TMEM175 modulators for the treatment of neurodegenerative disorders

Abstract

The present application provides compounds of Formula (I) and Formula (II) (I), (II), and pharmaceutically acceptable salts thereof, that are modulators of TMEM175. Also provided are pharmaceutical compositions of the subject compounds, and methods of treating neurodegenerative disorders using the same.

Description

TMEM175 MODULATORS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS[1] This application claims the benefit of U.S. Provisional patent application Nos. 63 / 676,025 filed on July 26, 2024, and 63 / 753,352 filed on February 3, 2025, each of which is hereby expressly incorporated by reference in its entirety.BACKGROUND[2] The field of the disclosure relates generally to modulators of TMEM175 for the treatment of neurodegenerative disorders, for example, Parkinson’s disease.[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.[4] Molecular mechanism studies of the pathogenesis of PD reveal that lysosomal homeostasis is a key pathway for PD. Lysosomal homeostasis is governed by channels and transporters that establish ion gradients across lysosomal membranes (Jung, Y. et al. (2023) The Korean Journal of Physiology & Pharmacology 27.4: 311.). TMEM175 is a lysosomal proton and potassium channel that maintains the lysosomal pH within an optimal range, ensuring the proper activity of lysosomal hydrolases. It was found that TMEM175 gene variants bidirectionally modify the risk of PD. Specifically, the reduced function of TMEM175(M393T) increases the risk of PD, while TMEM175(Q65P) reduces the risk of developing this condition (Hu, M. et al. (2022) Cell 185.13: 2292-2308). Furthermore, it was found that the TMEM175(M393T) variant leads to defects in lysosomal pH regulation and degradation, resulting in reduced autophagy, diminished activity of lysosomal hydrolases, and increased a-Synuclein (aSyn) pathology. Supporting the loss- of-function mechanism associated with TMEM175(M393T), genetic depletion of the TMEM175 protein in cellular and animal models mimics the effects observed with the TMEM175(M393T) variant, leading to impaired lysosomal function and increased aSyn pathology (Cang, C. et al. (2015) Cell 162.5: 1101-1112).[5] Despite decades of research, treatment options for PD remain limited, focusing mainly on symptom management rather than disease modification. Thus, there persists a significant unmet medical need in effectively halting or reversing the progression of this challenging indication. BRIEF DESCRIPTION [6] In one aspect, provided herein are compounds of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: ring A 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, each X is each independently H, D, halo, substituted or unsubstituted C1-5alkyl, substituted or unsubstituted C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, -O-C3-6cycloalkyl, -S(O)Ra, or – SO2Ra; wherein Rais -CH3or -(C6H4)CH3; R1is CH3, CH3CH2, CH3OCH2, CF3OCH2, C3-4cycloalkyl, CH2OH, or C1-3haloalkyl; R2is H, D, halo, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; Z1is substituted or unsubstituted 4-9 membered N-heterocycle; and m is 0, 1, 2 or 3. [7] In another aspect, also provided herein are compounds of Formula (II):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1is CH3, CH3CH2, C3-4cycloalkyl, C3-4cycloalkyl, CH2OH, or C1-3haloalkyl; R3is H, D, halo, oxo, CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R5is H, halo, oxo, CN, C1-3alkyl, or C1-3haloalkyl; Y is N or CH;Z2is selected from the group consisting of H, CN, haloalkyl, substituted or unsubstituted 6- membered aryl; substituted or unsubstituted C3-8cycloalkyl, 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; Z3is substituted or unsubstituted 4-9 membered N-heterocycle; and R2aand R2bare each independently H, C1-6alkyl, or C1-6haloalkyl. DETAILED DESCRIPTION [8] Provided herein are modulators of TMEM175, e.g., compounds of Formula (I) (e.g., quinazoline modulators) or compounds of Formula (II) (e.g., pyrimidine modulators), or a pharmaceutically acceptable salt thereof. Further provided are pharmaceutical compositions thereof, and methods for their use, e.g., for treating TMEM175-mediated diseases such as neurodegenerative disorders. Also provided are methods of making the modulators of TMEM175 described herein such as compounds of Formula (I) or Formula (II). Definitions [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.

[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.

[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. Non- limiting 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-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.

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

[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 C1-6haloalkyl and C1-4haloalkyl, are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4haloalkyl” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. Additionally, terms such as “haloalkoxy”, for instance C1-6haloalkoxy and C1-4haloalkoxy, are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4haloalkoxy” is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[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. Bicyclic cycloalkyl and cycloalkylene ring structures may be in any of a fused, bridged, or spiro conformation. 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-C8)cycloalkyl). In other particular embodiments cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-C6)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 embodiments, bicyclic cycloalkyl rings are fused rings sharing two carbon atoms. In some embodiments, bicyclic cycloalkyl rings are bridged bicyclic rings. In some specific embodiments, bicyclic cycloalkyl includes, , , . In some further embodiments, bicyclic cycloalkyl rings are spiro bicyclic rings.

[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. Bicyclic heterocycle, heterocycloalkyl, heterocyclyl and heterocycloalkylene ring structures may be in any of a fused, bridged, or spiro conformation. In some embodiments, bicyclic heterocyclic rings are 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 are bridged bicyclic rings. In some specific embodiments, bicyclic heterocyclic rings includeIn some further embodiments, bicyclic heterocyclic rings are spiro bicyclic ring structures. In some embodiments, spiro bicyclic rings include, , , ,, 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. In some embodiments, bicyclic heterocyclic rings include, , , In some embodiments, heterocycle ring comprises –S(O)- and / or –S(O)2-. In some embodiments, heterocycle ring comprises –S(O)-. In some embodiments, heterocycle ring comprises–S(O)2-.

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

[0017] The term "heteroaryl" is used in its conventional sense and refers to a monovalent aromatic radical of a 5 to 12-membered ring and includes fused ring systems (at least one of which is aromatic) of 7- to 10- membered rings containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups may be optionally substituted independently with one or more substituents described herein. 5 or 6 membered heteroaryl can be selected from the group consisting of optionally substituted pyridinyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinone and benzimidazolyl

[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.

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

[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.

[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.

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

[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.

[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.

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

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

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

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

[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.

[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.

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

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

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

[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

[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.

[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 aneurodegenerative 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.

[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.

[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.

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

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

[0041] Some embodiments of the present disclosure are directed to compounds of formula (I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, ring A 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, each X is each independently H, D, halo, substituted or unsubstituted C1-5alkyl, substituted or unsubstituted C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, -O-C3-6cycloalkyl, -S(O)Ra, or – SO2Ra; wherein Rais -CH3or -(C6H4)CH3; R1is CH3, CH3CH2, CH3OCH2, CF3OCH2, C3-4cycloalkyl, CH2OH or C1-3haloalkyl; R2is H, D, halo, C1-6alkyl, C1-6haloalkyl or C1-6alkoxy; Z1is substituted or unsubstituted 4-9 membered N-heterocycle; and m is 0, 1, 2 or 3.

[0042] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (I) is a compound of Formula (Ia):

[0043] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of Formula (I) is a compound of Formula (Ia’)

[0044] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of Formula (I) is a compound of:.

[0045] In some embodiments, Ring A 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.

[0046] In some embodiments, A is aryl. In some embodiments, A is a 5- or 6- membered heteroaryl. In some embodiments, A is 5-membered heteroaryl. In some embodiments, Ring A is a 5-membered heteroaryl comprises one or more heteroatoms selected from O, N and S. In some embodiments, Ring A is a 6-membered heteroaryl comprises one or more heteroatoms selected from O, N and S.

[0047] In some embodiments, each X is each independently H, D, halo, substituted or unsubstituted C1-5alkyl, substituted or unsubstituted C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, - O-C3-6cycloalkyl, -S(O)Ra, or –SO2Ra; wherein Rais -CH3or -(C6H4)CH3.

[0048] In some embodiments, each X is independently halo, C1-5haloalkyl, C1-5haloalkoxy, or –O-C3-6cycloalkyl. In some embodiments, each X is independently halo, C1-5haloalkyl, C1-5haloalkoxy. In some embodiments, each X is independently -Cl, -OCF3, -OCHF2, -CF2, -CF3, or - O-cyclopropyl. In some embodiments, each X is independently -Cl, -OCF3, -OCHF2, -CF2, or - CF3.

[0049] In some embodiments, each X is independently selected from halo, substituted or unsubstituted C1-5alkyl, substituted or unsubstituted C1-5alkoxy. In some embodiments, X is selected from halogen, C1-5haloalkyl and C1-5haloalkoxy. In some embodiments, X is selected from -Cl, -OCF3, -OCHF2and -CF2.

[0050] In some embodiments, R1is CH3, CH3CH2, CH3OCH2, CF3OCH2, C3-4cycloalkyl, CH2OH or C1-3haloalkyl. In some embodiments, R1is CH3, CH3CH2, or CH2OH. In some embodiments, R1is CH3.

[0051] In some embodiments, R1is selected from CH3or CH2OH. In some embodiments, R1is CH3. In some embodiments, R1is CH2OH.

[0052] In some embodiments, R1is CH3CH2.

[0053] In some embodiments, R2is H, D, halo, C1-6alkyl, C1-6haloalkyl or C1-6alkoxy. In some embodiments, R2is H, D, halo, C1-6alkyl, C1-6haloalkyl or C1-6alkoxy. In some embodiments, R2is H, halo or C1-6haloalkyl.

[0054] In some embodiments, R2 is H, D, halo, C1-5alkyl, halo- C1-5alkyl or C1-5alkoxy. In some embodiments R2is H. In some embodiments R2is methyl.

[0055] Z1is substituted or unsubstituted 4-9 membered N-heterocycle. In some embodiments, Z1is a substituted 4-9 membered N-heterocycle. In some embodiments, Z1is a substituted 4-6 membered N-heterocycle. In some embodiments, Z1is a substituted or unsubstituted 4-9 membered N-heterocycle, and wherein the substituted or unsubstituted 4-9 membered N-heterocycle further comprises one or more additional heteroatoms selected from O and S. In some Z1embodiments, the 4-6 membered or 4-9 membered N-heterocycle is substituted with one or more substituents each independently selected from halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, and C1-3haloalkoxy.

[0056] In some embodiments, Z1is substituted or unsubstituted 4-9 membered N- heterocycle. In some embodiments, Z1is a substituted 4-9 membered N-heterocycle. In some embodiments, Z1is a substituted 4-6 membered N-heterocycle. In some embodiments, Z1is a substituted or unsubstituted 4-9 membered N-heterocycle, wherein the substituted or unsubstituted 4-9 membered N-heterocycle further comprises one or more additional heteroatoms selected from O and S.

[0057] In some embodiments, m is 0, 1, 2 or 3. In some embodiments m is 0. In some embodiments m is 1 or 2. In some embodiments m is 1. In some embodiments m is 2. In some embodiments m is 3.

[0058] In some embodiments, m is 1.

[0059] In some embodiments, Z1is selected from:.

[0060] In some embodiments, Z1is selected from:.

[0061] In some embodiments, Z1is selected from:

[0062] In some embodiments, Z1is selected from:

[0063] In some embodiments, Z1is selected from:

[0064] In some embodiments, Z1is selected from:

[0065] In some embodiments, Z1is selected from:.

[0066] In some embodiments, Z1is

[0067] In some embodiments, Z1is selected from:In one embodiment, Z1is.

[0068] In some embodiments, the compound of Formula (I) is selected from the compounds listed in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: Table 1

[0069] In some embodiments, the disclosure comprises the compounds of formula (I), or more particularly the compounds of Table 1.

[0070] In some embodiments, the disclosure comprises the pharmaceutically acceptable salts of the compounds of formula (I), or more particularly the pharmaceutically acceptable salts of the compounds of Table 1.

[0071] In some embodiments, the compound of Formula (I) is selected from the compounds listed in Table 2 below, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0072] In some embodiments, the disclosure comprises the compounds of formula (I), or more particularly the compounds of Table 2.

[0073] In some embodiments, the disclosure comprises the pharmaceutically acceptable salts of the compounds of Formula (I), or more particularly the pharmaceutically acceptable salts of the compounds of Table 2.Compounds of Formula (II)

[0074] In another aspect, also provided in the present disclosure are compounds of Formula (II):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1is CH3, CH3CH2, C3-4cycloalkyl, C3-4cycloalkyl, CH2OH, or C1-3haloalkyl; R3is H, D, halo, oxo, CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R5is H, halo, oxo, CN, C1-3alkyl, or C1-3haloalkyl; Y is N or CH; Z2is selected from the group consisting of H, CN, haloalkyl, substituted or unsubstituted 6-membered aryl; substituted or unsubstituted C3-8cycloalkyl, 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.

[0075] In some embodiments, R1is CH3, CH3CH2, C3-4cycloalkyl, C3-4cycloalkyl, CH2OH, or C1-3haloalkyl. In some embodiments, R1is CH3, CH3CH2, or CH2OH. In some embodiments, R1is CH3.

[0076] In some embodiments, R3is H, D, halo, oxo, CN, C1-6alkyl, C1-6haloalkyl or C1-6alkoxy. In some embodiments R3is H. In some embodiments R3is methyl. In some embodiments, R3is H or F. In some embodiments, R3is H. In some embodiments, R3is F.

[0077] In some embodiments, R5is H, halo, oxo, CN, C1-3alkyl, or C1-3haloalkyl. In some embodiments, R5is H or F. In some embodiments, R5is H. In some embodiments, R5is F.

[0078] In some embodiments, Y is N or CH. In some embodiments, Y is N. In some embodiments, Y is CH.

[0079] In some embodiments, Z2is selected from the group consisting of substituted or unsubstituted 6-membered aryl, substituted or unsubstituted C3-8cycloalkyl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted or unsubstituted 4-8 membered heterocycle. In some embodiments, Z2is substituted or unsubstituted C3-8cycloalkyl; or substituted or unsubstituted 5-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from N and O.

[0080] In some embodiments, Z2is substituted or unsubstituted 4-8 membered heterocycle comprising 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, Z2is substituted or unsubstituted 4-7 membered heterocycle. In some embodiments, Z2is substituted or unsubstituted 4-6 membered heterocycle. In some embodiments, Z2is substituted or unsubstituted 5- or 6- membered heterocycle. In some embodiments, Z2is substituted or unsubstituted 5-membered heterocycle. In some embodiments, Z2is substituted or unsubstituted 6-membered heterocycle.

[0081] In some embodiments, Z2is substituted or unsubstituted 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, Z2is substituted or unsubstituted 5-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, Z2is substituted or unsubstituted 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, Z2comprises SO2in the heterocycle ring.

[0082] In some embodiments, Z2is a 5-membered heteroaryl having two heteroatoms selected from N, S, and O, wherein at least one heteroatom is N; and each 5-membered heteroaryl is optionally substituted with halo, cyano, C1-6alkyl, C1-6haloalkyl, or C1-6haloalkoxy.

[0083] In some embodiments, Z2is -NR2aR2b. In some embodiments, Z2is -N(H)- haloalkoxy or -N(CH3)-haloalkoxy.

[0084] In some embodiments, Z2is phenyl substituted with one or more substituents each independently selected from halo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

[0085] In some embodiments, Z2is 6-membered heteroaryl substituted with one or more substituents each independently selected from halo, cyano, oxo, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

[0086] In some embodiments, Z2is pyridyl substituted with one or more substituents each independently selected from halo, cyano, oxo, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

[0087] In some embodiments, Z2is:wherein X1is -CH- or -N-; n is 0, 1, 2, 3, or 4 when X1is –CH, and n is 0, 1, 2, or 3 when X1is N; and each R4is independently H, halo, oxo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy. In some embodiments, X1is –N-. In some embodiments, X1is –CH-. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiment, n is 1 or 2. In some embodiments n is 0 or 1.

[0088] In some embodiments, Z2is:wherein R4is H, -Cl, -F, or -CF3.

[0089] In some embodiments, Z2is:wherein n is 0, 1, 2, or 3; and each R9is independently H, halo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

[0090] In some embodiments, Z2is selected from:

[0091] In some embodiments, Z2is selected from:

[0092] In some embodiments, Z2is selected from:

[0093] In some embodiments, Z2is selected from:

[0094] In some embodiments, Z2is selected from:

[0095] In some embodiments, Z2is selected from:

[0096] In some embodiments, Z2is

[0097] In some embodiments, Z2is

[0098] In some embodiments, Z2iswherein Z is O or CH2; t is 0, 1, or 2; and each R7 is independently halo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy. In some embodiments, Z is O. In some embodiments, Z is CH2. In some embodiments, t is 0 or 1. In one embodiment t is 0. In another embodiment t is 1.

[0099] Z3is substituted or unsubstituted 4-9 membered N-heterocycle. In some embodiments, Z3is a substituted 4-9 membered N-heterocycle. In some embodiments, Z3is a substituted or unsubstituted 4-7 membered N-heterocycle. In some embodiments, Z3is a substituted or unsubstituted 4-9 membered N-heterocycle, and wherein the substituted or unsubstituted 4-9 membered N-heterocycle further comprises one or more additional heteroatoms selected from O and S. In some embodiments, the substituted or unsubstituted 4-9 membered N- heterocycle further comprises SO2in the N-heterocycle ring.

[0100] In some embodiments, Z3is selected from:

[0101] In some embodiments, Z3is selected from:

[0102] In some embodiments, Z3is selected from:

[0103] In some embodiments, Z3is selected from:

[0104] In some embodiments, Z3is a substituted or unsubstituted monocyclic 4-9 membered N-heterocycle. In some embodiments, Z3is a substituted or unsubstituted monocyclic 4-6 membered N-heterocycle. In some embodiments, Z3is a substituted or unsubstituted monocyclic 4- or 5-membered N-heterocycle.

[105] In some embodiments, Z3isselected from:.

[0106] In some embodiments, Z3is selected from:.

[0107] In some embodiments, Z3is selected from:.

[0108] In some embodiments, Z3is

[0109] In some embodiments, Z3is selected from:In one embodiment, Z3is In another embodimen3t, Z isIn yet another embodiment, Z3is

[0110] In some embodiments, R2aand R2bare each independently H, C1-6alkyl, or C1-6haloalkyl.

[0111] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (II), wherein the compound is a compound of Formula (IIa):

[0112] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (II), wherein the compound is a compound of Formula (IIIa):

[0113] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (II), wherein the compound is a compound of Formula (IIIb):

[0114] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (II), wherein the compound is a compound of Formula (IIIc):

[0115]

[0116] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (II), wherein the compound is a compound of Formula (II'):

[0117] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (II), wherein the compound is a compound of Formula (lIb) :

[0118] In some embodiments, the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of formula (II), wherein the compound is a compound of Formula (IVa):

[0119] In some embodiments, Z2is

[0120] wherein X1is -C- or -N-, and R4is selected from hydrogen, -Cl, -F, or -CF3. In some embodiments X1is -C-, and R4is -F.

[0121] Z3is substituted or unsubstituted 4-9 membered N-heterocycle. In some embodiments, Z3is a substituted 4-9 membered N-heterocycle. In some embodiments, Z3is a substituted or unsubstituted 4-7 membered N-heterocycle. In some embodiments, Z3is a substituted or unsubstituted 4-9 membered N-heterocycle, wherein the substituted or unsubstituted 4-9 membered heterocycle further comprises one or more additional heteroatoms selected from O and S.

[0122] In some embodiments, Z3is selected from:

[0123] In some embodiments, the compound of Formula (II) is selected from the compounds listed in Table 3 below, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Table 3

[0124] In some embodiments, the disclosure comprises the compounds of Formula (II), or more particularly the compounds of Table 3.

[0125] In some embodiments, the disclosure comprises the pharmaceutically acceptable salts of the compounds of Formula (II), or more particularly the pharmaceutically acceptable salts of the compounds of Table 3.

[0126] In some embodiments, the compound of Formula (II) is selected from the compounds listed in Table 4 below, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:Table 4

[0127] In some embodiments, the disclosure comprises the compounds of Formula (II), or more particularly the compounds of Table 4.

[0128] In some embodiments, the disclosure comprises the pharmaceutically acceptable salts of the compounds of Formula (II), or more particularly the pharmaceutically acceptable salts of the compounds of Table 4.Pharmaceutical Compositions

[0129] In some embodiments, pharmaceutical compositions of compound formula (I) and compound formula (II) are provided. In such embodiments, the pharmaceutical compositions comprise (i) compound formula (I) or a pharmaceutically acceptable salt thereof or (ii) compound formula (II) or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

[0130] 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 thisdisclosure or a combination of any of the compounds of this disclosure or a pharmaceutically acceptable salt thereof, is administered via any of the usual and acceptable methods known in the art. For instance, compounds or compositions of the present disclosure can be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form of solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.

[0131] Suitable excipients are known to those skilled in the art and are described in detail in, e.g . (i) Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; (ii) Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and (iii) Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Examples of pharmaceutically acceptable excipients include, without limitation, carriers, diluents, adjuvants, and vehicles. Non-limiting examples include, buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, and flavoring agents.

[0132] The compositions comprising compound Formulae (I) or (II) may be formulated as a pharmaceutical composition in accordance with standard pharmaceutical practice. A typical formulation is prepared by mixing a compound of the present disclosure and one or more excipients.

[0133] 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.

[0134] 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, andan inert liquid diluent. The tablets can optionally be coated or scored. Tablets may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay coating material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0135] 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.

[0136] 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.

[0137] In some embodiments, pharmaceutical compositions comprising formula (I) or compound formula (II), or a pharmaceutically acceptable salt thereof, further comprise an additional therapeutic agent.Combination Therapy

[0138] The compounds of the present disclosure may be administered in combination with one or more additional therapeutic agents, such as for instance and without limitation, standard of care agents appropriate for a neurodegenerative disease or disorder.

[0139] 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 can be coadministered with one or more additional therapeutic agents used and / or developed to treat a disease or condition mediated, at least in part, by TMEM175. In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agent that are being used and / or developed to treat Parkinson’s Disease (PD). In some embodiments, the one or more additional therapeutic agent may be dopamine-replacement therapies (levodopa / carbidopa), dopamine agonists (pramipexole, ropinirole, rotigotine, apomorphine), catechol-O- methyltransferase (COMT) inhibitors (entacapone, levodopa / carbidopa / entacapone, tolcapone,opicapone), monoamine oxidase B (MAO-B) inhibitors (selegiline hydrochloride, rasagiline, safinamide), amantadine, anticholinergic medications (trihexyphenidyl, benztropine mesylate), acetylcholinesterase inhibitors (rivastigmine), serotonin 5-HT2A receptor agonists (pimavanserin), or dopamine transporters for imaging (ioflupane 1-123)

[0140] 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.

[0141] 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.

[0142] Typically, any agent that has activity against a disease or condition being treated may be co-administered. 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.Methods of Treatment

[0143] 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.

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

[0145] 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 human a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0146] In some embodiments, provided herein are methods of modulating TMEM175 in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0147] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a disease, disorder or condition in a subject in need thereof.

[0148] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment of a TMEM 175 -mediated disorder in a subject in need thereof.

[0149] Use of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for modulating TMEM 175 in a subject.

[0150] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a disease, disorder or condition in a subject in need thereof.

[0151] The compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in the treatment of a TMEM 175 -mediated disorder in a subject in need thereof.

[0152] In some embodiments, the disorder is a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder includes, but is not limited to, a central nervous system (CNS) disorder, such as Parkinson’s disease (PD), Parkinsonism, Alzheimer’s disease (AD), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age related memory dysfunction, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer’s disease), argyrophilic grain disease, lysosomal disorders, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms / relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV- associated dementia (HAD). In some embodiments, the treatment is for neurodegenerative andcentral nervous system (CNS) disorders, such as Parkinson’s disease (PD) and rapid eye movement sleep behavior disorder (RBD).

[0153] 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.

[0154] 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.

[0155] The dosage regimen may be adjusted to provide the optimum desired response. For instance, a single dose may be administered, several doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Each unit dose may contain a predetermined quantity of a compound of formula (I) or a compound of formula (II) calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are influenced by (i) the unique characteristics of the particular active compound formula, (ii) and the particular therapeutic or prophylactic effect to be achieved, and (iii) pharmacokinetic factors associated with the drug and associated excipients, and the disease to be treated.

[0156] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen may be adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined. Dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient doseescalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0157] 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.

[0158] 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.

[0159] In some embodiments, a method of modulating TMEM175 in a subject suffering from a neurodegenerative disorder is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a pharmaceutical composition comprising formula (I) or formula (II) as described elsewhere herein.

[0160] In some embodiments, a method of treatment in a subject suffering from a neurodegenerative disorder is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a pharmaceutical composition comprising formula (I) or formula (II) as described elsewhere herein.

[0161] In some embodiments, a method of treating Parkinson’s Disease is provided. Such a method comprises administering to the subject an effective amount of: (i) the compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) the compound of formula (II) or a pharmaceutically acceptable salt thereof; (iii) a pharmaceutical composition comprising formula (I) or formula (II) as described elsewhere herein.

[0162] Additional Embodiments

[0163] Also provided herein are the following exemplary embodiments.

[0164] Embodiment 1. A compound of Formula (la’):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from the group consisting of halogen, substituted or unsubstituted C1-5alkyl, and substituted or unsubstituted C1-5alkoxy; R1is CH3or CH2OH; R2is H, D, halo, C1-5alkyl, halo- C1-5alkyl or C1-5alkoxy; and Z1is substituted or unsubstituted 4-9 membered N-heterocycle.

[0165] Embodiment 2. The compound of Embodiment 1, wherein X is selected from halogen, C1-5haloalkyl and C1-5haloalkoxy.

[0166] Embodiment 3. The compound of Embodiment 1 or Embodiment 2, wherein X is selected from -Cl, -OCF3, -OCHF2and -CF2.

[0167] Embodiment 4. The compound of any one of Embodiments 1 to 3, wherein Z1is a substituted 4-9 membered N-heterocycle.

[0168] Embodiment 5. The compound of any one of Embodiments 1 to 4, wherein Z1is a substituted 4-6 membered N-heterocycle.

[0169] Embodiment 6. The compound of any one of Embodiments 1 to 3, wherein Z1is a substituted or unsubstituted 4-9 membered N-heterocycle, and wherein the substituted or unsubstituted 4-9 membered N-heterocycle further comprises one or more additional heteroatoms selected from O and S.

[0170] Embodiment 7. The compound of any one of Embodiments 1 to 4, wherein Z1is selected from:

[0171] Embodiment 8. A compound of Formula (II’):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1is CH3or CH2OH; R2is H, D, halo, C1-5alkyl, halo- C1-5alkyl or C1-5alkoxy; Z2is 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; and substituted or unsubstituted 6-membered aryl; and Z3is substituted or unsubstituted 4-9 membered N-heterocycle.

[0172] Embodiment 9. The compound of Embodiment 8, wherein Z2is, wherein X1is -CH- or -N-, and R4 is selected from hydrogen, -Cl, -F, or -CF3.

[0173] Embodiment 10. The compound of Embodiment 9, wherein X1is -CH-, and R4is -F.

[0174] Embodiment 11. The compound of any one of Embodiments 8 to 10, wherein Z3is a substituted 4-9 membered N-heterocycle.

[0175] Embodiment 12. The compound of any one of Embodiments 8 to 11, wherein Z3is a substituted or unsubstituted 4-7 membered N-heterocycle.

[0176] Embodiment 13. The compound of any one of Embodiments 8 to 10, wherein Z3is a substituted or unsubstituted 4-9 membered N-heterocycle, and wherein the substituted or unsubstituted 4-9 membered heterocycle further comprises one or more additional heteroatoms selected from O and S.

