yljpropan- 1 -one (5.2 mg, 0.01 mmol, 2.8% yield) as a white solid and (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2- yl)amino)- l -((2 / ?.3.S)-2-mcthyl-3-(trifliioromcthyl)pyrrolidin- l -yl)propan- l -onc (9.9 mg, 0.03 mmol, 5.4% yield) as a white solid. The diastereoisomer (slower peak) was isolated by Prep-Chiral - HPLC with the following conditions: Column: (R, R)-WHELK-0 1 5pm Kromasil, 2.11*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 25; Wave Length: 220 / 254 nm; RTl(min): 9.588; RT2(min): 11.399; Sample Solvent: EtOH-HPLC; Injection Volume: 1.0 mL to afford (R)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-2-methyl-3-(trifluoromethyl)pyrrolidin-l- yl)propan-l-one (22.6 mg, 0.06 mmol, 12.3% yield) as a white solid and (7?)-2-((5-(4- fluorophenyl)-l, 3, 4-oxadiazol-2-yl)amino)- l -((2.S'.3 / ?)-2 -methyl -3-(trifluoromethyl)pyrrolidin- 1- yl)propan-l-one (24.9 mg, 0.06 mmol, 13.6% yield) as a white solid. LC-MS: (ESI, m / z) 387.1 [M+H]+.

[0389]

[0372] Example 36a: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((27?,45)- 2-methyl-4-(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one

[0390]

[0373] Example 36b: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,47?)- 2-methyl-4-(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one

[0391]

[0374] Step 1: tert-butyl ((7?)- l-(rac-(2S,47?)-2-methyl-4-(trifluoromethyl)pyrrolidin-l-yl)- 1 -oxopropan-2-yl)carbamate

[0392]

[0375] A mixture of rac-(2.S'.4 / ?)-2-mcthy I -4-(tri fl uoromcthy I [pyrrolidine hydrochloride (100.0 mg, 0.49 mmol), (tert-butoxycarbonyl)-D-alanine (102.1 mg, 0.54 mmol), 2-(7- azabcnzotriazol- l -yl)-A.A.A'.A'-tctramcthyluroniiim hexafluorophosphate (223.8 mg, 0.59 mmol) and A.A-diisopropylcthylaminc (190.2 mg, 1.47 mmol) in A.A-dimcthylfonnamidc (1 m ) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:4) to afford tert- butyl ((R)- 1 -(rac-(2.S'.4 / ?)-2-mcthy I -4-(trifl uoromcthy I )py rrol idin- 1 -yl)- 1 -oxopropan-2-yl)carbamate (150.2 mg, 0.37 mmol, 75.4% yield) as a light yellow solid. LC-MS: (ESI, m / z): 325.2 [M+H]+.

[0393]

[0376] Step 2: (R)-2 -amino- l-(rac-(2S,4R)-2 -methyl -4-(trifluoromethyl)pyrrolidin-l- yl)propan-l-one hydrochloride

[0394]

[0377] A solution of tert-butyl (( / ?)- l -(rac-(2.S'.4 / ?)-2-mcth l-4-(trifluoromcth l)pyrrolidin- l-yl)-l-oxopropan-2-yl)carbamate (135.0 mg, 0.33 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3 m ) was stirred at 25 °C for 1 hour. After completion, the solvent was concentrated under vacuum to afford (R)-2 -amino- l-(rac-(2S,4R)-2 -methyl -4-(trifluoromethyl)pyrrolidin-l-yl)propan- 1-one hydrochloride (95.2 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, z):225.1 [M+H]+.

[0395]

[0378] Step 3: ( / ?)-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)- l -(rac-(2 / ?.4.S)-2- methyl-4-(trifluoromethyl)pyrrolidin- 1 -yl)propan- 1 -one & ( / ?)-2-((5 -(4-fl uorophcnyl )- 1 ,3,4- oxadiazol-2-yl)amino)- 1 -(rac-(2.S'.4 / ?)-2-mcthyl-4-(trifluoromcthyl [pyrrol idin- 1 -yl)propan- 1 -one

[0396]

[0379] A solution of A.A-diisopropylcthylaminc (167.3 mg, 1.29 mmol), (R)-2-amino-l- (rac-(2.S'.4 / )-2-mcthyl-4-(trifliioromcthyl)pyrrolidin- l -yl)propan- l -onc hydrochloride (90.0 mg, 0.26 mmol), 5-(4-fluorophcnyl)- l .3.4-oxadiazol-2(3 / / )-onc (30.3 mg, 0.17 mmol) and 1H- benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (343.6 mg, 0.78 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 : 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.15 to afford the diastereoisomer. The diastereoisomer was isolated by Prep-Chiral-HPLC with the following conditions: Column: CHIRAL ART Amylose-C NEO, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NHs-MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RTl(min): 7.417; RT2(min): 9.537; Sample Solvent: EtOH— HPLC; Injection Volume: 1.0 mL to afford (R)-2-((5-(4-fhiorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2R,4S)-2- methyl-4-(trifluoromethyl)pyrrolidin-l-yl)propan-l-one (24.5 mg, 0.06 mmol, 24.5% yield) as a white solid and ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2.S'.4 / ?)-2-mcthyl-4- (trifhioromethyl)pyrrolidin-l-yl)propan-l-one (26.2 mg, 0.07 mmol, 25.4% yield) as a white solid. LC-MS: (ESI, m / z):387.1 [M+H]+.

[0380] Example 37: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-3-

[0397] (2,2,2-trifluoroethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0398] Synthetic Route

[0399]

[0381] Step 1: tert-butyl (S)-3-(2,2,2-trifluoroethoxy)pyrrolidine-l -carboxylate

[0400]

[0382] To a solution of tert-butyl (.S)-3-hydroxypyrrolidinc- 1 -carboxylate (1.00 g, 5.34 mmol) in tetrahydrofuran (10 m ) was added sodium hydride (854.4 mg, 21 .36 mmol, 60% dispersion in mineral oil) at 0 °C and the mixture was stirred at 25 °C for 30 min. Then 2,2,2- trifluoroethyl trifluoromethanesulfonate (1.61 g, 6.94 mmol) in tetrahydrofuran (5 mb) was added at 0 °C and the mixture was stirred at 25 °C for 1.5 hours. After completion, the reaction was quenched with ammonium chloride saturated solution, concentrated under vacuum, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:7) to afford tert-butyl (S)-3-(2,2,2-trifluoroethoxy)pyrrolidine- 1 -carboxylate (230.3 mg, 0.68 mmol, 12.8% yield) as a yellow oil. EC-MS: (ESI, m / z): 1GA [M+H]+.

[0401]

[0383] Step 2: (.S)-3 -(2.2.2-tri fl uorocthoxy [pyrrolidine hydrochloride

[0402]

[0384] A solution of tert-butyl (S)-3 -(2, 2, 2-trifluoroethoxy [pyrrolidine- 1 -carboxylate (220.0 mg, 0.68 mmol) in 4 M hydrochloric acid in 1,4-dioxane (5 m ) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to afford (S)-3-(2,2,2- trifluoroethoxy )pyrrolidine hydrochloride (160.2 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, mlz).' 170. 1 [M+H]+.

[0403]

[0385] Step 3: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-3-(2,2,2- trifluoroethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0404]

[0386] To a solution of '. '-diisopropylcthylaminc (392.2 mg, 3.03 mmol), (<S)-3 -(2,2,2- trifluoroethoxy)pyrrolidine hydrochloride (160.2 mg, crude) and (5-(4-chlorophenyl)-l,3,4- oxadiazol-2-yl)- / )-alaninc (81.2 mg, 0.30 mmol) in dichloromethane (3 mL) was added propylphosphonic anhydride (579.1 mg, 0.91 mmol, 50% in ethyl acetate) and the mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30%B to 50%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.3 to afford ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2- yl)amino)-l-((S)-3-(2,2,2-trifluoroethoxy)pyrrolidin-l-yl)propan-l-one (43.7 mg, 0.10 mmol, 17.1% yield) as a white solid. LC-MS: (ESI, z):419.0 [M+H]+.

[0405]

[0387] Example 38: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-methyl- 3 -(2,2,2-trifluoroethoxy)azetidin- 1 -yl)propan- 1 -one

[0406] Synthetic Route

[0407]

[0388] Step 1: tert-butyl 3-methyl-3-(2,2,2-trifluoroethoxy)azetidine-l-carboxylate

[0408]

[0389] With no precautions to exclude air or moisture, the ElectraSyn vial with a stir bar was charged with l-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid (968.6 mg, 4.50 mmol), 2,2,2-trifluoroethan-l-ol (1.35 g, 13.50 mmol), 2,4,6-trimethylpyridine (1.64 g, 13.50 mmol), tetrabutylammonium hexafluorophosphate (4.36 g, 11.25 mmol), 3 A molecular sieves (150 mg), silver hexafluorophosphate (1.71 g, 6.75 mmol), and dichloromethane (105 m ). The ElectraSyn vial cap equipped with anode and cathode were inserted into the mixture. After prestirring for 15 min, the reaction mixture was electrolyzed at a constant current of 10 mA for 48 hours. After completion, the reaction mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (10 / 1) to afford tert-butyl 3-methyl-3-(2,2,2-trifluoroethoxy)azetidine-l-carboxylate (550.2 mg, 0.31 mmol, 6.8% yield) as a light yellow oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0409]

[0390] Step 2: 3-methyl-3-(2,2,2-trifluoroethoxy)azetidine trifluoroacetate

[0410]

[0391] A solution of tert-butyl 3-methyl-3-(2,2,2-trifluoroethoxy)azetidine-l-carboxylate (550.2 mg, 0.31 mmol) in trifluoroacetic acid (1 mb) and dichloromethane (3 mb) was stirred at 25° C for 4 hours. After completion, the reaction mixture was concentrated under vacuum to afford 3-methyl-3-(2,2,2-trifluoroethoxy)azetidine trifluoroacetate (820.5 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, mlz).- 170.1 [M+H]+.

[0411]

[0392] Step 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(3-methyl-3- (2,2,2-trifluoroethoxy)azetidin- 1 -yl)propan- 1 -one

[0412]

[0393] To a solution of AA'-diisopropylcthylaminc (120.7 mg, 0.93 mmol), 3-methyl-3- (2, 2, 2-trifluoroethoxy)azetidine trifluoroacetate (820.5 mg, crude) and (5-(4-chlorophenyl)-l,3,4- oxadiazol-2-yl)- / )-alaninc (50.0 mg, 0.19 mmol) in dichloromethane (3 mb) was added propylphosphonic anhydride in ethyl acetate (154.4 mg, 0.24 mmol, 50% in ethyl acetate) and the mixture was stirred at 25 °C for 0.5 hours. After completion, the reaction mixture was diluted with dichloromethane, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse-phase column eluting with water / acetonitrile (7:3) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 30* 150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 52% B in 8min; Wave Length: 254 / 220 run; RTl(min): 8.18 to afford ( / ?)-2-((5-(4-chlorophcnyl)-l .3.4-oxadiazol-2- yl)amino)-l-(3-methyl-3-(2,2,2-trifluoroethoxy)azetidin-l-yl)propan-l-one (5.1 mg, 0.01 mmol, 6.3% yield) as a white solid. LC-MS: (ESI, z):419.0 [M+H]+.

[0413]

[0394] Example 39: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3R)-3- methoxy-2-methylazetidin- 1 -yl)propan- 1 -one

[0414]

[0395] Step 1: tert-butyl (2.S'.3 / ?)-3-mcthoxy-2-mcthylazctidinc- 1 -carboxylate

[0415]

[0396] To a solution of tert-butyl (2.S'.3 / ?)-3-hydroxy-2-mcthylazctidinc- 1 -carboxylate (500.0 mg, 2.67 mmol) in tetrahydrofuran (2.5 mb) was added sodium hydride (320.4 mg, 8.01 mmol, 60% dispersion in mineral oil) and the mixture was stirred at 0 °C for 10 minutes. Then iodomethane (758.1 mg, 5.34 mmol) was added and the mixture was stirred at 25°C for 2 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford tert-butyl (2.S'.3 / ?)-3-mcthoxy-2-mcthylazctidinc- 1 -carboxylate (450.0 mg, 2.24 mmol, 83.7% yield) as a yellow oil. LC-MS: (ESI, m / z): 202.1 [M+H]+.

[0416]

[0397] Step 2: (2.S'.3 / ?)-3-mcthoxy-2 -methylazetidine trifluoroacetate

[0417]

[0398] A solution of tert-butyl (2.S'.3 / ?)-3-mcthoxy-2-mcthylazctidinc- 1 -carboxylate (250.0 mg, 1.24 mmol) in 2,2,2-trifluoroacetic acid (1 m ) and dichloromethane (3 m ) was stirred at 25°C for 1 hour. After completion, the solvent was removed under vacuum to afford (2.S'.3 / ?)-3- methoxy-2 -methylazetidine trifluoroacetate (280.0 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. EC-MS: (ESI, m / z): 102. 1 [M+H]+.

[0418]

[0399] Step 3: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3R)-3- methoxy-2-methylazetidin- 1 -yl)propan- 1 -one

[0419]

[0400] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (100.0 mg, 0.37 mmol) and (2.S'.3 / ?)-3-mcthoxy-2 -methylazetidine trifluoroacetate (200.0 mg, crude) in dichloromethane (1 mb) was added A.A-diisopropylcthylaminc (241.4 mg, 1.87 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (285.3 mg, 0.45 mmol, 50% in ethyl acetate) and the mixture was stirred at 25°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / m ethanol (9: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25%B to 42%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 5.53 to afford ( / ?)-2-((5-(4-chlorophcnyl)-l .3.4-oxadiazol-2- yl)amino)-l-((2S,3R)-3 -methoxy -2 -methylazetidin-l-yl)propan-l -one (38.6 mg, 0.11 mmol, 29.3% yield) as a white solid. LC-MS: (ESI, m / z): 351.2 [M+H]+.

[0420]

[0401] Example 40a: ( / ?)-4.4-difluoro-2-((5-(4-fliiorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- 1 -((2.S'.3.S)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 -yl)butan- 1 -one

[0421]

[0402] Example 40b: (S)-4,4-difluoro-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3.S)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 -yl)butan- 1 -one

[0422]

[0403] Step 1: tert-butyl (4, 4-difluoro- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)- 1 -oxobutan-2-yl)carbamate

[0423]

[0404] To a solution of (2.S'.3.S)-2-mcth l-3-(trifluoromcthoxy)azctidinc hydrochloride (300.0 mg, crude) and 2-((tert-butoxycarbonyl)amino)-4,4-difluorobutanoic acid (425.3 mg, 1.78 mmol) in dichloromethane (3 mb) was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide (1.13 g, 1.78 mmol, 50% in ethyl acetate) and A.A-diisopropylcthylaminc (765.8 mg, 5.93 mmol). The mixture was stirred at room temperature for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (8: 1) to afford the title compound (250.0 mg, 0.66 mmol, 56. 1% yield) as a yellow oil. LC-MS: (ESI, mlz)-. 377.1 [M+H]+.

[0424]

[0405] Step 2: 2-amino-4.4-difluoro-l -((2.S'.3.S)-2-mcthyl-3-(trifliioromcthoxy)azctidin- l - yl)butan-l-one hydrochloride

[0425]

[0406] A solution of tert-butyl (4.4-diflnoro- 1 -((2.S'.3,S')-2-mcthyl-3- (trifluoromethoxy)azetidin-l-yl)-l-oxobutan-2-yl)carbamate (250.0 mg, 0.66 mmol) in 4 M hydrochloric acid in dioxane (4.0 mL) was stirred at 25°C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (250.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, mlz)-. 277.1 [M+H]+.

