Oxazole TRPML1 agonists and uses thereof

Abstract

Described herein are oxazole TRPML1 inhibitors and pharmaceutical compositions containing the inhibitors. The subject compounds and compositions are useful for treating TRPML1-mediated disorders or diseases.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 359,080, filed July 7, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] TRPML1, also known as mucolipin-1, is a ligand-gated cation channel that is expressed predominantly in intracellular organelles such as late endosomes and lysosomes in many mammalian cells. This channel is a member of a large family of transient receptor potential (TRP) channels and has two close homologs in TRPML2 and TRPML3. Loss-of-function mutations in the gene encoding TRPML1 (a 12,000-base-pair gene MCOLN-1 located on human chromosome 19p13) are the direct cause of mucolipidosis type IV (MLIV), an autosomal recessive lysosomal storage disease.

[0003] At the molecular level, TRPML1 is a Ca receptor agonist formed by four sixth transmembrane proteins, each consisting of 580 amino acids. 2+ TRPML1 is a permeable, nonselective cation channel. The channel opens upon binding of its endogenous ligand, phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), to the pore region. Channel activity is regulated by pH and PtdIns(4,5)P2 levels. TRPML1 is a Na + , K. + , Ca 2+ , and Fe 2+TRPML1 is an inwardly rectifying channel permeable to various monovalent and divalent cations, including TRPML1. Its N-terminal AP1 sequence targets the channel to lysosomes, while the C-terminal AP2 sequence contributes to intracellular trafficking and internalization. Furthermore, TRPML1 has four putative N-linked glycosylation sites between TM1 and TM2 in its luminal loop. It has been reported that TRPML channels can form not only as homotetramers (e.g., TRPML1, TRPML2, and TRPML3) but also, in some cases, as heterotetramers, in which a single channel is composed of different members of the TRPML family.

[0004] TRPML1 is found in all mammalian tissues, with highest expression levels in the brain, spleen, liver, kidney, and heart. Expression is found in many cell types, including neurons, myeloid cells, macrophages, microglia, podocytes, and muscle cells. TRPML1 is involved in late endosome / lysosome (LEL) function, more specifically in protein trafficking, lysis, and autophagy.

[0005] Lysosomes have a low luminal pH of about 5, a high luminal Ca of about 0.5 mM 2+ These are organelles filled with hydrolytic enzymes characterized by a high concentration of ATP and a membrane polarization of approximately +60 mV.

[0006] TRPML1 in the LEL has been reported to contribute to the formation of transport vesicles, many of which are Ca transporters. 2+ TRPML1 is required for the reformation of lysosomes from LEL hybrid organelles and autolysosomes due to permeability. TRPML1 is also likely important for the release of iron from lysosomes after the degradation of iron-binding proteins such as cytochrome C. Furthermore, TRPML1 has been reported to regulate autophagy, possibly in an mTOR-independent manner, by promoting TFEB translocation to the nucleus via calcineurin activation. Summary of the Invention

[0007] In MLIV, lack of functional TRPML1 leads to severe intellectual disability, motor impairment, retinal degeneration, and systemic disease symptoms that significantly reduce life expectancy. Cells from MLIV patients exhibit increased autophagosomes, lysofuscin accumulation, and lipid accumulation in lysosomes.

[0008] Defects in TRPML1-dependent autophagosome-lysosome fusion may also impair the clearance of apoptotic neurons by macrophages and microglia. Experimental evidence suggests the involvement of TRPML1 in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). For example, Alzheimer's disease-associated loss-of-function mutations in presenilin 1 inhibit lysosomal Ca uptake via regulation of TRPML1. 2+ This leads to dysregulation of homeostasis. On the other hand, overexpression of TRPML1 in a rodent Alzheimer's disease model reduced neuronal apoptosis and rescued memory impairment. Pharmacological activation of TRPML1 produced similar results, clearing accumulated sphingolipids and Aβ peptides from lysosomes. In another study, TRPML1 activation was sufficient to upregulate lysosomal exocytosis, rescue defective α-syn secretion, and prevent α-syn accumulation in iPSC-derived dopaminergic neurons from patients expressing mutant PARK9. Similarly, TRPML1 activation rescued motor neurons from death and ER stress induced by the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA), a model of ALS.

[0009] Therefore, it is desirable to develop TRPML1 modulators that rescue impaired lysosomal function and cellular autophagy in neurodegenerative diseases.

[0010] Despite widespread interest across the pharmaceutical industry for several years, currently described small-molecule TRPML1 agonists have not been optimized for functional activity and drug-like properties. Consequently, there remains an unmet need for compounds that can efficiently stimulate TRPML1 and be delivered to various target organs that represent the site of any TRPML1-mediated pathology.

[0011] As used herein, compounds of formula (I):

[0012] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0013] As used herein, compounds of formula (Ia):

[0014] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0015] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0016] Also disclosed herein is a method of treating a TRPML1-mediated disorder or disease in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0017] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout this specification and the claims that follow, the term "comprise" and variations such as "comprises" and "comprising" should be construed in an open and inclusive sense, i.e., "including, but not limited to." Additionally, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0019] Throughout this specification, a reference to "some embodiments" or "an embodiment" means that a particular feature, structure, or characteristic described with respect to that embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Furthermore, it should be noted that the term "or" is utilized throughout to include "and / or" unless the context clearly dictates otherwise.

[0020] As used herein, the following terms have the following meanings unless otherwise specified:

[0021] "Oxo" refers to the =O radical.

[0022] "Amine" refers to -NH2.

[0023] "Hydroxy" refers to --OH.

[0024] "Carboxyl" refers to --COOH.

[0025] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Whenever a numerical range such as "C1-C6 alkyl" appears herein, it means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1-C6 alkyl. 10In some embodiments, the alkyl is a C1-C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless specifically stated otherwise herein, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0026] "Alkenyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in the cis or trans, or Z or E, configuration about the double bond, and is understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0027] "Alkynyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" appears herein, it means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless specifically stated otherwise herein, alkynyl groups can be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0028] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified specifically herein, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0029] "Alkoxy" refers to a radical of the formula -Oalkyl, where alkyl is defined as above. Unless specifically stated otherwise herein, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an alkoxy is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0030] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless otherwise specified specifically herein, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, an aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with a halogen.

[0031] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spirocyclic ring systems, and / or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (e.g., C3-C4). 15 Fully saturated cycloalkyl or C3-C15 cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10-membered fully saturated cycloalkyl or a 3 to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6-membered fully saturated cycloalkyl or a 3 to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6-membered fully saturated cycloalkyl or a 5 to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and bicyclo[3.2.2]nonyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.Unless specifically stated otherwise in the specification, a cycloalkyl may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a cycloalkyl is optionally substituted with halogen.

[0032] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0033] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0034] "Haloalkoxy" refers to an --O-haloalkyl group with haloalkyl as defined above.

[0035] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0036] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0037] "Deuteroalkyl" refers to an alkyl radical, as defined above, substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD3, CHD, CHD, CHCD, CDCD, CHDCD, CHCHD, or CHCHD. In some embodiments, the deuteroalkyl is CD3.

[0038] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, and is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur, and is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless stated specifically herein, heteroalkyls can be optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, heteroalkyls are optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0039] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl is C-linked. In some embodiments, a heterocycloalkyl is N-linked. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless specifically stated otherwise in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spirocyclic, and / or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (e.g., C2-C 15 fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2-C 10 fully saturated heterocycloalkyl or C-C 10heterocycloalkenyl), 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyls include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, and piperidinyl. Examples of heterocycloalkyl include, but are not limited to, thiazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless specifically stated otherwise in the specification, a heterocycloalkyl can be optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, a heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0040] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. In some embodiments, a heteroaryl is C-linked. In some embodiments, a heteroaryl is N-linked. Heteroaryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may include fused ring systems (when fused to a cycloalkyl ring or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems, in which nitrogen, carbon, or sulfur atoms within the heteroaryl may be optionally oxidized, and nitrogen atoms may be optionally quaternized. In some embodiments, heteroaryls are 5-10 membered heteroaryls. In some embodiments, heteroaryls are 5-6 membered heteroaryls. In some embodiments, heteroaryls are 6 membered heteroaryls. In some embodiments, heteroaryls are 5-membered heteroaryls. In some embodiments, heteroaryls are 5-6 membered rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, and isoindoline. linyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in the specification, a heteroaryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, a heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0041] The terms "optional" or "optionally" mean that the described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl," as appropriate, as defined above. Furthermore, optionally substituted groups can be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at a level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any sterically impractical and / or synthetically infeasible substitution or substitution pattern (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which are defined to include, possibly without limitation, optionally substituted alkyl groups). Thus, any described substituents will be understood to have a maximum molecular weight, taken as a whole, of about 1000 daltons, more typically up to about 500 daltons.

[0042] The term "one or more," when referring to optional substituents, means that the group in question is optionally substituted with one, two, three, or four or more substituents. In some embodiments, the group in question is optionally substituted with one, two, three, or four substituents. In some embodiments, the group in question is optionally substituted with one, two, or three substituents. In some embodiments, the group in question is optionally substituted with one or two substituents. In some embodiments, the group in question is optionally substituted with one substituent. In some embodiments, the group in question is optionally substituted with two substituents.

[0043] An "effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce a desired therapeutic effect.

[0044] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural history of the individual or cell. In some embodiments, treatment involves administration of a pharmaceutical composition following the initiation of a pathological event or contact with a causative microorganism, and involves stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0045] "Synergistic" or "synergizing" refers to a combination whose effect is greater than the effect of each component alone at the same dose.

[0046] As used herein, "TRPML1-associated disease or disorder" or alternatively "TRPML1-mediated disease or disorder" means any disease or other deleterious condition in which TRPML1 or a mutant thereof is known or believed to play a role.

[0047] compound Described herein are compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that are useful for the treatment of TRPML1-mediated diseases or disorders.

[0048] As used herein, compounds of formula (I):

[0049] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 1 is C1-C6 alkyl optionally substituted with one or more R; R 2is C1-C6 alkyl optionally substituted with one or more R; Alternatively, R 1 and R 2 together form a heterocycloalkyl or heteroaryl, each of which may contain one or more R 1a optionally substituted with R 1a are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, two R on the same carbon atom 1a come together to form an oxo, R 3 is C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C alkenyl, C-C alkynyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R; Ring A is aryl or heteroaryl; R 4 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -O-cycloalkyl, -O-heterocycloalkyl, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NRb C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)R a , -NR b S(=O)2R a , -NR b -cycloalkyl, -NR b -heterocycloalkyl, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; n is 0 to 4, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R bare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; R each independently represents deuterium, halogen, -CN, -OH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3-6 membered heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogens; Alternatively, two R on the same atom form an oxo.

[0050] In some embodiments of the compound of Formula (I), n is 1 to 4. In some embodiments of the compound of Formula (I), n is 1 to 3. In some embodiments of the compound of Formula (I), n is 2 to 4. In some embodiments of the compound of Formula (I), n is 2 or 3. In some embodiments of the compound of Formula (I), n is 2. In some embodiments of the compound of Formula (I), n is 3.

[0051] In some embodiments of the compound of Formula (I), ring A is aryl or heteroaryl. In some embodiments of the compound of Formula (I), ring A is phenyl. In some embodiments of the compound of Formula (I), ring A is a 5- or 6-membered heteroaryl. In some embodiments of the compound of Formula (I), ring A is a 6-membered heteroaryl.

[0052] In some embodiments of the compound of Formula (I), ring A is a bicyclic ring. In some embodiments of the compound of Formula (I), ring A is a bicyclic aryl. In some embodiments of the compound of Formula (I), ring A is a bicyclic heteroaryl. In some embodiments of the compound of Formula (I), ring A is indolinyl.

[0053] In some embodiments of the compounds of Formula (I), R 4 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -O-cycloalkyl, -O-heterocycloalkyl, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)R a , -NR b S(=O)2R a , -NR b -cycloalkyl, -NR b -heterocycloalkyl, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R.

[0054] In some embodiments of the compounds of Formula (I), R 4 are each independently deuterium, halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b -heterocycloalkyl, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R.

[0055] In some embodiments of the compounds of Formula (I), R 4 are each independently deuterium, halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b-heterocycloalkyl, C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R.

[0056] In some embodiments of the compounds of Formula (I), R 4 are each independently deuterium, halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, heterocycloalkyl, or C1-C6 alkylene(heterocycloalkyl), wherein alkyl, alkylene, and heterocycloalkyl are each independently optionally substituted with one or more R.

[0057] In some embodiments of the compounds of Formula (I), R 4 are each independently deuterium, halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b -heterocycloalkyl, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of compounds of Formula (I), R 4are each independently deuterium, halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b -heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R.

[0058] In some embodiments of the compounds of Formula (I), R 4 are each independently a halogen, -CN, -OH, or -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b -heterocycloalkyl, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of compounds of Formula (I), R 4 are each independently a halogen, -CN, -OH, or -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, or heterocycloalkyl. In some embodiments of the compounds of Formula (I), R 4 are each independently a halogen, -CN, -OH, or -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b-cycloalkyl, C1-C6 alkyl, or heterocycloalkyl. In some embodiments of the compounds of Formula (I), R 4 are each independently halogen, —OH, —O-cycloalkyl, —O-heterocycloalkyl, or —NR c R d , -NR b -cycloalkyl, C1-C6 alkyl, or heterocycloalkyl.

[0059] In some embodiments of the compounds of Formula (I), R 4 are each independently halogen, —OH, —O-cycloalkyl, —O-heterocycloalkyl, or —NR c R d , -NR b In some embodiments of the compounds of Formula (I), R 4 are each independently halogen, -O-cycloalkyl, -O-heterocycloalkyl, -NR b -cycloalkyl, C1-C6 alkyl, or heterocycloalkyl. In some embodiments of the compounds of Formula (I), R 4 are each independently halogen, -O-cycloalkyl, -O-heterocycloalkyl, -NR b In some embodiments of the compounds of Formula (I), R 4 are each independently halogen, —O-cycloalkyl, —O-heterocycloalkyl, C1-C6 alkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I), R 4 are each independently halogen, -O-cycloalkyl, -O-heterocycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I), R 4 are each independently halogen, C1-C6 alkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I), R 4 are each independently halogen or heterocycloalkyl. In some embodiments of the compounds of Formula (I), R 4are each independently halogen, —O-cycloalkyl, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), R 4 are each independently halogen or -O-cycloalkyl. In some embodiments of the compounds of Formula (I), R 4 are each independently halogen, —O-heterocycloalkyl, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), R 4 are each independently halogen or —O-heterocycloalkyl.

[0060] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0061] [ka] is a compound of the formula R 4a are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 4b is deuterium, halogen, -CN, -NO2, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b -heterocycloalkyl, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R 4c is deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl.

[0062] In some embodiments of the compounds of Formula (Ia), R 4a represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (Ia), R 4a is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (Ia), R 4a is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (Ia), R 4a is hydrogen or halogen. In some embodiments of the compounds of Formula (Ia), R 4a is hydrogen. In some embodiments of the compounds of Formula (Ia), R 4a is halogen. In some embodiments of the compounds of Formula (Ia), R 4a is C1-C6 alkyl.

[0063] In some embodiments of the compounds of Formula (Ia), R 4b is deuterium, halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b-heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (Ia), R 4b is deuterium, halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b -cycloalkyl, -NR b -heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (Ia), R 4b -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d , -NR b In some embodiments of the compounds of Formula (Ia), R 4b represents -O-cycloalkyl, -O-heterocycloalkyl, -NR b In some embodiments of the compounds of Formula (Ia), R 4b In some embodiments of the compounds of Formula (Ia), R 4b is —O-cycloalkyl or —O-heterocycloalkyl. In some embodiments of the compounds of Formula (Ia), R 4b In some embodiments of the compounds of Formula (Ia), R 4b is -O-cycloalkyl, where the cycloalkyl is a monocyclic cycloalkyl. In some embodiments of the compounds of Formula (Ia), R 4b is -O-cycloalkyl, wherein the cycloalkyl is a bicyclic cycloalkyl. In some embodiments of the compounds of Formula (Ia), R 4b is heterocycloalkyl. In some embodiments of the compounds of Formula (Ia), R4b is a 3- to 10-membered heterocycloalkyl. In some embodiments of the compounds of Formula (Ia), R 4b is a 5-10 membered heterocycloalkyl. In some embodiments of the compounds of Formula (Ia), R 4b is a 5-8 membered heterocycloalkyl.

[0064] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0065] [ka] wherein ring B is cycloalkyl or heterocycloalkyl and m is 0 to 4. In some embodiments of compounds of Formula (Ia), R 4b teeth,

[0066] [ka] wherein ring B is cycloalkyl and m is 0 to 4. In some embodiments of compounds of Formula (Ia), R 4b teeth,

[0067] [ka] wherein ring B is a monocyclic cycloalkyl and m is 0 to 4. In some embodiments of compounds of Formula (Ia), R 4b teeth,

[0068] [ka] wherein ring B is a bicyclic cycloalkyl and m is 0-4.

[0069] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0070] [ka] wherein ring B is

[0071] [ka] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0072] [ka] wherein ring B is

[0073] [ka] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0074] [ka] wherein ring B is

[0075] [ka] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0076] [ka] wherein ring B is

[0077] [ka] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0078] [ka] wherein ring B is

[0079] [ka] is.

[0080] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0081] [ka] and m is 0 to 4. In some embodiments of compounds of Formula (Ia), R 4b teeth,

[0082] [ka] and m is 0 or 1. In some embodiments of compounds of Formula (Ia), R 4b teeth,

[0083] [ka] and m is 0 to 2. In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0084] [ka] and m is 0. In some embodiments of compounds of Formula (Ia), R 4b teeth,

[0085] [ka] and m is 1.

[0086] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0087] [ka] is.

[0088] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0089] [ka] is.

[0090] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0091] [ka] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0092] [ka] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0093] [ka] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0094] [ka] is.

[0095] In some embodiments of the compounds of Formula (Ia), R 4b teeth,

[0096] [ka] is.

[0097] In some embodiments of the compounds of Formula (Ia), R4c is deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (Ia), R 4c is halogen, —OH, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (Ia), R 4c is a halogen.

[0098] In some embodiments of compounds of Formula (I) or (Ia), R 1 is C1-C6 alkyl.

[0099] In some embodiments of compounds of Formula (I) or (Ia), R 2 is C1-C6 alkyl.

[0100] In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 together form a monocyclic heterocycloalkyl or a bicyclic heterocycloalkyl, each of which may be one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 together form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each of which may be joined by one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 are taken together to form pyrrolidinyl or piperidinyl, each of which may be joined by one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a to form a bicyclic heterocycloalkyl optionally substituted with

[0101] In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a In some embodiments of compounds of Formula (I) or (Ia), R 1 and R2 together with one or more R 1a In some embodiments of the compounds of Formula (I) or (Ia), R 1 and R 2 together with one or more R 1a to form a 5-membered heteroaryl optionally substituted with

[0102] In some embodiments of compounds of Formula (I) or (Ia), R 1 and R 2 are united,

[0103] [ka] each of which forms one or more R 1a is optionally replaced by

[0104] In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia), R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl), or C1-C6 alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia), R 1a are independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently a halogen, -CN, -OH, or -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0105] In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0106] In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently -OH, -OR a , C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl.

[0107] In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently -OR a , C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl.

[0108] In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently C1-C6 alkyl or C1-C6 hydroxyalkyl.

[0109] In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently -OR a or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia), R 1a are each independently -Omethyl or methyl.

[0110] In some embodiments of compounds of Formula (I) or (Ia), two R 1a together form an oxo.

[0111] In some embodiments of compounds of Formula (I) or (Ia), R 3is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia), R 3 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia), R 3 is C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia), R 3 is C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia), R 3 are -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2F, -CH2CF3, -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2,

[0112] [ka] In some embodiments of compounds of Formula (I) or (Ia), R 3 is -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2F, -CH2CF3, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH(CH3)2. In some embodiments of compounds of Formula (I) or (Ia), R 3 is —CH2CH3, —CH2CH2F, or —CH2CF3. In some embodiments of compounds of Formula (I) or (Ia), R 3 is —CH2CH3. In some embodiments of compounds of Formula (I) or (Ia), R 3 is —CH2CH2F. In some embodiments of compounds of Formula (I) or (Ia), R 3 is -CH2CF3.

[0113] In some embodiments of the compounds disclosed herein, R aare each independently C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a are each independently C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where the alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a are each independently C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a are each independently C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C-C alkyl or C-C haloalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a are each independently cycloalkyl or heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R aare each independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl.

[0114] In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where the alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl.

[0115] In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C-C alkyl, or C-C haloalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, cycloalkyl, or heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R b is hydrogen. In some embodiments of the compounds disclosed herein, R b are each independently C1-C6 alkyl.

[0116] In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein the alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), where the alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, or C-C haloalkyl, and each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, cycloalkyl, or heterocycloalkyl, and the cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R dare each hydrogen. In some embodiments of the compounds disclosed herein, R c and R d are each independently C1-C6 alkyl.

[0117] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0118] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, —CN, —OH, —S(═O)C1-C3 alkyl, —S(═O)2C1-C3 alkyl, —S(═O)2NH2, —S(═O)2NHC1-C3 alkyl, —S(═O)2N(C1-C3 alkyl)2, —NH2, —NHC1-C3 alkyl, —N(C1-C3 alkyl)2, —C(═O)C1-C3 alkyl, —C( =O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl.

[0119] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, —CN, —OH, —NH, —NHC-C alkyl, —N(C-C alkyl), —C(═O)C-C alkyl, —C(═O)OH, —C(═O)OC-C alkyl, —C(═O)NH, —C(═O)NHC-C alkyl, —C(═O)N(C-C alkyl), C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C deuteroalkyl, C-C haloalkoxy, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl; or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C deuteroalkyl, C-C haloalkoxy, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, or C-C cycloalkyl; or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C deuteroalkyl, or C-C haloalkoxy; or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -NH, C-C alkyl, or C-C alkoxy, or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, C-C alkyl, or C-C alkoxy, or two R on the same atom form oxo.