[0177] Embodiment 14. The compound of Embodiment 8, wherein Z3is selected from: ,

[0178] Embodiment 15. A pharmaceutical composition comprising the compound of any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0179] Embodiment 16. The pharmaceutical composition of Embodiment 15, further comprising an additional therapeutic agent.

[0180] Embodiment 17. 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 14, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of Embodiment 15 or Embodiment 16.

[0181] Embodiment 18. 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 14, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of Embodiment 15 or Embodiment 16.

[0182] Embodiment 19. The method of Embodiment 18, 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 graindisease, lysosomal disorders, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms / relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV-associated dementia (HAD).

[0183] Embodiment 20. The method of Embodiment 19, wherein the neurodegenerative disorder is Parkinson’s disease (PD). Examples

[0184] Example 1a: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-5-fluoro-2- methylindolin-1-yl)propan-1-one

[0185] Example 1b: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-5-fluoro-2- methylindolin-1-yl)propan-1-one Synthetic Route

[0186] Step 1: tert-butyl ((2R)-1-(5-fluoro-2-methylindolin-1-yl)-1-oxopropan-2- yl)carbamate

[0187] A solution of 5-fluoro-2-methyl-indoline (300.0 mg, 1.98 mmol), (2R)-2-(tert- butoxycarbonylamino)propanoic acid (375.3 mg, 1.98 mmol), 2-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (1.13 g, 2.98 mmol) and N,N- diisopropylethylamine (768.3 mg, 5.95 mmol) in dichloromethane (5 mL) was stirred at 25 °C for 1 hour. The solvent was 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 (600.0 mg, 1.77 mmol, 89.1% yield) as a brown oil. LC-MS: (ESI, m / z): 323.2[M+H]+.

[0188] Step 2: (2R)-2-amino-1-(5-fluoro-2-methylindolin-1-yl)propan-1-one trifluoroacetate

[0189] A solution of tert-butyl ((2R)-1-(5-fluoro-2-methylindolin-1-yl)-1-oxopropan-2- yl)carbamate (600.0 mg, 1.86 mmol) in trifluoroacetic acid (0.5 mL) and 1,1,1,3,3,3-hexafluoro-2- propanol (9.5 mL) was stirred at 25 °C for 4 hours. After completion, the solvent was removed under vacuum to afford the title compound (650.0 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 223.1 [M+H]+.

[0190] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-5-fluoro-2-methylindolin-1- yl)propan-1-one & (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-5-fluoro-2-methylindolin-1- yl)propan-1-one

[0191] A solution of (2R)-2-amino-1-(5-fluoro-2-methyl-indolin-1-yl)propan-1-one trifluoroacetate (150.0 mg, crude), N,N-diisopropylethylamine (261.2 mg, 2.02 mmol) and 4,7- dichloroquinazoline (148.2 mg, 0.74 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 30 minutes. After completion, the reaction solution was purified by flash chromatography on reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the product. The product was isolated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK RR 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RT1(min): 26.21; RT2(min): 35.355; Sample Solvent: EtOH; Injection Volume: 0.85 mL to afford (R)-2-((7-chloroquinazolin-4- yl)amino)-1-((S)-5-fluoro-2-methylindolin-1-yl)propan-1-one (12.5 mg, 0.03 mmol, 4.8% yield) as a yellow solid and (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-5-fluoro-2-methylindolin-1- yl)propan-1-one (12.2 mg, 0.03 mmol, 4.7% yield) as a white solid.

[0192] Example 2: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-4,4-difluoro-2- methylpyrrolidin-1-yl)propan-1-one Synthetic Route

[0193] Step 1: tert-butyl (S)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate

[0194] To a solution of tert-butyl (2S)-2-methyl-4-oxo-pyrrolidine-1-carboxylate (500.0 mg, 2.51 mmol) in dichloromethane (5 mL) was slowly added diethylaminosulfur trifluoride (2.02 g, 12.55 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. After completion, the reaction was quenched with methanol. The solvent was 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 (370.0 mg, 1.66 mmol, 66.0 % yield) as a brown oil. LC-MS: (ESI, m / z): 222.1[M+H]+.

[0195] Step 2: (S)-4,4-difluoro-2-methylpyrrolidine trifluoroacetate

[0196] A solution of tert-butyl (S)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate (360.0 mg, 1.63 mmol) in trifluoroacetic acid (0.5 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (9.5 mL) was stirred at 25 °C for 4 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (430.0 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 121.1 [M+H]+.

[0197] Step 3: tert-butyl ((R)-1-((S)-4,4-difluoro-2-methylpyrrolidin-1-yl)-1-oxopropan-2- yl)carbamate

[0198] A solution of (S)-4,4-difluoro-2-methylpyrrolidine trifluoroacetate (390.0 mg, crude), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (487.3 mg, 2.58 mmol), 2-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.84 g, 4.83 mmol) and N,N-diisopropylethylamine (1.25 g, 9.66 mmol) in dichloromethane (5 mL) was stirred at 25 °C for 2 hours. After completion, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to afford the title compound (500.0 mg, 1.71 mmol, 53.1% yield) as a brown oil. LC-MS: (ESI, m / z): 293.2 [M+H]+.

[0199] Step 4: (R)-2-amino-1-((S)-4,4-difluoro-2-methylpyrrolidin-1-yl)propan-1-one trifluoroacetate

[0200] A solution of tert-butyl ((R)-1-((S)-4,4-difluoro-2-methylpyrrolidin-1-yl)-1- oxopropan-2-yl)carbamate (60.0 mg, 0.21 mmol) in trifluoroacetic acid (0.5 mL) and 1,1,1,3,3,3- hexafluoro-2-propanol (9.5 mL) was stirred at 25 °C for 2 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (71.2 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 193.1 [M+H]+.

[0201] Step 5: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-4,4-difluoro-2- methylpyrrolidin-1-yl)propan-1-one

[0202] A solution of (2R)-2-amino-1-[(2S)-4,4-difluoro-2-methyl-pyrrolidin-1-yl]propan- 1-one trifluoroacetate (60.0 mg, crude), 4,7-dichloroquinazoline (49.7 mg, 0.25 mmol) and N,N- diisopropylethylamine (121.2 mg, 0.94 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 °C for 0.5 hours. After completion, the resulting residue was purified by Prep-HPLC with the following condition: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 46% B in10.5min; Wave Length: 254 / 220 nm; RT1(min): 9.95 to afford the title compound (74.7 mg, 0.21 mmol, 67.3% yield) as a white solid. LC-MS: (ESI, m / z): 355.1 [M+H]+.

[0203] Example 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-4,4-difluoro-2- methylpyrrolidin-1-yl)propan-1-one Synthetic Route

[0204] Step 1: tert-butyl (R)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate

[0205] To a solution of tert-butyl (2R)-2-methyl-4-oxo-pyrrolidine-1-carboxylate (500.0 mg, 2.51 mmol) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (2.02 g, 12.55 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. After completion, the reaction was quenched with methanol. The solvent was 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 (390.0 mg, 1.76 mmol, 70.1 % yield) as a brown oil. LC-MS: (ESI, m / z): 222.1[M+H]+.

[0206] Step 2: (R)-4,4-difluoro-2-methylpyrrolidine trifluoroacetate

[0207] A solution of tert-butyl (R)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate (380.0 mg, 1.72 mmol) in trifluoroacetic acid (0.5 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (9.5 mL) was stirred at 25 °C for 4 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (435.5 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 121.1 [M+H]+.

[0208] Step 3: tert-butyl ((R)-1-((R)-4,4-difluoro-2-methylpyrrolidin-1-yl)-1-oxopropan-2- yl)carbamate

[0209] A solution of (R)-4,4-difluoro-2-methylpyrrolidine trifluoroacetate (435.5 mg, crude), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (827.9 mg, 4.38 mmol), 2-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.50 g, 6.56 mmol) and N,N-diisopropylethylamine (1.69 g, 13.13 mmol) in dichloromethane (6 mL) was stirred at 25 °C for 2 hours. After completion, the reaction mixture was diluted with dichloromethane, and washedwith water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to afford the title compound (500.0 mg, 1.71 mmol, 53.1% yield) as a brown oil. LC-MS: (ESI, m / z): 293.2 [M+H]+.

[0210] Step 4: (R)-2-amino-1-((R)-4,4-difluoro-2-methylpyrrolidin-1-yl)propan-1-one trifluoroacetate

[0211] A solution of tert-butyl ((R)-1-((R)-4,4-difluoro-2-methylpyrrolidin-1-yl)-1- oxopropan-2-yl)carbamate (100.0 mg, 0.34 mmol) in trifluoroacetic acid (0.5 mL) and 1,1,1,3,3,3- hexafluoro-2-propanol (9.5 mL) was stirred at 25 °C for 2 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (125.6 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 193.1 [M+H]+.

[0212] Step 5: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-4,4-difluoro-2- methylpyrrolidin-1-yl)propan-1-one

[0213] A solution of (2R)-2-amino-1-[(2R)-4,4-difluoro-2-methyl-pyrrolidin-1-yl]propan- 1-one (100.0 mg, crude), 4,7-dichloroquinazoline(103.1 mg, 0.52 mmol) and N,N- diisopropylethylamine (201.3 mg, 1.56 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 0.5 hours. After completion, the resulting residue was purified by Prep-HPLC with the following condition: Column: Xselect CSH F-Phenyl OBD column30*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 9% B to 29% B in 10 min; Wave Length: 254nm / 220nm to afford the title compound (17.7 mg, 0.05 mmol, 9.60 % yield) as a white solid. LC-MS: (ESI, m / z): 355.1 [M+H]+.

[0214] Example 4: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-3- methylmorpholino)propan-1-one Synthetic Route

[0215] Step 1: tert-butyl ((R)-1-((R)-3-methylmorpholino)-1-oxopropan-2-yl)carbamate

[0216] A solution of (3R)-3-methylmorpholine (100.0 mg, 0.99 mmol), (2R)-2-(tert- butoxycarbonylamino)propanoic acid (187.1 mg, 0.99 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (563.9 mg, 1.48 mmol) and N,N- diisopropylethylamine (382.6 mg, 2.97 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 2 hours. After completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to afford the title compound (160.0 mg, 0.58 mmol, 58.8 % yield) as a brown oil. LC-MS: (ESI, m / z): 273.2 [M+H]+.

[0217] Step 2: (R)-2-amino-1-((R)-3-methylmorpholino)propan-1-one trifluoroacetate

[0218] A solution of tert-butyl ((R)-1-((R)-3-methylmorpholino)-1-oxopropan-2- yl)carbamate (70.0 mg, 0.21 mmol) in trifluoroacetic acid (0.1 mL) and 1,1,1,3,3,3-hexafluoro-2- propanol (1.9 mL) was stirred at 25 °C for 4 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (85.1 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 173.1 [M+H]+.

[0219] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-3- methylmorpholino)propan-1-one

[0220] Under nitrogen, a solution of (R)-2-amino-1-((R)-3-methylmorpholino)propan-1- one trifluoroacetate (70.0 mg, crude), N,N-diisopropylethylamine (157.3 mg, 1.22 mmol) and 4,7- dichloroquinazoline (121.4 mg, 0.61 mmol) in dimethyl sulfoxide (1 mL) was added at 100 °C for 30 minutes. After completion, the reaction mixture was purified by reverse phase chromatography (acetonitrile / 0.1 % NH4HCO3in water) to afford the title compound (37.9 mg, 0.11 mmol, 27.7 % yield) as a white solid. LC-MS: (ESI, m / z): 335.3 [M+H]+.

[0221] Example 5a: (R)-1-((R)-4-chloro-2-methylindolin-1-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one

[0222] Example 5b: (R)-1-((S)-4-chloro-2-methylindolin-1-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one Synthetic Route

[0223] Step 1: 4-chloro-2-methylindoline

[0224] To a solution of 4-chloro-2-methyl-1H-indole (300.0 mg, 1.81 mmol) in acetic acid (3 mL) was added sodium cyanoborohydride (342.2 mg, 5.43 mmol) at 0 °C. The mixture was stirred at 15 °C for 2 hours. After completion, the resulting solution was diluted withdichloromethane and the pH adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:1) to afford the title compound (100.0 mg, 0.57 mmol, 31.3 % yield) as a colorless oil. LC-MS: (ESI, m / z): 168.1 [M+H]+.

[0225] Step 2: tert-butyl ((2R)-1-(4-chloro-2-methylindolin-1-yl)-1-oxopropan-2- yl)carbamate

[0226] A solution of 4-chloro-2-methylindoline (90.0 mg, 0.54 mmol), N,N,N,N- tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (306.2 mg, 0.81 mmol), (2R)- 2-(tert-butoxycarbonylamino)propanoic acid (102.1 mg, 0.54 mmol) and N,N- diisopropylethylamine (208.2 mg, 1.61 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 combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to afford the title compound (170.0 mg, 0.45 mmol, 84.1 % yield) as a brown oil. LC-MS: (ESI, m / z): 339.1 [M+H]+.

[0227] Step 3: (2R)-2-amino-1-(4-chloro-2-methylindolin-1-yl)propan-1-one trifluoroacetate

[0228] A solution of tert-butyl ((2R)-1-(4-chloro-2-methylindolin-1-yl)-1-oxopropan-2- yl)carbamate (100.0 mg, 0.23 mmol) in trifluoroacetic acid (0.1 mL) and 1,1,1,3,3,3-hexafluoro-2- propanol (1.9 mL) was stirred at 25 °C for 3 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (125.3 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 239.1 [M+H]+.

[0229] Step 4: (R)-1-((R)-4-chloro-2-methylindolin-1-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one & (R)-1-((S)-4-chloro-2-methylindolin-1-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one

[0230] Under nitrogen, a solution of (2R)-2-amino-1-(4-chloro-2-methylindolin-1- yl)propan-1-one trifluoroacetate (100.0 mg, crude), N,N-diisopropylethylamine (162.2 mg, 1.26 mmol) and 4,7-dichloroquinazoline (125.2 mg, 0.63 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 °C for 30 minutes. After completion, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH F-Phenyl OBD column30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 42% B to62% B in 7 min; Wave Length: 254nm / 220nm; RT1(min): 6.4 to afford the product. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK RR 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RT1(min): 10.822; RT2(min): 12.32; Sample Solvent: ETOH; Injection Volume: 0.3 mL to afford (R)-1-((R)-4-chloro-2-methylindolin- 1-yl)-2-((7-chloroquinazolin-4-yl)amino)propan-1-one (10.5 mg, 0.026 mmol, 6.2 % yield) as a white solid and (R)-1-((S)-4-chloro-2-methylindolin-1-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one (12.4 mg, 0.03 mmol, 7.3 % yield) as a white solid.

[0231] Example 6: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-(1-methyl-2- azabicyclo[2.1.1]hexan-2-yl)propan-1-one Synthetic Route

[0232] Step 1: tert-butyl (R)-(1-(1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)-1-oxopropan-2- yl)carbamate

[0233] A solution of 1-methyl-2-azabicyclo[2.1.1]hexane hydrochloride (60.0 mg, 0.45 mmol), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (85.1 mg, 0.45mmol), 2-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (256.0 mg, 0.67 mmol) and N,N-diisopropylethylamine (174.2 mg, 1.35 mmol) in dichloromethane (1 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to afford the title compound (115.0 mg, 0.43 mmol, 95.6 % yield) as a brown oil. LC-MS: (ESI, m / z): 269.2[M+H]+.

[0234] Step 2: (R)-2-amino-1-(1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)propan-1-one trifluoroacetate

[0235] A solution of tert-butyl (R)-(1-(1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)-1- oxopropan-2-yl)carbamate (60.0 mg, 0.16 mmol) in trifluoroacetic acid (0.1 mL) and 1,1,1,3,3,3- hexafluoro-2-propanol (0.9 mL) was stirred at 25 °C for 2 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (81.5 mg, crude) as a yellowoil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 169.1[M+H]+.

[0236] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-(1-methyl-2- azabicyclo[2.1.1]hexan-2-yl)propan-1-one

[0237] A solution of (2R)-2-amino-1-(1-methyl-2-azabicyclo[2.1.1]hexan-2-yl)propan-1- one trifluoroacetate (60.0 mg, crude), 4,7-dichloroquinazoline(106.5 mg, 0.53 mmol) and N,N- diisopropylethylamine (121.2 mg, 0.94 mmol) in dimethyl sulfoxide (2 mL) 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 and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B in 10.5 min; Wave Length: 254 / 220 nm; RT1(min): 9.07 to afford the title compound (11.1 mg, 0.03 mmol, 9.1 % yield) as a white solid. LC-MS: (ESI, m / z): 331.1[M+H]+.

[0238] Example 7: (R)-1-(5-azaspiro[2.4]heptan-5-yl)-2-((6-(4- (trifluoromethyl)phenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0239] Step 1: 4-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine

[0240] Under nitrogen, a solution of 4-(trifluoromethyl)phenylboronic acid (3.44 g, 18.12 mmol), 4,6-dichloropyrimidine (3.00 g, 20.14 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.47 g, 2.01 mmol) and potassium carbonate (8.40 g, 60.41 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 80 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel elutingwith petroleum ether / ethyl acetate (1:1) to afford the title compound (1.00 g, 4.12 mmol, 20.5 % yield) as a white solid. LC-MS: (ESI, m / z): 259.0 [M+H]+.

[0241] Step 2: (R)-1-(5-azaspiro[2.4]heptan-5-yl)-2-((6-(4- (trifluoromethyl)phenyl)pyrimidin-4-yl)amino)propan-1-one

[0242] A solution of 4-chloro-6-(4-(trifluoromethyl)phenyl)pyrimidine (100.0 mg, 0.39 mmol), (2R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (118.7 mg, 0.58 mmol) and N,N-diisopropylethylamine (150.0 mg, 1.16 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (11.0 mg, 0.03 mmol, 7.3% yield) as a white solid. LC-MS: (ESI, m / z): 391.0 [M+H]+.

[0243] Example 8: (R)-2-((6-(5-chloropyridin-2-yl)pyrimidin-4-yl)amino)-1-(5- azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0244] Step 1: 4-chloro-6-(5-chloropyridin-2-yl)pyrimidine

[0245] Under nitrogen, a solution of 4,6-dichloropyrimidine (200.0 mg, 1.34 mmol), tributyl-(5-chloro-2-pyridyl)stannane (108.1 mg, 0.27 mmol), cuprous iodide (51.0 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium (155.2 mg, 0.13 mmol) in toluene (1 mL) was stirred at 110 °C for 30 minutes. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (140.0 mg, 0.43 mmol, 32.3% yield) as a brown solid. LC-MS: (ESI, m / z): 226.0 [M+H]+.

[0246] Step 2: (R)-2-((6-(5-chloropyridin-2-yl)pyrimidin-4-yl)amino)-1-(5- azaspiro[2.4]heptan-5-yl)propan-1-one

[0247] A solution of 4-chloro-6-(5-chloro-2-pyridyl)pyrimidine (200.0 mg, 0.88 mmol), (2R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (199.2 mg, 0.97 mmol) and N,N-diisopropylethylamine (341.9 mg, 2.65 mmol) in dimethyl sulfoxide (3 mL) was stirred at100°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 29% B to 49% B in 10.5min; Wave Length: 254 / 220 nm; RT1(min): 7.22 to afford the title compound (29.3 mg, 0.08 mmol, 9.1% yield) as a white solid. LC-MS: (ESI, m / z): 358.1 [M+H]+.

[0248] Example 9: (R)-2-((6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)amino)-1-(5- azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0249] Step 1: 4-chloro-6-(5-fluoropyridin-2-yl)pyrimidine

[0250] Under nitrogen, a solution of 4,6-dichloropyrimidine (200.0 mg, 1.34 mmol), tributyl-(5-fluoro-2-pyridyl)stannane (103.7 mg, 0.27 mmol), cuprous iodide (51.0 mg, 0.27 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (155.2 mg, 0.13 mmol) in toluene (3 mL) was stirred at 110 °C for 30 minutes. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then, the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (140.0 mg, 0.57 mmol, 42.3% yield) as a brown solid. LC-MS: (ESI, m / z): 210.0 [M+H]+.

[0251] Step 2: (R)-2-((6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)amino)-1-(5- azaspiro[2.4]heptan-5-yl)propan-1-one

[0252] A solution of 4-chloro-6-(5-fluoropyridin-2-yl)pyrimidine (100.0 mg, 0.48 mmol), (2R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (146.5 mg, 0.72 mmol) and N,N-diisopropylethylamine (184.6 mg, 1.43 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then, the organic layers were combined, washed with brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Prep Shield RP OBD C18 Column, 30*150 mm, 5qm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20%B to 44%B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 7.72 to afford the title compound (32.0 mg, 0.09 mmol, 19.5 % yield) as a white solid. LC-MS: (ESI, m / z): 342.3 [M+H]+.

[0253] Example 10: (R)-1-(3,3-dimethylpyrrolidin-1-yl)-2-((6-(4-fluorophenyl)pyrimidin- 4-yl)amino)propan-1-one Synthetic Route

[0254] To a solution of (2R)-2-[[6-(4-fluorophenyl)pyrimidin-4-yl]amino]propanoic acid (100.0 mg, 0.38 mmol), 3,3-dimethylpyrrolidine hydrochloride (155.8 mg, 1.15 mmol) and N,N- diisopropylethylamine (296.3 mg, 2.30 mmol) in dichloromethane (3 mL) was added propanephosphonic acid cyclic anhydride (365.2 mg, 0.56 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33%B to 58%B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 7.72 to afford the title compound (8.8 mg, 0.03 mmol, 6.7% yield) as a white solid. LC-MS: (ESI, m / z): 343.2[M+H]+.

[0255] Example 11: (2R)-1-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0256] To a solution of (2R)-2-[[6-(4-fluorophenyl)pyrimidin-4-yl]amino]propanoic acid (100.0 mg, 0.38 mmol), 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride (155.7 mg, 1.15 mmol) and N,N-diisopropylethylamine (296.3 mg, 2.30 mmol) in dichloromethane (3 mL) was added propanephosphonic acid cyclic anhydride (365.2 mg, 0.57 mmol, 50 % in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 18%B to 43%B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.2 to afford the title compound (10.9 mg, 0.03 mmol, 8.3% yield) as a white solid. LC-MS: (ESI, m / z): 343.1[M+H]+.

[0257] Example 12: (R)-1-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0258] To a solution of (2R)-2-[[6-(4-fluorophenyl)pyrimidin-4-yl]amino]propanoic acid (100.0 mg, 0.38 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (171.8 mg, 1.15 mmol) and N,N-diisopropylethylamine (296.3 mg, 2.30 mmol) in dichloromethane (3 mL) was added propanephosphonic acid cyclic anhydride (365.2 mg, 0.57 mmol, 50% in ethyl acetate). The mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with thefollowing condition: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 40% B in 10.5 min; Wave Length: 254 / 220 nm; RT1(min): 8.38 to afford the title compound (10.2 mg, 0.03 mmol, 7.5 % yield) as a white solid. LC-MS: (ESI, m / z): 357.1[M+H]+.

[0259] Example 13: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-(4-oxa-7- azaspiro[2.5]octan-7-yl)propan-1-one Synthetic Route

[0260] A solution of (2R)-2-[[6-(4-fluorophenyl)pyrimidin-4-yl]amino]propanoic acid (100.0 mg, 0.38 mmol), 4-oxa-7-azaspiro[2.5]octane hydrochloride (171.8 mg, 1.15 mmol) and N,N-diisopropylethylamine (296.3 mg, 2.30 mmol) in dichloromethane (3 mL) was prepared, and then propanephosphonic acid cyclic anhydride (365.2 mg, 0.57 mmol, 50% in ethyl acetate) 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 residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Shield RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26%B to 49%B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.13 to afford the title compound (11.7 mg, 0.03 mmol, 8.6 % yield) as a white solid. LC-MS: (ESI, m / z): 357.2[M+H]+.

[0261] Example 14: (R)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0262] Step 1: tert-butyl (R)-(1-oxo-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-2- yl)carbamate

[0263] To a solution of 4-oxa-7-azaspiro[2.5]octane hydrochloride (200.0 mg, 1.34 mmol) and (2R)-2-(tert-butoxycarbonylamino)propanoic acid (239.0 mg, 1.26 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (517.3 mg, 4.01 mmol) and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (762.4 mg, 2.01 mmol). The mixture was stirred at 25 ºC for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to afford the title compound (500.0 mg, 1.06 mmol, 78.9 % yield) as a white oil. LC-MS: (ESI, m / z): 285.2[M+H]+.

[0264] Step 2: (R)-2-amino-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-1-one hydrochloride

[0265] A solution of tert-butyl (R)-(1-oxo-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-2- yl)carbamate (200.0 mg, 0.70 mmol) in hydrogen chloride / 1,4-dioxane (2 mL, 4.0 M) was stirred at 25 ºC for 2 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (135.6 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 185.1 [M+H]+.

[0266] Step 3: (R)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0267] A solution of (2R)-2-amino-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-1-one hydrochloride (90.0 mg, crude), 4-chloro-7-(trifluoromethoxy)quinazoline (152.1 mg, 0.61 mmol) and N,N-diisopropylethylamine (157.8 mg, 1.22 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100°C for 30 min. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, 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, 19*250 mm, 5μm; Mobile Phase A: Water(10mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 33%B to 52%B in 9 min; Wave Length: 254 / 220 nm; RT1(min): 9 to afford the title compound (48.1 mg,0.12 mmol, 29.2 % yield) as a white solid. LC-MS: (ESI, m / z): 397.1 [M+H]+.

[0268] Example 15: (R)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0269] To a solution of (2R)-2-[[6-(4-fluorophenyl)pyrimidin-4-yl]amino]propanoic acid (100.0 mg, 0.38 mmol), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (155.7 mg, 1.15 mmol) and N,N-diisopropylethylamine (296.3 mg, 2.30 mmol) in dichloromethane (3 mL) was added propanephosphonic acid cyclic anhydride (365.2 mg, 0.57 mmol, 50% in ethyl acetate). The mixture was stirred at 25°C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH F-Phenyl OBD column30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 16% B to 36% B in 10 min; Wave Length: 254nm / 220nm to afford the title compound (15.6 mg, 0.04 mmol, 11.6 % yield) as a white solid. LC-MS: (ESI, m / z): 343.1[M+H]+.

[0270] Example 16: (R)-6-((1-oxo-1-(5-azaspiro[2.4]heptan-5-yl)propan-2-yl)amino)-4- (trifluoromethyl)nicotinonitrile: Synthetic Route:

[0271] A solution of 6-chloro-4-(trifluoromethyl)pyridine-3-carbonitrile (80.0 mg, 0.39 mmol), (2R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (118.9 mg, 0.58 mmol) and N,N-diisopropylethylamine (149.9 mg, 1.16 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate / petroleum ether (1:3) to afford the title compound (66.4 mg, 0.19 mmol, 49.8 % yield) as an off-white solid. LC-MS: (ESI, m / z): 339.0 [M+H]+.

[0272] Example 17: (R)-1-(2-oxa-6-azaspiro[3.4]octan-6-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0273] Step 1: tert-butyl (R)-(1-oxo-1-(2-oxa-6-azaspiro[3.4]octan-6-yl)propan-2- yl)carbamate

[0274] A solution of (tert-butoxycarbonyl)-D-alanine (150.4 mg, 0.8 mmol), 2-oxa-6- azaspiro[3.4]octane hydrochloride (100.0 mg, 0.67 mmol), N,N-diisopropylethylamine (410.3 mg, 3.18 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (453.6 mg, 1.19 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (170.4 mg, 0.60 mmol, 89.6% yield) as a white solid. LC-MS: (ESI, m / z): 285.2 [M+H]+.