[0407] Step 3: ( / ?)-4.4-difluoro-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l - ((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy jazctidin- 1 -yl)butan- 1 -one & (.S') -4.4-d ifl no ro -2 - (( 5 -(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-l- yl)butan-l-one

[0426]

[0408] To a solution of 5-(4-fluorophcnyl)- l .3.4-oxadiazol-2(3 / / )-onc (100.0 mg, 0.56 mmol) and 2-amino-4,4-difluoro- 1 -((2.S'.3.S')-2-mcthy 1-3 -(trifluoromethoxy )azetidin- 1 -yl)butan- 1 - one hydrochloride (249.3 mg, crude) in dichloromethane (2 m ) was added N.N- diisopropylethylamine (430.5 mg, 3.33 mmol) and 1H- 1,2, 3 -benzotriazol- 1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (736.6 mg, 1.67 mmol) and the mixture was stirred at 25°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the product. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 15; Wave Length: 220 / 254 nm; RTl(min): 9.491; RT2(min): 11.836; Sample Solvent: EtOH— HPLC; Injection Volume: 0.5 mL to afford (R)-4,4-difluoro-2-((5- (4-fluorophenyl)- 1 ,3,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3.S')-2-mcthyl-3-(trifluoromcthoxy jazctidin- 1 - yl)butan-l-one (20.1 mg, 0.05 mmol, 8.2% yield) as a yellow solid and (5)-4,4-difluoro-2-((5-(4- fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3.S)-2-mcthyl-3 -(trifhioromethoxy)azetidin- 1 - yl)butan-l-one (15.2 mg, 0.03 mmol, 6.2% yield) as an off-white solid.

[0427]

[0409] Example 41a: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-l -((.S)-3- (trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0428]

[0410] Example 41b: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((R)-3-

[0429] (trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0430] Synthetic Route

[0431]

[0411] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (250.0 mg, 0.77 mmol) and 3 -(trifluoromethoxy )pyrrolidine hydrochloride (221.7 mg, 1.16 mmol) in dichloromethane (2 mL) was added A'.A'-diisopropylcthylaminc (498.6 mg, 3.86 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (589.2 mg, 0.93 mmol, 50% in ethyl acetate). The mixture was stirred at 25°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (30: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 34%B to 50%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 8.48. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: JW-LUX-5UM Cellulose-4, 21.2*250mm, 5um; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Wave Length: 220 / 254 nm; RTl(min): 14.496; RT2(min): 16.647; Sample Solvent: EtOH; Injection Volume: 0.4 mL to afford (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-3-(trifhioromethoxy)pyrrolidin-l- yl)propan-l-one (23.7 mg, 0.06 mmol, 7.6% yield) as a white solid and (R)-2-((5-(4-chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -( (A ) -3 -(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one (24.8 mg, 0.06 mmol, 7.9% yield) as a white solid.

[0432]

[0412] Example 42a: ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((.S)-3- (trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0433]

[0413] Example 42b: ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -(( / ?)-3- (trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0434] Synthetic Route

[0435]

[0414] To a solution of (5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (200 mg, 0.80 mmol) and 3 -(trifluoromethoxy )pyrrolidine hydrochloride (183.4 mg, 0.96 mmol) in dichloromethane (2 mL) was added W-diisopropylcthylaminc (411.5 mg, 3.18 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (608.0 mg, 0.95 mmol, 50% in ethyl acetate) and the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (50: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 29%B to 45%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 10.53 to afford the product. The product was isolated by Chiral-Prep- HPLC with the following conditions: Column: JW-LUX-5UM Cellulose-4, 21.2*250mm, 5um; Mobile Phase A: HEX(0.5% 2M NtL-McOH). Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 15; Wave Length: 220 / 254 nm; RTl(min): 9.244; RT2(min): 10.859; Sample Solvent: EtOH; Injection Volume: 0.6 mL to afford (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2- yl)amino)-l-((S)-3-(trifluoromethoxy)pyrrolidin-l-yl)propan-l-one (35.5 mg, 0.09 mmol, 11.4% yield) as a white solid and (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((R)-3- (trifluoromethoxy)pyrrolidin-l-yl)propan-l-one (37.1 mg, 0.09 mmol, 11.9% yield) as a white solid.

[0436]

[0415] Example 43a: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-7- fluoro-5-azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0437]

[0416] Example 43b: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((7?)-7- fluoro-5-azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0438]

[0417] Step 1: tert-butyl ((2 / ?)- l -(7-fhioro-5-azaspiro|2.4|hcptan-5-yl)- l-oxopropan-2- yl)carbamate

[0439]

[0418] A solution of (tert-butoxycarbonyl)-D-alanine (561.6 mg, 2.97 mmol), 7-fluoro-5- azaspiro[2.4]heptane hydrochloride (300.0 mg, 1.98 mmol), 2-(7-azabenzotriazol-l-yl)-A,AA^^V- tetramethyluronium hexafluorophosphate (1.13 g, 2.97 mmol) and A.A-diisopropylcthylaminc (767.2 mg, 5.94 mmol) in dichloromethane (5 mL) was stirred at 25°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford tert-butyl ((2 / ?)- l -(7-fluoro-5-azaspiro|2.4|hcptan-5-yl)- l -oxopropan-2-yl)carbamatc (500.0 mg, 1.75 mmol, 88.2% yield) as a white solid. LC-MS: (ESI, m / z): 287.2 [M+H]+.

[0440]

[0419] Step 2: (2 / ?)-2-amino- l -(7-fluoro-5-azaspiro|2.4|hcptan-5-yl)propan- l -onc hydrochloride

[0441]

[0420] A solution of tert-butyl ((2 / ?)- l -(7-fluoro-5-azaspiro|2.4|hcptan-5-yl)- l -oxopropan- 2-yl)carbamate (500.0 mg, 1.75 mmol) in 4 M hydrochloric acid in 1,4-dioxane (6.0 mL) was stirred at 25°C for 1 hour. After completion, the solvent was removed under vacuum to afford (2R)- 2-amino-l-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)propan-l-one hydrochloride (230.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 187.1 [M+H]+.

[0442]

[0421] Step 3: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-7-fluoro-5- azaspiro [2 ,4]heptan-5 -yl)propan- 1 -one & ( / ) -2 -( ( 5 -(4-chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((R)-7 -fluoro-5 -azaspiro [2 ,4]heptan-5 -yl)propan- 1 -one

[0443]

[0422] To a solution of 5-(4-chlorophcnyl)- l .3.4-oxadiazol-2(3 / / )-onc (100.0 mg, 0.51 mmol) and (2 / ?)-2-amino-l -(7-fliioro-5-azaspiro|2.4|hcptan-5-yl)propan- l -onc hydrochloride (226.6 mg, crude) in AA'-dimcthylfonnamidc (1 mL) was added A.A-diisopropylcthylaminc (394.4 mg, 3.05 mmol) and lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (674.9 mg, 1.53 mmol). The mixture was stirred at 25° C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 : 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26%B to 46%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.27 to afford the product. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: Chiralcel OD-H, 4.6*250mm, 5um; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RTl(min): 18.643; RT2(min): 23.91; Sample Solvent: EtOH; Injection Volume: 0.5 mL to afford (R)-2-((5-(4-chlorophenyl)-

[0444] 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((<S)-7 -fluoro-5 -azaspiro [2 ,4]heptan-5 -yl)propan- 1 -one (34.9 mg, 0.09 mmol, 18.5% yield) as a white solid and (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2- yl)amino)-I-((R)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)propan-l-one (22.8 mg, 0.06 mmol, 12.3% yield) as a white solid.

[0445]

[0423] Example 44a: (R)-l-((S)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0446]

[0424] Example 44b: ( / ?)- l -(( / ?)-7-fluoro-5-azaspiro|2.4|hcptan-5-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0447]

[0425] To a solution of (2R)-2-amino-l-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)propan-l-one hydrochloride (247.2 mg, 1.11 mmol) and 5-(4-fltiorophcnyl)- l .3.4-oxadiazol-2(3 / / )-onc (100.0 mg, 0.56 mmol) in '.A-dimcthylfonnamidc (2 mL) was added '. '-diisopropylcthylaminc (430.5 mg, 3.33 mmol) and lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (736.6 mg, 1.67 mmol). The mixture was stirred at 25°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 21%B to 41%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.02. The product was purified by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% DEA)— HPLC, Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient: isocratic 7; Wave Length: 220 / 254 nm; RTl(min): 26.037; RT2(min): 31.721; Sample Solvent: EtOH; Injection Volume: 0.5 mL to afford (R)-I-((S)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((5-(4- fluorophenyl)-I,3,4-oxadiazol-2-yl)amino)propan-I-one (31.9 mg, 0.09 mmol, 16.3% yield) as a white solid and ( / ?)- l -(( / ?)-7-fhioro-5-azaspiro|2.4|hcptan-5-yl)-2-((5-(4-fluorophcnyl)- l .3.4- oxadiazol-2-yl)amino)propan-I-one (25.2 mg, 0.07 mmol, 12.9% yield) as a white solid.

[0448]

[0426] Example 45: (2R,3S)-2-((5-(4-chlorophenyl)-I,3,4-oxadiazol-2-yl)amino)-3- hydroxy- 1 -(5 -azaspiro [2.4]heptan-5 -yl)butan- 1 -one

[0449]

[0427] Step 1: tert-butyl ((2 / .3.S)-3-hydroxy- l -oxo- l -(5-azaspiro|2,4|hcptan-5-yl)butan-2- yl)carbamate

[0450]

[0428] A solution of 5-azaspiro[2.4]heptane hydrochloride (480 mg, 3.61 mmol), (tert- butoxycarbonyl)- / )-thrconinc (1.17 g, 5.35 mmol), AA'-diisopropylcthylaminc (1.85 g, 14.38 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A. ". A'-tctramcthyluroniiim hexafluorophosphate (2.05 g, 5.38 mmol) in dichloromethane (5 m ) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford tert-butyl ((2 / ?.3.S)-3-hydroxy- l-oxo- l -(5-azaspiro|2.4|hcptan-5-yl)butan-2-yl)carbamatc (900.0 mg, 3.02 mmol, 83.7% yield) as a yellow oil. LC-MS: (ESI, z): 299.2 [M+H]+.

[0451]

[0429] Step 2: (2 / ?.3.S)-2-amino-3-hydroxy- l -(5-azaspiro|2,4|hcptan-5-yl)butan- l -onc hydrochloride

[0452]

[0430] A solution of tert-butyl ((2 / ?.3.S)-3-hydroxy- l -oxo- l -(5-azaspiro|2,4|hcptan-5- yl)butan-2-yl)carbamate (600.0 mg, 2.01 mmol) in 4 M hydrochloride acid in 1,4-dioxane (10 mb) was stirred at 25° C for 2 hours. After completion, the solvent was removed under vacuum to afford (2 / ?.3.S)-2-amino-3-hydroxy- l -(5-azaspiro|2.4|hcptan-5-yl)butan- l -onc hydrochloride (500.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, z): 199.1 [M+H]+.

[0453]

[0431] Step 3: (27?,35)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-3-hydroxy-l-

[0454] (5 -azaspiro [2 ,4]heptan-5 -yl)butan- 1 -one

[0432] A solution of (2 / ?.3.S)-2-amino-3-hydroxy- l -(5-azaspiro|2,4|hcptan-5-yl)butan- l - one hydrochloride (60.5 mg, crude), 5-(4-chlorophenyl)-3H-l,3,4-oxadiazol-2-one (42.5 mg, 0.22 mmol), A.A-diisopropylcthylaminc (113.6 mg, 0.88 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (115.0 mg, 0.26 mmol) in dichloromethane (1 mL) was stirred at 25° C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford (2 / ?.3.S)-2-((5-(4-chlorophcnyl)- l.3.4-oxadiazol-2- yl)amino)-3 -hydroxy- 1 -(5 -azaspiro [2.4]heptan-5-yl)butan-l -one (37.0 mg, 0.10 mmol, 44.6% yield) as a white solid. LC-MS: (ESI, m / z . 377.1 [M+H]+.

[0455]

[0433] Example 46: (27?,37?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-3- hydroxy- 1 -(5 -azaspiro [2.4]heptan-5 -yl)butan- 1 -one

[0456]

[0434] Step 1: tert-butyl ((2 / ?.3 / ?)-3-hydroxy- l -oxo- l -(5-azaspiro|2.4|hcptan-5- l)butan- 2-yl)carbamate

[0457]

[0435] A solution of 5-azaspiro[2.4]heptane hydrochloride (500.0 mg, 3.76 mmol), (tert- biitoxycarbonyl)- / )-allothrconinc (823.5 mg, 3.76 mmol), N, A-diisopropylcthylaminc (1.94 g, 15.03 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A. A". A'-tctramcthyluroniiimhcxafliiorophosphatc (2.14 g, 5.63 mmol) in dichloromethane (5.0 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford tert-butyl ((2 / ?.3 / ?)-3-hydroxy- l -oxo- l -(5-azaspiro|2.4|hcptan-5-yl)butan-2-yl)carbamatc (1.00 g, 3.35 mmol, 89.2% yield) as a pink solid. LC-MS: (ESI, m z):299.2 [M+H]+.

[0458]

[0436] Step 2: (2 / ?.3 / ?)-2-amino-3-hydroxy- l -(5-azaspiro|2.4|hcptan-5-yl)butan- l -onc hydrochloride

[0459]

[0437] A solution of tert-butyl ((2R,3R)-3-hydroxy-l-oxo-l-(5-azaspiro[2.4]heptan-5- yl)butan-2-yl)carbamate (200.0 mg, 0.67 mmol) in 4 M hydrochloric acid in 1,4-dioxane (5 mL) was stirred at 25 °C for 1.5 hours. After completion, the reaction solution was concentrated under vacuum to afford (2 / ?.3 / ?)-2-amino-3 -hydroxy- 1 -(5 -azaspiro [2.4]heptan-5-yl)butan-l -one hydrochloride (200 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z : 199.1 [M+H]+.

[0460]

[0438] Step 3: (27?,37?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-3-hydroxy-l- (5 -azaspiro [2 ,4]heptan-5 -yl)butan- 1 -one

[0461]

[0439] A solution of (2 / ?.3 / ?)-2-amino-3-hydroxy- l -(5-azaspiro|2.4|hcptan-5-yl)butan- l - one hydrochloride (200.0 mg, crude), 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(327)-one (84.0 mg, 0.43 mmol), A. '-diisopropylcthylaminc (441.9 mg, 3.42 mmol) and IH-bcnzotriazol- l- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (566.6 mg, 1.28 mmol) in N,N- dimethylformamide (5.0 mL) was stirred at 25 °C for 0.5 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the product. The product was further purified by Prep-HPLC with the following conditions. Column: Xselect CSH C18 OBD Column 30*150mm 5pm, n; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Plow rate: 60 mL / min; Gradient: 33% B to 59% B in 9 min, 59% B; Wave Length: 254 / 220 nm; RTl(min): 8.18 to afford (2 / ?.3 / ?)-2-((5-(4-chlorophcnyl)- l .3.4- oxadiazol-2-yl)amino)-3-hydroxy-l-(5-azaspiro[2.4]heptan-5-yl)butan-l-one (38.5 mg, 0.10 mmol, 11.9% yield) as white solid. LC-MS: (ESI, m / z) :377.1[M+H]+.

[0462]

[0440] Example 47: ( / ?)-2-((5-(3.4-difluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -(5- azaspiro [2.4]heptan-5 -yl)propan- 1 -one

[0463]

[0442] Under nitrogen, a solution of methyl 3,4-difluorobenzoate (1.00 g, 5.81 mmol) and hydrazinium hydroxide solution (4 mL) in methyl alcohol (10 mL) was stirred at 25° C for 1.5 hours. After completion, the mixture was added into water. The solids were filtered, washed with water and dried under vacuum to afford 3,4-difluorobenzohydrazide (1.00 g, 5.81 mmol, 99% yield) as a white solid. LC-MS: (ESI, z): 173.0 [M+H]+.

[0464]

[0443] Step 2: 5-(3,4-difluorophenyl)-l,3,4-oxadiazol-2(327)-one

[0465]

[0444] To a solution of 3,4-difluorobenzohydrazide (320.0 mg, 1.86 mmol) in tetrahydrofuran (5 mL) was added triethylamine (564.3 mg, 5.58 mmol) and 1,1'- carbonyldiimidazole (904.3 mg, 5.58 mmol). The mixture was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:9) to afford 5-(3,4-difluorophenyl)-l,3,4- oxadiazol-2(327)-one (340.0 mg, 1.63 mmol, 87.7% yield) as a white solid. LC-MS: (ESI, m z): l 99.0| M+H| .

