TMEM175 modulators

Abstract

Provided herein are TMEM175 modulators having Formula (I) and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof. Also provided herein are pharmaceutical compositions of compounds of Formula (I) or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, and methods of treating neurodegenerative disorders using the same.

Description

[0001] PATENT

[0002] TMEM175 MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] [1] This application claims the benefit of U.S. Provisional patent application No. 63 / 691,615, filed on September 6, 2024, which is hereby incorporated by reference in its entirety.

[0004] BACKGROUND

[0005] [2] The field of the disclosure relates generally to heteroaryl 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-fimction 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 PATENT 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] R1is selected from the group consisting of hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted phenyl;

[0012] R2is selected from hydrogen, substituted or unsubstituted C1-3 alkyl, and substituted or unsubstituted C3-4 cycloalkyl;

[0013] R3is selected from the group consisting of substituted or unsubstituted C1-5 alkyl; substituted or unsubstituted C1-5 alkoxy; substituted or unsubstituted C3-6 cycloalkyl; substituted or unsubstituted aryl; and substituted or unsubstituted 3-6 membered heterocycle, wherein the substituted or unsubstituted 3-6 membered heterocycle comprises one or more heteroatoms selected from O, N and S; or

[0014] R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted aryl;

[0015] R4is a substituted or unsubstituted C1-3 alkyl;

[0016] A is a substituted or unsubstituted 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more heteroatoms selected from O, N and S; and

[0017] B is selected from the group consisting of substituted or unsubstituted 6-membered heteroaryl, wherein the substituted or unsubstituted 6-membered heteroaryl comprises one or more heteroatoms selected from O, N and S; substituted or unsubstituted aryl; substituted or unsubstituted C1-3 haloalkyl; substituted or unsubstituted C1-3 haloalkoxy; and halogen.

[0018] DETAILED DESCRIPTION

[0019] [7] Provided herein are heteroaryl modulators of TMEM175, e.g., compounds of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Further provided are pharmaceutical compositions thereof, and methods fortheir use, e.g., for treating TMEM 175 -mediated diseases such as neurodegenerative disorders (e.g., Parkinson’s disease). PATENT

[0020] Also provided are methods of making the modulators of TMEM175 described herein, such as compounds of Formula (I).

[0021] [8] 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, iso-butyl, 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 polyhalogenated 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. PATENT

[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-Cs)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 include 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 include 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 bicyclic 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, PATENT quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, fiirazanyl, benzofiirazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and fiiropyridinyl. 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. Non-limiting 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. PATENT

[0039] Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

[0040]

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

[0041]

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

[0042]

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

[0043]

[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, i.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.

[0044]

[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.

[0045]

[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'- PATENT 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).

[0046]

[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.

[0047]

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

[0048]

[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. PATENT

[0049]

[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.

[0050]

[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.

[0051]

[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.

[0052]

[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.

[0053]

[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 PATENT compound of Formula (I), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0054]

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

[0055]

[0041] Compounds of Formula (I)

[0056]

[0042] Some embodiments of the present disclosure are directed to compounds of

[0057] Formula (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0058]

[0043] R1is selected from the group consisting of: hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted phenyl. In some embodiments R1is selected from hydrogen, -CH3, CH2CH3, phenyl, or cyclopropyl. In some embodiments, R1is -CH3.

[0059]

[0044] R2is selected from: substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or hydrogen. In some embodiments, R2is hydrogen or -CH3.

[0060]

[0045] R3is selected from the group consisting of: substituted or unsubstituted C1-5 alkyl; substituted or unsubstituted C1-5 alkoxy; substituted or unsubstituted C3-6 cycloalkyl; substituted or unsubstituted aryl; and substituted or unsubstituted 3-6 membered heterocycle, wherein the substituted or unsubstituted 3-6 membered heterocycle comprises one or more heteroatoms selected from O, N and S. R3is selected from the group consisting of: substituted or unsubstituted C1-5 alkyl; substituted or unsubstituted C1-5 alkoxy; substituted or unsubstituted C3-6 cycloalkyl; and substituted or unsubstituted 3-6 membered heterocycle, wherein the substituted or unsubstituted 3-6 membered heterocycle comprises one or more heteroatoms selected from O, N and S. In some embodiments, R3is selected from the group consisting of: substituted or unsubstituted C1-3 alkyl; substituted or unsubstituted C1-5 alkoxy; substituted or unsubstituted C3-4 cycloalkyl; substituted or unsubstituted aryl; and substituted or unsubstituted 3-4 membered heterocycle, wherein the substituted or unsubstituted 3-4 membered heterocycle comprises one or more heteroatoms selected from O, N and S. In some embodiments, R3is selected from the group consisting of: substituted or unsubstituted C1-3 alkyl; substituted or unsubstituted C1-5 alkoxy; substituted or unsubstituted C3-4 cycloalkyl; and substituted or unsubstituted 3-4 membered heterocycle, wherein the substituted or unsubstituted 3-4 membered heterocycle comprises one or more heteroatoms PATENT selected from O, N and S. In some embodiments, R3is selected from a substituted C1-3 alkyl, substituted C1-3 alkoxy, substituted or unsubstituted cyclopropyl, unsubstituted aryl, and substituted 3-4 membered heterocycle, wherein the substituted 3-4 membered heterocycle comprises one or more heteroatoms selected from O, N and S. In some embodiments, R3is selected from a substituted C1-3 alkyl, substituted C1-3 alkoxy, substituted or unsubstituted cyclopropyl, and substituted 3-4 membered heterocycle, wherein the substituted 3-4 membered heterocycle comprises one or more heteroatoms selected from O, N and S. In some embodiments, R3 is selected from -CH3, -CF3, -CF2H, -CF2CH3, phenyl, -OCF3,

[0061] CH2(CH3)2, cyclopropyl, , and -7 Z-<F. In some embodiments, R3 is selected from

[0062] -CH3, -CF3, -CF2H, -CF2CH3, -OCF3, CFb CHs , cyclopropyl,

[0063]

[0046] In some embodiments, R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted aryl. In some embodiments, R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-4 cycloalkyl, or an unsubstituted aryl. In some embodiments, R2and R3together with the carbon atom attached thereto join to form a cyclopropyl,

[0064]

[0047] In some embodiments, R4is a substituted or unsubstituted C1-3 alkyl or a substituted or unsubstituted C3-4 cycloalkyl.

[0065]

[0048] In some embodiments, R4is a substituted or unsubstituted C1-3 alkyl. In some embodiments, R4is unsubstituted C1-3 alkyl. In some embodiments, R4is substituted C1-3 alkyl. In some embodiments, R4is methyl, ethyl, or n-propyl. In some embodiments, R4is methyl, ethyl, or -CH2CF2H. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl or -CH2CF2H. In some embodiments, R4is methyl. In some embodiments, R4is -CH2CF2H.

[0066]

[0049] In some embodiments, R4is a C1-3 alkyl substituted with one or more halogen, C1-5 haloalkyl, or OH. In some embodiments, R4is a substituted or unsubstituted C3-4 cycloalkyl.

[0067]

[0050] In some embodiments, R4is CH3, CH3CH2, CH3OCH2, CF3OCH2, C3-4 cycloalkyl, CH2OH, or C1-3 haloalkyl; PATENT

[0068]

[0051] A is selected from: a substituted or unsubstituted 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more heteroatoms selected from O, N and S; or a substituted or unsubstituted amide. In some embodiments, A is selected from: some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, some embodiments,

[0069]

[0052] B is selected from substituted or unsubstituted 6-membered heteroaryl, wherein the substituted or unsubstituted 6-membered heteroaryl comprises one or more heteroatoms selected from O, N and S; substituted or unsubstituted aryl; substituted or unsubstituted C1-3 haloalkyl; substituted or unsubstituted C1-3 haloalkoxy; and halogen. In some embodiments,

[0070] X2 is -Cl or -F. In some embodiments, B is , wherein Xi is -C- or -N-, and X2 is -Cl or -F.

[0071]

[0053] In some embodiments, the compound of Formula (I) is a compound of Formula (II): wherein: ring Y is aryl or 5- or 6- membered heteroaryl, wherein the 5- or 6-membered heteroaryl comprises one or more heteroatoms selected from O, N and S, PATENT each X is each independently H, D, halo, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, C1-5 haloalkyl, C1-5 haloalkoxy, -O-C3-6 cycloalkyl, - S(O)Ra, or -SChR3; wherein Rais -CH3 or -(CgHOCHs;

[0072] R1, R2, R3, and R4are defined as above;

[0073] R5is H, D, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; and m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0074]

[0054] In some embodiments, the compound of Formula (I) is a compound of Formula (Ila): wherein: each X is each independently H, D, halo, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, C1-5 haloalkyl, C1-5 haloalkoxy, -O-C3-6 cycloalkyl, - S(O)Ra, or -SChR3; wherein Rais -CH3 or -(CeH^CIt;

[0075] R1, R2, R3, and R4are defined as above;

[0076] R5is H, D, halo, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; and m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0077]

[0055] In some embodiments, the compound of Formula (I) is a compound of Formula (III): wherein:

[0078] R1, R2, R3, and R4are defined as above;

[0079] R6is H, D, halo, oxo, CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;

[0080] R7is H, halo, oxo, CN, C1-3 alkyl, or C1-3 haloalkyl;

[0081] W is N or CH;

[0082] Z is selected from the group consisting of H, CN, haloalkyl, substituted or unsubstituted 6-membered aryl; substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-9 PATENT membered heteroaryl, wherein the substituted or unsubstituted 5-9 membered heteroaryl comprises one or more heteroatoms selected from O, N and S; substituted or unsubstituted 4-8 membered heterocycle, wherein the substituted or unsubstituted 4-8 membered heterocycle comprises one or more ring atoms selected from O, N, and S; and -NR2aR2b; and

[0083] R2aand R2bare each independently H, Ci-6 alkyl, or Ci-6 haloalkyl; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0084]

[0056] In some embodiments, W is CH. In some embodiments, W is N.

[0085]

[0057] In some embodiments, R7is halo, CN, or C1-3 haloalkyl. In some embodiments, R7is halo or C1-3 haloalkyl. In some embodiments, R7is halo. In some embodiments, R7is CN. In some embodiments, R7is C1-3 haloalkyl. In some embodiments, R7is -F or -Cl. In one embodiment, R7is -F. In another embodiment, R7is -Cl.

[0086]

[0058] In some embodiments, R6is H, D, halo, CN, or C1-3 alkyl. In some embodiments, R6is H, D, or halo. In some embodiments, R6is H or D. In some embodiments, R6is H. In some embodiments, R6is D. In some embodiments, R6is halo.

[0087]

[0059] In some embodiments, R7is halo and R6is H, D, or halo. In some embodiments, R7is halo and R6is H or D. In some embodiments, R7is halo and R6is halo. In some embodiments, R7is halo and R6is H. In some embodiments, R7is halo and R6is D. In some embodiments, R7is -F and R6is H, D, or halo. In some embodiments, R7is -Cl and R6is H, D, or halo. In some embodiments, R7is -F and R6is H or D. In some embodiments, R7is -Cl and R6is H or D. In some embodiments, R7is -F and R6is H. In some embodiments, R7is -Cl and R6is H.

[0088]

[0060] In some embodiments, Z is substituted or unsubstituted 6-membered aryl. In some embodiments, Z is substituted phenyl. In some embodiments, Z is halo substituted phenyl. In some embodiments, Z is phenyl substituted with 1 or 2 halo.

[0089]

[0061] In some embodiments, the compound of Formula (I) is a compound of Formula (Illa): wherein:

[0090] R1, R2, R3, and R4are defined as above;

[0091] R6is H, D, halo, oxo, CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy;

[0092] R7is H, halo, oxo, CN, C1-3 alkyl, or C1-3 haloalkyl; PATENT

[0093] Z is selected from the group consisting of H, CN, haloalkyl, substituted or unsubstituted 6-membered aryl; substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 5-9 membered heteroaryl, wherein the substituted or unsubstituted 5-9 membered heteroaryl comprises one or more heteroatoms selected from O, N and S; substituted or unsubstituted 4-8 membered heterocycle, wherein the substituted or unsubstituted 4-8 membered heterocycle comprises one or more ring atoms selected from O, N, and S; and -NR2aR2b; and

[0094] R2aand R2bare each independently H, C1-6 alkyl, or C1-6 haloalkyl; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0095]

[0062] In some embodiments, R7is halo, CN, or C1-3 haloalkyl. In some embodiments, R7is halo or C1-3 haloalkyl. In some embodiments, R7is halo. In some embodiments, R7is CN. In some embodiments, R7is C1-3 haloalkyl. In some embodiments, R7is -F or -Cl. In one embodiment, R7is -F. In another embodiment, R7is -Cl.

[0096]

[0063] In some embodiments, R6is H, D, halo, CN, or C1-3 alkyl. In some embodiments, R6is H, D, or halo. In some embodiments, R6is H or D. In some embodiments, R6is H. In some embodiments, R6is D. In some embodiments, R6is halo.

[0097]

[0064] In some embodiments, R7is halo and R6is H, D, or halo. In some embodiments, R7is halo and R6is H or D. In some embodiments, R7is halo and R6is halo. In some embodiments, R7is halo and R6is H. In some embodiments, R7is halo and R6is D. In some embodiments, R7is -F and R6is H, D, or halo. In some embodiments, R7is -Cl and R6is H, D, or halo. In some embodiments, R7is -F and R6is H or D. In some embodiments, R7is -Cl and R6is H or D. In some embodiments, R7is -F and R6is H. In some embodiments, R7is -Cl and R6is H.

[0098]

[0065] In some embodiments, Z is substituted or unsubstituted 6-membered aryl. In some embodiments, Z is substituted phenyl. In some embodiments, Z is halo substituted phenyl. In some embodiments, Z is phenyl substituted with 1 or 2 halo.

[0099]

[0066] In some embodiments, the compound of Formula (I) is a compound of Formula (Illb): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0100]

[0067] In some embodiments, R7is halo, CN, or C1-3 haloalkyl. In some embodiments, R7is halo or C1-3 haloalkyl. In some embodiments, R7is halo. In some embodiments, R7is CN. In some embodiments, R7is C1-3 haloalkyl. In some embodiments, R7is -F or -Cl. In one embodiment, R7is -F. In another embodiment, R7is -Cl. PATENT

[0101]

[0068] In some embodiments, R6is H, D, halo, CN, or C1-3 alkyl. In some embodiments, R6is H, D, or halo. In some embodiments, R6is H or D. In some embodiments, R6is H. In some embodiments, R6is D. In some embodiments, R6is halo.

[0102]

[0069] In some embodiments, R7is halo and R6is H, D, or halo. In some embodiments, R7is halo and R6is H or D. In some embodiments, R7is halo and R6is halo. In some embodiments, R7is halo and R6is H. In some embodiments, R7is halo and R6is D. In some embodiments, R7is -F and R6is H, D, or halo. In some embodiments, R7is -Cl and R6is H, D, or halo. In some embodiments, R7is -F and R6is H or D. In some embodiments, R7is -Cl and R6is H or D. In some embodiments, R7is -F and R6is H. In some embodiments, R7is -Cl and R6is H.

[0103]

[0070] In some embodiments, Z is substituted or unsubstituted 6-membered aryl. In some embodiments, Z is substituted phenyl. In some embodiments, Z is halo substituted phenyl. In some embodiments, Z is phenyl substituted with 1 or 2 halo.

[0104]

[0071] In some embodiments, the compound of Formula (I) is a compound of Formula (IV): wherein:

[0105] R1, R2, R3, and R4are defined as above; and

[0106] X3 and X4 are independently selected from the group consisting of hydrogen, halogen, C1-5 haloalkyl, and OH; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0107]

[0072] In some embodiments, the disclosure comprises compounds of Formula (I) and a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0108]

[0073] In some embodiments, the compound of Formula (I) is selected from the compounds listed in Table 1 :

[0109]

[0074] Table 1 PATENT PATENT PATENT PATENT PATENT PATENT PATENT PATENT PATENT PATENT PATENT PATENT

[0110]

[0075] Pharmaceutical Compositions

[0111]

[0076] In some embodiments, pharmaceutical compositions of compound Formula (I) are provided. In such embodiments, the pharmaceutical compositions comprise (i) compound Formula (I) or a pharmaceutically acceptable salt, stereoisomer, and tautomer thereof in combination with at least one pharmaceutically acceptable excipient.

[0112]

[0077] 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 PATENT administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.

[0113]

[0078] 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.

[0114] 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.

[0115]

[0079] The compositions comprising the compound of Formula (I) 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.

[0116]

[0080] 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.

[0117]

[0081] 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 PATENT 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.

[0118]

[0082] 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.

[0119]

[0083] 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.

[0120]

[0084] In some embodiments, pharmaceutical compositions comprising the compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, further comprise an additional therapeutic agent.

[0121]

[0085] Combination Therapy

[0122]

[0086] 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.

[0123]

[0087] 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 co-administered 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, safmamide), amantadine, anticholinergic medications (trihexyphenidyl, PATENT benztropine mesylate), acetylcholinesterase inhibitors (rivastigmine), serotonin 5-HT2A receptor agonists (pimavanserin), or dopamine transporters for imaging (ioflupane 1-123).