[0275] Step 2: (R)-2-amino-1-(2-oxa-6-azaspiro[3.4]octan-6-yl)propan-1-one trifluoroacetate

[0276] A solution of tert-butyl (R)-(1-oxo-1-(2-oxa-6-azaspiro[3.4]octan-6-yl)propan-2- yl)carbamate (170.0 mg, 0.60 mmol) in hexafluoro-2-propanol (3.8 mL) and trifluoroacetic acid (0.2 mL) was stirred at 25 °C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (198.2 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 184.2 [M+H]+.

[0277] Step 3: (R)-1-(2-oxa-6-azaspiro[3.4]octan-6-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0278] A solution of (R)-2-amino-1-(2-oxa-6-azaspiro[3.4]octan-6-yl)propan-1-one trifluoroacetate (110.0 mg, crude), 4-chloro-7-(trifluoromethoxy)quinazoline (51.6 mg, 0.45 mmol), and N,N-diisopropylethylamine (192.7 mg, 1.49 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100°C for 0.5 hours. 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 C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (33.1 mg, 0.08 mmol, 23.6% yield) as a white solid. LC-MS: (ESI, m / z): 397.2 [M+H]+.

[0279] Example 18: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((2R,4S)-2- methyl-4-(trifluoromethoxy)piperidin-1-yl)propan-1-one Synthetic Route

[0280] Step 1: tert-butyl (2R,4S)-2-methyl-4-(trifluoromethoxy)piperidine-1-carboxylate

[0281] A mixture of silver trifluoromethanesulfonate (6.45 g, 25.08 mmol), potassium fluoride (2.19 g, 37.16 mmol) and selectfluoro (4.95 g, 13.93 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of tert-butyl (2R,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (2.00 g, 9.29 mmol) in ethyl acetate (20 mL) followed by the dropwise addition of 2-fluoro-pyridine (2.73 g, 27.87 mmol)) and then (trifluoromethyl)trimethylsilane (3.99 g, 27.87 mmol). The reaction mixture was then stirred at ambient temperature for 2 days. After filtration, the filtrate was 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 (1.10 g, 3.88 mmol, 41.8% yield) as a colorless oil. LC-MS: (ESI, m / z): 284.1 [M+H]+.

[0282] Step 2: (2R,4S)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride

[0283] A solution of tert-butyl (2R,4S)-2-methyl-4-(trifluoromethoxy)piperidine-1- carboxylate (1.10 g, 3.88 mmol) in hydrochloric acid / dioxane (11 mL, 4M) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (0.88 g, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 184.1 [M+H]+.

[0284] Step 3: tert-butyl ((R)-1-((2R,4S)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1- oxopropan-2-yl)carbamate

[0285] A solution of (2R,4S)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride (850.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (1.32 g, 6.96 mmol), N,N- diisopropylethylamine (2.90 g, 23.2 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (2.60 g, 6.96 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with 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 (3:1) to afford the title compound (807.1 mg, 2.28 mmol, 58.8% yield) as a colorless oil. LC-MS: (ESI, m / z): 355.2 [M+H]+.

[0286] Step 4: (R)-2-amino-1-((2R,4S)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)propan-1-one hydrochloride

[0287] A solution of tert-butyl ((R)-1-((2R,4S)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)-1-oxopropan-2-yl)carbamate (200.0 mg, 0.56 mmol) in hydrochloric acid (2 mL, 4 mol / L in 1.4- dioxane) was stirred at 25 °C for 30 minutes. After completion, the solvent was removed under vacuum to afford the title compound (180.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 255.1 [M+H]+.

[0288] Step 5: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((2R,4S)-2-methyl-4- (trifluoromethoxy)piperidin-1-yl)propan-1-one

[0289] A solution of 7-(difluoromethyl)quinazolin-4(3H)-one (55.0 mg, 0.28 mmol), N,N- diisopropylethylamine (180.8 mg, 1.40 mmol) and benzotriazole-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (218.8 mg, 0.42 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. Then (R)-2-amino-1-((2R,4S)-2-methyl-4- (trifluoromethoxy)piperidin-1-yl)propan-1-one hydrochloride (120.9 mg, crude) was added and the mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 36% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 7.77 to afford the title compound (37.6 mg, 0.08 mmol, 30.9% yield) as a white solid. LC-MS: (ESI, m / z): 433.2 [M+H]+.

[0290] Example 19: (R)-2-((7-(difluoromethyl)Synthetic Route

[0291] Step 1: tert-butyl (2S,4R)-2-methyl-4-(trifluoromethoxy)piperidine-1-carboxylate

[0292] A mixture of silver trifluoromethanesulfonate (6.45 g, 25.08 mmol), potassium fluoride (2.19 g, 37.16 mmol), and selectfluoro (4.95 g, 13.93 mmol) was stirred under a nitrogen atmosphere, in a flask wrapped with aluminum foil, and cooled with a water bath. To this was slowly added a solution of tert-butyl (2S,4R)-4-hydroxy-2-methylpiperidine-1-carboxylate (2.00 g, 9.29 mmol) in ethyl acetate (20 mL) followed by the dropwise addition of 2-fluoro-pyridine (2.73 g, 27.87 mmol)) and then (trifluoromethyl)trimethylsilane (3.99 g, 27.87 mmol). The reaction mixture then stirred at ambient temperature for 2 days. After filtration, the filtrate was 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 (1.21 g, 4.27 mmol, 46% yield) as a colorless oil. LC-MS: (ESI, m / z): 284.1 [M+H]+.

[0293] Step 2: (2S,4R)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride

[0294] A solution of tert-butyl (2S,4R)-2-methyl-4-(trifluoromethoxy)piperidine-1- carboxylate (1.21 g, 4.27 mmol) in hydrochloric acid (12 mL, 4 mol / L in 1.4-dioxane) was stirred at 25 °C for 30 minutes. After completion, the solvent was removed under vacuum to afford the title compound (1.00 g, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 184.1 [M+H]+.

[0295] Step 3: tert-butyl ((R)-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1- oxopropan-2-yl)carbamate

[0296] A solution of (2S,4R)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride (1.00 g, crude), (tert-butoxycarbonyl)-D-alanine (1.16 g, 6.13 mmol), N,N-diisopropylethylamine (2.6 g, 20.40 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.32 g, 6.13 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with 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 (3:1) to afford the title compound (1.15 g, 3.23 mmol, 79.3% yield) as a colorless oil. LC-MS: (ESI, m / z): 355.2 [M+H]+.

[0297] Step 4: (R)-2-amino-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)propan-1-one hydrochloride

[0298] A solution of tert-butyl ((R)-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)-1-oxopropan-2-yl)carbamate (500.0 mg, 1.71 mmol) in hydrochloric acid (5 mL, 4 mol / L in 1.4- dioxane) was stirred at 25 °C for 30 minutes. After completion, the solvent was removed under vacuum to afford the title compound (430.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 255.1 [M+H]+.

[0299] Step 5: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((2S,4R)-2-methyl-4- (trifluoromethoxy)piperidin-1-yl)propan-1-one

[0300] A solution of 7-(difluoromethyl)quinazolin-4(3H)-one (55.0 mg, 0.28 mmol), N,N- diisopropylethylamine (180.8 mg, 1.4 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (218.8 mg, 0.42 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. Then (R)-2-amino-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)propan-1-one hydrochloride (125 mg, crude) was added and stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 36% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 7.77 to afford the title compound (50.3 mg, 0.11 mmol, 41.4% yield) as a white solid. LC-MS: (ESI, m / z): 433.2 [M+H]+.

[0301] Example 20: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-(4-oxa-7- azaspiro[2.5]octan-7-yl)propan-1-one Synthetic Route:

[0302] Under nitrogen, a solution of (R)-2-amino-1-(4-oxa-7-azaspiro[2.5]octan-7- yl)propan-1-one hydrochloride (76.5 mg, crude), 4,7-dichloroquinazoline (63.6 mg, 0.32 mmol) and N,N-diisopropylethylamine (150.3 mg, 1.16 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 100 ºC for 0.5 hours. After completion, the solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18gel (acetonitrile / 0.1% ammoniumbicarbonate in water) to afford the title compound (59.6 mg, 0.17 mmol, 58.6% yield) as a white solid. LC-MS: (ESI, m / z):347.0 [M+H]+.

[0303] Example 21: (R)-1-(4-chloroindolin-1-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one Synthetic Route:

[0304] Step 1: tert-butyl (R)-(1-(4-chloroindolin-1-yl)-1-oxopropan-2-yl)carbamate

[0305] A solution of 4-chloroindoline (115.0 mg, 0.75 mmol) and (tert-butoxycarbonyl)- D-alamine (283.3 mg, 1.5 mmol) in fichloromethane (1.5 mL) was stirred at 0 ºC. Then o-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate (426.7 mg, 1.12 mmol) and N,N-diisopropylethylamine (387.0 mg, 2.99 mmol) was added and stirred at 25 ºC for 1 hour. After completion, the solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:4) to afford the title compound (200.0 mg, 0.58 mmol, 78.1% yield) as a yellow oil. LC-MS: (ESI, m / z):325.1[M+H]+.

[0306] Step 2: (R)-2-amino-1-(4-chloroindolin-1-yl)propan-1-one hydrochloride

[0307] A solution of tert-butyl (R)-(1-(4-chloroindolin-1-yl)-1-oxopropan-2-yl)carbamate (200.0 mg, 0.62 mmol) in hydrochloric acid (10.0 mL, 4 mol / L in 1,4-dioxane) was stirred at 25 ºC for 1 hour. After completion, the reaction solution was concentrated under vacuum to afford the title compound (166.0 mg, crude) as a purple solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z):225.1 [M+H]+.

[0308] Step 3: (R)-1-(4-chloroindolin-1-yl)-2-((7-chloroquinazolin-4-yl)amino)propan-1- one

[0309] Under nitrogen, a solution of (R)-2-amino-1-(4-chloroindolin-1-yl)propan-1-one hydrochloride (81.5 mg, crude), 4,7-dichloroquinazoline (58.9 mg, 0.3 mmol) and N,N- diisopropylethylamine (104.3 mg, 0.81 mmol) in dimethyl sulfoxide (0.1 mL) was stirred at 100 ºC for 0.5 hours. After completion, the solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on C18gel eluting with reverse phase chromatography (acetonitrile / 0.1%NH4HCO3in water) to afford crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 47% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 7.43 to afford the title compound (51.6 mg, 0.13 mmol, 49.3% yield) as a white solid. LC-MS: (ESI, m / z):387.0 [M+H]+.

[0310] Example 22: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-(5- azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0311] Under nitrogen, a solution of 4-chloro-6-(4-fluorophenyl)pyrimidine (70.0 mg, 0.34 mmol), N,N-diisopropylethylamine (0.23 mL, 1.34 mmol) and (R)-2-amino-1-(5- azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (115 mg, crude) in dimethyl sulfoxide (0.7 mL) was stirred at 100 ºC for 45 minutes. After completion, the solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 29% B to 54% B in 9 min; Wave Length: 254nm / 220nm to afford the title compound (43.7 mg, 0.12 mmol, 38.2% yield) as a white solid. LC-MS: (ESI, m / z):341.0[M+H]+.

[0312] Example 23a: (R)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)-1-((R)-3- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one

[0313] Example 23b: (R)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)-1-((S)-3- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one Synthetic Route

[0314] Step 1: tert-butyl ((2R)-1-oxo-1-(3-(trifluoromethyl)pyrrolidin-1-yl)propan-2- yl)carbamate

[0315] A solution of tert-butyl ((2R)-1-oxo-1-(3-(trifluoromethyl)pyrrolidin-1-yl)propan- 2-yl)carbamate (466.8 mg, 1.50 mmol) in hydrochloric acid (10.0 mL, 4 mol / L in 1,4-dioxane) was stirred at 25 ºC for 0.5 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (380.0 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 211.1 [M+H]+.

[0316] Step 2: (2R)-2-amino-1-(3-(trifluoromethyl)pyrrolidin-1-yl)propan-1-one hydrochloride

[0317] A solution of tert-butyl ((2R)-1-oxo-1-(3-(trifluoromethyl)pyrrolidin-1-yl)propan- 2-yl)carbamate (466.8 mg, 1.50 mmol) in hydrochloric acid (10.0 mL, 4 mol / L in 1,4-dioxane) was stirred at 25 " for 0.5 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (380.0 mg, crude) as a yellow solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 211.1 [M+H]+

[0318] Step 3: (R)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)-1-((R)-3- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one & (R)-2-((7-(trifluoromethoxy)quinazolin-4- yl)amino)-1-((S)-3-(trifluoromethyl)pyrrolidin-1-yl)propan-1-one

[0319] Under nitrogen, a solution of (2R)-2-amino-1-(3-(trifluoromethyl)pyrrolidin-1- yl)propan-1-one hydrochloride (158.0 mg, crude), N,N-diisopropylethylamine (0.38 mL, 2.2 mmol) and 4-chloro-7-(trifluoromethoxy)quinazoline (150.0 mg, 0.6 mmol) in dimethyl sulfoxide (1.5 mL) was stirred at 100 ºC for 0.5 hours. After completion, the solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:9) to afford crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Nobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 51% B in 10.5 min; Wave Length: 254 / 220 nm; RT1(min): 9.77 to afford the product. The product was isolated by Prep-Chiral-HPLC with the following condition:Column: CHIRAL ART Amylose-C NEO, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RT1(min): 9.18111.067; Sample Solvent: EtOH--HPLC; Injection Volume: 0.5 mL to afford (R)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)-1-((R)-3- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one (35.1 mg, 0.08 mmol, 14.9% yield) and (R)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)-1-((S)-3-(trifluoromethyl)pyrrolidin-1-yl)propan-1-one (30.5 mg, 0.07 mmol, 13% yield) as an off-white solid.

[0320] Example 24: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-(3- (trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0321] Under nitrogen, a solution of (R)-2-amino-1-(3-(trifluoromethoxy)azetidin-1- yl)propan-1-one hydrogen chloride (73.0 mg, crude), N,N-diisopropylethylamine (0.18 mL, 1.02 mmol) and 4,7-dichloroquinazoline (50.5 mg, 0.25 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 100 ºC for 0.5 hours. After completion, the solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18Column, 30*150 mm, 5 μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26%B to 46%B in10.5 min; Wave Length: 254 / 220 nm; RT1(min): 12.18 to afford the title compound (49.2 mg, 0.12 mmol, 51.1% yield) as a white solid. LC-MS: (ESI, m / z):375.0[M+H]+.

[0322] Example 25: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-(3- (trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0323] Under nitrogen, a solution of (R)-2-amino-1-(3-(trifluoromethoxy)azetidin-1- yl)propan-1-one hydrochloride (60.0 mg, crude), N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) and 4-chloro-6-(4-fluorophenyl)pyrimidine (72.7 mg, 0.29 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 100 ºC for 1 hour. After completion, the solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30%B to 50%B in10.5 min; Wave Length: 254 / 220 nm; RT1(min): 10.75 to afford the title compound (29.3 mg, 0.07 mmol, 31.2% yield) as a white solid. LC-MS: (ESI, m / z):385.0 [M+H]+.

[0324] Example 26a: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-5-methyl-6- azaspiro[2.5]octan-6-yl)propan-1-one

[0325] Example 26b: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-5-methyl-6- azaspiro[2.5]octan-6-yl)propan-1-one Synthetic Route

[0326] Step 1: tert-butyl 2-methyl-4-methylenepiperidine-1-carboxylate

[0327] Under nitrogen, to a solution of triphenylmethylphosphonium bromide (4.02 g, 11.25 mmol) in diethyl ether (25 mL) was added potassium tert-butoxide (12.19 mL, 12.19 mmol, 1 M in hexane) at 0 °C. The resulting solution was stirred for 1 hour at room temperature. Then tert- butyl 2-methyl-4-oxopiperidine-1-carboxylate (2.00 g, 9.38 mmol) in diethyl ether (25 mL) was added at 0 °C and stirred at 25 °C for 8 hours. After completion, the reaction was filtered and the filtrate was combined. The filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / dichloromethane (1:1) to afford the title compound (1.26 g, 5.96 mmol, 63.6% yield) as a colorless oil. LC-MS: (ESI, m / z): 156.2 [M-55]+.

[0328] Step 2: tert-butyl 5-methyl-6-azaspiro[2.5]octane-6-carboxylate

[0329] Under nitrogen, to a solution of diethylzinc (82.82 mL, 82.82 mmol, 1M in n- hexane) in dichloromethane (100 mL) was added the solution of trifluoroacetic acid (9.44 g, 82.82 mmol) in dichloromethane (100 mL) at 0 °C. The resulting solution was stirred for 0.5 hours at 0 °C. Then diiodomethane (6.67 mL, 82.82 mmol) in dichloromethane (100 mL) was added and stirred at 0 °C for 0.5 hours. Then tert-butyl 2-methyl-4-methylene-piperidine-1-carboxylate (7.0 g, 33.13 mmol) in dichloromethane (1.5 mL) was added and stirred at 0 °C for 10 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide a yellow oil. The residue was diluted in dichloromethane (100 mL) and then was added di-tert-butyl dicarbonate (36.11 g, 165.64 mmol), triethylamine (16.73 g, 165.64 mmol) and 4- (dimethylamino)pyridine (0.4 g, 3.31 mmol). The mixture was stirred at 25 °C for 4 hours. After completion, the resulting solution was diluted with water and extracted with dichloromethane. 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 (3.50 g, 15.53 mmol, 46.9% yield) as a yellow oil. LC- MS: (ESI, m / z): 170.2 [M-55]+.

[0330] Step 3: 5-methyl-6-azaspiro[2.5]octane hydrochloride

[0331] A solution of tert-butyl 5-methyl-6-azaspiro[2.5]octane-6-carboxylate (1.0 g, 4.44 mmol) in hydrochloric acid (10 mL, 4 mol / L in 1,4-dioxane) was stirred at 25 °C for 2 hours. After completion, the solvent was concentrated under vacuum to afford the title compound (750.0 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 126.1 [M+H]+.

[0332] Step 4: tert-butyl ((2R)-1-(5-methyl-6-azaspiro[2.5]octan-6-yl)-1-oxopropan-2- yl)carbamate

[0333] A solution of 5-methyl-6-azaspiro[2.5]octane hydrochloride (1.00 g, crude), (tert- butoxycarbonyl)-D-alanine (1.51 g, 7.99 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.64 g, 9.58 mmol) and N,N-diisopropylethylamine (3.09 g, 23.96 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25 °C for 2 hours. 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 washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (2:1) to afford the title compound (1.00 g, 3.37 mmol, 42.2% yield) as a yellow oil. LC-MS: (ESI, m / z): 241.2 [M-55]+.

[0334] Step 5: (2R)-2-amino-1-(5-methyl-6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride

[0335] A solution of tert-butyl ((2R)-1-(5-methyl-6-azaspiro[2.5]octan-6-yl)-1-oxopropan- 2-yl)carbamate (100.0 mg, 0.34 mmol) in hydrochloric acid (2 mL, 4 mol / L 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 (80.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 197.2 [M+H]+.

[0336] Step 6: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-5-methyl-6- azaspiro[2.5]octan-6-yl)propan-1-one and (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-5-methyl- 6-azaspiro[2.5]octan-6-yl)propan-1-one

[0337] A solution of (2R)-2-amino-1-(5-methyl-6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride (70.0 mg, crude), 4,7-dichloroquinazoline (67.0 mg, 0.34 mmol) and N,N- diisopropylethylamine (118.0 mg, 0.91 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °C for 0.5 hours. 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 C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: (R, R)-Whelk-O 15μm Kromasil 3*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 19.6; RT2(min): 26.23; Sample Solvent: EtOH; Injection Volume: 1.0 mL to afford (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-5-methyl-6-azaspiro[2.5]octan-6-yl)propan-1-one (23.0 mg, 0.06 mmol, 21% yield) as a yellow solid and (R)-2-((7-chloroquinazolin-4-yl)amino)-1- ((S)-5-methyl-6-azaspiro[2.5]octan-6-yl)propan-1-one (24.7 mg, 0.07 mmol, 22.5% yield) as a yellow solid.

[0338] Example 27a: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-6-methyl-5- azaspiro[2.5]octan-5-yl)propan-1-one

[0339] Example 27b: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-6-methyl-5- azaspiro[2.5]octan-5-yl)propan-1-one

[0340] Step 1: tert-butyl 2-methyl-5-methylenepiperidine-1-carboxylate

[0341] Under nitrogen, to a solution of triphenylmethylphosphonium bromide (1.21 g, 3.38 mmol) in diethyl ether (4 mL) was added potassium tert-butoxide (3.66 mL, 3.66 mmol, 1 mol / L in hexane) at 0 °C. The resulting solution was stirred for 1 hour at room temperature. Then tert-butyl 2-methyl-5-oxo-piperidine-1-carboxylate (600.0 mg, 2.81 mmol) in diethyl ether (4 mL) was added at 0 °C and stirred at 25 °C for 16 hours. After completion, the reaction was filtered and the filtrate was combined. The filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (10:1) to afford the title compound (520.0 mg, 2.46 mmol, 87.5% yield) as a yellow oil. LC-MS: (ESI, m / z): 156.2 [M-55]+.

[0342] Step 2: tert-butyl 6-methyl-5-azaspiro[2.5]octane-5-carboxylate

[0343] Under nitrogen, to a solution of diethylzinc (4.73 mL, 4.73 mmol, 1 mol / L in hexane) in dichloromethane (5 mL) was added trifluoroacetic acid (0.36 mL, 4.73 mmol) in dichloromethane (5 mL) at 0 °C. The resulting solution was stirred for 0.5 hours at 0 °C. Then diiodomethane (0.38 mL, 4.73 mmol) in dichloromethane (5 mL) was added and stirred at 0 °C for 0.5 hours. Then tert-butyl 2-methyl-5-methylenepiperidine-1-carboxylate (500.0 mg, 2.37mmol) in dichloromethane (5.0 mL) was added and stirred at 0 °C for 16 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, dried overanhydrous sodium sulfate, and concentrated under vacuum to provide a yellow oil. To the residue in dichloromethane (10.0 mL) was added di-tert-butyl dicarbonate (2.06 g, 9.46 mmol), triethylamine (956.4 mg, 9.46 mmol) and 4-(dimethylamino)pyridine (57.4 mg, 0.47 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / dichloromethane (1:1) to afford the title compound (140.0 mg, 0.62 mmol, 26.3% yield) as a yellow oil. LC-MS: (ESI, m / z): 170.2 [M-55]+.

[0344] Step 3: 6-methyl-5-azaspiro[2.5]octane hydrochloride

[0345] A solution of tert-butyl 6-methyl-5-azaspiro[2.5]octane-5-carboxylate (200.0 mg, 0.89 mmol) in hydrochloric acid (3.0 mL, 4 mol / L 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 (155.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 126.1 [M+H]+.

[0346] Step 4: tert-butyl ((2R)-1-(6-methyl-5-azaspiro[2.5]octan-5-yl)-1-oxopropan-2- yl)carbamate

[0347] A solution of 6-methyl-5-azaspiro[2.5]octane hydrochloride (170.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (271.0 mg, 1.43 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (591.0 mg, 1.55 mmol) and N,N-diisopropylethylamine (463.0 mg, 3.59 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25 °C for 2 hours. 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 C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (180 mg, 0.61 mmol, 50.7% yield) as a yellow solid. LC-MS: (ESI, m / z): 241.2 [M-55]+.

[0348] Step 5: (2R)-2-amino-1-(6-methyl-5-azaspiro[2.5]octan-5-yl)propan-1-one hydrochloride

[0349] A solution of tert-butyl ((2R)-1-(6-methyl-5-azaspiro[2.5]octan-5-yl)-1-oxopropan- 2-yl)carbamate (100.0 mg, 0.34 mmol) in hydrochloric acid (2.0 mL, 4 mol / L 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 (100.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 197.2 [M+H]+.

[0350] Step 6: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-6-methyl-5- azaspiro[2.5]octan-5-yl)propan-1-one & (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-6-methyl-5- azaspiro[2.5]octan-5-yl)propan-1-one

[0351] A solution of (2R)-2-amino-1-(6-methyl-5-azaspiro[2.5]octan-5-yl)propan-1-one hydrochloride (100.0 mg, crude), 4,7-dichloroquinazoline (102.0 mg, 0.51 mmol) and N,N- diisopropylethylamine (263.0 mg, 2.04 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 0.5 hours. 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 product was purified by Prep- HPLC with the following conditions: Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 38% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 6.07 to afford the product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK RR 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 11.223; RT2(min): 14.126; Sample Solvent: ETOH; Injection Volume: 1.2 mL to afford (R)-2-((7-chloroquinazolin-4- yl)amino)-1-((R)-6-methyl-5-azaspiro[2.5]octan-5-yl)propan-1-one (13.9 mg, 0.04 mmol, 7.6% yield) as a white solid and (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-6-methyl-5- azaspiro[2.5]octan-5-yl)propan-1-one (9.0 mg, 0.02 mmol, 4.9% yield) as a white solid.

[0352] Example 28: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((2S,4S)-2- methyl-4-(trifluoromethoxy)piperidin-1-yl)propan-1-one Synthetic Route

[0353] Step 1: tert-butyl (2S,4S)-2-methyl-4-(trifluoromethoxy)piperidine-1-carboxylate

[0354] Under nitrogen, to a solution of silver(I) trifluoromethanesulfonate (6.44 g, 25.08 mmol), potassium fluoride (2.16 g, 37.16 mmol) and 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate (4.94 g, 13.93 mmol) in ethyl acetate (20 mL) was added tert-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (2.0 g, 9.29 mmol) in ethyl acetate (20 mL) at 0 °C. Then 2-fluoropyridine (2.4 mL, 27.87 mmol) and trimethyl(trifluoromethyl)silane (3.96 g, 27.87 mmol) was added dropwise and stirred at room temperature for 2 days. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethylacetate (1:6) to afford the title compound (1.00 g, 3.53 mmol, 38.0% yield) as a yellow oil. LC-MS: (ESI, m / z): 228.1 [M-55]+.

[0355] Step 2: (2S,4S)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride

[0356] A solution of tert-butyl (2S,4S)-2-methyl-4-(trifluoromethoxy)piperidine-1- carboxylate (1.00 g, 3.53 mmol) in hydrochloric acid (10 mL, 4 mol / L in 1,4-dioxane) was stirred at 25 °C for 2 hours. After completion, the solvent was concentrated under vacuum to afford the title compound (800.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 184.1 [M+H]+.

[0357] Step 3: tert-butyl ((R)-1-((2S,4S)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1- oxopropan-2-yl)carbamate

[0358] A solution of (tert-butoxycarbonyl)-D-alanine (992.0 mg, 5.24mmol), (2S,4S)-2- methyl-4-(trifluoromethoxy)piperidine hydrochloride (800.0 mg, crude), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.49 g, 6.55 mmol) and N,N- diisopropylethylamine (2.25 g, 17.47 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at 25 °C for 2 hours. 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 dichloromethane / methanol (20:1) to afford the title compound (1.00 g, 2.82 mmol, 64.6% yield) as a yellow oil. LC-MS: (ESI, m / z): 355.2 [M+H]+.