[0466]

[0445] Step 3: (7?)-2-((5-(3,4-difluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(5- azaspiro [2.4]heptan-5 -yl)propan- 1 -one

[0467]

[0446] A solution of 5-(3,4-difluorophenyl)-l,3,4-oxadiazol-2(3E7)-one (70.0 mg, 0.35 mmol), (7?)-2-amino-l-(5-azaspiro[2.4]heptan-5-yl)propan-l-one hydrochloride (108.1 mg, 0.52 mmol), lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (234.0 mg, 0.53 mmol) and '. A'-diisopropylcthylaminc (228.3 mg, 1.77 mmol) in N, A'-dimcthylformamidc (3 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography on Cl 8 gel (acetonitrile / 0. 1% ammonium bicarbonate in water) to afford the product. The product was further purified by Prep-HPLC with the following conditions. Column: Xselect CSH C18 OBD Column 30*150mm 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 59% B in 9 min, 59% B; Wave Length: 254 / 220 nm; RTl(min): 8.18 to afford ( / ?)-2-((5-(3.4-difluorophcnyl)- l .3.4-oxadiazol-2- yl)amino)-l-(5-azaspiro[2.4]heptan-5-yl)propan-l-one (32.3 mg, 0.09 mmol, 26.2% yield) as a white solid. LC-MS: (ESI, m z):349. 1 | M+H| .

[0468]

[0447] Example 48: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-3- methoxy-2-methylazetidin- 1 -yl)propan- 1 -one

[0469]

[0448] Step 1: tert-butyl (2.S'.3.S)-3-mcthoxy-2-mcthylazctidinc- 1 -carboxylate

[0470]

[0449] To a solution of tert-butyl (2.S'.3.S)-3-hydroxy-2-mcthylazctidinc- 1 -carboxylate (440.0 mg, 2.35 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (187.9 mg, 4.70 mmol, 60% dispersion in mineral oil) and stirred at 0°C for 10 minutes. lodomethane (667.0 mg, 4.70 mmol) was then added and stirred at 25° C for 1 hour. After completion, the resulting solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (2.S'.3.S)-3-mcthoxy-2-mcthylazctidinc- 1-carboxylate (410.0 mg, 1.83 mmol, 78.0% yield) as a colorless oil. LC-MS: (ESI, m / z): 202.1 [M+H]+.

[0471]

[0450] Step 2: (2.S'.3.S)-3-mcthoxy-2 -methylazetidine trifluoroacetate

[0472]

[0451] A solution of tert-butyl (2S,3S)-3-methoxy-2 -methylazetidine- 1 -carboxylate (140.0 mg, 0.70 mmol) in dichloromethane (3 m ) and trifluoroacetic acid (1 m ) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2.S'.3.S)-3-mcthoxy-2- methylazetidine trifluoroacetate (140 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. EC-MS: (ESI, m / z): 102. 1 [M+H]+.

[0473]

[0452] Step 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-3- methoxy-2-methylazetidin- 1 -yl)propan- 1 -one

[0474]

[0453] To a solution of (2.S'.3.S)-3-mcthoxy-2 -methylazetidine trifluoroacetate (140.0 mg, crude) and (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (125.0 mg, 0.47 mmol) in dichloromethane (3 mb) was added A.A-diisopropylcthylaminc (301.7 mg, 2.33 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (445.7 mg, 0.70 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4- oxadiazol-2-yl)amino)- l -((2.S'.3.S)-3-mcthoxy-2-mcthylazctidin- l -yl)propan- l -onc (29.6 mg, 0.08 mmol, 18.0% yield) as a white solid. LC-MS: (ESI, m / z): 351.1 [M+H]+.

[0475]

[0454] Example 49: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2.S'.3.S)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0476] Synthetic Route

[0477]

[0455] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (80.0 mg, 0.30 mmol) and (2S,3S)-2-methyl-3-(trifluoromethoxy)pyrrolidine hydrochloride (92.2 mg, 0.45 mmol) in dichloromethane (2 mL) was added '. '-di isopropyl ethylamine (193.1 mg, 1.49 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (285.3 mg, 0.45 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2S,3S)-2 -methyl -3 -(trifluoromethoxy )pyrrolidin- 1 - yl)propan-l-one (23.6 mg, 0.06 mmol, 18.8% yield) as a white solid. LC-MS: (ESI, m / z): 419.1 [M+H]+.

[0478]

[0456] Example 50a: (J?)-l-((lS,5J?)-2-azabicyclo[3.1.0]hexan-2-yl)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0479]

[0457] Example 50b: (J?)-l-((17?,5S)-2-azabicyclo[3.1.0]hexan-2-yl)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0480] Synthetic Route

[0481]

[0458] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (190.0 mg, 0.71 mmol) and 2-azabicyclo[3.1.0]hexane hydrochloride (127.3 mg, 1.06 mmol) in dichloromethane (2 mL) was added W-diisopropylcthylaminc (458.7 mg, 3.55 mmol), and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (677.5 mg, 1.06 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IJ 2*25 cm, 5 pm; Mobile Phase A: MTBE(0.5% 2M NHs-MeOH), Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RTl(min): 8.984; RT2(min): 11.225; Sample Solvent: EtOH; Injection Volume: 0.5 mL to afford (R)-l-((lS,5R)-2- azabicyclo[3.1.0]hexan-2-yl)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one (22.4 mg, 0.07 mmol, 9.4% yield) as a white solid and (R)-l-((lR,5S)-2-azabicyclo[3.1.0]hexan-2- yl)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one (29.2 mg, 0.09 mmol, 12.3% yield) as a white solid. LC-MS: (ESI, m / z): 333.0 [M+H]+.

[0482]

[0459] Example 51: ( / ?)-2-((5-(4-fliiorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2S'.3 / ?)-2- methyl-3 -(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0483]

[0460] Step 1: tert-butyl (2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc- 1 -carboxylate

[0484]

[0461] Under nitrogen, to a mixture of silver trifluoromethanesulfonate ( 1.73 g, 6.71 mmol), potassium fluoride (577.2 mg, 9.94 mmol) and 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1.32 g, 3.73 mmol) in ethyl acetate (5 mL) was slowly added a solution of tert-butyl (2.S'.3 / ?)-3-hydroxy-2-mcthylpyrrolidinc- 1 -carboxylate (500.0 mg, 2.48 mmol) in ethyl acetate (5 mL) at 0 °C. Then 2-fluoropyridine (723.5 mg, 7.45 mmol) and (trifluoromethyl)trimethylsilane (1.06 g, 7.45 mmol) was added dropwise at 0 °C and stirred at 25 °C overnight. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (2.S'.3 / ?)-2-mcthyl-3- (trifluoromethoxy)pyrrolidine-l -carboxylate (130.0 mg, 0.43 mmol, 17.5% yield) as a colorless oil LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0485]

[0462] Step 2: (2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc hydrochloride

[0486]

[0463] A solution of tert-butyl (2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc-l- carboxylate (130.0 mg, 0.48 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2S,3R)-2- methyl-3-(trifluoromethoxy)pyrrolidine hydrochloride (100.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 170.1 [M+H]+.

[0464] Step 3: tert-butyl (( / ?)- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l -yl)- l- oxopropan-2-yl)carbamate

[0487]

[0465] A solution of (2S,3J?)-2-methyl-3-(trifluoromethoxy)pyrrolidine hydrochloride (100.0 mg, crude), (2 / ?)-2-( / crt-biitoxycarbonylamino)propanoic acid (92.0 mg, 0.49 mmol), N,N- diisopropylethylamine (314.3 mg, 2.43 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A.A- tetramethyluronium hexafluorophosphate (240.4 mg, 0.63 mmol) in A.A-dimcthylfonnamidc (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford tert-butyl (( / ?)- 1 -((25,3 R)-2 -methyl -3 -(trifluoromethoxy )pyrrolidin- 1 -yl)- 1 -oxopropan-2- yl)carbamate (110.0 mg, 0.30 mmol, 63.1% yield) as a yellow oil. LC-MS: (ESI, m / z): 341.2 [M+H]+.

[0488]

[0466] Step 4: ( / ?)-2-amino- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)propan-l-one hydrochloride

[0489]

[0467] A solution of tert-butyl (( / ?)- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)-l-oxopropan-2-yl)carbamate (110.0 mg, 0.32 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (R)-2 -amino- 1 -((2.S'.3 / ?)-2-mcthy I -3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one hydrochloride (75.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1 [M+H]+.

[0490]

[0468] Step 5: (J?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3J?)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0491]

[0469] A solution of ( / ?)-2-amino- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)propan-l-one hydrochloride (75.0 mg, crude), 5-(4-fluorophcnyl)-3H- l .3.4-oxadiazol-2-onc (45.6 mg, 0.25 mmol), A.A-diisopropylcthylaminc (129.2 mg, 1.26 mmol) and IH-bcnzotriazol-l - yloxytris(dimethylamino)phosphonium hexafluorophosphate (145.4 mg, 0.33 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4-fluorophcnyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3 / ?)-2-mcthy I -3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 - one (27.7 mg, 0.07 mmol, 27.2% yield) as a white solid. LC-MS: (ESI, m / z): 403.1 [M+H]+.

[0492]

[0470] Example 52: ( / ?)-2-((5-(4-fliiorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2S'.3.S)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0493]

[0471] Step 1: tert-butyl (2.S'.3.S')-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc- 1 -carboxylate

[0494]

[0472] Under nitrogen, to a mixture of silver trifluoromethanesulfonate ( 1.73 g, 6.71 mmol), potassium fluoride (577.3 mg, 9.94 mmol), and 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1.32 g, 3.73 mmol) in ethyl acetate (5 mL) was slowly added a solution of tert-butyl (2.S'.3.S')-3-hydroxy-2-mcthylpyrrolidinc- 1 -carboxylate (500.0 mg, 2.48 mmol) in ethyl acetate (5 mL) at 0 °C. Then 2-fluoropyridine (723.6 mg, 7.45 mmol) and (trifluoromethyl)trimethylsilane (1.06 g, 7.45 mmol) was added dropwise at 0 °C and stirred at 25 °C overnight. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (2.S'.3.S')-2-mcthyl-3- (trifluoromethoxy)pyrrolidine-l -carboxylate (130.0 mg, 0.43 mmol, 17.5% yield) as a colorless oil LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0495]

[0473] Step 2: (2.S'.3.S')-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc hydrochloride

[0496]

[0474] A solution of tert-butyl (2.S'.3.S')-2-mcthyl-3-(trifluoromcthoxy)pyrrolidinc-l- carboxylate (130.0 mg, 0.48 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2S,35)-2- methyl-3-(trifluoromethoxy)pyrrolidine hydrochloride (100 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 170.1 [M+H]+.

[0475] Step 3: tert-butyl (( / ?)- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l -yl)- l - oxopropan-2-yl)carbamate

[0497]

[0476] A solution of (2.S',3.S')-2-mcthyl-3 -(trifluoromethoxy )pyrrolidine hydrochloride (100.0 mg, crude), (27?)-2-(tert-butoxycarbonylamino)propanoic acid (92.0 mg, 0.49 mmol), N,N- diisopropylethylamine (314.3 mg, 2.43 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A.A- tetramethyluronium hexafluorophosphate (240.4 mg, 0.63 mmol) in AA'-dimcthylfonnamidc (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) (1: 1) to afford tert-butyl (( / ?)- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l -yl)- l -oxopropan-2- yl)carbamate (110.0 mg, 0.30 mmol, 63.1% yield) as a yellow oil. LC-MS: (ESI, m / z): 341.2 [M+H]+.

[0498]

[0477] Step 4: ( / ?)-2-amino- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)propan-l-one hydrochloride

[0499]

[0478] A solution of tert-butyl (( / ?)- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l- yl)-l-oxopropan-2-yl)carbamate (110.0 mg, 0.32 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mL) was stirred at 25 °C for 1 hours. After completion, the solvent was removed under vacuum to afford (7?)-2 -amino- 1 -((2.S'.3.S)-2-mcthy l-3-(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one hydrochloride (75.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1 [M+H]+.

[0500]

[0479] Step 5: ( / ?)-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)- l -((2.S'.3.S)-2- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0501]

[0480] A solution of ( / ?)-2-amino- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- l - yl)propan-l-one hydrochloride (75.0 mg, crude), 5-(4-fluorophcnyl)-3H- l .3.4-oxadiazol-2-onc (48.8 mg, 0.27 mmol), / V, / V-diisopropylethylamine (175.2 mg, 1.36 mmol) and IH-bcnzotriazol-l - yloxytris(dimethylamino)phosphonium hexafluorophosphate (155.8 mg, 0.35 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4-fluorophcnyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3.S)-2-mcthy I -3 -(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one (26.0 mg, 0.06 mmol, 23.5% yield) as a white solid. LC-MS: (ESI, m / z): 403.1 [M+H]+.

[0502]

[0481] Example 53: (J?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3J?)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0503] Synthetic Route

[0504]

[0482] A solution of ( / ?)-2-amino- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)propan-l-one hydrochloride (65.0 mg, crude), 5-(4-fluorophenyl)-3H-l,3,4-oxadiazol-2-one (51.8 mg, 0.29 mmol), A.A-diisopropylcthylaminc (185.6 mg, 1.44 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (152.5 mg, 0.34 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4-fluorophcnyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3 / ?)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one (20.2 mg, 0.05 mmol, 18.1% yield) as a white solid. LC-MS: (ESI, m / z): 389.1 [M+H]+.

[0505]

[0483] Example 54: (J?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0506] Synthetic Route

[0507]

[0484] A solution of 5-(4-fluorophenyl)-l,3,4-oxadiazol-2(3E7)-one (47.7 mg, 0.27 mmol), (R)-2 -amino- 1 -((2.S'.3.S')-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one hydrochloride (60.0 mg, 0.23 mmol), AA'-diisopropylcthylaminc (171.4 mg, 1.33 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (152.5 mg, 0.34 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography on Cl 8 gel (acetonitrile / 0.1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4- fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3.S)-2-mcthyl-3 -(trifhioromethoxy)azetidin- 1 - yl)propan-l-one (36.8 mg, 0.09 mmol, 35.5% yield) as a white solid. LC-MS: (ESI, m / z): 389.1 [M+H]+.

[0508]

[0485] Example 55: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((27?,37?)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0509] Synthetic Route

[0510]

[0486] A solution of ( / ?)-2-amino- l -((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)propan-l-one hydrochloride (70.0 mg, crude), 5-(4-fluorophcnyl)- l .3.4-oxadiazol-2(3 / / )-onc (48.0 mg, 0.27 mmol), AA'-diisopropylcthylaminc (172.2 mg, 1.33 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (153.2 mg, 0.35 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography on Cl 8 gel (acetonitrile / 0.1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4- fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2 / ?.3 / ?)-2-mcthyl-3 -(trifluoromethoxy)azetidin- 1 - yl)propan-l-one (27.5 mg, 0.07 mmol, 26.5 % yield) as a white solid. LC-MS: (ESI, m / z): 389.1 [M+H]+.

[0511]

[0487] Example 56: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2S'.3,S)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0512]

[0488] Step 1: tert-butyl (2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidinc- 1 -carboxylate

[0513]

[0489] Under nitrogen, to a mixture of silver trifluoromethanesulfonate (3.91 g, 15.14 mmol), potassium fluoride (1.30 g, 22.43 mmol) and 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (2.98 g, 8.41 mmol) in ethyl acetate (5 mb) was slowly added a solution of tert-butyl (2S,3S)-3 -hydroxy-2 -methylazetidine- 1 -carboxylate (1.05 g, 5.61 mmol) in ethyl acetate (5 mb) at 0 °C. Then, 2-fluoropyridine (1.63 g, 16.82 mmol) and (trifluoromethyl)trimethylsilane (2.39 g, 16.82 mmol) was added dropwise at 0 °C and stirred at 25 °C overnight. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (2.S'.3.S)-2-mcthyl-3- (trifluoromethoxy)azetidine-l -carboxylate (300.0 mg, 1.06 mmol, 17.5% yield) as a colorless oil. LC-MS: (ESI, m / z): 256.1 [M+H]+.

[0514]

[0490] Step 2: (2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidinc hydrochloride

[0515]

[0491] A solution of tert-butyl (2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidinc- l - carboxylate (300.0 mg, 1.18 mmol) in 4 M hydrochloric acid in 1,4-dioxane (6 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2S,35)-2- methyl-3-(trifluoromethoxy)azetidine hydrochloride (220.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 156. 1 [M+H]+.