[0120] All combinations of the groups described above for the various variables are contemplated herein. Throughout this specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0121] In some embodiments, the compound is selected from the compounds found in Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0122] [Table 1-1]

[0123] [Table 1-2]

[0124] [Table 1-3]

[0125] [Table 1-4]

[0126] [Table 1-5]

[0127] [Table 1-6]

[0128] [Table 1-7]

[0129] [Table 1-8]

[0130]

Table 1-9

[0131]

Table 1-10

[0132]

Table 1-11

[0133]

Table 1-12

[0134]

Table 1-13

[0135]

Table 1-14

[0136]

Table 1-15

[0137]

Table 1-16

[0138]

Table 1-17

[0139]

Table 1-18

[0140]

Table 1-19

[0141]

Table 1-20

[0142]

Table 1-21

[0143]

Table 1-22

[0144]

Table 1-23

[0145]

Table 1-24

[0146]

Table 1-25

[0147]

Table 1-26

[0148]

Table 1-27

[0149]

Table 1-28

[0150]

Table 1-29

[0151]

Table 1-30

[0152]

Table 1-31

[0153]

Table 1-32

[0154]

Table 1-33

[0155]

Table 1-34

[0156]

Table 1-35

[0157]

Table 1-36

[0158]

Table 1-37

[0159]

Table 1-38

[0160]

Table 1-39

[0161] [Table 1-40]

[0162] [Table 1-41]

[0163] [Table 1-42]

[0164] [Table 1-43]

[0165] [Table 1-44]

[0166] [Table 1-45]

[0167] In some embodiments, the compound is

[0168] [ka]

[0169] [ka]

[0170] [ka]

[0171] [ka]

[0172]

change

[0173]

change

[0174]

change

[0175]

change

[0176]

change

[0177]

change

[0178]

change

[0179]

change

[0180]

change

[0181]

change

[0182]

change

[0183]

change

[0184]

change

[0185]

change

[0186]

change

[0187]

change

[0188]

change

[0189]

change

[0190]

change

[0191]

change

[0192]

change

[0193] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as all corresponding mixtures thereof. In some circumstances, the compounds described herein possess one or more asymmetric centers, with each center independently existing in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as all corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers obtained by a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by exploiting these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0194] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein, but in which one or more atoms have been replaced with an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Cl, etc. Compounds described herein and pharmaceutically acceptable salts, solvates, or stereoisomers thereof that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Incorporation of radioactive isotopes such as 1C is useful for drug and / or substrate tissue distribution assays. Tritiated isotopes, i.e. 3 H, and carbon-14 isotopes, i.e. 14 C are particularly preferred for their ease of preparation and detectability. 2 Substitution with heavy isotopes, such as 3H, offers certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo and reduced dosage requirements.

[0195] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0196] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0197] In some embodiments, the compounds described herein contain acidic or basic groups and thus react with any of a number of inorganic or organic bases to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or in situ by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed.

[0198] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzyl, methyl methyl ester ... Tribenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybutyrate ... Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate The salts include, but are not limited to, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0199] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mannitol, methylisothiazolinone ... Examples of suitable organic acids include, but are not limited to, hydroxypropyl methyl esters, arylsulfonic acids, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, although not pharmaceutically acceptable per se, are utilized in the preparation of salts useful as intermediates for obtaining the compounds disclosed herein, or solvates or stereoisomers thereof, and their pharmaceutically acceptable acid addition salts.

[0200] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, sulfate, or the like, of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-C4 alkyl)4 hydroxide.

[0201] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization results in water- or oil-soluble or dispersible products.

[0202] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0203] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed using pharmaceutically acceptable solvents such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can optionally exist in solvated as well as unsolvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0204] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. Tautomers are compounds that are interchangeable due to the migration of a hydrogen atom accompanied by the switching of a single bond and one or more adjacent double bonds. In bonding configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH.

[0205] Treatment method Provided herein are methods for treating a TRPML1-mediated disorder in a human or animal subject in need thereof, comprising administering to the subject an amount of a compound described herein effective to reduce or prevent the disorder in the subject, in combination with at least one additional agent known in the art for treating the disorder. Certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for treating a TRPML1-mediated disorder.

[0206] Also provided herein are compounds for use in the manufacture of a medicament for the treatment of a TRPML1-mediated disease. Further provided herein are methods for treating a disease mediated by TRPML1 activity in a mammalian subject, comprising administering a therapeutically effective amount of a compound disclosed herein.

[0207] TRPML1-mediated diseases include proliferative disorders such as cancer, inflammatory disorders, pain, neurodegenerative disorders, cognitive and psychiatric disorders, and other diseases discussed below.

[0208] The TRPML1-mediated disorder or disease is aging, bone disease, heart disease, congenital developmental disorder, eye disease, hematological or solid malignancy, infectious disease, inflammatory disease, liver disease, metabolic disease, neurological or neurodegenerative disease, pancreatitis, kidney disease, skeletal muscle disorder, obesity, lysosomal storage disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget's disease, or lung disease.

[0209] In some embodiments, the TRPML1-mediated disorder or disease is Aicardi-Goutières syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, autistic disorder, Batten disease, bipolar disorder, cerebral ataxia, Charcot-Marie-Tooth variant diseases, chronic wasting disease, corticobasal degeneration, corticobasal syndrome, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Danon disease, Duchenne muscular dystrophy, exotic ungulate encephalopathy, Fabry disease, fatal familial insomnia, Friedreich's ataxia, feline spongiform encephalopathy, Fragile X syndrome, or the like. X), frontotemporal dementia, Gaucher disease, Gerstmann-Sträussler-Scheinker disease, giant axonal neuropathy, GM1 and GM2 gangliosidosis, Huntington's disease, infantile Refsum disease, JUNQ and IPOD, Krabbe disease, kuru, leukoencephalopathy, dementia with Lewy bodies, gait ataxia, Lyme disease, Machado-Joseph disease, major depressive disorder, MPS-III, mucolipidosis, multiple sulfatase deficiency, multiple system atrophy, myofibrillar myopathy, myotonic dystrophy, Niemann-Pierre-Pierre-Schmidt syndrome, and others. The following conditions are considered to be pathological conditions: Parkinson's disease, Parkinsonism, Pick's disease, polyglutamine disorders, Pompe disease, pontocerebellar hypoplasia, prion diseases, progressive nuclear palsy, progressive supranuclear palsy, pyruvate dehydrogenase deficiency, Sandhoff disease, schizophrenia, scrapie disease, Shy-Drager syndrome, spinal muscular atrophy, spinocerebellar ataxia, disseminated familial insomnia, subacute degeneration of the spinal cord, subacute sclerosing panencephalitis, Tay-Sachs disease, neuronal ceroid lipofuscinosis, Parkinson's disease, parkinsonism syndrome, Pick's disease, polyglutamine disorders, Pompe disease, pontocerebellar hypoplasia, prion diseases, progressive nuclear palsy, progressive supranuclear palsy, pyruvate dehydrogenase deficiency, Sandhoff disease, schizophrenia, scrapie disease, Shy-Drager syndrome, spinal muscular atrophy, spinocerebellar ataxia, disseminated familial insomnia, subacute degeneration of the spinal cord, subacute sclerosing panencephalitis, Tay-Sachs disease, neuronal transection degeneration, tuberous sclerosis, spinocerebellar ataxia, or vascular dementia.

[0210] In some embodiments, the TRPML1-mediated disorder or disease is age-related macular degeneration, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), retinal cell degeneration in glaucoma, retinitis pigmentosa, acute kidney injury, atherosclerosis, Crohn's disease, diabetic nephropathy, female infertility, Helicobacter pylori infection, hypochlorhydria, pancreatitis, retinal detachment, type 2 diabetes, ulcerative colitis, or sarcopenia.

[0211] The compounds disclosed herein are useful for treating neurodegenerative disorders of various origins, such as Alzheimer's disease, and other dementias, such as Lewy body dementia, frontotemporal dementia, and other tauopathies; amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and other parkinsonian syndromes; Huntington's disease; HIV-induced neuroinflammation; essential tremor; neurological disorders, such as other spinocerebellar degenerations, Charcot-Marie-Tooth disease, and other TRPML1-mediated diseases, such as mucolipidosis type IV (MLIV). The compounds disclosed herein are also useful for treating neurological disorders, such as epilepsy, including simple partial seizures, complex partial seizures, and secondary generalized seizures, including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, generalized tonic-clonic seizures, and atonic seizures, as well as for the prevention and treatment of status epilepticus (SE).

[0212] The compounds disclosed herein are also useful for treating cognitive disorders and psychiatric disorders.Psychiatric disorders include, but are not limited to, major depression, dysthymia, mania, bipolar disorder (such as type I bipolar disorder and type II bipolar disorder), cycling disorder, rapid cycling, diurnal cycling, mania, hypomania, schizophrenia, schizophreniform disorder, schizoaffective disorder, personality disorder, attention disorder with or without hyperactivity, delusional disorder, brief psychosis, affected psychosis, psychosis due to general medical conditions, substance-induced psychotic disorder, or psychosis not otherwise specified, anxiety disorder, such as generalized anxiety disorder, panic disorder, post-traumatic stress disorder, impulse control disorder, phobic disorder, and dissociative state.The compounds disclosed herein are also useful for treating smoking addiction, drug addiction, or alcoholism.The compounds disclosed herein are particularly useful for treating bipolar disorder, psychosis, anxiety, or addiction.

[0213] The compounds disclosed herein are useful for preventing or treating neuroinflammation and CNS damage induced by HIV infection, as well as HIV-associated neurocognitive deficits. The compounds disclosed herein are useful for preventing or treating neuropathic pain. Neuropathic pain syndromes include, but are not limited to, chemotherapy-induced peripheral neuropathy, diabetic neuropathy, sciatica, nonspecific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-associated neuropathy, neuralgia such as postherpetic neuralgia and trigeminal neuralgia, Morton's neuralgia, and causative pain; pain caused by physical trauma, amputation, phantom limb, cancer, toxins, or chronic inflammatory disease; and central pain such as that observed in thalamic syndromes, a mixed central-limbic form of pain, such as complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy.

[0214] The compounds disclosed herein are also useful for treating pain, including chronic pain, including, but not limited to, chronic pain caused by inflammation or inflammation-related diseases, osteoarthritis, rheumatoid arthritis, acute injury or trauma, upper or lower back pain (due to systemic, local, or primary spinal diseases such as radiculopathy), bone pain (due to osteoarthritis, osteoporosis, bone metastasis, or unknown reasons), pelvic pain, pain associated with spinal cord injury, cardiac chest pain, non-cardiac chest pain, central post-stroke pain, myofascial pain, sickle cell pain, cancer pain, Fabry disease, AIDS pain, geriatric pain, or pain caused by headache, temporomandibular joint syndrome, gout, fibrosis, or thoracic outlet syndrome, especially in rheumatoid arthritis and osteoarthritis.

[0215] The compounds disclosed herein are also useful for treating acute pain caused by acute injury, illness, sports medicine injuries, carpal tunnel syndrome, burns, musculoskeletal sprains and strains, muscle-tendon strains, cervicobrachial syndrome, dyspepsia, gastric ulcers, duodenal ulcers, dysmenorrhea, endometriosis, or surgery (such as open heart or bypass surgery), post-operative pain, kidney stone pain, gallbladder pain, gallstone pain, obstetric pain, or dental pain.

[0216] The compounds disclosed herein are also useful for treating headaches such as migraine, tension-type headache, transformed migraine, or evolutive headache, cluster headache, as well as secondary headaches, such as those resulting from infections, metabolic disorders, or other systemic diseases, and other acute headaches resulting from the exacerbation of the above-mentioned primary and secondary headaches, such as paroxysmal migraine.

[0217] The compounds disclosed herein are also useful for treating diseases such as dizziness, tinnitus, muscle spasms, and other disorders, including, but not limited to, cardiac diseases (such as cardiac arrhythmias, myocardial infarction, or angina pectoris, hypertension, cardiac ischemia, cerebral ischemia), endocrine disorders (such as acromegaly or diabetes insipidus), diseases whose pathophysiology involves excessive or hypersecretion, or other inappropriate cellular secretion of endogenous substances (such as catecholamines, hormones, or growth factors).

[0218] The compounds disclosed herein are also useful for the selective treatment of liver diseases such as inflammatory liver diseases, e.g., chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver disease, primary biliary cirrhosis, autoimmune hepatitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and liver transplant rejection.

[0219] The compounds disclosed herein inhibit the inflammatory process that affects all body systems. These compounds are therefore useful in the treatment of inflammatory processes of the musculoskeletal system, including, but not limited to, the following target disorders: arthritic diseases such as ankylosing spondylitis, cervical arthritis, fibrositis, gout, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, and rheumatic diseases; disorders affecting the skin and related tissues: inflammatory diseases such as eczema, psoriasis, dermatitis, and sunburn; disorders of the respiratory system: asthma, allergic rhinitis, and respiratory distress syndrome, pulmonary diseases accompanied by inflammation such as asthma and bronchitis; chronic obstructive pulmonary disease; disorders of the immune and endocrine systems: polyarteritis nodosa, thyroiditis, aplastic anemia, scleroderma, myasthenia gravis, multiple sclerosis, and other demyelinating disorders, encephalomyelitis, sarcoidosis, nephritic syndrome, Behcet's syndrome, polymyositis, and gingivitis.

[0220] The compounds disclosed herein are also useful for the treatment of gastrointestinal (GI) tract disorders, such as inflammatory bowel disease (IBD), including, but not limited to, ulcerative colitis, Crohn's disease, ileitis, proctitis, celiac disease, enteropathy, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis occurring after proctocolectomy and ileonatal anastomosis, and any disorder associated with abdominal discomfort, such as abdominal pain, and / or irritable bowel syndrome, including pyloric spasm, neurogenic dyspepsia, spastic colon, spastic colitis, spastic bowel, enteric neurosis, functional colitis, mucous colitis, laxative colitis, and functional dyspepsia, as well as atrophic gastritis, poxform gastritis, and the like. variolioforme), ulcerative colitis, pepsin ulcers, heartburn, and other functional bowel disorders such as GI tract damage caused by Helicobacter pylori, gastroesophageal reflux disease, and diabetic gastroparesis; and non-ulcer dyspepsia (NUD); pancreatitis, vomiting, diarrhea, visceral inflammation, and hypochlorhydria.

[0221] The compounds disclosed herein are also useful for treating disorders of the reproductive and urinary tract, such as overactive bladder, prostatitis (chronic bacterial and chronic non-bacterial prostatitis), prostadynia, interstitial cystitis, urinary incontinence, and benign prostatic hyperplasia, annexes, pelvic inflammation, bartholinitis, and vaginitis, particularly for overactive bladder and urinary incontinence.

[0222] The compounds disclosed herein are also useful for treating renal disorders including diabetic nephropathy, renal allograft rejection, infectious nephropathy, IgA nephropathy, fibrotic nephropathy, lupus nephritis, glomerulonephritis, acute kidney injury, and renal cancer.

[0223] The compounds disclosed herein are also useful in treating ocular diseases such as retinitis, retinitis pigmentosa, retinopathy, uveitis, acute damage to ocular tissue, age-related macular degeneration, glaucoma, retinal cell degeneration in glaucoma, conjunctivitis, and retinal detachment.

[0224] The compounds disclosed herein are also useful for treating eating disorders such as anorexia nervosa, including restrictive and binge-purging subtypes; hyperorexia nervosa, including purging and non-purging subtypes; obesity; compulsive eating disorder; binge eating disorder; and other eating disorders not otherwise specified.

[0225] The compounds disclosed herein are also useful for treating allergic dermatitis, airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, Sjogren's syndrome, glomerulonephritis, atherosclerosis, malignant cell growth and metastasis, myoblastic leukemia, diabetes (type 2 diabetes), meningitis, osteoporosis, burns, ischemic heart disease, stroke, peripheral vascular disease, varicose veins, glaucoma, and female infertility.

[0226] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful for treating or preventing the progression of cancer. In some embodiments, the cancer is a hematological malignancy or solid tumor. Hematological malignancies include leukemia, lymphoma, multiple myeloma, and their subtypes. Lymphomas can be classified in various ways, often based on the underlying type of malignant cell, including Hodgkin's lymphoma (often Reed-Sternberg cell carcinoma, and sometimes B-cell origin; all other lymphomas are non-Hodgkin's lymphomas), B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, Burkitt's lymphoma, follicular lymphoma, and others defined herein and known in the art.

[0227] B-cell lymphomas include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL) / small cell lymphocytic lymphoma (SLL), and others defined herein and known in the art.

[0228] T-cell lymphomas include T-cell acute lymphoblastic leukemia / lymphoma (T-ALL), marginal T-cell lymphoma (PTCL), T-cell chronic lymphocytic leukemia (T-CLL) Sézary syndrome, and others defined herein and known in the art.

[0229] Leukemias include acute myeloid (or myelogenous) leukemia (AML), chronic myeloid (or myelogenous) leukemia (CML), acute lymphocytic (or lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (sometimes classified as a lymphoma), and others defined herein and known in the art.

[0230] Plasma cell malignancies include lymphoplasmacytic lymphoma, plasmacytoma, and multiple myeloma.

[0231] Solid tumors include melanoma, neuroblastoma, glioma, or five carcinomas, such as tumors of the brain, head and neck, breast, lung (e.g., non-small cell lung cancer NSCLC), reproductive organs (e.g., ovaries), upper gastrointestinal tract, pancreas, liver, renal system (e.g., kidney), bladder, prostate, and colon.

[0232] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for the veterinary treatment of companion animals, exotic animals, and farm animals, including mammals and rodents, with more preferred animals including horses, dogs, and cats.

[0233] dosage In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or partially prevent at least one symptom of the disease or condition. The amount effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose-ranging clinical trials.

[0234] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the precise amount will depend, among other factors, on the patient's health and weight. When used in a patient, the amount effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously suffered from but is now in remission of at least one symptom or risk factor for the disease being treated, in order to prevent the return of the disease or condition symptoms.

[0235] In certain embodiments where the patient's condition does not improve, at the physician's discretion, the compound is administered chronically, i.e., for an extended period of time, including the patient's entire lifespan, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0236] Once the patient's condition has improved, a maintenance dose is administered as needed. In certain embodiments, the dosage or frequency of administration, or both, is then reduced, depending on the symptoms, to a level at which improvement in the disease, disorder, or condition is maintained. In certain embodiments, however, the patient will require intermittent or daily treatment over the long term upon any recurrence of symptoms.

[0237] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0238] In general, however, dosages utilized in adult human treatment typically range from 0.01 mg / day to 5000 mg / day. In one aspect, dosages employed in adult human treatment are from about 1 mg / day to about 1000 mg / day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., as two, three, four, or more subdoses daily.

[0239] In one embodiment, a suitable daily dosage for a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dosage or amount of active ingredient in a dosage form will be lower or higher than the ranges set forth herein, depending on many variables related to the particular treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the health care professional.

[0240] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 10 and ED90 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD. 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dose range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is at or above the ED500 dose range with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending upon the dosage form utilized and the route of administration used.

[0241] Any of the foregoing aspects are further embodiments in which an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0242] Any of the foregoing aspects are further embodiments that include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times to the mammal during the course of a day.

[0243] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, buccal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, and intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0244] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, by injecting the compound directly into an organ, often in a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to and selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, a sustained-release formulation, or an intermediate-release formulation. In some embodiments, the compounds described herein are administered locally.

[0245] Pharmaceutical Compositions / Formulations The compounds described herein may be administered to a subject in need thereof alone or in combination with a pharmaceutically acceptable carrier, additive, or vehicle in a pharmaceutical composition according to standard pharmaceutical practice. In one embodiment, the compounds disclosed herein may be administered to an animal. The compounds may be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally, and topically.

[0246] In another aspect, this paper describes pharmaceutical compositions comprising the compound described herein or its pharmaceutically acceptable salt, solvate or stereoisomer and at least one pharmaceutically acceptable excipient.Pharmaceutical compositions are conventionally formulated with one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into pharmaceutical preparations that can be used as pharmaceuticals.Suitable formulation depends on the selected route of administration. Summary summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0247] In some embodiments, the pharmaceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetener, a disintegrant, a dispersing agent, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizer, a humectant, a plasticizer, a stabilizer, a penetration enhancer, a wetting agent, an antifoaming agent, an antioxidant, a preservative, and any combination thereof.

[0248] The pharmaceutical formulations described herein may be administered to a subject by any suitable route, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosol dispersions, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-dissolve formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed-release formulations, sustained-release formulations, pulsed-release formulations, multiparticulate formulations, and combination immediate-controlled-release formulations.

[0249] Pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured conventionally, for example, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0250] Oral pharmaceutical compositions can be prepared by mixing one or more solid excipients with one or more of the compounds described herein, optionally pulverizing the resulting mixture, and optionally adding suitable excipients to process the granular mixture to obtain tablets or dragee cores.Suitable excipients include, for example, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; and others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, are added.In some embodiments, dyes or pigments are added to tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0251] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0252] Pharmaceutical compositions for parenteral administration are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the compounds described herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms.

[0253] combination Disclosed herein are methods of treating a TRPML-mediated disorder or disease using the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0254] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered before administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. [Example]

[0255] The following examples illustrate the invention. Unless expressly indicated otherwise, all measurements (especially percentages and amounts) relate to weight.

[0256] Preparation of intermediate ethyl 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate (VII):

[0257] [ka]

[0258] Step 1: Synthesis of 3-bromo-1,1,1-trifluoropropane: To a solid mixture of CBr (45.43 g, 136.84 mmol) and PhP (35.85 g, 136.84 mmol), 3,3,3-trifluoropropan-1-ol (13.0 g, 114.03 mmol) was added at room temperature. The reaction was initiated by a strong exotherm, while the solid reaction mass became liquid. The mixture was heated at 90 °C for 3 h under a condenser, with circulating cold (5–10 °C) water. The compound was then removed using short-path distillation to give 3-bromo-1,1,1-trifluoropropane (15.5 g, 76.81%) as a colorless liquid.

[0259] Step 2: Synthesis of ethyl 5,5,5-trifluoro-2-oxopentanoate: To a suspension of Mg turning (2.87 g, 119.76 mmol) in THF (5 mL) was added a catalytic amount of 1,2-dibromoethane and stirred until effervescence began. Once effervescence began, a solution of 3-bromo-1,1,1-trifluoropropane 2 (10 g, 59.88 mmol) in THF (50 mL) was added dropwise to the warm suspension, maintaining the temperature at approximately 50° C. After the addition was complete, the mixture was stirred at room temperature for approximately 30 minutes.

[0260] The above freshly prepared Grignard solution was added dropwise to a −78° C. solution of diethyl oxalate (6.12 g, 41.91 mmol) in THF (50 mL), which was then allowed to warm gradually to room temperature over 3 min, at which point the reaction mixture became clear. After completion of the reaction (monitored by TLC (KMnO staining)), the reaction mixture was quenched with a saturated aqueous solution of NH4Cl (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, and concentrated to give the desired compound, ethyl 5,5,5-trifluoro-2-oxopentanoate (6.2 g), as a brown viscous liquid (crude), which was used directly in the next step without further purification.

