Oxazole TRPML1 agonists and uses thereof

Abstract

Oxazole TRPML1 inhibitors and pharmaceutical compositions comprising the inhibitors are described herein. The subject compounds and compositions are useful for the treatment of TRPML1 mediated disorders or diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 359,080, filed on July 7, 2022, the entire contents of which are hereby incorporated by reference. Background Art

[0003] TRPML1, also known as Mucolipin-1, is a ligand-gated cation channel that is primarily expressed in intracellular organelles such as late endosomes and lysosomes in many mammalian cells. This channel is a member of the large family of transient receptor potential (TRP) channels and has two close analogs, TRPML2 and TRPML3. Loss-of-function mutations in the gene encoding TRPML1 (the 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 disorder.

[0004] At the molecular level, TRPML1 is a Ca 2+ A permeable, non-selective cation channel composed of four six-transmembrane spanning proteins, each with 580 amino acids. The channel opens upon binding of the endogenous ligand phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) to its pore region. Channel activity is regulated by pH and PtdIns(4,5)P2 levels. TRPML1 is an inwardly rectifying channel that is permeable to various monovalent and divalent cations, including Na + , K + , Ca 2+ and Fe 2+ Its N-terminal AP1 sequence targets the channel to lysosomes, while the C-terminal AP2 sequence is responsible for intracellular trafficking and internalization. In addition, TRPML1 has four putative N-linked glycosylation sites in its luminal loop between TM1 and 2. It has been reported that TRPML channels can form as homotetramers (e.g., TRPML1, TRPML2, TRPML3), but in some cases can also form as heterotetramers, in which one channel is composed of different members of the TRPML family.

[0005] 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, cleavage, and autophagy.

[0006] Lysosomes are organelles filled with hydrolytic enzymes and characterized by a low luminal pH of approximately 5, a high luminal Ca2+ of approximately 0.5 mM, and a 2+ concentration and a membrane polarization of approximately +60 mV.

[0007] It has been reported that TRPML1 in the LEL is responsible for the formation of transport vesicles and is mainly responsible for its Ca 2+ TRPML1 is a key regulator of autophagy, which is required for the re-formation of lysosomes from LEL hybrid organelles and autophagolysosomes. TRPML1 may also be important for the release of iron from lysosomes following degradation of iron-binding proteins such as cytochrome C. Furthermore, it has been reported that TRPML1 may regulate autophagy in an mTOR-independent manner by promoting the translocation of TFEB to the nucleus via calcineurin activation. Summary of the Invention

[0008] In MLIV, the lack of functional TRPML1 leads to severe intellectual disability, motor deficits, retinal degeneration, and systemic symptoms, resulting in a significantly shortened life expectancy. Cells from MLIV patients exhibit increased autophagosomes, accumulation of lipofuscin, and lipid accumulation in lysosomes.

[0009] TRPML1-dependent failure of autophagosome-lysosome fusion is also thought to impair the clearance of apoptotic neurons by macrophages and microglia. Experimental results suggest that TRPML1 is associated with neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). For example, the loss-of-function mutation of presenilin 1 associated with Alzheimer's disease leads to lysosomal Ca 2+ accumulation through TRPML1 regulation. 2+ Homeostasis disorders. 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 exhibited similar effects, 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 β-methylamino-L-alanine (L-BMAA), a model of ALS.

[0010] Therefore, the development of TRPML1 modulators is needed to rescue the impaired lysosomal function and autophagy in neurodegenerative diseases.

[0011] Despite years of significant interest across the pharmaceutical industry, the currently described small-molecule TRPML1 agonists have not been optimized for functional activity and drug-like properties. Consequently, there is an unmet need for compounds that can potently stimulate TRPML1 and deliver to diverse target organs at any site of TRPML1-mediated pathology.

[0012] Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:

[0013]

[0014] Formula (I) as defined herein.

[0015] Disclosed herein are compounds of formula (Ia), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:

[0016]

[0017] Formula (Ia) as defined herein.

[0018] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and a pharmaceutically acceptable excipient.

[0019] Also disclosed herein is a method of treating a TRPML1-mediated disorder or disease in a subject in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0020] Incorporation by reference

[0021] 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

[0022] definition

[0023] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, those skilled in the art will appreciate that the present invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and the claims that follow, the words "comprise" and variations thereof, such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, i.e., "including but not limited to." In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0024] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense that includes "and / or" unless the content clearly dictates otherwise.

[0025] Unless otherwise indicated, the following terms as used herein have the following meanings:

[0026] "Oxo" refers to =0.

[0027] "Amine" means -NH2;

[0028] "Hydroxyl" means -OH;

[0029] "Carboxyl" refers to -COOH.

[0030] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monovalent group 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range appears herein, such as "C1-C6 alkyl" 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, but this definition also encompasses the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C1-C6. 10 Alkyl. In some embodiments, the alkyl group is a C1-C6 alkyl group. In some embodiments, the alkyl group is a C1-C5 alkyl group. In some embodiments, the alkyl group is a C1-C4 alkyl group. In some embodiments, the alkyl group is a C1-C3 alkyl group. Unless otherwise expressly stated in this specification, the alkyl group may be optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups. In some embodiments, the alkyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkyl group is optionally substituted with one or more halogen, -CN, -OH or -OMe. In some embodiments, the alkyl group is optionally substituted with halogen.

[0031] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group can be cis or trans or Z or E conformation about the double bond, and should be understood to include two isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkenyl" without specifying a numerical range. Unless otherwise clearly stated in this specification, alkenyl group can be optionally replaced by such as one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl etc.In some embodiments, alkenyl is optionally replaced by one or more oxo, halogen ,-CN ,-COOH ,-COOMe ,-OH ,-OMe ,-NH Or-NO Replace.In some embodiments, alkenyl is optionally replaced by one or more halogen ,-CN ,-OH or-OMe.In some embodiments, alkenyl is optionally replaced by halogen.

[0032] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and 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, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" without specifying a numerical range. Unless otherwise expressly stated in this specification, the alkynyl group may be optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, the alkynyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl groups are optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl groups are optionally substituted with halogen.

[0033] " alkylene " refers to the divalent hydrocarbon chain of straight or branched chain.Unless otherwise clearly stated in this specification, alkylene can be optionally substituted by, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.In some embodiments, alkylene is optionally substituted by one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO.In some embodiments, alkylene is optionally substituted by one or more halogen, -CN, -OH or -OMe.In some embodiments, alkylene is optionally substituted by halogen.

[0034] " alkoxy " refers to the group of formula -O alkyl, wherein alkyl is defined as above. Unless otherwise clearly stated in this specification, alkoxy can be optionally substituted by, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. In some embodiments, alkoxy is optionally substituted by one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkoxy is optionally substituted by one or more halogen, -CN, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0035] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6 to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group (phenyl). Aryl groups include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, In some embodiments, aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, aryl groups can be optionally substituted with halogen.

[0036] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through non-aromatic ring atoms), a spirocyclic and / or a bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (e.g., C3-C 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), cycloalkyl having 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl or C3-C 10In some embodiments, the cycloalkyl group is a 3-10 fully saturated cycloalkyl group or a 3-10 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3-6 fully saturated cycloalkyl group or a 3-6 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5-6 fully saturated cycloalkyl group or a 5-6 membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyl includes such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.Unless this specification sheets clearly state otherwise, cycloalkyl is optionally replaced by such as one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.In some embodiments, cycloalkyl is optionally replaced by one or more oxo, halogen, methyl, ethyl ,-CN ,-COOH ,-COOMe ,-CF ,-OH ,-OMe ,-NH or-NO Replace.In some embodiments, cycloalkyl is optionally replaced by one or more oxo, halogen, methyl, ethyl ,-CN ,-CF ,-OH or-OMe.In some embodiments, cycloalkyl is optionally replaced by halogen.