[0492] Step 3: tert-butyl (( / ?)- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l -yl)- l - oxopropan-2-yl)carbamate

[0516]

[0493] A solution of (2S,3S)-2-methyl-3-(trifluoromethoxy)azetidine hydrochloride (220.0 mg, crude), (2 / ?)-2-( / crt-biitoxycarbonylamino)propanoic acid (217.2 mg, 1.15 mmol), N,N- diisopropylethylamine (742.0 mg, 5.74 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A.A- tetramethyluronium hexafluorophosphate (567.6 mg, 1.49 mmol) in AA'-dimcthylfonnamidc (5 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% NH4HCO3 in water) to afford tert-butyl (( / ?)- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l-yl)- l - oxopropan-2-yl)carbamate (250.0 mg, 0.68 mmol, 60.0% yield) as a yellow oil. LC-MS: (ESI, m / z): 327.1 [M+H]+.

[0517]

[0494] Step 4: ( / ?)-2-amino- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l -yl)propan- 1-one hydrochloride

[0518]

[0495] A solution of tert-butyl (( / ?)- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)-l-oxopropan-2-yl)carbamate (69.0 mg, 0.21 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (7?)-2 -amino- 1 -((2.S'.3.S)-2-mcthy l-3-(trifluoromethoxy )azetidin- 1 -yl)propan- 1 -one hydrochloride (50 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 227.1 [M+H]+.

[0519]

[0496] Step 5: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0520]

[0497] A solution of ( / ?)-2-amino- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)propan-l-one hydrochloride (50.0 mg, crude), 5-(4-fluorophcnyl)-3H- l .3.4-oxadiazol-2-onc (43.4 mg, 0.22 mmol), / V, / V-diisopropylethylamine (142.8 mg, 1.11 mmol) and IH-bcnzotriazol-l - yloxytris(dimethylamino)phosphonium hexafluorophosphate (127.0 mg, 0.29 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4- chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((2.S'.3.S)-2-mcthyl-3-(trifluoromcthoxy)azctidin- 1- yl)propan-l-one (25.0 mg, 0.06 mmol, 27.9% yield) as a white solid. LC-MS: (ESI, m / z): 405.1 [M+H]+.

[0498] Example 57: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,37?)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0521]

[0499] Step 1: tert-butyl (2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidinc- 1 -carboxylate

[0522]

[0500] Under nitrogen, to a mixture of silver trifluoromethanesulfonate (3.72 g, 14.42 mmol), potassium fluoride (1.24 g, 21.36 mmol), and 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (2.84 g, 8.01 mmol) in ethyl acetate (5 m ) was slowly added a solution of tert-butyl (2.S'.3 / ?)-3-hydroxy-2-mcthylazctidinc- 1 -carboxylate (1.00 g, 5.34 mmol) in ethyl acetate (7 m ) at 0 °C. Then 2-fluoropyridine (1.56 g, 16.02 mmol) and (trifluoromethyl)trimethylsilane (2.28 g, 16.02 mmol) was added dropwise at 0 °C and the mixture was stirred at 25 °C overnight. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (2.S'.3 / ?)-2-mcthyl-

[0523] 3 -(trifluoromethoxy)azetidine- 1 -carboxylate (500.0 mg, 1.76 mmol, 33.0% yield) as a colorless oil. EC-MS: (ESI, m / z): 256.1 [M+H]+.

[0524]

[0501] Step 2: (2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidinc hydrochloride

[0525]

[0502] A solution of tert-butyl (2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidinc- l - carboxylate (500.0 mg, 1.96 mmol) in 4 M hydrochloric acid in 1,4-dioxane (10 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2S,37?)-2- methyl-3-(trifluoromethoxy)azetidine hydrochloride (410 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 156. 1 [M+H]+.

[0526]

[0503] Step 3: tert-butyl (( / ?)- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l -yl)- l - oxopropan-2-yl)carbamate

[0527]

[0504] A solution of (2S,3J?)-2-methyl-3-(trifluoromethoxy)azetidine hydrochloride (410.0 mg, crude), (2 / ?)-2-( / / 7-biitoxycarbonylamino)propanoic acid (500.1 mg, 2.64 mmol), N,N- diisopropylethylamine (1.71 g, 13.22 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A'.A'- tetramethyluronium hexafluorophosphate (1.31 g, 3.44 mmol) in A. A-di meth l form am ide (6 m ) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% NH4HCO3 in water) to afford tert-butyl (( / ?)- 1 -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- 1 -yl)- 1 - oxopropan-2-yl)carbamate (550.0 mg, 1.52 mmol, 57.4% yield) as a yellow oil. LC-MS: (ESI, m / z): 327.1 [M+H]+.

[0528]

[0505] Step 4: ( / ?)-2-amino- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l- yl)propan-l-one hydrochloride

[0529]

[0506] A solution of tert-butyl (( / ?)- l -((2.S'.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- 1 - yl)-l-oxopropan-2-yl)carbamate (67.0 mg, 0.21 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (R)-2 -amino- 1 -((2.S'.3 / ?)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one hydrochloride (50 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 227.1 [M+H]+.

[0530]

[0507] Step 5: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3J?)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0531]

[0508] A solution of (J?)-2-amino-l-((2S,3J?)-2-methyl-3-(trifluoromethoxy)azetidin-l- yl)propan-l-one hydrochloride (50.0 mg, crude), 5-(4-fluorophenyl)-3H-l,3,4-oxadiazol-2-one (52.1 mg, 0.27 mmol), A.A-diisopropylcthylaminc (171.4 mg, 1.33 mmol) and IA-bcnzotriazol-1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (140.8 mg, 0.32 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography on Cl 8 gel (acetonitrile / 0.1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.3 / ?)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 - yl)propan-l-one (24.8 mg, 0.06 mmol, 23.0% yield) as a white solid. LC-MS: (ESI, m / z): 405.1 [M+H]+.

[0532]

[0509] Example 58: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2J?,3J?)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0533]

[0510] Step 1: tert-butyl (2 / ?.3 / ?)-2-mcth l -3 -(trifluoromcthoxy)azctidinc- 1 -carbox late

[0534]

[0511] Under nitrogen, to a mixture of silver trifluoromethanesulfonate (3.72 g, 14.42 mmol), potassium fluoride (1.24 mg, 21.36 mmol), and 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (2.84 g, 8.01 mmol) in ethyl acetate (8 mb) was slowly added a solution of tert-butyl (2 / ?.3 / ?)-3-hydroxy-2-mcthylazctidinc- 1 -carboxylate (1.00 g, 5.34 mmol) in ethyl acetate (8 mb) at 0 °C. Then 2-fluoropyridine (1.56 g, 16.02 mmol) and (trifluoromethyl)trimethylsilane (2.28 g, 16.02 mmol) was added dropwise sequentially. The reaction mixture was stirred at 25 °C overnight. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (2J?,3J?)-2-methyl-3-(trifluoromethoxy)azetidine-l-carboxylate (300.0 mg, 1.06 mmol, 19.8 % yield) as a colorless oil. LC-MS: (ESI, m / z): 256.1 [M+H]+.

[0535]

[0512] Step 2: (2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidinc hydrochloride

[0536]

[0513] A solution of tert-butyl (2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidinc- 1 - carboxylate (300.0 mg, 1.18 mmol) in 4 M hydrochloric acid in 1,4-dioxane (5 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2R,3R)-2- methyl-3-(trifluoromethoxy)azetidine hydrochloride (220 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 156. 1 [M+H]+.

[0537]

[0514] Step 3 : tert-butyl (( / ?)- I -((2 / ?.3 / ?)-2-mcth l -3-(trifluoromcthoxy)azctidin- 1 -yl)- 1 - oxopropan-2-yl)carbamate

[0538]

[0515] A solution of (2R,3R)-2 -methyl -3-(trifluoromethoxy)azetidine hydrochloride (220.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (217.3 mg, 1.15 mmol), A.A-diisopropylcthylaminc (742.0 mg, 5.74 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A'.A'-tctramcthyluroniiim hexafluorophosphate (567.6 mg, 1.49 mmol) in A.A-dimcthylfonnamidc (3 m ) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on Cl 8 gel (acetonitrile / 0. 1% NH4HCO3 in water) to afford tertbutyl (( )- 1 -((27?, 3R)-2 -methyl -3-(trifluoromethoxy)azetidin- 1 -yl)- 1 -oxopropan-2-yl)carbamate (280.0 mg, 0.77 mmol, 67.2% yield) as a yellow oil. LC-MS: (ESI, m / z): 327. 1 [M+H]+.

[0539]

[0516] Step 4: (7?)-2-amino- l -((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- l - yl)propan-l-one hydrochloride

[0540]

[0517] A solution of tert-butyl (( / ?)- 1 -((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)azctidin- 1 - yl)-l-oxopropan-2-yl)carbamate (90.0 mg, 0.32 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (R)-2 -amino- 1 -((2 / ?.3 / ?)-2-mcth l-3-(trifluoromcthoxy)azctidin- 1 -yl)propan- 1 -one hydrochloride (60.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 227.1 [M+H]+.

[0541]

[0518] Step 5: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((27?,37?)-2- methyl-3 -(trifluoromethoxy)azetidin- 1 -yl)propan- 1 -one

[0542]

[0519] A solution of (7?)-2-amino- 1 -((2 / ?.3 / ?)-2-mcthyl-3-(trifluoromcthoxy)pyrrolidin- 1 - yl)propan-l-one hydrochloride (60.0 mg, crude), 5-(4-fluorophcnyl)-3 / 7- l .3.4-oxadiazol-2-onc (44.9 mg, 0.23 mmol), A.A-diisopropylcthylaminc (147.6 mg, 1.14 mmol) and 177-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (131.3 mg, 0.30 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography on Cl 8 gel (acetonitrile / 0.1% NH4HCO3 in water) to afford (7?)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2 / ?.37?)-2-mcthy I -3 -(trifluoromethoxy)azetidin- 1 - yl)propan-l-one (25.5 mg, 0.06 mmol, 27.6 % yield) as a white solid. LC-MS: (ESI, m / z): 405.1 [M+H]+.

[0543]

[0520] Example 59: ( / ?)-2-((5-(4-chlorophcnyl)-l.3.4-oxadiazol-2-yl)amino)-l-((2.S'.4.S)-2- methyl-4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0544]

[0521] Step 1: tert-butyl (2.S'.4.S)-2-mcthyl-4-(trifluoromcthoxy [pyrrolidine- 1 -carboxylate

[0545]

[0522] Under nitrogen, to amixture of silver trifluoromethanesulfonate (5.19 g, 20.12 mmol), potassium fluoride (1.73 g, 29.81 mmol) and 1 -chloromethyl -4-fluoro- 1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (3.96 g, 11.18 mmol) in ethyl acetate (7 mb) was slowly added a solution of tert-butyl (2.S'.4.S)-4-hydroxy-2-mcthylpyrrolidinc-l -carboxylate (1.50 g, 7.45 mmol) in ethyl acetate (7 mb) at 0 °C. Then 2-fluoropyridine (2.17 g, 22.36 mmol) and (trifluoromethyl)trimethylsilane (3.18 g, 22.36 mmol) were added dropwise at 0 °C and the mixture was stirred at 25 °C overnight. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl (2.S'.4.S)-2-mcthyl-4-(trifliioromcthoxy)pyrrolidinc-l-carboxylatc (200.0 mg, 0.66 mmol, 9.0 % yield) as a colorless oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0546]

[0523] Step 2: (2.S'.4.S)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidinc hydrochloride

[0547]

[0524] A solution of tert-butyl ( 2.8'.4.S)-2-mcthyl-4-(trifl uoromcthoxy [pyrrolidine- 1 - carboxylate (200.0 mg, 0.74 mmol) in 4 M hydrochloric acid in 1,4-dioxane (5 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2S,45)-2- methyl-4-(trifluoromethoxy)pyrrolidine hydrochloride (120 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 170. 1 [M+H]+.

[0548]

[0525] Step 3: tert-butyl ((7?)- l -((2.S',4.S)-2 -methyl -4-(trifluoromethoxy)pyrrolidin-l-yl)-l- oxopropan-2-yl)carbamate

[0549]

[0526] A solution of (2S,4S)-2-methyl-4-(trifluoromethoxy)pyrrolidine hydrochloride (120.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (134.2 mg, 0.71 mmol), A.A- diisopropylethylamine (458.4 mg, 3.55 mmol) and 2-(7-azabcnzotriazol- l -yl)-A.A.A.A- tetramethyluronium hexafluorophosphate (350.6 mg, 0.92 mmol) in AA'-dimcth lfon amidc (3 m ) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford tert-butyl (( / ?)- 1 -((2.S'.4.S)-2-mcthy l-4-(trifluoromethoxy )pyrrolidin- 1 -yl)- 1 -oxopropan-2- yl)carbamate (150.0 mg, 0.40 mmol, 55.9 % yield) as a yellow oil. LC-MS: (ESI, m / z): 341.2 [M+H]+.

[0550]

[0527] Step 4: (R)-2 -amino- l -((2.S',4.S)-2 -methyl -4-(trifluoromethoxy)pyrrolidin- 1- yl)propan-l-one hydrochloride

[0551]

[0528] A solution of tert-butyl (( / ?)- l -((2.S'.4.S)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidin- l- yl)-l-oxopropan-2-yl)carbamate (65.0 mg, 0.19 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (R)-2 -amino- 1 -((2.S'.4.S)-2-mcth l-4-(trifluoromcthoxy [pyrrol idin- 1 -yl)propan- 1 -one hydrochloride (50.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 241.2 [M+H]+.

[0552]

[0529] Step 5: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,4S)-2- methyl-4-(trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0553]

[0530] A solution of (R)-2 -amino- l -((2.S',4.S)-2 -methyl-4-(trifluoromethoxy)pyrrolidin- 1- yl)propan-l-one hydrochloride (50.0 mg, crude), 5-(4-chlorophcnyl)-3H- l .3.4-oxadiazol-2-onc (35.5 mg, 0.18 mmol), / V, / V-diisopropylethylamine (116.7 mg, 0.90 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (95.9 mg, 0.22 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2.S'.4.S)-2-mcth l -4-(trifl uoromcthoxy [pyrrol idin- 1 - yl)propan-l-one (28.5 mg, 0.06 mmol, 36.5 % yield) as a white solid. LC-MS: (ESI, m / z): 419.1 [M+H]+.

[0554]

[0531] Example 60a: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-2- (difluoromethyl)azetidin- 1 -yl)propan- 1 -one

[0555]

[0532] Example 60b: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((R)-2-

[0556] (difluoromethyl)azetidin- 1 -yl)propan- 1 -one

[0557] Synthetic Route

[0558]

[0533] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (124.0 mg, 0.46 mmol), and 2-(difluoromethyl)azetidine hydrochloride (99.7 mg, 0.69 mmol) in dichloromethane (2 mL) was added W-diisopropylcthylaminc (299.4 mg, 2.32 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (442.2 mg, 0.69 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the product. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: Column: CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NHs-MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RTl(min): 6.771; RT2(min): 12.32; Sample Solvent: EtOH; Injection Volume: 1.0 mL to afford (R)-2-((5-(4- chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((.S)-2-(difl uoromcthy I jazctidin- 1 -yljpropan- 1 -one (25.5 mg, 0.07 mmol, 15.3% yield) as a white solid and (R)-2-((5-(4-chlorophenyl)-l,3,4- oxadiazol-2-yl)amino)- l -(( / ?)-2-(difluoromcthyl)azctidin- l -yl)propan- l -onc (24.3 mg, 0.07 mmol, 14.7% yield) as a white solid.

[0559]

[0534] Example 61: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-2- methyl-3 -(2,2,2-trifluoroethoxy)azetidin- 1 -yl)propan- 1 -one

[0560]

[0535] Step 1: tert-butyl (2S,3S)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidine- 1 -carboxylate

[0561]

[0536] To a solution of tert-butyl (2.S'.3.S)-3-hydroxy-2-mcthylazctidinc- 1 -carboxylate (200.0 mg, 1.07 mmol) in N, A-dimethylformamide (3.0 m ) was added sodium hydride (1.86 g, 3.20 mmol, 60% dispersion in mineral oil) and the mixture was stirred for 10 minutes at 0 °C, then 2,2,2-trifhioroethyhrifhioromethanesulfonate (371.8 mg, 1.60 mmol) was added and stirred at 0 °C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford tertbutyl (2.S'.3.S)-2-mcthyl-3-(2.2.2-trifliiorocthoxy)azctidinc- l -carboxylatc (200.0 mg, 0.74 mmol, 69.2% yield) as a colorless oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0562]

[0537] Step 2: (2S,35)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidine trifluoroacetate

[0538] A solution of tert-butyl (2.S'.3.S)-2-mcthyl-3-(2.2.2-trifluorocthoxy)azctidinc- l - carboxylate (110.0 mg, 0.41 mmol) in dichloromethane (3.0 mb) and trifluoroacetic acid (1.0 mb) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2.S'.3.S)-2-mcthyl-3-(2.2.2-trifluorocthoxy)azctidinc trifluoroacetate (130.0 mg, crude) as a yellow oil. LC-MS: (ESI, m / z): 170.1 [M+H]+.