[0124]

[0088] 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.

[0125]

[0089] 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.

[0126]

[0090] 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.

[0127]

[0091] Methods of Treatment

[0128]

[0092] 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.

[0129]

[0093] 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) as described herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein. PATENT

[0130]

[0094] 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 a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein.

[0131]

[0095] 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 a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein.

[0132]

[0096] Use of a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a disease, disorder or condition in a subject in need thereof.

[0133]

[0097] Use of a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a TMEM 175 -mediated disorder in a subject in need thereof.

[0134]

[0098] Use of a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for modulating TMEM 175 in a subject.

[0135]

[0099] The compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer 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.

[0136]

[0100] The compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer 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.

[0137]

[0101] 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), PATENT 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).

[0138]

[0102] 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.

[0139]

[0103] 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.

[0140]

[0104] 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) 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.

[0141]

[0105] 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 dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the PATENT 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.

[0142]

[0106] 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.

[0143]

[0107] 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.

[0144]

[0108] 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, stereoisomer, or tautomer thereof; or (ii) a pharmaceutical composition comprising Formula (I) as described elsewhere herein.

[0145]

[0109] 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, stereoisomer, or tautomer thereof; or (ii) a pharmaceutical composition comprising Formula (I) as described elsewhere herein.

[0146]

[0110] 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, stereoisomer, or tautomer thereof; or (ii) a pharmaceutical composition comprising Formula (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof as described elsewhere herein.

[0147]

[0111] Embodiments

[0148]

[0112] Also provided herein are exemplary embodiments: PATENT

[0149]

[0113] Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

[0150] R1is selected from the group consisting of hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted phenyl;

[0151] R2is selected from hydrogen, substituted or unsubstituted C1-5 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;

[0152] R3is selected from the group consisting of substituted or unsubstituted C1-5 alkyl; substituted or unsubstituted C1-5 alkoxy; substituted or unsubstituted C3-6 cycloalkyl; substituted or unsubstituted aryl; and substituted or unsubstituted 3-6 membered heterocycle, wherein the substituted or unsubstituted 3-6 membered heterocycle comprises one or more heteroatoms selected from O, N and S; or

[0153] R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted aryl;

[0154] R4is a substituted or unsubstituted C1-3 alkyl;

[0155] A is a substituted or unsubstituted 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more heteroatoms selected from O, N and S; and

[0156] B is selected from the group consisting of substituted or unsubstituted 6-membered heteroaryl, wherein the substituted or unsubstituted 6-membered heteroaryl comprises one or more heteroatoms selected from O, N and S; substituted or unsubstituted aryl; substituted or unsubstituted C1-3 haloalkyl; substituted or unsubstituted C1-3 haloalkoxy; and halogen.

[0157]

[0114] Embodiment 2. The compound of Embodiment 1, wherein R1is selected from the group consisting of substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C3- 4 cycloalkyl, hydrogen, and substituted or unsubstituted phenyl.

[0158]

[0115] Embodiment 3. The compound of Embodiment 1, wherein R1is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and cyclopropyl.

[0159]

[0116] Embodiment 4. The compound of any one of Embodiments 1 to 3, wherein R1is methyl.

[0160]

[0117] Embodiment 5. The compound of any one of Embodiments 1 to 3, wherein R2is hydrogen or -CH3. PATENT

[0161]

[0118] Embodiment 6. The compound of any one of Embodiments 1 to 5, wherein R3is selected from the group consisting of substituted or unsubstituted C1-3 alkyl; substituted or unsubstituted C1-3 alkoxy; substituted or unsubstituted C3-4 cycloalkyl; unsubstituted aryl; and substituted or unsubstituted 3-4 membered heterocycle, wherein the substituted 3-4 membered heterocycle comprises one or more heteroatoms selected from O, N and S.

[0162]

[0119] Embodiment 7. The compound of any one of Embodiments 1 to 6, wherein R3is selected from a substituted C1-3 alkyl, substituted C1-3 alkoxy, substituted or unsubstituted cyclopropyl, unsubstituted aryl, and substituted 3-4 membered heterocycle, wherein the substituted 3-4 membered heterocycle comprises one or more heteroatoms selected from O, N and S.

[0163]

[0120] Embodiment 8. The compound of any one of Embodiments 1 to 7, wherein R3is selected from the group consisting of -CH3, -CF3, -CF2H, -CF2CH3, phenyl, -OCF3, -

[0164]

[0121] Embodiment 9. The compound of any one of Embodiments 1 to 3, wherein R2and R3together with the carbon atom attached thereto j oin to form a substituted or unsubstituted C3-6 cycloalkyl, or an unsubstituted aryl.

[0165]

[0122] Embodiment 10. The compound of Embodiment 9, wherein R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-6 cycloalkyl.

[0166]

[0123] Embodiment 11 . The compound of Embodiment 9 or Embodiment 10, wherein R2and R3together with the carbon atom attached thereto j oin to form a substituted or unsubstituted C3-4 cycloalkyl.

[0167]

[0124] Embodiment 12. The compound of Embodiment 11, wherein R2and R3together with the carbon atom attached thereto join to form a cyclopropyl, or

[0168]

[0125] Embodiment 13. The compound of any one of Embodiments 1 to 12, wherein R4is unsubstituted C1-3 alkyl.

[0169]

[0126] Embodiment 14. The compound of any one of Embodiments 1 to 12, wherein R4is substituted C1-3 alkyl. PATENT

[0170]

[0127] Embodiment 15. The compound of any one of Embodiments 1 to 12, wherein R4is methyl or -CH2CF2H.

[0171]

[0128] Embodiment 16. The compound of any one of Embodiments 1 to 15, wherein A

[0172]

[0129] Embodiment 17. The compound of any one of Embodiments 1 to 16, wherein B wherein X1is -CH- or -N-, and X2is -Cl or -F.

[0173]

[0130] Embodiment 18. A pharmaceutical composition comprising the compound of any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and at least one pharmaceutically acceptable excipient.

[0174]

[0131] Embodiment 19. The pharmaceutical composition of Embodiment 18, further comprising an additional therapeutic agent.

[0175]

[0132] Embodiment 20. A method of modulating TMEM175 in a subject, the method comprising administering to the subject: (i) the compound of any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; or (ii) the pharmaceutical composition of Embodiment 18 or Embodiment 19.

[0176]

[0133] Embodiment 21. 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 Embodiments 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; or (ii) the pharmaceutical composition of Embodiment 18 or Embodiment 19.

[0177]

[0134] Embodiment 22. The method of Embodiment 21, 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 PATENT symptoms / relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV-associated dementia (HAD).

[0178]

[0135] Embodiment 23. The method of Embodiment 22, wherein the neurodegenerative disorder is Parkinson’s disease (PD).

[0179]

[0136] Examples

[0180]

[0137] Example 1: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)-A'-

[0181] (cyclopropylmcthyl)-A'-mcthylpropanamidc

[0182]

[0138] Step 1: 5-(5-chloropyridin-2-yl)oxazole. A solution of 5 -chloropyridine -2- carbaldehyde (10.00 g, 70.64 mmol),p-toluenesulfonylacetonitrile (16.50 g, 84.51 mmol) and potassium carbonate (19.50 g, 141.30 mmol) in methyl alcohol (200 mb) was stirred at 80 °C for 2 hours. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4: 1) to afford the title compound (8.00 g, 44.30 mmol, 62.7% yield) as a yellow solid. LC-MS: (ESI, m / z): 181.0 [M+H]+

[0183]

[0139] Step 2: 2-chloro-5-(5-chloropyridin-2-yl)oxazole. Under nitrogen, to a solution of 5-(5-chloro-2-pyridyl)oxazole (6.80 g, 37.65 mmol) in tetrahydrofuran (70 mL) was added lithium bis(trimethylsilyl)amide (45.19 mL, 45.19mmol, IM in tetrahydrofuran) dropwise at - 78 °C. The resulting solution was stirred for 0.5 hours at -78 °C. Then hexachloroethane (6.39 mL, 56.48 mmol) in tetrahydrofuran (10 mL) was added into the mixture dropwise at - 78 °C and stirred at room temperature for 2 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and the organic layers were PATENT 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 (4: 1) to afford the title compound (7.30 g, 33.95 mmol, 90.2% yield) as a white solid. LC-MS: (ESI, m / z): 215.0 [M+H]+

[0184]

[0140] Step 3: tert-butyl (5-(5-chloropyridin-2-yl)oxazol-2-yl)-D-alaninate. A solution of 2-chloro-5-(5-chloro-2-pyridyl)oxazole (1.00 g, 4.65 mmol), tert-butyl D-alaninate hydrochloride (1.69 g, 9.30 mmol), A'.A'-diisopropylcthylaminc (3.00 g, 23.26 mmol) in dimethyl sulfoxide (5 m ) was stirred at 100 °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 residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (5: 1) to afford the title compound (1.00 g, 3.09 mmol, 66.4% yield) as a white solid. LC-MS: (ESI, m / z): 324.1 [M+H]+

[0185]

[0141] Step 4: (5-(5-chloropyridin-2-yl)oxazol-2-yl)-D-alanine. A solution of tert-butyl (5- (5-chloropyridin-2-yl)oxazol-2-yl)- / )-alaninatc (1.00 g, 3.09 mmol) in trifluoroacetic acid (5 mL) and dichloromethane (15 mL) was stirred at 25 °C for 15 hours. After completion, the solvent was removed under vacuum to afford the title compound (830 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 268.0 [M+H]+

[0186]

[0142] Step 5: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)-A'-(cyclopropylmcthyl)- A-methylpropanamide. To a solution of (5-(5-chloropyridin-2-yl)oxazol-2-yl)- / )-alaninc (80.0 mg, 0.30 mmol), 1-cyclopropyl-A-methylmethanamine (43.8 mg, 0.36 mmol) and N,N- diisopropylethylamine (192.7 mg, 1.49 mmol) in dichloromethane (1 mL) was added 2-(7- azabenzotriazol- l-yl)- / V, N, N', A'-tetramethyluronium hexafluorophosphate (170.4 mg, 0.45 mmol). The mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 45% B inl0.5min; Wave Length: 254 / 220 nm; RTl(min): 8.42 to afford the title compound (17.7 mg, 0.05 mmol, 17.5% yield) as a white solid. LC-MS: (ESI, m / z): 335.2 [M+H]+

[0187]

[0143] Example 2: (R)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)-N-ethyl-N- isobutylpropanamide PATENT

[0188] Synthetic Route:

[0189]

[0144] To a solution of (5-(5-chloropyridin-2-yl)oxazol-2-yl)-D-alanine (100.0 mg, 0.37 mmol), A-ethyl-2-methylpropan-l -amine (61.9 mg, 0.45 mmol) and N.N- diisopropylethylamine (240.9 mg, 1.87 mmol) in dichloromethane (2 mb) was added 2-(7- azabcnzotriazol- l-yl)-A. ' ". "-tctramcthyluroniiim hexafluorophosphate (213.0 mg, 0.56 mmol). The mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture 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 on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (44.2 mg, 0.12 mmol, 33.6% yield) as a white soild.LC-MS: (ESI, m / z): 351.1 [M+H]+

[0190]

[0145] Example 3: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- '-mcthyl-A- (2,2,2-trifluoroethyl)propanamide PATENT

[0191] Synthetic Route:

[0192]

[0146] Step 1: tert-butyl (5-(4-chlorophenyl)-l, 3, 4-oxadiazol-2-yl)- / )-alaninatc. To a solution of 5-(4-chlorophcnyl)-3H- l .3.4-oxadiazol-2-onc (1.00 g, 5.09 mmol) and tert-butyl (2 / ?)-2-aminopropanoatc hydrochloride (1.39 g, 7.63 mmol) in dichloromethane (20 mL) was added A'.A'-diisopropylcthylaminc (3.28 g, 25.43 mmol) and IH-bcnzotriazol- 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]+.

[0193]

[0147] Step 2: (5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)-D-alanine. A solution of tertbutyl (5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)-D-alaninate (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]+.

[0194]

[0148] Step 3: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A'-mcthyl-A'-(2.2.2- trifhioroethyl)propanamide. To a solution of (5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)-D- alanine (100.0 mg, 0.37 mmol), methyl(2,2,2-trifluoroethyl)amine hydrochloride (83.8 mg, 0.56 mmol) and A'A'-diisopropylcthylaminc (241.0 mg, 1.87 mmol) in dichloromethane (2 mL) was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (364.1 mg, 0.56 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 2 hours. 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 Prep-HPLC with the PATENT following conditions: Column: XBridge BEH Shield RP18 Column, 30* 150 mm, 5 gm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 30%B to 52%B in 9 min; Wave Length: 254 / 220 nm to afford the title compound (31.6 mg, 0.09 mmol, 23.2% yield) as a white solid. LC-MS: (ESI, m / z): 362.9 [M+H]+.

[0195]

[0149] Example 4: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- '-cyclopropyl-A- methylpropanamide

[0196] Synthetic Route:

[0197]

[0150] To a solution of (2 / ?)-2-| |5-(5-chloro-2-pyridyl)oxazol-2-yl |amino|propanoic acid (100.0 mg, 0.37 mmol), A-cyclopropyl-mcthylaminc hydrochloride (120.6 mg, 1.12 mmol) and A'.A'-diisopropylcthylaminc (144.6 mg, 1.12 mmol) in dichloromethane (1.00 mb) was added 2-(7-azabcnzotriazol- l -yl)-A. '.A.A-tctramcthyliironiiim hexafluorophosphate (213.1 mg, 0.56 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 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 (31.0 mg, 0.10 mmol, 25.5% yield) as a white solid. LC-MS: (ESI, m / z): 321.1[M+H]+.

[0198]

[0151] Example 5: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)- / V-((l.s',3S)-3- methoxycyclobutyl)- / V-methylpropanamide PATENT

[0199]

[0152] To a solution of (2 / ?)-2-| |5-(4-chlorophcnyl)- 1 ,3,4-oxadiazol-2-yl ]amino]propanoic acid (100.0 mg, 0.37 mmol), ( l.s.3.s)-3-mcthoxy- '-mcthylcyclobiitan- l -aminc (55.9 mg, 0.49 mmol) and '. '-diisopropylcthylaminc (241.0 mg, 1.87 mmol) in dichloromethane (1 mL) was added propanephosphonic acid cyclic anhydride (262.0 mg, 0.41 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. 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: 27%B to 41%B inlO min; Wave Length: 254 / 220 nm; RTl(min): 7.7 to afford the title compound (31.4 mg, 0.08 mmol, 22.8% yield) as a white solid. LC-MS: (ESI, m / z): 365.0 [M+H]+.

[0200]

[0153] Example 6: (R)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- / V-(2,2- difluorocthyl)-A'-mcthylpropanamidc PATENT

[0201] Synthetic Route:

[0202]

[0154] Step 1 : tert-butyl (R)-( 1 -((2,2-difluoroethyl)(methyl)amino)- 1 -oxopropan-2- yl)carbamate. A solution of (tert-butoxycarbonyl)-D-alanine (1.09 g, 5.78 mmol), 2-(7- azabcnzotriazol- l-yl)-A. ' A'.N'-tctramcthyliironiiim hexafluorophosphate (2.40 g, 6.31 mmol), (2,2-difhioroethyl)(methyl)amine hydrochloride (689.1 mg, 5.26 mmol) and N,N- diisopropylethylamine (2.04 g, 15.77 mmol) in dichloromethane (5.00 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 title compound (700.0 mg, 2.62 mmol, 50.0% yield) as a yellow oil. LC-MS: (ESI, m / z): 267.1 [M+H]+.

[0203]

[0155] Step 2: ( / ?)-2-amino-A'-(2.2-difliiorocthyl)-A'-mcthylpropanamidc hydrochloride. A solution of tert-butyl ( / ?)-( I -((2.2-difl uorocthyl)(mcthyl )amino)- 1 -oxopropan-2-yl [carbamate (80.0 mg, 0.30 mmol) in hydrochloric acid (1 mL, 4 M in 1,4-dioxane) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (92.7 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 167.0 [M+H]+.

[0204]

[0156] Step 3: (R)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)-N-(2,2-difluoroethyl)-N- methylpropanamide. A solution of 2-chloro-5-(5-chloropyridin-2-yl)oxazole (80.0 mg, 0.37 mmol), ( / ?)-2-amino-A'-(2.2-difliiorocthyl)-A'-mcthylpropanamidc hydrochloride (92.7 mg, crude) and 'A'-diisopropylcthylaminc (144.2 mg, 1.12 mmol) in dimethyl sulfoxide (0.4 mL) PATENT was stirred at 100 °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 dichloromethane / methanol (8 / 1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions:

[0205] XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: water (10 mmol / L

[0206] NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 21% B to 41% B inl0.5min; Wave Length: 254 / 220 nm; RT1: 10.8 min to afford the title compound (28.8 mg, 0.08 mmol, 22.3% yield) as a white solid. LC-MS: (ESI, m / z): 345.2 [M+H]+.