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0038] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0039] "Haloalkoxy" refers to an -O-haloalkyl group where haloalkyl is as defined above.

[0040] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxy groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0041] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0042] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0043] " assorted alkyl " refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms (e.g., oxygen, nitrogen, sulphur, phosphorus or a combination thereof) other than carbon. Assorted alkyl is connected to the rest of the molecule at a carbon atom of the assorted alkyl group. In one aspect, assorted alkyl is a C1-C6 assorted alkyl group, wherein assorted alkyl is composed of 1 to 6 carbon atoms and one or more atoms (e.g., oxygen, nitrogen, sulphur, phosphorus or a combination thereof) other than carbon, and wherein assorted alkyl is connected to the rest of the molecule at a carbon atom of the assorted alkyl group. In one aspect, assorted alkyl is a C1-C6 assorted alkyl group, wherein assorted alkyl is composed of 1 to 6 carbon atoms and one or two atoms selected from oxygen, nitrogen and sulphur, and wherein assorted alkyl is connected to the rest of the molecule at a carbon atom of the assorted alkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, heteroalkyl groups are optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl groups. In some embodiments, heteroalkyl groups are optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl groups are optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl groups are optionally substituted with halogen.

[0044] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-attached. In some embodiments, the heterocycloalkyl is N-attached. In some embodiments, the heterocycloalkyl contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains one to three nitrogens. In some embodiments, the heterocycloalkyl contains one or two nitrogens. In some embodiments, the heterocycloalkyl contains one nitrogen. In some embodiments, the heterocycloalkyl contains one nitrogen and one oxygen. Unless otherwise expressly stated in the specification, the heterocycloalkyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused ring system (when fused to an aryl ring or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom), a spirocyclic or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), heterocycloalkyl having 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkyl group), a heterocycloalkyl group having 2 to 8 carbon atoms (e.g., a C2-C8 fully saturated heterocycloalkyl group or a C2-C8 heterocycloalkenyl group), a heterocycloalkyl group having 2 to 7 carbon atoms (e.g., a C2-C7 fully saturated heterocycloalkyl group or a C2-C7 heterocycloalkenyl group), a heterocycloalkyl group having 2 to 6 carbon atoms (e.g., a C2-C6 fully saturated heterocycloalkyl group or a C2-C7 heterocycloalkenyl group), a heterocycloalkyl group having 2 to 5 carbon atoms (e.g., a C2-C5 fully saturated heterocycloalkyl group or a C2-C5 heterocycloalkenyl group), or a heterocycloalkyl group having 2 to 4 carbon atoms (e.g., a C2-C4 fully saturated heterocycloalkyl group or a C2-C4 heterocycloalkenyl group). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidine The term "heterocycloalkyl" refers to any of the following: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 71, 72, 73, 74, 75, 76, 77, 78, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 109, 111 In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise expressly stated herein, heterocycloalkyl is optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, heterocycloalkyl is optionally substituted by one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF , -OH, -OMe, -NH or -NO .In some embodiments, heterocycloalkyl is optionally substituted by one or more halogen, methyl, ethyl, -CN, -CF , -OH or -OMe.In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0045] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group comprises one to three nitrogen atoms. In some embodiments, the heteroaryl group comprises one or two nitrogen atoms. In some embodiments, the heteroaryl group comprises one nitrogen atom. In some embodiments, the heteroaryl group is C-linked. In some embodiments, the heteroaryl group is N-linked. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur. Examples include, but are not limited to, aza azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolane benzothiophenyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine Unless otherwise expressly stated herein, heteroaryl is optionally substituted by, for example, one or more halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl. In some embodiments, heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0046] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, such groups are not intended to introduce any sterically impractical and / or synthetically unfeasible substitutions or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl, which in turn is defined to include optionally substituted alkyl, which may be infinite). Thus, any substituent described will generally be understood to have a maximum molecular weight of about 1000 Daltons, and more typically will have a molecular weight of up to about 500 Daltons.

[0047] When mentioning optional substituent, term " one or more " means that the subject group is optionally replaced by one, two, three, four or more substituents. In some embodiments, the subject group is optionally replaced by one, two, three or four substituents. In some embodiments, the subject group is optionally replaced by one, two or three substituents. In some embodiments, the subject group is optionally replaced by one or two substituents. In some embodiments, the subject group is optionally replaced by a substituent. In some embodiments, the subject group is optionally replaced by two substituents.

[0048] An "effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, in a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.

[0049] "Treatment" of an individual (e.g., a mammal such as a human) or cell refers to any type of intervention used to attempt to alter the natural course of an individual or cell. In some embodiments, treatment comprises administering a pharmaceutical composition after the onset of a pathological event or exposure to a pathogen and includes stabilizing the condition (e.g., the condition does not worsen) or ameliorating the condition.

[0050] "Synergy" or "synergy" means that the effect of the combination is greater than the sum of the individual effects of each component at the same dose.

[0051] As used herein, a "disease or disorder associated with TRPML1" or, alternatively, a "TRPML1-mediated disease or disorder" means any disease or other deleterious condition in which TRPML1 or a mutant thereof is known or suspected to play a role.

[0052] Compound

[0053] Described herein are compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, for use in treating a disease or disorder mediated by TRPML1.

[0054] Disclosed herein are compounds of formula (I), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof:

[0055]

[0056] in:

[0057] R 1 is a C1-C6 alkyl group optionally substituted by one or more R;

[0058] R 2 is a C1-C6 alkyl group optionally substituted by one or more R;

[0059] or R 1 and R2 together to form a heterocycloalkyl or heteroaryl group; each optionally substituted by one or more R 1a replace;

[0060] Each R 1a are 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 deuterated alkyl, 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0061] or two R on the same atom 1a Together they form an oxo group;

[0062] R 3is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R;

[0063] Ring A is an aryl group or a heteroaryl group;

[0064] Each R 4 are 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 deuterated alkyl, 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0065] n is 0-4;

[0066] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0067] Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0068] Each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0069] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0070] 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 deuterated alkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogens;

[0071] Or two R on the same atom form an oxo group.

[0072] In some embodiments of the compound of formula (I), n is 1-4. In some embodiments of the compound of formula (I), n is 1-3. In some embodiments of the compound of formula (I), n is 2-4. 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.

[0073] In some embodiments of the compound of formula (I), Ring A is an aryl or heteroaryl group. In some embodiments of the compound of formula (I), Ring A is a phenyl group. In some embodiments of the compound of formula (I), Ring A is a 5- or 6-membered heteroaryl group. In some embodiments of the compound of formula (I), Ring A is a 6-membered heteroaryl group.

[0074] In some embodiments of the compounds of formula (I), Ring A is bicyclic. In some embodiments of the compounds of formula (I), Ring A is bicyclic aryl. In some embodiments of the compounds of formula (I), Ring A is bicyclic heteroaryl. In some embodiments of the compounds of formula (I), Ring A is indolinyl.

[0075] In some embodiments of the compound of formula (I), each R 4 are 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 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R.