[0261] Step 3: Synthesis of ethyl 3-bromo-5,5,5-trifluoro-2-oxopentanoate: To a solution of ethyl 5,5,5-trifluoro-2-oxopentanoate (6.2 g, 31.31 mmol) in ethyl acetate (390 mL) and DCM (230 mL), CuBr (24.44 g, 109.59 mmol) was added, and the resulting reaction mixture was stirred at 90 °C for 16 h. Upon completion (monitored by TLC (KMnO staining)), the reaction mixture was filtered through Celite, and the filtrate was concentrated to give ethyl 3-bromo-5,5,5-trifluoro-2-oxopentanoate (8.6 g) as a brown viscous liquid (crude), which was used directly in the next step without further purification.

[0262] Step 4: Synthesis of ethyl 2-amino-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate: To a stirred solution of ethyl 3-bromo-5,5,5-trifluoro-2-oxopentanoate (8.6 g, 31.04 mmol) in ethanol (100 mL), urea (7.45 g, 124.18 mmol) was added at room temperature and then refluxed for 16 hours. After completion (monitored by TLC and LC-MS), the reaction mixture was concentrated to remove ethanol. The crude reaction mixture was then treated with a saturated aqueous solution of NaHCO (100 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure. The crude residue thus obtained was triturated with 50% ether / pentane, and the resulting precipitate was filtered through a sintered glass funnel and dried under vacuum to give ethyl 2-amino-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate (VI) (2.9 g, 39.2%) as an off-white solid.

[0263] Step 5: Synthesis of ethyl 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate: A suspension of CuCl (1.72 g, 12.86 mmol) and t-BuONO (2.10 g, 20.42 mmol) in 60 mL of acetonitrile was stirred at 70 °C for 15 minutes. Then, a suspension of ethyl 2-amino-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate in acetonitrile (90 mL) was added dropwise to the warm reaction mixture. After the addition, the reaction mixture was stirred at 75 °C for 1 hour. Upon completion (monitored by TLC), the reaction mixture was concentrated to remove acetonitrile and diluted with ethyl acetate (200 mL) and water (100 mL). The reaction mixture was filtered through a celite bed, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash column chromatography using 10% EtOAC-hexane as the eluent to give ethyl 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate (VII) as a pale yellow liquid (1.9 g, 58.5%).

[0264] Preparation of 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline:

[0265] [ka]

[0266] Step 1: Synthesis of 2-(2-fluoro-4-nitrophenoxy)cyclopentan-1-one: To a stirred suspension of 2-fluoro-4-nitrophenol (2.0 g, 63.69 mmol) and potassium carbonate (5.2 g, 38.21 mmol) in acetone (20 mL), 2-chlorocyclopentan-1-one (2.4 g, 12.74 mmol) was added, and the resulting reaction mixture was stirred at 70 °C for 8 h. The reaction was then concentrated in vacuo to remove acetone, and the crude material was diluted with ethyl acetate (200 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 10% EtOAc / hexane as the eluent to afford 2-(2-fluoro-4-nitrophenoxy)cyclopentan-1-one (X) (1.2 g, 39.38%) as a yellow liquid.

[0267] Step 2: Synthesis of 1-((2,2-difluorocyclopentyl)oxy)-2-fluoro-4-nitrobenzene: To a stirred solution of 2-(2-fluoro-4-nitrophenoxy)cyclopentan-1-one (X) (0.7 g, 2.93 mmol) in DCM (20 mL) was added DAST (2.36 g, 14.64 mmol) dropwise at 0 °C. After the addition, the reaction mixture was stirred at room temperature for 16 h. After completion [monitored by LC-MS], the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (100 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using 10% EtOAc-hexane as the eluent to afford 1-((2,2-difluorocyclopentyl)oxy)-2-fluoro-4-nitrobenzene (0.42 g, 54.9%) as a yellow liquid.

[0268] Step 3: Synthesis of 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline: To a stirred solution of 1-((2,2-difluorocyclopentyl)oxy)-2-fluoro-4-nitrobenzene (460 mg, 1.99 mmol) in 10 mL of 1,4-dioxane:water (5:1), zinc powder and ammonium chloride (633 mg, 11.91 mmol) were added at 0° C. The resulting reaction mixture was stirred at room temperature for 3 h. After completion [monitored by LC-MS], the reaction mixture was filtered through sintered glass. The filtrate was dried over anhydrous NaSO and concentrated under reduced pressure, and the resulting crude was purified by combiflash column chromatography using 10% EtOAc-hexane to give 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline (255 mg, 62.58%) as a brown viscous liquid.

[0269] General scheme for preparing Examples 1-24.

[0270] [ka]

[0271] Step 1: To a stirred solution of intermediate (VII) (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / g VII), RNH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by flash column chromatography to give intermediates of structure XIII.

[0272] Step 2: To a stirred solution of XIII (1.0 equiv.) and 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline (XII) (0.8 equiv.) in dry toluene (30 mL / g XIII), trimethylaluminum (1 M in toluene, 4.0 equiv.) was added dropwise at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 h. After completion [monitored by TLC / LCMS], the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to afford the product of basic structure XIV.

[0273] All amines (R2NH) used in the synthesis of product (XIV) were purchased from chemical suppliers.

[0274] Example 1 The title compound was prepared as described in the general scheme above utilizing isoindoline as the amine in step 1 to afford N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-2-(2,3-dihydro-1H-isoindol-2-yl)-5-(2,2,2-trifluoroethyl)-1,3-oxazole-4-carboxamide (20 mg, 19%).

[0275] Example 2 The title compound was prepared as described in the general scheme above, utilizing 3-cyanoazetidine as the amine in step 1 to afford 2-(3-cyanoazetidin-1-yl)-N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-5-(2,2,2-trifluoroethyl)-1,3-oxazole-4-carboxamide (45 mg, 17%).

[0276] Example 3 The title compound was prepared as described in the general scheme above utilizing 3-(hydroxymethyl)pyrrolidine as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 19.5%).

[0277] Example 4 The title compound was prepared as described in the general scheme above utilizing 2,2-dimethylmorpholine as the amine in step 1 to afford N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-2-(2,2-dimethylmorpholin-4-yl)-5-(2,2,2-trifluoroethyl)-1,3-oxazole-4-carboxamide (20 mg, 13%).

[0278] Example 5 The title compound was prepared as described in the general scheme above utilizing indoline as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(indolin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (14 mg, 45.3%).

[0279] Example 6 The title compound was prepared as described in the general scheme above utilizing morpholine as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-morpholino-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (23 mg, 15.95%).

[0280] Example 7 The title compound was prepared as described in the general scheme above utilizing 3-(methoxymethyl)pyrrolidine as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(3-(methoxymethyl)pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 11%).

[0281] Example 8 The title compound was prepared as described in the general scheme above utilizing 3-methoxyazetidine as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 10.41%).

[0282] Example 9 The title compound was prepared as described in the general scheme above, utilizing 7-azabicyclo[2.2.1]heptane as the amine in step 1 to afford 2-{7-azabicyclo[2.2.1]heptan-7-yl}-N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (12 mg, 16%).

[0283] Example 10 The title compound was prepared as described in the general scheme above utilizing 6,6-difluoro-3-azabicyclo[3.1.0]hexane as the amine in step 1 to afford 2-{6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl}-N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 22%).

[0284] Example 11 The title compound was prepared as described in the general scheme above utilizing 4-azaspiro[2.4]heptane as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(4-azaspiro[2.4]heptan-4-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (18 mg, 19%).

[0285] Example 12 The title compound was prepared as described in the general scheme above utilizing hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (8 mg, 26%).

[0286] Example 13 The title compound was prepared as described in the general scheme above utilizing 2-oxa-7-azaspiro[4.4]nonane as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 20.66%).

[0287] Example 14 The title compound was prepared as described in the general scheme above utilizing 7-oxa-2-azaspiro[3.5]nonane as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 22%).

[0288] Example 15 The title compound was prepared as described in the general scheme above utilizing 6-azaspiro[3.4]octane as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(6-azaspiro[3.4]octan-6-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 18.33%).

[0289] Example 16 The title compound was prepared as described in the general scheme above, utilizing 3,3-difluoroazetidine as the amine in step 1 to afford 2-(3,3-difluoroazetidin-1-yl)-N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 17%).

[0290] Example 17 The title compound was prepared as described in the general scheme above, utilizing 6,6-difluoro-2-azaspiro[3.3]heptane as the amine in step 1 to afford 2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (70 mg, 50%).

[0291] Example 18 The title compound was prepared as described in the general scheme above utilizing 3-trifluoromethylazetidine as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)-2-(3-(trifluoromethyl)azetidin-1-yl)oxazole-4-carboxamide (70 mg, 50%).

[0292] Example 19 The title compound was prepared as described in the general scheme above, utilizing 2-oxa-6-azaspiro[3.4]octane as the amine in step 1 to afford N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-2-{2-oxa-6-azaspiro[3.4]octan-6-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (45 mg, 29%).

[0293] Example 20 The title compound was prepared as described in the general scheme above utilizing 3,3-dimethylazetidine as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(3,3-dimethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 23%).

[0294] Example 21 The title compound was prepared as described in the general scheme above, utilizing 5-azaspiro[2.4]heptane as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(5-azaspiro[2.4]heptan-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 14.4%).

[0295] Example 22 The title compound was prepared as described in the general scheme above utilizing pyrrolidine as the amine in step 1 to afford N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 51%).

[0296] Example 23 The title compound was prepared as described in the general scheme above utilizing octahydrocyclopenta[c]pyrrole as the amine in step 1 to afford N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-2-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (11 mg, 15.68%).

[0297] Example 24 The title compound was prepared as described in the general scheme above utilizing 3-isopropylazetidine as the amine in step 1 to afford N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-2-[3-(propan-2-yloxy)azetidin-1-yl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 32%).

[0298] General scheme for preparing Examples 25-33.

[0299] [ka]

[0300] Step 1: To a stirred solution of intermediate VII (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / g), amine compound (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 2 h. Upon completion (monitored by TLC or LCMS), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude material was subjected to flash column chromatography to afford XV.

[0301] Step 2: To a stirred solution of XV (1.0 equiv.) in dry toluene (30 mL / g) was added 3-fluoro-4-(piperidin-1-yl)aniline (XVI) (0.8 equiv.), followed by dropwise addition of trimethylaluminum (1 M in toluene, 4.0 equiv.) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion (monitored by TLC or LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to give examples of basic structure XVII.

[0302] All amines used as starting materials were purchased from commercial sources.

[0303] Example 25 The title compound was prepared as described in the general scheme above utilizing 2-thia-7-azaspiro[3,5]nonane-2,2-dioxide as the amine in step 1 to afford 2-(2,2-dioxo-2-thia-7-azaspiro[3.5]nonan-7-yl)-N-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 13%).

[0304] Example 26 The title compound was prepared as described in the general scheme above, utilizing (3aR,6aR)-hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 1 to afford 2-[(3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl]-N-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (16 mg, 22%).

[0305] Example 27 The title compound was prepared as described in the general scheme above, utilizing 5-azaspiro[2.4]heptane as the amine in step 1 to afford 2-{5-azaspiro[2.4]heptan-5-yl}-N-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(2,2,2-trifluoroethyl)-1,3-oxazole-4-carboxamide (30 mg, 32%).

[0306] Example 28 The title compound was prepared as described in the general scheme above, utilizing 2,2-difluoro-6-azaspiro[3.4]octane as the amine in step 1 to afford 2-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 11.88%).

[0307] Example 29 The title compound was prepared as described in the general scheme above utilizing 2-methylpyrrolidine as the amine in step 1 to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(2-methylpyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (12 mg, 13.47%).

[0308] Example 30 The title compound was prepared as described in the general scheme above, utilizing 6,6-difluoro-2-azaspiro[3.3]heptane as the amine in step 1 to afford 2-{6,6-difluoro-2-azaspiro[3.3]heptan-2-yl}-N-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (18 mg, 31%).

[0309] Example 31 The title compound was prepared as described in the general scheme above, utilizing 2-oxa-7-azaspiro[4.4]nonane as the amine in step 1 to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(2-oxa-7-azaspiro[4.4]nonan-7-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (35 mg, 27%).

[0310] Example 32 The title compound was prepared as described in the general scheme above, utilizing pyrrolidine as the amine in step 1 to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (9 mg, 21%).

[0311] Example 33 The title compound was prepared as described in the general scheme above, utilizing 2-oxa-6-azaspiro[3.4]octane as the amine in step 1 to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (28 mg, 24.23%).

[0312] Preparation of 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluoroaniline (XXI):

[0313] [ka]

[0314] Step 1: To a stirred solution of 1,2,3-trifluoro-5-nitrobenzene (500 mg, 3.14 mmol) and KOH powder (547 mg, 9.43 mmol) in DMSO (5 mL), bicyclo[3.1.0]hexan-3-ol was added and stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product (XX) was purified by flash column chromatography using 5% EtOAc in hexane as the eluent to give 3-(2,6-difluoro-4-nitrophenoxy)bicyclo[3.1.0]hexane (XX, 530 mg, 66.04%).

[0315] Step 2: To a stirred solution of 3-(2,6-difluoro-4-nitrophenoxy)bicyclo[3.1.0]hexane (XX) (500 mg, 1.97 mmol) in 10 mL of 1,4-dioxane:water (5:1), zinc powder (639 mg, 9.84 mmol) was added along with ammonium chloride (637 mg, 11.81 mmol) at 0 °C. This was then stirred at room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product (XXI) was purified by flash column chromatography using 10% EtOAc in hexane to give 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluoroaniline (XXI) (400 mg, 90.22%).

[0316] General scheme for preparing Examples 34-41.

[0317] [ka]

[0318] Step 1: To a stirred solution of intermediate (VII) (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / mmol), an amine of general formula RNH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 2 h. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by flash column chromatography to afford intermediates of general formula XXII.

[0319] Step 2: To a stirred solution of XXII (1.0 equiv.) in dry toluene (30 mL / g), 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluoroaniline (XXI) (0.8 equiv.) was added, followed by the dropwise addition of trimethylaluminum (2 M in toluene, 4.0 equiv.) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude XXIII was purified by flash column chromatography to give examples having the general formula XXIII.

[0320] All amines used as starting materials were purchased from commercial suppliers.

[0321] Example 34 The title compound was prepared as described in the general scheme above, utilizing 6,6-difluoro-2-azaspiro[3.3]heptane as the amine in step 1 to afford N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 16.59%).

[0322] Example 35 The title compound was prepared as described in the general scheme above, utilizing 2-oxa-6-azaspiro[3.4]octane as the amine in step 1 to afford N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3,5-difluorophenyl)-2-{2-oxa-6-azaspiro[3.4]octan-6-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 30%).

[0323] Example 36 The title compound was prepared as described in the general scheme above, utilizing hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 1 to give N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3,5-difluorophenyl)-2-{hexahydro-5H-furo[2,3-c]pyrrol-5-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 26%).

[0324] Example 37 The title compound was prepared as described in the general scheme above, utilizing 3,3-dimethylazetidine as the amine in step 1 to afford N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3,5-difluorophenyl)-2-(3,3-dimethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (18 mg, 11%).

[0325] Example 38 The title compound was prepared as described in the general scheme above, utilizing 5-azaspiro[2.4]heptane as the amine in step 1 to afford N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3,5-difluorophenyl)-2-{hexahydro-2H-furo[2,3-c]pyrrol-5-yl}-5-(2,2,2-trifluoroethyl)-1,3-oxazole-4-carboxamide (49 mg, 33%).

[0326] Example 39 The title compound was prepared as described in the general scheme above utilizing pyrrolidine as the amine in step 1 to afford N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (15 mg, 10.93%).

[0327] Example 40 The title compound was prepared as described in the general scheme above utilizing octahydrocyclopenta[c]pyrrole as the amine in step 1 to afford N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3,5-difluorophenyl)-2-{octahydrocyclopenta[c]pyrrol-2-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (15 mg, 10.93%).

[0328] Example 41 The title compound was prepared as described in the general scheme above, utilizing 2-azaspiro[3.4]octane as the amine in step 1 to afford N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(2-azaspiro[3.4]octan-2-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (70 mg, 45.4%).

[0329] Basic conditions for preparing examples of the general formula identified by structure XXIX (Examples 42-76):

[0330] [ka]

[0331] Step 1. To a stirred solution of XXIV (1.0 equiv.) and XXV (1.2 equiv.) in DMSO (3 mL / mmol) was added KOH (3.0 equiv.). The reaction was stirred at room temperature for 2 h. Upon completion [monitored by TLC], the resulting reaction mixture was partitioned between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography using EtOAc in hexane as the eluent to give the desired product (XXVI).

[0332] Step 2: To a stirred solution of (XXVI) (2 mmol) in 10 mL of 1,4 dioxane:water (5:1) was added zinc powder (639 mg, 9.84 mmol) along with ammonium chloride (637 mg, 11.81 mmol) at 0° C. This was then stirred at room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude (XXVII) was purified by flash column chromatography using 10% EtOAc in hexane to give pure (XXVII).

[0333] Step 3: To a stirred solution of intermediate (VII) (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / mmol), an amine of general formula RNH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 2 h. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by flash column chromatography to afford intermediates of general formula XXII.

[0334] Step 4: To a stirred solution of XXII (1.0 equiv.) in dry toluene (30 mL / g) was added compound XXVII (0.8 equiv.) from Step 2, followed by dropwise addition of trimethylaluminum (2 M in toluene, 4.0 equiv.) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product XXIX was purified by flash column chromatography to give examples having the general formula XXIX.

[0335] All alcohols used as starting materials were purchased from commercial suppliers.

[0336] All amines used in step 3 of the above procedure were purchased from commercial suppliers.

[0337] Example 42 The above compound was synthesized using the procedure described in the general scheme above, using 2,2,2-trifluoroethanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (19 mg, 16%).

[0338] Example 43 The above compound was synthesized using the procedure described in the general scheme above, using 3-methoxycyclopentanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-{3-fluoro-4-[(3-methoxycyclopentyl)oxy]phenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 24%).

[0339] Example 44 The above compound was synthesized using the procedure described in the general scheme above, using 3,3-difluorocyclobutanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-[4-(3,3-difluorocyclobutoxy)-3-fluorophenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 45%).

[0340] Example 45 The above compound was synthesized using the procedure described in the general scheme above, using 5,5-dimethyltetrahydrofuran-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-{4-[(5,5-dimethyloxolan-3-yl)oxy]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 16%).

[0341] Example 46 The above compound was synthesized utilizing the procedure described in the general scheme above, using 6,6-difluorobicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-[4-({6,6-difluorobicyclo[3.1.0]hexan-3-yl}oxy)-3-fluorophenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 22%).

[0342] Example 47 The above compound was synthesized using the procedure described in the general scheme above, using tetrahydrofuran-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-[3-fluoro-4-(oxolan-3-yloxy)phenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 36%).

[0343] Example 48 The above compound was synthesized using the procedure described in the general scheme above, using cyclopentanol as the alcohol in step 1 and 6,6-difluoro-2-azaspiro[3.3]heptane as the amine in step 4, to give N-[4-(cyclopentyloxy)-3-fluorophenyl]-2-{6,6-difluoro-2-azaspiro[3.3]heptan-2-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 36%).

[0344] Example 49 The above compound was synthesized using the procedure described in the general scheme above, using 4,4-difluorotetrahydrofuran-3-ol as the alcohol in Step 1 and pyrrolidine as the amine in Step 4, to yield the racemic title compound. Chiral separation was performed on an Agilent 1200 series instrument. Column: CHIRALPAK IG (250 times 21 mm) particle size 5 μm. The separation was performed at ambient temperature at a flow rate of 21.0 mL / min. The mobile phase was a mixture of 70% hexane and 30% EtOH, maintained as an isocratic mixture for 40 minutes at a wavelength of 280 nm. The separation yielded enantiomerically pure (R)-N-(4-((4,4-difluorotetrahydrofuran-3-yl)oxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (15 mg, 29%).

[0345] Example 50 The above compound was synthesized utilizing the procedure described in the general scheme above, using 3-methylcyclopentanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(3-fluoro-4-((3-methylcyclopentyl)oxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 16.03%).

[0346] Example 51 The above compound was synthesized utilizing the procedure described in the general scheme above, using bicyclo[3.1.0]hexan-2-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(4-{bicyclo[3.1.0]hexan-2-yloxy}-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 16.03%).

[0347] Example 52 The above compound was synthesized using the procedure described in the general scheme above, using spiro[2.4]heptan-4-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(3-fluoro-4-(spiro[2.4]heptan-4-yloxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (8 mg, 14.28%).

[0348] Example 53 The above compound was synthesized utilizing the procedure described in the general scheme above, using (2,2-difluorocyclopentyl)methanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-{4-[(2,2-difluorocyclopentyl)methoxy]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 25%).

[0349] Example 54 The above compound was synthesized using the procedure described in the general scheme above, using cyclopentanol as the alcohol in step 1 and 2-methylpyrrolidine as the amine in step 4, to give N-(4-(cyclopentyloxy)-3-fluorophenyl)-2-(2-methylpyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (18 mg, 20%).

[0350] Example 55 The above compound was synthesized utilizing the procedure described in the general scheme above, using 2,2-dimethylcyclopentanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(4-((2,2-dimethylcyclopentyl)oxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (12 mg, 14.2%).

[0351] Example 56 The above compound was synthesized using the procedure described in the general scheme above, using tetrahydro-2H-pyran-4-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-[3-fluoro-4-(oxan-4-yloxy)phenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (47 mg, 37%).

[0352] Example 57 The above compound was synthesized using the procedure described in the general scheme above, using cyclopentanol as the alcohol in step 1 and 5-azaspiro[2.4]heptane as the amine in step 4, to give N-(4-(cyclopentyloxy)-3-fluorophenyl)-2-(5-azaspiro[2.4]heptan-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 26%).

[0353] Example 58 The above compound was synthesized using the procedure described in the general scheme above, using 3,3,3-trifluoropropanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(3-fluoro-4-(3,3,3-trifluoropropoxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 31%).

[0354] Example 59 The above compound was synthesized using the procedure described in the general scheme above, using 2-butanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(4-(sec-butoxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 26%).

[0355] Example 60 The above compound was synthesized using the procedure described in the general scheme above, using 4,4,4-trifluorobutan-2-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(3-fluoro-4-((4,4,4-trifluorobutan-2-yl)oxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (17 mg, 12.85%).