[0207]

[0157] Example 7: (R)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- / V-isobutyl- / V- methylpropanamide

[0208] Synthetic Route:

[0209]

[0158] A solution of (2 / ?)-2-amino-A'-isobutyl-A'-mcthyl-propanamidc hydrochloride (98.9 mg, 0.51 mmol), 'A'-diisopropylcthylaminc (260.5 mg, 2.02 mmol) and 2-chloro-5-(5- chloropyridin-2-yl)oxazole (108.7 mg, 0.51 mmol) in dimethyl sulfoxide (0.3 mb) was stirred at 100 °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 (1: 1) to afford crude solid. The crude product was purified by Prep-HPLC with the following conditions: Column: PATENT

[0210] XBridge Prep Shield RP OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31%B to 56%B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 7.45 to afford the title compound (67.0 mg, 0.19 mmol, 39.3% yield) as a white solid. LC-MS: (ESI, m / z): 337.0 [M+H]+

[0211]

[0159] Example 8: (J?)-2-((5-(4-fhiorophenyl)-l,3,4-oxadiazol-2-yl)amino)- / V-methyl- / V-

[0212] (2,2,2-trifluoroethyl)propanamide

[0213] Synthetic Route:

[0214]

[0160] To a solution of ( / ?)-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)-A'-mcthyl- A'-(2.2.2-trifluorocthyl)propanamidc hydrochloride (57.0 mg, crude) and 5-(4-fluorophenyl)- l .3.4-oxadiazol-2(3 / / )-onc (46.6 mg, 0.26 mmol) in N, / V-dimethylformamide (0.8 mL) was added I / / -benzotri azol - 1 -yloxytris(dimethylamino)phosphoniumhexafluorophosphate (171.7 mg, 0.39 mmol) and '. '-diisopropylcthylaminc (134.2 mg, 1.04 mmol). The mixture was stirred at 25 °C for 1 hour. After completion, the solution was washed with water, and diluted with dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C 18 gel (acetonitrile / 0. 1% ammonium bicarbonate in water) to afford crude product. The crude 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; Flow rate: 60 mL / min; Gradient: 33% B to 59% B in 9 min, 59% B; PATENT

[0215] Wave Length: 254 / 220 nm; RTl(min): 8.18 to afford the title compound (25.6 mg, 0.07 mmol, 28.5% yield) as a white solid. LC-MS: (ESI, m, / z):347.0[ M+H| .

[0216]

[0161] Example 9a: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)-A'-mcthyl-A'-(( / ?)-

[0217] 1,1,1 -trifluoropropan-2-yl)propanamide

[0218]

[0162] Example 9b: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)-A'-mcthyl-A'-((.S)-

[0219] 1,1,1 -trifluoropropan-2-yl)propanamide

[0220]

[0163] To a solution of (5-(5-chloropyridin-2-yl)oxazol-2-yl)-D-alanine (230 mg, 0.60 mmol), l,l,l-trifhroro-N-methylpropan-2 -amine hydrochloride (383.3 mg, 3.02 mmol) and 'A'-diisopropylcthylaminc (390.1 mg, 3.02 mmol) in dichloromethane (1.00 mL) was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (640.2 mg, 0.95 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. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford crude product. The crude product was further separated by Prep-HPLC with the following conditions: Column: Xselect CSH Prep Fluoro Phenyl 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 in 10 PATENT min; Wave Length: 254 / 220 nm to afford product. The product was isolated by Chiral-Prep- HPLC with the following conditions: Column: (R, R)-WHELK-Ol-Kromasil, 2.11*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient: isocratic 25; Wave Length: 220 / 254 nm; RTl(min): 8.619; RT2(min): 14.612; Sample Solvent: EtOH; Injection Volume: 0.3 mL to afford (R)-2-((5-(5- chloropyridin-2-y 1 joxazol -2-y 1 jam ino)-A'-mcthyl - N-((R)- 1,1,1 -trifluoropropan-2- yljpropanamide (19.4 mg, 0.05 mmol, 8.3% yield) as a white solid and (R)-2-((5-(5- chloropyridin-2-y 1 joxazol -2-y 1 jam ino)-A'-mcthyl - N-((S)- 1,1,1 -trifluoropropan-2- yljpropanamide (25.9 mg, 0.06 mmol, 10.0% yield) as a white solid. LC-MS: (ESI, m / z . 377.0 [M+H]+.

[0221]

[0164] Example 10: (R)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- / V-methyl- / V-(2,2,2- trifluoroethyljpropanamide

[0222]

[0165] Step 1 : tert-butyl ( / ?)-( 1 -(methyl(2,2,2-trifluoroethyljaminoj- 1 -oxopropan-2- yljcarbamate . A solution of 2.2.2-trifl uoro- '-mcthy Icthan- 1 -amine hydrochloride (1.07 g, 7.16 mmol), (tert-butoxycarbonylj-D-alanine (1.35 g, 7.16 mmol), 2-(7-azabenzotriazol-l- ylj- 'A'.V.V-tctramcthyliironiiim hexafluorophosphate (4.08 g, 10.74 mmol) and N,N- diisopropylethylamine (4.99 mb, 28.63 mmol) in dichloromethane (10.0 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 residue was purified by flash PATENT chromatography on silica gel eluting with methanol / dichloromethane (1:9) to afford the title compound (2.00 g, 7.03 mmol, 98.3% yield) as a white solid. LC-MS: (ESI, m z):285. 1 | M+H| .

[0223]

[0166] Step 2: ( / ?)-2-amino-A'-mcthyl-A'-(2.2.2-trifluorocthyl)propanamidc hydrochloride.

[0224] A solution of tert-butyl ( / ?)-( I -(methyl (2.2.2-trifluorocthy I )amino)- 1 -oxop ropan-2- yl)carbamate (320.0 mg, 1.13 mmol) in hydrochloric acid (5.0 mL, 4 M in 1,4-dioxane) was stirred at 25 °C for 1 hour. After completion, the reaction solution was concentrated under vacuum to afford the title compound (300 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z .185.1 [M+H]+.

[0225]

[0167] Step 3: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)-A-mcthyl-A-(2.2.2- trifluoroethyl)propanamide. Under nitrogen, a solution of ( / ?)-2-amino-A-mcthyl-A-(2.2.2- trifhroroethyl)propanamide hydrochloride (104.0 mg, crude), 2-chloro-5-(5-chloropyridin-2- yl)oxazole (101.6 mg, 0.47 mmol) and A. '-diisopropylcthylaminc (304.4 mg, 2.36 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °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 on Cl 8 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford crude product. The crude 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 the title compound (56.1 mg, 0.15 mmol, 32.5% yield) as a white solid. LC-MS: (ESI, m z):363.0| M+H | .

[0226]

[0168] Example 11: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- '-cyclopropyl-A- isobutylpropanamide PATENT

[0227] Synthetic Route:

[0228]

[0169] To a solution of (5-(5-chloropyridin-2-yl)oxazol-2-yl)-D-alanine (100.0 mg, 0.26 mmol) and A'-isobutylcyclopropanaminc hydrochloride (78.2 mg, crude) in dichloromethane (1.0 mL) was added '. '-diisopropylcth laminc (202.5 mg, 1.57 mmol) and 2-(7- azabcnzotriazol- l-yl)-A'.A'.A''.A''-tctramcthyluroniiim hexafluorophosphate (149.6 mg, 0.39 mmol) was added and 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 C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column

[0229] 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 the title compound (40.3 mg, 0.11 mmol, 45.4% yield) as a white solid. LC-MS: (ESI, m z):363. I | M+H| .

[0230]

[0170] Example 12: (R)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- / V-((3- fluorooxctan-3-yl)mcthyl)-A'-mcthylpropanamidc PATENT

[0231] Synthetic Route:

[0232]

[0171] To a solution of (5-(5-chloropyridin-2-yl)oxazol-2-yl)-D-alanine (60.0 mg, 0.22 mmol) and l-(3-fluorooxetan-3-yl)-JV-methyhnethanamine hydrochloride (41.9 mg, 0.27 mmol) in dichloromethane (1.00 mL) was added A'.A'-diisopropylcthylaminc (115.9 mg, 0.90 mmol) and 2-(7-azabcnzotriazol- l -yl)-A'.A'.AW-tctramcthyluroniiim hexafluorophosphate (127.9 mg, 0.34 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 combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17%B to 45%B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 8. 15 to afford the title compound (17.4 mg, 0.05 mmol, 20.7% yield) as a white solid. LC-MS: (ESI, m / z): 369.1 [M+H]+.

[0233]

[0172] Example 13: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- '-mcthyl-A- (2-(trifluoromethoxy)ethyl)propanamide PATENT

[0234] Synthetic Route:

[0235]

[0173] Step 1: tert-butyl (2-(trifluoromethoxy)ethyl)carbamate. A solution of 2-

[0236] (trifluoromethoxy)ethan-l -amine hydrochloride (3.0 g, 18.18 mmol), triethylamine (9.2 g, 90.91 mmol) and di-tert-butyl dicarbonate (11.9 g, 54.55 mmol) in tetrahydrofuran (30 mL) 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 in vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (70:30) to afford the title compound (2.3 g, 10.04 mmol, 55.2% yield) as a yellow oil. LC-MS: (ESI, m / z): 230.1 [M+H]+.

[0237]

[0174] Step 2: tert-butyl methyl(2-(trifluoromethoxy)ethyl)carbamate. To a solution of tert-butyl (2-(trifluoromethoxy)ethyl)carbamate (1.00 g, 4.36 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (261.8 mg, 6.54 mmol, 60% dispersion in mineral oil), the mixture was stirred at 0 °C for 10 minutes, then iodomethane (1.86 g, 13.09 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 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 the title compound (1.00 g, 4.11 mmol, 94.2% yield) as a white solid. LC-MS: (ESI, m / z): 244.1 [M+H]+.

[0238]

[0175] Step 3: A-methyl-2-(trifluoromethoxy)ethan-l -amine hydrochloride. A solution of tert-butyl methyl(2-(trifluoromethoxy)ethyl)carbamate (150.0 mg, 0.74 mmol) in hydrochloric acid (2 mL, 4 M in 1,4-dioxane) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (100 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 144.1 [M+H]+. PATENT

[0239]

[0176] Step 4: ( / )-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- '-mcthyl- '-(2- (trifluoromethoxy)ethyl)propanamide. To a solution of (5-(4-chlorophenyl)-l,3,4-oxadiazol- 2-yl)- / )-alaninc (100.0 mg, 0.37 mmol) and A'-mcthyl-2-(trifluoromcthoxy)cthan- l -amine hydrochloride (100.0 mg, crude) in dichloromethane (1 mL) was added N,N- diisopropylethylamine (241.1 mg, 1.87 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (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 dichloromethane. The organic layers were combined. The organic layer was 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 (40:60). The 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: 33%B to 58%B inl0.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.48 to afford the title compound (29.2 mg, 0.07 mmol, 19.9% yield) as a white solid. LC-MS: (ESI, m / z): 393.1 [M+H]+.

[0240]

[0177] Example 14: (R)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- / V-((l- fliiorocyclopropyl)mcthyl)- '-mcthylpropan amide

[0241]

[0178] Step 1: / rvv-butyl (( I -fluorocy clopropyl [methyl [carbarn ate. A solution of (1- fluorocyclopropyl)methanamine (2.0 g, 22.44 mmol), di- / e / 7-butyl dicarbonate (24.5 g,

[0242] 112.22 mmol) and triethylamine (6.81 g, 67.33 mmol) in tetrahydrofuran (20 mL) was stirred PATENT 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 / di chloromethane (1:20) to afford the title compound (2.50 g, 12.95 mmol, 57.7% yield) as a yellow solid. LC-MS: (ESI, m / z):

[0243] 190.1 [M+H]+.

[0244]

[0179] Step 2: tert-butyl ((l-fluorocyclopropyl)methyl)(methyl)carbamate. To a solution of tert-butyl ((l-fluorocyclopropyl)methyl)carbamate (1000.0 mg, 5.28 mmol) in A.A- dimethylformamide (10 m ) was added potassium tert-butoxide (7.93 m , 7.93 mmol, IM in tetrahydrofuran) and iodomethane (2.25 g, 15.85 mmol) at 0 °C. The mixture was stirred at 0 °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, and dried over anhydrous sodium sulfate. The organic layer was concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (97:3) to afford the title compound (300.0 mg, 1.48 mmol, 27.9% yield) as a yellow oil. EC-MS: (ESI, m / z):

[0245] 204.1 [M+H]+.

[0246]

[0180] Step 3: l-(l-fluorocyclopropyl)- / V-methylmethanamine trifluoroacetate. A solution of tert-butyl ((l-fluorocyclopropyl)methyl)(methyl)carbamate (150.0 mg, 0.74 mmol) in

[0247] 1,1, 1,3, 3, 3-hexafluoro-2 -propanol (3.8 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (100 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 104.1 [M+H]+.

[0248]

[0181] Step 4: (J?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- / V-((l- fluorocyclopropyl)methyl)-A-methylpropanamide. To a solution of (5-(5-chloropyridin-2- yl)oxazol-2-yl)- / )-alaninc (100.0 mg, 0.24 mmol) and I -(I -fluorocyclopropyl) -N- methylmethanamine trifluoroacetate (63.1 mg, crude) in dichloromethane (1 mL) was added 'A'-diisopropylcthylaminc (135.2 mg, 1.05 mmol) and 2-(7-azabcnzotriazol- l-yl)-A.A.A.A'- tetramethyluronium hexafluorophosphate (149.2 mg, 0.39 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 combined. The organic layer was 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 (60:40). The 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 PATENT mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23%B to 43%B inlO min; Wave Length: 254 / 220 nm; RTl(min): 10.47 to afford (7?)-2-((5-(5- chloropyridin-2-yl)oxazol-2-yl)amino)- / V-((l-fluorocyclopropyl)methyl)- / V- methylpropanamide (29.1 mg, 0.08 mmol, 31.4% yield) as a white solid. LC-MS: (ESI, m / z): 353.0 [M+H]+.

[0249]

[0182] Example 15: ( / ?)-2-((5-(5-chloropyridin-2-yl)oxazol-2-yl)amino)- '-mcthyl- '-(3.3.3- trifluoropropyl)propanamide

[0250] Synthetic Route:

[0251]

[0183] To a solution of (5-(5-chloropyridin-2-yl)oxazol-2-yl)-D-alanine (60.0 mg, 0.22 mmol) and 3,3,3-trifluoro-A-methylpropan-l-amine hydrochloride (55.0 mg, 0.34 mmol) in dichloromethane (1.00 mL) was added 'A'-diisopropylcthylaminc (86.9 mg, 0.67mmol) and 2-(7-azabcnzotriazol- l -yl)- 'A'.A.A-tctramcthyliironiiim hexafluorophosphate (127.9 mg, 0.34 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 combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1 % NH4HCO3 in water) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B inl0.5min; Wave Length: 254 / 220 PATENT nm; RTl(min): 8.7 to afford the title compound (19.7 mg, 0.05 mmol, 23.3% yield) as a white solid. LC-MS: (ESI, m / z): 377.1 [M+H]+.

[0252]

[0184] Example 16: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)- / V-(2,2- difluorocthyl)-A'-mcthylpropanamidc

[0253] Synthetic Route:

[0254]

[0185] To a solution of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(3E7)-one (100. Omg, 0.51mmol) and ( / ?)-2-amino-A'-(2.2-difluorocthyl)-A'-mcthylpropanamidc hydrochloride (206.1 mg, crude) in '. '-dimcthylformamidc (2 mL) was added A'.A'-diisopropylcthylaminc (328.7 mg, 2.54 mmol) and lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (450.0 mg, 1.02 mmol). The mixture was stirred at room temperature 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 organic layer was concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (55:45) 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 (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25%B to47%B in8min; Wave Length: 254 / 220 nm; RTl(min): 7.97 to afford ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A'-(2.2-difliiorocthyl)-A- methylpropanamide (24.8 mg, 0.07 mmol, 14.0% yield) as a white solid. LC-MS: (ESI, m / z): 345.1 [M+H]+. PATENT

[0255]

[0186] Example 17: ( / ?)-2-((6-(4-fliiorophcnyl)pyrimidin-4-yl)amino)-A'-isobutyl-A- methylpropanamide

[0256] Synthetic Route:

[0257]

[0187] Under nitrogen, a solution of ( / ?)-2-amino-A'-isobutyl-A'-mcthylpropanamidc hydrochloride (98.9 mg, crude), A'.A'-diisopropylcthylaminc (260.5 mg, 2.02 mmol) and 4- chloro-6-(4-fluorophenyl)pyrimidine (105.4 mg, 0.51 mmol) in dimethyl sulfoxide (0.3 mb) was stirred at 100 °C for 30 minutes. 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 (31.7 mg, 0.09 mmol, 19.0% yield) as a white solid. LC-MS: (ESI, m / z): 331.1 [M+H]+.