[0076] In some embodiments of the compound of formula (I), each R 4 are 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R.

[0077] In some embodiments of the compound of formula (I), each R 4 are 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, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R.

[0078] In some embodiments of the compound of formula (I), each R 4 are 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 each alkyl, alkylene and heterocycloalkyl is independently and optionally substituted with one or more R.

[0079] In some embodiments of the compound of formula (I), each R 4 are 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of formula (I), each R 4 are 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 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R.

[0080] In some embodiments of the compound of formula (I), each R 4 are independently 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 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of formula (I), each R 4 are independently halogen, -CN, -OH, -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 compound of formula (I), each R 4 are independently halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d 、-NR b -cycloalkyl, C1-C6 haloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), each R 4 are independently halogen, -OH, -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d 、-NR b - cycloalkyl, C1-C6 alkyl or heterocycloalkyl.

[0081] In some embodiments of the compound of formula (I), each R 4 are independently halogen, -OH, -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d 、-NR b -cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), each R 4 are independently halogen, -O-cycloalkyl, -O-heterocycloalkyl, -NR b -cycloalkyl, C1-C6 alkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), each R4 are independently halogen, -O-cycloalkyl, -O-heterocycloalkyl, -NR b -cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), each R 4 is independently halogen, -O-cycloalkyl, -O-heterocycloalkyl, C1-C6 alkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), each R 4 is independently halogen, -O-cycloalkyl, -O-heterocycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), each R 4 are independently halogen, C1-C6 alkyl or heterocycloalkyl. In some embodiments of the compound of formula (I), each R 4 In some embodiments of the compound of formula (I), each R 4 is independently halogen, -O-cycloalkyl or C1-C6 alkyl. In some embodiments of the compound of formula (I), each R 4 is independently halogen or -O-cycloalkyl. In some embodiments of the compound of formula (I), each R 4 In some embodiments of the compound of formula (I), each R 4 is independently halogen or -O-heterocycloalkyl.

[0082] In some embodiments of the compound of formula (I), the compound has formula (Ia):

[0083]

[0084] in:

[0085] R 4a For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl;

[0086] R 4b Deuterium, halogen, -CN, -NO2, -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; and

[0087] R 4c Deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl.

[0088] In some embodiments of the compound of Formula (Ia), R 4a For hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (Ia), R 4a is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound 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 compound of formula (Ia), R 4a In some embodiments of the compound of formula (Ia), R 4a In some embodiments of the compound of formula (Ia), R 4a It is a C1-C6 alkyl group.

[0089] In some embodiments of the compound of Formula (Ia), R 4b 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (Ia), R 4b 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 the compound of formula (Ia), R 4b For-OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d 、-NR b -cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (Ia), R 4b is -O-cycloalkyl, -O-heterocycloalkyl, -NR b -cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (Ia), R 4b In some embodiments of the compound of formula (Ia), R 4b In some embodiments of the compound of formula (Ia), R 4b In some embodiments of the compound of formula (Ia), R 4b is -O-cycloalkyl, wherein the cycloalkyl is a monocyclic cycloalkyl. In some embodiments of the compound of formula (Ia), R 4b is -O-cycloalkyl, wherein the cycloalkyl is a bicyclic cycloalkyl. In some embodiments of the compound of formula (Ia), R 4b In some embodiments of the compound of formula (Ia), R 4b is a 3- to 10-membered heterocycloalkyl group. In some embodiments of the compound of formula (Ia), R 4b is a 5- to 10-membered heterocycloalkyl group. In some embodiments of the compound of formula (Ia), R 4b is a 5- to 8-membered heterocycloalkyl group.

[0090] In some embodiments of the compound of Formula (Ia), R 4b for wherein Ring B is cycloalkyl or heterocycloalkyl and m is 0-4. In some embodiments of the compound of formula (Ia), R 4b for wherein Ring B is cycloalkyl and m is 0-4. In some embodiments of the compound of Formula (Ia), R 4b for wherein Ring B is a monocyclic cycloalkyl group and m is 0-4. In some embodiments of the compound of Formula (Ia), R 4b for wherein Ring B is a bicyclic cycloalkyl group and m is 0-4.

[0091] In some embodiments of the compound of Formula (Ia), R 4b for wherein ring B is In some embodiments of the compound of Formula (Ia), R 4b for wherein ring B is In some embodiments of the compound of Formula (Ia), R 4b for wherein ring B is In some embodiments of the compound of Formula (Ia), R 4b for wherein ring B is In some embodiments of the compound of Formula (Ia), R 4b for wherein ring B is

[0092] In some embodiments of the compound of Formula (Ia), R 4b for and m is 0-4. In some embodiments of the compound of formula (Ia), R 4b for and m is 0 or 1. In some embodiments of the compound of formula (Ia), R 4b for and m is 0-2. In some embodiments of the compound of formula (Ia), R 4b for and m is 0. In some embodiments of the compound of Formula (Ia), R 4b for And m is 1.

[0093] In some embodiments of the compound of Formula (Ia), R 4b for

[0094] In some embodiments of the compound of Formula (Ia), R 4b for

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

[0096] In some embodiments of the compound of Formula (Ia), R 4b for

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

[0098] In some embodiments of the compound of Formula (I) or (Ia), R 1 It is a C1-C6 alkyl group.

[0099] In some embodiments of the compound of Formula (I) or (Ia), R 2 It is a C1-C6 alkyl group.

[0100] In some embodiments of the compound of Formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together to form a monocyclic heterocycloalkyl or a bicyclic heterocycloalkyl; each optionally substituted by one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together to form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl; each optionally substituted by one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of Formula (I) or (Ia), R 1 and R 2 together to form a pyrrolidinyl or piperidinyl group; each optionally substituted by one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a Substituted bicyclic heterocycloalkyl.

[0101] In some embodiments of the compound of Formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a In some embodiments of the compound of formula (I) or (Ia), R 1 and R 2 together forming optionally one or more R 1a Substituted 5-membered heteroaryl.

[0102] In some embodiments of the compound of Formula (I) or (Ia), R 1 and R 2 Formed together Each optionally represented by one or more R 1areplace.

[0103] In some embodiments of the compound of Formula (I) or (Ia), each R 1a are independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, 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 each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compound 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 each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound 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 each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compound of formula (I) or (Ia), each 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 or C1-C6 heteroalkyl. In some embodiments of the compound of formula (I) or (Ia), each R 1a is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl. In some embodiments of the compound of formula (I) or (Ia), each R 1aare independently halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0104] In some embodiments of the compound of Formula (I) or (Ia), each R 1a are independently -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

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

[0106] In some embodiments of the compound of Formula (I) or (Ia), each R 1a Independently -OR a , C1-C6 alkyl, C1-C6 hydroxyalkyl or C1-C6 heteroalkyl.

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

[0108] In some embodiments of the compound of Formula (I) or (Ia), each R 1a Independently -OR a or C1-C6 alkyl. In some embodiments of the compound of formula (I) or (Ia), each R 1a In some embodiments of the compound of formula (I) or (Ia), each R 1a is independently -Omethyl or methyl.

[0109] In some embodiments of the compounds of Formula (I) or (Ia), two R 1a Together they form an oxo group.