[0356] Example 61 The above compound was synthesized utilizing the procedure described in the general scheme above, using cyclopentanol as the alcohol in step 1 and (3aR,6aR)-hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 4, to give N-(4-(cyclopentyloxy)-3-fluorophenyl)-2-((3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 21.59%).

[0357] Example 62 The above compound was synthesized using the procedure described in the general scheme above, using cyclopentanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-[4-(cyclopentyloxy)-3-fluorophenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 30%).

[0358] Example 63 The compound above was synthesized using the procedure described in the general scheme above, using 4,4-difluorotetrahydrofuran-3-ol as the alcohol in step 1 and 5-azaspiro[2.4]heptane as the amine in step 4, to give N-(4-((4,4-difluorotetrahydrofuran-3-yl)oxy)-3-fluorophenyl)-2-(5-azaspiro[2.4]heptan-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 20.97%).

[0359] Example 64 The above compound was synthesized using the procedure described in the general scheme above, using cyclopentanol as the alcohol in step 1 and 2-oxa-6-azaspiro[3.4]octane as the amine in step 4, to give N-(4-(cyclopentyloxy)-3-fluorophenyl)-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 34.54%).

[0360] Example 65 The above compound was synthesized using the procedure described in the general scheme above, using cyclohexanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(4-(cyclohexyloxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (24 mg, 18.62%).

[0361] Example 66 The above compound was synthesized using the procedure described in the general scheme above, using tetrahydro-2H-pyran-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-[3-fluoro-4-(oxan-3-yloxy)phenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 31%).

[0362] Example 67 The above compound was synthesized using the procedure described in the general scheme above, using spiro[3.4]octan-5-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(3-fluoro-4-{spiro[3.4]octan-5-yloxy}phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 31%).

[0363] Example 68 The above compound was synthesized utilizing the procedure described in the general scheme above, using 2,2-difluorocyclohexanol as the alcohol in step 1 and 2-oxa-6-azaspiro[3.4]octane as the amine in step 4, to give N-(4-((2,2-difluorocyclohexyl)oxy)-3-fluorophenyl)-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (16 mg, 14%).

[0364] Example 69 The above compound was synthesized using the procedure described in the general scheme above, using 4,4-difluorotetrahydrofuran-3-ol as the alcohol in Step 1 and pyrrolidine as the amine in Step 4, to yield the racemic title compound. Chiral separation was performed on an Agilent 1200 series instrument. Column: CHIRALPAK IG (250 times 21 mm) particle size 5 μm. The separation was performed at ambient temperature at a flow rate of 21.0 mL / min. The mobile phase was a mixture of 70% hexane and 30% EtOH, maintained as an isocratic mixture for 40 minutes at a wavelength of 280 nm. The separation yielded enantiomerically pure (S)—N-(4-((4,4-difluorotetrahydrofuran-3-yl)oxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 29%).

[0365] Example 70 The above compound was synthesized utilizing the procedure described in the general scheme above, using 4,4-difluorotetrahydrofuran-3-ol as the alcohol in step 1 and 3,3-dimethylazetidine as the amine in step 4, to give N-{4-[(4,4-difluorotetrahydrofuran-3-yl)oxy]-3,5-difluorophenyl}-2-(3,3-dimethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 30%).

[0366] Example 71 The compound above was synthesized using the procedure described in the general scheme above, using 4,4-difluorotetrahydrofuran-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give the racemic title compound N-(4-((4,4-difluorotetrahydrofuran-3-yl)oxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 36%).

[0367] Example 72 The above compound was synthesized using the procedure described in the general scheme above, using tetrahydro-2H-pyran-3-ol as the alcohol in step 1 and 3,3-dimethylazetidine as the amine in step 4, to give the racemic title compound N-(3,5-difluoro-4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)-2-(3,3-dimethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 22%).

[0368] Example 73 The compound above was synthesized using the procedure described in the general scheme above, using cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and 2-oxa-6-azaspiro[3.4]octane as the amine in step 4, to give N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3-fluorophenyl)-2-{2-oxa-6-azaspiro[3.4]octan-6-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 30%).

[0369] Example 74 The above compound was synthesized utilizing the procedure described in the general scheme above, using cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 77%).

[0370] Example 75 The compound above was synthesized using the procedure described in the general scheme above, using cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and 5-azaspiro[2.4]heptane as the amine in step 4, to give 2-{5-azaspiro[2.4]heptan-5-yl}-N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 21%).

[0371] Example 76 The above compound was synthesized using the procedure described in the general scheme above, using 2,2-difluorocyclohexanol as the alcohol in step 1 and pyrrolidine as the amine in step 4, to give N-{4-[(2,2-difluorocyclohexyl)oxy]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 36%).

[0372] General procedure for synthesizing examples of General Structure XXXV (Examples 77-83).

[0373] [ka]

[0374] Step 1: To a stirred solution of compound (XXX) (1.0 equiv.) and potassium carbonate (2.0 equiv.) in acetonitrile (3 mL / mmol) was added amine R a R b NH (1.1 equiv.) was added. The reaction mass was stirred at 80° C. for 16 h. After completion [monitored by TLC or LC-MS], the reaction mixture was concentrated to remove volatiles. The crude reaction mixture was then diluted with EtOAc and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash column chromatography using EtOAc / hexane as the eluent to give intermediate compound XXXI.

[0375] Step 2: To a stirred solution of compound XXXI in 1,4 dioxane:water (5:1) was added zinc powder (5.0 equiv.) followed by ammonium chloride (6.0 equiv.) at 0° C. The reaction mixture was then stirred at room temperature for 3 h. Upon completion [monitored by TLC], the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous NaSO, concentrated under reduced pressure, and purified by flash column chromatography using EtOAc-hexane as the eluent to give intermediate compound XXXII.

[0376] Step 3: To a stirred solution of compound VII (1.0 equiv.) in dioxane (3 mL / g) was added amine R c R d NH (1.1 equiv.) and DIPEA (3.0 equiv.) were added, and the resulting reaction mixture was stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by flash column chromatography using EtOAc-hexane as the eluent to give XXXIV.

[0377] Step 4: To a stirred solution of XXXIV (1.0 equiv.) in dry toluene (30 mL / g) was added XXXII (0.8 equiv.), followed by the dropwise addition of trimethylaluminum (1 M in toluene, 4.0 equiv.) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 h. After completion [monitored by TLC / LCMS], the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to give XXXV.

[0378] All amines used as starting materials were purchased from commercial suppliers.

[0379] Example 77 The above compound was synthesized utilizing the procedures described in the general scheme above, where compound XXX is 3,4-difluoronitrobenzene, 4,4-difluoropiperidine is used as the amine in step 1, and 6,6-difluoro-2-azaspiro[3.3]heptane is used as the amine in step 4, to yield 2-{6,6-difluoro-2-azaspiro[3.3]heptan-2-yl}-N-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (58 mg, 48%).

[0380] Example 78 The above compound was synthesized utilizing the procedures described in the general scheme above, where compound XXX is 4-fluoro-3-trifluoromethylnitrobenzene, piperidine is used as the amine in step 1, and 6,6-difluoro-2-azaspiro[3.3]heptane is used as the amine in step 4, to yield 2-{6,6-difluoro-2-azaspiro[3.3]heptan-2-yl}-N-[4-(piperidin-1-yl)-3-(trifluoromethyl)phenyl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (45 mg, 29%).

[0381] Example 79 The above compound was synthesized utilizing the procedures described in the general scheme above, where compound XXX is 3,4-difluoronitrobenzene, N-methylcyclopentanamine is used as the amine in step 1, and 6,6-difluoro-2-azaspiro[3.3]heptane is used as the amine in step 4, to yield N-{4-[cyclopentyl(methyl)amino]-3-fluorophenyl}-2-{6,6-difluoro-2-azaspiro[3.3]heptan-2-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (64 mg, 33%).

[0382] Example 80 The above compound was synthesized utilizing the procedures described in the general scheme above, where compound XXX is 3,4-difluoronitrobenzene, N-methylbicyclo[3.1.0]hexan-3-amine is used as the amine in step 1, and pyrrolidine is used as the amine in step 4, to yield N-(4-{bicyclo[3.1.0]hexan-3-yl(methyl)amino}-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 18%).

[0383] Example 81 The above compound was synthesized utilizing the procedures described in the general scheme above, where compound XXX is 3,4,5-trifluoronitrobenzene, 2,2-difluoro-N-methylcyclopentan-1-amine is used as the amine in step 1, and pyrrolidine is used as the amine in step 4, to yield N-{4-[(2,2-difluorocyclopentyl)(methyl)amino]-3,5-difluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 18%).

[0384] Example 82 The above compound was synthesized utilizing the procedures described in the general scheme above, where compound XXX is 3,4-difluoronitrobenzene, 2,2-difluoro-N-methylcyclopentan-1-amine is used as the amine in step 1, and pyrrolidine is used as the amine in step 4, to yield N-{4-[(2,2-difluorocyclopentyl)(methyl)amino]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 21%).

[0385] Example 83 The above compound was synthesized utilizing the procedures described in the general scheme above, where compound XXX is 3,4-difluoronitrobenzene, 6-azabicyclo[3.1.1]heptane is used as the amine in step 1, and pyrrolidine is used as the amine in step 4, to yield N-(4-{6-azabicyclo[3.1.1]heptan-6-yl}-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (16 mg, 12%).

[0386] Example 84

[0387] [ka]

[0388] Step 1: Synthesis of 5-nitro-2-(piperidin-1-yl)phenol: To a stirred suspension of 2-fluoro-5-nitrophenol (0.8 g, 5.10 mmol) and potassium carbonate (2.1 g, 15.30 mmol) in DMF (5 mL), piperidine (0.86 g, 10.2 mmol) was added and the reaction was stirred at 80 °C for 16 h. After completion [monitored by TLC], the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2 x 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 10% ethyl acetate in hexane to give 5-nitro-2-(piperidin-1-yl)phenol (0.85 g, 75%) as a yellow liquid.

[0389] Step 2: Synthesis of 5-amino-2-(piperidin-1-yl)phenol: To a stirred solution of 5-nitro-2-(piperidin-1-yl)phenol (XXXVII) (200 mg, 0.90 mmol) in 10 mL of 1,4 dioxane:water (5:1), zinc powder (292 mg, 4.5 mmol) was added along with ammonium chloride (287 mg, 5.4 mmol) at 0° C. This was then stirred at room temperature for 3 hours. After completion (monitored by LC-MS), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous NaSO, concentrated, and purified by flash column chromatography using 15% ethyl acetate in hexane to give 5-amino-2-(piperidin-1-yl)phenol (55 mg, 31.75%).

[0390] Step 3: Synthesis of N-(3-hydroxy-4-(piperidin-1-yl)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide. To a stirred solution of XXXVIII (38 mg, 0.185 mmol) in dry toluene (5 mL), XXXIX (60 mg, 0.205 mmol) was added, followed by the dropwise addition of trimethylaluminum (2 M in toluene, 0.4 mL, 0.80 mmol) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography to give N-(3-hydroxy-4-(piperidin-1-yl)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (10 mg, 11%).

[0391] Example 85

[0392] [ka]

[0393] Step 1: To a stirred solution of 2-methoxy-5-nitrophenol (XL) (500 mg, 2.95 mmol) in DMF (10 mL), K2CO3 (407 mg, 2.95 mmol) and benzyl bromide (505 mg, 2.95 mmol) were added and stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was diluted with cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic portion was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using 2-5% EtOAc-hexane as the eluent to afford 2-(benzyloxy)-1-methoxy-4-nitrobenzene (XLII) (475 mg, 62%) as a pale yellow solid.

[0394] Step 2: To a stirred solution of compound XLII (475 mg, 1.83 mmol) in DMSO (10 mL), 10 N NaOH solution (0.5 mL) was added and stirred at 100° C. for 5 h. After completion (monitored by TLC), the reaction mixture was acidified with 1 N HCl solution (approximately 2 mL) and extracted with EtOAc (2×20 mL). The organic portion was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using 2–5% EtOAc-hexane as the eluent to give 2-(benzyloxy)-4-nitrophenol (XLIII) (360 mg, 80%).

[0395] Step 3: To a stirred solution of XLIII (360 mg, 1.46 mmol) in DMF (8 mL), bromocyclopentane (218.89 mg, 1.46 mmol), K2CO3, and stirred at 120 °C for 16 h. After completion (monitored by TLC), the reaction mixture was diluted with cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic portion was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using 15% EtOAc-hexane to give 2-(benzyloxy)-1-(cyclopentyloxy)-4-nitrobenzene (XLIV) (300 mg, 65%).

[0396] Step 4: To a stirred solution of XLIV (150 mg, 0.47 mmol) in ethanol (4 mL), Pd / C (20%) (approximately 80 mg) was added and stirred under a hydrogen atmosphere for 1 h. After completion (monitored by TLC), the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was then purified by flash column chromatography using 50% EtOAc-hexane to give 5-amino-2-(cyclopentyloxy)phenol XLV (60 mg, 64%) as a brown solid.

[0397] Step 5: To a stirred solution of XXXIX (100 mg, 0.34 mmol) in dry toluene (4 mL) was added 5-amino-2-(cyclopentyloxy)phenol (66 mg, 0.34 mmol), followed by the dropwise addition of trimethylaluminum (2 M in toluene, 0.68 mL, 1.36 mmol) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 h. After completion [monitored by TLC], the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and partitioned with EtOAc [2×30 mL]. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography using 35% EtOAc-hexane as the eluting solvent to give N-(4-(cyclopentyloxy)-3-hydroxyphenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 13%).

[0398] Example 86

[0399] [ka]

[0400] Step 1: To a stirred solution of 2-(benzyloxy)-4-nitrophenol (XLVI) (600 mg, 2.44 mmol) in acetone (8 mL), KCO (1 g, 7.34 mmol) and chloropentanone (319 mg, 2.69 mmol) were added and stirred at 80 °C for 16 h. After completion [monitored by TLC], the reaction mixture was concentrated under reduced pressure to give crude XLVII. The resulting crude material was purified by flash column chromatography on silica gel with a gradient elution of 0-50% EtOAc-hexane to give 2-[2-(benzyloxy)-4-nitrophenoxy]cyclopentan-1-one XLVII (293 mg, 37%).

[0401] Step 2: To a stirred solution of 2-[2-(benzyloxy)-4-nitrophenoxy]cyclopentan-1-one (XLVII) (293 mg, 0.89 mmol) in DCM (5 mL) was added DAST (720 mg, 4.47 mmol) at 0 °C and stirred at room temperature for 1 h. After completion (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution (ca. 20 mL) and extracted with EtOAc (2 x 20 mL). The organic portion was separated, dried over sodium sulfate, and concentrated under reduced pressure to give crude XLVIII. The resulting crude material was purified by flash column chromatography on silica gel with a gradient elution of 10% EtOAc-hexane to give 2-(benzyloxy)-1-[(2,2-difluorocyclopentyl)oxy]-4-nitrobenzene, i.e., XLVIII (233 mg, 75%).

[0402] Step 3: To a stirred solution of 2-(benzyloxy)-1-[(2,2-difluorocyclopentyl)oxy]-4-nitrobenzene XLVIII (100 mg, 0.66 mmol) in THF:EtOH (4 mL), Pd / C (approximately 80 mg) was added and stirred under a hydrogen atmosphere for 16 h. After completion (monitored by TLC), the reaction mixture was filtered and concentrated under reduced pressure to give crude XLIX. The resulting crude material was purified by flash column chromatography on silica gel with a gradient elution of 30–40% EtOAc-hexane to give 5-amino-2-[(2,2-difluorocyclopentyl)oxy]phenol XLIX (80 mg, 52%) as a brown viscous liquid.

[0403] Step 4: Trimethylaluminum (2 M in toluene, 0.5 mL, 1.0 mmol) was added dropwise to a stirred solution of ethyl 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate XXXIX (70 mg, 0.24 mmol) and 5-amino-2-[(2,2-difluorocyclopentyl)oxy]phenol XLIX (55 mg, 0.24 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and partitioned with EtOAc [2×30 mL]. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 35% EtOAc-hexane as the eluent to give N-{4-[(2,2-difluorocyclopentyl)oxy]-3-hydroxyphenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)-1,3-oxazole-4-carboxamide, Example 86 (20 mg, 18%).

[0404] Example 87

[0405] [ka]

[0406] Step 1: To a stirred solution of 1,2-difluoro-4-nitrobenzene (500 mg, 3.14 mmol) in DMSO (5 mL), NaHCO (924 mg, 11.0 mmol) and 2,2-difluorocyclopentan-1-amine hydrochloride (495 mg, 3.14 mmol) were added, and the mixture was heated to 100 °C (sealed tube) and stirred for 20 h. After completion (monitored by TLC), the reaction mixture was concentrated, diluted with water (20 mL), and extracted with EtOAc (2 x 30 mL). The combined organic layers were separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 0-6% EtOAc in hexanes as the eluent to afford the desired product, N-(2,2-difluorocyclopentyl)-2-fluoro-4-nitroaniline LII (500 mg, 61%), as a yellow, viscous liquid.

[0407] Step 2: To a stirred solution of N-(2,2-difluorocyclopentyl)-2-fluoro-4-nitroaniline (300 mg, 1.15 mmol) in DMF (5 mL) was added NaH (92 mg, 2.3 mmol) at 0 °C and stirred for 30 min. Ethyl iodide (0.186 mL, 2.30 mmol) was then added, and the mixture was allowed to warm to room temperature with stirring for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated, diluted with water (20 mL), and extracted with EtOAc (2 x 30 mL). The resulting crude material was purified by flash column chromatography using 10% EtOAc in hexane as the eluent to afford the desired product, N-(2,2-difluorocyclopentyl)-N-ethyl-2-fluoro-4-nitroaniline LIII (160 mg, 48%) as a yellow solid.

[0408] Step 3: To a stirred solution of N-(2,2-difluorocyclopentyl)-N-ethyl-2-fluoro-4-nitroaniline LIII (160 mg, 0.55 mmol) in dioxane (6 mL), NH4Cl.HO (300 mg, 5.55 mmol) and Zn powder (361 mg, 5.55 mmol) were added and stirred for 6 h. After completion [monitored by TLC], the reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated and purified by flash column chromatography using 30% EtOAc in hexanes as the eluent to give the desired product, N1-(2,2-difluorocyclopentyl)-N1-ethyl-2-fluorobenzene-1,4-diamine LIV (110 mg, 77%) as a brown liquid.

[0409] Step 4: To a stirred solution of ethyl 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate XXXIX (75 mg, 0.25 mmol) in dry toluene (3 mL), N1-(2,2-difluorocyclopentyl)-N1-ethyl-2-fluorobenzene-1,4-diamine (53 mg, 0.20 mmol) was added, followed by the dropwise addition of trimethylaluminum (2 M in toluene, 0.5 mL, 1.0 mmol) at 0 °C, and the resulting reaction mixture was stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and partitioned with EtOAc (2 x 30 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 20% EtOAc-hexane as the eluent to give N-(4-((2,2-difluorocyclopentyl)(ethyl)amino)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide Example 87 (26 mg, 20%).

[0410] Example 88

[0411] [ka]

[0412] To a stirred solution of 2-(3-(aminomethyl)azetidin-1-yl)-N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (Example 2) (70 mg, 0.14 mmol) in MeOH (3 mL) was added Raney Ni and stirred under 1 atm of hydrogen at room temperature for 3 h. Upon completion [monitored by TLC], the reaction mixture was filtered through Celite and concentrated to give the crude product. The crude residue was dissolved in DCM (3 mL) and purified by column chromatography using silica gel with a gradient elution of 0-5% MeOH-DCM to give 2-[3-(aminomethyl)azetidin-1-yl]-N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide, Example 88 (22 mg, 71%).

[0413] Preparation of intermediate ethyl 2-chloro-5-methyloxazole-4-carboxylate (LXI):

[0414] [ka]

[0415] Step 1: To a stirred solution of ethyl 2-oxobutanoate (16.0 g, 123.07 mmol) in EtOAc (1000 mL) and DCM (600 mL), CuBr (109.78 g, 492.30 mmol) was added at room temperature. The mixture was then heated at 90 °C for 16 h. After completion (monitored by TLC), the reaction mixture was filtered through Celite, and the filtrate was concentrated to give ethyl 3-bromo-2-oxobutanoate (LIX) (25.0 g) as a brown viscous liquid (crude), which was used in the next step without further purification.

[0416] Step 2: To a solution of ethyl 3-bromo-2-oxobutanoate (25.0 g, 120.19 mmol) in ethanol (200 mL), urea (28.84 g, 480.76 mmol) was added at room temperature and stirred at 80 °C for 24 h. After completion [monitored by TLC], the reaction mixture was concentrated to remove ethanol. The crude mass was then treated with a saturated aqueous solution of NaHCO (200 mL) and extracted with EtOAc (2 x 300 mL). The organic portion was dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was triturated with EtO, and the resulting precipitate was filtered through a sintered glass filter and dried under vacuum to give pure ethyl 2-amino-5-methyloxazole-4-carboxylate (LX) (13.6 g) as an off-white solid.

[0417] Step 3: A suspension of CuCl (6.51 g, 48.47 mmol) and tert-butyl nitrite (7.75 g, 75.29 mmol) in acetonitrile (80 mL) was heated to 70 °C and stirred for 15 min. Then, a suspension of ethyl 2-amino-5-methyloxazole-4-carboxylate (LX) (8.0 g, 47.05 mmol) in acetonitrile (120 mL) was added dropwise to the reaction mixture at 70 °C and stirred at room temperature for 16 h. After completion [monitored by TLC], the reaction mixture was concentrated to remove volatiles and then diluted with ethyl acetate (250 mL) and water (250 mL), and the resulting suspension was filtered through a sintered glass filter. The organic layer was separated, dried over anhydrous NaSO, and concentrated under reduced pressure. The resulting crude material was purified by silica gel flash column using 5% EtOAc-hexane as the eluent to give ethyl 2-chloro-5-methyloxazole-4-carboxylate (LXI) (5.6 g, 62.77%).

[0418] General procedure for synthesizing examples of main structure LXIII (Examples 89-90).

[0419] [ka]

[0420] Step 1: To a stirred solution of amine / amine salt (1.2 equiv.) and CsCO (3.0 equiv.) in dioxane (30 mL / g), ethyl 2-chloro-5-methyloxazole-4-carboxylate (LXI) (1.0 equiv.) was added, and the resulting reaction mixture was stirred at 80 °C for 16 h. Upon completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter, and the filtrate was concentrated under reduced pressure. The resulting crude was purified by column chromatography to give LXII.