[0563]

[0539] Step 3: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-2- methyl-3 -(2,2,2-trifluoroethoxy)azetidin- 1 -yl)propan- 1 -one

[0564]

[0540] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (63.0 mg, 0.25 mmol) and (2.S'.3.S)-2-mcthyl-3-(2.2.2-trifluorocthoxy)azctidinc trifluoroacetate (63.6 mg, crude) in dichloromethane(1.0 mb) was added A, A-diisopropylcthylaminc (97.2 mg, 0.75 mmol). Then 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (477.3 mg, 0.75 mmol, 50% in ethyl acetate) was added, and the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (20: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32%B to 50%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 6.48 to afford ( / ?)-2-((5-(4-chlorophcnyl)-l .3.4-oxadiazol-2- yl)amino)-l-((2S,3S)-2-methyl-3-(2,2,2-trifhioroethoxy)azetidin-l-yl)propan-l-one (28.5 mg, 0.07 mmol, 27.1% yield) as a white solid. LC-MS: (ESI, m / z): 419.0 [M+H]+.

[0565]

[0541] Example 62a: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((R)-l- oxa-6-azaspiro[3 ,4]octan-6-yl)propan- 1 -one

[0566]

[0542] Example 62b: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((5)-l- oxa-6-azaspiro[3 ,4]octan-6-yl)propan- 1 -one

[0567] Synthetic Route

[0568]

[0543] To a solution of l-oxa-6-azaspiro[3.4]octane hemioxalate (209.2 mg, 0.68 mmol) and (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (165.0 mg, 0.61 mmol) in dichloromethane (3.0 mL) was added / V, '-diisopropylcthylaminc (239.0 mg, 1.85 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (588.4 mg, 0.92 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (20: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17%B to 37%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.46 to afford the product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: JW-LUX-5UM Cellulose-4, 21.2*250mm, 5um; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 70; Wave Length: 220 / 254 nm; RTl(min): 5.763; RT2(min): 11.202; Sample Solvent: EtOH; Injection Volume: 2.0 mL to afford ( / ?)-2-((5-(4-chlorophcnyl)- 1.3.4-oxadiazol-2-yl)amino)- 1 -(( / ?)- l-oxa-6-azaspiro[3.4]octan-6-yl)propan-l-one (32.8 mg, 0.09 mmol, 14.4% yield) as a white solid and (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-l-oxa-6-azaspiro[3.4]octan-6- yl)propan-l-one (30.6 mg, 0.082 mmol, 13.2% yield) as a white solid. LC-MS: (ESI, m / z): 363.0 [M+H]+.

[0569]

[0544] Example 63a: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-2- isopropylazetidin- 1 -yl)propan- 1 -one

[0570]

[0545] Example 63b: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((R)-2- isopropylazetidin- 1 -yl)propan- 1 -one

[0571]

[0546] To a solution of 2-isopropylazetidine hydrochloride (162.0 mg, 1.19 mmol) and (5- (4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-Z)-alanine (200.0 mg, 0.80 mmol) in dichloromethane (3.0 mL) was added N, / V-diisopropylethylamine (514.5 mg, 3.98 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (760.0 mg, 1.19 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23%B to 43%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 6.98 to afford the product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: Lux 5um Cellulose-4, 2.12*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NI F-McOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RTl(min): 9.025; RT2(min): 12.059; Sample Solvent: EtOH— HPLC; Injection Volume: 1.0 mL to afford (R)-2-((5-(4- fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((.S)-2-i sopropy lazctidin- 1 -yljpropan- 1 -one (21.5 mg, 0.06 mmol, 8.1% yield) as a white solid and (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2- yl)amino)-l-((R)-2-isopropylazetidin-l-yl)propan-l-one (37.6 mg, 0.11 mmol, 14.2% yield) as a white solid.

[0572]

[0547] Example 64a: ( / ?)- l -((.S)-2-cyclopropylazctidin- l -yl)-2-((5-(4-fliiorophcnyl)- l .3.4- oxadiazol-2-yl)amino)propan- 1 -one

[0548] Example 64b: ( / ?)-l-(( / ?)-2-cyclopropylazctidin-l-yl)-2-((5-(4-fluorophcnyl)-l.3.4- oxadiazol-2-yl)amino)propan- 1 -one

[0573]

[0549] To a solution of 2-cyclopropylazetidine hydrochloride (160.0 mg, 1.19 mmol) in dichloromethane was added the solution of (5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (200.0 mg, 0.80 mmol) in dichloromethane (3.0 mL), A, '-diisopropylcthylaminc (308.6 mg, 2.39 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (760.0 mg, 1.19 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25%B to 45%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 7.53 to afford the product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RTl(min): 5.169; RT2(min): 7.128; Sample Solvent: EtOH; Injection Volume: 0.8 mL to afford (R)-l-((S)-2- cyclopropylazetidin- 1 -y 1) -2 -(( 5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one (20.1 mg, 0.06 mmol, 7.6% yield) as a white solid and (R)-l-((R)-2-cyclopropylazetidin-l-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one (40.7 mg, 0.12 mmol, 15.4% yield) as a white solid.

[0574]

[0550] Example 65a: ( / ?)-2-((5-(4-fluorophcnyl)-l.3.4-oxadiazol-2-yl)amino)-l-(( / ?)-4- methyl-5 -azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0551] Example 65b: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-4- methyl-5 -azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0575]

[0552] Step 1: tert-butyl 2-methyl-3-methylenepyrrolidine-l-carboxylate

[0576]

[0553] Under nitrogen, potassium tert-butoxide (19.57 mb, 19.57 mmol, 1.0 M in tetrahydrofuran) were added to a solution of methyltriphenylphosphonium bromide (6.45 g, 18.07 mmol) in diethyl ether (40 mb) at 0 °C, then the temperature was increased to 25 °C and stirred for 2 hours. Then a solution of tert-butyl 2-methyl-3-oxopyrrolidine-l-carboxylate (3.00 g, 15.06 mmol) in diethyl ether (30 mb) was slowly dropped into the reaction mixture at 0 °C for 45 min. Then the temperature was increased to 25 °C and stirred at 25 °C for 2 hours. After completion, the reaction was filtered. The filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (20: 1) to afford the title compound (2.50 g, 12.67 mmol, 84.2% yield) as a colorless oil. EC-MS: (ESI, mlz . 198.1 [M+H]+.

[0577]

[0554] Step 2: tert-butyl 4-methyl-5-azaspiro[2.4]heptane-5-carboxylate

[0578]

[0555] Under nitrogen, diethylzinc (17.24 m , 17.24 mmol, 1.0 M in hexanes) was dissolved in anhydrous dichloromethane (10 m ). The solution was cooled to 0 °C and then a solution of dichloroacetic acid (2.09 g, 16.22 mmol) in dichloromethane (10 mL) was added dropwise over 10 minutes. The solution was stirred at 0 °C for an additional 30 minutes. A solution of diiodomethane (4.34 g, 16.22 mmol) in anhydrous dichloromethane (10 mL) was added dropwise quickly, and the resulting solution was stirred at 0 °C for 30 minutes. After that, a solution of tert-butyl 2-methyl-3-methylenepyrrolidine-l-carboxylate (1.00 g, 5.07 mmol) in anhydrous dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was stirred in a thawing ice bath for 90 hours, then quenched with saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated under vacuum to provide the crude product as a yellow oil. The oil was dissolved in ethyl acetate (20 mL), and di-tert-butyl dicarbonate (1.49 g, 6.84 mmol) and triethylamine (2.31 g, 22.81 mmol) were sequentially added. The reaction mixture was then stirred at room temperature for 2 hours. After completion, the reaction was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (20: 1) to afford the title compound (900.2 mg, 4.26 mmol, 84.0% yield) as a colorless oil. LC-MS: (ESI, z):212.2 [M+H]+.

[0579]

[0556] Step 3: 4-methyl-5-azaspiro[2.4]heptane hydrochloride

[0580]

[0557] A mixture of tert-butyl 4-methyl -5 -azaspiro [2.4] heptane-5 -carboxylate (250.0 mg, 1.2 mmol) in 4 M hydrochloric acid in dioxane (3.0 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford 4-methyl-5-azaspiro[2.4]heptane hydrochloride (174.0 mg, crude) as a white solid. LC-MS: (ESI, m / z): 112.1 [M+H]+.

[0581]

[0558] Step 4: ( / ?)-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)- l -(( / ?)-4-mcthyl-5- azaspiro [2 ,4]heptan-5 -yl)propan- 1 -one & ( / ) -2 -( ( 5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((.S)-4-mcthy I -5 -azaspiro [2 ,4]heptan-5 -yl)propan- 1 -one

[0582]

[0559] To a solution of 4-methyl-5-azaspiro[2.4]heptane hydrochloride (174.0 mg, crude) and (5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (200.0 mg, 0.80 mmol) in dichloromethane (3.0 mL) was added A, A-diisopropylethylamine (308.7 mg, 2.39 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (760.0 mg, 1.19 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP 18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 25%B to 46%B in lOmin; Wave Length: 254 / 220 nm to afford product. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 40; Wave Length: 220 / 254 nm; RTl(min): 8.109; RT2(min): 12.718; Sample Solvent: EtOH; Injection Volume: 1.0 mL to afford (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2- yl)amino)-l-((R)-4-methyl-5-azaspiro[2.4]heptan-5-yl)propan-l-one (29.9 mg, 0.08 mmol, 10.8% yield) as a white solid and ( / ?)-2-((5-(4-fluorophcnyl)-l.3.4-oxadiazol-2-yl)amino)-l-((.S)-4-mcthyl- 5-azaspiro[2.4]heptan-5-yl)propan-l-one (35.9 mg, 0.10 mmol, 13.1% yield) as a white solid.

[0583]

[0560] Example 66: ( / ?)-l-((.S)-3-fhioro-3-mcthylpyrrolidin-l-yl)-2-((5-(4-fliiorophcnyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0584] Synthetic Route

[0585]

[0561] To a solution of (.S')-3-fluoro-3-mcthylpyrrolidinc hydrochloride (61.6 mg, 0.44 mmol) and (5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (74.0 mg, 0.29 mmol) in dichloromethane (2.0 mL) was added W-diisopropylcthylaminc (114.2 mg, 0.88 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (281.2 mg, 0.44 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20%B to 40%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 7.12 to afford (R)-l-((S)-3-fluoro-3- methylpyrrolidin- 1 -y 1) -2 -((5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one (32.2 mg, 0.09 mmol, 31.8% yield) as a white solid. LC-MS: (ESI, m / z): 337.2 [M+H]+.

[0562] Example 67: ( / ?)- l -(( / ?)-3-fluoro-3-mcthylpyrrolidin- l -yl)-2-((5-(4-fluorophcnyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0586] Synthetic Route

[0587]

[0563] To a solution of (5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (70.0 mg, 0.28 mmol) and ( / ?)-3-fluoro-3-mcthylpyrrolidinc hydrochloride (58.3 mg, 0.42 mmol) in dichloromethane (1.0 mL) was added N, '-diisopropylcthylaminc (108.0 mg, 0.83 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (266.0 mg, 0.42 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 19%B to 39%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 9 to afford (R)-l-((R)-3-fluoro-3- methylpyrrolidin- 1 -yl)-2-((5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one (24.3 mg, 0.07 mmol, 25.9% yield) as a white solid. LC-MS: (ESI, m / z): 337.2 [M+H]+.

[0588]

[0564] Example 68: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(5- azaspiro [2.3]hexan-5 -yl)propan- 1 -one

[0589]

[0565] Step 1: tert-butyl (5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninatc

[0590]

[0566] A mixture of 5-(4-fluorophenyl)-l,3,4-oxadiazol-2(327)-one (300.0 mg, 1.66 mmol), tert-butyl D-alaninate hydrochloride (363.0 mg, 2.00 mmol), A, A-diisopropylcthylaminc (1.29 g, 10.00 mmol) and lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.21 g, 5.00 mmol) in dichloromethane (4.0 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford tert-butyl (5-(4-fluorophenyl)- l.3.4-oxadiazol-2-yl)- / )-alaninatc (390.0 mg, 1.26 mmol, 76.2% yield) as a white solid. LC-MS: (ESI, m / z): 308.1 [M+H]+.

[0591]

[0567] Step 2: (5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc

[0592]

[0568] A mixture of tert-butyl (5-(4-fluorophenyl)- 1 ,3.4-oxadiazol-2-yl)- / )-alaninatc (90.0 mg, 0.29 mmol) in trifluoroacetic acid (0.5 mL) and dichloromethane (1.5 mL) was stirred at 25 °C for 6 hours. After completion, the solvent was removed under vacuum to afford (5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (70.0 mg, 0.28 mmol, 96.1% yield) as a yellow oil. LC-MS: (ESI, m / z): 252.1 [M+H]+.

[0593]

[0569] Step 3: ( / ?)-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)- l -(5- azaspiro [2.3]hexan-5 -yl)propan- 1 -one

[0570] To a solution of (5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (63.0 mg, 0.25 mmol) and 5-azaspiro[2.3]hexane hydrochloride (45.0 mg, 0.38 mmol) in dichloromethane (1.0 mL) was added N, A'-diisopropylcthylaminc (97.2 mg, 0.75 mmol) and 2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (239.4 mg, 0.37 mmol, 50% in ethyl acetate), the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford (7?)-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2- yl)amino)-l-(5-azaspiro[2.3]hexan-5-yl)propan-l-one (24.5 mg, 0.07 mmol, 30.6% yield) as a white solid. LC-MS: (ESI, m / z): 317.1 [M+H]+.

[0594]

[0571] Example 69: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl) amino)- 1 -((2 / ?.47?)- 2-methyl-4-(trifluoromethoxy) pyrrolidin-l-yl) propan- 1 -one

[0595]

[0572] Step 1: tert-butyl (2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy) pyrrolidine -1 -carboxylate

[0596]

[0573] Under nitrogen, to a mixture of silver trifluoromethanesulfonate (3.46 g, 13.41 mmol), potassium fluoride (1.17 g, 19.87 mmol) and 1 -chloromethyl -4-fluoro-l,4-diazoniabicyclo [2.2.2] octane bis tetrafluoroborate (2.64 g, 7.45 mmol) in ethyl acetate (6.0 mL) was slowly added to a solution of tert-butyl (2 / ?.4 / ?)-4-hydroxy-2-mcthylpyrrolidinc- 1 -carboxylate (1.00 g, 4.96 mmol) in ethyl acetate (6 mL) at 0 °C. Then 2-fluoropyridine (1.44 g, 14.90 mmol) and (trifluoromethyl)trimethylsilane (2.12 g, 14.90 mmol) were added dropwise at 0 °C and stirred at 25 °C for 24 hours. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4: 1) to afford tert-butyl (2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy) pyrrolidine -1 -carboxylate (290.0 mg, 1.07 mmol, 21.7% yield) as ayellow oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0597]

[0574] Step 2: (2 / ?.4 / ?)-2-mcthy I -4-(trifluoromcthoxy [pyrrolidine hydrochloride

[0598]

[0575] A mixture of tert-butyl (2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy) pyrrolidine- 1- carboxylate (280.0 mg, 1.04 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3.0 m ) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2RAR)-2- methyl-4-(trifluoromethoxy)pyrrolidine hydrochloride (200.0 mg, crude) as a white solid. LC-MS: (ESI, m / z): 170.1 [M+H]+.