[0359] Step 4: (R)-2-amino-1-((2S,4S)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)propan-1-one hydrochloride

[0360] A solution of tert-butyl ((R)-1-((2S,4S)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)-1-oxopropan-2-yl)carbamate (1.00 g, 2.82 mmol) in hydrochloric acid (1.0 mL, 4 mol / L in 1,4- dioxane) was stirred at 25 °C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (900.0 mg. crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 255.1 [M+H]+.

[0361] Step 5: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((2S,4S)-2-methyl-4- (trifluoromethoxy)piperidin-1-yl)propan-1-one

[0362] A solution of 7-(difluoromethyl)-3H-quinazolin-4-one (60.0 mg, 0.31 mmol), N,N- diisopropylethylamine (158.0 mg, 1.22 mmol), (R)-2-amino-1-((2S,4S)-2-methyl-4- (trifluoromethoxy)piperidin-1-yl)propan-1-one hydrochloride (200 mg, crude) and benzotriazole-1- yl-oxytripyrrolidinophosphonium hexafluorophosphate (238.58 mg, 0.46 mmol) in dichloromethane was stirred at 25 °C for 0.5 hours. After completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions:Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 19% B to 36% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 7.7. to afford the title compound (33.7 mg, 0.08 mmol, 25.5% yield) as a white solid. LC-MS: (ESI, m / z): 433.1 [M+H]+.

[0363] Example 29: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-2-methylindolin-1- yl)propan-1-one Synthetic Route

[0364] Step 1: tert-butyl ((R)-1-((S)-2-methylindolin-1-yl)-1-oxopropan-2-yl)carbamate

[0365] To a solution of (S)-2-methylindoline (200.0 mg, 1.50 mmol), (tert- butoxycarbonyl)-D-alanine (340.9 mg, 1.80 mmol) and N,N-diisopropylethylamine (970.3 mg, 7.51 mmol) in dichloromethane (3 mL) was added 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (742.2 mg, 1.95 mmol) and the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9:1) to afford the title compound (470.0 mg, 1.39 mmol, 92.5% yield) as a white solid. LC-MS: (ESI, m / z): 305.2 [M+H]+.

[0366] Step 2: (R)-2-amino-1-((S)-2-methylindolin-1-yl)propan-1-one hydrochloride

[0367] A solution of tert-butyl ((R)-1-((S)-2-methylindolin-1-yl)-1-oxopropan-2- yl)carbamate (470.0 mg, 1.54 mmol) in hydrochloric acid / 1,4-dioxane (8 mL, 4M) was stirred at 25 °C for 1 hour. After completion, the reaction was concentrated under vacuum to afford the title compound (380.0 mg, crude) as a white solid. LC-MS: (ESI, m / z): 205.2 [M+H]+.

[0368] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-2-methylindolin-1- yl)propan-1-one

[0369] A solution of (R)-2-amino-1-((S)-2-methylindolin-1-yl)propan-1-one hydrochloride (30.0 mg, crude), N,N-diisopropylethylamine (56.9 mg, 0.44 mmol) and 4,7-dichloroquinazoline (29.2 mg, 0.15 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 ºC for 1 hour. After completion, the residue was purified by flash chromatography on reverse phase column eluting with water / acetonitrile (3:2) to afford the title compound (22.5 mg, 0.06 mmol, 41.8% yield) as a light brown solid. LC-MS: (ESI, m / z): 367.0 [M+H]+.

[0370] Example 30: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2-methylindolin-1- yl)propan-1-one Synthetic Route

[0371] Step 1: tert-butyl ((R)-1-((R)-2-methylindolin-1-yl)-1-oxopropan-2-yl)carbamate

[0372] To a solution of (R)-2-methylindoline (200.0 mg, 1.50 mmol), (tert- butoxycarbonyl)-D-alanine (340.9 mg, 1.80 mmol) and N,N-diisopropylethylamine (970.3 mg, 7.51 mmol) in dichloromethane (5 mL) was added 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (742.3 mg, 1.95 mmol). The mixture was stirred at 25 ºC for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4:1) to afford the title compound (450.0 mg, 1.48 mmol, 98.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 305.2 [M+H]+.

[0373] Step 2: (R)-2-amino-1-((R)-2-methylindolin-1-yl)propan-1-one hydrochloride

[0374] A solution of tert-butyl ((R)-1-((R)-2-methylindolin-1-yl)-1-oxopropan-2- yl)carbamate (450.0 mg, 1.48 mmol) in hydrochloric acid / 1,4-dioxane (6 mL, 4M) was stirred at 25 ºC for 1 hour. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (400.0 mg, crude) as a yellow solid. LC-MS: (ESI, m / z): 205.1 [M+H]+.

[0375] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2-methylindolin-1- yl)propan-1-one

[0376] A solution of (R)-2-amino-1-((R)-2-methylindolin-1-yl)propan-1-one hydrochloride (30.0 mg, crude), N,N-diisopropylethylamine (56.9 mg, 0.44 mmol) and 4,7-dichloroquinazoline (29.2 mg, 0.15 mmol) in dimethyl sulfoxide (0.7 mL) was stirred at 100 ºC for 1 hour. After completion, the residue was purified by flash chromatography on reverse-phase column eluting with water / acetonitrile (3:7) to afford the title compound (32.7 mg, 0.09 mmol, 60.7% yield) as a light pink solid. LC-MS: (ESI, m / z): 367.0 [M+H]+.

[0377] Example 31: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0378] Step 1: tert-butyl (S)-2-methyl-4-methylenepyrrolidine-1-carboxylate

[0379] Under nitrogen, methyltriphenylphosphonium bromide (2.15 g, 6.02 mmol) and potassium tert-butoxide (6.52 mL, 6.52 mmol, 1 M in tetrahydrofuran) were added to diethyl ether (20 mL) at 0 °C. Then the temperature was increased to 25 °C and the reaction mixture was stirred for 2 hours. A solution of tert-butyl (S)-2-methyl-4-oxopyrrolidine-1-carboxylate (1.00 g, 5.02 mmol) in diethyl ether (20 mL) was dripped into the reaction mixture in 25 min at 0 °C. Then the temperature was increased to room temperature and the mixture was stirred at 25 °C for 16 hours. After completion, the reaction was filtered and the filtrate was combined. The filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (94:6) to afford the title compound (600.3 mg, 3.04 mmol, 60.6% yield) as a colorless oil. LC-MS: (ESI, m / z): 198.1 [M+H]+.

[0380] Step 2: tert-butyl (S)-6-methyl-5-azaspiro[2.4]heptane-5-carboxylate

[0381] Under nitrogen, diethylzinc (10.34 mL, 10.34 mmol, 1.0 M in hexanes) was dissolved in anhydrous dichloromethane (10 mL) and the solution was cooled to 0 °C. Then a solution of dichloroacetic acid (1.26 g, 9.73 mmol) in dichloromethane (10 mL) was added dropwise over a 10 min period. The solution was stirred at 0 °C for an additional 30 min. A solution of diiodomethane (2.61 g, 9.73 mmol) in anhydrous dichloromethane (10 mL) was added dropwise quickly and the resulting solution was stirred at 0 °C for 30 min. After that, a solution of tert-butyl (S)-2-methyl-4-methylenepyrrolidine-1-carboxylate (600.3 mg, 3.04 mmol) in anhydrous dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was stirred in a thawing ice-bath for 18 hours. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide a yellow oil. The oil was dissolved in ethyl acetate (10 mL), and then triethylamine (1.54 g, 15.21 mmol) and di-tert-butyl dicarbonate (995.7 mg, 4.56 mmol) were sequentially added at 25 °C. The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (96:4) to afford the title compound (400.2 mg, 1.70 mmol, 56.0% yield) as a colorless oil. LC-MS: (ESI, m / z):212.2 [M+H]+.

[0382] Step 3: (S)-6-methyl-5-azaspiro[2.4]heptane hydrochloride

[0383] A solution of tert-butyl (S)-6-methyl-5-azaspiro[2.4]heptane-5-carboxylate (220.0 mg, 0.95 mmol) in hydrochloric acid / 1,4-dioxane (5.0 mL, 4.0 M) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to (S)-6-methyl-5- azaspiro[2.4]heptane hydrochloride (130.2 mg, 0.79 mmol, crude) as a white solid. LC-MS: (ESI, m / z): 112.1 [M+H]+.

[0384] Step 4: tert-butyl ((R)-1-((S)-6-methyl-5-azaspiro[2.4]heptan-5-yl)-1-oxopropan-2- yl)carbamate

[0385] 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (356.2 mg, 0.94 mmol) was added to a solution of N,N-diisopropylethylamine (302.7 mg, 2.34 mmol), (S)-6-methyl-5-azaspiro[2.4]heptane hydrochloride (130.2 mg, crude) and (tert- butoxycarbonyl)-D-alanine (164.9 mg, 0.87 mmol) in N,N-dimethylformamide (2 mL) and 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 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 (50:50) to afford the title compound (220.3 mg, 0.69 mmol, 87.5% yield) as a light yellow solid. LC-MS: (ESI, m / z): 283.2 [M+H]+.

[0386] Step 5: (R)-2-amino-1-((S)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one trifluoroacetate

[0387] A solution of tert-butyl ((R)-1-((S)-6-methyl-5-azaspiro[2.4]heptan-5-yl)-1- oxopropan-2-yl)carbamate (120.0 mg, 0.42 mmol) in trifluoroacetic acid (0.3 mL) and 1,1,1,3,3,3- hexafluoro-2-propanol (5.7 mL) was stirred at 25 °C for 2 hours. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (90.6 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 183.1 [M+H]+.

[0388] Step 6: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-1-one

[0389] A solution of (R)-2-amino-1-((S)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1- one trifluoroacetate (90.0 mg, crude), 4,7-dichloroquinazoline (72.1 mg, 0.36 mmol) and N,N- diisopropylethylamine (234.0 mg, 1.81 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 30 min. After completion, the residue was purified by flash chromatography on reverse-phase column eluting with (acetonitrile / 0.1% ammonium bicarbonate in water) (4:6) to afford product. The product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 48% B in 10.5 min; WaveLength: 254 / 220 nm; RT1(min): 8.52 to afford the title compound (55.0 mg, 0.16 mmol, 44.0% yield) as a white solid. LC-MS: (ESI, m / z):345.1 [M+H]+.

[0390] Example 32: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((R)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0391] Step 1: tert-butyl ((R)-1-((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)-1-oxopropan-2- yl)carbamate

[0392] To a solution of (R)-6-methyl-5-azaspiro[2.4]heptane hydrochloride (70.0 mg, 0.47 mmol), (tert-butoxycarbonyl)-D-alanine (107.6 mg, 0.57 mmol) and N,N-diisopropylethylamine (183.8 mg, 1.42 mmol) in dichloromethane (5 mL) was added 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (216.3 mg, 0.57 mmol). The mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (110.0 mg, 0.39 mmol, 82.2% yield) as a yellow solid. LC-MS: (ESI, m / z): 283.2 [M+H]+.

[0393] Step 2: (R)-2-amino-1-((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride

[0394] A solution of tert-butyl ((R)-1-((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)-1- oxopropan-2-yl)carbamate (110.0 mg, 0.39 mmol) in hydrochloric acid / 1,4-dioxane (5.0 mL, 4 M) was stirred at 25 ºC for 0.5 hours. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (99.0 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 183.1 [M+H]+.

[0395] Step 3: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((R)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-1-one

[0396] A solution of (R)-2-amino-1-((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1- one hydrochloride (40.0 mg, crude), 4-chloro-6-(4-fluorophenyl)pyrimidine (45.8 mg, 0.22 mmol)and N,N-diisopropylethylamine (113.5 mg, 0.88 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on reverse-phase column eluting with (acetonitrile / 0.1% ammonium bicarbonate in water) (2:3) to afford the title compound (19.8 mg, 0.06 mmol, 25.5% yield) as a white solid. LC- MS: (ESI, m / z): 355.2 [M+H]+.

[0397] Example 33a: (R)-1-((R)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0398] Example 33b: (R)-1-((S)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0399] Step 1: tert-butyl ((2R)-1-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1-oxopropan-2- yl)carbamate

[0400] A solution of (tert-butoxycarbonyl)-D-alanine (561.6 mg, 2.97 mmol), 7-fluoro-5- azaspiro[2.4]heptane hydrochloride (300.0 mg, 1.98 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (1.13 g, 2.97 mmol) and N,N-diisopropylethylamine (767.2 mg, 5.94 mmol) in dichloromethane (5 mL) was stirred at 25ºC for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:1) to afford tert-butyl ((2R)-1-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1-oxopropan-2-yl)carbamate (500.0 mg, 1.75 mmol, 88.2% yield) as a white solid. LC-MS: (ESI, m / z): 287.2 [M+H]+.

[0401] Step 2: (2R)-2-amino-1-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride

[0402] A solution of tert-butyl ((2R)-1-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)-1-oxopropan- 2-yl)carbamate (500.0 mg, 1.75 mmol) in 4 M hydrochloric acid in 1,4-dioxane (6.0 mL) was stirred at 25ºC for 1 hour. After completion, the solvent was removed under vacuum to afford (2R)- 2-amino-1-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (230.0 mg, crude) as a white solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 187.1 [M+H]+.

[0403] Step 3: (R)-1-((R)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one & (R)-1-((S)-7-fluoro-5- azaspiro[2.4]heptan-5-yl)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0404] A solution of (2R)-2-amino-1-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (143.0 mg, 0.77 mmol), 4-chloro-7-(trifluoromethoxy)quinazoline (190.8 mg, 0.77 mmol) and N,N-diisopropylethylamine (496.2 mg, 3.84 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 °C for 0.5 hour. After completion, the residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the product. Then the product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IG 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 9.789; RT2(min): 13.622; Sample Solvent: ETOH; Injection Volume: 0.5 mL to afford (R)-1-((R)-7-fluoro-5- azaspiro[2.4]heptan-5-yl)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one (13.5 mg, 0.03 mmol, 4.3% yield) as a white solid and (R)-1-((S)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one (13.0 mg, 0.03 mmol, 4.1% yield) as a white solid. LC-MS: (ESI, m / z): 399.1 [M+H]+

[0405] Example 34a: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((R)-5-methyl- 6-azaspiro[2.5]octan-6-yl)propan-1-one

[0406] Example 34b: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((S)-5-methyl- 6-azaspiro[2.5]octan-6-yl)propan-1-one Synthetic Route

[0407] Step 1: tert-butyl 4-(7-bromoquinazolin-4-yl)piperazine-1-carboxylate

[0408] N,N-diisopropylethylamine (7.95 g, 61.60 mmol) was added to a solution of 7- bromo-4-chloroquinazoline (5.00 g, 20.54 mmol) and tert-butyl piperazine-1-carboxylate (4.59 g, 24.64 mmol) in 1,4-dioxane (40.0 mL) and stirred at 60 °C for 0.5 hours. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / ethyl acetate (80:20) to afford the title compound (8.10 g, 20.66 mmol, 84% yield) as a white solid. LC-MS: (ESI, m / z): 393.0 [M+H]+.

[0409] Step 2: tert-butyl 4-(7-formylquinazolin-4-yl)piperazine-1-carboxylate

[0410] Under nitrogen, to a solution of tert-butyl 4-(7-bromoquinazolin-4-yl)piperazine-1- carboxylate (6.30 g, 16.02 mmol) in tetrahydrofuran (50.0 mL) was added n-butyllithium (6.4 mL, 16.00 mmol, 2.5 M in tetrahydrofuran) and the mixture was stirred at -78 °C for 20 min. Then N,N- dimethylformamide (3.7 mL, 48.06 mmol) was added to the mixture and the mixture was stirred at -78 °C for 0.5 hours. After completion, the reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane. 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 dichloromethane / ethyl acetate (4:1) to afford the title compound (2.30 g, 6.73 mmol, 42% yield) as a light yellow solid. LC-MS: (ESI, m / z): 343.1 [M+H]+.

[0411] Step 3: tert-butyl 4-(7-(difluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate

[0412] Under nitrogen, to a solution of tert-butyl 4-(7-formylquinazolin-4-yl)piperazine-1- carboxylate (900.2 mg, 2.63 mmol) in dichloromethane (30.0 mL) was added diethylaminosulfur trifluoride (2.54 g, 15.77 mmol) in dichloromethane (4.0 mL) dropwise at 0 °C, and the mixture was stirred at room temperature for 12 hours. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate solution at 0 °C and extracted with dichloromethane. The organic layers were combined and 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 (3:1) to afford the title compound (500.2 mg, 1.37 mmol, 52% yield) as a light yellow solid. LC-MS: (ESI, m / z): 365.2 [M+H]+.

[0413] Step 4: 7-(difluoromethyl)quinazolin-4(3H)-one

[0414] A mixture of sodium hydroxide (659.0 mg, 16.47 mmol) was added to a solution of tert-butyl 4-(7-(difluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate (1.20 g, 3.29 mmol) in dimethyl sulfoxide (3.0 mL) and water (0.6 mL) at room temperature. The mixture was stirred at 60 °C for 3 hours. After completion, the reaction was acidified with 2N hydrochloric acid aqueous solution and concentrated under vacuum. The residue was purified by flash chromatography onreverse-phase column eluting with (0.1% formic acid in water / acetonitrile (80:20) to afford the title compound (370.2 mg, 1.87 mmol, 57% yield) as a white solid. LC-MS: (ESI, m / z): 197.0 [M+H]+.

[0415] Step 5: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((R)-5-methyl-6- azaspiro[2.5]octan-6-yl)propan-1-one & (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((S)- 5-methyl-6-azaspiro[2.5]octan-6-yl)propan-1-one

[0416] A mixture of 7-(difluoromethyl)quinazolin-4(3H)-one (100.0 mg, 0.51 mmol), N,N- diisopropylethylamine (197.4 mg, 1.53 mmol) and benzotriazole-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (397.9 mg, 0.77 mmol) in dichloromethane (4.0 mL) was stirred at room temperature for 1 hour. Then a solution of (2R)-2-amino-1-(5-methyl- 6-azaspiro[2.5]octan-6-yl)propan-1-one hydrochloride (178.0 mg, 0.77 mmol) and N,N- diisopropylethylamine (197.4 mg, 1.53 mmol) in dichloromethane (2.0 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / ethyl acetate (4:1) to afford the product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 34% B to 54% B in10.5 min; Wave Length: 254 / 220 nm; RT1(min): 10.92 to afford product. The product was isolated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AD-H, 2*25 cm, 5 μm; Mobile Phase A: HEX (0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 11.965; RT2(min): 16.667; Sample Solvent: EtOH; Injection Volume: 1.0 mL to afford (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((R)-5-methyl-6-azaspiro[2.5]octan-6- yl)propan-1-one (34.6 mg, 0.10 mmol, 18.1% yield) as a white solid and (R)-2-((7- (difluoromethyl)quinazolin-4-yl)amino)-1-((S)-5-methyl-6-azaspiro[2.5]octan-6-yl)propan-1-one (31.9 mg, 0.09 mmol, 16.7% yield) as a white solid.

[0417] Example 35: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-(5- azaspiro[2.3]hexan-5-yl)propan-1-one Synthetic Route

[0418] Step 1: tert-butyl (R)-(1-oxo-1-(5-azaspiro[2.3]hexan-5-yl)propan-2-yl)carbamate

[0419] A solution of 5-azaspiro[2.3]hexane hydrochloride (200.0 mg, 1.67 mmol), (tert- butoxycarbonyl)-D-alanine (348.1 mg, 1.84 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (763.1 mg, 2.01 mmol) and N,N-diisopropylethylamine (648.4 mg, 5.02 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (400.0 mg, 1.57 mmol, 94.0% yield) as a yellow solid. LC-MS: (ESI, m / z): 255.2 [M+H]+.

[0420] Step 2: (R)-2-amino-1-(5-azaspiro[2.3]hexan-5-yl)propan-1-one hydrochloride

[0421] A solution of tert-butyl (R)-(1-oxo-1-(5-azaspiro[2.3]hexan-5-yl)propan-2- yl)carbamate (80.0 mg, 0.22 mmol) in hydrochloric acid / 1,4-dioxane (3 mL, 4M) was stirred at 25 ºC for 0.5 hours. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (300.0 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 155.1 [M+H]+.

[0422] Step 3: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-(5-azaspiro[2.3]hexan- 5-yl)propan-1-one

[0423] A solution of (R)-2-amino-1-(5-azaspiro[2.3]hexan-5-yl)propan-1-one hydrochloride (300.0 mg, crude), 4-chloro-6-(4-fluorophenyl)pyrimidine (493.9 mg, 2.37 mmol) and N,N-diisopropylethylamine (815.9 mg, 6.31 mmol) in dimethyl sulfoxide (5 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (70.4 mg, 0.22 mmol, 13.7% yield) as a white solid. LC-MS: (ESI, m / z): 327.1 [M+H]+.

[0424] Example 36a: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((S)-6-methyl- 5-azaspiro[2.4]heptan-5-yl)propan-1-one

[0425] Example 36b: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((R)-6-methyl- 5-azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0426] A mixture of 7-(difluoromethyl)quinazolin-4(3H)-one (100.0 mg, 0.51 mmol), N,N- diisopropylethylamine (197.7 mg, 1.53 mmol) and benzotriazole-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (397.9 mg, 0.76 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 1 hour. Then, a solution of (2R)-2-amino-1-(6-methyl- 5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (167.2 mg, 0.76 mmol) and N,N- diisopropylethylamine (197.7 mg, 1.53 mmol) in dichloromethane (1.0 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / ethyl acetate (4:1) to afford crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 32% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 6.82 to afford product. The product was isolated by Prep-Chiral- HPLC with the following conditions: Column: (R, R)-WHELK-O 15μm Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 13.976; RT2(min): 19.308; Sample Solvent: EtOH--HPLC; Injection Volume: 2.0 mL to afford (R)-2-((7- (difluoromethyl)quinazolin-4-yl)amino)-1-((S)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one (25.7 mg, 0.07 mmol) as a white solid and (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1- ((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one (26.5 mg, 0.07 mmol, 14.4% yield) as a white solid.

[0427] Example 37a: (R)-1-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0428] Example 37b: (R)-1-((2R,4S)-4-methoxy-2-methylpiperidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0429] Example 37c: (R)-1-((2S,4R)-4-methoxy-2-methylpiperidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0430] Example 37d: (R)-1-((2S,4S)-4-methoxy-2-methylpiperidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0431] Step 1: tert-butyl ((2R)-1-(4-methoxy-2-methylpiperidin-1-yl)-1-oxopropan-2- yl)carbamate

[0432] To a solution of 4-methoxy-2-methylpiperidine hydrochloride (500.0 mg, 3.87 mmol), (tert-butoxycarbonyl)-D-alanine (732.2 mg, 3.87 mmol) and N,N-diisopropylethylamine (1.50 g, 11.61 mmol) in N,N-dimethylformamide (5 mL) was added 2-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (1.77 g, 4.64 mmol) and 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 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 (1.00 g, 3.33 mmol, 86.0% yield) as a yellow solid. LC-MS: (ESI, m / z): 301.2 [M+H]+.

[0433] Step 2: (2R)-2-amino-1-(4-methoxy-2-methylpiperidin-1-yl)propan-1-one hydrochloride

[0434] A solution of tert-butyl ((2R)-1-(4-methoxy-2-methylpiperidin-1-yl)-1-oxopropan- 2-yl)carbamate (240.0 mg, 0.80 mmol) in hydrochloric acid / 1,4-dioxane (7 mL, 4.0M) was stirred at 25 ºC for 0.5 hours. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (180.0 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z):201.2 [M+H]+.

[0435] Step 3: (R)-1-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one & (R)-1-((2R,4S)-4-methoxy-2-methylpiperidin- 1 -yl)-2-((7 -(trifluoromethoxy)quinazolin-4-yl)amino)propan- 1 -one & (R)-1- ((2S,4R)-4-methoxy-2-mcthylpiperidin-l-yl)-2-((7-(trifluoromethoxy)quinazolin-4- yl)amino)propan-l-one & (R)- 1-((2S,4S)-4-methoxy-2 -methylpiperidin- l-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan- 1 -one

[0436] A solution of (2R)-2-amino- 1 -(4-methoxy-2 -methylpiperidin- 1 -yl)propan- 1 -one hydrochloride (180.0 mg, crude), 4-chloro-7-(trifluoromethoxy)quinazoline (189.5mg, 0.76mmol) and N,N-diisopropylethylamine (492.6 mg, 3.81 mmol) in dimethyl sulfoxide (5 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1: 1) 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 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31%B to 51%B in 10.5 min; Wave Length: 254 / 220 nm; RTl(min): 9.68 to afford two peaks. The faster peak was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IG 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RTl(min): 12.544; RT2(min): 16.19; Sample Solvent: ETOH; Injection Volume: 0.7 mL to afford (R)-l-((2R,4R)-4-methoxy-2-methylpiperidin- l-yl)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)propan-l-one (28.3 mg, 0.07 mmol, 9.0% yield) as a white solid and (R)-1-((2R,45)-4-methoxy-2-methylpiperidin-l-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-l-one (27.6 mg, 0.07 mmol, 8.8% yield) as a white solid, the slower peak was isolated by Chiral-Prep-HPLC with the following conditions: Column: (S, S)-WHELK-Ol-Kromasil 2.12*25 cm, 5 μm; Mobile Phase A: MtBE(0.5% 2M NH3- MeOH)— HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RTl(min): 11.356; RT2(min): 13.444; Sample Solvent: EtOH— HPLC; Injection Volume: 1.0 mL to afford (R)-l-((2S,4R)-4-methoxy-2-methylpiperidin-l-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-l-one (25.6 mg, 0.06 mmol, 8.1% yield) as a white solid and (R)-1 -((2, S.4,S)-4-methoxy-2 -methylpiperidin- 1 -yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-l-one (27.6 mg, 0.07 mmol, 8.8% yield) as a white solid.

[0437] Example 38a: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,4S)-2,4- dimethylazetidin- 1 -yl)propan- 1 -one

[0438] Example 38b: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,4R)-2,4- dimethylazetidin- 1 -yl)propan- 1 -one

[0439] Example 38c: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2R,4R)-2,4- dimethylazetidin-1-yl)propan-1-one Synthetic Route

[0440] Step 1: tert-butyl ((2R)-1-(2,4-dimethylazetidin-1-yl)-1-oxopropan-2-yl)carbamate

[0441] A solution of 2,4-dimethylazetidine hydrochloride (100.0 mg, 0.82 mmol), (tert- butoxycarbonyl)-D-alanine (222.2 mg, 1.17 mmol), N,N-diisopropylethylamine (455.3 mg, 3.52 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (535.8 mg, 1.41 mmol) in dichloromethane (1.0 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with 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 (178.0 mg, 0.69 mmol, 73.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 257.2 [M+H]+.

[0442] Step 2: (2R)-2-amino-1-(2,4-dimethylazetidin-1-yl)propan-1-one trifluoroacetate

[0443] A solution of tert-butyl ((2R)-1-(2,4-dimethylazetidin-1-yl)-1-oxopropan-2- yl)carbamate (150.0 mg, 0.58 mmol) in 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (4 mL) was stirred at 25 °C for 5 hours. 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): 157.1 [M+H]+.