[0421] Step 2: To a stirred solution of LXII (1.0 equiv.) in dry toluene (10 mL / mmol) was added 3-fluoro-4-(piperidin-1-yl)aniline (XVI) (0.8 equiv.), followed by the dropwise addition of trimethylaluminum (1 M in toluene, 4.0 equiv.) at 0° C., and the resulting reaction mixture was stirred at 90° C. for 16 hours. Upon completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography to give examples of the basic structure LXIII.

[0422] All amines used as starting materials were purchased from commercial providers.

[0423] Example 89 The compound described above was synthesized utilizing the procedure outlined in the scheme above, where the amine in step 1 is 6,6-difluoro-2-azaspiro[3.3]heptane, to yield 2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (25 mg, 19.39%).

[0424] Example 90 The compound described above was synthesized utilizing the procedure outlined in the scheme above, where the amine in step 1 was 2-oxa-6-azaspiro[3.4]octane, to yield N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)oxazole-4-carboxamide (54 mg, 43.4%).

[0425] Preparation of intermediate 2-chloro-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (LXVI):

[0426] [ka]

[0427] Step 1: To a solution of ethyl 2-chloro-5-methyloxazole-4-carboxylate (2.9 g, 15.4 mmol) in THF (4 mL) was added a solution of LiOH.HO (0.96 g, 23 mmol) in water (2 mL) at 0 °C, which was then stirred at room temperature for 3 h. After completion [monitored by LC-MS], the reaction mixture was acidified with aqueous HCl (1 N) and partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 2.4 g of 2-chloro-5-methyloxazole-4-carboxylic acid (LXIV) as an off-white solid (96%).

[0428] Step 2: To a stirred solution of 2-chloro-5-methyloxazole-4-carboxylic acid (0.82 g, 5.09 mmol) and 3-fluoro-4-(piperidin-1-yl)aniline (1 g, 5.6 mmol) in DMF (3 mL) was added DIPEA (1.9 g, 15.28 mmol), EDC (1.7 g, 9.16 mmol), and HOBT (1.2 g, 9.6 mmol), and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by LC-MS), the reaction mixture was partitioned between EtOAc (50 mL) and water (200 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 10% EtOAc-hexane as the eluent to give 2-chloro-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (LXV) (0.47 g, 27.3%).

[0429] Preparation of Examples Having Basic Structure LXVI:

[0430] [ka]

[0431] Step 1: To a suspension of 2-chloro-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (LXV) and CsCO (1.5 equivalents) in dioxane, an amine (2 equivalents) was added, which was then heated at 90° C. for 16 hours. After completion (monitored by LC-MS), the reaction mixture was filtered through a sintered glass frit. The organic layer was separated and concentrated under reduced pressure. The resulting crude was purified by silica flash column chromatography using a gradient elution of EtOAc-hexane or MeOH-DCM to give examples with the basic structure LXVI.

[0432] Example 91 The compound described above was synthesized using the procedure outlined in the scheme above, where the amine in step 1 was 5-azaspiro[2.4]heptane, to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(5-azaspiro[2.4]heptan-5-yl)oxazole-4-carboxamide (30 mg, 25%).

[0433] Example 92 The compound described above was synthesized using the procedure outlined in the scheme above, where the amine in step 1 was 6-azaspiro[3.4]octane, to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(6-azaspiro[3.4]octan-6-yl)oxazole-4-carboxamide (70 mg, 56%).

[0434] Example 93 The compound above was synthesized using the procedure outlined in the scheme above, where the amine in step 1 was pyrrolidin-2-ylmethanol, to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-5-methyloxazole-4-carboxamide (20 mg, 24%).

[0435] Example 94 The compound above was synthesized using the procedure outlined in the scheme above where the amine in step 1 was 1-cyclopropylpiperazine to give 2-(4-cyclopropylpiperazin-1-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (20 mg, 23%).

[0436] Example 95 The compound described above was synthesized utilizing the procedure outlined in the scheme above where the amine in step 1 was 1-oxaspiro[4.4]nonan-6-amine to give 2-((1-oxaspiro[4.4]nonan-6-yl)amino)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (30 mg, 23%).

[0437] Example 96

[0438] [ka]

[0439] Step 1: To a suspension of ethyl 2-chloro-5-methyloxazole-4-carboxylate (200 mg, 1.05 mmol) and CsCO (687 mg, 2.11 mmol) in dioxane, pyrrolidin-3-ylmethanol (128 mg, 1.26 mmol) was added, which was then heated at 90 °C for 16 h. After completion [monitored by LC-MS], the reaction mixture was filtered through a sintered glass filter. The organic layer was separated and concentrated under reduced pressure. The resulting crude material was purified by silica flash column chromatography using 30% EtOAc-hexane to afford ethyl 2-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-methyloxazole-4-carboxylate LXVII as a pale yellow solid (90 mg, 33%).

[0440] Step 2: To a solution of ethyl 2-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-methyloxazole-4-carboxylate (90 mg, 0.35 mmol) in THF (5 mL) was added a solution of LiOH.HO (27 mg, 0.7 mmol) in water (1 mL) at 0 °C, which was then stirred at room temperature for 3 h. After completion [monitored by LC-MS], the reaction mixture was acidified with aqueous HCl (1 N) and partitioned between EtOAc (50 mL) and water (25 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 2-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-methyloxazole-4-carboxylic acid as an off-white solid (LXVIII) (77 mg, 96%).

[0441] Step 3: To a stirred solution of 2-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-methyloxazole-4-carboxylic acid (77 mg, 0.34 mmol) and 3-fluoro-4-(piperidin-1-yl)aniline (72 mg, 0.37 mmol) in DMF (3 mL), DIPEA (0.13 mL, 1 mmol), EDC (98 mg, 0.51 mmol), and HOBT (68 mg, 0.51 mmol) were added, and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion [monitored by LC-MS], the reaction mixture was partitioned between EtOAc (30 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by silica flash column chromatography using 30% EtOAc-hexane as the eluent to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-methyloxazole-4-carboxamide (Example 96) (50 mg, 36%).

[0442] Amines were obtained from commercial suppliers.

[0443] Example 97 The compound above was synthesized using the procedure outlined in the scheme above, where the amine in step 1 was 3-hydroxy-pyrrolidine, to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(3-hydroxypyrrolidin-1-yl)-5-methyloxazole-4-carboxamide (35 mg, 20%).

[0444] Example 98 The compound described above was synthesized using the procedure outlined in the scheme above, where the amine in step 1 was 3-oxa-8-azabicyclo[3.2.1]octane, to give 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (90 mg, 43%).

[0445] Preparation of Examples Having General Formula LXXIV (Examples 99-104):

[0446] [ka]

[0447] Step 1: To a mixture of ethyl 2-chloro-5-methyloxazole-4-carboxylate (LXI) (4.4 g, 23.21 mmol) in benzene, NBS (6.16 g, 34.82 mmol) and DBPO (1.12 g, 4.64 mmol) were added, and then heated at 70 °C for 9 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The crude material was purified by silica flash column chromatography using 5% ethyl acetate in hexane as the eluent to give ethyl 5-(bromomethyl)-2-chlorooxazole-4-carboxylate (LXVIII) (4.6 g, 73%) as a pale yellow liquid.

[0448] Step 2: To a solution of ethyl 5-(bromomethyl)-2-chlorooxazole-4-carboxylate (5.5 g, 20.52 mmol) in DMF (50 mL) was added sodium acetate (3.36 g, 41.04 mmol) at room temperature, which was then stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered, and the filtrate was diluted with ethyl acetate, washed with water, and concentrated to give the crude material, which was purified by silica gel flash column chromatography using 10% EtOAc / hexane as the eluent to give ethyl 5-(acetoxymethyl)-2-chlorooxazole-4-carboxylate (LXIX) (3.3 g, 64.94%) as a pale yellow liquid.

[0449] Step 3: To a suspension of ethyl 5-(acetoxymethyl)-2-chlorooxazole-4-carboxylate (1.2 g, 4.85 mmol) and CsCO (3.16 g, 9.71 mmol) in dioxane (15 mL), amine (7.29 mmol) was added, and the resulting mixture was heated at 90 °C for 16 h. After completion of the reaction [monitored by TLC], the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography using 30% EtOAc in hexane as the eluent to give intermediate LXX (0.51 g, 37.19%) as a liquid.

[0450] Step 4: To a suspension of LXX in EtOH (15 mL) was added K2CO3 (1.34 g, 9.71 mmol), which was then stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography using 80% EtOAc in hexane as an eluent to give intermediate LXXI (0.71 g, 60.83%) as an off-white solid.

[0451] Step 5: To a stirred solution of LXXI (1.0 equiv.) in DMF (5 mL / mmol) was added NaH (2.0 equiv.) in small portions under ice-cooled conditions. After 15 min, R c I (3.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. After completion [monitored by TLC], the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The resulting crude material was purified by silica gel flash column chromatography using EtOAc-hexane as the eluent to give LXXII as an off-white solid.

[0452] Step 6: To a solution of LXXII (1 eq) in THF (5 mL) was added a solution of LiOH.HO (3 eq) in water (1 mL) at 0 °C, which was then stirred at room temperature for 3 h. After completion [monitored by LC-MS], the reaction mixture was acidified with aqueous HCl (1 N) and partitioned between EtOAc and water. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the acid product of structure LXXIII.

[0453] Step 7: To a stirred solution of LXXIII (0.18 mmol) and the appropriate fluoroaniline (1 equiv.) in DMF (3 mL), DIPEA (0.057 mL, 0.56 mmol), EDC (54 mg, 0.28 mmol), and HOBT (38 mg, 0.28 mmol) were added, and the resulting reaction mixture was stirred at room temperature for 16 h. After completion (monitored by LC-MS), the reaction mixture was partitioned between EtOAc (50 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash column chromatography using 10% EtOAc-hexane as the eluent to afford the pure final product of general formula LXXIV. All amines used as starting materials were purchased from commercial providers.

[0454] Example 99 The above compound was synthesized by the general procedure outlined in the scheme above, utilizing pyrrolidine as the amine in step 3, iodomethane in step 5, and 3-fluoro-4-(piperidin-1-yl)aniline in step 7 to yield N-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (15 mg, 15%).

[0455] Example 100 The above compound was synthesized by the general procedure outlined in the scheme above, utilizing pyrrolidine as the amine in step 3, iodoethane in step 5, and 3-fluoro-4-(piperidin-1-yl)aniline in step 7 to yield 5-(ethoxymethyl)-N-[3-fluoro-4-(piperidin-1-yl)phenyl]-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (19 mg, 24.3%).

[0456] Example 101 The above compound was synthesized by the general procedure outlined in the scheme above, utilizing pyrrolidine as the amine in step 3, iodomethane in step 5, and 4-(cyclopentyloxy)-3-fluoroaniline in step 7 to yield N-[4-(cyclopentyloxy)-3-fluorophenyl]-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (19 mg, 24.3%).

[0457] Example 102 The above compound was synthesized by the general procedure outlined in the scheme above, utilizing pyrrolidine as the amine in step 3, iodomethane in step 5, and 3,5-difluoro-4-(piperidin-1-yl)aniline in step 7 to yield N-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (32 mg, 19%).

[0458] Example 103 The above compound was synthesized by the general procedure outlined in the scheme above, utilizing 2-methylpyrrolidine as the amine in step 3, iodomethane in step 5, and 3-fluoro-4-(piperidin-1-yl)aniline in step 7 to yield N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-(methoxymethyl)-2-(2-methylpyrrolidin-1-yl)oxazole-4-carboxamide (80 mg, 23%).

[0459] Example 104 The above compound was synthesized by the general procedure outlined in the scheme above, utilizing 2-6,6-difluoro-2-azaspiro[3.3]heptane as the amine in step 3, iodomethane in step 5, and 3-fluoro-4-(piperidin-1-yl)aniline in step 7 to yield 2-{6,6-difluoro-2-azaspiro[3.3]heptan-2-yl}-N-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(methoxymethyl)oxazole-4-carboxamide (10 mg, 7%).

[0460] Example 105 The above compound was synthesized by the general procedure outlined in the scheme above, utilizing pyrrolidine as the amine in step 3, iodomethane in step 5, and 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline in step 7 to yield N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (12 mg, 9.9%).

[0461] Example 106

[0462] [ka]

[0463] Step 1. To a stirred solution of t-butyl-3-formylpyrrolidine-1-carboxylate (100 mg, 0.503 mmol) and azetidine (34 mg, 0.603 mmol) in methanol, one drop of acetic acid was added. The reaction was stirred at room temperature for 3 hours. Then, sodium cyanoborohydride (62 mg, 1.0 mmol) was added to the reaction mixture at 0°C and stirred overnight. After completion of the reaction [monitored by GCMS], the reaction mass was concentrated to remove methanol. The crude material was diluted with DCM and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography to give t-butyl 3-(azetidin-1-ylmethyl)pyrrolidine-1-carboxylate LXXVI (90 mg, 74.5%) as a viscous liquid.

[0464] Step 2: To a stirred solution of t-butyl 3-(azetidin-1-ylmethyl)pyrrolidine-1-carboxylate (90 mg, 0.38 mmol) in 1,4-dioxane (1 mL) was added HCl in 1,4-dioxane (4 M, 1.0 mL, 4.0 mmol) at 0° C., followed by stirring at room temperature for 3 hours. The reaction mixture was then concentrated to give crude 3-(azetidin-1-ylmethyl)pyrrolidine hydrochloride (LXXVII) (60 mg) as a viscous liquid, which was used directly in Step 3.

[0465] Step 3: To a stirred solution of LXXVII (60 mg, 0.34 mmol) in dioxane, cesium carbonate (328 mg, 1.023 mmol) was added, followed by intermediate LXV (80 mg, 0.239 mmol), and the mixture was heated at 90° C. for 6 hours. After completion of the reaction (monitored by LC-MS), the reaction mass was filtered, and the filtrate was evaporated to give the crude product. The crude material was purified by silica gel chromatography using 5% MeOH in DCM to give 2-(3-(azetidin-1-ylmethyl)pyrrolidin-1-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (Example 106) (30 mg, 20%).

[0466] Example 107

[0467] [ka]

[0468] Step 1. To a stirred solution of tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (100 mg, 0.38 mmol) and 4,4-difluoropiperidine (46 mg, 0.38 mmol) in DMF (3 mL) was added cesium carbonate (365 mg, 1.141 mmol). The reaction was then heated at 80° C. After completion of the reaction (monitored by TLC), the reaction mass was filtered. The filtrate was diluted with ethyl acetate (10 mL) and washed with water (2×20 mL). The organics were concentrated to give the crude product, which was purified by silica gel column chromatography using 55% EtOAc-hexane as the eluent to give tert-butyl 3-((4,4-difluoropiperidin-1-yl)methyl)pyrrolidine-1-carboxylate (LXXIX) (110 mg, 95%).

[0469] Step 2: To a stirred solution of tert-butyl-3-((4,4-difluoropiperidin-1-yl)methyl)pyrrolidine-1-carboxylate (100 mg, 0.33 mmol) in 1,4-dioxane (2 mL) was added HCl in 1,4-dioxane (4 M, 1.0 mL, 4.0 mmol) at 0° C., followed by stirring at room temperature for 3 hours. The reaction mixture was then concentrated to give 4,4-difluoro-1-(pyrrolidin-3-ylmethyl)piperidine hydrochloride LXXX (68 mg) as a viscous liquid, which was used crude in the next step.

[0470] Step 3: To a stirred solution of 4,4-difluoro-1-(pyrrolidin-3-ylmethyl)piperidine hydrochloride LXXX (68 mg, 0.29 mmol) and cesium carbonate (235 mg, 0.712 mmol) in dioxane (5 mL), 2-amino-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide LXV (80 mg, 0.24 mmol) was added and the reaction mixture was heated at 90° C. for 6 hours. After completion of the reaction [monitored by LC-MS], the reaction mass was filtered and the filtrate was evaporated to give the crude product. The crude material was purified by silica gel chromatography using 70% ethyl acetate in hexane as the eluent to give 2-(3-((4,4-difluoropiperidin-1-yl)methyl)pyrrolidin-1-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (Example 107) (30 mg, 20%).

[0471] Examples 108 and 109

[0472] [ka]

[0473] Step 1: To a solution of ethyl 5-(hydroxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxylate (200 mg, 0.83 mmol) in isopropanol (2 mL) was added yttrium triflate (45 mg, 0.083 mmol) at room temperature, and the mixture was stirred at 70 °C for 2 hours. After completion [monitored by TLC], the reaction mixture was quenched with a saturated solution of NaHCO and extracted with ethyl acetate. The combined organic layers were dried over anhydrous NaSO and concentrated to give the crude product. The crude was purified by silica gel flash column chromatography using ethyl acetate to give ethyl 5-(isopropoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxylate LXXXI (22 mg, 9.3%) as a solid.

[0474] Step 2: To a stirred solution of ethyl 5-(isopropoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxylate LXXXI (60 mg, 0.19 mmol) and 3-fluoro-4-(piperidin-1-yl)aniline LXV (38 mg, 0.17 mmol) in dry toluene (3 mL), trimethylaluminum (0.4 mL, 0.80 mmol) was added at 0 °C, and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and partitioned with EtOAc (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 20-30% EtOAc-hexane as the eluent to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-(isopropoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (Example 108) (15 mg, 17%) as an off-white solid.

[0475] Step 3: To a stirred solution of ethyl 5-(isopropoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxylate LXXXI (50 mg, 0.177 mmol) and 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline XII (31 mg, 0.16 mmol) in dry toluene (3 mL), trimethylaluminum (0.35 mL, 0.70 mmol) was added at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and partitioned with EtOAc [2×10 mL]. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography using 20-30% EtOAc-hexane as the eluent to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-(isopropoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (Example 109) (20 mg, 26.2%).

[0476] General scheme for synthesizing Examples 110 and 111

[0477] [ka]

[0478] Step 1. To a stirred solution of LXXXII (1 equivalent) in ethyl acetate and DCM (6:4 ratio), CuBr2 (3.5 equivalents) was added at room temperature. The mixture was then heated at 90°C for 16 hours. After completion of the reaction [monitored by TLC], the reaction mixture was filtered through Celite, and the filtrate was concentrated to give crude LXXXIII as a brown viscous liquid (crude), which was used directly in the next step without further purification.

[0479] Step 2: To a solution of LXXXIII (1 eq) in ethanol (200 mL) was added urea (4 eq) at room temperature, and then the mixture was refluxed for 24 hours. After completion of the reaction [monitored by TLC], the reaction mixture was concentrated to remove ethanol. The crude mass was then treated with a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organics were dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude material was purified by trituration with ether. The solid was filtered and dried to give LXXXIV as an off-white solid.

[0480] Step 3: A suspension of CuCl (1.6 equiv.) and tert-butyl nitrite (1.05 equiv.) in acetonitrile (80 mL) was heated to 70° C. and stirred for 15 minutes. A suspension of LXXXIV (1 equiv.) in acetonitrile (120 mL) was added dropwise to the above reaction mixture at 70° C. The reaction was stirred at 70° C. for 16 hours. After completion of the reaction [monitored by TLC], the reaction mixture was concentrated to remove volatiles, then diluted with ethyl acetate (250 mL) and water (250 mL) and filtered through Celite. The organic layer was separated, dried over anhydrous NaSO, and concentrated to give the crude product. The crude material was purified by silica gel column chromatography using 5% ethyl acetate in hexane to give LXXXV (5.6 g, 62.77%) as a colorless liquid.

[0481] Step 4: To a stirred solution of pyrrolidine (1.2 equiv.) and CsCO (3.0 equiv.) in dioxane (30 mL / g), LXXXV (1.0 equiv.) was added, and the resulting reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction [monitored by TLC], the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove volatiles. The resulting crude material was purified by silica gel column chromatography to give LXXXVI.

[0482] Step 5: To a stirred solution of LXXXVI (1.0 equiv.) in dry toluene (10 mL) was added 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline XII (0.8 equiv.), followed by cooling to 0° C. and dropwise addition of trimethylaluminum (1 M in toluene, 4.0 equiv.), and the resulting reaction mixture was heated at 90° C. for 16 h. After completion [monitored by TLC], the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give LXXXVII.

[0483] Example 110 The above compound was synthesized utilizing the general procedure outlined in the scheme above, using ethyl 2-oxohexanoate as the keto-ester in step 1 to yield N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-propyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (20 mg, 17%).

[0484] Example 111 The above compound was synthesized utilizing the general procedure outlined in the scheme above, using ethyl 5-methyl-2-oxohexanoate as the keto-ester in step 1 to give N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-isobutyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (25 mg, 31%).

[0485] General scheme for synthesizing Examples 112-123

[0486] [ka]

[0487] Step 1. To a mixture of commercially available ethyl 2-bromo-5-methyloxazole-4-carboxylate (1 equivalent) in DMF was added K2CO3 (1 equivalent) and commercially available amine (1.2 equivalents). The resulting solution was heated to 90 °C and stirred thoroughly for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and treated with a solution of 0.1 M NaOH in EtOH (2 equivalents). After completion of the reaction, HCl (2 M aqueous solution) was added and the material was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and evaporated under reduced pressure to give intermediate LXXVIII, which was used in the next step without purification.

[0488] Step 2. To the carboxylic acid derivative LXXXVIII (1 equivalent) in DCM was added HATU (1.2 equivalents) and TEA (3 equivalents). The solution was stirred for 10 minutes, after which the appropriate commercially available aniline (1.2 equivalents) was added. The reaction was stirred at room temperature for 12 hours. After evaporation of the solvent under reduced pressure, examples of the basic structure LXXXIX were obtained by purification as described below.

[0489] Amine derivatives are from commercial suppliers.

[0490] Example 112 The title compound was prepared following the general procedure shown in the above scheme, utilizing pyrrolidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by HPLC (linear gradient, 30% to 80% HO in CHCN) to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (32%).

[0491] Example 113 The title compound was prepared following the general procedure shown in the above scheme, utilizing pyrrole as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexane to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(1H-pyrrol-1-yl)oxazole-4-carboxamide (50%).

[0492] Example 114 The title compound was prepared following the general procedure shown in the above scheme, utilizing piperidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by HPLC (linear gradient, 30% to 95% HO in CHCN) to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(piperidin-1-yl)oxazole-4-carboxamide (41%).

[0493] Example 115 The title compound was prepared following the general procedure shown in the above scheme, utilizing isopropylmethylamine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by HPLC (linear gradient, HO 30% to 95%) to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(isopropyl(methyl)amino)-5-methyloxazole-4-carboxamide (37%).

[0494] Example 116 The title compound was prepared following the general procedure shown in the above scheme, utilizing morpholine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexane to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-morpholinoxazole-4-carboxamide (Y=42%).