[0110] In some embodiments of the compound of Formula (I) or (Ia), R 3 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl. In some embodiments of the compound of formula (I) or (Ia), R 3 is C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 heteroalkyl. In some embodiments of the compound of formula (I) or (Ia), R 3 is a C1-C6 haloalkyl group. In some embodiments of the compound of formula (I) or (Ia), R3 is a C1-C6 heteroalkyl group. In some embodiments of the compound of formula (I) or (Ia), R 3 -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2F, -CH2CF3, -CH2OCH3, -CH2OCH2CH3, -CH2OCH(CH3)2, In some embodiments of the compound 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 the compound of formula (I) or (Ia), R 3 is -CH2CH3, -CH2CH2F or -CH2CF3. In some embodiments of the compound of formula (I) or (Ia), R 3 In some embodiments of the compound of formula (I) or (Ia), R 3 In some embodiments of the compound of formula (I) or (Ia), R 3 is -CH2CF3.

[0111] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a are independently C1-C6 alkyl.

[0112] In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl.

[0113] In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, cycloalkyl, or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b are independently C1-C6 alkyl.

[0114] In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. c and R d is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, cycloalkyl, or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R dis independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d In some embodiments of the compounds disclosed herein, each R c and R d are independently C1-C6 alkyl.

[0115] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached, they form a heterocycloalkyl group optionally substituted with one or more R groups.

[0116] 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 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 deuterated alkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl.

[0117] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -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 deuterated alkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 deuterated alkyl, or C1-C3 haloalkoxy; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -NH2, C1-C3 alkyl, or C1-C3 alkoxy; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, C1-C3 alkyl, or C1-C3 alkoxy; or two R on the same atom form an oxo.

[0118] Any combination of the above-described groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

[0119] In some embodiments, the compound is selected from the compounds found in Table 1:

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0167] In some embodiments, the compound is selected from the group consisting of:

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0193] Other forms of the compounds disclosed herein

[0194] Isomers / stereoisomers

[0195] In some embodiments, the compounds described herein exist in the form of geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds proposed herein include all cis (cis), trans (trans), cis (syn), trans (anti), entgegen (E) and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers and each center exists independently in the R configuration or S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimers and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, enantiomers and / or mixtures of diastereoisomers produced by a single preparation step, combination or interconversion can be used 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 diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and these differences are utilized to separate. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / fractionation techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered together with a resolving agent by any practical method that does not result in racemization.

[0196] Labeled compounds

[0197] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number that is different from the atomic mass or mass number typically 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, such as, respectively. 2 H. 3 H. 13 C. 14 C. l5 N. 18 O. 17 O. 31 P.32 P. 35 S. 18 F and 36 Cl. The compounds described herein and pharmaceutically acceptable salts, solvates or stereoisomers thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example, those incorporating radioactive isotopes (such as 3 H and 14 C) compounds can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 isotopes (i.e. 14 C) is particularly preferred due to its ease of preparation and detectability. In addition, heavy isotopes (such as deuterium, i.e. 2 H) Substitutions may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0198] 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.

[0199] Pharmaceutically acceptable salts

[0200] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0201] In some embodiments, the compounds described herein have acidic or basic groups and can react with a variety of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or their solvates or stereoisomers, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0202] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral, organic, or inorganic bases, such salts include, but are not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma- hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0203] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such 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, benzenesulfonic acid, benzoic ... Formic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, 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, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids (such as oxalic acid), while not pharmaceutically acceptable themselves, are used to prepare salts used as intermediates to obtain the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0204] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate), ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-C4 alkyl) 4 hydroxide, etc.

[0205] Representative organic amines for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0206] Solvates

[0207] 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 also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0208] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed from pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed in the methods described herein. As an example only, hydrates of the compounds described herein can be conveniently prepared from a water / organic solvent mixture using organic solvents including but not limited to dioxane, tetrahydrofuran, or methanol. In addition, provided herein are compounds that can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to unsolvated forms.

[0209] Tautomers

[0210] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that interconvert via the migration of hydrogen atoms, accompanied by a conversion of a single bond and one or more adjacent double bonds. In bonding arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0211] Treatment

[0212] Provided herein are methods for treating a TRPML1-mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject a combination of a compound disclosed herein in an amount effective to alleviate or prevent the disorder in the subject, and 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.

[0213] Also provided herein are compounds for use in the manufacture of a medicament for treating a TRPML1 mediated disease. Also provided herein is a method of treating a disease mediated by TRPML1 activity in a mammalian subject comprising administering a therapeutically effective amount of a compound disclosed herein.

[0214] TRPML1-mediated diseases include proliferative disorders such as cancer, inflammatory disorders, pain, neurodegenerative disorders, cognitive and psychiatric disorders, and others as disclosed below.

[0215] The TRPML1-mediated disorder or disease is aging, bone disease, cardiovascular disease, congenital developmental disorder, eye disease, hematological and solid malignancies, 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.

[0216] In some embodiments, the TRPML1-mediated disorder or disease is Aicardi-Goutières syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, autism spectrum disorder, Batten disease, bipolar disorder, cerebral ataxia, Charcot-Marie-Tooth variant diseases, chronic wasting disease, corticobasal degeneration, corticobasal syndrome, bovine spongiform encephalopathy, Creutzfeldt-Jacob disease, Danon disease, Duchenne muscular dystrophy, exotic cloven-toed encephalopathy, Fabre disease, fatal familial insomnia, Friedreich ataxia, ataxia), feline spongiform encephalopathy, fragile X syndrome, frontotemporal dementia, Gaucher disease, Gerstmann-Straussler-Scheinker disease, giant axonal neuropathy, GM1 and GM2 gangliosidosis, Huntington's disease, infantile Refsum disease, JUNQ and IPOD, Krabbe's disease, kuru, leukoencephalopathy, dementia with Lewy bodies, 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 disease), neuronal ceroid lipofuscinosis, Parkinson's disease, Parkinsonism, Pick's disease, polyglutamine disease, Pompe disease, pontocerebellar dysgenesis, prion disease, progressive nuclear palsy, progressive supranuclear palsy, pyruvate dehydrogenase deficiency, Sandhoff disease, schizophrenia, scrapie, Shy-Drager syndromesyndrome), spinal muscular atrophy, spinocerebellar ataxia, sporadic familial insomnia, subacute degeneration of the spinal cord, subacute sclerosing panencephalitis, Tay-Sachs disease, transneuronal degeneration, tuberous sclerosis, spinocerebellar ataxia, or vascular dementia.

[0217] 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 (H. pylori) infection, hypochlorhydria, pancreatitis, retinal detachment, type 2 diabetes, ulcerative colitis, or sarcopenia.

[0218] The compounds disclosed herein can be used to treat neurodegenerative disorders of various origins, such as Alzheimer's disease and other dementias, such as Lewy body dementia, frontotemporal dementia and other taupathies; amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and other parkinsonian syndromes; Huntington's disease; HIV-induced neuroinflammation; essential tremor; other spinocerebellar degeneration, neuropathies, such as Charcot-Marie-Tooth neuropathy and other TRPML1-mediated diseases, such as mucolipidosis type IV (MLIV). The compounds disclosed herein can also be used to treat nervous system conditions, such as epilepsy, including simple partial seizures, complex partial seizures, secondary generalized seizures, and also absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures and atonic seizures, and for the prevention and treatment of status epilepticus (SE).