[0599]

[0576] Step 3: tert-butyl (( / ?)-l-((2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidin-l-yl)-l- oxopropan-2-yl)carbamate

[0600]

[0577] A mixture of (2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy) pyrrolidine hydrochloride (200 mg, crude), (tert-butoxycarbonyl)-D-alanine (276.07 mg, 1.45 mmol), A, N- diisopropylethylamine (377.1 mg, 2.91 mmol) and 2-(7-azabenzotriazol-l-yl)-A, A, A, A- tetramethyluronium hexafluorophosphate (554.7 mg, 1.45 mmol) in dichloromethane (3.0 mb) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4: 1) to afford tert-butyl (( / ?)- 1 -((2 / ?.4 / ?)-2-mcthyl-4- (trifluoromethoxy)pyrrolidin-l-yl)-l-oxopropan-2-yl)carbamate (270.0 mg, 0.79 mmol, 81.6% yield) as ayellow solid. LC-MS: (ESI, m / z): 341.1 [M+H]+.

[0601]

[0578] Step 4: ( / ?)-2-amino-l-((2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy) pyrrolidin-l-yl) propan- 1 -one hydrochloride

[0602]

[0579] A mixture of tert-butyl (( / ?)- 1 -((2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy)pyrrolidin- 1- yl)-l-oxopropan-2-yl)carbamate (260.0 mg, 0.76 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3.0 mL) was stirred for 30 minutes at room temperature. After completion, the solvent was removed under vacuum to afford ( / ?)-2-amino- 1 -((2 / ?.4 / ?)-2-mcthyl-4-(trifluoromcthoxy) pyrrolidin-l-yl) propan-l-one hydrochloride (200.0 mg, crude) as a white solid. LC-MS: (ESI, m / z): 241.1 [M+H]+.

[0603]

[0580] Step 5: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl) amino)- 1 -((27?, 4R)-2- methyl-4-(trifluoromethoxy) pyrrolidin-l-yl) propan-l-one

[0604]

[0581] A mixture of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(377)-one (50.0 mg, 0.25 mmol), (R)-2 -amino- 1 -((2 / ?.4 / ?)-2-mcth l -4-(trifl uoromcthox ) pyrrolidin- 1 -yl) propan- 1 -one hydrochloride (91.6 mg, crude), lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (168.7 mg, 0.38 mmol) and '. A'-diisopropylcthylaminc (131.8 mg, 1.01 mmol) in dichloromethane (1.0 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (20: 1) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 34%B to 54%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.87 to afford ( / ?)-2-((5-(4-chlorophcnyl)-l .3.4-oxadiazol-2-yl) amino)- l -((2 / ?.4 / ?)-2- methyl-4-(trifluoromethoxy) pyrrolidin-l-yl) propan-l-one (49.1 mg, 0.11 mmol, 46.1% yield) as a white solid. LC-MS: (ESI, m / z): 419.0 [M+H]+.

[0605]

[0582] Example 70: (R)-l-(l,l-difluoro-5-azaspiro[2.3]hexan-5-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0606] Synthetic Route

[0607]

[0583] To a solution of l,l-difluoro-5-azaspiro[2.3]hexane hydrochloride (92.8 mg, 0.59 mmol) and (5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (100.0 mg, 0.39 mmol) in dichloromethane (2.0 mL) was added N, JV-diisopropylethylamine (154.3 mg, 1.19 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (379.8 mg, 0.59 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22%B to 42%B inl0.5 min; Wave Length: 254 / 235 nm; RTl(min): 8.85 to afford (R)-l-(l,l-difluoro-5- azaspiro [2.3]hexan-5 -yl)-2-((5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one (27.1 mg, 0.07 mmol, 18.7% yield) as a white solid. LC-MS: (ESI, m / z): 353.1 [M+H]+.

[0608]

[0584] Example 71a: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-6- methyl-5 -azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0609]

[0585] Example 71b: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(( / ?)-6- methyl-5 -azaspiro[2 ,4]heptan-5 -yl)propan- 1 -one

[0610] Synthetic Route

[0611]

[0586] A mixture of 5-(4-chlorophenyl)-3H- 1 ,3,4-oxadiazol-2-one (76.0 mg, 0.38 mmol), (2 / ?)-2-amino- l -(6-mcthyl-5-azaspiro|2.4|hcptan-5-yl)propan- l -onc hydrochloride (91.6 mg, 0.42 mmol), I / / -benzotri azol - 1 -yloxy tri s(dimcthy lam ino)phosphoni urn hexafluorophosphate (256.4 mg, 0.57 mmol) and A'.A'-diisopropylcthylaminc (199.8 mg, 1.54 mmol) in '. '-dimcthylformamidc (2.0 mb) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford the product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex: DCM 3: 1(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm;

[0612] RTl(min): 7.31; RT2(min): 10.48; Sample Solvent: EtOH; Injection Volume: 1.0 mL; Number Of Runs: 4 to afford ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- l -((.S')-6-mcthyl-5- azaspiro[2.4]heptan-5-yl)propan-l-one (19.8 mg, 0.05 mmol, 14.0% yield) as a white solid and (R)- 2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((R)-6-methyl-5-azaspiro[2.4]heptan-5- yl)propan-l-one (31.5 mg, 0.08 mmol, 22.3% yield) as a white solid.

[0613]

[0587] Example 72a: (R)-l-((S)-6-methyl-5-azaspiro[2.4]heptan-5-yl)-2-((5-(4- (trifluoromethyl)phenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0614]

[0588] Example 72b: (R)-l-((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)-2-((5-(4- (trifluoromethyl)phenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0615]

[0589] A mixture of (2 / ?)-2-amino- 1 -(6-mcthyl-5-azaspiro|2.4|hcptan-5-yl)propan- 1 -one hydrochloride (172.9 mg, 0.79 mmol), 5-[4-(trifhioromethyl)phenyl |-3 / / -l .3.4-oxadiazol-2-onc (130.0 mg, 0.56 mmol), M '-diisopropylcthylaminc (309.0 mg, 0.56 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (249.8 mg, 0.56 mmol) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35%B to 55%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 10.18 to afford product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK AD 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NJ L-McOH). Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RTl(min): 7.104; RT2(min): 12.359; Sample Solvent: ETOH; Injection Volume: 1.5 mL to afford ( / ?)-l-((.S')-6-mcthyl-5- azaspiro [2 ,4]heptan-5 -yl)-2-((5 -(4-(trifluoromethyl)phenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 - one (20.8 mg, 0.05 mmol, 9.2% yield) as a white solid and (R)-l-((R)-6-methyl-5- azaspiro [2 ,4]heptan-5 -yl)-2-((5 -(4-(trifluoromethyl)phenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 - one (25.1 mg, 0.06 mmol, 11.2% yield) as a white solid.

[0616]

[0590] Example 73a: (R)-l-((2S,3S)-3-fluoro-2,3-dimethylpyrrolidin-l-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0617]

[0591] Example 73b: ( / ?)-l-((2.S'.3 / ?)-3-fluoro-2.3-dimcthylpyrrolidin-l-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0618] Synthetic Route

[0619]

[0620]

[0592] Step 1: tert-butyl (2.S)-3-hydroxy-2.3-dimcthylpyrrolidinc- 1 -carboxylate

[0621]

[0593] Under nitrogen, to a solution of tert-butyl (.S')-2-mcthyl-3-oxopyrrolidinc- 1 - carboxylate (2.00 g, 10.04 mmol) in tetrahydrofuran (20 mb) was added methyl magnesium bromide (50 mb, 50 mmol, 1 M in tetrahydrofuran) dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (7:3) to afford tert-butyl (2S)-3 -hydroxy-2,3 -dimethylpyrrolidine-1 -carboxylate (600.0 mg, 2.78 mmol, 27.8% yield) as a yellow oil. LC-MS: (ESI, m / z): 216.2 [M+H]+.

[0622]

[0594] Step 2: tert-butyl (2.S)-3-fluoro-2.3 -dimethylpyrrolidine-1 -carboxylate

[0623]

[0595] To a solution of tert-butyl (2.S)-3-hydroxy-2.3-dimcthylpyrrolidinc- 1 -carboxylate (580.0 mg, 2.69 mmol) in dichloromethane (5 mb) was slowly added diethylaminosulfur trifluoride (1.07 mL, 8.08 mmol) at 0 °C. The mixture was stirred at 0°C for 1 hour. The reaction was quenched with methanol. The solvent was removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4: 1) to afford tertbutyl (2.S)-3-fluoro-2.3 -dimethylpyrrolidine-1 -carboxylate (150.0 mg, 0.68 mmol, 25.6% yield) as a yellow oil. LC-MS: (ESI, m / z): 218.2[M+H]+.

[0624]

[0596] Step 3: (2.S)-3-fluoro-2.3-dimcthylpyrrolidinc hydrochloride

[0625]

[0597] A mixture of tert-butyl (2.S)-3-fluoro-2.3-dimcthylpyrrolidinc- 1 -carboxylate (120.0 mg, 0.55 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1 mL) was stirred at 25 °C for 0.5 hours. After completion, the solvent was removed under vacuum to afford (2.S)-3-fluoro-2.3- dimethylpyrrolidine hydrochloride (83.2 mg, crude) as a white solid. LC-MS: (ESI, m / z): 118.1 [M+H]+.

[0626]

[0598] Step 4: (R)-l-((2S,3S)-3-fhioro-2,3-dimethylpyrrolidin-l-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one & ( / ?)- l -((2.S'.3 / ?)-3-fluoro-2.3- dimethylpyrrolidin- 1 -y 1) -2 -(( 5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0627]

[0599] To a mixture of (5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (94.0 mg, 0.37 mmol) and (2.S)-3-fluoro-2.3-dimcthylpyrrolidinc hydrochloride (83.2 mg, crude) in dichloromethane (2 mL) was added A.A-diisopropylcthylaminc (193.1 mg, 1.50 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (357.0 mg, 0.56 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 0.5 hours. After completion, the reaction was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the product. The product was isolated by Prep- Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 40; Wave Length: 220 / 254 nm; RTl(min): 5.429; RT2(min): 8.067; Sample Solvent: EtOH; Injection Volume: 0.7 mL to afford ( / ?)- l -((2.S'.3.S)-3-fluoro-2.3-dimcthylpyrrolidin- l -yl)-2- ((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one (5.9 mg, 0.02 mmol, 4.5% yield) as a white solid and (R)-l-((2S,3R)-3-fhioro-2,3-dimethylpyrrolidin-l-yl)-2-((5-(4-fluorophenyl)- I,3,4-oxadiazol-2-yl)amino)propan-l-one (22.4 mg, 0.06 mmol, 17.1% yield) as a white solid.

[0628]

[0600] Example 74a: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-l -((.S)-4- methyl-5 -azaspiro [2.3 ]hexan-5 -yl)propan- 1 -one

[0629]

[0601] Example 74b: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-I-((R)-4- methyl-5 -azaspiro [2.3 ]hexan-5 -yl)propan- 1 -one

[0630] Synthetic Route

[0631]

[0602] Step 1: tert-butyl 5 -azaspiro [2.3]hexane-5 -carboxylate

[0632]

[0603] A mixture of 5-azaspiro[2.3]hexane hydrochloride (4.50 g, 37.82 mmol), di-tert- butyl dicarbonate (24.63 g, 113.0 mmol) and triethylamine (11.41 g, 113.0 mmol) in dichloromethane (50 mL) was stirred at 25 °C for 2 hours. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / dichloromethane (2: 1) to afford tert-butyl 5-azaspiro[2.3]hexane-5- carboxylate (4.20 g, 22.92 mmol, 42.3% yield) as a white solid. LC-MS: (ESI, m / z): 184.1 [M+H]+.

[0633]

[0604] Step 2: tert-butyl 4-methyl-5-azaspiro[2.3]hexane-5-carboxylate

[0634]

[0605] Under nitrogen, a mixture of tert-butyl 5-azaspiro[2.3]hexane-5-carboxylate (2.50 g, 13.64 mmol), l,3-dioxoisoindolin-2-yl acetate (5.60 g, 27.29 mmol), tetra-n-butylammonium decatungstate (2.26 g, 0.68 mmol) and trisodium phosphate (4.47 g, 27.29 mmol) were dissolved in acetone (20 mL). To this was added the mixture of nickel(II) acetylacetonate (349.3 mg, 1.36 mmol). Then potassium tris(3, 5 -dimethyl- l-pyrazolyl)borate (3,5-dimethylpyrazol-l-yl)borate (458.4 mg, 1.36 mmol) in acetone (5 mL) was added and stirred at 25 °C for 24 hours with blue LED. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9: 1) to afford tert-butyl 4-methyl-5-azaspiro[2.3]hexane-5- carboxylate (1.00 g, 1.87 mmol, 37% purity, 13.7 % yield) as yellow oil. LC-MS: (ESI, m / z): 198.2[M+H]+.

[0635]

[0606] Step 3: 4-methyl-5-azaspiro[2.3]hexane trifluoroacetate

[0636]

[0607] A mixture of tert-butyl 4-methyl-5-azaspiro[2.3]hexane-5-carboxylate (1.00 g, 1.87 mmol, 37% purity) in trifluoroacetic acid (10 mL) was stirred at 25 °C for 30 minutes. After completion, the solvent was removed under vacuum to afford 4-methyl-5-azaspiro[2.3]hexane trifluoroacetate (500 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 98.1 [M+H]+.

[0637]

[0608] Step 4: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-4-methyl-5- azaspiro [2.3]hexan-5 -yl)propan- 1 -one & (R)-2-((5 -(4-chlorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -(( / ?)-4-mcthy I -5 -azaspiro [2.3]hexan-5 -yl)propan- 1 -one

[0638]

[0609] To a mixture of (5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine (350.0 mg, 0.96 mmol) and 4-methyl-5-azaspiro[2.3]hexane trifluoroacetate (139.5 mg, crude) in dichloromethane (3 mL) was added W-diisopropylcthylaminc (838.4 mg, 3.83 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (916.4 mg, 1.44 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 0.5 hours. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 29%B to 49%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 8.88 to afford product. Then the product was isolated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NFL-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 50; Wave Length: 220 / 254 nm; RTl(min): 5.741; RT2(min): 8.171; Sample Solvent: EtOH; Injection Volume: 0.6 mL to afford (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-I-((S)-4-methyl-5-azaspiro[2.3]hexan-5- yl)propan-l-one (5.6 mg, 0.01 mmol, 1.7% yield) as a white solid and (R)-2-((5-(4-chlorophenyl)- I,3,4-oxadiazol-2-yl)amino)-I-((R)-4-methyl-5-azaspiro[2.3]hexan-5-yl)propan-l-one (5.1 mg, 0.01 mmol, 1.5% yield) as a white solid.

[0639]

[0610] Example 75: (R)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-3- isopropoxy-2-methylazetidin- 1 -yl)propan- 1 -one Synthetic Route

[0640]

[0611] Step 1: tert-butyl (2.S'.3.S)-3-isopropoxy-2-mcthylazctidinc- 1 -carboxylate

[0641]

[0612] Under nitrogen, to a solution of tert-butyl (2.S'.3.S')-3-hydroxy-2-mcthylazctidinc- l - carboxylate (1.00 g, 5.34 mmol) in A.A-dimcthylfonnamidc (10 mb) was added sodium hydride (640.8 mg, 16.02 mmol, 60% dispersion in mineral oil) and stirred at 0° C for 5 min. Then 2- iodopropane (18.16 g, 106.81 mmol) was added and stirred at 80 °C for 8 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4: 1) to afford tert-butyl (2S,3S)-3 -isopropoxy-2 -methylazetidine- 1 -carboxylate (200.0 mg, 0.87 mmol, 16.3% yield) as yellow oil. LC-MS: (ESI, m / z): 230.3 [M+H]+.

[0642]

[0613] Step 2: (2.S'.3.S)-3-isopropoxy-2 -methylazetidine trifluoroacetate

[0643]

[0614] A mixture of tert-butyl (2.S'.3.S)-3-isopropoxy-2-mcthy laze tidinc- 1 -carboxy late (120.0 mg, 0.37 mmol) in trifluoroacetic acid (1 m ) and dichloromethane (1 m ) was stirred at 25 °C for 0.5 hours. After completion, the solvent was removed under vacuum to afford (2S,35)-3- isopropoxy-2 -methylazetidine trifluoroacetate (135.0 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification.EC-MS: (ESI, m / z): 130.2[M+H]+.