[0258]

[0188] Example 18: ( / ?)-A'-isobiityl-A'-mcthyl-2-((7-(trifluoromcthoxy)qiiinazolin-4- yl)amino)propanamide PATENT

[0259] Synthetic Route:

[0260]

[0189] Step 1: tert-butyl ( / ?)-( I -(isobutyl(mcthyl )amino)- 1 -oxopropan-2-yl [carbamate. A solution of A,2-dimethylpropan-l -amine (500.0 mg, 5.74 mmol), (tert-butoxycarbonyl)-D- alanine (1.19 g, 6.31 mmol), A'A'-diisopropylcthylaminc (2.96 g, 22.95 mmol) and 2-(7- azabcnzotriazol- l-yl)-A'.A'.AW-tctramcthyluroniiim hexafluorophosphate (2.61 g, 6.88 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 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 (800.0 mg, 3.09 mmol, 53.8% yield) as a yellow solid. LC- MS: (ESI, m / z): 259.2 [M+H]+.

[0261]

[0190] Step 2: ( / ?)-2-amino-A'-isobiityl-A'-mcthylpropanamidc hydrochloride. A solution of tert-butyl (7?)-(l -(isobutyl (methyl)amino)-l-oxopropan-2-yl)carbamate (182.3 mg, 0.94 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (130 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 159.1 [M+H]+.

[0262]

[0191] Step 3: ( / ?)-A'-isobiityl-A'-mcthyl-2-((7-(trifluoromcthoxy)qiiinazolin-4- yl)amino)propanamide. Under nitrogen, a solution of ( / ?)-2-amino-A'-isobiityl-A- methylpropanamide hydrochloride (73.7 mg, crude), A'.A'-diisopropylcthylaminc (196.0 mg, 1.52 mmol) and 4-chloro-7-(trifluoromethoxy)quinazoline (94.2 mg, 0.38 mmol) in dimethyl sulfoxide (0.2 mL) was stirred at 100 °C for 30 minutes. 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 crude solid. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase PATENT

[0263] B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 67% B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 8.53 to afford the title compound (19.5 mg, 0.05 mmol, 13.9% yield) as a white solid. LC-MS: (ESI, m / z): 371.1 [M+H]+.

[0264]

[0192] Example 19: ( / ?)-2-((5-(4-fliiorophcnyl)oxazol-2-yl)amino)- '-mcthyl- '-(2.2.2- trifluoroethyl)propanamide

[0265]

[0193] Step 1: tert-butyl ( / ?)-( l -(mcthyl(2.2.2-trifluorocthyl)amino)- l -oxopropan-2- yl)carbamate. To a solution of methyl(2,2,2-trifhroroethyl)amine hydrochloride (2.00 g, 13.37 mmol), (2 / ?)-2-(tcrt-biitoxycarbonylamino)propanoic acid (2.53 g, 13.37 mmol) and N.N- diisopropylethylamine (5.18 g, 40.12 mmol) in dichloromethane (10 mL) was added 2-(7- azabcnzotriazol- l-yl)- '. '.AW-tctramcthyluroniiim hexafluorophosphate (7.63 g, 20.06 mmol), the mixture was stirred at 25 °C for 2 hours. 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 (3.60 g, 12.41 mmol, 92.8% yield) as a colorless oil. LC-MS: (ESI, m / z): 285.1 [M+H]+.

[0266]

[0194] Step 2: ( / ?)-2-amino-A'-mcthyl-A'-(2.2.2-trifluorocthyl)propanamidc hydrochloride. To a solution of tert-butyl ( / ?)-( l -(mcthyl(2.2.2-trifluorocthyl)amino)- l-oxopropan-2- yl)carbamate (3.59 g, 12.63 mmol) in hydrochloric acid (5 mL, 4 M in 1,4-dioxane) was stirred PATENT at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (2.60 g, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 185.1 [M+H]+.

[0267]

[0195] Step 3: ( / )-2-((5-(4-fluorophcnyl)oxazol-2-yl)amino)-A-mcthyl-A-(2.2.2- trifluoroethyl)propenamide. A solution of ( / ?)-2-amino-A-mcthyl-A-(2.2.2- trifhroroethyl)propanamide hydrochloride (161.0 mg, crude), 2-chloro-5-(4- fluorophenyl)oxazole (120.0 mg, 0.61 mmol) and A.A-diisopropylcthylaminc (235.0 mg, 1.82 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °C for 1 hour. After completion, the resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (42.1 mg, 0.12 mmol, 20.0 % yield) as a yellow solid. LC-MS: (ESI, m / z): 346.1 [M+H]+.

[0268]

[0196] Example 20: ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)amino)-A-mcthyl-A- (2,2,2-trifluoroethyl)propanamide

[0269]

[0197] Under nitrogen, a solution of 2-bromo-5-(4-fluorophenyl)-l,3,4-thiadiazole (100.0 mg, 0.39 mmol), (2 / ?)-2-amino-A-mcthyl-A-(2.2.2-trifluorocthyl)propanamidc (107.6 mg, 0.58 mmol), Pd-PEPPSI-IPentCI o-picoline (32.4 mg, 0.04 mmol) and cesium carbonate (377.5 mg, 1.16 mmol) in 1,4-dioxane (1 mL) was added, the mixture was stirred at 100 °C for 0.5 hours. 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 PATENT anhydrous sodium sulfate and concentrated. The resulting residue 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: 30% B to 46% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 8.8 to afford the title compound (25.0 mg, 0.07 mmol, 17.8% yield) as a white solid. LC-MS: (ESI, m / z): 363.0 [M+H]+.

[0270]

[0198] Example 21: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)- '-mcthyl- '-(2.2.2- trifluoroethyl)propanamide

[0271] Synthetic Route:

[0272]

[0199] A solution of (2 / ?)-2-amino-A'-mcthyl-A'-(2.2.2- trifhroroethyl)propanamide;hydrochloride (100.0 mg, crude), 4,7-dichloroquinazoline (135.3 mg, 0.68 mmol) and A'.A'-diisopropylcthylaminc (175.4 mg, 1.36 mmol) in dimethyl sulfoxide (0.5 mb) was stirred at 100 °C for 0.5 hours. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (34.9 mg, 0.10 mmol, 21.9% yield) as awhite solid. LC-MS: (ESI, m / z): 347.1 [M+H]+.

[0273]

[0200] Example 22a: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-4.4-difliioro- '-mcthyl-A-

[0274] (2,2,2-trifluoroethyl)butanamide

[0275]

[0201] Example 22b: (S)-2-((7-chloroquinazolin-4-yl)amino)-4,4-difluoro- / V-methyl-JV-

[0276] (2,2,2-trifluoroethyl)butanamide PATENT

[0277]

[0202] Step 1: tert-butyl (4,4-difluoro-l-(methyl(2,2,2-trifluoroethyl)amino)-l-oxobutan-2- yl)carbamate. To a solution of 2-(( / ert-biitoxycarbonyl)amino)-4.4-difliiorobiitanoic acid (500.0 mg, 2.09 mmol) and 2,2,2-trifluoro-JV-methylethan-l -amine hydrochloride (375.1 mg, 2.51 mmol) in dichloromethane (3 mL) was added A'.A'-diisopropylcthylaminc (1.40 g, 10.45 mmol) and 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.60 g, 2.51 mmol, 50% in ethyl acetate), 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 combined. The organic layer was 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 (67:33) to afford the title compound (650.0 mg, 1.94 mmol, 92.8% yield) as a yellow oil. LC-MS: (ESI, m / z): 335.1 [M+H]+.

[0278]

[0203] Step 2: 2-amino-4.4-difluoro-A'-mcthyl-A'-(2.2.2-trifliiorocthyl)biitanamidc hydrochloride. A solution of tert-butyl (4,4-difluoro-l-(methyl(2,2,2-trifluoroethyl)amino)- l-oxobutan-2-yl)carbamate (200.0 mg, 0.60 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3.0 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (190.0 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, mlz).- 235. 1 [M+H]+.

[0279]

[0204] Step 3: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-4.4-difliioro-A'-mcthyl-A'-(2.2.2- trifluoroethyl)butanamide & (.S)-2-((7-chloroqiiinazolin-4-yl)amino)-4.4-difluoro-A'-mcthyl- A-(2,2,2-trifluoroethyl)butanamide. A solution of 2-amino-4.4-difliioro-A'-mcthyl-A'-(2.2.2- trifluoroethyl)butanamide hydrochloride (190.0 mg, crude) in dimethyl sulfoxide (0.5 mL), PATENT

[0280] A'.A'-diisopropylcthylaminc (389.6 mg, 3.01 mmol) and 4,7-dichloroquinazoline (120.0 mg, 0.60 mmol) was stirred at 100 °C for 0.5 hours. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford product. The product was separated by Prep-Chiral -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: DCM=1: 1; Flow rate: 20 mL / min; Gradient (B%): isocratic 20; Wave Length: 220 / 254 nm; RTl(min): 5.019; RT2(min): 6.617; Sample Solvent: EtOH; Injection Volume: 0.5 mL to afford (R)-2-((7-chloroquinazolin-4-yl)amino)-4,4-difluoro- / V-methyl- / V- (2,2,2-trifluoroethyl)butanamide (35.9 mg, 0.09 mmol, 14.9% yield) as a white solid and (.8')- 2-((7-chloroqiiinazolin-4-yl)amino)-4.4-difliioro-A'-mcthyl-A'-(2.2.2- trifluoroethyl)butanamide (23.7 mg, 0.06 mmol, 9.8% yield) as a white solid.

[0281]

[0205] Example 22a: *HNMR (300 MHz, DMSO-tA / yw?) 38.85 - 8.68 (m, 1H), 8.57 - 8.40 (m, 2H), 7.78 (d, J= 2.1 Hz, 1H), 7.71 - 7.61 (m, 1H), 6.53 - 5.94 (m, 1H), 5.54 - 5.31 (m, 1H), 5.03 - 4.02 (m, 2H), 3.32 - 2.93 (m, 3H), 2.74 - 2.25 (m, 2H). LC-MS: (ESI, mlz\. 397.0 [M+H]+. Chiral HPLC: Column: CHIRALPAK IF-3 4.6*50 mm 3 um; Hex(0.1%DEA):(EtOH:DCM=l: l)=80:20; Flow rate: 1.0 mL / min; Injection Volume: 3 uL; Retention time: 1.155 min(faster peak).

[0282]

[0206] Example 22b:1HNMR(500 MHz, DMSO-t / e. / ^m) d 8.87 - 8.72 (m, 1H), 8.56 - 8.41 (m, 2H), 7.81 - 7.76 (m, 1H), 7.70 - 7.63 (m, 1H), 6.43 - 6.05 (m, 1H), 5.49 - 5.33 (m, 1H), 4.98 - 4.10 (m, 2H), 3.34 - 2.88 (m, 3H), 2.65 - 2.25 (m, 2H). LC-MS: (ESI, mlz\. 397.0 [M+H]+. Chiral HPLC: Column: CHIRALPAK IF-3 4.6*50 mm 3 um; Hex(0.1%DEA):(EtOH:DCM=l: l)=80:20; Flow rate: 1.0 mL / min; Injection Volume: 3 uL; Retention time: 1.535 min(slower peak).

[0283]

[0207] Example 23a: (R)-4,4-difluoro-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)- A'-mcthyl-A'-(2.2.2-tri fl uorocthyljbutan amide

[0284]

[0208] Example 23b: (5)-4,4-difluoro-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)- A'-mcthyl-A'-(2.2.2-tri fl uorocthyljbutan amide PATENT

[0285] Synthetic Route:

[0286]

[0209] To a solution of 5-(4-fluorophenyl)-l,3,4-oxadiazol-2(327)-one (75.0 mg, 0.42 mmol) and 2-amino-4.4-difliioro- '-mcthyl- '-(2.2.2-trifluorocthyl)biitanamidc hydrochloride (146.1 mg, crude) in dichloromethane (2 mL) was added W-diisopropylcthylaminc (269.0 mg, 2.08 mmol) and \H- 1,2, 3 -benzotriazol- l-yloxy)tris(dimethylamino)phosphanium (368.3 mg, 0.83 mmol), the mixture was stirred at room temperature for 16 hours. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1 % NH4HCO3 in water) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge C18 OBD Prep Column, 100 A, 5 pm, 19 mm X 250 mm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 25 mL / min; Gradient (B%): 52%B to 70%B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 8.05 to afford product. The product was separated by Prep-Chiral- HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: ETOH: DCM=1: 1; Gradient (B%): isocratic 30; Wave Length: 220 / 254 nm; RTl(min): 5.149; RT2(min): 7.613; Sample Solvent: EtOH— HPLC to afford ( / ?)-4.4-difluoro-2-((5-(4-fluorophcnyl)- l.3.4-oxadiazol-2-yl)amino)- A'-mcthyl-A'-(2.2.2-trifluorocthyl)biitanamidc (28.0 mg, 0.07 mmol, 16.9% yield) as a white solid and (.S)-4.4-difliioro-2-((5-(4-fliiorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- '-mcthyl-A- (2,2,2-trifhroroethyl)butanamide (31.4 mg, 0.08 mmol, 19.0% yield) as a white solid.

[0287]

[0210] Example 23a:1HNMR (400 MHz, DMSO-rie. / ^m) d 8.64 - 8.49 (m, 1H), 7.91 - 7.81 (m, 2H), 7.44 - 7.35 (m, 2H), 6.42 - 6.03 (m, 1H), 4.89 - 4.81 (m, 1H), 4.78 - 4.10 (m, 2H), 3.29 - 2.95 (m, 3H), 2.43 - 2.19 (m, 2H). LC-MS: (ESI, mlz . 397.1 [M+H]+. Chiral HPLC: Column: CHIRALPAK IF-3 4.6*50 mm 3 um; Hex(0.1%DEA):(EtOH:DCM=l: l)=70:30; Flow rate: 1.0 mL / min; Injection Volume: 3 uL; Retention time: 1 .095 min (faster peak) PATENT

[0288]

[0211] Example 23b:JHNMR(400 MHz, DMSO-^. / yw?) h 8.66 - 8.49 (m, 1H), 7.91 - 7.81 (m, 2H), 7.45 - 7.35 (m, 2H), 6.41 - 6.05 (m, 1H), 4.90 - 4.79 (m, 1H), 4.77 - 4.06 (m, 2H), 3.30 - 2.93 (m, 3H), 2.44 - 2.18 (m, 2H). LC-MS: (ESI, m / z): 397.1 [M+H]+. Chiral HPLC: Column: CHIRALPAK IF-3 4.6*50 mm 3 um; Hex(0.1%DEA):(EtOH:DCM=l:l)=70:30; Flow rate: 1.0 mL / min; Injection Volume: 3 uL; Retention time: 1.614 min (slower peak)

[0289]

[0212] Example 24a: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-A-methyl-A- ((7?)-l, 1, l-trifluoropropan-2-yl)propanamide

[0290]

[0213] Example 24b: (7?)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)-A-methyl-A- ( (.S') - 1,1,1 -trifluoropropan-2-yl)propanamide

[0291]

[0214] Step 1: tert-butyl ((2 / ?)-l-(mcthyl( l. l. l -trifluoropropan-2-yl)amino)-l-oxopropan-2- yljcarbamate. A mixture of 1,1,1 -trifluoro -A-methylpropan-2 -amine hydrochloride (1.00 g, 6.36 mmol), (tert-butoxycarbonyl)-D-alanine (2.40 g, 12.72 mmol), N,N- diisopropylethylamine (2.46 g, 19.09 mmol) and 2-(7-azabenzotriazol-l-yl)-ArVrV,V- tetramethyluronium hexafluorophosphate (3.63 g, 9.54 mmol) in A'A'-dimcthylformamidc (1 mL) was stirred at 25 °C for 1 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 title compound (1.80 g, 6.03 mmol, 94.8% yield) as yellow oil. LC-MS: (ESI, m / z): 299.1 [M+H]+. PATENT

[0292]

[0215] Step 2: (2 / ?)-2-amino- '-mcthyl- '-( 1,1,1 -trifluoropropan -2 -yl)propanamide hydrochloride . A mixture of tert-butyl ((2R)- 1 -(methyl( 1,1,1 -trifluorop ropan-2-yl)amino)- 1 - oxopropan-2-yl)carbamate (1.80 g, 6.03mmol) in hydrochloric acid (1 m , 4M in 1,4-dioxane) was stirred at 25 °C for 0.5 hours. After completion, the solvent was removed under vacuum to afford the title compound (1.30 g, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 199. 1 [M+H]+.

[0293]

[0216] Step 3: ( / ?)-2-((5-(4-fliiorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A'-mcthyl-A'-(( / ?)- 1, 1, 1 -trifluoropropan -2-yl)propanami de & ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2- yl)amino)- '-mcthyl- '-((.S')- l . l . l -trifluoropropan-2-yl)propcnamidc. A mixture of 5-(4- fluorophenyl)-l,3,4-oxadiazol-2(3E7)-one (150.0 mg, 0.83 mmol), (2 / ?)-2-amino- '-mcthyl-A- (l,l,l-trifhroropropan-2-yl)propanamide hydrochloride (293.1 mg, crude), IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (552.4 mg, 1.25 mmol) and N,N- diisopropylethylamine (429.7 mg, 3.33 mmol) in dichloromethane (3 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford product. The product was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IF 3*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3- MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 30 mL / min; Gradient (B%): isocratic 40; Wave Length: 220 / 254 nm; RTl(min): 8.791; RT2(min): 13.116; Sample Solvent: EtOH— HPLC; Injection Volume: 2.0 mL to afford ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol- 2-yl)amino)- '-mcthyl- '-(( / ?)- l . l . l -trifluoropropan-2-yl)propanamidc (58.6 mg, 0.16 mmol, 19.5% yield) as a white solid and ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A- mcthyl-A-((.S)- l . l . l -trifluoropropan-2-yl)propanamidc (74.5 mg, 0.20 mmol, 24.8% yield) as a white solid. LC-MS: (ESI, m / z): 361.1[M+H]+.