[0444] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,4S)-2,4-dimethylazetidin-1- yl)propan-1-one & (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,4R)-2,4-dimethylazetidin-1- yl)propan-1-one & (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2R,4R)-2,4-dimethylazetidin-1- yl)propan-1-one

[0445] Under nitrogen, a solution of (2R)-2-amino-1-(2,4-dimethylazetidin-1-yl)propan-1- one trifluoroacetate (100.0 mg, crude), N,N-diisopropylethylamine (190.9 mg, 1.48 mmol) and 4,7- dichloroquinazoline (51.2 mg, 0.25 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 100 °C for 40 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 residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:2) 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, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 43% B in 10.5 min; Wave Length: 254 / 220 nm; RT1(min): 8.98 to afford product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 15; Wave Length: 220 / 254 nm; RT1(min): 14.862; RT2(min): 19.042; Sample Solvent: EtOH; Injection Volume: 0.8 mL to afford (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,4S)-2,4-dimethylazetidin-1-yl)propan- 1-one (17.7 mg, 0.05 mmol, 13.5% yield) as a white solid and (R)-2-((7-chloroquinazolin-4- yl)amino)-1-((2S,4R)-2,4-dimethylazetidin-1-yl)propan-1-one (8.7 mg, 0.02 mmol, 5.4% yield) as a white solid and (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2R,4R)-2,4-dimethylazetidin-1- yl)propan-1-one (16.8 mg, 0.05 mmol, 13.5% yield) as a white solid.

[0446] Example 39: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0447] Under nitrogen, a solution of (R)-2-amino-1-((R)-6-methyl-5-azaspiro[2.4]heptan- 5-yl)propan-1-one hydrochloride (47.3 mg, crude), N,N-diisopropylethylamine (82.56 mg, 0.64 mmol) and 4,7-dichloroquinazoline (34.8 mg, 0.17 mmol) in dimethyl sulfoxide (1.0 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 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: Xselect CSH Prep Phenyl-Hexy OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 44% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.5 to afford the title compound (47.5 mg, 0.14 mmol, 62.5% yield) as a white solid. LC-MS: (ESI, m / z): 345.1 [M+H]+.

[0448] Example 40: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-3- methylmorpholino)propan-1-one Synthetic Route

[0449] Step 1: tert-butyl ((R)-1-((S)-3-methylmorpholino)-1-oxopropan-2-yl)carbamate

[0450] A solution of (tert-butoxycarbonyl)-D-alanine (205.7 mg, 1.08 mmol), (S)-3- methylmorpholine (100.0 mg, 0.98 mmol), N,N-diisopropylethylamine (374.1, 2.90 mmol) and 2- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (451.0 mg, 1.18 mmol) in dichloromethane (1.5 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 (202.0 mg, 0.74 mmol, 75.5% yield) as a white solid. LC-MS: (ESI, m / z): 273.2 [M+H]+.

[0451] Step 2: (R)-2-amino-1-((S)-3-methylmorpholino)propan-1-one trifluoroacetate

[0452] A solution of tert-butyl ((R)-1-((S)-3-methylmorpholino)-1-oxopropan-2- yl)carbamate (80.0 mg, 0.29 mmol) in 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2-propanol (3 mL) was stirred at 25 °C for 5 hours. After completion, the solvent was removed under vacuum to afford the title compound (80.0 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 173.1 [M+H]+.

[0453] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-3-methylmorpholino)propan- 1-one

[0454] A solution of (R)-2-amino-1-((S)-3-methylmorpholino)propan-1-one trifluoroacetate (80.0 mg, 0.27 mmol), 4,7-dichloroquinazoline (63.5 mg, 0.32 mmol) and N,N- diisopropylethylamine (141.9mg, 1.10 mmol) in dimethyl sulfoxide (1.0 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 (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (19.0 mg, 0.05 mmol, 18.51% yield) as a white solid. LC-MS: (ESI, m / z): 335.1 [M+H]+.

[0455] Example 41a: (R)-1-((1R,6R)-3-azabicyclo[4.1.0]heptan-3-yl)-2-((7- chloroquinazolin-4-yl)amino)propan-1-one

[0456] Example 41b: (R)-1-((1S,6S)-3-azabicyclo[4.1.0]heptan-3-yl)-2-((7- chloroquinazolin-4-yl)amino)propan-1-one Synthetic Route

[0457] Step 1: tert-butyl ((2R)-1-(3-azabicyclo[4.1.0]heptan-3-yl)-1-oxopropan-2- yl)carbamate

[0458] A solution of 3-azabicyclo[4.1.0]heptane hydrochloride (100.0 mg, 0.75 mmol), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (214.2 mg, 1.13 mmol), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (469.6 mg, 1.23 mmol) and N,N- diisopropylethylamine (387.0 mg, 3.00 mmol) in dichloromethane (1.5 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 (200.0 mg, 0.74 mmol, 93.3% yield) as a white solid. LC-MS: (ESI, m / z): 269.2 [M+H]+.

[0459] Step 2: (2R)-2-amino-1-(3-azabicyclo[4.1.0]heptan-3-yl)propan-1-one trifluoroacetate

[0460] A solution of tert-butyl ((2R)-1-(3-azabicyclo[4.1.0]heptan-3-yl)-1-oxopropan-2- yl)carbamate (160.0 mg, 0.59 mmol) in 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (4 mL) was stirred at 25 °C for 5 hours. After completion, the solvent was removed under vacuum to afford the title compound (160 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 169.1 [M+H]+.

[0461] Step 3: (R)-1-((1R,6R)-3-azabicyclo[4.1.0]heptan-3-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one & (R)-1-((1S,6S)-3-azabicyclo[4.1.0]heptan-3-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one

[0462] Under nitrogen, a solution of (2R)-2-amino-1-(3-azabicyclo[4.1.0]heptan-3- yl)propan-1-one trifluoroacetate (160.0 mg, crude), N,N-diisopropylethylamine (296.7 mg, 2.30 mmol) and 4,7-dichloroquinazoline (130.1 mg, 0.65 mmol) in dimethyl sulfoxide (1.5 mL) wasstirred 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 residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:2) 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, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 50% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 9.7 to afford product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IC 2*25 CM, 5 μM; mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RT1(min): 19.093; RT2(min): 21.68; Sample Solvent: EtOH; Injection Volume: 0.6 mL to afford (R)-1-((1R,6R)-3-azabicyclo[4.1.0]heptan-3-yl)-2-((7-chloroquinazolin-4- yl)amino)propan-1-one (30.4 mg, 0.09 mmol, 25.71% yield) as a white solid and (R)-1-((1S,6S)-3- azabicyclo[4.1.0]heptan-3-yl)-2-((7-chloroquinazolin-4-yl)amino)propan-1-one (29.9 mg, 0.09 mmol, 25.71% yield) as a white solid. LC-MS: (ESI, m / z): 331.1 [M+H]+.

[0463] Example 42: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-(5-azaspiro[2.4]heptan-5- yl)propan-1-one Synthetic Route

[0464] Under nitrogen, a solution of (R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1- one hydrochloride (120.0 mg, crude), 4,7-dichloroquinazoline (65.0 mg, 0.34 mmol) and N,N- diisopropylethylamine (141.9 mg, 1.11 mmol) in dimethyl sulfoxide (1.0 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 (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (21.2 mg, 0.06 mmol, 21.42% yield) as a white solid. LC-MS: (ESI, m / z): 331.2 [M+H]+.

[0465] Example 43: (R)-1-(5-azaspiro[2.4]heptan-5-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0466] A solution of 7-(trifluoromethoxy)quinazolin-4(3H)-one (100.0 mg, 0.43 mmol)$ (2R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one trifluoroacetate (132.2 mg, crude), N,N- diisopropylethylamine (167.7 mL, 1.30 mmol) and benzotriazole-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (338.9 mg, 0.65 mmol) in dichloromethane (2.0 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 chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:2) to afford crude solid. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH F-Phenyl OBD column30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 35% B to 55% B in 7 min; Wave Length: 254 nm / 220 nm; RT1(min): 5.7 to afford the title compound (19.8 mg, 0.05 mmol, 12.0% yield) as a white solid. LC-MS: (ESI, m / z): 381.2 [M+H]+.

[0467] Example 44: (R)-2-((6-phenylpyrimidin-4-yl)amino)-1-(5-azaspiro[2.4]heptan-5- yl)propan-1-one Synthetic Route

[0468] A solution of 4-chloro-6-phenyl-pyrimidine (70.0 mg, 0.37 mmol), (2R)-2-amino- 1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one trifluoroacetate (112.0 mg, crude) and N,N- diisopropylethylamine (141.9 mg, 1.10 mmol) 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 on C18gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (17.6 mg, 0.05 mmol, 14.9% yield) as a white solid. LC-MS: (ESI, m / z): 323.1 [M+H]+.

[0469] Example 45: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-(2-azaspiro[3.3]heptan-2- yl)propan-1-one Synthetic Route

[0470] Step 1: tert-butyl (R)-(1-oxo-1-(2-azaspiro[3.3]heptan-2-yl)propan-2-yl)carbamate

[0471] A solution of (tert-butoxycarbonyl)-D-alanine (292.1 mg, 1.54 mmol), 2- azaspiro[3.3]heptane hydrochloride (199.5 mg, 1.54 mmol), N,N-diisopropylethylamine (593.4 mg, 4.63 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (704.4 mg, 1.85 mmol) in dichloromethane (1.5 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 (200.0 mg, 0.74 mmol, 48.31% yield) as a yellow solid. LC-MS: (ESI, m / z): 269.3 [M+H]+.

[0472] Step 2: (R)-2-amino-1-(2-azaspiro[3.3]heptan-2-yl)propan-1-one trifluoroacetate

[0473] A solution of tert-butyl (R)-(1-oxo-1-(2-azaspiro[3.3]heptan-2-yl)propan-2- yl)carbamate (150.0 mg, 0.55 mmol) in 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (4 mL) was stirred at 25 °C for 8 hours. After completion, the solvent was removed under vacuum to afford the title compound (112.8 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 169.1 [M+H]+.

[0474] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-(2-azaspiro[3.3]heptan-2- yl)propan-1-one

[0475] Under nitrogen, a solution of (R)-2-amino-1-(2-azaspiro[3.3]heptan-2-yl)propan-1- one trifluoroacetate (112.8 mg, 0.40 mmol), N,N-diisopropylethylamine (245.1mg, 1.90 mmol) and 4,7-dichloroquinazoline (104.1 mg, 0.52 mmol) in dimethyl sulfoxide (0.3 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 residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:2) 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, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 51% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8 to afford the title compound (17.5 mg, 0.05 mmol, 11.1% yield) as a white solid. LC-MS: (ESI, m / z): 331.2 [M+H]+.

[0476] Example 46a: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-3,3-difluoro-2- methylazetidin-1-yl)propan-1-one

[0477] Example 46b: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-3,3-difluoro-2- methylazetidin-1-yl)propan-1-one Synthetic Route

[0478] Step 1: tert-butyl ((2R)-1-(3,3-difluoro-2-methylazetidin-1-yl)-1-oxopropan-2- yl)carbamate

[0479] A solution of 3,3-difluoro-2-methyl-azetidine hydrochloride (202.2 mg, 1.40 mmol), (tert-butoxycarbonyl)-D-alanine (265.0 mg, 1.40 mmol), 2-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (639.0 mg, 1.68 mmol) and N,N- diisopropylethylamine (722.4 mg, 5.60 mmol) in dichloromethane (2.0 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 chromatography on silica gel eluting withpetroleum ether / ethyl acetate (1:1) to afford the title compound (200.0 mg, 0.71 mmol, 51.3% yield) as a yellow solid. LC-MS: (ESI, m / z): 279.1 [M+H]+.

[0480] Step 2: (2R)-2-amino-1-(3,3-difluoro-2-methylazetidin-1-yl)propan-1-one trifluoroacetate

[0481] A solution of tert-butyl ((2R)-1-(3,3-difluoro-2-methylazetidin-1-yl)-1-oxopropan- 2-yl)carbamate (140.0 mg, 0.50 mmol) and 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (4 mL) was stirred at 25 °C for 8 hours. After completion, the solvent was removed under vacuum to afford the title compound (163.5 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 179.1 [M+H]+.

[0482] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-3,3-difluoro-2- methylazetidin-1-yl)propan-1-one & (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-3,3-difluoro-2- methylazetidin-1-yl)propan-1-one

[0483] A solution of (2R)-2-amino-1-(3,3-difluoro-2-methylazetidin-1-yl)propan-1-one trifluoroacetate (163.5 mg, 0.56 mmol), N,N-diisopropylethylamine (288.9 mg, 2.24 mmol) and 4,7-dichloroquinazoline (122.8 mg, 0.62 mmol) in dimethyl sulfoxide (0.3 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 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 (1:2) 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, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B in10.5min; Wave Length: 254 / 220 nm; RT1(min): 6.53 to afford product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RT1(min): 9.804; RT2(min): 13.737; Sample Solvent: ETOH; Injection Volume: 0.7 mL to afford (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-3,3-difluoro-2-methylazetidin-1- yl)propan-1-one (21.8 mg,0.06 mmol, 11.4% yield) as a white solid and (R)-2-((7-chloroquinazolin- 4-yl)amino)-1-((S)-3,3-difluoro-2-methylazetidin-1-yl)propan-1-one (18.6 mg, 0.05 mmol, 9.7% yield) as a white solid. LC-MS: (ESI, m / z): 341.1 [M+H]+.

[0484] Example 47: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-2- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one Synthetic Route

[0485] Step 1: tert-butyl ((R)-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2- yl)carbamate

[0486] A solution of (tert-butoxycarbonyl)-D-alanine (136.0 mg, 0.72 mmol), (S)-2- (trifluoromethyl)pyrrolidine (100.0 mg, 0.72 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (327.9 mg, 0.86 mmol) and N,N-diisopropylethylamine (278.6 mg, 2.16 mmol) in dichloromethane (1 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 (170.0 mg, 0.54 mmol, 76.2% yield) as a yellow solid. LC-MS: (ESI, m / z): 311.2 [M+H]+.

[0487] Step 2: (R)-2-amino-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-1-one trifluoroacetate

[0488] A solution of tert-butyl ((R)-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)carbamate (150.0 mg, 0.48 mmol) and 5% trifluoroacetic acid in 1,1,1,3,3,3- hexafluoro-2-propanol (4 mL) was stirred at 25 °C for 8 hours. 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): 211.1 [M+H]+.

[0489] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-2- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one

[0490] A solution of (R)-2-amino-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-1-one trifluoroacetate (93.9 mg, 0.29 mmol), N,N-diisopropylethylamine (147.0 mg, 1.14 mmol) and 4,7- dichloroquinazoline (62.5 mg, 0.31 mmol) in dimethyl sulfoxide (0.3 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 residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:2) 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, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 51% B in10.5min; Wave Length: 254 / 220 nm; RT1(min): 9.03 toafford the title compound (17.6 mg, 0.04 mmol, 16.5% yield) as a white solid. LC-MS: (ESI, m / z): 373.1 [M+H]+.

[0491] Example 48: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one Synthetic Route

[0492] Step 1: tert-butyl ((R)-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2- yl)carbamate

[0493] A solution of (tert-butoxycarbonyl)-D-alanine (136.0 mg, 0.72 mmol), (R)-2- (trifluoromethyl)pyrrolidine (100.0 mg, 0.72 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (327.9 mg, 0.86 mmol) and N,N-diisopropylethylamine (278.6 mg, 2.16 mmol) in dichloromethane (1 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 (170.0 mg, 0.54 mmol, 76.20 % yield) as a yellow solid. LC-MS: (ESI, m / z): 311.2 [M+H]+.

[0494] Step 2: (R)-2-amino-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-1-one trifluoroacetate

[0495] A solution of tert-butyl ((R)-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)carbamate (150.0 mg, 0.48 mmol) and 5% trifluoroacetic acid in 1,1,1,3,3,3- hexafluoro-2-propanol (4 mL) was stirred at 25 °C for 8 hours. 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): 211.1 [M+H]+.

[0496] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one

[0497] A solution of (R)-2-amino-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-1-one trifluoroacetate (93.9 mg, crude), N,N-diisopropylethylamine (147.0 mg, 1.14 mmol) and 4,7- dichloroquinazoline (62.5 mg, 0.31 mmol) in dimethyl sulfoxide (0.3 mL) was stirred at 100 °C for 30 minutes. After completion, the resulting solution was diluted with water and extracted with ethylacetate. 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: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 51% B in 10.5min; Wave Length: 254 / 220 nm; RT1(min): 8.98 to afford the title compound (17.3 mg, 0.04 mmol, 16.3% yield) as a white solid. LC-MS: (ESI, m / z): 373.1 [M+H]+.

[0498] Example 49: (R)-1-(3,3-difluoropyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0499] Step 1: tert-butyl (R)-(1-(3,3-difluoropyrrolidin-1-yl)-1-oxopropan-2-yl)carbamate

[0500] A solution of 3,3-difluoropyrrolidine (2.67 g, 18.67 mmol), (tert-butoxycarbonyl)- D-alanine (3.89 g, 20.54 mmol), N,N-diisopropylethylamine (9.63 g, 74.70 mmol) and 2-(7- azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.52 g, 22.41 mmol) in dichloromethane (20 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 (2:1) to afford the title compound (3.65 g, 13.11 mmol, 70.2 % yield) as a yellow solid. LC-MS: (ESI, m / z): 279.1 [M+H]+.

[0501] Step 2: (R)-2-amino-1-(3,3-difluoropyrrolidin-1-yl)propan-1-one hydrochloride

[0502] A solution of tert-butyl (R)-(1-(3,3-difluoropyrrolidin-1-yl)-1-oxopropan-2- yl)carbamate (200.0 mg, 0.72 mmol) in 4 M hydrochloric acid in 1,4-dioxane (2 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (120 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 179.1 [M+H]+.

[0503] Step 3: (R)-1-(3,3-difluoropyrrolidin-1-yl)-2-((7-(trifluoromethoxy)quinazolin-4- yl)amino)propan-1-one

[0504] A solution of (R)-2-amino-1-(3,3-difluoropyrrolidin-1-yl)propan-1-one hydrochloride (72.7 mg, crude), N,N-diisopropylethylamine (174.1 mg, 1.35 mmol) and 4-chloro-7- (trifluoromethoxy)quinazoline (83.7 mg, 0.34 mmol) in dimethyl sulfoxide (0.3 mL) was stirred at 100 °C for 30 minutes. After completion, the resulting residue was purified by reverse phase chromatography on C18gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (29.7 mg, 0.08 mmol, 22.6% yield) as a white solid. LC-MS: (ESI, m / z): 391.1 [M+H]+.

[0505] Example 50: (R)-1-(4-(trifluoromethoxy)piperidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0506] Step 1: tert-butyl (R)-(1-oxo-1-(4-(trifluoromethoxy)piperidin-1-yl)propan-2- yl)carbamate

[0507] A solution of 4-(trifluoromethoxy)piperidine hydrochloride (241.9 mg, 1.18 mmol), (tert-butoxycarbonyl)-D-alanine (223.7 mg, 1.18 mmol), N,N-diisopropylethylamine (610.1 mg, 4.73 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (539.5 mg, 1.42 mmol) in dichloromethane (2 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 (345.0 mg, 1.01 mmol, 85.71 % yield) as a yellow solid. LC-MS: (ESI, m / z): 341.2 [M+H]+.

[0508] Step 2: (R)-2-amino-1-(4-(trifluoromethoxy)piperidin-1-yl)propan-1-one hydrochloride

[0509] A solution of tert-butyl (R)-(1-oxo-1-(4-(trifluoromethoxy)piperidin-1-yl)propan-2- yl)carbamate (320.0 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 titlecompound (250.0 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1 [M+H]+.

[0510] Step 3: (R)-1-(4-(trifluoromethoxy)piperidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0511] A solution of (R)-2-amino-1-(4-(trifluoromethoxy)piperidin-1-yl)propan-1-one hydrochloride (69.0 mg, 0.25 mmol), N,N-diisopropylethylamine (129.0 mg, 1.00 mmol) and 4- chloro-7-(trifluoromethoxy)quinazoline (62.0 mg, 0.25 mmol) in dimethyl sulfoxide (0.4 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 (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (22.9 mg, 0.05 mmol, 20.3% yield) as a white solid. LC-MS: (ESI, m / z): 453.3 [M+H]+.

[0512] Example 51: (R)-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0513] Step 1: tert-butyl (R)-(1-oxo-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-2- yl)carbamate

[0514] A solution of 1-(2,2,2-trifluoroethyl)piperazine hydrochloride (241.6 mg, 1.18 mmol), (tert-butoxycarbonyl)-D-alanine (225.0 mg, 1.19 mmol), N,N-diisopropylethylamine (614.5 mg, 4.76 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (543.0 mg, 1.43 mmol) in dichloromethane (2 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 (356.0 mg, 1.05 mmol, 88.2 % yield) as a yellow solid. LC-MS: (ESI, m / z): 340.2 [M+H]+.

[0515] Step 2: (R)-2-amino-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-1-one hydrochloride

[0516] A solution of tert-butyl (R)-(1-oxo-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan- 2-yl)carbamate (356.0 mg, 1.05 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 (300 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 240.1 [M+H]+.

[0517] Step 3: (R)-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0518] A solution of (R)-2-amino-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)propan-1-one hydrochloride (68.7 mg, crude), N,N-diisopropylethylamine (129.0 mg, 1.00 mmol) and 4-chloro-7- (trifluoromethoxy)quinazoline (74.8 mg, 0.30 mmol) in dimethyl sulfoxide (0.4 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 (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (34.4 mg, 0.08 mmol, 30.4% yield) as a white solid. LC-MS: (ESI, m / z): 452.0 [M+H]+.

[0519] Example 52: (R)-1-(3-(trifluoromethoxy)azetidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0520] Step 1: tert-butyl (R)-(1-oxo-1-(3-(trifluoromethoxy)azetidin-1-yl)propan-2- yl)carbamate

[0521] A solution of 3-(trifluoromethoxy)azetidine hydrochloride (200 mg, 1.14 mmol), (tert-butoxycarbonyl)-D-alanine (268.2 mg, 1.42 mmol), N,N-diisopropylethylamine (732.8 mg, 5.67 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (520.2 mg, 1.37 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Theorganic 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 (340.0 mg, 1.09 mmol, 95.61 % yield) as a yellow solid. LC-MS: (ESI, m / z): 313.1 [M+H]+.

[0522] Step 2: (R)-2-amino-1-(3-(trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride

[0523] A solution of tert-butyl (R)-(1-oxo-1-(3-(trifluoromethoxy)azetidin-1-yl)propan-2- yl)carbamate (340.0 mg, 1.09 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 (250 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 213.1 [M+H]+.

[0524] Step 3: (R)-1-(3-(trifluoromethoxy)azetidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0525] A solution of (R)-2-amino-1-(3-(trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (100.0 mg, crude), N,N-diisopropylethylamine (146.2 mg, 1.13 mmol) and 4-chloro- 7-(trifluoromethoxy)quinazoline (84.4 mg, 0.33 mmol) in dimethyl sulfoxide (0.3 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 (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (33.3 mg, 0.08 mmol, 27.8% yield) as a white solid. LC-MS: (ESI, m / z): 425.1 [M+H]+.

[0526] Example 55a: (R)-2-((7-(difluoromethoxy)quinazolin-4-yl)amino)-1-((S)-6- methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one

[0527] Example 55b: (R)-2-((7-(difluoromethoxy)quinazolin-4-yl)amino)-1-((R)-6- methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0528] Step 1: tert-butyl 4-(7-hydroxyquinazolin-4-yl)piperazine-1-carboxylate

[0529] Under nitrogen, a mixture of tert-butyl 4-(7-bromoquinazolin-4-yl)piperazine-1- carboxylate (4.00 g, 10.17 mmol), tris(dibenzylideneacetone)dipalladium (0.93 g, 1.02 mmol), 2-di- tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.86 g, 2.03 mmol) and potassium hydroxide(1.71 g, 30.51 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 100 °C for 2 hours. After completion, the solvent was removed under vacuum. The resulting residue was purified by reverse phase chromatography on C18gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (1.00 g, 3.02 mmol, 29.8% yield) as a yellow solid. LC-MS: (ESI, m / z): 331.2 [M+H]+.

[0530] Step 2: tert-butyl 4-(7-(difluoromethoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0531] A solution of tert-butyl 4-(7-hydroxyquinazolin-4-yl)piperazine-1-carboxylate (1.00 g, 3.03 mmol), difluoromethyl trifluoromethanesulfonate (1.82 g, 9.08 mmol) and 6 M potassium hydroxide (2.5 mL) in acetonitrile (10 mL) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1:20) to afford the title compound (500.0 mg, 1.31 mmol, 43.4% yield) as a yellow solid. LC-MS: (ESI, m / z): 381.2 [M+H]+.

[0532] Step 3: 7-(difluoromethoxy)quinazolin-4(3H)-one

[0533] A solution of tert-butyl 4-(7-(difluoromethoxy)quinazolin-4-yl)piperazine-1- carboxylate (450.0 mg, 1.18 mmol) and sodium hydroxide (473.1 mg, 11.83 mmol) in dimethyl sulfoxide (5 mL) and water (1 mL) was stirred at 60 °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 on C18gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (180.0 mg, 0.84 mmol, 71.7% yield) as a yellow solid. LC-MS: (ESI, m / z): 213.0 [M+H]+.

[0534] Step 4: (R)-2-((7-(difluoromethoxy)quinazolin-4-yl)amino)-1-((S)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-1-one & (R)-2-((7-(difluoromethoxy)quinazolin-4-yl)amino)-1- ((R)-6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one

[0535] A solution of 7-(difluoromethoxy)quinazolin-4(3H)-one (120.0 mg, 0.57 mmol), (2R)-2-amino-1-(6-methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (148.2 mg, crude), N,N-diisopropylethylamine (291.5 mg, 2.26 mmol) and benzotriazole-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (441.1 mg, 0.85 mmol) in dichloromethane (1.5 mL) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (20:1) 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 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B:ACN; Flow rate: 60 mL / min; Gradient: 32% B to 52% B in 10.5 min; Wave Length: 254 / 220 nm; RT1(min): 10.57 to afford product. The product was separated by Chiral-Prep-HPLC with the following conditions: Column: (R, R)-WHELK-O1-Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 13.625; RT2(min): 20.187; Sample Solvent: EtOH; Injection Volume: 1.0 mL to afford (R)-2-((7-(difluoromethoxy)quinazolin-4-yl)amino)-1-((S)-6- methyl-5-azaspiro[2.4]heptan-5-yl)propan-1-one (25.7 mg, 0.06 mmol, 12.1% yield) as a white solid and (R)-2-((7-(difluoromethoxy)quinazolin-4-yl)amino)-1-((R)-6-methyl-5- azaspiro[2.4]heptan-5-yl)propan-1-one (21.6 mg, 0.05 mmol, 10.1% yield) as a white solid.

[0536] Example 56: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((2R,4R)-2- methyl-4-(trifluoromethoxy)piperidin-1-yl)propan-1-one Synthetic Route

[0537] Step 1: tert-butyl (2R,4R)-2-methyl-4-(trifluoromethoxy)piperidine-1-carboxylate

[0538] Under nitrogen, to a mixture of silver trifluoromethanesulfonate (6.45 g, 25.08 mmol), potassium fluoride (2.19 g, 37.16 mmol) and 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (4.95 g, 13.93 mmol) in ethyl acetate (10 mL) was slowly added a solution of tert-butyl (2R,4R)-4-hydroxy-2-methyl-piperidine-1-carboxylate (2.00 g, 9.29 mmol) in ethyl acetate (10 mL) at 0 °C. Then, 2-fluoropyridine (2.73g, 27.87mmol) and (trifluoromethyl)trimethylsilane (3.99 g, 27.87 mmol) was added dropwise at 0 °C and stirred at 25 °C for 24 hours. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the title compound (1.00 g, 3.53 mmol, 38.0% yield) as a yellow solid. LC-MS: (ESI, m / z): 284.1 [M+H]+.