[0495] Example 117 The title compound was prepared following the general procedure shown in the above scheme, utilizing dimethylamine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexane to afford 2-(dimethylamino)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (52%).

[0496] Example 118 The title compound was prepared following the general procedure shown in the above scheme, utilizing pyrazole as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexane to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(1H-pyrazol-1-yl)oxazole-4-carboxamide (48%).

[0497] Example 119 The title compound was prepared following the general procedure shown in the above scheme, utilizing 2-methylpyrrolidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by HPLC (linear gradient, HO 30% to 95%) to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(2-methylpyrrolidin-1-yl)oxazole-4-carboxamide (38%).

[0498] Example 120 The title compound was prepared following the general procedure shown in the above scheme, utilizing pyrrolidine as the amine in step 1 and commercially available aniline CAS: 1039868-84-2 in step 2. Purification was achieved by HPLC (linear gradient, HO 30% to 80%) to afford N-(4-(cyclopentyloxy)-3-fluorophenyl)-5-methyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (55%).

[0499] Example 121 The title compound was prepared following the general procedure shown in the above scheme, utilizing 3,3-difluoropyrrolidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by HPLC (linear gradient, HO 30% to 95%) to afford 2-(3,3-difluoropyrrolidin-1-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (67%).

[0500] Example 122 The title compound was prepared following the general procedure shown in the above scheme, utilizing 3-methylpyrrolidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by HPLC (linear gradient, HO 30% to 95%) to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(3-methylpyrrolidin-1-yl)oxazole-4-carboxamide (38%).

[0501] Example 123 The title compound was prepared following the general procedure shown in the above scheme, utilizing (3aR,6aR)-hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was achieved by HPLC (linear gradient, HO 30% to 95%) to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-((3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-5-methyloxazole-4-carboxamide (36%).

[0502] Basic conditions for preparing examples of the general formula identified by structure XCV (Examples 124-190):

[0503] [ka]

[0504] Step 1. To a stirred solution of XC (1.0 equiv.) and XCI (1.2 equiv.) in DMSO (3 mL / mmol) was added KOH (3.0 equiv.). The reaction was stirred at room temperature for 2 h. Upon completion (monitored by TLC), the resulting reaction mixture was partitioned between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography using EtOAc in hexane as the eluent to give the desired product XCII.

[0505] Step 2: To a stirred solution of XCII (1.0 equiv.) in 1,4 dioxane:water (5:1) (3 mL / mmol) was added zinc powder (5.0 equiv.) and ammonium chloride (6.0 equiv.) at 0°C. This was then stirred at room temperature for 3 h. Upon completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography to give pure XCIII.

[0506] Step 3: To a stirred solution of intermediate XVII (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / mmol), an amine of general formula RNH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 2 h. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by flash column chromatography to afford intermediates of general formula XCIV.

[0507] Step 4: To a stirred solution of XCIV (1.0 equiv.) in dry toluene (30 mL / g) was added compound XCIII (0.8 equiv.) from Step 2, followed by dropwise addition of trimethylaluminum (2 M in toluene, 4.0 equiv.) at 0° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to give examples with the general formula XCV.

[0508] All amines used as starting materials were purchased from commercial suppliers.

[0509] Synthesis of amines (RNH)

[0510] [ka]

[0511] Step 1: To a stirred solution of tert-butyl 3,3-bis(hydroxymethyl)azetidine-1-carboxylate XCVI (300 mg, 1.38 mmol) in DMF (5 mL) was added NaH (221.19 mg, 5.52 mmol, 60% in oil) at 0 °C. After 20 min of stirring, CHCl (783 mg, 5.53 mmol) was added to the reaction mixture, which was then stirred at room temperature for 16 h. Upon completion (monitored by TLC), the resulting reaction mixture was quenched with saturated NH Cl solution and partitioned between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography using EtOAc in hexane as the eluent to afford the desired product, tert-butyl 3,3-bis(methoxymethyl)azetidine-1-carboxylate XCVII (245 mg, 72%), as a colorless oil.

[0512] Step 2: Tert-butyl 3,3-bis(methoxymethyl)azetidine-1-carboxylate XCVII (490 mg, 1.99 mmol) was dissolved in 4 N HCl in dioxane (5 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, triturated with diethyl ether, and dried to give the desired compound, 3,3-bis(methoxymethyl)azetidine hydrochloride, XCVIII (300 mg, 83%), as a colorless viscous liquid.

[0513] All alcohols used as starting materials were purchased from commercial suppliers.

[0514] Synthesis of spiro[3.5]nonan-6-ol

[0515] [ka]

[0516] To a stirred solution of spiro[3.5]nonan-6-one, XCIX (100 mg, 0.72 mmol) in CHOH (5 mL) was added NaBH (82.4 mg, 2.17 mmol) under ice-cold conditions, and the reaction mixture was stirred at room temperature for 1 h. Upon completion, the reaction was quenched with acetone and concentrated in vacuo to give the crude product. The crude product was then partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired alcohol spiro[3.5]nonan-6-ol, C (90 mg, 89%) as a pale yellow solid.

[0517] Example 124 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-(methoxymethyl)-3-methylazetidine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-methylphenyl)-2-(3-(methoxymethyl)-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (35 mg, 23%).

[0518] Example 125 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-(methoxymethyl)-3-ethylazetidine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-methylphenyl)-2-(3-(methoxymethyl)-3-ethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 26%).

[0519] Example 126 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1-chloro-2,3-difluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and (3-ethylazetidin-3-yl)methanol hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-2-(3-ethyl-3-(hydroxymethyl)azetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (55 mg, 43%).

[0520] Example 127 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1-chloro-2,3-difluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 31%).

[0521] Example 128 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and (3-methylazetidin-3-yl)methanol as the amine in step 3 to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-methylphenyl)-2-(3-(methoxymethyl)-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 39%).

[0522] Example 129 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC, bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1, and (3-methylazetidin-3-yl)methanol as the amine in step 3 to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-fluoro-5-methylphenyl)-2-(3-(hydroxymethyl)-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 12%).

[0523] Example 130 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1-chloro-2,3-difluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-methoxy-3-methylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (45 mg, 28%).

[0524] Example 131 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-methylphenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (13 mg, 9%).

[0525] Example 132 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, spiro[2.5]octan-5-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield 2-(3,3-diethylazetidin-1-yl)-N-(3,5-difluoro-4-(spiro[2.5]octan-5-yloxy)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (70 mg, 46%).

[0526] Example 133 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, 3-oxabicyclo[3.2.1]octan-8-ol as the alcohol in step 1, and 3-methoxy-3-methylazetidine hydrochloride as the amine in step 3, to yield N-(4-((8-oxabicyclo[3.2.1]octan-3-yl)oxy)-3-fluorophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 21%).

[0527] Example 134 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, spiro[3.5]nonan-6-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield 2-(3,3-diethylazetidin-1-yl)-N-(3,5-difluoro-4-(spiro[3.5]nonan-6-yloxy)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 41%).

[0528] Example 135 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1, and (3-methylazetidin-3-yl)methanol as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-fluorophenyl)-2-(3-(hydroxymethyl)-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (55 mg, 32.36%).

[0529] Example 136 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, bicyclo[1.1.1]pentan-1-ylmethanol as the alcohol in step 1, and pyrrolidine as the amine in step 3, to yield N-(4-(bicyclo[1.1.1]pentan-1-ylmethoxy)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 18.6%).

[0530] Example 137 The above compound was synthesized using the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, tetrahydro-2H-pyran-3-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield 2-(3,3-diethylazetidin-1-yl)-N-(3,5-difluoro-4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 37.97%).

[0531] Example 138 The above compound was synthesized using the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, spiro[2.4]heptan-5-ol as the alcohol in step 1, and pyrrolidine as the amine in step 3, to yield N-(3,5-difluoro-4-(spiro[2.4]heptan-5-yloxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (14 mg, 7.02%).

[0532] Example 139 The above compound was synthesized using the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, spiro[3.3]heptan-2-ol as the alcohol in step 1, and pyrrolidine as the amine in step 3, to yield N-(3,5-difluoro-4-(spiro[3.3]heptan-2-yloxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (21 mg, 13.48%).

[0533] Example 140 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, bicyclo[3.1.0]hexan-2-ol as the alcohol in step 1, and 3,3-dimethylazetidine hydrochloride as the amine in step 3, to yield N-(4-(bicyclo[3.1.0]hexan-2-yloxy)-3-fluorophenyl)-2-(3,3-dimethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 29.77%).

[0534] Example 141 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, bicyclo[2.2.1]heptan-2-ol as the alcohol in step 1, and pyrrolidine as the amine in step 3, to yield N-(4-(bicyclo[2.2.1]heptan-2-yloxy)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (17 mg, 10.23%).

[0535] Example 142 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 2,3-difluoro-5-nitrobenzonitrile as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-methoxy-3-methylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-cyano-5-fluorophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (27 mg, 48%).

[0536] Example 143 The above compound was synthesized using the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1, and pyrrolidine as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 12%).

[0537] Example 144 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and hexahydro-1H-furo[3,4-b]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(hexahydro-1H-furo[3,4-b]pyrrol-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 29%).

[0538] Example 145 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3,5-difluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (28 mg, 17.7%).

[0539] Example 146 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 2-fluoro-5-nitrobenzonitrile as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-methoxy-3-methylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-cyanophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 6%).

[0540] Example 147 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and N-(2-methoxyethyl)-2-methylpropan-1-amine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(isobutyl(2-methoxyethyl)amino)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 16%).

[0541] Example 148 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (15 mg, 10%).

[0542] Example 149 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-fluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 33%).

[0543] Example 150 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, bicyclo[2.2.1]heptan-2-ol as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine as the amine in step 3, to yield N-(4-(bicyclo[2.2.1]heptan-2-yloxy)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19%).

[0544] Example 151 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, (1S,4R)-bicyclo[2.2.1]heptan-2-ol as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine as the amine in step 3 to yield N-(4-(((1S,4R)-bicyclo[2.2.1]heptan-2-yl)oxy)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (15 mg, 10%).

[0545] Example 152 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and N-(2-methoxyethyl)propan-1-amine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-((2-methoxyethyl)(propyl)amino)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (45 mg, 29%).

[0546] Example 153 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and tetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (36 mg, 22%).

[0547] Example 154 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 2-azabicyclo[3.1.0]hexane as the amine in step 3, to yield 2-(2-azabicyclo[3.1.0]hexan-2-yl)-N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 10%).

[0548] Example 155 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, bicyclo[3.1.0]hexan-2-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield N-(4-(bicyclo[3.1.0]hexan-2-yloxy)-3,5-difluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 27%).

[0549] Example 156 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-azabicyclo[3.1.0]hexane as the amine in step 3, to yield 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 24%).

[0550] Example 157 The above compound was synthesized using the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and N-(2-methoxyethyl)propan-1-amine as the amine in step 3, to give hexahydro-2H-furo[3,2-b]pyrrole (35 mg, 38%).

[0551] Example 158 The above compound was synthesized using the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, tetrahydro-2H-pyran-3-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to give 2-(3,3-diethylazetidin-1-yl)-N-(3-fluoro-4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 22%).

[0552] Example 159 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-methoxy-3-ethylazetidine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (52 mg, 35%).

[0553] Example 160 The above compound was synthesized using the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, tetrahydro-2H-pyran-3-ol as the alcohol in step 1, and 3-methoxy-3-ethylazetidine as the amine in step 3, to give N-(3,5-difluoro-4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (52 mg, 33%).

[0554] Example 161 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-azabicyclo[3.2.0]heptane as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(3-azabicyclo[3.2.0]heptan-3-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 37.37%).

[0555] Example 162 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and octahydrocyclopenta[b]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(hexahydrocyclopenta[b]pyrrole-1(2H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (18 mg, 10%).

[0556] Example 163 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and octahydro-1H-indole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(octahydro-1H-indol-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (17 mg, 11.21%).

[0557] Example 164 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-methoxy-3-methylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-methylphenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 10.79%).

[0558] Example 165 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-(methoxymethyl)-3-ethylazetidine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3-ethyl-3-(methoxymethyl)azetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 26%).

[0559] Example 166 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 5,6-dihydro-4H-pyrrolo[3,4-c]isoxazole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(4H-pyrrolo[3,4-c]isoxazol-5(6H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 52%).

[0560] Example 167 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-methoxy-3-ethylazetidine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 30%).

[0561] Example 168 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3,3-bis(methoxymethyl)azetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3,3-bis(methoxymethyl)azetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (45 mg, 30%).

[0562] Example 169 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1, and pyrrolidine as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 11.58%).

[0563] Example 170 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 1-azaspiro[3.3]heptane as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(1-azaspiro[3.3]heptan-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 17.76%).

[0564] Example 171 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 7-oxa-2-azaspiro[3.5]nonane as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (70 mg, 45.58%).

[0565] Example 172 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 2,2-dimethylpyrrolidine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(2,2-dimethylpyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (15 mg, 19.2%).

[0566] Example 173 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 5-oxa-2-azaspiro[3.4]octane as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (18 mg, 21.3%).

[0567] Example 174 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and azepane as the amine in step 3, to yield 2-(azepan-1-yl)-N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19.23%).

[0568] Example 175 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 2-azabicyclo[2.1.1]hexane as the amine in step 3, to yield 2-(2-azabicyclo[2.1.1]hexan-2-yl)-N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (32 mg, 28%).

[0569] Example 176 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 2,6-dimethylmorpholine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(2,6-dimethylmorpholino)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 32.6%).

[0570] Example 177 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-azabicyclo[3.2.0]heptane as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3-azabicyclo[3.2.0]heptan-3-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19.18%).

[0571] Example 178 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3-methoxy-3-methylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (6.0 g, 38.65%).

[0572] Example 179 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and (3aR,6aR)-hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-((3aR,6aR)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (27 mg, 17.56%).

[0573] Example 180 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and (3aS,6aS)-hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-((3aS,6aS)-hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (32 mg, 20.82%).

[0574] Example 181 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and morpholine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-morpholino-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (38 mg, 40%).

[0575] Example 182 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 2-oxa-5-azabicyclo[2.2.1]heptane as the amine in step 3, to yield 2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (19 mg, 18.2%).

[0576] Example 183 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (22 mg, 15.9%).

[0577] Example 184 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 2,2-dimethylmorpholine as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(2,2-dimethylmorpholino)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (16 mg, 11.6%).

[0578] Example 185 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and octahydrocyclopenta[b]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(hexahydrocyclopenta[b]pyrrole-1(2H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 17%).

[0579] Example 186 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and hexahydro-1H-furo[3,4-c]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 39%).

[0580] Example 187 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 26.96%).

[0581] Example 188 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 7-oxa-2-azaspiro[3.5]nonane as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 39.58%).

[0582] Example 189 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2,3-trifluoro-5-nitrobenzene as compound XC, cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1, and 6-oxa-2-azaspiro[3.4]octane as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(6-oxa-2-azaspiro[3.4]octan-2-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (65 mg, 44%).

[0583] Example 190 The above compound was synthesized utilizing the procedure outlined in the scheme above, using 1,2-difluoro-4-nitrobenzene as compound XC, bicyclo[3.1.0]hexan-3-ylmethanol as the alcohol in step 1, and pyrrolidine as the amine in step 3, to yield N-(4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 15.62%).

[0584] Example 191

[0585] [ka]

[0586] Step 1: To a stirred solution of bicyclo[3.1.0]hexan-3-ol, XVIV (300 mg, 3.12 mmol), NaH (300 mg, 9.37 mmol) in THF (6 mL) was added 2,3-difluoro-5-nitropyridine, CI (500 mg, 3.12 mmol) under ice-cooled conditions, which was then stirred at 70 °C for 3 h. After completion (monitored by TLC), the reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NH₄Cl. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography using 5% EtOAc in hexane as the eluent to afford 2-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-nitropyridine, CII (295 mg, 39%) as a pale yellow oil.

[0587] Step 2: To a stirred solution of 2-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-nitropyridine, CII (295 mg, 1.23 mmol) in 1,4 dioxane:water (6 mL, 5:1), zinc powder (550 mg, 8.66 mmol) was added along with ammonium chloride (463.7 mg, 8.66 mmol) at 0 °C. This was then stirred at room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using 10% EtOAc in hexane as the eluent to give 6-(cis-bicyclo[3.1.0]hexan-3-yloxy)-5-fluoropyridin-3-amine, CIII (180 mg, 69%) as a brown solid.

[0588] Step 3: To a stirred solution of ethyl 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate, i.e., VII (500 mg, 1.95 mmol) and DIPEA (1.77 mL, 9.72 mmol) in dioxane (6 mL), compound 6 (306 mg, 2.04 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude material was purified by flash column chromatography using 20% EtOAc in hexane as the eluent to give ethyl 2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate, i.e., CIV (480 mg, 74%).

[0589] Step 4: To a stirred solution of ethyl 2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate, CIV (100 mg, 0.29 mmol), in dry toluene (5 mL) was added 6-(cis-bicyclo[3.1.0]hexan-3-yloxy)-5-fluoropyridin-3-amine, CIII (50 mg, 0.23 mmol), followed by dropwise addition of trimethylalumina (0.6 mL, 1.2 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 15% EtOAc in hexanes as the eluent to give N-(6-(cis-bicyclo[3.1.0]hexan-3-yloxy)-5-fluoropyridin-3-yl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide, Example 191 (60 mg, 31%).

[0590] General procedure for synthesizing examples of base structure CIX (Examples 192-216).

[0591] [ka]

[0592] Step 1: To a stirred suspension of fluoro-nitrobenzene CV (1.0 equiv.) and KCO (3.0 equiv.) in CHCN (3 mL / g CV) was added R a R b NH (1.2 equiv.) was added, and the resulting reaction mixture was stirred in a sealed tube at 80 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove CHCN. The resulting crude was purified by flash column chromatography to give the intermediate of structure CVI.

[0593] Step 2: To a stirred solution of compound CVI in 1,4 dioxane:water (5:1) was added zinc powder (5.0 equiv.) followed by ammonium chloride (6.0 equiv.) at 0° C. This was then stirred at room temperature for 2 hours. Upon completion (monitored by TLC), the reaction mixture was filtered through a sintered glass. The filtrate was dried over anhydrous NaSO, concentrated under reduced pressure, and purified by flash column chromatography using EtOAc-hexane as the eluent to give intermediate compound CVII.

[0594] Step 3: To a stirred solution of intermediate VII (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / mmol) was added R c R d NH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 16 h. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by CombiFlash column chromatography using EtOAc-hexane as the eluent to give CVIII.

[0595] Step 4: To a stirred solution of CVIII (1.0 equiv.) and CVII (1.0 equiv.) in dry THF (30 mL / g), MeMgCl (3 M in THF, 2.4 equiv.) was added dropwise and stirred at room temperature for 1 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with 1 N HCl, extracted with EtOAc, and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by CombiFlash column chromatography to give the desired compound CIX. Examples 192 to 195 were synthesized under the following condition (ii): To a stirred solution of CVIII (1.0 equiv.) and amine CVII (0.8 equiv.) in dry toluene (30 mL / g CVIII), trimethylaluminum (2 M in toluene, 4.0 equiv.) was added dropwise at 0 °C, and the resulting reaction mixture was stirred at room temperature. After completion [monitored by TLC / LCMS], the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to give the product of basic structure CIX.

[0596] All amines used as starting materials were purchased from chemical suppliers.

[0597] Example 192 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]heptan-3-amine was used as the amine in step 1 [reaction temperature 120° C., reaction time 48 hours], and 3,3-diethylazetidine hydrochloride was used as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-ylamino)-3-fluoro-5-methylphenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 13.3%).

[0598] Example 193 Compound CV is 1,2-difluoro-3-methyl-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, using bicyclo[3.1.1]heptan-3-amine as the amine in step 1 [reaction temperature 120° C., reaction time 48 hours] and pyrrolidine as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-ylamino)-3-fluoro-5-methylphenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (10 mg, 5.42%).

[0599] Example 194 The compound CV is 1,2-difluoro-3-methyl-5-nitrobenzene, and was synthesized using the procedure outlined in the scheme above, where bicyclo[3.2.1]octan-8-amine was used as the amine in step 1 and pyrrolidine was used as the amine in step 3, to yield N-(4-(bicyclo[3.2.1]octan-8-ylamino)-3-fluoro-5-methylphenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 25.48%).

[0600] Example 195 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.2.1]octan-8-amine is used as the amine in step 1, and 3-methoxy-3-methylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(bicyclo[3.2.1]octan-8-ylamino)-3-fluoro-5-methylphenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (15 mg, 10.52%).

[0601] Example 196 Compound CV is 2,3-difluoro-5-nitrobenzonitrile, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where 8-azabicyclo[3.2.1]octane was used as the amine in step 1 and 3-methoxy-3-methylazetidine hydrochloride was used as the amine in step 3, to yield N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3-cyano-5-fluorophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (77 mg, 28.84%).

[0602] Example 197 Compound CV is 2-fluoro-5-nitrobenzonitrile, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where 8-azabicyclo[3.2.1]octane was used as the amine in step 1 and 3-methoxy-3-methylazetidine hydrochloride was used as the amine in step 3, to yield N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3-cyanophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19.19%).

[0603] Example 198 The above compound was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene and hexahydro-2H-furo[3,2-b]pyrrole is used as the amine in step 1 and pyrrolidine is used as the amine in step 3, to yield N-(3,5-difluoro-4-(hexahydro-4H-furo[3,2-b]pyrrol-4-yl)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 15%).

[0604] Example 199 The compound CV is 1,2,3-trifluoro-5-nitrobenzene, and was synthesized using the procedure outlined in the scheme above, where 8-azabicyclo[3.2.1]octane was used as the amine in step 1 and 1,4-oxazepane was used as the amine in step 3, to give N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-(1,4-oxazepan-4-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 12.53%).

[0605] Example 200 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, 8-azabicyclo[3.2.1]octane as the amine in step 1, and 3,3-dimethylazetidine hydrochloride as the amine in step 3, to yield N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-(3,3-dimethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 18.43%).

[0606] Example 201 The compound CV is 1,2,3-trifluoro-5-nitrobenzene, and was synthesized utilizing the procedures outlined in the scheme above, using 8-azabicyclo[3.2.1]octane as the amine in step 1 and hexahydro-1H-furo[3,4-c]pyrrole as the amine in step 3, to yield N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 31.75%).

[0607] Example 202 The compound CV is 3,4-difluoronitrobenzene, and was synthesized using the procedure outlined in the scheme above, where 3-azabicyclo[3.1.1]heptane was used as the amine in step 1 and 2-oxa-6-azaspiro[3.4]octane was used as the amine in step 3, to give N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3-fluorophenyl)-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 17%).