[0644]

[0615] Step 3: (J?)-2-((5-(4-fhrorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((2S,3S)-3- isopropoxy-2-methylazetidin- 1 -yl)propan- 1 -one

[0645]

[0616] To a mixture of (5-(4-fluorophenyl)- 1 ,3.4-oxadiazol-2-yl)- / )-alaninc (88.0 mg, 0.35 mmol) and (2.S'.3.S)-3-isopropoxy-2 -methylazetidine trifluoroacetate (120.0 mg, crude) in dichloromethane (2 mb) was added A.A-diisopropylcthylaminc (180.7 mg, 1.40 mmol) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (334.2 mg, 0.53 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 0.5 hours. After completion, the reaction was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography on Cl 8 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford (R)-2- ((5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)- 1 -((2S,3S)-3 -isopropoxy-2-methylazetidin- 1 - yl)propan-l-one (34.5 mg, 0.10 mmol, 27.2% yield) as a white solid. LC-MS: (ESI, m / z): 363.2[M+H]+.

[0646]

[0617] Example 76a: ( / ?)- l -((2.S'.4 / ?)-4-fluoro-2.4-dimcthylpyrrolidin- l -yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0647]

[0618] Example 76b: ( / ?)- l -((2.S'.4.S)-4-fluoro-2.4-dimcthylpyrrolidin- l -yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0648]

[0619] Step 1: tert-butyl (2.S)-4-hydroxy-2.4-dimcth lpyrrolidinc- l -carboxylate

[0649]

[0620] Under nitrogen, to a solution of tert-butyl (2.S)-2-mcth l-4-oxo-pyrrolidinc- 1 - carboxylate (500.0 mg, 2.51 mmol) in tetrahydrofuran (5.0 mb) was added methylmagnesium bromide (12.5 mb, 12.5 mmol, IM in tetrahydrofuran) at 0 °C dropwise. The resulting solution was stirred at 25 °C for 2 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford tert-butyl (2.S)-4-hydroxy-2.4-dimcthylpyrrolidinc-l- carboxylate (368.0 mg, 1.7mmol, 68.1% yield) as a yellow solid. LC-MS: (ESI, m / z) 216.2 [M+H]+.

[0650]

[0621] Step 2: tert-butyl (2.S)-4-fluoro-2.4-dimcthylpyrrolidinc- 1 -carboxylate

[0651]

[0622] To a solution of tert-butyl (2.S)-4-hydroxy-2.4-dimcthylpyrrolidinc-l -carboxylate (350.0 mg, 1.63 mmol) in dichloromethane (4 m ) was added diethylaminosulfur trifluoride (819.3 mg, 4.88 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 2 hours. After completion, the reaction was quenched with methanol. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford tert-butyl (2.S)-4-fluoro-2.4- dimethylpyrrolidine-1 -carboxylate (220.0 mg, 1.0 mmol, 62.3% yield). LC-MS: (ESI, z): 218.1 [M+H]+.

[0652]

[0623] Step 3: (2.S)-4-fluoro-2.4-dimcthylpyrrolidinc hydrochloride

[0653]

[0624] A solution of tert-butyl (2.S)-4-fluoro-2.4-dimcthylpyrrolidinc-l -carboxylate (150.0 mg, 0.69 mmol) in 4 M hydrochloric acid in 1,4-dioxane (1.5 mb) was stirred at 25 °C for 2 hours. After completion, the solvent was removed under vacuum to afford (2.S)-4-fluoro-2.4- dimethylpyrrolidine hydrochloride (80 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z)'. 118.1 [M+H]+.

[0654]

[0625] Step 4: ( / ?)-l-((2.S'.4 / ?)-4-fluoro-2.4-dimcthylpyrrolidin-l-yl)-2-((5-(4- fluorophenyl)- l,3,4-oxadiazol-2-yl)amino)propan- 1 -one & (R)- 1 -((2.S'.4.S)-4-fluoro-2.4- dimethylpyrrolidin- 1 -yl)-2-((5 -(4-fluorophenyl)- 1 ,3 ,4-oxadiazol-2-yl)amino)propan- 1 -one

[0655]

[0626] To a solution of (2.S)-4-fluoro-2.4-dimcthylpyrrolidinc hydrochloride (80.0 mg, crude) and (2 / ?)-2-||5-(4-fluorophcnyl)-l.3.4-oxadiazol-2-yl |amino|propanoic acid (188.6 mg, 0.75 mmol) in dichloromethane (1 mL) was added A.A-diisopropylcthylaminc (551.5 mg, 2.05 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (260.5 mg, 0.82 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the product. The product was further purified by Prep-HPLC with the following conditions (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 31% B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 9.56) to afford the product. The product was separated by Chiral-Prep- HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 70; Wave Length: 220 / 254 nm; RTl(min): 4.726; RT2(min): 5.959; Sample Solvent: ETOH; Injection Volume: 0.7 mL to afford ( / ?)-l-((2.S'.4 / ?)-4-fluoro-2.4-dimcthylpyrrolidin-l-yl)-2- ((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one (11.6 mg, 0.03 mmol, 4.8% yield) as a white solid and (7?)-l-((2S,4S)-4-fhioro-2,4-dimethylpyrrolidin-l-yl)-2-((5-(4-fluorophenyl)- l,3,4-oxadiazol-2-yl)amino)propan-l-one (47.6 mg, 0.1 mmol, 19.9% yield) as a white solid.

[0656]

[0627] Example 77: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(5- azaspiro [2.3]hexan-5 -yl)propan- 1 -one

[0657]

[0628] Step 1: tert-butyl (5-(4-chlorophcnyl)-l.3.4-oxadiazol-2-yl)- / )-alaninatc

[0658]

[0629] To a solution of 5-(4-chlorophenyl)-3H-l,3,4-oxadiazol-2-one (1.00 g, 5.09 mmol) and tert-butyl (2 / ?)-2-aminopropanoatc hydrochloride (1.39 g, 7.63 mmol) in dichloromethane (20 mb) was added W-diisopropylcthylaminc (3.28 g, 25.43 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (6.75 g, 15.26 mmol). The mixture was stirred at room temperature for 3 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (3:1) to afford tert-butyl (5-(4-chlorophenyl)- l,3,4-oxadiazol-2-yl)-D-alaninate (1.50 g, 4.63 mmol, 91.1% yield) as a white solid. LC-MS: (ESI, m / z): 324.1[M+H]+.

[0659]

[0630] Step 2: (5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine

[0631] A solution of tert-butyl (5-(4-chlorophcnyl)- 1 ,3.4-oxadiazol-2-yl)- / )-alaninatc (100.0 mg, 0.31 mmol) in trifluoroacetic acid (5 mL) and dichloromethane (15 mL) was stirred at room temperature for 8 hours. After completion, the solvent was removed under vacuum to afford the title compound (110 mg, crude). The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 268.0 [M+H]+.

[0660]

[0632] Step 3: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(5- azaspiro [2.3]hexan-5 -yl)propan- 1 -one

[0661]

[0633] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (100.0 mg, 0.37 mmol) and 5-azaspiro[2.3]hexane hydrochloride (54.0 mg, 0.45 mmol) in dichloromethane (1 mL) was added A.A-diisopropylcthylaminc (241.0 mg, 1.87 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (235.3 mg, 0.37 mmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4- oxadiazol-2-yl)amino)-l-(5-azaspiro[2.3]hexan-5-yl)propan-l-one (28.8 mg, 0.08 mmol, 22.5% yield) as a white solid. LC-MS: (ESI, m / z): 333.0 [M+H]+.

[0662]

[0634] Example 78a: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-3- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0663]

[0635] Example 78b: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-(( / ?)-3- methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0664]

[0636] Synthetic Route

[0665]

[0637] Step 1: / / V-butyl 4-bromo-3 -meth l -3 -(trifl uoromcthox [pyrrolidine- 1 -carbox late

[0666]

[0638] Under nitrogen, to a solution of silver fluoride (104.0 mg, 0.819 mmol), hydroquinidine 1,4-phthalazinediyldiether (213.0 mg, 0.27 mmol), cesium fluoride (829.0 mg, 5.46 mmol) and l,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (780.0 mg, 2.73 mmol) in acetonitrile (8.0 mb) and dichloromethane (4.0 mb) was added trifluoromethyl 4-fluorobenzenesulfonate (2.00 g, 8.19 mmol) in acetonitrile (2.0 mb), the mixture was stirred for 30 minutes at 25 °C. Then the mixture was cooled to -20 °C, to the reaction mixture was added tert-butyl 3-methyl-2,5- dihydropyrrole-1 -carboxylate (500 mg, 2.73 mmol) in dichloromethane (1.0 mb) dropwise and the mixture was stirred at -20 °C to room temperature for a further 24 hours. After completion, the reaction was quenched with a saturated aqueous solution of sodium sulfite and ammonium chloride at -20 °C. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuum and the residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4: 1) to afford the title compound as a light yellow oil (588.0 mg, 1.69 mmol, 61.9% yield). LC-MS: (ESI, m / z): 291.9 & 293.9 [M-55]+.

[0667]

[0639] Step 2: tert-butyl 3 -methyl-3 -(trifluoromethoxy )pyrrolidine-l -carboxylate

[0668]

[0640] A mixture of tert-butyl 4-bromo-3-methyl-3-(trifluoromethoxy)pyrrolidine-l- carboxylate (588.0, 1.69 mmol), 2,2'-azobis(2-methylpropionitrile) (555.4 mg, 3.38 mmol) and tributylhydridotin(IV) (2.46 g, 8.45 mmol) in toluene (6.0 mb) was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (10: 1) to afford the title compound as a white solid (400.0 mg, 1.48 mmol, 87.9% yield). LC-MS: (ESI, m / z): 214.0 [M -55]+.

[0669]

[0641] Step 3: 3 -methyl-3 -(trifluoromethoxy )pyrrolidine hydrochloride

[0670]

[0642] A solution of tert-butyl (3.S)-3-mcthyl-3-(trifluoromcthoxy)pyrrolidinc-l- carboxylate (300.0 mg, 1.11 mmol) in hydrochloric acid (4.0 m , 4M in 1,4-dioxane) was stirred at room temperature for 1 hour. After completion, the reaction solution was concentrated under vacuum to afford the title compound (250.0 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 170.0 [M+H]+.

[0671]

[0643] Step 4: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((S)-3-methyl-3- (trifluoromethoxy)pyrrolidin- 1 -yl)propan- 1 -one & (R)-2-((5 -(4-chlorophenyl)- 1 ,3 ,4-oxadiazol-2- yl)amino)- 1 -(( / ?)-3 -methyl-3 -(trifluoromethoxy )pyrrolidin- 1 -yl)propan- 1 -one

[0672]

[0644] To a mixture of (5-(4-chlorophcnyl)- 1.3.4-oxadiazol-2-yl)- / )-alaninc (229.0 mg, 0.86 mmol), (35)-3-methyl-3-(trifluoromethoxy)pyrrolidine hydrochloride (229.0 mg, 1.12 mmol) and A.A-diisopropylcthylaminc (665.0 mg, 5.15 mmol) in dichloromethane (6.0 mb) was added propylphosphonic anhydride (818.0 mg, 1.27 mmol, 50% solution in ethyl acetate), the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3: 1) to afford the product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 29%B to 51%B in lOmin; Wave Length: 254 / 220 nm; RTl(min): 9.23 to afford product. The product was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 15; Wave Length: 220 / 254 nm; RTl(min): 20.628; RT2(min): 29.5; Sample Solvent: EtOH; Injection Volume: 0.8 mL to afford ( / ?)-2-((5-(4-chlorophcnyl)- 1.3.4- oxadiazol-2-yl)amino)- 1 -((.S)-3-mcthyl-3-(trifluoromcthoxy jpyrrolidin- 1 -yljpropan- 1 -one (28.7 mg, 0.07 mmol, 8.0% yield) as a white solid and (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2- yl)amino)-l-(( / ?)-3 -methyl-3 -(trifluoromethoxy jpyrrolidin- l-yl)propan-l -one (37.7 mg, 0.09 mmol, 10.5% yield) as a white solid.

[0673]

[0645] Example 79: (R)-l-((2S,3S)-3-cyclopropoxy-2-methylazetidin-l-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0674]

[0646] Synthetic Route

[0675]

[0647] Step 1: tert-butyl (2.S'.3.S)-2-mcthyl-3-(vinyloxy)azctidinc- 1 -carboxylate

[0676]

[0648] Under nitrogen, to a mixture of tert-butyl (2S,3S)-3-hydroxy-2 -methylazetidine- 1 - carboxylate (1.00 g, 5.34 mmol) in n-butyl vinyl ether (20.0 mb) was added triethylamine (237.8 mg, 2.35 mmol), bathophenanthroline (177.3 mg, 0.53 mmol) and palladium(II)acetate (120.9 mg, 0.53 mmol), the mixture was stirred at 80 °C for 2 hours under microwave irradiation. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (92:8) to afford the title compound (620.0 mg, 2.91 mmol, 54.4% yield) as a yellow oil. LC-MS: (ESI, m / z): 214.1 [M+H]+.

[0677]

[0649] Step 2: tert-butyl (2.S'.3.S)-3-cyclopropoxy-2-mcthylazctidinc- l -carboxylate

[0678]

[0650] Under nitrogen, to a solution of dichloroacetic acid (1.16 g, 9.00 mmol) and diiodomethane (2.41 g, 9.00 mmol) in dichloromethane (5 mb) was added diethylzinc (9.56 m , 9.56 mmol, 1.0 M in hexanes) dropwise at 0 °C , the mixture was stirred for 30 minutes at 0 °C . Then tert-butyl (2.S'.3.S)-2-mcthyl-3-(vinyloxy)azctidinc- 1 -carboxylate (600.0 mg, 2.81 mmol) in dichloromethane (5 mL) was added and stirred for 1 hour at 0 °C. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (90: 10) to afford tert-butyl (2S,35)-3- cyclopropoxy-2-methylazetidine-l -carboxylate (310.0 mg, 1.36 mmol, 48.5% yield) as a colorless oil. LC-MS: (ESI, m / z): 228.2 [M+H]+.

[0679]

[0651] Step 3: (2S,35)-3-cyclopropoxy-2 -methylazetidine trifluoroacetate

[0680]

[0652] A mixture of tert-butyl (2.S'.3.S)-3-cyclopropoxy-2-mcthylazctidinc- 1 -carboxylate (200.0 mg, 0.61 mmol) in trifluoroacetic acid (1.0 mL) and dichloromethane (3.0 mL) was stirred for 5 hours at 25 °C. After completion, the reaction solution was concentrated under vacuum to afford the title compound (180.0 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 128.1 [M+H]+.

[0681]

[0653] Step 4: (J?)-l-((2S,3S)-3-cyclopropoxy-2-methylazetidin-l-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0682]

[0654] To a solution of (5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (90.0 mg, 0.36 mmol), (2S,3S)-3 -cyclop ropoxy-2 -methylazetidine trifluoroacetate (180.0 mg, crude) and N.N- diisopropylethylamine (138.9 mg, 1.07 mmol) in dichloromethane (2.0 mL) was added propylphosphonic anhydride (342.0 mg, 0.54 mmol, 50% in ethyl acetate), the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (54.9 mg, 0.15 mmol, 42.4% yield) as a white solid. LC-MS: (ESI, m / z): 361.1 [M+H]+.

[0683]

[0655] Example 80a: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((47?,77?)- 7 -methyl- 1 -oxa-6-azaspiro[3.4] octan-6-yl)propan- 1 -one

[0684]

[0656] Example 80b: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((4S,7J?)- 7 -methyl- 1 -oxa-6-azaspiro[3.4] octan-6-yl)propan- 1 -one

[0657] Synthetic Route

[0685]

[0658] Step 1: tert-butyl (2 / ?)-4-(2-c thoxy-2-oxocthy I )-4-hydroxy-2-mcthy I pyrrolidine- 1- carboxylate

[0686]

[0659] Under nitrogen, to a solution of ethyl acetate (1.59 g, 18.07 mmol) in tetrahydrofuran (20.00 mL) was added lithiumdiisopropylamide (11.29 mb, 22.58 mmol, 2M in tetrahydrofuran), the mixture was stirred at -78 °C for 0.5 hours. Then tert-butyl (2 / ?)-2-mcthyl-4- oxo-pyrrolidine-1 -carboxylate (3.00 g, 15.06 mmol) in tetrahydrofuran (10.00 mL) was added and stirred at -78 °C for 2 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (97:3) to afford the title compound (3.90 g, 13.57 mmol, 90.1% yield) as a yellow oil. LC-MS: (ESI, m / z): 288.2 [M+H]+.