[0294]

[0217] Example 24a:1HNMR (300 MHz, DMSO-ri6. / yw?) d 8.42 - 8.18 (m, 1H), 7.91 - 7.77 (m, 2H), 7.47 - 7.32 (m, 2H), 5.35 - 5.06 (m, 1H), 4.88 - 4.61 (m, 1H), 3.17 - 2.75 (m, 3H), 1.52 - 1.22 (m, 6H). LC-MS: (ESI, mlz . 361.1 [M+H]+. Chiral HPLC: Column: CHIRALPAK IF-3 4.6*50 mm 3 um; Hex(0.1%DEA):EtOH=60:40; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 1.12 min(faster peak).

[0295]

[0218] Example 24b: 'H NMR (300 MHz. DMSO-rie. / yw?) 4 8.30 - 8. 1 I (m, 1H), 7.91 - 7.79 (m, 2H), 7.46 - 7.32 (m, 2H), 5.41 - 5.20 (m, 1H), 5.00 - 4.61 (m, 1H), 3.14 - 2.74 (m, 3H), 1.54 - 1.21 (m, 6H). LC-MS: (ESI, m / z) 361.1 [M+H]+. Chiral HPLC: Column: CHIRALPAK IF-3 4.6*50 mm 3 um; Hex(0.1%DEA):EtOH=60:40; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 1.69 min(slower peak). PATENT

[0296]

[0219] Example 25: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A'-(2.2-difluoropropyl)-A- methylpropanamide

[0297]

[0220] Step 1: tert-butyl (2, 2-difluoropropyl)carbamate. A solution of 2,2-difluoropropan-l- amine hydrochloride (1.50 g, 11.40 mmol), di-tert-butyl dicarbonate (7.46 g, 34.21 mmol) and triethylamine (3.46 g, 34.21 mmol) in tetrahydrofuran (30 m ) was stirred at 25 °C for 1 hour. After completion, 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 (2.00 g, 10.25 mmol, 89.9% yield) as a colorless oil. LC-MS: (ESI, m / z): 196.1 [M+H]+

[0298]

[0221] Step 2: / ert-but l (2.2-difluoroprop l )(mcth l [carbarn ate. To a solution of tert-butyl (2,2-difluoropropyl)carbamate (2.00 g, 10.25 mmol) in A'.A'-dimcthylformamidc (20 mb) was added potassium / ert-butoxidc (3.44 g, 30.74 mmol) and iodomethane (4.36 g, 30.74 mmol), the mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. PATENT

[0299] The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) to afford the title compound (1.20 g, 5.73 mmol, 56.0% yield) as a colorless oil. LC-MS: (ESI, m / z): 210.1 [M+H]+

[0300]

[0222] Step 3: 2,2-difluoro-A-methylpropan-l -amine trifluoroacetate. A solution of tertbutyl (2,2-difluoropropyl)(methyl)carbamate (1.20 g, 5.74 mmol) in trifluoroacetic acid (4.0 mL) and dichloromethane (12.0 mb) was stirred at 25 °C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (1182 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 110.1 [M+H]+

[0301]

[0223] Step 4: tert-butyl ( / ?)-( l -((2.2-difluoropropyl)(mcthyl)amino)- l -oxopropan-2- yl)carbamate. A solution of 2,2-difhroro-A-methylpropan-l -amine trifluoroacetate (1.18 g, crude), (tert-butoxycarbonyl)-D-alanine (1.40 g, 7.42 mmol), A'A'-diisopropylcthylaminc (4.42 g, 34.24 mmol) and 2-(7-azabcnzotriazol- l -yl)-A'A'.A.IV-tctramcthyluroniiim hexafluorophosphate (2.60 g, 6.85 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with ethyl acetate, washed with brine 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 (1.40 g, 4.99 mmol, 87.5% yield) as a colorless oil. LC-MS: (ESI, m / z): 281.2 [M+H]+

[0302]

[0224] Step 5: ( / ?)-2-amino-A'-(2.2-difliioropropyl)-A'-mcthylpropanamidc hydrochloride. A solution of tert-butyl ( / ?)-( l -((2.2-difluoropropyl)(mcthyl)amino)- l-oxopropan-2- yl)carbamate (1.40 g, 4.99 mmol) in 4M hydrochloric acid in 1,4-dioxane (20 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (1.00 g, crude) as a yellow solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 181.1 [M+H]+

[0303]

[0225] Step 6: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A'-(2.2-difluoropropyl)-A- methylpropanamide. Under nitrogen, a solution of 4,7-dichloroquinazoline (100.0 mg, 0.50 mmol), ( / ?)-2-amino-A'-(2.2-difliioropropyl)-A'-mcthylpropanamidc hydrochloride (108.8 mg, crude) and A'A'-diisopropylcthylaminc (389.6 mg, 3.01 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The 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), PATENT

[0304] Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 26%B to 56%B in 7min; Wave Length: 254 / 220 nm to afford the title compound (47.0 mg, 0.14 mmol, 27.3% yield) as a white solid. LC-MS: (ESI, m / z): 343.0 [M+H]+

[0305]

[0226] Example 26: (7?)-JV-(2,2-difluoropropyl)-2-((5-(4-fhiorophenyl)-l,3,4-oxadiazol-2- yl)amino)-A-methylpropanamide

[0306] Synthetic Route:

[0307]

[0227] A solution of 5-(4-fluorophenyl)-l,3,4-oxadiazol-2(377)-one (150.0 mg, 0.83 mmol), ( / ?)-2-ammo-A-(2.2-difluoropropyl)-A-mcthylpropanamidc hydrochloride (270.6 mg, crude), 'A'-diisopropylcthylaminc (860.9 mg, 6.66 mmol) and I / / -benzotri azol- 1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.10 g, 2.50 mmol) in dichloromethane (5 mb) was stirred at 25 °C for 2 hours. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH Prep Phenyl-Hexy OBD Column, 30* 150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 20%B to 50%B in 7min; Wave Length: 254 / 220 nm to afford the title compound (97.2 mg, 0.28 mmol, 34.1% yield) as a white solid. LC-MS: (ESI, m / z): 343.1 [M+H]+

[0308]

[0228] Example 27: ( / ?)-2-((6-(4-fliiorophcnyl)pyrimidin-4-yl)amino)- '-mcthyl- '-(2.2.2- trifluoroethyl)propanamide PATENT

[0309] Synthetic Route:

[0310]

[0229] A solution of (2 / ?)-2-amino-A'-mcthyl-A'-(2.2.2-trifliiorocthyl)propanamidc hydrochloride (158.4 mg, crude), 'A'-diisopropylcthylaminc (464.6 mg, 3.60 mmol) and 4- chloro-6-(4-fluorophenyl)pyrimidine (150.0 mg, 0.72 mmol) in dimethyl sulfoxide (0.5 mb) was stirred at 100 °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% NH4HCO3 in water) to afford the title compound (82.2 mg, 0.23 mmol, 31.9% yield) as a white solid. LC-MS: (ESI, m / z): 357.2 [M+H]+

[0311]

[0230] Example 28: ( / ?)-2-((5-(5-fliioropyridin-2-yl)oxazol-2-yl)amino)- '-mcthyl- '-(2.2.2- trifluoroethyl)propanamide PATENT

[0312]

[0231] Step 1: 5-(5-fluoropyridin-2-yl)oxazole. A solution of 5-fluoropicolinaldehyde (2.00 g, 15.99 mmol), potassium carbonate (4.41 g, 31.97 mmol) and tosylmethyl isocyanide (3.75 g, 19.18 mmol) in methyl alcohol (20.0 mL) was stirred at 85 °C for 16 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 title compound (2.10 g, 12.79 mmol, 80.0% yield) as ayellow solid. LC-MS: (ESI, m / z): 165.0 [M+H]+.

[0313]

[0232] Step 2: 2-chloro-5-(5-fluoropyridin-2-yl)oxazole. To a solution of 5-(5-fluoropyridin- 2-yl)oxazole (500.0 mg, 3.05 mmol) in tetrahydrofuran (5.0 mL) was added lithium bis(trimethylsilyl)amide (3.6 mL, 3.6 mmol, IM in tetrahydrofuran) at -78 °C, the mixture was stirred at -78 °C for 30 minutes. Then hexachloroethane (1.08 g, 4.57 mmol) was added, the mixture was stirred at -78 °C for 1 hour and stirred at 25 °C for 4 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 (1: 1) to afford the title compound (380.0 mg, 1.91 mmol, 62.8% yield) as a yellow solid. LC-MS: (ESI, m / z): 199.0 [M+H]+.

[0314]

[0233] Step 3: ( / ?)-2-((5-(5-fliioropyridin-2-yl)oxazol-2-yl)amino)- '-mcthyl- '-(2.2.2- trifluoroethyl)propenamide. A solution of 2-chloro-5-(5-fluoropyridin-2-yl)oxazole (150.0 mg, 0.76 mmol), (2 / ?)-2-amino-A'-mcthyl-A'-(2.2.2-trifluorocthyl)propanamidc hydrochloride (166.9 mg, crude) and N, A'-diisopropylcthylaminc (0.3 mL, 2.27 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °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 PATENT on silica gel eluting with dichloromethane / methanol (8: 1) to afford crude product. The crude product was 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: 13%B to 43%B in lOmin; Wave Length: 254 / 220 nm to afford the title compound (89.4 mg, 0.25 mmol, 34. 1% yield) as a light yellow solid. LC- MS: (ESI, m / z): 347.0 [M+H]+.

[0315]

[0234] Example 29: ( / ?)-2-((5-(3.4-difluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A'-mcthyl-

[0316] A'-(2.2.2-trifluorocthyl)propanamidc

[0317] Synthetic Route:

[0318]

[0235] A solution of 5-(3,4-difluorophenyl)-l,3,4-oxadiazol-2(327)-one (150.0 mg, 0.76 mmol), (2 / ?)-2-amino-A'-mcthyl-A'-(2.2.2-trifluorocthyl)propanamidc hydrochloride (167.2 mg, crude), A'.A'-diisopropylcthylaminc (293.5 mg, 2.27 mmol) and I / / -benzotri azol- 1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (669.2 mg, 1.51 mmol) in dichloromethane (1.50 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 resulting residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford crude solid. The 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: 19%B PATENT to 49%B in lOmin; Wave Length: 254 / 220 nm to afford the title compound (46.6 mg, 0.12 mmol, 15.7% yield) as a white solid. LC-MS: (ESI, m / z)'. 365.0 [M+H]+

[0319]

[0236] Example 30: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A'-mcthyl-A-

[0320] ( 1 -(trifluoromethyl)cyclopropyl)propanamide

[0321]

[0237] Step 1: tert-butyl ( / ?)-( l -(mcthyl( l -(trifluoromcthyl)cyclopropyl)amino)-l - oxopropan-2-yl)carbamate. A mixture of (tert-butoxycarbonyl)-D-alanine (430.0 mg, 2.27 mmol), A-mcthyl- l -(trifliioromcthyl)cyclopropan- l -amine hydrochloride (200.0 mg, 1.14 mmol), 2-(7-azabcnzotriazol- l -yl)-A'.A'W.IV-tctramcthyliironium hexafluorophosphate (648.1 mg, 1.7 mmol) and A'A'-diisopropylcthylaminc (439.8 mg, 3.41 mmol) in dichloromethane (3 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 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 the title compound (180 mg, 0.58 mmol, 51.0% yield) as a yellow oil. LC-MS: (ESI, m / z): 311.1 [M+H]+.

[0322]

[0238] Step 2: ( / ?)-2-amino-A-mcthyl-A'-( l -(trifliioromcthyl)cyclopropyl)propanamidc trifluoroacetate. A mixture of tert-butyl ( / ?)-( I -(mcthy 1( 1 -

[0323] (trifhioromethyl)cyclopropyl)amino)-l-oxopropan-2-yl)carbamate (160.0 mg, 0.39 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was stirred at 25 °C for 0.5 hours. After completion, the reaction solution was concentrated under vacuum to afford the title PATENT compound (157.6 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 211.1[M+H]+.

[0324]

[0239] Step 3: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- '-mcthyl- '-( l - (trifluoromethyl)cyclopropyl)propenamide. A mixture of (.S')-2-amino-A-mcthyl-A-( l - (trifluoromethyl)cyclopropyl)propanamide trifluoroacetate (157.6 mg, crude), 5-(4- chlorophenyl)-l,3,4-oxadiazol-2(327)-one (67.0 mg, 0.34 mmol), IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (226.1 mg, 0.51 mmol) and N,N- diisopropylethylamine (175.9 mg, 1.36 mmol) in dichloromethane (2 mb) was stirred at 25 °C for 1 hour. The solution was concentrated in vacuum. The residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford 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 (B%): 34% B to 47% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 8.67 to afford the title compound (15.6 mg, 0.04 mmol, 11.8% yield) as a white solid. LC-MS: (ESI, m / z): 389.0[M+H]+.

[0325]

[0240] Example 31a: (R)-N-((R)-1, l-difluoropropan-2-yl)-2-((5-(4-fluorophenyl)-l,3,4- oxadiazol-2-yl)amino)-A'-mcthylpropan amide

[0326]

[0241] Example 31b: l-difluoropropan-2-yl)-2-((5-(4-fluorophenyl)-l,3,4- oxadiazol-2-yl)amino)- '-mcthylpropan amide

[0327] PATENT

[0328] Synthetic Route:

[0329]

[0242] Step 1: tert-butyl (l,l-difluoropropan-2-yl)carbamate. A solution of 1,1- difluoropropan-2 -amine hydrochloride (2.0 g, 15.2 mmol), trimethylamine (3.07 g, 30.41 mmol) and di-tert-butyl dicarbonate (3.66 g, 16.72 mmol) in dichloromethane (15 mL) was stirred at 25 °C for 2 hours. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. 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 (5: 1) to afford the title compound (2.80 g, 12.90 mmol, 84.9% yield) white solid. LC-MS: (ESI, m / z): 196.1 [M+H]+

[0330]

[0243] Step 2: tert-butyl (1,1 -difluoropropan-2 -yl)(methyl)carbamate To a solution of tertbutyl (l,l-difluoropropan-2-yl)carbamate (2.78 g, 14.24 mmol) in A'.A'-dimcthylfomiamidc wad added sodium hydride (0.57 g, 14.24 mmol, 60% dispersion in mineral oil), the mixture was stirred at 0 °C for 5 minutes. Then iodomethane (5.06 g, 35.6 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 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 (5 : 1) to afford the title compound (2.00 g, 8.60 mmol, 60.4% yield) as a white solid. LC-MS: (ESI, m / z): 210.1 [M+H]+

[0331]

[0244] Step 3: 1. 1 -difluoro-A'-mcthylpropan-2-aminc hydrochloride. A solution of tert-butyl ( 1,1 -difluoropropan-2 -yl)(methyl)carbamate (1.5 g, 7.17 mmol) in 4 M hydrochloric acid in 1,4-dioxane (15.0 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (1.32 g, crude) as a colorless oil. The crude PATENT product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 110. 1 [M+H]+

[0332]

[0245] Step 4: tert-butyl ((2 / ?)- l-(( l. l -difluoropropan-2-yl)(mcthyl)amino)- l -oxopropan-2- yl)carbamate. A solution of I . l -difluoro-A'-mcthylpropan-2-aminc hydrochloride (1.10 g, crude), (tert-butoxycarbonyl)-.D-alanine (1.72 g, 9.07 mmol), A'.A'-diisopropylcthylaminc (4.87 g, 37.78 mmol) and 2-(7-azabcnzotriazol- l - l)-A'.A'. A". A"-tctramcthyluronium hexafluorophosphate (4.31 g, 11.33 mmol) in dichloromethane (11 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. 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 (960.0 mg, 3.08 mmol, 40.8% yield) as a white solid. LC-MS: (ESI, m / z): 281.2 [M+H]+

[0333]

[0246] Step 5: (2 / ?)-2-amino-A'-( l . l-difluoropropan-2-yl)-A'-mcthylpropanamidc hydrochloride. A solution of tert-butyl ((2 / ?)- l -(( l . l -difluoropropan-2-yl)(mcthyl)amino)- l - oxopropan-2-yl)carbamate (960 mg, 3.08 mmol) in 4 M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (740.5 mg, crude) as a colorless oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 181.1 [M+H]+

[0334]

[0247] Step 6: (R)-A-((R)-l,l-difluoropropan-2-yl)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-

[0335] 2-yl )amino)-A'-mcthylpropanamidc & (R)-N-((S)- 1 , 1 -difluoropropan-2-yl)-2-((5-(4- fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)- / V-methylpropanamide. A solution of 5-(4- fluorophenyl)-l,3,4-oxadiazol-2(3 / / )-one (80.0 mg, 0.44 mmol), (2 / ?)-2-amino-A'-( l . l - difluoropropan-2-yl)- / V-methylpropanamide hydrochloride (144.3 mg, crude mmol), NJM- diisopropylethylamine (477.4 mg, 2.22 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (294.6 mg, 0.67 mmol) in dichloromethane (3 ml) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: Kinetex EVO C18 Column, 30*250 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 42%B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 7.73 afford the product. Then the product was separated by Prep- Chiral-HPLC with the following conditions: Column: (R, R)-WHELK-Ol-Kromasil, 2.11*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: ETOH; Flow rate: PATENT

[0336] 20 mL / min; Gradient (B%): isocratic 10; Wave Length: 220 / 254 nm; RTl(min): 19.818; RT2(min): 24.215; Sample Solvent: EtOH; Injection Volume: 1.0 mL to afford (R)-V-((R)-1,1- difhioropropan-2-yl)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)- / V- methylpropanamide (26.8 mg, 0.07 mmol, 17.4% yield) as a white solid and (R)- / V-((S)-1,1- difhroropropan-2-yl)-2-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)amino)- / V- methylpropanamide (29.1 mg, 0.08 mmol, 19.0% yield) as a white solid. LC-MS: (ESI, m / z): 343.2 [M+H]+

[0337]

[0248] Example 3 la:1HNMR (400 MHz, DMSO< / 6. / yw?) d 8.33 - 8.15 (m, 1H), 7.89 - 7.80 (m, 2H), 7.44 - 7.34 (m, 2H), 6.43 - 5.84 (m, 1H), 4.78 - 4.45 (m, 2H), 3.12 - 2.70 (m, 3H),

[0338] 1.39 - 1.13 (m, 6H). LC-MS: (ESI, m / z): 343.2 [M+H]+. Chiral HPLC: Column: (R,R)-Whelk 4.6*50mm 3.5um; HEX(0.1%DEA):EtOH=90:10; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 2.68 min(faster peak).