[0539] Step 2: (2R,4R)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride

[0540] A solution of tert-butyl (2R,4R)-2-methyl-4-(trifluoromethoxy)piperidine-1- carboxylate (1.00 g, 3.53 mmol) in 4 M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25 °C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (718.3 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 184.1 [M+H]+.

[0541] Step 3: tert-butyl ((R)-1-((2R,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1-yl)-1- oxopropan-2-yl)carbamate

[0542] A solution of (2R,4R)-2-methyl-4-(trifluoromethoxy)piperidine hydrochloride (718.3 mg, crude), (tert-butoxycarbonyl)-D-alanine (743.7 mg, 3.93 mmol), N,N- diisopropylethylamine (1.68 g, 13.10 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (1.49 g, 3.93 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the title compound (800.0 mg, 2.25 mmol, 68.9% yield) as a yellow solid. LC-MS: (ESI, m / z): 355.2 [M+H]+.

[0543] Step 4: (R)-2-amino-1-((2R,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)propan-1-one hydrochloride

[0544] A solution of tert-butyl (2R,4R)-2-methyl-4-(trifluoromethoxy)piperidine-1- carboxylate (500 mg, 1.72 mmol) in 4 M hydrochloric acid in 1,4-dioxane (5 mL) was stirred at 25 °C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (400 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 255.1 [M+H]+.

[0545] Step 5: (R)-2-((7-(difluoromethyl)quinazolin-4-yl)amino)-1-((2R,4R)-2-methyl-4- (trifluoromethoxy)piperidin-1-yl)propan-1-one

[0546] A solution of (R)-2-amino-1-((2R,4R)-2-methyl-4-(trifluoromethoxy)piperidin-1- yl)propan-1-one hydrochloride (70.0 mg, 0.24 mmol), 7-(difluoromethyl)-3H-quinazolin-4-one (50.9 mg, 0.26 mmol), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (184.0 mg, 0.35 mmol) and N,N-diisopropylethylamine (152.2 mg, 1.18mmol) in dichloromethane (1 mL) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford crude solid. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 36%B to 56%B in 10.5 min; Wave Length: 254 / 228 nm; RT1(min): 10.02 to afford the title compound (24.2 mg, 0.05 mmol, 23.7% yield) as a white solid. LC-MS: (ESI, m / z): 433.1 [M+H]+.

[0547] Example 57a: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-1-methylisoindolin- 2-yl)propan-1-one

[0548] Example 57b: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-1-methylisoindolin- 2-yl)propan-1-one Synthetic Route

[0549] Step 1: tert-butyl ((2R)-1-(1-methylisoindolin-2-yl)-1-oxopropan-2-yl)carbamate

[0550] A mixture of 1-methylisoindoline hydrochloride (170.0 mg, 1.00 mmol), (tert- butoxycarbonyl)-D-alanine (362.3 mg, 1.91 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (727.9 mg, 1.91 mmol) and N,N-diisopropylethylamine (493.9 mg, 3.83 mmol) in dichloromethane (1 mL) was stirred at 25 ºC for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase chromatography on C18gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (110 mg, 0.36 mmol, 28.3% yield) as a white solid. LC-MS: (ESI, m / z): 305.2 [M+H]+.

[0551] Step 2: (2R)-2-amino-1-(1-methylisoindolin-2-yl)propan-1-one trifluoroacetate

[0552] A mixture of tert-butyl ((2R)-1-(1-methylisoindolin-2-yl)-1-oxopropan-2- yl)carbamate (100.0 mg, 0.33 mmol) and 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (2 mL) was stirred at 25 ºC 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): 205.1[M+H]+.

[0553] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-1-methylisoindolin-2- yl)propan-1-one & (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-1-methylisoindolin-2-yl)propan- 1-one

[0554] Under nitrogen, a mixture of (2R)-2-amino-1-(1-methylisoindolin-2-yl)propan-1- one trifluoroacetate (150.0 mg, crude), 4,7-dichloroquinazoline (175.4 mg, 0.88 mmol) and N,N- diisopropylethylamine (473.6 mg, 3.67 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 ºC for 0.5 hours. After completion, the resulting residue was purified by reverse phase chromatography on C18gel (acetonitrile / 0.1% ammonium bicarbonate 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, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 57% B in 10.5 min; Wave Length: 254 / 220 nm;RT1(min): 8.5 to afford product. Then the product was isolated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK ID, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RT1(min): 13.101; RT2(min): 16; Sample Solvent: EtOH--HPLC; Injection Volume: 0.5 mL to afford (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-1- methylisoindolin-2-yl)propan-1-one (18.7 mg, 0.05 mmol, 6.9% yield) as a white solid and (R)-2- ((7-chloroquinazolin-4-yl)amino)-1-((S)-1-methylisoindolin-2-yl)propan-1-one (17.5 mg, 0.05 mmol, 6.5% yield) as a white solid.

[0555] Example 58: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2- methylmorpholino)propan-1-one Synthetic Route

[0556] Step 1: tert-butyl ((R)-1-((R)-2-methylmorpholino)-1-oxopropan-2-yl)carbamate

[0557] A solution of (tert-butoxycarbonyl)-D-alanine (561.2 mg, 2.97 mmol), (R)-2- methylmorpholine (200.0 mg, 1.98 mmol), N,N-diisopropylethylamine (158.0 mg, 1.22 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (139.3 mg, 0.37 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (300.0 mg, 1.10 mmol, 55.7% yield) as a white solid. LC-MS: (ESI, m / z): 273.2 [M+H]+.

[0558] Step 2: (R)-2-amino-1-((R)-2-methylmorpholino)propan-1-one trifluoroacetate

[0559] A mixture of tert-butyl ((R)-1-((R)-2-methylmorpholino)-1-oxopropan-2- yl)carbamate (150.0 mg, 0.55 mmol) and 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (4 mL) was stirred at 25 ºC for 1 hour. After completion. the solvent was concentrated under vacuum to afford the title compound (150 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 173.1 [M+H]+.

[0560] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2- methylmorpholino)propan-1-one

[0561] A solution of (R)-2-amino-1-((R)-2-methylmorpholino)propan-1-one trifluoroacetate (150.0 mg, crude), 4,7-dichloroquinazoline (165.7 mg, 0.83 mmol) and N,N- diisopropylethylamine (215.2 mg, 1.67 mmol) in dimethyl sulfoxide (0.50 mL) was stirred at 100 ºC for 0.5 hours. After completion, 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 resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (23.3 mg, 0.07 mmol, 12.4% yield) as a white solid. LC-MS: (ESI, m / z): 335.0 [M+H]+.

[0562] Example 59a: (R)-1-((R)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one

[0563] Example 59b: (R)-1-((S)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0564] Step 1: 4-chloro-6-(4-fluorophenyl)pyrimidine

[0565] Under nitrogen, a solution of 4,6-dichloropyrimidine (10.0 g, 67.12 mmol), (4- fluorophenyl)boronic acid (8.5 g, 60.41 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (5.0 g, 6.71 mmol) and potassium carbonate (27.8 g, 201.37 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was stirred at 80 ºC for 1 hour. After completion, the solids were filtered out. After filtration, the filtrate was concentrated. The resulting mixture was diluted with water and extracted with dichloromethane. The organic layers were combined, 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 (87:13) to afford the title compound (5.90 g, 26.58 mmol, 39.6% yield) as a white solid. LC-MS: (ESI, m / z): 209.0 [M+H]+.

[0566] Step 2: tert-butyl (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alaninate

[0567] Under nitrogen, a solution of tert-butyl D-alaninate hydrochloride (6.4 g, 35.47 mmol), N,N-diisopropylethylamine (6.9 g, 53.21 mmol) and 4-chloro-6-(4-fluorophenyl)pyrimidine (3.7 g, 17.74 mmol) in dimethyl sulfoxide (15 mL) was stirred at 100 ºC 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. Theresidue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (65:35) to afford tert-butyl (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alaninate (3.0 g, 8.60 mmol, 48.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 318.2 [M+H]+.

[0568] Step 3: (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alanine trifluoroacetate

[0569] A solution of tert-butyl (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alaninate (200.0 mg, 0.63 mmol) in 2,2,2-trifluoroacetic acid (1.5 mL) and dichloromethane (4.5 mL) was stirred at 25 ºC for 16 hours. After completion, the solvent was removed under vacuum to afford the title compound (150 mg, 0.57 mmol, 90.87% yield) as a white solid. LC-MS: (ESI, m / z): 262.1 [M+H]+.

[0570] Step 4: (R)-1-((R)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one & (R)-1-((S)-7-fluoro-5-azaspiro[2.4]heptan-5- yl)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)propan-1-one

[0571] To a solution of (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alanine trifluoroacetate (150.0 mg, 0.57 mmol) and 7-fluoro-5-azaspiro[2.4]heptane hydrochloride (189.9 mg, 1.25 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (158.0 mg, 1.22 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (797.1 mg, 1.25 mmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 1 hour. After completion, the resulting solution was diluted with water, extracted with dichloromethane and the organic layers were combined. The organic layer was 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 (50:50) 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, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 46% B in10.5min; Wave Length: 254 / 220 nm; RT1(min): 9.88. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: MtBE(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; RT1(min): 6.708; RT2(min): 8.091; Sample Solvent: EtOH--HPLC; Injection Volume: 0.5 mL to afford (R)-1-((R)-7-fluoro-5-azaspiro[2.4]heptan-5-yl)-2-((6-(4-fluorophenyl)pyrimidin-4- yl)amino)propan-1-one (19.9 mg, 0.06 mmol, 13.3% yield) as a white solid and (R)-1-((S)-7-fluoro- 5-azaspiro[2.4]heptan-5-yl)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)propan-1-one (21.3 mg, 0.06 mmol, 14.2% yield) as a white solid.

[0572] Example 60a: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((R)-3- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one

[0573] Example 60b: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((S)-3- (trifluoromethyl)pyrrolidin-1-yl)propan-1-oneSynthetic Route

[0574] To a solution of (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alanine (150.0 mg, 0.57 mmol) and 3-(trifluoromethyl)pyrrolidine hydrochloride (100.8 mg, 0.57 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (158.0 mg, 1.22 mmol) and 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.10 g, 1.72 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, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (40:60) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 14% B to 37% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 6.43 to afford product. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK AD 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3- MeOH), Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20; Wave Length: 220 / 254 nm; RT1(min): 11.519; RT2(min): 13.164; Sample Solvent: ETOH; Injection Volume: 0.35 mL to afford (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((S)-3- (trifluoromethyl)pyrrolidin-1-yl)propan-1-one (12.1 mg, 0.03 mmol, 5.5% yield) as a white solid and (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((R)-3-(trifluoromethyl)pyrrolidin-1- yl)propan-1-one (11.9 mg, 0.03 mmol, 5.4% yield) as a white solid.

[0575] Example 61: (R)-1-(3,3-difluoropyrrolidin-1-yl)-2-((6-(4-fluorophenyl)pyrimidin- 4-yl)amino)propan-1-one Synthetic Route

[0576] To a solution of (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alanine (80.0 mg, 0.31 mmol) and 3,3-difluoropyrrolidine hydrochloride (131.9 mg, 0.92 mmol) in N,N- dimethylformamide (1 mL) was added N,N-diisopropylethylamine (118.7 mg, 0.92 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (292.3 mg, 0.46 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 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 (50:50) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 20*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B in10.5min; Wave Length: 254 / 220 nm; RT1(min): 6.18 to afford the title compound (12.0 mg, 0.03 mmol, 11.% yield) as a white solid. LC-MS: (ESI, m / z): 351.1 [M+H]+.

[0577] Example 62a: (R)-1-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0578] Example 62b: (R)-1-((S)-3-(trifluoromethoxy)pyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0579] Step 1: tert-butyl ((2R)-1-oxo-1-(3-(trifluoromethoxy)pyrrolidin-1-yl)propan-2- yl)carbamate

[0580] A solution of 3-(trifluoromethoxy)pyrrolidine hydrochloride (246.3 mg, 1.29 mmol), (tert-butoxycarbonyl)-D-alanine (243.9 mg, 1.29 mmol), N,N-diisopropylethylamine (665.6 mg, 5.16 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (588.2 mg, 1.55 mmol) in dichloromethane (2 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 ethyl acetate / dichloromethane (1:20) to afford the title compound (341.0 mg, 1.04 mmol, 81.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 327.1 [M+H]+.

[0581] Step 2: (2R)-2-amino-1-(3-(trifluoromethoxy)pyrrolidin-1-yl)propan-1-one hydrochloride

[0582] A solution of tert-butyl ((2R)-1-oxo-1-(3-(trifluoromethoxy)pyrrolidin-1-yl)propan- 2-yl)carbamate (200.0 mg, 0.61 mmol) in 4 M hydrochloric acid in 1,4-dioxane (2 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (133.6 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 227.1 [M+H]+.

[0583] Step 3: (R)-1-((R)-3-(trifluoromethoxy)pyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one & (R)-1-((S)-3- (trifluoromethoxy)pyrrolidin-1-yl)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0584] Under nitrogen, a solution of (2R)-2-amino-1-(3-(trifluoromethoxy)pyrrolidin-1- yl)propan-1-one hydrochloride (133.6 mg, crude), 4-chloro-7-(trifluoromethoxy)quinazoline (191.6 mg, 0.77 mmol) and N,N-diisopropylethylamine (198.6 mg, 1.54 mmol) in N,N-dimethylformamide (1 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 residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford product. The product was isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRALPAK IK 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA; Flow rate: 20 mL / min; Gradient: isocratic 7; Wave Length: 220 / 254 nm; RT1(min): 9.438; RT2(min): 13.165; Sample Solvent: EtOH; Injection Volume: 0.6 mL to afford (R)-1-((R)-3-(trifluoromethoxy)pyrrolidin-1- yl)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one (20.6 mg, 0.04 mmol, 9.1% yield) as a white solid and (R)-1-((S)-3-(trifluoromethoxy)pyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one (20.2 mg, 0.04 mmol, 8.9% yield) as a white solid.

[0585] Example 63: (R)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)-1-(3- (trifluoromethyl)azetidin-1-yl)propan-1-one

[0586] Synthetic Route

[0587] Step 1: tert-butyl (R)-(1-oxo-1-(3-(trifluoromethyl)azetidin-1-yl)propan-2- yl)carbamate

[0588] To a solution of (tert-butoxycarbonyl)-D-alanine (351.4 mg, 1.86 mmol) and (trifluoromethyl)azetidine hydrochloride (200.0 mg, 1.24 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (158.0 mg, 1.22 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (706.1 mg, 1.86 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 dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (70:30) to afford the title compound (300.0 mg, 1.01 mmol, 81.8% yield) as a white solid. LC-MS: (ESI, m / z): 297.1 [M+H]+.

[0589] Step 2: (R)-2-amino-1-(3-(trifluoromethyl)azetidin-1-yl)propan-1-one trifluoroacetate

[0590] A mixture of tert-butyl (R)-(1-oxo-1-(3-(trifluoromethyl)azetidin-1-yl)propan-2- yl)carbamate (200.0 mg, 0.68 mmol) and 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (3 mL) was stirred at 25 ºC 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): 197.1 [M+H]+.

[0591] Step 3: (R)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)-1-(3- (trifluoromethyl)azetidin-1-yl)propan-1-one

[0592] Under nitrogen, a solution of (R)-2-amino-1-(3-(trifluoromethyl)azetidin-1- yl)propan-1-one trifluoroacetate (100.0 mg, crude), 4-chloro-7-(trifluoromethoxy)quinazoline (253.5 mg, 1.02 mmol) and N,N-diisopropylethylamine (263.6 mg, 2.04 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 ºC 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% NH4HCO3in water) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge PrepOBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 48% B in 10.5 min; Wave Length: 254 / 220 nm; RT1(min): 9.6 to afford the title compound (12.7 mg, 0.03 mmol, 9.1% yield) as a white solid. LC-MS: (ESI, m / z): 409.1 [M+H]+.

[0593] Example 64: (R)-2-((6-(4-chlorophenyl)pyrimidin-4-yl)amino)-1-(5- azaspiro[2.4]heptan-5-yl)propan-1-one Synthetic Route

[0594] Step 1: tert-butyl (R)-(1-oxo-1-(5-azaspiro[2.4]heptan-5-yl)propan-2-yl)carbamate

[0595] A solution of 5-azaspiro[2.4]heptane hydrochloride (900.0 mg, 9.26 mmol), 2-(7- Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.2 g, 11.12 mmol) in dichloromethane (10.0 mL) was added N,N-diisopropylethylamine (4.8 mL, 27.79 mmol) and (tert- butoxycarbonyl)-D-alanine (1.9 g, 10.19 mmol) and stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated and purified y flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (1.80 g, 6.70 mmol, 72.4% yield) as a yellow oil. LC-MS: (ESI, m / z): 269.2 [M+H]+.

[0596] Step 2: (R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride

[0597] A solution of tert-butyl (R)-(1-oxo-1-(5-azaspiro[2.4]heptan-5-yl)propan-2- yl)carbamate (1.80 g, 6.71 mmol) in hydrochloric acid / 1,4-dioxane (20.0 mL, 4M) was stirred at 25 °C for 1 hour. After completion, the reaction was concentrated to afford the title compound (1.41 g, crude). The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 169.1 [M+H]+.

[0598] Step 3: 4-chloro-6-(4-chlorophenyl)pyrimidine

[0599] Under nitrogen, a solution of 4,6-dichloropyrimidine (500.0 mg, 3.36 mmol), (4- chlorophenyl)boronic acid (472.3 mg, 3.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (249.0 mg, 0.34 mmol) and potassium carbonate (1.39 g, 10.07 mmol) in 1.4-dioxane (10 mL) and water (1 mL) was stirred at 80 ºC for 3 hours. After completion, the solids were filtered out. After filtration, the filtrate was concentrated. The resulting mixture was diluted with water and extracted with dichloromethane. The organic layers were combined, 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 (96:4) to afford the title compound (390.0 mg, 1.70 mmol, 50.6% yield) as a white solid. LC-MS: (ESI, m / z): 225.0 [M+H]+.

[0600] Step 4: (R)-2-((6-(4-chlorophenyl)pyrimidin-4-yl)amino)-1-(5-azaspiro[2.4]heptan- 5-yl)propan-1-one

[0601] A solution of (R)-2-amino-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (70.0 mg, 0.34 mmol), 4-chloro-6-(4-chlorophenyl)pyrimidine (70.0 mg, 0.31 mmol) and N,N-diisopropylethylamine (120.6 mg, 0.93 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 ºC 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% NH4HCO3in water) to afford the title compound (31.3 mg, 0.09 mmol, 27.6% yield) as a white solid. LC-MS: (ESI, m / z): 357.1 [M+H]+.

[0602] Example 65: (R)-1-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0603] To a solution of (6-(4-fluorophenyl)pyrimidin-4-yl)-D-alanine (70.0 mg, 0.27 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (109.0 mg, 0.80 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (692.6 mg, 5.36 mmol) and 2,4,6- tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (511.5 mg, 0.80 mmol, 50% in ethylacetate). 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 dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (40:60) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: Xselect CSH F-Phenyl OBD column30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient: 16% B to 34% B in 10 min; Wave Length: 254nm / 220nm nm to afford the title compound (13.4 mg, 0.04 mmol, 14.6% yield) as a white solid. LC-MS: (ESI, m / z): 343.1 [M+H]+.

[0604] Example 66: (R)-3-hydroxy-1-(5-azaspiro[2.4]heptan-5-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0605] Step 1: tert-butyl (R)-(3-hydroxy-1-oxo-1-(5-azaspiro[2.4]heptan-5-yl)propan-2- yl)carbamate

[0606] A solution of (tert-butoxycarbonyl)-D-serine (422.4 mg, 2.06 mmol), 5- azaspiro[2.4]heptane hydrochloride (273.9 mg, 2.06 mmol), N,N-diisopropylethylamine (1.06 g, 8.24 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.17 g, 3.09 mmol) in dichloromethane (4 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 ethyl acetate / dichloromethane (1:20) to afford the title compound (354.0 mg, 1.24 mmol, 60.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 285.2 [M+H]+.

[0607] Step 2: (R)-2-amino-3-hydroxy-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride

[0608] A solution of tert-butyl(R)-(3-hydroxy-1-oxo-1-(5-azaspiro[2.4]heptan-5- yl)propan-2-yl)carbamate (350.0 mg, 1.23 mmol) in 4 M hydrochloric acid in 1,4-dioxane (4 mL)was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (300 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 185.1 [M+H]+.

[0609] Step 3: (R)-3-hydroxy-1-(5-azaspiro[2.4]heptan-5-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0610] A solution of (R)-2-amino-3-hydroxy-1-(5-azaspiro[2.4]heptan-5-yl)propan-1-one hydrochloride (60.0 mg, 0.27 mmol), 4-chloro-7-(trifluoromethoxy)quinazoline (101.4 mg, 0.41 mmol) and N,N-diisopropylethylamine (140.5 mg, 1.09 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 ºC 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% NH4HCO3in water) to afford the title compound (60.7 mg, 0.15 mmol, 56.3% yield) as an off-white solid. LC-MS: (ESI, m / z): 397.1 [M+H]+.

[0611] Example 67: (R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0612] Step 1: tert-butyl (2S,3S)-2-methyl-3-(trifluoromethoxy)azetidine-1-carboxylate

[0613] Under nitrogen, to a mixture of silver trifluoromethanesulfonate (3.91 g, 15.14 mmol), potassium fluoride (1.30 g, 22.43 mmol) and 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (2.98 g, 8.41 mmol) in ethyl acetate (5 mL) was slowly added a solution of tert-butyl (2S,3S)-3-hydroxy-2-methylazetidine-1-carboxylate (1.05 g, 5.61 mmol) in ethyl acetate (5 mL) at 0 °C. Then 2-fluoropyridine (1.63 g, 16.82 mmol) and (trifluoromethyl)trimethylsilane (2.39 g, 16.82 mmol) was added dropwise at 0 °C and stirred at 25 °C overnight. After completion, the solids were filtered out. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (9:1) to afford tert-butyl (2S,3S)-2-methyl-3- (trifluoromethoxy)azetidine-1-carboxylate (300.0 mg, 1.06 mmol, 17.5% yield) as a colorless oil. LC-MS: (ESI, m / z): 256.1 [M+H]+.

[0614] Step 2: (2S,3S)-2-methyl-3-(trifluoromethoxy)azetidine hydrochloride

[0615] A solution of tert-butyl (2S,3S)-2-methyl-3-(trifluoromethoxy)azetidine-1- carboxylate (300.0 mg, 1.18 mmol) in 4 M hydrochloric acid in 1,4-dioxane (6 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (2S,3S)-2-methyl- 3-(trifluoromethoxy)azetidine hydrochloride (220.0 mg, crude) as a white solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 156.1 [M+H]+.

[0616] Step 3: tert-butyl ((R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-1- oxopropan-2-yl)carbamate

[0617] A solution of (2S,3S)-2-methyl-3-(trifluoromethoxy)azetidine hydrochloride (220.0 mg, crude), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (217.2 mg, 1.15 mmol), N,N- diisopropylethylamine (742.0 mg, 5.74 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (567.6 mg, 1.49 mmol) in N,N-dimethylformamide (5 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% NH4HCO3in water) to afford tert-butyl ((R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-1- oxopropan-2-yl)carbamate (250.0 mg, 0.68 mmol, 60.0% yield) as a yellow oil. LC-MS: (ESI, m / z): 327.1 [M+H]+.

[0618] Step 4: (R)-2-amino-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl)propan-1-one hydrochloride

[0619] A solution of tert-butyl ((R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl)-1-oxopropan-2-yl)carbamate (200 mg, 0.61 mmol) in 4 M hydrochloric acid in 1,4-dioxane (2.9 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford (R)-2-amino-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-onehydrochloride (145 mg, crude) as a white solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 227.1 [M+H]+.

[0620] Step 5: (R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0621] A solution of (2R)-2-amino-1-[(2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl]propan-1-one hydrochloride (100.0 mg, crude), 4-chloro-7-(trifluoromethoxy)quinazoline (94.6 mg, 0.38 mmol) and N,N-diisopropylethylamine (387.0 mg, 1.14 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 °C for 1 hour. After completion, the resulting solution was diluted with ethyl acetate and washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (50.3 mg, 0.11 mmol, 29.7 % yield) as a white solid. LC-MS: (ESI, m / z): 439.2 [M+H]+.

[0622] Example 68: (R)-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)pyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0623] Step 1: tert-butyl ((R)-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)pyrrolidin-1-yl)-1- oxopropan-2-yl)carbamate A solution of (2S,4R)-2-methyl-4-(trifluoromethoxy)pyrrolidine hydrochloride (260.1 mg, 1.26 mmol), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (239.0 mg, 1.26 mmol), N, N- diisopropylethylamine (489.3 mg, 3.79 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (721.2 mg, 1.90 mmol) in dichloromethane (5 mL) was stirred at 25 ºC for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane. The organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1:5) to afford the titlecompound (390.1 mg, 1.09 mmol, 86.1% yield) as a white oil. LC-MS: (ESI, m / z): 341.2[M+H]+.

[0624] Step 2: (R)-2-amino-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)pyrrolidin-1- yl)propan-1-one hydrogen chloride A solution of tert-butyl ((R)-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)pyrrolidin-1-yl)-1- oxopropan-2-yl)carbamate (200.0 mg, 0.59 mmol) in hydrogen chloride / 1,4-dioxane (2 mL, 4.0 M) was stirred at 25 ºC for 2 hours. After completion, the reaction solution was concentrated under vacuum to afford the title compound (150.6 mg, crude). The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1[M+H]+.

[0625] Step 3: (R)-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)pyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0626] A solution of (R)-2-amino-1-((2S,4R)-2-methyl-4-(trifluoromethoxy)pyrrolidin-1- yl)propan-1-one hydrochloride (80.0 mg, crude), N,N-diisopropylethylamine (150.9 mg, 1.17 mmol) and 4-chloro-7-(trifluoromethoxy)quinazoline (72.44 mg, 0.29 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (31.3 mg, 0.06 mmol, 23.7% yield) as a white solid. LC-MS: (ESI, m / z): 453.2 [M+H]+.

[0627] Example 69: (R)-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0628] Step 1: tert-butyl ((R)-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)-1-oxopropan-2- yl)carbamate

[0629] A solution of (2S,4R)-4-fluoro-2-methylpyrrolidine hydrochloride (100.0 mg, 0.72 mmol), (tert-butoxycarbonyl)-D-alanine (220.1 mg, 1.16 mmol), N,N-diisopropylethylamine (0.6 mL, 3.88 mmol) and 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (478.9 mg, 1.26 mmol) in dichloromethane (2.0 mL) was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate(1:1) to afford the title compound (200.0 mg, 0.72 mmol, 75.2% yield) as a yellow oil. LC-MS: (ESI, m / z): 275.2 [M+H]+.

[0630] Step 2: (R)-2-amino-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)propan-1-one hydrochloride

[0631] A solution of tert-butyl ((R)-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)-1- oxopropan-2-yl)carbamate (150.0 mg, 0.55 mmol) in hydrochloric acid / 1,4-dioxane (2.0 mL, 4M) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (158.2 mg, crude). The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 175.1 [M+H]+.