[0219] Compounds disclosed herein can also be used to treat cognitive impairment and mental disorders. Mental disorders include but are not limited to major depression, dysthymia, mania, bipolar disorder (such as bipolar I disorder, bipolar II disorder), cyclothymic disorder, rapid cycle, sub-circadian cycle (ultradian cycling), mania, hypomania, schizophrenia, schizophrenia-like disorder, schizoaffective disorder, personality disorder, with or without attention disorders of overactive behavior, delusional disorder, short-term mental disorder, shared mental disorder, mental disorder due to general medical conditions, substance-induced mental disorder or mental disorder not otherwise specified, anxiety disorder (such as generalized anxiety disorder), panic disorder, post-traumatic stress disorder, impulse control disorder, terror disorder, dissociative disorder. Compounds disclosed herein can also be used to treat smoking addiction, drug addiction or alcoholism. Compounds disclosed herein are particularly useful for treating bipolar disorder, psychosis, anxiety or addiction.

[0220] The compounds disclosed herein can be used to prevent or treat neuroinflammation and CNS damage induced by HIV infection and HIV-related neurocognitive deficits. The compounds disclosed herein can be used to prevent or treat 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-related neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia, Morton's neuralgia, causalgia; and pain caused by physical trauma, amputation, phantom limb, cancer, toxins, or chronic inflammatory conditions; central neuralgia, such as pain observed in thalamic syndrome, mixed central and peripheral forms of pain, such as complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy.

[0221] The compounds disclosed herein can also be used to treat pain, including chronic pain. Chronic pain includes, but is not limited to, chronic pain caused by inflammation or inflammatory conditions, osteoarthritis, rheumatoid arthritis, acute injury or trauma, upper back pain or lower back pain (caused by systemic, regional or primary spinal disease (such as radiculopathy)), bone pain (due to osteoarthritis, osteoporosis, bone metastasis or unknown causes), pelvic pain, spinal cord injury-related pain, cardiac chest pain, non-cardiac chest pain, central post-stroke pain, myofascial pain, sickle cell pain, cancer pain, Fabry's disease, AIDS pain, pain in the elderly, or pain caused by headache, temporomandibular joint syndrome, gout, fibrosis or thoracic outlet syndrome, particularly pain caused by rheumatoid arthritis and osteoarthritis.

[0222] The compounds disclosed herein can be used to treat acute pain caused by acute injury, illness, sports medicine injury, carpal tunnel syndrome, burns, musculoskeletal sprains and strains, muscle tendon strains, cervicobrachial pain syndrome, dyspepsia, gastric ulcer, duodenal ulcer, dysmenorrhea, endometriosis, or surgery (such as open heart surgery or bypass surgery), postoperative pain, kidney stone pain, gallbladder pain, gallstone pain, obstetric pain, or dental pain.

[0223] The compounds disclosed herein are also useful in treating headaches such as migraine, tension headache, transformed migraine or evolutive headache, cluster headache, and secondary headache disorders such as headaches and other acute headaches resulting from infections, metabolic disorders or other systemic diseases, paroxysmal hemicrania, etc., which are caused by exacerbations of the above primary and secondary headaches.

[0224] The compounds disclosed herein may also be used to treat diseases such as vertigo, tinnitus, muscle spasms, and other conditions, including but not limited to cardiovascular diseases (such as arrhythmias, myocardial infarction or angina, hypertension, myocardial ischemia, cerebral ischemia), endocrine diseases (such as acromegaly or diabetes insipidus), where the pathophysiology of the condition involves excess or oversecretion of endogenous substances (such as catecholamines, hormones, or growth factors) or other inappropriate cellular secretion.

[0225] The compounds disclosed herein may also be used to selectively treat liver diseases, such as inflammatory liver diseases, for example, chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, liver fibrosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and liver transplant rejection.

[0226] The compounds disclosed herein inhibit inflammatory processes that affect all body systems. Therefore, they can be used to treat inflammatory processes of the musculoskeletal system. The following is a list of some examples, but not all of the target conditions: arthritic conditions such as ankylosing spondylitis, cervical spondylitis, fibromyalgia, gout, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, rheumatism; conditions affecting the skin and related tissues: eczema, psoriasis, dermatitis and inflammatory conditions such as sunburn; conditions of the respiratory system: asthma, allergic rhinitis and respiratory distress syndrome, lung conditions involving inflammation such as asthma and bronchitis; chronic obstructive pulmonary disease; conditions of the immune and endocrine systems: nodular periarthritis, thyroiditis, aplastic anemia, scleroderma, myasthenia gravis, multiple sclerosis and other demyelinating conditions, encephalomyelitis, sarcoidosis, nephritic syndrome, Bechet's syndrome, polymyositis, gingivitis.

[0227] The compounds disclosed herein may also be used to treat gastrointestinal (GI) 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 following proctocolectomy and ileonatal anastomosis, and irritable bowel syndrome, including any disorder associated with abdominal pain and / or discomfort, such as pylorospasm, nervous dyspepsia, spastic colon, spastic colitis, spastic bowel syndrome, and irritable bowel syndrome. It is also used to treat atrophic gastritis, gastritis variolioforme, ulcerative colitis, peptic ulcer, heartburn and other damage to the gastrointestinal tract, for example, by Helicobacter pylori, gastroesophageal reflux disease, gastroparesis, such as diabetic gastroparesis; and other functional bowel disorders, such as non-ulcer dyspepsia (NUD); pancreatitis, vomiting, diarrhea, visceral inflammation and hypochlorhydria.

[0228] The compounds disclosed herein may also be used to treat genitourinary tract disorders such as overactive bladder, prostatitis (chronic bacterial and chronic nonbacterial prostatitis), prostadynia, interstitial cystitis, urinary incontinence, and benign prostatic hyperplasia, adnexitis, pelvic inflammatory disease, bartholinitis, and vaginitis, particularly overactive bladder and urinary incontinence.

[0229] The compounds disclosed herein may also be used to treat renal disorders, including diabetic nephropathy, renal transplant rejection, infectious nephropathy, IgA nephropathy, fibrotic nephropathy, lupus nephritis, glomerulonephritis, acute kidney injury, and renal cancer.

[0230] The compounds disclosed herein may also be used to treat ophthalmic diseases such as retinitis, retinitis pigmentosa, retinopathy, uveitis, acute injury to ocular tissue, age-related macular degeneration, glaucoma, retinal cell degeneration in glaucoma, conjunctivitis, and retinal detachment.

[0231] The compounds disclosed herein may also be used to treat eating disorders such as anorexia nervosa (including restrictive subtypes and binge-eating / purging type subtypes); bulimia nervosa including purging and non-purging subtypes; obesity; compulsive eating disorder; binge eating disorder; and eating disorders not otherwise specified.

[0232] The compounds disclosed herein may also be used to treat allergic dermatitis, airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, Sjögren's syndrome ( syndrome), glomerulonephritis, atherosclerosis, growth and metastasis of malignant cells, myoblastic leukemia, diabetes mellitus (type 2 diabetes), meningitis, osteoporosis, burns, ischemic heart disease, stroke, peripheral vascular disease, varicose veins, glaucoma, and female infertility.

[0233] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to treat or prevent the progression of cancer. In some embodiments, the cancer is a hematological malignancy or solid tumor. Hematological malignancies include leukemias, lymphomas, multiple myeloma, and subtypes thereof. Lymphomas can be classified in a variety of ways, generally based on the underlying type of malignant cells, including Hodgkin's lymphoma (usually a cancer of Reed-Sternberg cells, but sometimes also originating from B cells; all other lymphomas are non-Hodgkin's lymphomas), B-cell lymphomas, T-cell lymphomas, mantle cell lymphomas, Burkitt's lymphomas, follicular lymphomas, and other lymphomas as defined herein and known in the art.