[0339]

[0249] Example 31b:1HNMR(400 MHz, DMSO-tA / yw?) d 8.24 - 8.13 (m, 1H), 7.90 - 7.80 (m, 2H), 7.43 - 7.35 (m, 2H), 6.42 - 5.93 (m, 1H), 4.85 - 4.34 (m, 2H), 3.10 - 2.74 (m, 3H),

[0340] 1.40 - 1.14 (m, 6H). LC-MS: (ESI, m / z): 343.2 [M+H]+. Chiral HPLC: Column: (R,R)-Whelk 4.6*50mm 3.5um; HEX(0.1%DEA):EtOH=90:10; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 3.16 min(slower peak).

[0341]

[0250] Example 32: (R)-2-((7-chloroquinazolin-4-yl)amino)- / V-((l- fliiorocyclopropyl)mcthyl)-A'-mcthylpropan amide

[0342] PATENT

[0343] Synthetic Route:

[0344]

[0251] Step 1: tert-butyl ((l-fluorocyclopropyl)methyl)carbamate. A solution of (1- fluorocyclopropyl)methanamine hydrochloride (1.46 g, 11.67 mmol), triethylamine (3.54 g, 35.00 mmol) and di-tert-butyldicarbonate (7.64 g, 35.00 mmol) in tetrahydrofuran (20 mL) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with ethyl acetate 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 (9: 1) to afford the title compound (2.16 g, 11.41 mmol, 97.8% yield) as a brown oil. LC-MS: (ESI, m / z): 190. 1 [M+H]+.

[0345]

[0252] Step 2: tert-butyl ((l-fluorocyclopropyl)methyl)(methyl)carbamate. To a solution of tert-butyl ((l-fluorocyclopropyl)methyl)carbamate (2.16 g, 11.41 mmol) in N.N- dimethylformamide (30 mL) was added potassium tert-butoxide (5.16 g, 45.95 mmol) and iodomethane (5.29 g, 37.26 mmol), the mixture was stirred at 25 °C for 2 hours. 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 residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (24: 1) to afford the title compound (1.50 g, 7.38 mmol, 64.7% yield) as a white solid. LC-MS: (ESI, m / z): 204.1 [M+H]+.

[0346]

[0253] Step 3: l-(l-fluorocyclopropyl)-A-methylmethanamine hydrochloride. A solution of tert-butyl ((l-fluorocyclopropyl)methyl)(methyl)carbamate (1.50 g, 7.38 mmol) in hydrochloric acid (20 mL, 4 M in 1,4-dioxane) was stirred at 25 °C for 1 hour. After completion, the solvent was concentrated under vacuum to afford the title compound (1.50 g, PATENT crude) as a white solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 104.1 [M+H]+.

[0347]

[0254] Step 4: tert-butyl ( / ?)-( l -((( l-fliiorocyclopropyl)mcthyl)(mcthyl)amino)- l- oxopropan-2-yl)carbamate. A solution of 1-(1 -fluorocyclop ropy l)- / V-methylmethanamine hydrochloride (1.50 g, crude), (tert-butoxycarbonyl)-D-alanine (2.03 g, 10.74 mmol), N.N- diisopropylethylamine (6.94 g, 53.72 mmol) and 2-(7-azabcnzotriazol- l -yl)-A'A'.A.A''- tetramethyluronium hexafluorophosphate (5.31 g, 13.97 mmol) in dichloromethane (20 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 the title compound (1.00 g, 3.28 mmol, 30.5% yield) as a white solid. LC-MS: (ESI, m / z): 275.2 [M+H]+.

[0348]

[0255] Step 5: ( / ?)-2-amino-A'-(( l -fliiorocyclopropyl)mcthyl)-A'-mcthylpropanamidc hydrochloride. A solution of tert-butyl ( / ?)-( I -((( I -fluorocyclopropyl)mcthyl)(mcthyl)amino)- l-oxopropan-2-yl)carbamate (170.0 mg, 0.62 mmol) in hydrochloric acid (3 mL, 4 M in 1,4- dioxane) was stirred at 25 °C for 1 hour. After completion, the solvent was concentrated under vacuum to afford the title compound (100.0 mg, crude) as a white solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 175.1 [M+H]+.

[0349]

[0256] Step 6: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A'-(( l -fliiorocyclopropyl)mcthyl)-A- methylpropanamide. A solution of ( / ?)-2-amino-A'-(( l -fliiorocyclopropyl)mcthyl)-A- methylpropanamide hydrochloride (100.0 mg, crude), A'A'-diisopropylcthylaminc (306.7 mg, 2.37 mmol) and 4,7-dichloroquinazoline (94.4 mg, 0.47 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °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 residue was purified by reverse phase chromatography (acetonitrile / 0. 1% NH4HCO3 in water) to afford ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A'-(( l -fliiorocyclopropyl)mcthyl)-A- methylpropanamide (101.0 mg, 0.29 mmol, 63.% yield) as an off-white solid. LC-MS: (ESI, m / z): 337.1 [M+H]+.

[0350]

[0257] Example 33: ( / ?)-A'-cthyl-2-((5-(4-fluorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A- (2,2,2-trifluoroethyl)propanamide PATENT

[0351] Synthetic Route:

[0352]

[0258] To a solution of 5-(4-fluorophenyl)-l,3,4-oxadiazol-2(3E7)-one (80.0 mg, 0.44 mmol) and (J?)-2-amino-A-ethyl-JV-(2,2,2-trifluoroethyl)propanamide hydrochloride (135.5 mg, crude) in dichloromethane (1 mL) was added A'.A'-diisopropylcthylaminc (287.0 mg, 2.22 mmol) and I / / -benzotri azol- 1 -yloxy tri s(di cthy la ino (phosphonium hexafluorophosphate (785.7 mg, 1.78 mmol), the mixture was stirred at room temperature for 0.5 hours. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were combined. The organic layer was 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 (77:23) to afford crude product. The 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%): 25%B to 55%B in 7min; Wave Length: 254 / 220 nm to afford the title compound (76.0 mg, 0.21 mmol, 46.6% yield) as a white solid. LC-MS: (ESI, m / z): 361.2 [M+H]+.

[0353]

[0259] Example 34: ( / ?)-A'-mcthyl-A'-(2.2.2-trifluorocthyl)-2-((7-

[0354] (trifluoromethoxy)quinazolin-4-yl)amino)propanamide PATENT

[0355] Synthetic Route:

[0356]

[0260] A solution of 4-chloro-7-(trifhroromethoxy)quinazoline (90.0 mg, 0.36 mmol), N.N- diisopropylethylamine (233.4 mg, 1.81 mmol) and (2 / ?)-2-amino-A'-mcthyl-A'-(2.2.2- trifluoroethyl)propanamide hydrochloride (79.2 mg, crude) in dimethyl sulfoxide (0.3 mL) was stirred at 100 °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 (64.5 mg, 0.16 mmol, 44.4% yield) as a white solid. LC-MS: (ESI, m / z): 397.0 [M+H]+

[0357]

[0261] Example 35: (7?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-JV-((l- fliiorocyclopropyl)mcthyl)-A'-mcthylpropan amide PATENT

[0358] Synthetic Route:

[0359]

[0262] A solution of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(3E7)-one (150.0 mg, 0.76 mmol), ( / ?)-2-amino- '-(( 1 -fluorocyclopropyl )mcthyl)- '-mcthylpropanamidc hydrochloride (160.7 mg, crude), A.A-diisopropylcthylaminc (493.0 mg, 3.82 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (438.7 mg, 0.99 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 the title compound (58.7 mg, 0.16 mmol, 21.8% yield) as a white solid. LC-MS: (ESI, m / z): 353.1 [M+H]+.

[0360]

[0263] Example 36: ( / ?)-A-(( l-fluorocyclopropyl)mcthyl)-2-((5-(4-fliiorophcnyl)- l .3.4- oxadiazol-2-yl)amino)-A'-mcthylpropan amide PATENT

[0361] Synthetic Route:

[0362]

[0264] A solution of 5-(4-fluorophcnyl)-3 / / - l .3.4-oxadiazol-2-onc (150.0 mg, 0.83 mmol), ( / ?)-2-amino-A'-(( I -fliiorocyclopropyl)mcthyl)-A'-mcthylpropanamidc hydrochloride (263. 1 mg, crude), A'A'-diisopropylcthylaminc (538.1 mg, 4.16 mmol), and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (847.0 mg, 1.92 mmol) in dichloromethane (4 mL) was stirred at 25 °C for 2 hours. After completion, the resulting solution 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 reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (40.5 mg, 0.12 mmol, 14.4% yield) as a white oil. LC-MS: (ESI, m / z): 337.1 [M+H]+.

[0363]

[0265] Example 37: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A'-cy clopropyl- A'-(2.2.2-trifluorocthyl)propanamidc

[0364] Synthetic Route: PATENT

[0365]

[0266] Step 1: tert-butyl ( / ?)-( ! -(cyclopropyl (2.2.2-tri fl uorocthy I )amino)- 1 -oxopropan-2- yl)carbamate. A solution of A'-(2.2.2-trifluorocthyl)cyclopropanaminc hydrochloride (100.0 mg, 0.57 mmol), (2 / ?)-2-( / crt-butoxycarbonylamino)propanoic acid (129.3 mg, 0.68 mmol), A'A'-diisopropylcthylaminc (129.2 mg, 1.71 mmol) and 2-(7-azabcnzotriazol- l -yl)-A'.A'.A',.A- tetramethyluronium hexafluorophosphate (281.5 mg, 0.74 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 the title compound (80.0 mg, 0.24 mmol, 43.0 % yield) as a white solid. LC-MS: (ESI, m / z): 311.2 [M+H]+.

[0366]

[0267] Step 2: ( / ?)-2-amino-A'-cyclopropyl-A'-(2.2.2-trifliiorocthyl)propanamidc hydrochloride. A solution of tert-butyl (R)-(l -(cyclopropyl (2,2, 2-trifluoroethyl)amino)-l- oxopropan-2-yl)carbamate (70.0 mg, 0.23 mmol) in hydrochloric acid (1 mL, 4 M in 1,4- dioxane) was stirred at 25 °C for 0.5 hours. After completion, the solvent was concentrated under vacuum to afford the title compound (70.0 mg, crude) as a white solid. The crude product would be directly used inthe next step without purification. LC-MS: (ESI, m / z): 211.1 [M+H]+.

[0367]

[0268] Step 3: ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)-A'-cyclopropyl-A- (2,2,2-trifluoroethyl)propenamide. A solution of ( / ?)-2-amino-A'-cyclopropyl-A'-(2.2.2- trifluoroethyl)propanamide hydrochloride (70.0 mg, crude), 5-(4-chlorophcnyl)-3H- 1,3,4- oxadiazol-2-one (55.7 mg, 0.28 mmol), A'.A'-diisopropylcthylaminc (183.4 mg, 1.42 mmol) and I / / -benzotri azol- 1 -y loxy tri s(dimcthy lam ino)phosphonium hexafluorophosphate (288.6 mg, 0.65 mmol) in dichloromethane (1 mL) was stirred at 25 °C for 5 hours. 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) (3:2) to afford the title compound (48.9 mg, 0.12 mmol, 43.6% yield) as a white solid. LC-MS: (ESI, m / z): 389.1 [M+H]+.

[0368]

[0269] Example 38a: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-A-((J?)-l,l- difluoropropan-2-yl)-A'-mcthylpropan amide

[0369]

[0270] Example 38b: (J?)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)- / V-((S)-l,l- difluoropropan-2-yl)-A'-mcthylpropan amide PATENT

[0370]

[0271] A solution of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(3 / / )-one (80.0 mg, 0.41 mmol), (2R)-2- aniino-\-( l. l-difluoropropan-2-yl)-\ -nicthylpropananiidc hydrochloride (132.2 mg, 0.61 mmol), 'A'-diisopropylcthylaminc (81.3 mg, 2.03 mmol) and I / / -benzotri azol- 1 - yloxytris(dimethylamino)phosphonium hexafluorophosphate (269.9 mg, 0.61 mmol) in dichloromethane (3 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column: Kinetex 5pm EVO C18 Column, 30* 150 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 23%B to 53%B in 7 min; Wave Length: 254 / 220 nm afford product. Then the product was separated by Prep-Chiral-HPLC with the following conditions: Column: (R, R)-WHELK-Ol-Kromasil, 2.11*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient (B%): isocratic 7; Wave Length: 220 / 254 nm; RTl(min): 26.227; RT2(min): 32.028; Sample Solvent: EtOH; Injection Volume: 1.2 mL to afford ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2- yl)amino)-A'-(( / ?)- l . l -difliioropropan-2-yl)- '-mcthylpropanamidc (29.3 mg, 0.08 mmol, 21.3% yield) as a white solid and ( / ?)-2-((5-(4-chlorophcnyl)- l .3.4-oxadiazol-2-yl)amino)- '-((.S')- l . l - difluoropropan-2-yl)- / V-methylpropanamide (27.9 mg, 0.07 mmol, 19.1% yield) as a white solid. LC-MS: (ESI, m / z): 359.0 [M+H]+ PATENT

[0371]

[0272] Example 38a: 'HNMR (300 MHz, DMSO-6, ppm) 38.38 - 8.20 (m, 1H), 7.85 - 7.75 (m, 2H), 7.66 - 7.57 (m, 2H), 6.48 - 5.80 (m, 1H), 4.80 - 4.43 (m, 2H), 3.09 - 2.73 (m, 3H), 1.40 - 1.11 (m, 6H). LC-MS: (ESI, m / z): 359.0 [M+H]+. Chiral HPLC: Column: (R,R)-Whelk 4.6*50mm 3.5um; HEX(0.1%DEA):EtOH=93:7; Flow rate: 1.0 mL / min; Injection Volume: 5 uL; Retention time: 3.41 min(faster peak).

[0372]

[0273] Example 38b:1HNMR(300 MHz, DMSO-t / e. / ^m) d 8.30 - 8.19 (m, 1H), 7.85 - 7.76 (m, 2H), 7.66 - 7.57 (m, 2H), 6.49 - 5.86 (m, 1H), 4.88 - 4.34 (m, 2H), 3.14 - 2.70 (m, 3H), 1.45 - 1.10 (m, 6H). LC-MS: (ESI, m / z): 359.0 [M+H]+. Chiral HPLC: Column: (R,R)-Whelk 4.6*50mm 3.5um; HEX(0.1%DEA):EtOH=93:7; Flow rate: 1.0 mL / min; Injection Volume: 5 uL; Retention time: 4.08 min(slower peak).

[0373]

[0274] Example 39: (R)-2-((7-chloroquinazolin-4-yl)amino)- / V-ethyl- / V-(2,2,2- trifluoroethyl)propanamide

[0374] Synthetic Route:

[0375]

[0275] Step 1: tert-butyl ( / ?)-( l-(cthyl(2.2.2-trifluorocthyl)amino)-l-oxopropan-2- yl)carbamate. To a solution of A'-cthyl -2,2, 2-trifluoroethan-l -amine hydrochloride (300.0 mg, 1.83 mmol) and (tert-butoxycarbonyl)-D-alanine (416.4 mg, 2.20 mmol) in dichloromethane (1 mL) was added A'.A'-diisopropylcthylaminc (1.20 g, 9.17 mmol) and 2-(7-azabenzotriazol- l-yl)-A.A.A'.IV-tctramcthyhironiiim hexafluorophosphate (836.9 mg, 2.20 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 combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum. The PATENT residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (84: 16) to afford the title compound (330.0 mg, 1.11 mmol, 60.3% yield) as a colorless oil. LC-MS: (ESI, m / z): 299.2 [M+H]+.