[0608] Example 203 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane is used as the amine in step 1, and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 11.66%).

[0609] Example 204 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[4.1.0]heptane is used as the amine in step 1, and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(4-(3-azabicyclo[4.1.0]heptan-3-yl)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19.61%).

[0610] Example 205 The above compound was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, octahydrocyclopenta[b]pyrrole is used as the amine in step 1, and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(3,5-difluoro-4-(hexahydrocyclopenta[b]pyrrol-1(2H)-yl)phenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (12 mg, 7.64%).

[0611] Example 206 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, 8-azabicyclo[3.2.1]octane as the amine in step 1, and 3-ethyl-3-methoxyazetidine as the amine in step 3, to yield N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 42.41%).

[0612] Example 207 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, 8-azabicyclo[3.2.1]octane is used as the amine in step 1, and 3-methoxy-3-methylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-(3-methoxy-3-methylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 64.58%).

[0613] Example 208 Compound CV is 1,2,3-trifluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where 3-azabicyclo[3.1.1]heptane was used as the amine in step 1 and 2-oxa-6-azaspiro[3.4]octane was used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19.56%).

[0614] Example 209 Compound CV is 1,2,3-trifluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where 3-azabicyclo[3.1.1]heptane was used as the amine in step 1 and pyrrolidine was used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 22.17%).

[0615] Example 210 Compound CV is 1,2,3-trifluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where 8-azabicyclo[3.2.1]octane was used as the amine in step 1 and pyrrolidine was used as the amine in step 3, to yield N-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (90 mg, 72.39%).

[0616] Example 211 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[4.1.0]heptane is used as the amine in step 1, and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(3-azabicyclo[4.1.0]heptan-3-yl)-3,5-difluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (36 mg, 16.76%).

[0617] Example 212 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 3,4-difluoronitrobenzene, 3-azabicyclo[4.1.0]heptane is used as the amine in step 1, and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(3-azabicyclo[4.1.0]heptan-3-yl)-3-fluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (13 mg, 8.78%).

[0618] Example 213 The above compound was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene and 3,3-dimethylpiperidine is used as the amine in step 1 and pyrrolidine is used as the amine in step 3, to yield N-(4-(3,3-dimethylpiperidin-1-yl)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 15%).

[0619] Example 214 The compound above was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene and octahydrocyclopenta[b]pyrrole is used as the amine in step 1 and pyrrolidine is used as the amine in step 3, to give N-(3,5-difluoro-4-(hexahydrocyclopenta[b]pyrrol-1(2H)-yl)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 23%).

[0620] Example 215 The above compound was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 1,2,3-trifluoro-5-nitrobenzene, piperidine is used as the amine in step 1, and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield 2-(3,3-diethylazetidin-1-yl)-N-(3,5-difluoro-4-(piperidin-1-yl)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (16 mg, 21.35%).

[0621] Example 216 The above compound was synthesized utilizing the procedures outlined in the scheme above, where Compound CV is 3,4-difluoronitrobenzene, piperidine is used as the amine in step 1, and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield 2-(3,3-diethylazetidin-1-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (38 mg, 26.3%).

[0622] Example 217

[0623] [ka]

[0624] Step 1: To a stirred suspension of 1,2-difluoro-3-methyl-5-nitrobenzene CX (281 mg, 1.62 mmol) and KCO (748 mg, 5.42 mmol) in CHCN (10 mL), bicyclo[3.1.1]heptan-3-amine (150 mg, 1.35 mmol) was added, and the resulting reaction mixture was stirred in a sealed tube at 120 °C for 48 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove CHCN. The resulting crude product was purified by CombiFlash column chromatography using 5% EtOAc in hexane as the eluent to afford the intermediate N-(2-fluoro-6-methyl-4-nitrophenyl)bicyclo[3.1.1]heptan-3-amine CXI (250 mg, 69.8%) as a pale yellow solid.

[0625] Step 2: To a stirred ice-cold solution of CXI (100 mg, 0.378 mmol) in DMF (3 mL) was added NaH (45 mg, 1.1 mmol) under a nitrogen atmosphere. Then, MeI (107 mg, 0.757 mmol) was added at 0 °C and stirred at room temperature for 1 h. After completion (monitored by TLC), the reaction mixture was quenched with aqueous NH4Cl (5 mL), extracted with EtOAc, and concentrated under reduced pressure. The resulting crude was then purified by column chromatography using 5% EtOAc in hexane as the eluent to give N-(2-fluoro-6-methyl-4-nitrophenyl)-N-methylbicyclo[3.1.1]heptan-3-amine, i.e., CXII (80 mg, 76%), as a colorless oil.

[0626] Step 3: To a stirred solution of CXII (80 mg, 0.287 mmol) in 1,4-dioxane (8 mL) was added zinc powder (190 mg, 2.84 mmol) under ice-cooled conditions, followed by the addition of ammonium chloride (153 mg, 2.84 mmol) dissolved in water (3 mL). The reaction mixture was stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was filtered through a Celite bed. The filtrate was evaporated, and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography using 30% EtOAc in hexane as the eluent to give N1-(bicyclo[3.1.1]heptan-3-yl)-2-fluoro-N1,6-dimethylbenzene-1,4-diamine CXIII (60 mg, 84%) as a colorless oil.

[0627] Step 4: To a stirred solution of amine CXIII (60 mg, 0.256 mmol) and XCIV (90 mg, 0.307 mmol) in dry THF (5 mL), MeMgCl (0.26 mL, 3 M in THF) was added dropwise and stirred at room temperature for 2 hours. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with 1N HCl, extracted with EtOAc, and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 20% EtOAc in hexane as the eluent to give N-(4-(bicyclo[3.1.1]heptan-3-yl(methyl)amino)-3-fluoro-5-methylphenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide, i.e., Example 217 (32 mg, 25.27%).

[0628] Example 218

[0629] [ka]

[0630] Step 1: To a stirred solution of dimethyl malonate (2.5 mL, 22.599 mmol) in THF (20 mL), NaH (1.50 gm, 22.599 mmol, 60% in oil) was added portionwise under ice-cooled conditions. The resulting reaction mixture was stirred at 0°C for 1 hour. To this was then added a solution of 3,4,5-trifluoronitrobenzene, i.e., CXIV (2.0 g, 11.299 mmol) in THF (5 mL), and the reaction mass was stirred at room temperature for 16 hours. After completion (monitored by TLC), the resulting reaction mixture was partitioned between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 15% EtOAc in hexane as the eluent to give dimethyl 2-(2,6-difluoro-4-nitrophenyl)malonate, i.e., CXV (3.0 g, 91%) as a colorless liquid.

[0631] Step 2: To a stirred solution of dimethyl 2-(2,6-difluoro-4-nitrophenyl)malonate, i.e., CXV (3.0 g, 10.381 mmol) in 0.5 N aqueous NaOH (84 mL) was added solid KMnO (8.2 g, 51.903 mmol) in small portions at 50 °C. The resulting mixture was refluxed at 100 °C for 3 hours. It was then filtered through a Celite bed under hot conditions. The Celite bed was washed with warm water. The aqueous layer was acidified with concentrated HCl to a maximum pH of 1, followed by extraction with ethyl acetate. The combined organic layers were then washed with water and brine solution, dried over anhydrous NaSO, and concentrated under vacuum to give crude 2,6-difluoro-4-nitrobenzoic acid, i.e., CXVI (1.3 gm).

[0632] Step 3: To a stirred solution of 2,6-difluoro-4-nitrobenzoic acid, i.e., CXVI (1.3 g, 6.40 mmol) in THF (27 mL) was added borane-DMS complex (3.6 mL, 38.42 mmol) under ice-cooled conditions. After stirring at room temperature for 2 hours, borane-DMS complex (1.82 mL, 19.22 mmol) was again added to the reaction mixture and heated at 60°C for 3 hours. After completion (monitored by TLC), the resulting reaction mixture was quenched portionwise with MeOH at 0°C and stirred at room temperature for 30 minutes. The reaction mass was then concentrated and the crude product was purified by flash column chromatography using 15% EtOAc in hexane as the eluent to give 2,6-difluoro-4-nitrophenyl)methanol, i.e., CXVII (1.0 gm, 82%) as a colorless liquid.

[0633] Step 4: To an ice-cold solution of 2,6-difluoro-4-nitrophenyl)methanol, i.e., CXVII (500 mg, 2.64 mmol), in DCM, Dess-Martin periodinane (2.46 gm, 5.82 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After TLC analysis, another portion of Dess-Martin periodinane (1.122 gm, 2.64 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 13 hours. Upon completion (monitored by TLC), the resulting reaction mixture was quenched with saturated aqueous NaHCO3 and 10% aqueous sodium thiosulfate, followed by extraction with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by flash column chromatography using 10% EtOAc in hexane as the eluent to give 2,6-difluoro-4-nitrobenzaldehyde, i.e., CXVIII (240 mg, 48%) as a semi-solid.

[0634] Step 5: To a solution of 3-azabicyclo[3.1.0]hexane (244 mg, 2.94 mmol) in methanol (20 mL), DIPEA (864 mg, 6.68 mmol) was added and stirred at room temperature for 15 minutes. 2,6-Difluoro-4-nitrobenzaldehyde, i.e., CXVIII (500 mg, 2.67 mmol), followed by acetic acid (513.36 mg, 8.556 mmol) were then added and stirred at room temperature for 16 hours. Sodium cyanoborohydride (420 mg, 6.68 mmol) was then added to the reaction mass at 0° C. and stirred at room temperature for another 6 hours. After completion (monitored by TLC), the resulting reaction mixture was quenched with NaHCO solution and diluted with DCM. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated to give the crude material, which was purified by Combi-Flash column chromatography using 50% EtOAc in hexane as the eluent to give 3-(2,6-difluoro-4-nitrobenzyl)-3-azabicyclo[3.1.0]hexane or CXIX (260 mg, 38.5) as an off-white solid.

[0635] Step 6: To a solution of 3-[(2,6-difluoro-4-nitrophenyl)methyl]-3-azabicyclo[3.1.0]hexane, i.e., CXIX (240 mg, 0.95 mmol) in dioxane, an aqueous solution of NH4Cl (715 mg, 13.23 mmol) and Zn powder (860 mg, 13.29 mmol) was added, followed by stirring at room temperature for 1.5 h. After completion (monitored by TLC), the reaction mixture was filtered through a Celite bed, and the filtrate was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated to give the crude material, which was purified by CombiFlash column chromatography using 60% EtOAc in hexane as the eluent to give 4-{3-azabicyclo[3.1.0]hexan-3-ylmethyl}-3,5-difluoroaniline, i.e., CXX (150 mg, 70.5%) as an off-white solid.

[0636] Step 7: To an ice-cold solution of ethyl 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate, i.e., XCIV (125.14 mg, 0.429 mmol) in toluene and 4-{3-azabicyclo[3.1.0]hexan-3-ylmethyl}-3,5-difluoroaniline, i.e., CXX (80 mg, 0.357 mmol) in toluene, trimethylalumina (2 M in toluene, 0.80 mL, 1.60 mmol) was added and stirred at room temperature for 1.5 hours. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 40% EtOAc in hexane as the eluent to give N-(4-{3-azabicyclo[3.1.0]hexan-3-ylmethyl}-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)-1,3-oxazole-4-carboxamide, Example 218 (32 mg, 19%).

[0637] Preparation of intermediate ethyl 2-chloro-5-ethyloxazole-4-carboxylate (CXXV):

[0638] [ka]

[0639] Step 1: To a stirred suspension of Mg (25 g, 1033.05 mmol) in THF (20 mL) under a nitrogen atmosphere, 1,2-dibromoethane (1.5 mL) was slowly added, followed by the slow addition of 1-bromopropane (50 g, 413.22 mmol) dissolved in THF (600 mL) [the exotherm was neutralized using a conventional water bath] and stirred at room temperature for 1 h. The resulting Grignard solution was slowly added to a stirred solution of diethyl oxalate, CXXI (45.11 mL, 330.58 mmol), in THF (700 mL). The external temperature was maintained at −78 °C, and the mixture was gradually warmed to 0 °C. After 1.5 h of stirring [monitored by TLC, 10% EtOAc / hexane, Rf −0.2 (KMnO activity)], the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2×500 mL). The organic layer was washed with brine solution (300 mL x 1), dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel (100-200 mesh) with a gradient elution of 10% EtOAc / hexane to give ethyl 2-oxopentanoate, CXXII (42 g, 70.5%) as a light brown liquid.

[0640] Step 2: To a stirred solution of ethyl 2-oxopentanoate, CXXII (150 g, 1041.67 mmol) in a 3:2 EtOAc:DCM mixture (6000 mL), CuBr (464.58 g, 2083.33 mmol) was added, and the reaction mixture was heated to 80 °C for 16 h. Upon completion [monitored by TLC (20% EtOAc / hexanes), Rf -0.3 (KMnO activity)], the reaction mixture was filtered through a sintered funnel, and the filtrate was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude product was purified by column chromatography using silica gel (100-200 mesh) with a gradient elution of 20% EtOAc / hexanes to give ethyl 3-bromo-2-oxopentanoate, CXXIII, as a brown liquid (160 g, 68.86%).

[0641] Step 3: To a stirred solution of ethyl 3-bromo-2-oxopentanoate, CXXIII (330 g, 1479.82 mmol) in ethanol (6600 mL) was added urea (266.37 g, 4439.46 mmol). The reaction was heated to 90 °C for 16 h. Upon completion [monitored by TLC, 20% EtOAc / hexane, Rf -0.1], the reaction mixture was concentrated under reduced pressure. The resulting crude material was diluted with ethyl acetate (1000 mL) and washed with saturated NaHCO3 solution (1 x 500 mL) and brine solution (1 x 300 mL). The organic portion was dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. The crude material was triturated three times with 70% n-pentane in diethyl ether solution [once with approximately 300 mL (70% pentane-ether), followed by twice with approximately 150 mL of the same solvent] to give pure ethyl 2-amino-5-ethyloxazole-4-carboxylate, CXXIV, as an off-white solid (170 g, 62.37%).

[0642] Step 4: To a stirred solution of CuCl (111.42 g, 831.52 mmol) in acetonitrile (4000 mL), tert-butyl nitrite (158.17 mL, 1320.65 mmol) was added and heated to 60° C. for 30 minutes. Ethyl 2-amino-5-ethyloxazole-4-carboxylate, CXXIV (150 g, 815.22 mmol), dissolved in acetonitrile (2000 mL), was then added, and the reaction mixture was heated to 80° C. and stirred for 2 hours. After completion [monitored by TLC (40% EtOAc / hexane, Rf −0.7)], the reaction mixture was concentrated under reduced pressure. The mixture was diluted with EtOAc (2000 mL) and water (1000 mL) and filtered through a Celite bed. The organic portion was separated, washed with brine solution (1×500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by column chromatography using silica gel (100-200 mesh) with a gradient elution of 0-10% EtOAc / hexane to give ethyl 2-chloro-5-ethyloxazole-4-carboxylate, CXXV, as a colorless liquid (115 g, 69.52%).

[0643] Basic conditions for preparing examples of the general formula identified by structure CXXXI (Examples 219-247):

[0644] [ka]

[0645] Step 1. To a stirred solution of CXXVI (1.0 equiv.) and CXXVII (1.2 equiv.) in DMSO (3 mL / mmol) was added KOH (3.0 equiv.). The reaction was stirred at room temperature for 2 h. Upon completion (monitored by TLC), the resulting reaction mixture was partitioned between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography using EtOAc in hexane as the eluent to give the desired product CXXVIII.

[0646] Step 2: 20 mL / g of CXXVIII. To a stirred solution of CXXVIII (1 eq) in 1,4 dioxane:water (5:1) was added zinc powder (7 eq) along with ammonium chloride (7 eq) at 0°C. This was then stirred at room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was filtered through sintered glass. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using EtOAc in hexane to give pure CXXIX.

[0647] Step 3: To a stirred solution of CXXV (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / mmol), RNH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by flash column chromatography using EtOAc in hexane to give pure CXXX.

[0648] Step 4: To a stirred solution of CXXX (1.0 equiv.) and CXXIX (1.0 equiv.) in dry THF (30 mL / g), MeMgCl (3 M in THF, 2.4 equiv.) was added dropwise and stirred at room temperature for 1 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with 1N HCl, extracted with EtOAc, and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by CombiFlash column chromatography to give examples of the basic structure CXXXI. All alcohols and amines used as starting materials were purchased from commercial suppliers.

[0649] Example 219 Compound CXXVI is 1-chloro-2,3-difluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 3-ethyl-3-methoxyazetidine was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (25 mg, 12.29%).

[0650] Example 220 Compound CXXVI is 1-chloro-2,3-difluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and (3-ethylazetidin-3-yl)methanol hydrochloride was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-5-ethyl-2-(3-ethyl-3-(hydroxymethyl)azetidin-1-yl)oxazole-4-carboxamide (30 mg, 11.8%).

[0651] Example 221 Compound CXXVI is 1-chloro-2,3-difluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-ethyloxazole-4-carboxamide (94 mg, 47.59%).

[0652] Example 222 Compound CXXVI is 1-chloro-2,3-difluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and pyrrolidine is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-5-ethyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (40 mg, 22.22%).

[0653] Example 223 Compound CXXVI is 1-chloro-2,3-difluoro-5-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 3-methoxy-3-methylazetidine hydrochloride was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloro-5-fluorophenyl)-5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxamide (45 mg, 23.38%).

[0654] Example 224 Compound CXXVI is 1,2-difluoro-3-methyl-5-nitrobenzene. Using the procedure outlined in the scheme above, where bicyclo[3.1.1]heptan-3-ol is used as the alcohol in step 1 and (3-methylazetidin-3-yl)methanol is used as the amine in step 3, the compound described above was synthesized to give N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-fluoro-5-methylphenyl)-5-ethyl-2-(3-(hydroxymethyl)-3-methylazetidin-1-yl)oxazole-4-carboxamide (30 mg, 17.57%).

[0655] Example 225 Compound CXXVI is 1,2-difluoro-3-methyl-5-nitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, where bicyclo[3.1.1]heptan-3-ol is used as the alcohol in step 1 and pyrrolidine is used as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-fluoro-5-methylphenyl)-5-ethyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (15 mg, 16.71%).

[0656] Example 226 The compound CXXVI is 1,2-difluoro-3-methyl-5-nitrobenzene, and was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 3-methoxy-3-methylazetidine hydrochloride was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-methylphenyl)-5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxamide (20 mg, 20.14%).

[0657] Example 227 The compound CXXVI is 1,2-difluoro-3-methyl-5-nitrobenzene, and was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 3-ethyl-3-methoxyazetidine was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluoro-5-methylphenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (15 mg, 10.28%).

[0658] Example 228 The compound CXXVI is 1,2-difluoro-4-nitrobenzene, and was synthesized utilizing the procedure outlined in the scheme above, where bicyclo[3.1.1]heptan-3-ol is used as the alcohol in step 1 and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-fluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (18 mg, 10.58%).

[0659] Example 229 Compound CXXVI is 3,4,5-trifluoronitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, where bicyclo[3.1.1]heptan-3-ol is used as the alcohol in step 1 and pyrrolidine is used as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (23 mg, 12.7%).

[0660] Example 230 The compound above was synthesized utilizing the procedures outlined in the scheme above, where compound CXXVI is 3,4,5-trifluoronitrobenzene and bicyclo[3.1.1]heptan-3-ol is used as the alcohol in step 1 and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (20 mg, 11.87%).

[0661] Example 231 Compound CXXVI is 3,4,5-trifluoronitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 1,4-oxazepane was used as the amine in step 3, to give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(1,4-oxazepan-4-yl)oxazole-4-carboxamide (12 mg, 6%).

[0662] Example 232 Compound CXXVI is 3,4,5-trifluoronitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and 1H-pyrazole is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(1H-pyrazol-1-yl)oxazole-4-carboxamide (60 mg, 30.96%).

[0663] Example 233 Compound CXXVI is 3,4,5-trifluoronitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, using cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)oxazole-4-carboxamide (30 mg, 18.3%).

[0664] Example 234 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound CXXVI is 3,4,5-trifluoronitrobenzene, tetrahydrofuran-3-ol is used as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(3,5-difluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (30 mg, 18.74%).

[0665] Example 235 The compound CXXVI is 3,4,5-trifluoronitrobenzene, and was synthesized using the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 5-azaspiro[2.4]heptane was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(5-azaspiro[2.4]heptan-5-yl)oxazole-4-carboxamide (20 mg, 11.91%).

[0666] Example 236 The above compound was synthesized utilizing the procedure outlined in the scheme above, where compound CXXVI is 3,4,5-trifluoronitrobenzene, tetrahydro-2H-pyran-3-ol is used as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield 2-(3,3-diethylazetidin-1-yl)-N-(3,5-difluoro-4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)-5-ethyloxazole-4-carboxamide (22 mg, 14.77%).

[0667] Example 237 Compound CXXVI is 3,4,5-trifluoronitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, using cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and hexahydro-1H-furo[3,4-c]pyrrole as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)oxazole-4-carboxamide (30 mg, 16.64%).

[0668] Example 238 The compound above was synthesized utilizing the procedure outlined in the scheme above, where compound CXXVI is 3,4,5-trifluoronitrobenzene, and cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (40 mg, 27.16%).

[0669] Example 239 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound CXXVI is 3,4,5-trifluoronitrobenzene, and cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1, and 3-methoxy-3-methylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxamide (2.7 g, 53.9%).

[0670] Example 240 The compound above was synthesized utilizing the procedures outlined in the scheme above, where compound CXXVI is 3,4,5-trifluoronitrobenzene and cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and octahydrocyclopenta[c]pyrrole is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)oxazole-4-carboxamide (18 mg, 10.95%).

[0671] Example 241 The compound CXXVI is 3,4,5-trifluoronitrobenzene, and was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 3-azabicyclo[3.2.0]heptane was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3-azabicyclo[3.2.0]heptan-3-yl)-5-ethyloxazole-4-carboxamide (25 mg, 24.8%).

[0672] Example 242 Compound CXXVI is 3,4,5-trifluoronitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and azepane is used as the amine in step 3, to yield 2-(azepan-1-yl)-N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyloxazole-4-carboxamide (30 mg, 14.93%).

[0673] Example 243 The compound above was synthesized utilizing the procedures outlined in the scheme above, where compound CXXVI is 3,4,5-trifluoronitrobenzene and cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-ethyloxazole-4-carboxamide (10 mg, 10.16%).