[0234] B cell lymphomas include, but are not limited to, diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), and other lymphomas as defined herein and known in the art.

[0235] T-cell lymphomas include T-cell acute lymphoblastic leukemia / lymphoma (T-ALL), peripheral T-cell lymphoma (PTCL), T-cell chronic lymphocytic leukemia (T-CLL), Sezary syndrome, and other lymphomas as defined herein and known in the art.

[0236] Leukemias include acute myeloid (or myeloid) leukemia (AML), chronic myeloid (or myeloid) leukemia (AML), acute lymphoblastic (or lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia (sometimes classified as lymphoma), and other leukemias as defined herein and known in the art.

[0237] Plasma cell malignancies include lymphoplasmacytic lymphoma, plasmacytoma, and multiple myeloma.

[0238] Solid tumors include melanoma, neuroblastoma, glioma, or 5 cancers such as tumors of the brain, head and neck, chest, lung (e.g., non-small cell lung cancer, NSCLC), reproductive tract (e.g., ovary), upper gastrointestinal tract, pancreas, liver, renal system (e.g., kidney), bladder, prostate, and colorectum.

[0239] In addition to being useful in human therapy, certain compounds and formulations disclosed herein are also useful in the veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs, and cats.

[0240] Drug administration

[0241] In certain embodiments, compositions containing the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, an amount of the composition sufficient to cure or at least partially prevent at least one symptom of a disease or condition is administered to a patient already suffering from the disease or condition. The effective dose for such use depends on the severity and course of the disease or condition, previous treatment, the patient's health, weight, and response to the drugs, and the judgment of the attending physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose-ranging clinical trials.

[0242] In preventive applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In such applications, the precise amount also depends on the patient's health, weight, etc. When used in a patient, the effective amount for such use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health status and response to drugs, and the judgment of the attending physician. In one aspect, preventive treatment comprises administering a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor for the disease being treated and is currently in remission, in order to prevent the recurrence of symptoms of the disease or condition.

[0243] In certain embodiments, where the patient's condition does not improve, the compound may be administered chronically, i.e., for an extended period of time, including throughout the patient's life, in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition, at the physician's discretion.

[0244] Once the patient's condition has improved, a maintenance dose is administered, if necessary. Subsequently, in specific embodiments, depending on the symptoms, the dosage or frequency of administration, or both, is reduced to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, upon recurrence of any symptoms, the patient requires intermittent or daily treatment on a long-term basis.

[0245] The amount of a given agent that corresponds to such an amount depends on a variety of factors, such as the specific compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., weight, sex), but is determined on a case-by-case basis, including, for example, the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0246] However, in general, the dosage used for adult treatment is generally in the range of 0.01 mg to 5000 mg per day. In one aspect, the dosage used for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose can be conveniently administered in a single dose or in divided doses simultaneously or at appropriate intervals, for example, two, three, four or more sub-doses per day.

[0247] In one embodiment, the daily dose suitable for the compounds described herein, or a pharmaceutically acceptable salt thereof, is from about 0.01 to about 50 mg / kg body weight. In some embodiments, the amount of active ingredient in the daily dose or dosage form is lower or higher than the ranges shown herein based on a number of variables related to the individual treatment regimen. In various embodiments, the daily dose and unit dose vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition to be treated, and the judgment of the physician.

[0248] Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical methods in cell culture or experimental animals, including but not limited to LD 10 and ED 90 The dose ratio between toxic effect and therapeutic effect is the therapeutic index, expressed as LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within a range that includes the ED 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 employed and the route of administration utilized.

[0249] In any of the above aspects, there are further embodiments wherein the effective amount of the 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 locally to a mammal.

[0250] Within any of the above aspects, there are further embodiments comprising a single administration of an effective amount of the compound, including further embodiments wherein (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times over the span of a single day.

[0251] Route of administration

[0252] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0253] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by directly injecting the compound into an organ, typically in the form of a depot preparation or a sustained-release formulation. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. In addition, in other embodiments, the drug is delivered with a targeted drug delivery system, for example, delivered with liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to the organ and selectively absorbed by the organ. In yet other embodiments, the compounds described herein are provided in the form of a quick-release formulation, an extended-release formulation, or a medium-release formulation. In some embodiments, the compounds described herein are topically administered.

[0254] Pharmaceutical composition / dosage form

[0255] The compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent as a pharmaceutical composition to a subject in need thereof, according to standard pharmaceutical practice. In one embodiment, the compounds disclosed herein can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0256] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that aid in processing the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the chosen route of administration. A summary of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 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), the disclosures of which are incorporated herein by reference.

[0257] 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 dispersant, a surfactant, a lubricant, a colorant, a diluent, a solubilizer, a wetting agent, a plasticizer, a stabilizer, a penetration enhancer, a humectant, a defoaming agent, an antioxidant, a preservative, and any combination thereof.

[0258] The pharmaceutical compositions described herein are administered to a subject by an appropriate route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. The pharmaceutical dosage forms described herein include but are not limited to aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate-release dosage forms, controlled-release dosage forms, fast-dissolving dosage forms, tablets, capsules, pills, powders, dragees, effervescent dosage forms, lyophilized dosage forms, delayed-release dosage forms, extended-release dosage forms, pulsatile-release dosage forms, multiparticulate dosage forms, and mixed immediate-release and controlled-release dosage forms.

[0259] Pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0260] The pharmaceutical composition for oral use is obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if necessary) 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, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other (such as polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate). If necessary, disintegrants are added, such as cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. In some embodiments, dyes or pigments are added to tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0261] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer (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 a fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0262] The pharmaceutical composition for parenteral use is formulated as an infusion or injection. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution or dispersion or sterile powder comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or a liquid dispersion medium, including, for example, water, saline, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), a vegetable oil, a non-toxic glyceride and any combination thereof. In some embodiments, the pharmaceutical composition also includes a preservative to prevent the growth of microorganisms.

[0263] combination

[0264] Disclosed herein are methods of treating TRPML1-mediated disorders or diseases using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0265] In some embodiments, the additional therapeutic agent is administered concurrently with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to the administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compounds disclosed herein.

[0266] The following examples illustrate the invention. Unless expressly stated otherwise, all measurements (especially percentages and amounts) relate to weight.

[0267] Preparation of intermediate ethyl 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate (VII):

[0268]

[0269] Step 1: Synthesis of 3-bromo-1,1,1-trifluoropropane: To a solid mixture of CBr4 (45.43 g, 136.84 mmol) and Ph3P (35.85 g, 136.84 mmol) was added 3,3,3-trifluoropropan-1-ol (13.0 g, 114.03 mmol) at room temperature. The initiation of the reaction was indicated by a vigorous exotherm, while the solid reaction mass became liquid. The mixture was heated at 90 ° C for 3 hours under a condenser, circulating cooling (5-10 ° C) water. The compound was then distilled out using short-path distillation to obtain 3-bromo-1,1,1-trifluoropropane (15.5 g, 76.81%) as a colorless liquid.

[0270] Step 2: Synthesis of ethyl 5,5,5-trifluoro-2-oxopentanoate: To a suspension of magnesium turnings (2.87 g, 119.76 mmol) in THF (5 mL) was added a catalytic amount of 1,2-dibromoethane and stirred until effervescence began. When 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 hot suspension, maintaining the temperature at approximately 50° C. After the addition was complete, the mixture was stirred at room temperature (rt) for another 30 minutes.