[0632] Step 3: (R)-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one

[0633] A solution of (R)-2-amino-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)propan-1- one hydrochloride (100.0 mg, crude), N,N-diisopropylethylamine (306.7 mg, 2.37 mmol) and 4- chloro-7-(trifluoromethoxy)quinazoline (88.5 mg, 0.36 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) (1:1) to afford the title compound (34.7 mg, 0.08 mmol, 18.6% yield) as a white solid. LC-MS: (ESI, m / z): 387.1 [M+H]+.

[0634] Example 70: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0635] A solution of 4,7-dichloroquinazoline (60.0 mg, 0.30 mmol), (2R)-2-amino-1- [(2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl]propan-1-one hydrochloride (79.2 mg, crude) and N,N-diisopropylethylamine (116.7 mg, 0.90 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 0.5 hours. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (41.5 mg, 0.11 mmol, 35.3% yield) as a white solid. LC-MS: (ESI, m / z): 389.1 [M+H]+.

[0636] Example 71: (R)-2-((7-fluoroquinazolin-4-yl)amino)-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0637] A solution of 4-chloro-7-fluoro-quinazoline (100.0 mg, 0.55 mmol), (2R)-2-amino- 1-[(2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl]propan-1-one hydrochloride (158.3 mg, 0.60 mmol) and N,N-diisopropylethylamine (212.0 mg, 1.64 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °C for 30 minutes. After completion, the reaction mixture was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (64.7 mg, 0.17 mmol, 31.6% yield) as a white solid. LC-MS: (ESI, m / z): 373.1 [M+H]+.

[0638] Example 72: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0639] A solution of 4-chloro-6-(4-fluorophenyl)pyrimidine (80.0 mg, 0.38 mmol), (2R)-2- amino-1-[(2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl]propan-1-one hydrochloride (120.9 mg, crude) and N,N-diisopropylethylamine (148.4 mg, 1.15 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 combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH F-Phenyl OBD column 19*250 mm, 6μm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min;Gradient: 32%B to 54%B in10min; Wave Length: 254 / 220 nm; RT1(min): 9.21 to afford the title compound (34.5 mg, 0.09 mmol, 22.5 % yield) as a white solid. LC-MS: (ESI, m / z): 399.2 [M+H]+.

[0640] Example 73: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2- (difluoromethyl)azetidin-1-yl)propan-1-one Synthetic Route

[0641] Step 1: tert-butyl ((R)-1-((R)-2-(difluoromethyl)azetidin-1-yl)-1-oxopropan-2- yl)carbamate

[0642] A solution of (2R)-2-(difluoromethyl)azetidine hydrochloride (140.0 mg, 0.98 mmol), (tert-butoxycarbonyl)-D-alanine (184.5 mg, 0.98 mmol), N,N-diisopropylethylamine (503.2 mg, 3.9 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (482.0 mg, 1.27 mmol) in dichloromethane (2.0 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (240.0 mg, 0.86 mmol, 88.4% yield) as a yellow solid. LC-MS: (ESI, m / z): 279.1 [M+H]+.

[0643] Step 2: (R)-2-amino-1-((R)-2-(difluoromethyl)azetidin-1-yl)propan-1-one hydrochloride

[0644] A solution of tert-butyl ((R)-1-((R)-2-(difluoromethyl)azetidin-1-yl)-1-oxopropan- 2-yl)carbamate (220.0 mg, 0.79 mmol) in hydrochloric acid (4.0 mL, 4 mol / L in 1,4-dioxane) was stirred at 25 °C for 2 hours. After completion, the solvent was concentrated under vacuum to afford the title compound (160.0 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 179.1 [M+H]+.

[0645] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-2-(difluoromethyl)azetidin- 1-yl)propan-1-one

[0646] A solution of (R)-2-amino-1-((R)-2-(difluoromethyl)azetidin-1-yl)propan-1-one hydrochloride (70.0 mg, crude), 4,7-dichloroquinazoline (58.4 mg, 0.29 mmol) and N,N- diisopropylethylamine (168.3 mg, 1.31 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 100 °C for 0.5 hours. After completion, the reaction mixture was purified by flash chromatography on C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (39.4 mg, 0.12 mmol, 35.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 341.1 [M+H]+.

[0647] Example 74: (R)-1-((R)-2-(difluoromethyl)azetidin-1-yl)-2-((7- (trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0648] A solution of (R)-2-amino-1-((R)-2-(difluoromethyl)azetidin-1-yl)propan-1-one hydrochloride (70.0 mg, crude), 4-chloro-7-(trifluoromethoxy)quinazoline (78.1 mg, 0.31 mmol) and N,N-diisopropylethylamine (180.1 mg, 1.41 mmol) in dimethyl sulfoxide (1.0 mL) was stirred at 100 °C for 0.5 hours. After completion, the reaction mixture was purified by flash chromatography on C18gel eluting with (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (35.1 mg, 0.09 mmol, 25.8% yield) as a white solid. LC-MS: (ESI, m / z): 391.0 [M+H]+.

[0649] Example 75: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3S)-3-ethoxy-2- methylazetidin-1-yl)propan-1-one Synthetic Route

[0650] Step 1: (2S,3S)-3-ethoxy-2-methylazetidine trifluoroacetic

[0651] A solution of tert-butyl (2S,3S)-3-ethoxy-2-methyl-azetidine-1-carboxylate (100.0 mg, 0.46 mmol) in trifluoroacetic acid (0.3 mL) and dichloromethane (0.9 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (125.6 mg, crude) as a yellow solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 116.1 [M+H]+.

[0652] Step 2: tert-butyl ((R)-1-((2S,3S)-3-ethoxy-2-methylazetidin-1-yl)-1-oxopropan-2- yl)carbamate

[0653] A solution of (2S,3S)-3-ethoxy-2-methylazetidine trifluoroacetic (60.8 mg, crude), N,N-diisopropylethylamine (0.1 mL, 1.06 mmol), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (50.0 mg, 0.26 mmol) and 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (130.5 mg, 0.34 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (70.0 mg, 0.24 mmol, 92.5% yield) as a yellow solid. LC- MS: (ESI, m / z): 287.2 [M+H]+.

[0654] Step 3: (R)-2-amino-1-((2S,3S)-3-ethoxy-2-methylazetidin-1-yl)propan-1-one hydrochloride

[0655] A solution of tert-butyl ((R)-1-((2S,3S)-3-ethoxy-2-methylazetidin-1-yl)-1- oxopropan-2-yl)carbamate (60.0 mg, 0.21 mmol) in hydrochloric acid / 1,4-dioxane (1.0 mL, 4M) was stirred at 25 °C for 0.5 hour. After completion, the solvent was removed under vacuum to afford the title compound (52.5 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 186.1 [M+H]+.

[0656] Step 4: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3S)-3-ethoxy-2- methylazetidin-1-yl)propan-1-one

[0657] A solution of 4,7-dichloroquinazoline (40.0 mg, 0.20 mmol), (R)-2-amino-1- ((2S,3S)-3-ethoxy-2-methylazetidin-1-yl)propan-1-one hydrochloride (37.4 mg, crude) and N,N- diisopropylethylamine (0.1 mL, 0.60 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °C for 0.5 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 the product. The product was further purified by Prep- HPLC with the following conditions: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 31%B to 47%B in10 min; Wave Length: 254 / 220 nm; RT1(min): 7.83 to afford the title compound (28.1 mg, 0.08 mmol, 39.8% yield) as a white solid. LC-MS: (ESI, m / z): 349.1 [M+H]+.

[0658] Example 76: (R)-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0659] A solution of 4-chloro-6-(4-fluorophenyl)pyrimidine (80.0 mg, 0.38 mmol), (R)-2- amino-1-((2S,4R)-4-fluoro-2-methylpyrrolidin-1-yl)propan-1-one hydrochloride (80.7 mg, 0.38 mmol) and N,N-diisopropylethylamine (247.8 mg, 1.92 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 1 hour. After completion, the solvent was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (41.0 mg, 0.11 mmol, 30.7% yield) as a white solid. LC-MS: (ESI, m / z): 347.2 [M+H]+.

[0660] Example 77: (R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-2-((6- (trifluoromethyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0661] Under nitrogen, to a solution of (R)-2-amino-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (103.4 mg, crude) and N,N- diisopropylethylamine (212.4 mg, 1.64 mmol) in dimethyl sulfoxide (0.5 mL) was added 4-chloro- 6-(trifluoromethyl)pyrimidine (60.0 mg, 0.33 mmol). The resulting solution was stirred for 1 hour at 100 ºC. After completion, the mixture was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (86.8 mg, 0.23 mmol, 70.8% yield) as a white solid. LC-MS: (ESI, m / z): 373.1 [M+H]+.

[0662] Example 78: (R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-2-((2- methyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0663] Under nitrogen, to a solution of (R)-2-amino-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (96.2 mg, 0.37 mmol) and N,N- diisopropylethylamine (197.2 mg, 1.53 mmol) in dimethyl sulfoxide (0.5 mL) was added 4-chloro- 2-methyl-6-(trifluoromethyl)pyrimidine (60.0 mg, 0.31 mmol) at room temperature. The mixture was stirred 1 hour at 100 ºC. After completion, the mixture was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (59.4 mg, 0.15 mmol, 50.3% yield) as a white solid. LC-MS: (ESI, m / z): 387.1 [M+H]+.

[0664] Example 79: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,4R)-2-methyl-4- (trifluoromethoxy)pyrrolidin-1-yl)propan-1-one Synthetic Route

[0665] Under nitrogen, to a solution of (R)-2-amino-1-((2S,4R)-2-methyl-4- (trifluoromethoxy)pyrrolidin-1-yl)propan-1-one hydrochloride (83.4 mg, crude) and N,N- diisopropylethylamine (194.8 mg, 1.51 mmol) in dimethyl sulfoxide (0.5 mL) was added 4,7- dichloroquinazoline (60.0 mg, 0.30 mmol) and the mixture was stirred for 0.5 hour at 100 ºC. After completion, the mixture was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (62.7 mg, 0.15 mmol, 51.3% yield) as an off- white solid. LC-MS: (ESI, m / z): 403.1 [M+H]+.

[0666] Example 80: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-3-fluoro-3- methylpyrrolidin-1-yl)propan-1-one Synthetic Route

[0667] Step 1: tert-butyl ((R)-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)-1-oxopropan-2- yl)carbamate

[0668] A solution of (3S)-3-fluoro-3-methyl-pyrrolidine hydrochloride (201.5 mg, 1.45 mmol), (2R)-2-(tert-butoxycarbonylamino)propanoic acid (302.6 mg, 1.60 mmol), N,N- diisopropylethylamine (750.7 mg, 5.82 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (829.4 mg, 2.18 mmol) in dichloromethane (2 mL) was stirred at 25°C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the title compound (212.0 mg, 0.77 mmol, 53.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 275.2 [M+H]+.

[0669] Step 2: (R)-2-amino-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)propan-1-one hydrochloride

[0670] A solution of tert-butyl ((R)-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)-1-oxopropan- 2-yl)carbamate (200.0 mg, 0.73 mmol) in hydrochloric acid / 1,4-dioxane (3 mL, 4 M) was stirred at 25 °C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (168.9 mg, crude) as a white solid. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 175.1 [M+H]+.

[0671] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-3-fluoro-3-methylpyrrolidin- 1-yl)propan-1-one

[0672] A solution of (R)-2-amino-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)propan-1-one hydrochloride (84.0 mg, 0.40 mmol), N,N-diisopropylethylamine (207.7 mg, 1.61 mmol) and 4,7- dichloroquinazoline (79.9 mg, 0.40 mmol) in dimethyl sulfoxide (0.4 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% NH4HCO3in water) to afford the title compound (66.9 mg, 0.19 mmol, 49.4% yield) as a white solid. LC-MS: (ESI, m / z): 337.1 [M+H]+.

[0673] Example 81: (R)-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0674] A solution of (2R)-2-amino-1-[(3S)-3-fluoro-3-methyl-pyrrolidin-1-yl]propan-1- one hydrochloride (71.4 mg, 0.34 mmol), N,N-diisopropylethylamine (173.4 mg, 1.34 mmol) and 4- chloro-6-(4-fluorophenyl)pyrimidine (70.0 mg, 0.34 mmol) in dimethyl sulfoxide (0.4 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% NH4HCO3in water) to afford the title compound (47.3 mg, 0.13 mmol, 40.7% yield) as a white solid. LC-MS: (ESI, m / z): 347.1 [M+H]+.

[0675] Example 82: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3R)-3-ethoxy-2- methylazetidin-1-yl)propan-1-one Synthetic Route

[0676] Step 1: tert-butyl (2S,3R)-3-ethoxy-2-methylazetidine-1-carboxylate

[0677] To a solution of tert-butyl (2S,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (1.00 g, 5.34 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (640.9 mg, 16.02 mmol, 60% dispersion in mineral oil) and the mixture was stirred at 0 °C for 10 minutes. Then, iodoethane (2.50 g, 16.02 mmol) was slowly added and stirred at 25 °C for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried overanhydrous 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 (1.00 g, 4.64 mmol, 86.9% yield) as a colorless oil. LC-MS: (ESI, m / z): 216.2 [M+H]+.

[0678] Step 2: (2S,3R)-3-ethoxy-2-methylazetidine trifluoroacetate

[0679] A solution of tert-butyl (2S,3R)-3-ethoxy-2-methylazetidine-1-carboxylate (600.0 mg, 2.79 mmol) in trifluoroacetic acid (4 mL) and dichloromethane (12 mL) was stirred at 25 °C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (650.0 mg, crude) as a yellow oil. The crude product was directly used in the next step without purification. LC-MS: (ESI, m / z): 116.1 [M+H]+.

[0680] Step 3: tert-butyl ((R)-1-((2S,3R)-3-ethoxy-2-methylazetidin-1-yl)-1-oxopropan-2- yl)carbamate

[0681] A solution of (2S,3R)-3-ethoxy-2-methylazetidine trifluoroacetate (580 mg, crude), (tert-butoxycarbonyl)-D-alanine (1478.5 mg, 7.81 mmol), N,N-diisopropylethylamine (4.04 g, 31.3 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.38 g, 6.25 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:1) to afford the title compound (780.0 mg, 2.72 mmol, 52.3% yield) as a yellow solid. LC-MS: (ESI, m / z): 287.2 [M+H]+.

[0682] Step 4: (R)-2-amino-1-((2S,3R)-3-ethoxy-2-methylazetidin-1-yl)propan-1-one hydrochloride

[0683] A solution of tert-butyl ((R)-1-((2S,3R)-3-ethoxy-2-methylazetidin-1-yl)-1- oxopropan-2-yl)carbamate (95.0 mg, 0.33 mmol) in 4 M hydrochloric acid in 1,4-dioxane (3 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated under vacuum to afford the title compound (100.5 mg, crude) as a white solid. The crude product was directly used in the next step without purification.LC-MS: (ESI, m / z):187.1 [M+H]+.

[0684] Step 5: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3R)-3-ethoxy-2- methylazetidin-1-yl)propan-1-one

[0685] A solution of (R)-2-amino-1-((2S,3R)-3-ethoxy-2-methylazetidin-1-yl)propan-1- one hydrochloride (100.5 mg, crude), 4,7-dichloroquinazoline (134.7 mg, 0.68 mmol) and N,N- diisopropylethylamine (349.9 mg, 2.71 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, 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 titlecompound (48.4 mg, 0.14 mmol, 38.6% yield) as an off-white solid. LC-MS: (ESI, m / z): 349.1 [M+H]+.

[0686] Example 83a: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-1-oxa-6- azaspiro[3.4]octan-6-yl)propan-1-one

[0687] Example 83b: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-1-oxa-6- azaspiro[3.4]octan-6-yl)propan-1-one Synthetic Route

[0688] Step 1: tert-butyl ((2R)-1-oxo-1-(1-oxa-6-azaspiro[3.4]octan-6-yl)propan-2- yl)carbamate

[0689] To a solution of 1-oxa-6-azaspiro[3.4]octane hemioxalate (179.4 mg, 1.59 mmol), tert-butoxycarbonyl)-D-alanine (250.0 mg, 1.32 mmol) and N,N-diisopropylethylamine (512.2 mg, 3.96 mmol) in dichloromethane (2.00 mL) was added 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (753.6 mg, 1.98 mmol), the mixture was stirred at 25 °C for 1 hour. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (84:16) to afford the title compound (300.0 mg, 1.05 mmol, 79.8% yield) as a yellow solid. LC-MS: (ESI, m / z): 285.1 [M+H]+.

[0690] Step 2: (2R)-2-amino-1-(1-oxa-6-azaspiro[3.4]octan-6-yl)propan-1-one trifluoroacetate

[0691] A mixture of tert-butyl ((2R)-1-oxo-1-(1-oxa-6-azaspiro[3.4]octan-6-yl)propan-2- yl)carbamate (290.0 mg, 0.04 mmol) and 5% trifluoroacetic acid in 1,1,1,3,3,3-hexafluoro-2- propanol (3 mL) was stirred at 25 °C for 1 hour. After completion, the solvent was removed under vacuum to afford the title compound (200 mg, 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]+.

[0692] Step 3: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((R)-1-oxa-6-azaspiro[3.4]octan- 6-yl)propan-1-one & (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((S)-1-oxa-6-azaspiro[3.4]octan-6- yl)propan-1-one

[0693] Under nitrogen, a solution of (2R)-2-amino-1-(1-oxa-6-azaspiro[3.4]octan-6- yl)propan-1-one trifluoroacetate (84.0 mg, crude), N,N-diisopropylethylamine (115.3 mg, 0.89 mmol) and 4,7-dichloroquinazoline (59.2 mg, 0.30 mmol) in acetonitrile (0.30 mL) was stirred at 60 °C for 30 minutes. After completion, the solvent was removed under vacuum. The resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the mixture of the title compounds. The title Compounds 83a and 83b were isolated by Chiral-Prep-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SZ 250 *20mm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RT1(min): 9.129; RT2(min): 11.573; Sample Solvent: EtOH--HPLC; Injection Volume: 1.0 mL to afford 83a (38.6 mg, 0.11 mmol, 37.0% yield) as a white solid and 83b (32.1 mg, 0.09 mmol, 30.9% yield) as a white solid.

[0694] Example 84: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3R)-2-methyl-3-(2,2,2- trifluoroethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0695] Step 1: tert-butyl (2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate

[0696] To a mixture of tert-butyl (2S,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (2.00 g, 6.86 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (0.82 g, 20.59 mmol, 60% dispersion in mineral oil), the mixture was stirred at 0 ºC for 0.5 hours. Then 2,2,2- trifluoroethyl trifluoromethanesulfonate (2.55 g, 10.98 mmol) was added and stirred at 0 °C for 12 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 (8:2) to afford to afford the title compound (720 mg, 2.67 mmol, 39.0% yield) as a colorless oil. LC-MS: (ESI, m / z): 270.1 [M+H]+.

[0697] Step 2: (2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidine trifluoroacetate

[0698] A mixture of tert-butyl (2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidine-1- carboxylate (700.0 mg, 1.91 mmol) in trifluoroacetic acid (4.0 mL) and dichloromethane (4.0 mL) was stirred at 25 °C for 0.5 hours. The solution was concentrated in vacuum. After completion, the solvent was removed under vacuum to afford the title compound (440 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 268.0[M+H]+.

[0699] Step 3: tert-butyl ((R)-1-((2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidin-1-yl)- 1-oxopropan-2-yl)carbamate

[0700] A mixture of (2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidine trifluoroacetate (440.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (342.8 mg, 1.81 mmol), 2-(7-azabenzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (939.3 mg, 2.47 mmol) and N,N- Diisopropylethylamine (637.3 mg, 4.94 mmol) in dichloromethane (5 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 (1:1) to afford the title compound (520.0 mg, 1.53 mmol, 92.8% yield) as a colorless oil. LC-MS: (ESI, m / z): 341.1[M+H]+.

[0701] Step 4: (R)-2-amino-1-((2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidin-1- yl)propan-1-one trifluoroacetate

[0702] A mixture of tert-butyl ((R)-1-((2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidin- 1-yl)-1-oxopropan-2-yl)carbamate (190.0 mg, 0.43 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (1 mL) was stirred at 25 °C for 0.5 hours. After completion, the solvent was removed under vacuum to afford the title compound (190 mg, crude) as a yellow oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 241.1[M+H]+.

[0703] Step 5: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3R)-2-methyl-3-(2,2,2- trifluoroethoxy)azetidin-1-yl)propan-1-one

[0704] A solution of (R)-2-amino-1-((2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidin-1- yl)propan-1-one trifluoroacetate (186.94 mg, crude), N,N-Diisopropylethylamine (178.24 mg, 1.38 mmol) and 4,7-dichloroquinazoline (55.0 mg, 0.28 mmol) in dimethyl sulfoxide (0.3 mL) was stirred at 100 °C for 0.5 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 resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (43.1 mg, 0.11 mmol, 38.7% yield) as a white solid. LC-MS: (ESI, m / z): 403.0[M+H]+.

[0705] Example 85: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3R)-2- methyl-3-(2,2,2-trifluoroethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0706] A solution of (R)-2-amino-1-((2S,3R)-2-methyl-3-(2,2,2-trifluoroethoxy)azetidin-1- yl)propan-1-one trifluoroacetate (138.1 mg, crude), N,N-diisopropylethylamine (185.5 mg, 1.44 mmol) and 4-chloro-6-(4-fluorophenyl)pyrimidine (60.0 mg, 0.29 mmol) in dimethyl sulfoxide (0.3 mL) was stirred at 100 °C for 0.5 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 resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (28.2 mg, 0.05 mmol, 19.2% yield) as a white solid.LC-MS: (ESI, m / z): 413.2 [M+H]+.

[0707] Example 86: (R)-2-((7-methoxyquinazolin-4-yl)amino)-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route:

[0708] A solution of 4-chloro-7-methoxy-quinazoline (60.0 mg, 0.31 mmol), (2R)-2- amino-1-[(2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl]propan-1-one hydrochloride (81.0 mg, crude) and N,N-diisopropylethylamine (158.7 mg, 1.23 mmol) in dimethyl sulfoxide (0.3 mL) was stirred at 100 °C for 0.5 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 resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (38.2 mg, 0.10 mmol, 31.9% yield) as a white solid. LC-MS: (ESI, m / z): 385.1 [M+H]+.

[0709] Example 87: (R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-2-((7- methylquinazolin-4-yl)amino)propan-1-one Synthetic Route:

[0710] A solution of 4-chloro-7-methyl-quinazoline (60.0 mg, 0.34 mmol), (2R)-2-amino- 1-[(2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl]propan-1-one hydrochloride (88.2 mg, crude) and N,N-diisopropylethylamine (172.9 mg, 1.34 mmol) in dimethyl sulfoxide (0.3 mL) was stirred at 100 °C for 0.5 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 resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (25.9 mg, 0.07 mmol, 20.9% yield) as a white solid. LC-MS: (ESI, m / z): 369.1 [M+H]+.

[0711] Example 88: (R)-2-((6-(5-chloropyridin-2-yl)pyrimidin-4-yl)amino)-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route:

[0712] Step 1: 4-chloro-6-(5-chloropyridin-2-yl)pyrimidine

[0713] Under nitrogen, a solution of 4,6-dichloropyrimidine (200.0 mg, 1.34 mmol), 5- chloro-2-(tributylstannyl)pyridine (486.5 mg, 1.21 mmol), tetrakis(triphenylphosphine)palladium (155.2 mg, 0.13 mmol) and cuprous iodide (51.0 mg, 0.27 mmol) in toluene (5 mL) was stirred at 110 °C for 3 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 residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (5:1) to afford the title compound (140 mg, 0.56 mmol, 41.5% yield) as a colorless oil. LC-MS: (ESI, m / z): 226.0 [M+H]+.

[0714] Step 2: (R)-2-((6-(5-chloropyridin-2-yl)pyrimidin-4-yl)amino)-1-((2S,3S)-2-methyl- 3-(trifluoromethoxy)azetidin-1-yl)propan-1-one

[0715] To a solution of 4-chloro-6-(5-chloropyridin-2-yl)pyrimidine (90.0 mg, 0.40 mmol) in dimethyl sulfoxide (0.50 mL) was added ((R)-2-amino-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (104.6 mg, 0.40 mmol) and N,N- diisopropylethylamine (0.21 mL, 1.19 mmol), the mixture was stirred at 100 °C for 0.5 hours. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (32.5 mg, 0.08 mmol, 19.4% yield) as a white solid. LC-MS: (ESI, m / z): 416.2 [M+H]+.

[0716] Example 89: (R)-2-((6-(5-chloropyridin-2-yl)-2-methylpyrimidin-4-yl)amino)-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route:

[0717] Step 1: 4-chloro-6-(5-chloropyridin-2-yl)-2-methylpyrimidine

[0718] Under nitrogen, a solution of 4,6-dichloro-2-methylpyrimidine (300.0 mg, 1.84 mmol), 5-chloro-2-(tributylstannyl)pyridine (666.9 mg, 1.66 mmol), tetrakis(triphenylphosphine)palladium (212.8 mg, 0.18 mmol) and cuprous iodide (69.9 mg, 0.37 mmol) in toluene (5 mL) was stirred at 110 °C for 3 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 residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (5:1) to afford the title compound (180.0 mg, 0.74 mmol, 40.3% yield) as a colorless oil. LC-MS: (ESI, m / z): 240.0 [M+H]+.

[0719] Step 2: (R)-2-((6-(5-chloropyridin-2-yl)-2-methylpyrimidin-4-yl)amino)-1-((2S,3S)- 2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one

[0720] A solution of 4-chloro-6-(5-chloropyridin-2-yl)-2-methylpyrimidine (90.0 mg, 0.37 mmol), (R)-2-amino-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (98.5 mg, 0.37 mmol) and N,N-diisopropylethylamine (145.3 mg, 1.12 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 °C for 0.5 hours. After completion, the resultingresidue was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (40.1 mg, 0.09 mmol, 23.9% yield) as a white solid. LC-MS: (ESI, m / z): 430.2 [M+H]+.

[0721] Example 90: (R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-2-((6-(3- (trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route:

[0722] Step 1: (R)-2-((6-bromopyrimidin-4-yl)amino)-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one

[0723] Under nitrogen, a solution of (R)-2-amino-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (500.0 mg, 1.90 mmol), N,N- diisopropylethylamine (1.23 g, 9.52 mmol) and 4-bromo-6-fluoro-pyrimidine (370.6 mg, 2.09 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100 ºC for 1 hour. After completion, the resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (667.0 mg, 1.57 mmol, 82.3% yield) as a white solid. LC-MS: (ESI, m / z): 383.0 & 385.0 [M+H]+.

[0724] Step 2: (R)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)-2-((6-(3- (trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)amino)propan-1-one

[0725] Under nitrogen, a solution of (R)-2-((6-bromopyrimidin-4-yl)amino)-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one (100.0 mg, 0.26 mmol), 3- (trifluoromethyl)azetidine; hydrochloride (253.0 mg, 1.57 mmol), Pd-PEPPSI-IPentCl o-picoline (21.9 mg, 0.03 mmol) and cesium carbonate (680.6 mg, 2.09 mmol) in 1,4-dioxane (1 mL) was stirred at 100 °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 overanhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 31% B to 46% B in 13 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.33 to afford the title compound (48.4 mg, 0.11 mmol, 43.4% yield) as a white solid. LC-MS: (ESI, m / z): 428.3 [M+H]+.