[0674] Example 244 Compound CXXVI is 3,4,5-trifluoronitrobenzene, and the above compound was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and pyrrolidine was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-5-ethyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (1.17 g, 38.12%).

[0675] Example 245 The compound CXXVI is 1,2-difluoro-4-nitrobenzene, and was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and 3,3-diethylazetidine hydrochloride was used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(3,3-diethylazetidin-1-yl)-5-ethyloxazole-4-carboxamide (24 mg, 10.15%).

[0676] Example 246 The compound CXXVI is 1,2-difluoro-4-nitrobenzene, and was synthesized utilizing the procedure outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (27 mg, 17.19%).

[0677] Example 247 Compound CXXVI is 1,2-difluoro-4-nitrobenzene, and the above compound was synthesized utilizing the procedures outlined in the scheme above, where cis-bicyclo[3.1.0]hexan-3-ol is used as the alcohol in step 1 and 3-azabicyclo[3.2.0]heptane is used as the amine in step 3, to yield N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(3-azabicyclo[3.2.0]heptan-3-yl)-5-ethyloxazole-4-carboxamide (25 mg, 25.85%).

[0678] Example 248

[0679] [ka]

[0680] Step 1: To a stirred solution of bicyclo[3.1.0]hexan-3-ol, XVIV (285 mg, 2.90 mmol), KOH powder (331 mg, 5.80 mmol) in DMSO (5 mL), 1-fluoro-2-methyl-4-nitrobenzene, CXXXII (300 mg, 1.94 mmol), was added and stirred at room temperature for 2.5 h. After completion (monitored by TLC), the reaction mixture was partitioned between EtOAc (10 mL) and water (2 x 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography using 5% EtOAc in hexane to give 3-(2-methyl-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXXXIII (300 mg, 66%) as a pale yellow oil.

[0681] Step 2: To a stirred solution of 3-(2-methyl-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXXXIII (200 mg, 0.86 mmol) in 1,4 dioxane:water (6 mL, 5:1), zinc powder (280 mg, 4.23 mmol) was added along with ammonium chloride (230 mg, 4.23 mmol) at 0° C. This was then stirred at room temperature for 3 hours. After completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 10% EtOAc in hexane to give 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-methylaniline, CXXXIV (140 mg, 80%) as an off-white solid.

[0682] Step 3: To a stirred solution of ethyl 5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxylate, CXXX (150 mg, 0.449 mmol), in dry THF (5 mL) was added 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-methylaniline, CXXXIV (75 mg, 0.36 mmol), followed by dropwise addition of MeMgCl (3 M in THF, 0.4 mL, 1.20 mmol) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 10% EtOAc in hexanes to give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-methylphenyl)-5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxamide, Example 248 (47.3 mg, 31%).

[0683] Example 249

[0684] [ka]

[0685] Step 1: To a stirred solution of bicyclo[3.1.0]hexan-3-ol, XVIV (135 mg, 1.37 mmol), KOH powder (192 mg, 3.429 mmol) in DMSO (3 mL), CXXXV (200 mg, 1.143 mmol) was added and stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 5% EtOAc in hexane to give 3-(2-chloro-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXXXVI (170 mg, 56%) as a pale yellow oil.

[0686] Step 2: To a stirred solution of 3-(2-chloro-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXXXVI (410 mg, 1.62 mmol) in 1,4 dioxane:water (6 mL, 5:1), zinc powder (737 mg, 11.34 mmol) was added along with ammonium chloride (700 mg, 12.97 mmol) at 0° C. This was then stirred at room temperature for 3 hours. After completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 10% EtOAc in hexane to give 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloroaniline, CXXXVII (350 mg, 96%) as an off-white solid.

[0687] Step 3: To a stirred solution of ethyl 5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxylate, CXXX (150 mg, 0.559 mmol), in dry THF (5 mL) was added 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chloroaniline, CXXXVII (99.834 mg, 0.448 mmol), followed by dropwise addition of MeMgCl (3 M in THF, 0.5 mL, 1.39 mmol) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 5-10% EtOAc in hexanes to give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chlorophenyl)-5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxamide Example 249 (30 mg, 12%).

[0688] Example 250

[0689] [ka]

[0690] Step 1: To a stirred solution of bicyclo[3.1.0]hexan-3-ol, XVIV (609 mg, 6.21 mmol), KOH powder (950 mg, 16.94 mmol) in DMSO (5 mL), 1,2,3-trifluoro-4-nitrobenzene, CXXXVIII (1000 mg, 5.64 mmol), was added and stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was partitioned between EtOAc (10 mL) and water (2 x 30 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography using 5% EtOAc in hexane as the eluent to afford 3-(2,3-difluoro-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXXXIX (100 mg, 28%) as a pale yellow oil.

[0691] Step 2: To a stirred solution of 3-(2,3-difluoro-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXXXIX (200 mg, 0.78 mmol) in 1,4 dioxane:water (6 mL, 5:1), zinc powder (410 mg, 6.27 mmol) was added along with ammonium chloride (336 mg, 6.27 mmol) at 0 °C. This was then stirred at room temperature for 3 h. Upon completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 10% EtOAc in hexane to give 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-2,3-difluoroaniline, CXL (120 mg, 68%) as an off-white solid.

[0692] Step 3: To a stirred solution of 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-2,3-difluoroaniline, or CXL (7.60 mg, 0.21 mmol) in dry toluene (3 mL), ethyl 5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxylate, or CXXX (72 mg, 0.32 mmol), was added, followed by dropwise addition of MeAl (2 M in toluene, 0.42 mL, 0.84 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 20% EtOAc in hexanes to give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-chlorophenyl)-5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxamide, Example 250 (40 mg, 41%).

[0693] Example 251

[0694] [ka]

[0695] Step 1: To a stirred solution of bicyclo[3.1.0]hexan-3-ol, XVIV (332.25 mg, 3.39 mmol), KOH powder (474.31 mg, 8.47 mmol) in DMSO (5 mL), 1,2,4-trifluoro-5-nitrobenzene, CXLI (500 mg, 2.82 mmol), was added and stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography using 5% EtOAc in hexane as the eluent to afford 3-(2,5-difluoro-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXLII (255 mg, 41%) as a pale yellow oil.

[0696] Step 2: To a stirred solution of 3-(2,5-difluoro-4-nitrophenoxy)bicyclo[3.1.0]hexane, CXLII (300 mg, 1.176 mmol) in 1,4 dioxane:water (6 mL, 5:1), zinc powder (535 mg, 8.23 mmol) was added along with ammonium chloride (508 mg, 9.41 mmol) at 0 °C. This was then stirred at room temperature for 3 h. After completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography using 10% EtOAc in hexane to give 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-2,5-difluoroaniline, CXLIII (220 mg, 83%) as a brown viscous liquid.

[0697] Step 3: To a stirred solution of ethyl 5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxylate, CXXX (100 mg, 0.354 mmol), in dry toluene (5 mL) was added 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-2,5-difluoroaniline, CXLIII (64 mg, 0.284 mmol), followed by the dropwise addition of trimethylaluminum (2 M in toluene, 0.7 mL, 1.418 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion (monitored by TLC / LCMS), the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 5-10% EtOAc in hexanes to give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-2,5-difluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide Example 251 (15 mg, 9.2%).

[0698] General Procedure for the Synthesis of Examples of Basic Structure CLVII (Examples 252-259)

[0699] [ka]

[0700] Step 1: To a stirred solution of fluoro-nitrobenzene XC (1.0 equiv.) and KCO (3.0 equiv.) in CHCN (3 mL / g VII) in a sealed tube, R a R b NH (1.2 equiv.) was added, and the resulting reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove CHCN. The resulting crude was purified by flash column chromatography to give an intermediate of structure CXLIV.

[0701] Step 2: To a stirred solution of compound CXLIV in 1,4 dioxane:water (5:1) was added zinc powder (7.0 equiv.) followed by ammonium chloride (7.0 equiv.) at 0° C. This was then stirred at room temperature for 3 hours. Upon completion (monitored by TLC), the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous NaSO, concentrated under reduced pressure, and purified by flash column chromatography using EtOAc-hexane as the eluent to give intermediate compound CXLV.

[0702] Step 3: To a stirred solution of CXXV (1.0 equiv) and DIPEA (3.0 equiv) in dioxane (3 mL / mmol) was added R C R D NH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 16 h. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by CombiFlash column chromatography using EtOAc-hexane as the eluent to give intermediate compound CXLVI.

[0703] Step 4: To a stirred solution of CXLVI (1.0 equiv.) and CXLV (1.0 equiv.) in dry THF (30 mL / g), MeMgCl (3 M in THF, 2.4 equiv.) was added dropwise and stirred at room temperature for 1 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with 1 N HCl, extracted with EtOAc, and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash column chromatography to give the desired compound. Examples 252 and 253 were synthesized according to condition (ii) as follows: To a stirred solution of CXLVI (1.0 equiv.) and amine CXLV (0.8 equiv.) in dry toluene (30 mL / g CXLVI), trimethylaluminum (2 M in toluene, 4.0 equiv.) was added dropwise at 0° C., and the resulting reaction mixture was stirred at room temperature. After completion [monitored by TLC / LCMS], the reaction mixture was quenched with saturated ammonium chloride solution and partitioned with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to give the product of basic structure CXLVII.

[0704] All amines used as starting materials in step 1 were purchased from chemical suppliers.

[0705] Example 252 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound XC is 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]heptan-3-amine is used as the amine in step 1, and pyrrolidine is used as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-ylamino)-3-fluoro-5-methylphenyl)-5-ethyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (25 mg, 13.89%).

[0706] Example 253 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound XC is 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]heptan-3-amine is used as the amine in step 1, and 3,3-diethylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(bicyclo[3.1.1]heptan-3-ylamino)-3-fluoro-5-methylphenyl)-2-(3,3-diethylazetidin-1-yl)-5-ethyloxazole-4-carboxamide (31 mg, 22%).

[0707] Example 254 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound XC is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane is used as the amine in step 1, and 3-ethyl-3-methoxyazetidine is used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (10 mg, 8.76%).

[0708] Example 255 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound XC is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane is used as the amine in step 1, and pyrrolidine is used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-5-ethyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (40 mg, 19.05%).

[0709] Example 256 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound XC is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane is used as the amine in step 1, and 3,3-dimethylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-2-(3,3-dimethylazetidin-1-yl)-5-ethyloxazole-4-carboxamide (21 mg, 10%).

[0710] Example 257 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound XC is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane is used as the amine in step 1, and hexahydro-1H-furo[3,4-c]pyrrole is used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-5-ethyl-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)oxazole-4-carboxamide (70 mg, 47.55%).

[0711] Example 258 The above compound was synthesized utilizing the procedures outlined in the scheme above, where compound XC is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane is used as the amine in step 1, and 3-methoxy-3-methylazetidine hydrochloride is used as the amine in step 3, to yield N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxamide (15 mg, 9%).

[0712] Example 259 The compound above was synthesized using the procedure outlined in the scheme above, where compound XC is 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane as the amine in step 1, and 6,6-difluoro-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate as the amine in step 3, to give N-(4-(3-azabicyclo[3.1.1]heptan-3-yl)-3,5-difluorophenyl)-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-5-ethyloxazole-4-carboxamide (65 mg, 42.9%).

[0713] General Procedure for the Synthesis of Examples of Basic Structure CLII (Examples 260-270)

[0714] [ka]

[0715] Step 1. To a stirred solution of CXXVI (1.0 equiv.) and CXXVII (1.2 equiv.) in DMSO (3 mL / mmol) was added KOH (3.0 equiv.). The reaction was stirred at room temperature for 2 h. Upon completion (monitored by TLC), the resulting reaction mixture was partitioned between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography using EtOAc in hexane as the eluent to give the desired product CXLVIII.

[0716] Step 2: To a stirred solution of CXLVIII (1.0 equiv.) and KOH powder (3.0 equiv.) in DMSO (10 mL / g CXLVIII), BnOH (1.2 equiv.) was added and stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude was purified by silica column chromatography to give the product of basic structure CXLIX.

[0717] Step 3: To a stirred solution of CXLIX (1.0 equiv.) in ethanol (20 mL / g CXLIX), 20% Pd / C (wt%) was added and stirred under a hydrogen atmosphere at room temperature for 4 h. Upon completion (monitored by TLC), the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was then purified by flash column chromatography to give the amine, CL.

[0718] Step 4: To a stirred solution of VII (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / mmol), RNH (1.1 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 16 h. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude was purified by CombiFlash column chromatography to afford the product of basic structure CLI.

[0719] Step 5: To a stirred so...

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R １ is C optionally substituted with one or more R １ -C ６ is alkyl, R ２ is C optionally substituted with one or more R １ -C ６ is alkyl, Or, R １ and R ２ together form a heterocycloalkyl or heteroaryl, each of which may be one or more R １ａ optionally substituted with R １ａ are each independently deuterium, halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S(=O)R ａ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, two R on the same carbon atom １ａ come together to form an oxo, R ３ is C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R; Ring A is aryl or heteroaryl; R ４ are each independently deuterium, halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , —O-cycloalkyl, —O-heterocycloalkyl, —SH, —SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S(=O)R ａ , -NR ｂ S (= O) ２ R ａ , -NR ｂ -cycloalkyl, -NR ｂ -heterocycloalkyl, -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; n is 0 to 4; R ａ are each independently C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R ｃ and R ｄ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Or, R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently deuterium, halogen, —CN, —OH, or —S(═O)C. １ -C ３ Alkyl, —S(═O) ２ C １ -C ３ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ -C ３ Alkyl, —S(═O) ２ N (C １ -C ３ alkyl) ２ , -NH ２ , -NHC １ -C ３ Alkyl, —N(C １ -C ３ alkyl) ２ , -C(=O)C １ -C ３ Alkyl, —C(═O)OH, —C(═O)OC １ -C ３ Alkyl, —C(═O)NH ２ , -C(=O)NHC １ -C ３ Alkyl, —C(═O)N(C １ -C ３ alkyl) ２ , C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkyl, C １ -C ３ Deuteroalkyl, C １ -C ３ Haloalkoxy, C １ -C ３ Hydroxyalkyl, C １ -C ３ Aminoalkyl, C １ -C ３ Heteroalkyl, C ３ -C ６ cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more halogens; Alternatively, two R on the same atom form an oxo. The compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2 or 3.

3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl.

4. R ４ each independently represents deuterium, halogen, —CN, —OH, or —OR ａ , —O-cycloalkyl, —O-heterocycloalkyl, —NR ｃ R ｄ , -NR ｂ -cycloalkyl, -NR ｂ -heterocycloalkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, cycloalkyl, heterocycloalkyl, C １ -C ６ Alkylene (cycloalkyl), or C １ -C ６ alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

5. R ４ each independently represents a halogen, —CN, —OH, or —OR ａ , —O-cycloalkyl, —O-heterocycloalkyl, —NR ｃ R ｄ , -NR ｂ -cycloalkyl, C １ -C ６ Alkyl, C １ -C ６ 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl, or heterocycloalkyl.

6. R ４ each independently represents halogen, —OH, —O-cycloalkyl, —O-heterocycloalkyl, —NR ｃ R ｄ , -NR ｂ -cycloalkyl, C １ -C ６ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is alkyl, or heterocycloalkyl.

7. R ４ each independently represents halogen, —O-cycloalkyl, —O-heterocycloalkyl, —NR ｂ -cycloalkyl, C １ -C ６ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is alkyl, or heterocycloalkyl.

8. R ４ are each independently halogen, —O-cycloalkyl, C １ -C ６ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is alkyl, or heterocycloalkyl.

9. R ４ are each independently halogen, —O-cycloalkyl, or C １ -C ６ 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl.

10. The compound has the formula (Ia): 【Chemistry 2】 wherein: R ４ａ represents hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; R ４ｂ represents deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , —O-cycloalkyl, —O-heterocycloalkyl, —NR ｃ R ｄ , -NR ｂ -cycloalkyl, -NR ｂ -heterocycloalkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R; R ４ｃ represents deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

11. R ４ａ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, or C １ -C ６ 11. The compound of claim 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

12. R ４ａ But hydrogen, halogen, C １ -C ６ Alkyl, or C １ -C ６ 12. The compound of claim 10 or 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

13. R ４ａ 13. The compound of any one of claims 10 to 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen or halogen.

14. R ４ａ 14. The compound of any one of claims 10 to 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

15. R ４ａ is C １ -C ６ 13. The compound of any one of claims 10 to 12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is alkyl.

16. R ４ｂ Deuterium, halogen, -CN, -OH, -OR ａ , —O-cycloalkyl, —O-heterocycloalkyl, —NR ｃ R ｄ , -NR ｂ -cycloalkyl, -NR ｂ -heterocycloalkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ 16. The compound of any one of claims 10 to 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

17. R ４ｂ Deuterium, halogen, -CN, -OH, -OR ａ , —O-cycloalkyl, —O-heterocycloalkyl, —NR ｃ R ｄ , -NR ｂ -cycloalkyl, -NR ｂ -heterocycloalkyl, C １ -C ６ Alkyl, C １ -C ６ 17. The compound of any one of claims 10 to 16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl, or heterocycloalkyl.

18. R ４ｂ But, -OR ａ , —O-cycloalkyl, —O-heterocycloalkyl, —NR ｃ R ｄ , -NR ｂ 18. The compound of any one of claims 10 to 17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: - cycloalkyl, or heterocycloalkyl.

19. R ４ｂ is —O-cycloalkyl, —O-heterocycloalkyl, —NR ｂ 19. The compound of any one of claims 10 to 18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: - cycloalkyl, or heterocycloalkyl.

20. R ４ｂ 20. The compound of any one of claims 10 to 19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is -O-cycloalkyl, -O-heterocycloalkyl, or heterocycloalkyl.

21. R ４ｂ 21. The compound of any one of claims 10 to 20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is -O-cycloalkyl.

22. R ４ｃ is halogen, —OH, or C １ -C ６ 22. The compound of any one of claims 10 to 21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

23. R ４ｃ 23. The compound of any one of claims 10 to 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

24. R １ and R ２ together form one or more R １ａ 24. The compound of any one of claims 10 to 23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which forms a heterocycloalkyl optionally substituted with:

25. R １ and R ２ together form a monocyclic heterocycloalkyl or a bicyclic heterocycloalkyl, each of which is one or more R １ａ 25. The compound of any one of claims 10 to 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, optionally substituted with:

26. R １ and R ２ together form one or more R １ａ 26. The compound of any one of claims 10 to 25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which forms a monocyclic heterocycloalkyl optionally substituted with

27. R １ and R ２ taken together form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each of which is selected from one or more R １ａ 27. The compound of any one of claims 10 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, optionally substituted with:

28. R １ and R ２ taken together form a pyrrolidinyl or piperidinyl, each of which is joined by one or more R １ａ 28. The compound of any one of claims 10 to 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, optionally substituted with:

29. R １ and R ２ together form one or more R １ａ 28. The compound of any one of claims 10 to 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which forms an azetidinyl optionally substituted with

30. R １ and R ２ together form one or more R １ａ 26. The compound of any one of claims 10 to 25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which forms a bicyclic heterocycloalkyl optionally substituted with:

31. R １ａ each independently represents a halogen, —CN, —OH, or —OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heteroalkyl.

32. R １ａ are each independently -OR ａ , C １ -C ６ Alkyl, C １ -C ６ hydroxyalkyl, or C １ -C ６ 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heteroalkyl.

33. R １ａ are each independently -OR ａ or C １ -C ６ 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is alkyl;

34. R １ａ However, each independently C １ -C ６ 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

35. R ３ But C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ 35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heteroalkyl.

36. R ３ But C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is heteroalkyl.

37. R ３ is C １ -C ６ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

38. R ３ But -CH ２ CH ３ , -CH ２ CH ２ F, or -CH ２ CF ３ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

39. A compound selected from the compounds found herein and in Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

40. 40. A pharmaceutical composition comprising a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

41. 40. A method of treating a TRPML1-mediated disorder or disease, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

42. The method of claim 41, wherein the TRPML1-mediated disorder or disease is aging, bone disease, heart disease, congenital developmental disorder, eye disease, hematological or solid malignant tumor, infectious disease, inflammatory disease, liver disease, metabolic disease, neurological or neurodegenerative disease, pancreatitis, kidney disease, skeletal muscle disorder, obesity, lysosomal storage disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget's disease, or lung disease.

43. The TRPML1-mediated disorder or disease is selected from the group consisting of Aicardi-Goutieres syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, autistic disorder, Batten disease, bipolar disorder, cerebral ataxia, Charcot-Marie-Tooth variant diseases, chronic wasting disease, corticobasal degeneration, corticobasal syndrome, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Danon disease, Duchenne muscular dystrophy, exotic ungulate encephalopathy, Fabry disease, and the like. disease), fatal familial insomnia, Friedreich's ataxia, feline spongiform encephalopathy, fragile X syndrome, frontotemporal dementia, Gaucher's disease, Gerstmann-Sträussler-Scheinker disease, giant axonal neuropathy, GM1 and GM2 gangliosidosis, Huntington's disease, infantile Refsum's disease, JUNQ and IPOD, Krabbe's disease, kuru, leukoencephalopathy, dementia with Lewy bodies, gait ataxia, Lyme disease, Machado-Joseph disease, major depressive disorder, MPS-III, mucolipidosis, multiple sulfatase deficiency, multiple system atrophy, myofibrillar myopathy, myotonic dystrophy, Niemann-Pick disease, and neutropenia.

42. The method of claim 41, wherein the disease is selected from the group consisting of ceroid lipofuscinosis, Parkinson's disease, Parkinsonism, Pick's disease, polyglutamine diseases, Pompe's disease, pontocerebellar hypoplasia, prion diseases, progressive nuclear palsy, progressive supranuclear palsy, pyruvate dehydrogenase deficiency, Sandhoff's disease, schizophrenia, scrapie disease, Shy-Drager syndrome, spinal muscular atrophy, spinocerebellar ataxia, disseminated familial insomnia, subacute degeneration of the spinal cord, subacute sclerosing panencephalitis, Tay-Sachs disease, neuronectomy degeneration, tuberous sclerosis, spinocerebellar ataxia, and vascular dementia.

44. 42. The method of claim 41, wherein the TRPML1-mediated disorder or disease is age-related macular degeneration, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), retinal cell degeneration in glaucoma, retinitis pigmentosa, acute kidney injury, atherosclerosis, Crohn's disease, diabetic nephropathy, female infertility, Helicobacter pylori infection, hypochlorhydria, pancreatitis, retinal detachment, type 2 diabetes, ulcerative colitis, or sarcopenia.

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