[0376]

[0276] Step 2: ( / ?)-2-amino-A'-cthyl-A'-(2.2.2-trifluorocthyl)propanamidc hydrochloride. A solution of tert-butyl ( / ?)-( l-(cthyl(2.2.2-trifluorocthyl)amino)-l-oxopropan-2-yl)carbamatc (300.0 mg, 1.01 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3.0 mL) 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) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 199.1 [M+H]+.

[0377]

[0277] Step 3: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A-cthyl-A-(2.2.2- trifluoroethyl)propenamide. A solution of ( / ?)-2-amino-A-cthyl-A-(2.2.2- trifluoroethyl)propanamide hydrochloride (90.8 mg, crude), 4,7-dichloroquinazoline (70.0 mg, 0.35 mmol) and A.A-diisopropylcthylaminc (227.3 mg, 1.76 mmol) in dimethyl sulfoxide (0.50 mL) was stirred at 100 °C for 0.5 hour. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford the title compound (97.4 mg, 0.26 mmol, 75.2% yield) as an off-white solid. LC-MS: (ESI, m / z): 361.0 [M+H]+.

[0378]

[0278] Example 40: ( / ?)-2-((5-(4-chlorophcnyl)-l.3.4-oxadiazol-2-yl)amino)-A-(2.2- difluoropropyl)-A-mcthylpropan amide

[0379] Synthetic Route: PATENT

[0380]

[0279] A solution of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(327)-one (150.0 mg, 0.76 mmol), (J?)-2-amino-A-(2,2-difluoropropyl)- / V-methylpropanamide hydrochloride (248.0 mg, crude), 'A'-diisopropylcthylaminc (788.9 mg, 6.10 mmol) and IH-benzotriazol-l- yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.01 g, 2.29 mmol) in dichloromethane (5 mL) was stirred at 25 °C for 2 hours. 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 water / acetonitrile (60 / 40) to afford the title compound (96.2 mg, 0.27 mmol, 35.1% yield) as a white solid. LC-MS: (ESI, m / z): 359.1 [M+H]+.

[0381]

[0280] Example 41a: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A'-mcthyl-A'-((.S)- l . l . l - trifluoropropan-2-yl)propanamide

[0382]

[0281] Example 41b: ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A'-mcthyl-A'-(( / ?)- 1,1,1 - trifluoropropan-2-yl)propanamide assumed assumed

[0383] Synthetic Route:

[0384]

[0282] A mixture of (2 / ?)-2-amino-A'-mcthyl-A'-( l . l . l -trifluoropropan-2-yl)propanamidc hydrochloride (235.2 mg, crude), 4,7-dichloroquinazoline (133.0 mg, 0.67 mmol) and N.N- diisopropylethylamine (431.0 mg, 3.34 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 PATENT

[0385] °C for 0.5 hours. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford product. The product was separated by Prep-Chiral-HPLC with the following conditions: Column: Column: (R, R)- WHELK-Ol-Kromasil 2.12*25 cm, 5 pm+W75R75: Y7R75: S75; Mobile Phase A: Hex(0.5% 2M NHs-MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 10; Wave Length: 220 / 254 nm; RTl(min): 18.422; RT2(min): 20.097; Sample Solvent: EtOH— HPLC; Injection Volume: 1.0 mL to afford ( / ?)-2-((7-chloroquinazolin-4- yl)ammo)-A-mcthyl-A-((.S')-l. l. l-trifliioropropan-2-yl)propanamidc (38.3 mg, 0.11 mmol, 15.9% yield) as a white solid and ( / ?)-2-((7-chloroqiiinazolin-4-yl)amino)-A'-mcthyl-A'-(( / ?)- l,l,l-trifhroropropan-2-yl)propanamide (31.8 mg, 0.09 mmol, 13.2% yield) as a white solid. LC-MS: (ESI, m / z): 361.1[M+H]+.

[0386]

[0283] Example 41a:1HNMR (300 MHz, DMSO< / 6. / yw?) d 8.71 - 8.54 (m, 1H), 8.53 - 8.38 (m, 2H), 7.77 - 7.72 (m, 1H), 7.65 - 7.58 (m, 1H), 5.51 - 5.05 (m, 2H), 3.19 - 2.71 (m, 3H), 1.53 - 1.30 (m, 6H). LC-MS: (ESI, mlz\. 361.1 [M+H]+. Chiral HPLC: Column: (R,R)-Whelk 4.6*50 mm 3.5 um; Hex(0.1%DEA):EtOH=90: 10; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 2.40 min (faster peak).

[0387]

[0284] Example 41b:1HNMR(300 MHz, DMSO-t / e. / ^m) d 8.64 - 8.53 (m, 1H), 8.52 - 8.39 (m, 2H), 7.74 (d, J= 2.1 Hz, 1H), 7.65 - 7.57 (m, 1H), 5.46 - 4.96 (m, 2H), 3.21 - 2.75 (m, 3H), 1.51 - 1.27 (m, 6H). LC-MS: (ESI, mlz\. 361.1 [M+H]+. Chiral HPLC: Column: (R,R)- Whelk 4.6*50 mm 3.5 um; Hex(0.1%DEA):EtOH=90: 10; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 2.83 min (slower peak).

[0388]

[0285] Example 42a: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)- / V-methyl- / V-((S)- I , I , I -trifluoropropan-2-yl)propanamide

[0389]

[0286] Example 42b: ( / ?)-2-((6-(4-fliiorophcnyl)pyrimidin-4-yl)amino)-A'-mcthyl-A'-(( / ?)- I , I , I -trifluoropropan-2-yl)propanamide assumed assumed PATENT

[0390] Synthetic Route:

[0391]

[0287] A mixture of (2 / ?)-2-amino-A'-mcthyl-A'-( l . l . l -trifluoropropan-2-yl)propanamidc hydrochloride (271.6 mg, crude), 4-chloro-6-(4-fluorophenyl)pyrimidine (161.0 mg, 0.77 mmol) and A'A'-diisopropylcthylaminc (497.8 mg, 3.86 mmol) in dimethyl sulfoxide (0.8 mL) was stirred at 100 °C for 1 hour. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: Xselect CSH pre C18 Column, 30* 150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 30%B to 50%B in 10 min; Wave Length: 254 / 220 nm; RTl(min): 5.5 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% 2MNH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient (B%): isocratic 40; Wave Length: 220 / 254 nm; RTl(min): 6.143; RT2(min): 8.792; Sample Solvent: ETOH; Injection Volume: 1.0 mL to afford (R)-2-((6-(4- fl uorophcny I jpy rim idin-4-y I jam ino)- '-mcthy l- '-(( / ?j- 1,1,1 -trifluoropropan-2- yljpropanamide (38.3 mg, 0.10 mmol, 13.4% yield) as a white solid and (R)-2-((6-(4- fl uorophcny I jpy rim idin-4-y I jam ino)-A'-mcthy l- '-((.S'j- 1,1,1 -trifluoropropan-2- yljpropanamide (25.1 mg, 0.07 mmol, 8.8% yield) as a white solid. LC-MS: (ESI, m / z): 371.1[M+H]+.

[0392]

[0288] Example 42a: ‘HNMR (500 MHz, DMSO-6, ppm) 3 8.52 - 8.45 (m, 1H), 8.07 - 7.99 (m, 2H), 7.96 - 7.71 (m, 1H), 7.37 - 7.29 (m, 2H), 7.10 - 6.97 (m, 1H), 5.42 - 5.20 (m, 1H), 5.11 - 4.97 (m, 1H), 3.14 - 2.73 (m, 3H), 1.50 - 1.27 (m, 6H). LC-MS: (ESI, m / z): 371.2 [M+H]+. Chiral HPLC: Column CHIRALPAK IG-3 4.6*50 mm 3 um; Hex(0. l%DEA):EtOH=60:40; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 1.32 min(faster peak). PATENT

[0393]

[0289] Example 42b: ' H NMR (500 MHz, DMSO-J6, ppm) 3 8.50 (d, J = 1.1 Hz, 1H), 8.09 - 7.97 (m, 2H), 7.86 - 7.68 (m, 1H), 7.38 - 7.28 (m, 2H), 7.05 (s, 1H), 5.40 - 4.95 (m, 2H), 3.17 - 2.76 (m, 3H), 1.47 - 1.27 (m, 6H). LC-MS: (ESI, mlz\. 31)2 [M+H]+. Chiral HPLC: Column: CHIRALPAK IG-3 4.6*50 mm 3 um; Hex(0.1%DEA):EtOH=60:40; Flow rate: 1.0 mL / min; Injection Volume: 1 uL; Retention time: 2.08 min(slower peak).

[0394]

[0290] Example 43a: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-A-methyl-A- ((R)-I, I, I-trifluoropropan-2-yl)propanamide

[0395]

[0291] Example 43b: (R)-2-((5-(4-chlorophenyl)-l,3,4-oxadiazol-2-yl)amino)-A-methyl-A- ( (.S') - 1,1,1 -trifluoropropan-2-yl)propanamide

[0396]

[0292] A mixture of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(327)-one (150.0 mg, 0.76 mmol), (2 / ?)-2-amino-A'-mcthyl-A'-( 1.1. l-trifluoropropan-2-yl)propanamidc hydrochloride (268.6 mg, crude), I / / -benzotri azol - 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (506.2 mg, 1.14 mmol) and A'.A'-diisopropylcthylaminc (393.7 mg, 3.05 mmol) in dichloromethane (2 mb) was stirred at 25 °C for 1 hours. The solution was concentrated in vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3 in water) to afford product. The product was separated by Prep- Chiral-HPLC with the following conditions: Column: CHIRALPAK IG 2*25 cm, 5 pm; PATENT

[0397] Mobile Phase A: HEX(0.5% 2MNH3-MeOH), Mobile Phase B: ETOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient (B%): isocratic 20; Wave Length: 220 / 254 nm; RTl(min): 9.692; RT2(min): 12.371; Sample Solvent: ETOH; Injection Volume: 0.6 mL to afford (R)-2-((5-(4- chlorophenyl)- 1 ,3.4-oxadiazol-2-yl )amino)- '-mcthyl- '-(( / ?)- 1,1,1 -trifluoropropan-2- yljpropanamide (51.4 mg, 0.14 mmol, 17.9% yield) as a white solid and (R)-2-((5-(4- chlorophenyl)- 1 ,3,4-oxadiazol-2-yl )amino)- '-mcthyl- '-((.S')- 1,1,1 -trifluoropropan-2- yljpropanamide (64.2 mg, 0.17 mmol, 22.3% yield) as a white solid. LC-MS: (ESI, m / z): 377.0[M+H]+.

[0398]

[0293] Example 43a: *HNMR (300 MHz, DMSO-t / e. ppm) 38.46 - 8.24 (m, 1H), 7.86 - 7.75 (m, 2H), 7.66 - 7.57 (m, 2H), 5.35 - 4.63 (m, 2H), 3.14 - 2.76 (m, 3H), 1.51 - 1.29 (m, 6H). LC-MS: (ESI, m / z): 377.0 [M+H]+. Chiral HPLC: Column: CHIRALPAK IG-3 4.6*50 mm 3 um; Hex(0.1%DEA):(EtOH:DCM=l: l)=80:20; Flow rate: 1.0 mL / min; Injection Volume: 3 uL; Retention time: 2.344 min(faster peak).

[0399]

[0294] Example 43b:1HNMR(300 MHz, DMSO-^. / yw?) d 8.37 - 8.17 (m, 1H), 7.85 - 7.75 (m, 2H), 7.66 - 7.58 (m, 2H), 5.41 - 5.21 (m, 1H), 5.00 - 4.63 (m, 1H), 3.11 - 2.76 (m, 3H), 1.50 - 1.25 (m, 6H). LC-MS: (ESI, m / z): 377.0 [M+H]+. Chiral HPLC: Column: CHIRALPAK IG-3 4.6*50 mm 3 um; Hex(0.1%DEA):(EtOH:DCM=l:l)=80:20; Flow rate: 1.0 mL / min; Injection Volume: 3 uL; Retention time: 3.027 min (slower peak).

[0400]

[0295] Example 44: ( / ?)-2-((5-(4-fhiorophcnyl)-l.3.4-thiadiazol-2-yl)amino)-N-isobutyl-N- methylpropanamide

[0401] Synthetic Route:

[0402]

[0296] To a solution of (5-(4-fluorophenyl)-l,3,4-thiadiazol-2-yl)-D-alanine (26.7 mg, 0.100 mmol) and N,2-dimethylpropan-l -amine (10.4 mg, 0.120 mmol) in dimethyl formamide (1 mL) was added N, N-diisopropylethylamine (51.6 mg, 0.400 mmol,) and O-(7- Azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (45.6 mg, 0.120 mmol). The reaction mixture was shaken at 50 °C for 2 hrs. After completion, the reaction mixture was concentrated by Speedvac. The resulting residue was purified by prep. HPLC [Purified on Shimadzu LCMS system equipped with UV and MS detector: Mobile Phase: PATENT

[0403] 0.225% FA in water (solvent A) and CH3CN (solvent B); Gradient: using the elution gradient 30%-70% (solvent B) over 10 minutes; Flow rate: 30 ml / min; Column: Boston Prime C18 150*30mm*5um or Phenomenex Gemin-NX 150*30mm*5um; Wavelength: UV 220 nm; Column temperature: 30 °C; MS ionization: ESI] to afford the title compound (20.9 mg, 0.06 mmol, 62.2% yield).

[0404]

[0297] Example 45: ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)amino)-N-mcthyl-N- phenylpropanamide

[0405]

[0298] To a solution of (5-(4-fluorophenyl)-l,3,4-thiadiazol-2-yl)-D-alanine (26.7 mg, 0.100 mmol) and N-methylaniline (12.8 mg, 0.120 mmol) in dimethyl formamide (1 mL) was added N, N-diisopropylethylamine (51.6 mg, 0.400 mmol,) and propanephosphonic acid cyclic anhydride (0.12 mL, 50% in ethyl acetate). The reaction mixture was shaken at 30 °C for 16 hrs. After completion, the reaction mixture was concentrated by Speedvac. The resulting residue was purified by prep. HPLC [Purified on Shimadzu LCMS system equipped with UV and MS detector: Mobile Phase: 0.225% FA in water (solvent A) and CH3CN (solvent B); Gradient: using the elution gradient 30%-70% (solvent B) over 10 minutes; Flow rate: 30 ml / min; Column: Boston Prime C18 150*30mm*5um or Phenomenex Gemin-NX 150*30mm*5um; Wavelength: UV 220 nm; Column temperature: 30 °C; MS ionization: ESI] to afford the title compound (10.7 mg, 0.03 mmol, 30.1% yield). LC-MS: (ESI, m / z): 357.1 [M+H]+.

[0406]

[0299] Example 46: ( / ?)-N-(3.3-difliiorocyclobiityl)-2-((5-(4-fliiorophcnyl)- l .3.4-thiadiazol- 2-yl)amino)-N-methylpropanamide PATENT

[0407]

[0300] To a solution of (5-(4-fluorophenyl)-l,3,4-thiadiazol-2-yl)-D-alanine (26.7 mg, 0.100 mmol) and 3,3-difluoro-N-methylcyclobutan-l-amine hydrochloride (18.8 mg, 0.120 mmol) in dimethyl formamide (1 mL) was added N, N-diisopropylethylamine (51.6 mg, 0.400 mmol,) and O-(7-Azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (45.6 mg, 0.120 mmol). The reaction mixture was shaken at 50°C for 2 hrs. After completion, the reaction mixture was concentrated by Speedvac. The resulting residue was purified by prep. HPLC [Purified on Shimadzu LCMS system equipped with UV and MS detector: Mobile Phase: 0.225% FA in water (solvent A) and CH3CN (solvent B); Gradient: using the elution gradient 30%-70% (solvent B) over 10 minutes; Flow rate: 30 ml / min; Column: Boston Prime C18 150*30mm*5um or Phenomenex Gemin-NX 150*30mm*5um; Wavelength: UV 220 nm; Column temperature: 30 °C; MS ionization: ESI] to afford the title compound (15.8 mg, 0.04 mmol, 42.7% yield).