[0726] Example 91: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-3-hydroxy-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0727] Step 1: tert-butyl ((R)-3-hydroxy-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin- 1-yl)-1-oxopropan-2-yl)carbamate

[0728] A solution of (tert-butoxycarbonyl)-D-serine (500.0 mg, 2.44 mmol), (2S,3S)-2- methyl-3-(trifluoromethoxy)azetidine hydrochloride (466.8 mg, 2.44 mmol), N,N- diisopropylethylamine (942.9 mg, 7.31 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (1.39 g, 3.65 mmol) in dichloromethane (5 mL) was stirred at 25 ºC for 2 hours. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to afford the title compound (450 mg, 1.31 mmol, 54.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 343.2 [M+H]+

[0729] Step 2: (R)-2-amino-3-hydroxy-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin- 1-yl)propan-1-one hydrochloride

[0730] A solution of tert-butyl ((R)-3-hydroxy-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)-1-oxopropan-2-yl)carbamate (135.0 mg, 0.39 mmol) in hydrochloric acid (3 mL, 4 mol / L in 1,4-dioxane) was stirred at 25 ºC for 2 hours. After completion, the solvent was concentrated under vacuum to afford (R)-2-amino-3-hydroxy-1-((2S,3S)-2-methyl- 3-(trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (100 mg, crude) as a white solid. Thecrude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 243.2 [M+H]+

[0731] Step 3: (R)-2-((6-(4-fluorophenyl)pyrimidin-4-yl)amino)-3-hydroxy-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one

[0732] Under nitrogen, a solution of (R)-2-amino-3-hydroxy-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (80.0 mg, 0.29 mmol), 4-chloro-6-(4- fluorophenyl)pyrimidine (59.9 mg, 0.29 mmol) and N,N-diisopropylethylamine (185.2 mg, 1.44 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 ºC for 1.5 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 C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (27.7 mg, 0.07 mmol, 23.3% yield) as a white solid. LC-MS: (ESI, m / z): 415.0 [M+H]+

[0733] Example 92: (R)-2-((5-fluoro-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)- 2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0734] Step 1: (R)-2-((6-chloro-5-fluoropyrimidin-4-yl)amino)-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one

[0735] A solution of (R)-2-amino-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl)propan-1-one hydrochloride (100.0 mg, 0.38 mmol), 4,6-dichloro-5-fluoropyrimidine (63.6 mg, 0.38 mmol) and N,N-diisopropylethylamine (246.0 mg, 1.90 mmol) in dimethyl sulfoxide (0.5 mL) was stirred at 100 ºC 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 residue was purified by flash chromatography on silica geleluting with petroleum ether / ethyl acetate (73:27) to afford the title compound (110.0 mg, 0.30 mmol, 79.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 357.1 [M+H]+.

[0736] Step 2: (R)-2-((5-fluoro-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one

[0737] Under nitrogen, a solution of (R)-2-((6-chloro-5-fluoropyrimidin-4-yl)amino)-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one (100.0 mg, 0.28 mmol), (4- fluorophenyl)boronic acid (78.5 mg, 0.56 mmol), XPhos Pd G2 (22.1 mg, 0.03 mmol) and potassium phosphate (178.5 mg, 0.84 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL) was stirred at 25 ºC for 2 hours. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layers were combined, 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 (72:28) 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 μm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 43% B to 58% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 7.72 to afford the title compound (35.2 mg, 0.08 mmol, 30.1% yield) as a white solid. LC-MS: (ESI, m / z): 417.1 [M+H]+.

[0738] Example 93: (R)-2-((6-(3-fluorobicyclo[1.1.1]pentan-1-yl)pyrimidin-4-yl)amino)- 1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0739] Step 1: 5-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-2,2-dimethyl-1,3-dioxane-4,6- dione

[0740] To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (2.33 g, 16.14 mmol) in dichloromethane (15 mL) was added 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (2.00 g, 15.37 mmol) and 4-dimethylaminopyridine (3.00 g, 24.59 mmol) at 0 °C and stirred for 10 min. Then 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.39 g, 17.68 mmol) in dichloromethane (15 mL) was added dropwise at 0 °C and stirred at 25 °C for 1 hour. After completion, the reaction was diluted with dichloromethane, washed with 1M hydrochloric acid and water, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% FA in water) to afford the title compound (3.02 g, 10.77 mmol, 70.1% yield) as a colorless oil. LC-MS: (ESI, m / z): 255.1 [M-H]+

[0741] Step 2: ethyl 3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-3-oxopropanoate

[0742] A solution of 5-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.30 g 5.07 mmol) in ethanol (10 mL) was stirred at 80 °C for 1 hour. After completion, the crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 201.1 [M+H]+

[0743] Step 3: 6-(3-fluorobicyclo[1.1.1]pentan-1-yl)pyrimidin-4-ol

[0744] To a solution of ethyl 3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-3-oxopropanoate (crude) in ethanol (10 mL) was added formimidamide hydrochloride (542.9 mg, 6.74 mmol) and 1,8- diazabicyclo[5,4,0]-7-undecene (3.42 g, 22.48 mmol), the mixture was stirred at 80 °C for 1 hour. After completion, the residue was purified by flash chromatography on reverse-phase column eluting with 0.1% FA in water / acetonitrile (9:1) to afford the title compound (1.70 g, 3.77 mmol, 84.0% yield) as a light yellow oil. LC-MS: (ESI, m / z): 181.1[M+H]+

[0745] Step 4: 4-chloro-6-(3-fluorobicyclo[1.1.1]pentan-1-yl)pyrimidine

[0746] A solution of 6-(3-fluorobicyclo[1.1.1]pentan-1-yl)pyrimidin-4-ol (700.0 mg, 1.55 mmol), N,N-dimethylformamide (11.4 mg, 0.16 mmol) and phosphorus oxychloride (1.19 g, 7.77 mmol) in toluene (8 mL) was stirred at 80 °C for 25 minutes. After completion, the reaction mixture was concentrated under vacuum and diluted with dichloromethane. The resulting mixture was quenched with sodium bicarbonate saturated solution, extracted with dichloromethane and the organic layers were combined. The organic layers were 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 (98 / 2) to afford the title compound (170.2 mg, 0.71 mmol, 45.7% yield) as a yellow oil. LC-MS: (ESI, m / z): 199.0[M+H]+

[0747] Step 5: (R)-2-((6-(3-fluorobicyclo[1.1.1]pentan-1-yl)pyrimidin-4-yl)amino)-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one

[0748] A solution of (R)-2-amino-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl)propan-1-one hydrochloride (66.4 mg, 0.25 mmol), 4-chloro-6-(3-fluorobicyclo[1.1.1]pentan-1- yl)pyrimidine (55.0 mg, 0.23 mmol) and N,N-diisopropylethylamine (118.8 mg, 0.92 mmol) in dimethyl sulfoxide (1 mL) was stirred at 100 °C for 2 hours. After completion, the reaction mixture was purified by flash chromatography on reverse-phase column eluting with 0.1% NH4HCO3in water / acetonitrile (7:3) to afford product. The product was further purified by Prep-HPLC with the following conditions: Column: Xselect CSH PBD Column. 30*150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10% B to 25% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 10.45 to afford the title compound (30.9 mg, 0.08 mmol, 34.4% yield) as an off-white solid. LC-MS: (ESI, m / z): 389.1 [M+H]+

[0749] Example 94: (R)-2-((6-(4-chlorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0750] A solution of (R)-2-amino-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl)propan-1-one hydrochloride (100.0 mg, 0.38 mmol), 4-chloro-6-(4-chlorophenyl)pyrimidine (128.5 mg, 0.57 mmol) and N,N-diisopropylethylamine (246.0 mg, 1.90 mmol) in dimethyl sulfoxide (0.50 mL) was stirred at 100 ºC for 1 hour. After completion, the solution was purified by reverse phase chromatography (acetonitrile / 0.1% ammonium bicarbonate in water) to afford (R)-2-((6-(4- chlorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl)propan-1-one (34.8 mg, 0.08 mmol, 22.0% yield) as a white solid. LC-MS: (ESI, m / z): 415.1 [M+H]+.

[0751] Example 95: (R)-3-hydroxy-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1- yl)-2-((7-(trifluoromethoxy)quinazolin-4-yl)amino)propan-1-one Synthetic Route

[0752] A solution of (R)-2-amino-3-hydroxy-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (61.5 mg, crude), 4-chloro-7- (trifluoromethoxy)quinazoline (50.0 mg, 0.20 mmol) and N,N-diisopropylethylamine (130.0 mg, 1.01 mmol) in dimethyl sulfoxide (0.50 mL) was stirred at 100 ºC for 0.5 hours. The solution was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (35.8 mg, 0.08 mmol, 38.8% yield) as a white solid. LC-MS: (ESI, m / z): 455.1 [M+H]+.

[0753] Example 96: (R)-2-((5-fluoro-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-3-hydroxy- 1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route

[0754] Step 1: (R)-2-((6-chloro-5-fluoropyrimidin-4-yl)amino)-3-hydroxy-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one

[0755] A solution of (R)-2-amino-3-hydroxy-1-((2S,3S)-2-methyl-3- (trifluoromethoxy)azetidin-1-yl)propan-1-one hydrochloride (110.0 mg, crude), N,N-diisopropylethylamine (255.0 mg, 1.97 mmol) and 4,6-dichloro-5-fluoropyrimidine (79.0 mg, 0.47 mmol) in acetonitrile (2 mL) was stirred at 80 °C for 2 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 flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (100.0 mg, 0.26 mmol, 68.0% yield) as a white solid. LC-MS: (ESI, m / z): 373.1 [M+H]+

[0756] Step 2: (R)-2-((5-fluoro-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-3-hydroxy-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one

[0757] Under nitrogen, a solution of (R)-2-((6-chloro-5-fluoropyrimidin-4-yl)amino)-3- hydroxy-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one (100.0 mg, 0.27 mmol), (4-fluorophenyl)boronic acid (75.0 mg, 0.54 mmol), potassium phosphate (170.8 mg, 0.80 mmol) and XPhos Pd G2(21.1 mg, 0.03 mmol) in tetrahydrofuran (2 mL) and water (0.4 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 resulting residue was purified by reverse phase chromatography (acetonitrile / 0.1% NH4HCO3in water) to afford the title compound (33.3 mg, 0.07 mmol, 28.5% yield) as a white solid. LC-MS: (ESI, m / z): 433.1 [M+H]+

[0758] Example 97: (R)-2-((6-(4-chlorophenyl)-5-fluoropyrimidin-4-yl)amino)-1-((2S,3S)- 2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route:

[0759] Under nitrogen, a solution of (R)-2-((6-chloro-5-fluoropyrimidin-4-yl)amino)-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one (70.0 mg, 0.20 mmol), 4- chlorophenylboronicacid (61.4 mg, 0.39 mmol), XPhos Pd G2 (15.4 mg, 0.02 mmol) and potassium phosphate (124.8 mg, 0.59 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL) was stirred at 25 °Cfor 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 crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 49% B to 62% B in 7 min; Wave Length: 254nm / 220nm; RT1(min): 7.83 to afford the title compound (23.1 mg, 0.053 mmol, 27.2% yield) as a white solid. LC-MS: (ESI, m / z): 433.1 [M+H]+.

[0760] Example 98: (R)-2-((6-(3,4-difluorophenyl)-5-fluoropyrimidin-4-yl)amino)-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route:

[0761] Under nitrogen, a solution of (R)-2-((6-chloro-5-fluoropyrimidin-4-yl)amino)-1- ((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one (70.0 mg, 0.20 mmol), 2-(3,4- difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (94.2 mg, 0.39 mmol), XPhos Pd G2 (15.4 mg, 0.02 mmol) and potassium phosphate (124.8 mg, 0.59 mmol) in tetrahydrofuran (2 mL) and water (0.4 mL) 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 crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water(10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 40% B to 55% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 11.65 to afford the title compound (50.9 mg, 0.11 mmol, 58.4% yield) as a white solid. LC-MS: (ESI, m / z): 435.1 [M+H]+.

[0762] Example 99a: (R)-4,4-difluoro-2-((5-fluoro-6-(4-fluorophenyl)pyrimidin-4- yl)amino)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)butan-1-one

[0763] Example 99b: (S)-4,4-difluoro-2-((5-fluoro-6-(4-fluorophenyl)pyrimidin-4- yl)amino)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)butan-1-one Synthetic Route

[0764] Step 1: 4-chloro-5-fluoro-6-(4-fluorophenyl)pyrimidine

[0765] Under nitrogen, a solution of 4,6-dichloro-5-fluoropyrimidine (1.00 g, 5.99 mmol), 4-fluorophenylboronicacid (921.8 mg, 6.59 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (444.2 mg, 0.60 mmol) and potassium carbonate (2.48 g, 17.97 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred at 100°C 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 ethyl acetate / petroleum ether (1:5) to afford the title compound (769.0 mg, 3.39 mmol, 56.7% yield) as a yellow solid. LC-MS: (ESI, m / z): 227.1 [M+H]+.Step 2: (R)-4,4-difluoro-2-((5-fluoro-6-(4- fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)butan- 1-one & (S)-4,4-difluoro-2-((5-fluoro-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)butan-1-one

[0767] A solution of 4-chloro-5-fluoro-6-(4-fluorophenyl)pyrimidine (160.0 mg, 0.71 mmol), N,N-diisopropylethylamine (455.3 mg, 3.53 mmol) and 2-amino-4,4-difluoro-1-[(2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl]butan-1-one (292.5 mg, 1.06 mmol) in dimethyl sulfoxide (1mL) 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 residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane(1:20) to afford the product. The product was further purified by Prep-HPLC with the following conditions (Column: Xselect CSH Prep Fluoro Phenyl Column, 30*150 mm, 5 μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 35% B to 52% B in 10 min; Wave Length: 254 / 220 nm; RT1(min):10.15) to afford the product. The product was separated by Chiral-SFC with the following conditions: Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 100 mL / min; Gradient (B%): isocratic 20% B; RT1(min): 2.7; RT2(min): 4; Sample Solvent: MEOH; Injection Volume: 2 mL to afford (R)-4,4-difluoro-2-((5-fluoro-6-(4- fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)butan- 1-one (31.8 mg, 0.06 mmol, 9.7% yield) as a white solid and (S)-4,4-difluoro-2-((5-fluoro-6-(4- fluorophenyl)pyrimidin-4-yl)amino)-1-((2S,3S)-2-methyl-3-(trifluoromethoxy)azetidin-1-yl)butan- 1-one (27.7 mg, 0.05 mmol, 8.4% yield) as a white solid.

[0768] Example 100: (R)-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one Synthetic Route

[0769] Step 1: tert-butyl ((R)-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)-1-oxopropan-2- yl)carbamate

[0770] A solution of (3S)-3-fluoro-3-methyl-pyrrolidine hydrochloride (201.5 mg, 1.45 mmol), (tert-butoxycarbonyl)-D-alanine (302.6 mg, 1.60 mmol), N,N-diisopropylethylamine (750.7 mg, 5.82 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (829.4 mg, 2.18 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1:20) to afford the title compound (212.0 mg, 0.77 mmol, 53.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 275.2 [M+H]+

[0771] Step 2: (R)-2-amino-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)propan-1-one hydrochloride

[0772] A solution of tert-butyl ((R)-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)-1-oxopropan- 2-yl)carbamate (200.0 mg, 0.73 mmol) in hydrochloric acid / 1,4-dioxane (3 mL, 4 M in 1,4-dioxane)was stirred at 25 °C for 2 hours. After completion, the solvent was removed under vacuum to afford the title compound (150.0 mg, crude) as a yellow solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 175.1 [M+H]+

[0773] Step 3: (R)-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)-2-((6-(4- fluorophenyl)pyrimidin-4-yl)amino)propan-1-one

[0774] A solution of (R)-2-amino-1-((S)-3-fluoro-3-methylpyrrolidin-1-yl)propan-1-one hydrochloride (71.4 mg, crude), N,N-diisopropylethylamine (173.4 mg, 1.34 mmol) and 4-chloro-6- (4-fluorophenyl)pyrimidine (70.0 mg, 0.34 mmol) in dimethyl sulfoxide (0.4 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% ammonium bicarbonate in water) to afford the title compound (47.3 mg, 0.13 mmol, 40.7% yield) as a white solid. LC-MS: (ESI, m / z): 347.0 [M+H]+

[0775] Example 101: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3R)-3-ethoxy-2- methylazetidin-1-yl)propan-1-one Synthetic Route

[0776] Step 1: tert-butyl (2S,3R)-3-ethoxy-2-methylazetidine-1-carboxylate

[0777] To a solution of tert-butyl (2S,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (1.00 g, 5.34 mmol) in tetrahydrofuran (8 mL) was added sodium hydride (640.9 mg, 16.02 mmol, 60% dispersion in mineral oil) and stirred at 0 °C for 10 minutes. Then iodoethane (2.50 g, 16.02 mmol) was slowly added and stirred at 25 °C for 1 hour. After completion, the reaction was quenched withsaturated ammonium chloride solution. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (3:1) to afford the title compound (1.00 g, 4.64 mmol, 87.0% yield) as a colorless oil. LC-MS: (ESI, m / z): 216.2 [M+H]+

[0778] Step 2: (2S,3R)-3-ethoxy-2-methylazetidine trifluoroacetate

[0779] A solution of tert-butyl (2S,3R)-3-ethoxy-2-methylazetidine-1-carboxylate (600.0 mg, 2.79 mmol) in trifluoroacetic acid (4 mL) and dichloromethane (12 mL) was stirred at 25 °C for 30 minutes. After completion, the reaction solution was concentrated under vacuum to afford the title compound (600 mg, crude) as a light brown oil. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 116.1 [M+H]+

[0780] Step 3: tert-butyl ((R)-1-((2S,3R)-3-ethoxy-2-methylazetidin-1-yl)-1-oxopropan-2- yl)carbamate

[0781] A solution of (2S,3R)-3-ethoxy-2-methylazetidine trifluoroacetate (600.0 mg, crude), (tert-butoxycarbonyl)-D-alanine (1.48 g, 7.81 mmol), N,N-diisopropylethylamine (4.04 g, 31.26 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.38 g, 6.25 mmol) in dichloromethane (10 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, washed with water and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (780.0 mg, 2.72 mmol, 52.3% yield) as a yellow solid. LC-MS: (ESI, m / z): 287.2 [M+H]+

[0782] Step 4: (R)-2-amino-1-((2S,3R)-3-ethoxy-2-methylazetidin-1-yl)propan-1-one hydrochloride

[0783] A solution of tert-butyl ((R)-1-((2S,3R)-3-ethoxy-2-methylazetidin-1-yl)-1- oxopropan-2-yl)carbamate (80.0 mg, 0.28 mmol) in hydrochloric acid / 1,4-dioxane (5 mL, 4 M in 1,4-dioxane) was stirred at 25 °C for 0.5 hours. After completion, the reaction was concentrated under vacuum to afford the title compound (100.1 mg, crude) as a yellow solid. The crude product would be directly used in the next step without purification. LC-MS: (ESI, m / z): 187.1 [M+H]+

[0784] Step 5: (R)-2-((7-chloroquinazolin-4-yl)amino)-1-((2S,3R)-3-ethoxy-2- methylazetidin-1-yl)propan-1-one

[0785] Under nitrogen, a solution of (R)-2-amino-1-((2S,3R)-3-ethoxy-2-methylazetidin-1- yl)propan-1-one hydrochloride (100.5 mg, crude), 4,7-dichloroquinazoline (134.7 mg, 0.68 mmol) and N,N-diisopropylethylamine (349.9 mg, 2.71 mmol) in dimethyl sulfoxide (4 mL) was stirred at 100 °C for 0.5 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 driedover anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18 gel (acetonitrile / 0.1% ammonium bicarbonate in water) to afford the title compound (48.4 mg, 0.14 mmol, 30.7% yield) as an off-white solid. LC-MS: (ESI, m / z): 349.1 [M+H]+

[0786] Example 102: (R)-2-((6-(5-fluoropyridin-2-yl)pyrimidin-4-yl)amino)-1-((2S,3S)-2- methyl-3-(trifluoromethoxy)azetidin-1-yl)propan-1-one Synthetic Route:

[0787] Step 1: 4-chloro-6-(5-fluoropyridin-2-yl)pyrimidine

[0788] Under nitrogen, a solution of 4,6-dichloropyrimidine (200.0 mg, 1.34 mmol), tributyl-(5-fluoro-2-pyridyl)stannane (466.6 mg, 1.21 mmol), tetrakis(triphenylphosphine)palladium (155.2mg, 0.13mmol) and cuprous iodide (51.0 mg, 0.27 mmol) in toluene (5 mL) was stirred at 110 °C for 3 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 residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (5:1) to afford the title c...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: ring A 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, each X is each independently H, D, halo, substituted or unsubstituted C1-5alkyl, substituted or unsubstituted C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, -O-C3-6cycloalkyl, -S(O)Ra, or – SO2Ra; wherein Rais -CH3or -(C6H4)CH3; R1is CH3, CH3CH2, CH3OCH2, CF3OCH2, C3-4cycloalkyl, CH2OH, or C1-3haloalkyl; R2is H, D, halo, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; Z1is substituted or unsubstituted 4-9 membered N-heterocycle; and m is 0, 1, 2 or 3.

2. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 1, wherein A is aryl.

3. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 1 or 2, wherein the compound is a compound of Formula (Ia):

4. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 1, wherein A is 5- or 6- membered heteroaryl.

5. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 4, wherein A is 5-membered heteroaryl.

6. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 5, wherein m is 1 or 2.

7. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 6, wherein m is 1.

8. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 6, wherein m is 2.

9. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 7, wherein the compound is a compound of Formula (Ia’):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

10. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 9, wherein each X is independently halo, C1-5haloalkyl, C1-5haloalkoxy, or –O-C3-6cycloalkyl.

11. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 9, wherein each X is independently –Cl, -OCF3, -OCHF2, -CF2, -CF3, or -O-cyclopropyl.

12. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 11, wherein Z1is a substituted 4-9 membered N-heterocycle.

13. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 12, wherein Z1is a substituted 4-6 membered N-heterocycle.

14. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 11, wherein Z1is a substituted or unsubstituted 4-9 membered N-heterocycle, and wherein the substituted or unsubstituted 4-9 membered N-heterocycle further comprises one or more additional heteroatoms selected from O and S.

15. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 12 to 14, wherein the 4-6 membered or 4-9 membered N-heterocycle is substituted with one or more substituents each independently halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl or C1-3haloalkoxy.

16. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 11, wherein Z1is selected from:

17. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 13, wherein Z1is selected from:

18. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 17, wherein Z1is selected from:

19. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 18, wherein R1is CH3, CH3CH2, or CH2OH.

20. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 19, wherein R1is CH3.

21. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 18, wherein R2is H, D, halo, C1-6alkyl, C1-6haloalkyl or C1-6alkoxy.

22. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 21, wherein R2is H, halo or C1-6haloalkyl.

23. A compound of Formula (II)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1is CH3, CH3CH2, C3-4cycloalkyl, C3-4cycloalkyl, CH2OH, or C1-3haloalkyl; R3is H, D, halo, oxo, CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R5is H, halo, oxo, CN, C1-3alkyl, or C1-3haloalkyl; Y is N or CH; Z2is selected from the group consisting of H, CN, haloalkyl, substituted or unsubstituted 6- membered aryl; substituted or unsubstituted C3-8cycloalkyl, 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; Z3is substituted or unsubstituted 4-9 membered N-heterocycle; and R2aand R2bare each independently H, C1-6alkyl, or C1-6haloalkyl.

24. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 23, wherein the compound is a compound of Formula (IIa):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

25. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 24, wherein the compound is a compound of Formula (IIIa):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

26. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 25, wherein the compound is a compound of Formula (II’):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

27. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 23, wherein the compound is a compound of Formula (IIb):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

28. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 27, wherein the compound is a compound of Formula (IVa):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

29. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 28, wherein Z3is a substituted 4-9 membered N-heterocycle.

30. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 29, wherein Z3is a substituted or unsubstituted 4-7 membered N-heterocycle.

31. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer compound of any one of claims 23 to 28, wherein Z3is a substituted or unsubstituted 4-9 membered N- heterocycle, and wherein the substituted or unsubstituted 4-9 membered N-heterocycle further comprises one or more additional heteroatoms selected from O and S.

32. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer compound of claim 31, wherein the substituted or unsubstituted 4-9 membered N-heterocycle further comprises SO2in the N-heterocycle ring.

33. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 28, wherein Z3is selected from:

34. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 30, wherein Z3is selected from:

35. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 34, wherein Z3is selected from:

36. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 33, wherein Z3is selected from:

37. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 36, wherein Z2is selected from the group consisting of substituted or unsubstituted 6- membered aryl, substituted or unsubstituted C3-8cycloalkyl, substituted or unsubstituted 5- or 6- membered heteroaryl, and substituted or unsubstituted 4-8 membered heterocycle.

38. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 37, wherein Z2is phenyl substituted with one or more substituents each independently selected from halo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

39. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 37, wherein Z2is 6-membered heteroaryl substituted with one or more substituents each independently selected from halo, cyano, oxo, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

40. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 39, wherein Z2is pyridyl substituted with one or more substituents each independently selected from halo, cyano, oxo, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

41. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 37, wherein Z2is:, wherein X1is -CH- or -N-; n is 0, 1, 2, 3, or 4 when X1is –CH, and n is 0, 1, 2, or 3 when X1is N; and each R4is independently H, halo, oxo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

42. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 41, wherein Z2is, wherein R4is H, -Cl, -F, or -CF3.

43. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 37, wherein Z2is:, wherein n is 0, 1, 2, or 3; and each R9is independently H, halo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

44. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 38, wherein Z2is: substituted or unsubstituted C3-8cycloalkyl; or substituted or unsubstituted 5- membered heteroaryl comprising 1 or 2 heteroatoms independently selected from N and O.

45. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 44, wherein Z2 is46. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 38, wherein Z2is substituted or unsubstituted 4-8 membered heterocycle.

47. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 39, wherein Z2comprises SO2in the heterocycle ring.

48. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 46, wherein Z2is selected from:

49. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 48, wherein Z2is:, wherein Z is O or CH2; t is 0, 1, or 2; and each R7is independently halo, cyano, C1-6alkyl, C1-6haloalkyl or C1-6haloalkoxy.

50. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 36, wherein: Z2is a 5-membered heteroaryl having two heteroatoms selected from N, S, and O, wherein at least one heteroatom is N; and each 5-membered heteroaryl is optionally substituted with halo, cyano, C1-6alkyl, C1-6haloalkyl, or C1-6haloalkoxy.

51. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 36, wherein: Z2is -N(H)-haloalkoxy or -N(CH3)-haloalkoxy.

52. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 51, wherein R3is H or F.

53. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 52, wherein R3is H.

54. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 52, wherein R3is F.

55. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 23 to 25 and 27 to 54, wherein R5is H or F.

56. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 55, wherein R5is H.

57. The compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of claim 55, wherein R5is F.

58. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 57, and at least one pharmaceutically acceptable excipient.

59. The pharmaceutical composition of claim 58, further comprising an additional therapeutic agent.

60. A method of modulating TMEM175 in a subject, the method comprising administering to the subject: (i) the compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 58.

61. 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 or pharmaceutically acceptable salt, stereoisomer, or tautomer of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof; or (ii) the pharmaceutical composition of claim 58.

62. The method of claim 61, wherein the neurodegenerative disorder is selected from Parkinson’s disease (PD), Parkinsonism, Alzheimer’s disease (AD), dementia (including Lewybody dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age related memory dysfunction, mild cognitive impairment, argyrophilic grain disease, lysosomal disorders, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms / relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV-associated dementia (HAD).

63. The method of claim 62, wherein the neurodegenerative disorder is Parkinson’s disease (PD).

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