[0271] To the solution of -78 DEG C of diethyl oxalate (6.12g, 41.91mmol) in THF (50mL) dropwise add above freshly prepared Grignard solution, then when the reaction mixture becomes clear, it is gradually warmed to room temperature, continue 3 hours.After the completion of the reaction [by TLC (KMnO4 staining) monitoring], quenched with NH4Cl saturated aqueous solution (200mL), and extracted with ethyl acetate (2x 200mL).The organic layer merged is washed with saline solution, through anhydrous Na2SO4 dry and concentrated, to obtain the required compound 5,5,5-trifluoro-2-oxopentanoic acid ethyl ester (6.2g) as brown colloidal liquid (crude product). It is directly used in the next step without further purification.

[0272] Step 3: Synthesis of 3-bromo-5,5,5-trifluoro-2-oxopentanoic acid ethyl ester: To a solution of 5,5,5-trifluoro-2-oxopentanoic acid ethyl ester (6.2 g, 31.31 mmol) in ethyl acetate (390 mL) and DCM (230 mL) was added CuBr2 (24.44 g, 109.59 mmol), and the resulting reaction mixture was stirred at 90 ° C for 16 hours. After completion [monitored by TLC (KMnO4 staining)], the reaction mixture was filtered through celite, and the filtrate was concentrated to give 3-bromo-5,5,5-trifluoro-2-oxopentanoic acid ethyl ester (8.6 g) as a brown gummy liquid (crude product). It was used directly in the next step without further purification.

[0273] Step 4: the synthesis of 2-amino-5-(2,2,2-trifluoroethyl) oxazole-4-ethyl formate: at room temperature, to 3-bromo-5,5,5-trifluoro-2-oxopentanoic acid ethyl ester (8.6g, 31.04mmol) in ethanol (100mL) stirring solution, add urea (7.45g, 124.18mmol), then reflux 16 hours.After completion [by TLC, LC-MS monitoring], reaction mixture is concentrated to remove ethanol.Then crude reaction mixture is treated with saturated NaHCO3 aqueous solution (100mL) and extracted with ethyl acetate (2x200mL).By organic layer through anhydrous Na2SO4 drying and under reduced pressure concentrated. The crude residue thus obtained was triturated with 50% diethyl 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.

[0274] Step 5: Synthesis of 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-ethyl formate: A suspension of CuCl2 (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 2-amino-5-(2,2,2-trifluoroethyl)oxazole-4-ethyl formate in acetonitrile (90 mL) was added dropwise to the hot reaction mixture. After addition, the reaction mixture was stirred at 75 ° C for 1 hour. After 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 bed of celite 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-hexanes as eluent to give ethyl 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylate (VII) as a light yellow liquid (1.9 g, 58.5%).

[0275] Preparation of 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline:

[0276]

[0277] 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) was added 2-chlorocyclopentan-1-one (2.4 g, 12.74 mmol), and the resulting reaction mixture was stirred at 70 ° C for 8 hours. The reaction was then concentrated under vacuum 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 crude product was purified by flash column chromatography using 10% EtOAc / hexane as eluent to give 2-(2-fluoro-4-nitrophenoxy)cyclopentan-1-one (X) (1.2 g, 39.38%) as a yellow liquid.

[0278] 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 addition, the reaction mixture was stirred at room temperature for 16 hours. 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 crude product was purified by flash column chromatography using 10% EtOAc-hexane as eluent to give 1-((2,2-difluorocyclopentyl)oxy)-2-fluoro-4-nitrobenzene (0.42 g, 54.9%) as a yellow liquid.

[0279] 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) at 0°C was added zinc powder and ammonium chloride (633 mg, 11.91 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. Upon completion [monitored by LC-MS], the reaction mixture was filtered through sintered glass. The filtrate was dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was purified by combiflash column chromatography using 10% EtOAc-hexane to afford 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline (255 mg, 62.58%) as a brown viscous liquid.

[0280] General protocol for the preparation of Examples 1-24.

[0281]

[0282] Step 1: To a stirred solution of intermediate (VII) (1.0 equivalent) and DIPEA (3.0 equivalents) in dioxane (3 mL / g VII) was added R2NH (1.1 equivalents), and the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete [monitored by TLC], the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude product was purified by flash column chromatography to obtain an intermediate of structure XIII.

[0283] Step 2: At 0 ° C, to a stirred solution of XIII (1.0 equiv) and 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline (XII) (0.8 equiv) in anhydrous toluene (30 mL / g XIII) was added dropwise trimethylaluminum (1M in toluene, 4.0 equiv), and the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed [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 obtain a product of general structure XIV.

[0284] All amines (R2NH) used in the synthesis of product (XIV) were purchased from chemical suppliers.

[0285] Example 1

[0286] The title compound was prepared as described in the general scheme above using isoindoline as the amine in step 1 to give 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%).

[0287] Example 2

[0288] 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%).

[0289] Example 3

[0290] The title compound was prepared as described in the general scheme above using 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%).

[0291] Example 4

[0292] The title compound was prepared as described in the general scheme above using 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%).

[0293] Example 5

[0294] The title compound was prepared as described in the general scheme above using 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%).

[0295] Example 6

[0296] The title compound was prepared as described in the general scheme above using 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%).

[0297] Example 7

[0298] The title compound was prepared as described in the general scheme above using 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%).

[0299] Example 8

[0300] 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%).

[0301] Example 9

[0302] The title compound was prepared as described in the general scheme above using 7-azabicyclo[2.2.1]heptane as the amine in step 1 to give 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%).

[0303] Example 10

[0304] The title compound was prepared as described in the general scheme above using 6,6-difluoro-3-azabicyclo[3.1.0]hexane as the amine in step 1 to give 2-{6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}-N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 22%).

[0305] Example 11

[0306] The title compound was prepared as described in the general scheme above using 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%).

[0307] Example 12

[0308] The title compound was prepared as described in the general scheme above using 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%).

[0309] Example 13

[0310] The title compound was prepared as described in the general scheme above using 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%).

[0311] Example 14

[0312] The title compound was prepared as described in the general scheme above using 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%).

[0313] Example 15

[0314] The title compound was prepared as described in the general scheme above using 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%).

[0315] Example 16

[0316] 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%).

[0317] Example 17

[0318] The title compound was prepared as described in the general scheme above using 6,6-difluoro-2-azaspiro[3.3]heptane as the amine in step 1 to give 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%).

[0319] Example 18

[0320] 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%).

[0321] Example 19

[0322] The title compound was prepared as described in the general scheme above using 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%).

[0323] Example 20

[0324] 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%).

[0325] Example 21

[0326] The title compound was prepared as described in the general scheme above using 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%).

[0327] Example 22

[0328] The title compound was prepared as described in the general scheme above using pyrrolidine as the amine in step 1 to give N-{4-[(2,2-difluorocyclopentyl)oxy]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 51%).

[0329] Example 23

[0330] The title compound was prepared as described in the general scheme above using 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%).

[0331] Example 24

[0332] 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%).

[0333] General protocol for the preparation of Examples 25-33.

[0334]

[0335] Step 1: To a stirred solution of intermediate VII (1.0 eq) and DIPEA (3.0 eq) in dioxane (3 mL / g) was added the amine compound (1.1 eq) and the resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion [monitored by TLC or LCMS], the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude product was subjected to flash column chromatography to afford XV.