[0408]

[0301] Example 47: ( / ?)-N-bcnzyl-2-((5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)amino)-N- methylpropanamide

[0409] Synthetic Route:

[0410]

[0302] To a solution of (5-(4-fluorophenyl)-l,3,4-thiadiazol-2-yl)-D-alanine (26.7 mg, 0.100 mmol) and N-methyl-l-phenylmethanamine (14.5 mg, 0.120 mmol) in dimethyl formamide (1 mL) was added N, N-diisopropylethylamine (51.6 mg, 0.400 mmol,) and O-(7- Azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (45.6 mg, 0.120 mmol). The reaction mixture was shaken at 50 °C for 2 hrs. After completion, the reaction mixture was concentrated by Speedvac. The resulting residue was purified by prep. HPLC [Purified on Shimadzu LCMS system equipped with UV and MS detector: Mobile Phase: 0.225% FA in water (solvent A) and CH3CN (solvent B); Gradient: using the elution gradient 30%-70% (solvent B) over 10 minutes; Flow rate: 30 ml / min; Column: Boston Prime C18 150*30mm*5um or Phenomenex Gemin-NX 150*30mm*5um; Wavelength: UV 220 nm; Column temperature: 30 °C; MS ionization: ESI] to afford the title compound (11.8 mg, 0.03 mmol, 31.9% yield).

[0411]

[0303] Example 48: ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)amino)-N-mcthyl-N- ( (.S') - 1 -phenyl ethyl)propanamide PATENT

[0412] Synthetic Route:

[0413]

[0304] To a solution of (5-(4-fluorophenyl)-l,3,4-thiadiazol-2-yl)-D-alanine (26.7 mg, 0.100 mmol) and (.S)-N-mcthyl- l -phcnylcthan- l -amine (16.2 mg, 0.120 mmol) in dimethyl formamide (1 mL) was added N, N-diisopropyl ethylamine (51.6 mg, 0.400 mmol,) and O-(7- Azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (45.6 mg, 0.120 mmol). The reaction mixture was shaken at 50 °C for 2 hrs. After completion, the reaction mixture was concentrated by Speedvac. The resulting residue was purified by prep. HPLC [Purified on Shimadzu LCMS system equipped with UV and MS detector: Mobile Phase: 0.225% FA in water (solvent A) and CH3CN (solvent B); Gradient: using the elution gradient 30%-70% (solvent B) over 10 minutes; Flow rate: 30 ml / min; Column: Boston Prime C18 150*30mm*5um or Phenomenex Gemin-NX 150*30mm*5um; Wavelength: UV 220 nm; Column temperature: 30 °C; MS ionization: ESI] to afford the title compound (9.9 mg, 0.03 mmol, 25.8% yield).

[0414]

[0305] Example 49: ( / ?)-2-((5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)amino)-N-mcthyl-N-

[0415] (( / ?)- ! -phenylethyl)propanamide PATENT

[0416]

[0306] Step 1: 2-bromo-5-(4-fluorophenyl)-l,3,4-thiadiazole. Under nitrogen, a solution of 2,5-dibromo-l,3,4-thiadiazole (9.00 g, 36.90 mmol) and potassium carbonate (15.30 g, 110.70 mmol) in 1,4-dioxane (90.0 mL) and water (18.0 mL) was added (4-fluorophenyl)boronic acid (5.16 g, 36.90 mmol) and tetrakis(triphenylphosphine)palladium (4.26 g, 3.69 mmol) and stirred at 100°C for 1.5 hours. After completion, the resulting solution was concentrated in vacuum to remove 1,4-dioxane, diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / dichloromethane (5: 1) to afford the title compound (3.50 g, 10.67 mmol, 28.9% yield) as a white solid. LC-MS: (ESI, m / z): 258.9 [M+H]+.

[0417]

[0307] Step 2: tert-butyl (5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)- / )-alaninatc. Under nitrogen, a solution of 2-bromo-5-(4-fluorophenyl)-l,3,4-thiadiazole (500.0 mg, 1.93 mmol) and sodium benzenolate (896.1 mg, 7.72 mmol) in toluene (5 mL) was added 2-(di-t- butylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i -propyl- l,l'-biphenyl (187.1 mg, 0.39 mmol), tertbutyl D-alaninate (701.1 mg, 3.86 mmol) and methanesulfonato 2-di-t-butylphosphino-3,6- dimethoxy-2'-4'-6'-tri-i-propyl- 1 , 1 '-bipheny)(2'-amino- 1 , 1 '-biphenyl-2-yl)palladium(ii) (165.1 mg, 0.19 mmol) and stirred at 90°C for 40 minutes. After completion, the resulting solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. 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-SFC to remove undesired isomer with the following condition: Column: CHIRALPAKIA 50*250mm, 5 u m; Mobile Phase A : CO2; Mobile Phase B: MeOH(0.5%2MNH3-MeOH);Gradient: isocratic 40% B; Flow rate: 200mL / min to afford the title compound (400.0 mg, 0.74 mmol, 38.5% yield) as a white solid. LC-MS: (ESI, m / z): 324.1 [M+H]+.

[0418]

[0308] Step 3: (5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)- / )-alaninc. A solution of tert-butyl (5-(4-fluorophenyl)-l,3,4-thiadiazol-2-yl)-D-alaninate (4.70 g, 14.53 mmol) in trifluoroacetic acid (25.0 mL) and dichloromethane (75.0 mL) was stirred at 25°C for 6 hours. After completion, the reaction mixture was concentrated in vacuum to afford the title compound (4.00 g, 10.63 mmol, 73.2% yield) as an off-white solid. LC-MS: (ESI, m / z): 268.0 [M+H]+.

[0419]

[0309] Step 4: (J?)-2-((5-(4-fluorophenyl)-l,3,4-thiadiazol-2-yl)amino)-N-methyl-N-((J?)-l- phenylethyl)propenamide. To a solution of (5-(4-fluorophcnyl)- l .3.4-thiadiazol-2-yl)- / )- alanine (26.7 mg, 0.100 mmol) and ( / ?)-N-mcthyl- l -phcnylcthan- l -amine (16.2 mg, 0.120 PATENT mmol) in dimethyl formamide (1 mL) was added N, N-diisopropylethylamine (51.6 mg, 0.400 mmol,) and O-(7-Azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (45.6 mg, 0. 120 mmol). The reaction mixture was shaken at 50 °C for 2 hrs. After completion, the reaction mixture was concentrated by Speedvac. The resulting residue was purified by prep. HPLC [Purified on Shimadzu LCMS system equipped with UV and MS detector: Mobile Phase: 0.225% FA in water (solvent A) and CH3CN (solvent B); Gradient: using the elution gradient 30%-70% (solvent B) over 10 minutes; Flow rate: 30 ml / min; Column: Boston Prime C18 150*30mm*5um or Phenomenex Gemin-NX 150*30mm*5um; Wavelength: UV 220 nm; Column temperature: 30 °C; MS ionization: ESI] to afford the title compound (7.4 mg, 0.02 mmol, 19.3% yield).

[0420] PATENT

[0421]

[0310] Table 2: Characterization Table PATENT PATENT PATENT PATENT PATENT a b PATENT PATENT PATENT PATENT PATENT PATENT PATENT PATENT PATENT

[0422]

[0311] Example Bl: Biological Assays

[0423] RLB, K Ephys, and H Ephys Assays

[0424]

[0312] Radioligand binding for hTMEMl 75 Ki

[0425]

[0313] To determine compound binding affinity to the target, hTMEM175 (NM_032326.4) protein was overexpressed in Expi293 cells (Thermo Fisher Scientific Inc). Cell pellet was resuspended in 40 times volume of membrane protein buffer (50 mM Tris pH 7.5, lx protease inhibitor) and lysed using a dounce homogenizer. The samples were centrifuged at 200 g for 15 min at 4 °C to remove cell debris and unlysed cells. Supernatant was centrifuged at 40,000 g for 50 min at 4 °C to recover the membranes. The membrane pellet was resuspended in the buffer by using a dounce homogenizer, and the resuspended membrane fraction was run through a 25 5 / 8 gauge needle. After the determination of total protein concentration by Bradford assay, membrane solution aliquots were flash frozen in liquid nitrogen, and stored at -80 °C. Competitive radioligand binding was performed to determine compound affinity to hTMEMl 75. Briefly, various concentrations of test compounds with membranes (1 qg / wcll) were incubated with a radioligand standard at a final concentration of 10 nM in a total volume of 200 pL binding buffer (20 mM HEPES, pH7.4) with a 0.5% DMSO final concentration. PATENT

[0426] Nonspecific binding was determined in the presence of 2 pM the radioligand standard. The mixture was incubated at 23 °C for 1 h, filtered through UniFilter-96 GF / C plates (PerkinElmer, Massachusetts) presaturated with 0.3% polyethylenimine, and washed with cold binding buffer 200 uL for 4 times, then dried at 50 °C for 1 h. 40 pl / well of scintillation cocktail was added to each well, and bound radioligand standard was counted on a MicroBeta2 (PerkinElmer) microplate scintillation counter. Competition binding IC50s were analyzed by using Prism 8 (GraphPad, CA). The equilibrium dissociation constant (Ki) was calculated with equation: Ki = IC50 / (l + ([L] / KD)), in which [L] = the concentration of labeled ligand, KD = measured radioligand standard dissociation constant 19.2 nM. Each condition was repeated with n > 2.

[0427]

[0314] Electrophysiological Recordings and Data Analysis

[0428]

[0315] A TMEM175 stable expression cell line is generated in a HEK293 host cell and the functional activity on plasma membrane is measured using whole-cell patch clamping recordings. For K+conductance, a planner well format automated patch clamp system (SyncroPatch 768PE, Nanion Technologies, Germany), with using 4-hole medium resistance 384 well plate (NPC-384T 4x S-Type chip, Nanion), is employed. Data is acquired by using PatchControl384 1.9.7 software and analysis is performed with DataControl384 2.2 software and Prism 8. The intracellular solution contains (in mM): 120 CsF, 10 NaCl, 10 EGTA, 10 HEPES, with pH 7.2, and extracellular solution contains (in mM): 144 CsCl, 2 CaCh, 1 MgCh, 5 Glucose, 10 HEPES, with pH 7.4. The holding potential is set at 0 mV, and currents are elicited by applying a voltage ramp protocol from -100 mV to +100 mV in 300 ms, with sweep interval set at 10 seconds. Currents are sampled at 10 kHz and filtered with Bessel filter, and inward current was measured at -60 mV. In a pharmacological experiment, current is continually measured from baseline 3 min (I Base), followed by 7 min with compound onboard (ICpd), and ended with 2 min full block (IFB) by applying 4-Aminopyridine to reach a final concentration at 2 mM. All recording is subject to quality checks (QC) to exclude poor recordings by the following criteria: baseline current between 0.3 to 4 nA; full block current < 5 nA; baseline minus full block current > 100 pA; maximum current < 33 nA; seal resistance after full block > 25 MQ. Compound effect in each recording is calculated by using the equation: 100% * (ICpd - Ihase)l(IBase - IFB).

[0429]

[0316] For H+conductance, a microfluidic format high throughput automated patch clamp system Qube384 using 10-hole medium resistance 384 well plate (QChip 384X, Sophion Bioscience, Denmark) is employed. Data acquisition and analysis are performed by using Qube system software and Screener (Genedata, Switzerland). The intracellular solution contains (in mM): 120 CsF, 20 CsCl, 1 EGTA, 10 HEPES with pH 7.2, and extracellular PATENT solution contains (in mM): 120 NMDG, 2 CaCh, 1 MgCh, 10 Glucose, 10 HEPES with pH 7.4 for baseline solution, and pH 5.5 for reference, compound and full block solutions. The holding potential is set at 0 mV, and currents are elicited by applying a voltage ramp protocol from -100 mV to +100 mV in 100 ms, with sweep interval set at 10 seconds. Currents are sampled at 10 kHz and filtered with Bessel filter, and inward current is measured at -100 mV. In the pharmacological experiment, current is continually measured from baseline 10 min (I Base), followed by 8 min reference solution (I Ref ), then with compound on-board (ICpd) for 8 min, and ended with 6 min full block (IFB) by applying 4-Aminopyridine at 6 mM. All recording was subject to quality check (QC) to exclude poor recordings by following criteria: baseline minus full block current > 400 pA; reference pH 5.5 signal stable and activation > 10% of baseline; and seal resistance after full block > 25 MQ. Compound effect in each recording is calculated by using equation: 100% * ICpd — IRef) / ( I Ref — IFB).

[0430]

[0317] Results from all electrophysiological studies are presented as the means ± SEM, with n > 5. EC50 and maximum effect (Emax) values are derived from dose response curve fitting analyzed by using Prism 8. Comparisons were made by using Student’s t test, with P < 0.05 considered significant.

[0431]

[0318] hERG ICso

[0432]

[0319] Whole cell patch clamp recordings are conducted by using hERG (KCNH2) high expression Chinese hamster ovary (CHO) cell and the SyncroPatch 384PE system following FDA recommended protocol. A voltage step protocol from -90 mV (holding potential) to +20 mV followed by a step to -50 mV is applied to the cell every 20 seconds for pharmacology experiments. Peak amplitude at -50 mV is used for analysis. IC50 is determined by using Prism 8 curve fitting, with n > 2 for each data point.

[0433]

[0320] The results of the biological assays are summarized in Table 3 below.

[0434] PATENT

[0435]

[0321] Table 3 Biological Data

[0436] N.T .= not tested PATENT

[0437]

[0322] This writen description uses examples to describe the disclosed technology, including the best mode, and also to enable any person skilled in the art to practice the disclosed technology, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosed technology is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims

PATENTWHAT IS CLAIMED IS:

1. A compound of formula (I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:R1is selected from the group consisting of hydrogen, substituted or unsubstituted C1-5 alkyl, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted phenyl;R2is selected from hydrogen, substituted or unsubstituted C1-5 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;R3is selected from the group consisting of substituted or unsubstituted C1-5 alkyl; substituted or unsubstituted C1-5 alkoxy; substituted or unsubstituted C3-6 cycloalkyl; substituted or unsubstituted aryl; and substituted or unsubstituted 3-6 membered heterocycle, wherein the substituted or unsubstituted 3-6 membered heterocycle comprises one or more heteroatoms selected from O, N and S; orR2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-6 cycloalkyl, or a substituted or unsubstituted aryl;R4is a substituted or unsubstituted C1-3 alkyl;A is a substituted or unsubstituted 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl comprises one or more heteroatoms selected from O, N and S; andB is selected from the group consisting of substituted or unsubstituted 6-membered heteroaryl, wherein the substituted or unsubstituted 6-membered heteroaryl comprises one or more heteroatoms selected from O, N and S; substituted or unsubstituted aryl; substituted or unsubstituted C1-3 haloalkyl; substituted or unsubstituted C1-3 haloalkoxy; and halogen.

2. The compound of claim 1, wherein R1is selected from the group consisting of substituted or unsubstituted C1-3 alkyl, substituted or unsubstituted C3-4 cycloalkyl, hydrogen, and substituted or unsubstituted phenyl.

3. The compound of claim 1, wherein R1is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and cyclopropyl.

4. The compound of any one of claims 1 to 3, wherein R1is methyl.PATENT5. The compound of any one of claims 1 to 3, wherein R2is hydrogen or -CH3.

6. The compound of any one of claims 1 to 5, wherein R3is selected from the group consisting of substituted or unsubstituted C1-3 alkyl; substituted or unsubstituted C1-3 alkoxy; substituted or unsubstituted C3-4 cycloalkyl; unsubstituted aryl; and substituted or unsubstituted 3-4 membered heterocycle, wherein the substituted 3-4 membered heterocycle comprises one or more heteroatoms selected from O, N and S.

7. The compound of any one of claims 1 to 6, wherein R3is selected from a substituted C1-3 alkyl, substituted C1-3 alkoxy, substituted or unsubstituted cyclopropyl, unsubstituted aryl, and substituted 3-4 membered heterocycle, wherein the substituted 3-4 membered heterocycle comprises one or more heteroatoms selected from O, N and S.

8. The compound of any one of claims 1 to 7, wherein R3is selected from the group consisting of -CH3, -CF3, -CF2H, -CF2CH3, phenyl, -OCF3, -CFh CFE , cyclopropyl,9. The compound of any one of claims 1 to 3, wherein R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-6 cycloalkyl, or an unsubstituted aryl.

10. The compound of claim 9, wherein R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-6 cycloalkyl.

11. The compound of claim 9 or 10, wherein R2and R3together with the carbon atom attached thereto join to form a substituted or unsubstituted C3-4 cycloalkyl.

12. The compound of claim 11, wherein R2and R3together with the carbon atom attached thereto join to form a cyclopropyl,PATENT13. The compound of any one of claims 1 to 12, wherein R4is unsubstituted C1-3 alkyl.

14. The compound of any one of claims 1 to 12, wherein R4is substituted C1-3 alkyl.

15. The compound of any one of claims 1 to 12, wherein R4is methyl or -CH2CF2H.

16. The compound of any one of claims 1 to 15, wherein A is selected from the group consisting17. The compound of any one of claims 1 to 16, wherein B is -OCF3, Cl, or, wherein X1is -CH- or -N-, and X2is -Cl or -F.

18. A pharmaceutical composition comprising the compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and at least one pharmaceutically acceptable excipient.

19. The pharmaceutical composition of claim 18, further comprising an additional therapeutic agent.

20. 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 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; or (ii) the pharmaceutical composition of claim 18 or claim 19.

21. 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 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; or (ii) the pharmaceutical composition of claim 18 or claim 19.

22. The method of claim 21, 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, inheritedPATENT 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).

23. The method of claim 22, wherein the neurodegenerative disorder is Parkinson’s disease (PD).

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