[0687]

[0660] Step 2: tert-butyl (2 / ?)-4-hydroxy-4-(2-hydroxycthyl)-2-mcthylpyrrolidinc- l - carboxylate

[0688]

[0661] To a mixture of tert-butyl (2 / ?)-4-(2-cthoxy-2-oxocthyl)-4-hydroxy-2- methylpyrrolidine-1 -carboxylate (3.90 g, 13.57 mmol) in tetrahydrofuran (1.00 mL) was added lithiumaluminumhydride (1.54 g, 40.72 mmol), the mixture was stirred for 0.5 hours at 0 °C . After completion, the reaction was quenched with sodium sulfate decahydrate at 0 °C . The solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure to afford crude solid. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (80:20) to afford the title compound (3.20 g, 13.04 mmol, 96.1% yield) as a yellow oil. LC-MS: (ESI, m / z): 246.2 [M+H]+.

[0689]

[0662] Step 3: tert-butyl (7 / ?)-7-mcthyl- l -oxa-6-azaspiro|3.4|octanc-6-carbox latc

[0663] To a solution of tert-butyl (2 / ?)-4-hydroxy-4-(2-hydroxycthyl)-2- methylpyrrolidine-1 -carboxylate (1.00 g, 4.08 mmol) in tetrahydrofuran (18.00 mL) was added sodium tert-butoxide (1.18 g, 12.23 mmol) and -toluene sulfonylchloride (0.78 g, 4.08 mmol) at 0 °C, the mixture was stirred at 60 °C under nitrogen for 3 hours . Then sodium tert-butoxide (1.18 g, 12.23 mmol) was added again and stirred at 60 °C under nitrogen for 14 hours. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / m ethanol (92:8) to afford the title compound (320.0 mg, 1.40 mmol, 34.5% yield) as a yellow oil. LC-MS: (ESI, m / z): 228.2 [M+H]+.

[0690]

[0664] Step 4: (7 / ?)-7-mcthyl- l -oxa-6-azaspiro|3.4|octanc trifluoroacetate

[0691]

[0665] A mixture of tert-butyl (7 / ?)-7-mcthyl- l-oxa-6-azaspiro[3.4]octane-6-carboxylate (207.0 mg, 0.91 mmol) in trifluoroacetic acid (0.10 mL) and 1,1, 1,3, 3, 3-hexafluoro-2 -propanol (1.90 mL) was stirred at 25 °C for 30 minutes. After completion, the solvent was removed under vacuum to afford the title compound (217.9 mg, crude) as a yellow oil. The crude product is directly used in the next step without purification. LC-MS: (ESI, m / z): 113.1 [M+H]+.

[0692]

[0666] Step 5: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((4R,7R)-7- methyl- 1 -oxa-6-azaspiro[3.4] octan-6-yl)propan- 1 -one & ( / ?)-2-((5 -(4-chlorophcn l )- 1 ,3,4- oxadiazol-2-yl)amino)-l-((4S,7R)-7-methyl-l-oxa-6-azaspiro[3.4]octan-6-yl)propan-l-one

[0693]

[0667] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (260.0 mg, 0.97 mmol) and A.A-diisopropylcthylaminc (376.6 mg, 2.91 mmol) in dichloromethane (4.00 mL) was added (7 / ?)-7-mcthyl-l -oxa-6-azaspiro|3.4 |octanc trifluoroacetate (217.9 mg, crude) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (927.2 mg, 1.46 mmol, 50% in ethyl acetate), the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (96:4) to afford two crude products. The first crude product was purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (lOmmol NH4CO3), Mobile Phase B: ACN; Plow rate: 60 mL / min; Gradient (B%): 23% B to 40% B in 7 min; Wave Length: 254 / 220 nm; RTl(min): 7.8 to afford ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4- oxadiazol-2-yl)amino)-l-((4R,7R)-7-methyl-l-oxa-6-azaspiro[3.4]octan-6-yl)propan-l-one (42.0 mg, 0.11 mmol, 11.5% yield) as a white solid. The second crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 23%B to 41%B inlO min; Wave Length: 254 / 220 nm; RTl(min): 8.38 to afford (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((4S,77?)-7-methyl-l-oxa-6- azaspiro[3.4]octan-6-yl)propan-l-one (10.1 mg, 0.02 mmol, 2.7% yield) as a white solid.

[0694]

[0668] Example 80c: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((47?,75)-

[0695] 7 -methyl- 1 -oxa-6-azaspiro[3.4] octan-6-yl)propan- 1 -one

[0696]

[0670] Step 1: tert-butyl (2S)-4-(2-ethoxy-2-oxoethyl)-4-hydroxy-2-methylpyrrolidine-l- carboxylate

[0697]

[0671] Under nitrogen, to a solution of ethyl acetate (2.2 m , 22.84 mmol) in tetrahydrofuran (30 m ) was added lithiumdiisopropylamide (28.1 mb, 28.11 mmol, IM in tetrahydrofuran) at -78 °C, the mixture was stirred at -78 °C for 0.5 hours. Then tert-butyl (S)-2- methyl-4-oxopyrrolidine-l -carboxylate (3.50 g, 17.57 mmol) in tetrahydrofuran (5 mb) was added and stirred at -78 °C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were washed with brine and dried over anhydrous sodium sulfate. After concentration under vacuum, the residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (95:5) to afford the title compound (2.10 g, 7.31 mmol, 41.6% yield) as a light yellow oil. EC-MS: (ESI, m / z): 288.2 [M+H]+

[0698]

[0672] Step 2: tert-butyl (2.S)-4-hydroxy-4-(2-hydroxycthyl)-2-mcthylpyrrolidinc- l - carboxylate

[0673] To a solution of tert-butyl (2.S)-4-(2-cthoxy-2-oxocthyl)-4-hydroxy-2- methylpyrrolidine-1 -carboxylate (2.10 g, 7.31 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (833.1 mg, 21.92 mmol), the mixture was stirred at 0 °C for 1 hour. After completion, the reaction was quenched with sodium sulfate decahydrate. The solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure to afford crude solid. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (80:20) to afford the title compound (1.20 g, 4.89 mmol, 66.9% yield) as a colorless oil. LC- MS: (ESI, m / z): 246.2 [M+H]+.

[0699]

[0674] Step 3: tert-butyl (7.S)-7-mcthyl- l-oxa-6-azaspiro|3.4 |octanc-6-carboxylatc

[0700]

[0675] Under nitrogen, to a solution of tert-butyl (2.S)-4-hydroxy-4-(2-hydroxycthyl)-2- methylpyrrolidine-1 -carboxylate (1.17 g, 4.77 mmol) and sodium tert-butoxide (1.37 g, 14.31 mmol) in tetrahydrofuran (15 mL) was added tosyl chloride (1.09 g, 5.72 mmol) at 0 °C. The resulting solution was stirred for 2 hours at 60 °C. Then sodium tert-butoxide (1.37 g, 14.31 mmol) was added again and stirred at 60 °C under nitrogen for 14 hours. After completion, the reaction mixture was diluted with ethyl acetate, washed with water and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (75: 15) to afford the title compound (290.0 mg, 1.28 mmol, 26.8% yield) as a yellow solid. LC-MS: (ESI, m / z): 228.2 [M+H]+.

[0701]

[0676] Step 4: (7.S)-7-mcthyl- l -oxa-6-azaspiro|3.4|octanc trifluoroacetate

[0702]

[0677] A solution of tert-butyl (7.S)-7-mcthyl- l-oxa-6-azaspiro[3.4]octane-6-carboxylate (290.0 mg, 1.28 mmol) in trifluoroacetic acid (0.3 mL) and l,l,l,3,3,3-hexafluoro-2-propanol (6.0 mL) was stirred at 25 °C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (73 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 128. 1 [M+H]+.

[0703]

[0678] Step 5: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((4J?,75)-7- methyl- 1 -oxa-6-azaspiro[3 ,4]octan-6-yl)propan- 1 -one

[0704]

[0679] To a solution of (5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)- / )-alaninc (184.4 mg, 0.69 mmol) and A.A-diisopropylcthylaminc (593.4 mg, 4.59 mmol) in dichloromethane (5 mL) was added (7.S)-7-mcthyl- l -oxa-6-azaspiro|3.4|octanc trifluoroacetate (73.0mg, crude) and 2,4,6- tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (547.5 mg, 0.86 mmol, 50% in ethyl acetate), the mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with ethyl acetate, washed with water and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (lOmmol NH4CO3), Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 26% B to 39% B in 7 min; Wave Length: 254 / 225 nm; RTl(min): 7.37 to afford the title compound (11.0 mg, 0.03 mmol, 5.1% yield) as a white solid. LC-MS: (ESI, m / z): 377.1 [M+H]+.

[0705]

[0680] Example 81: ( / ?)- l -((2.S'.3 / ?)-3-cthoxy-2-mcthylazctidin-l -yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)propan-l-one

[0706]

[0681] Synthetic Route

[0707]

[0682] To a solution of ( / ?)-2-amino- l-((2.S'.3 / ?)-3-cthoxy-2-mcthylazctidin- l -yl)propan- l - one hydrochloride (100.0 mg, crude) and 5-(4-fluorophcnyl)-3 / / - l .3.4-oxadiazol-2-onc (80.9 mg, 0.45 mmol) in dichloromethane (1 mb) was added A.A-diisopropylcthylaminc (232.2 mg, 1.80 mmol) and lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (595.8 mg, 1.35 mmol), the mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane. The organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30* 150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 65 mL / min; Gradient: 23% B to 36% B in 7 min; Wave Length: 254 / 225 nm; RTl(min): 7.36 to afford the title compound (27.1 mg, 0.08 mmol, 17.2% yield) as a white solid. LC-MS: (ESI, m / z): 349.5 [M+H]+.

[0708]

[0683] Example 82a: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((7?)-3- methyl-3 -(2,2,2-trifluoroethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0709]

[0684] Example 82b: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-l-((5)-3- methyl-3 -(2,2,2-trifluoroethoxy)pyrrolidin- 1 -yl)propan- 1 -one

[0710]

[0686] Step 1: l-benzyl-3-((2,2,6,6-tetramethylpiperidin-l-yl)oxy)pyrrolidin-2-one

[0687] To a solution of sodium phosphate monobasic (178.60 g, 1488.37 mmol), sodium chlorite (40.19 g, 446.51 mmol) and 2,2,6,6-tetramethyl-l-piperinedinyloxy (46.51 g, 297.67 mmol) in acetonitrile (720 mL) was added 3% sodium hypochlorite solution (547.2 mL, 223.26 mmol) at 0 °C. Then 1-benzylpyrrolidine (24.00 g, 148.84 mmol) in acetonitrile (720 mL) was added and stirred at 25 °C for 2 hours. After completion, sodium hydroxide solution was added dropwise to quench the reaction until the red-wine color was turned into a clear-red color. The reaction mixture was diluted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (3.40 g, 10.29 mmol, 6.9% yield) as a red oil. LC-MS: (ESI, m / z): 331.2 [M+H]+.

[0711]

[0688] Step 2: l-benzyl-3-hydroxypyrrolidin-2-one

[0712]

[0689] To a solution of l-benzyl-3-((2,2,6,6-tetramethylpiperidin-l-yl)oxy)pyrrolidin-2- one (3.40 g, 10.29 mmol) and zinc powder (6.69 g, 102.88 mmol) in tetrahydrofuran (20 mL) was added acetic acid (60 mL) and water (20 mL) at 25 °C and the mixture was stirred at 70 °C for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was diluted with ethyl a...

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:Xi to X5 are independently selected from the group consisting of hydrogen, halogen, C1-5 haloalkyl, and OH;Rlaand Rlbare independently selected from the group consisting of hydrogen, halogen substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy; each Rlcis independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted 3-6 membered cycloalkyl, and substituted or unsubstituted 3-6 membered cycloalkoxy; orRlaand one Rlctogether with the atoms attached thereto form a 3-6 membered cycloalkyl fused to the ring to which Rlaand Rlcare attached; n is 0 or 1; m is 0 or 1; provided that n + m is 1 or 2; and p is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein the compound is of formula (la):or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is of formula (lb) or formula (Ic):or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1 to 3, wherein Xi is selected from -F, -Cl, -CH3, - CHF2and -CF3.

5. The compound of any one of claims 1 to 3, wherein X2is -H or -F.

6. The compound of any one of claims 1 to 3, wherein X3 to X5 are each independently selected from hydrogen and halogen.

7. The compound of any one of claims 1 to 6, wherein X3 and X4 are each independently -F.

8. The compound of any one of claims 1 to 7, wherein n is 1.

9. The compound of any one of claims 1 to 8, wherein m is 1.

10. The compound of any one of claims 1 to 9, wherein Rlais independently selected from hydrogen, halogen, C1-3 haloalkyl, unsubstituted C1-3 alkyl, unsubstituted C1-3 alkoxy, C1-3 haloalkoxy, substituted or unsubstituted 3-4 membered cycloalkyl, and substituted or unsubstituted 3-4 membered cycloalkoxy.

11. The compound of any one of claims 1 to 10, wherein Rlbis independently selected from hydrogen, halogen, C1-3 haloalkyl, unsubstituted C1-3 alkyl, unsubstituted C1-3 alkoxy, C1-3 haloalkoxy, substituted or unsubstituted 3-4 membered cycloalkyl, and substituted or unsubstituted 3-4 membered cycloalkoxy.

12. The compound of any one of claims 1 to 11, wherein each Rlcis independently selected from hydrogen, halogen, C1-3 haloalkyl, unsubstituted C1-3 alkyl, unsubstituted C1-3 alkoxy, C1-3 haloalkoxy, substituted or unsubstituted 3-4 membered cycloalkyl, and substituted or unsubstituted 3-4 membered cycloalkoxy.

13. The compound of any one of claims 1 to 12, wherein Rlaand one Rlctogether with the atoms attached thereto form a 3 -membered cycloalkyl fused to the ring to which Rlaand Rlcare attached.

14. The compound of any one of claims 1 and 3 to 13, wherein p is 1 or 2.

15. A compound of formula (II)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:Xi to X5 are independently selected from the group consisting of hydrogen, halogen, C1-5 haloalkyl, C1-5 alkyl, and OH;Xe is selected from the group consisting of -C-, -O-, -N-, or -S-;Rlaand Rlbare independently selected from hydrogen or -F; each Rlcis independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted 3-5 membered cycloalkyl, substituted or unsubstituted C1-5 alkoxy, and halogen; n is 0 or 1; m is 0 or 1; provided that n + m is 1 or 2; p is 0, 1, 2, 3, 4, or 5; andq is 0 or 1; provided that when Xi is halogen or C1-5 haloalkyl, n is 1, m is 1 and q is 0, then Rlaand Rlbare not both -F.

16. The compound of claim 15, wherein the compound is of formula (Ila):or a pharmaceutically acceptable salt thereof.

17. The compound of claim 15 or claim 16, wherein Xi is selected from -F, -Cl and -CF3.

18. The compound of claim 15 or claim 16, wherein X2 is hydrogen or -F.

19. The compound of claim 15 or claim 16, wherein X3 to X5 are each independently selected from hydrogen, -CH3 and -OH.

20. The compound of any one of claims 15 to 19, wherein X3and X4are each independently - CH3.

21. The compound of any one of claims 15 to 20, wherein Xe is -C- or -O-.

22. The compound of any one of claims 15 to 21, wherein n is 1.

23. The compound of any one of claims 15 to 22, wherein m is 1.

24. The compound of any one of claims 15 to 23, wherein Rlaand Rlbare both hydrogen.

25. The compound of any one of claims 15 to 24, wherein each Rlcis independently selected from hydrogen, C1-3 alkyl, and halogen.

26. The compound of any one of claims 15 to 25, wherein p is 1 or 2.

27. The compound of any one of claims 15 to 26, wherein q is 1.

28. A pharmaceutical composition comprising the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

29. The pharmaceutical composition of claim 28, further comprising an additional therapeutic agent.

30. A method of modulating TMEM175 in a subject, the method comprising administering to the subject: (i) the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 28 or claim 29.

31. A method of treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 28 or claim 29.

32. The method of claim 31, wherein the neurodegenerative disorder is selected from Parkinson’s disease (PD), Parkinsonism, Alzheimer’s disease (AD), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age related memory dysfunction, mild cognitive impairment, argyrophilic grain disease, lysosomal disorders, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms / relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV-associated dementia (HAD).

33. The method of claim 32, wherein the neurodegenerative disorder is Parkinson’s disease (PD).

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