[0336] Step 2: To a stirred solution of XV (1.0 equiv.) in anhydrous 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. After completion of the reaction [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 crude product was purified by flash column chromatography to obtain an embodiment of general structure XVII.

[0337] All amines used as starting materials were purchased from commercial sources.

[0338] Example 25

[0339] The title compound was prepared as described in the general scheme above using 2-thia-7-azaspiro[3,5]nonane-2,2-dioxide as the amine in step 1 to give 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%).

[0340] Example 26

[0341] The title compound was prepared as described in the general scheme above using (3aR,6aR)-hexahydro-2H-furo[2,3-c]pyrrole as the amine in step 1 to give 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%).

[0342] Example 27

[0343] The title compound was prepared as described in the general scheme above using 5-azaspiro[2.4]heptane as the amine in step 1 to give 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%).

[0344] Example 28

[0345] The title compound was prepared as described in the general scheme above using 2,2-difluoro-6-azaspiro[3.4]octane as the amine in step 1 to give 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%).

[0346] Example 29

[0347] The title compound was prepared as described in the general scheme above using 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%).

[0348] Example 30

[0349] The title compound was prepared as described in the general scheme above using 6,6-difluoro-2-azaspiro[3.3]heptane as the amine in step 1 to give 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%).

[0350] Example 31

[0351] The title compound was prepared as described in the general scheme above using 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%).

[0352] Example 32

[0353] The title compound was prepared as described in the general scheme above using pyrrolidine as the amine in step 1 to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (9 mg, 21%).

[0354] Example 33

[0355] The title compound was prepared as described in the general scheme above using 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%).

[0356] Preparation of 4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluoroaniline] (XXI):

[0357]

[0358] 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) was added bicyclo[3.1.0]hexane-3-ol and stirred at room temperature for 2 hours. 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 eluent to give 3-(2,6-difluoro-4-nitrophenoxy)bicyclo[3.1.0]hexane (XX, 530 mg, 66.04%).

[0359] Step 2: At 0 ° C, 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) was added zinc powder (639 mg, 9.84 mmol) and ammonium chloride (637 mg, 11.81 mmol). It 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 product (XXI) was purified by flash column chromatography using 10% EtOAc in hexane to obtain 4- (cis-bicyclo [3.1.0] hexane-3-yloxy) -3,5-difluoroaniline (XXI) (400 mg, 90.22%).

[0360] General protocol for the preparation of Examples 34-41.

[0361]

[0362] Step 1: To a stirred solution of intermediate (VII) (1.0 equivalent) and DIPEA (3.0 equivalents) in dioxane (3 mL / mmol) was added an amine of formula R2NH (1.1 equivalents), and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude product was purified by flash column chromatography to obtain an intermediate of formula XXII.

[0363] Step 2: To a stirred solution of XXII (1.0 equiv.) in anhydrous toluene (30 mL / g) was added 4-(cis-bicyclo[3.1.0]hex-3-yloxy)-3,5-difluoroaniline (XXI) (0.8 equiv.), followed by dropwise addition of trimethylaluminum (2M in toluene, 4.0 equiv.) at 0°C, and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction [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 XXIII was purified by flash column chromatography to obtain an embodiment of the general formula XXIII.

[0364] All amines used as starting materials were purchased from commercial suppliers.

[0365] Example 34

[0366] The title compound was prepared as described in the general scheme above using 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%).

[0367] Example 35

[0368] The title compound was prepared as described in the general scheme above using 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%).

[0369] Example 36

[0370] The title compound was prepared as described in the general scheme above using 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%).

[0371] Example 37

[0372] 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%).

[0373] Example 38

[0374] 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%).

[0375] Example 39

[0376] The title compound was prepared as described in the general scheme above using pyrrolidine as the amine in step 1 to give 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%).

[0377] Example 40

[0378] The title compound was prepared as described in the general scheme above using octahydrocyclopenta[c]pyrrole as the amine in step 1 to give 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%).

[0379] Example 41

[0380] The title compound was prepared as described in the general scheme above using 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%).

[0381] General conditions for preparing Examples of the general formula shown in Structure XXIX (Examples 42-76):

[0382]

[0383] Step 1. KOH (3.0 equivalents) is added to a stirred solution of XXIV (1.0 equivalents) and XXV (1.2 equivalents) in DMSO (3 mL / mmol). The reaction is stirred at room temperature for 2 hours. After completion [monitored by TLC], the resulting reaction mixture is distributed between EtOAc and water. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Using the EtOAc in the hexane as eluent, the crude product is purified by flash column chromatography to obtain the required product (XXVI).

[0384] Step 2: At 0 ° C, zinc powder (639 mg, 9.84 mmol) and ammonium chloride (637 mg, 11.81 mmol) were added to a stirred solution of (XXVI) (2 mmol) in 10 mL of 1,4-dioxane: water (5: 1). 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 crude product (XXVII) was purified by flash column chromatography using 10% EtOAc in hexane to obtain pure (XXVII).

[0385] Step 3: To a stirred solution of intermediate (VII) (1.0 equivalent) and DIPEA (3.0 equivalents) in dioxane (3 mL / mmol) was added an amine of formula R2NH (1.1 equivalents), and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was concentrated under reduced pressure to remove dioxane. The resulting crude product was purified by flash column chromatography to obtain an intermediate of formula XXII.

[0386] Step 4: Compound XXVII (0.8 equiv.) from step 2 was added to a stirred solution of XXII (1.0 equiv.) in anhydrous toluene (30 mL / g), 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 obtain an embodiment of the general formula XXIX.

[0387] All alcohols used as starting materials were purchased from commercial suppliers.

[0388] All amines used in step 3 of the above methods were purchased from commercial suppliers.

[0389] Example 42

[0390] The above mentioned compounds were synthesized using the method as 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 afford N-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (19 mg, 16%).

[0391] Example 43

[0392] The above mentioned compounds were synthesized using the method as described in the general scheme above using 3-methoxycyclopentanol as the alcohol in step 1 and pyrrolidine as the amine in step 4 to afford N-{3-fluoro-4-[(3-methoxycyclopentyl)oxy]phenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 24%).

[0393] Example 44

[0394] The above mentioned compounds were synthesized using the method as 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 afford N-[4-(3,3-difluorocyclobutoxy)-3-fluorophenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 45%).

[0395] Example 45

[0396] The above-mentioned compounds were synthesized using the method as 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 afford 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%).

[0397] Example 46

[0398] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0399] Example 47

[0400] The above mentioned compounds were synthesized using the method as 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 afford N-[3-fluoro-4-(oxolan-3-yloxy)phenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 36%).

[0401] Example 48

[0402] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0403] Example 49

[0404] The above-mentioned compounds were synthesized using the method 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 obtain the racemic title compound. Chiral separations were performed on an Agilent 1200 series instrument. Column: CHIRALPAK IG (250 x 21 mm) 5 μm particle size. The separation was performed at ambient temperature with 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 at a wavelength of 280 nm for 40 minutes. 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%) was isolated.

[0405] Example 50

[0406] The above mentioned compounds were synthesized using the method as described in the general scheme above using 3-methylcyclopentanol as the alcohol in step 1 and pyrrolidine as the amine in step 4 to afford N-(3-fluoro-4-((3-methylcyclopentyl)oxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20 mg, 16.03%).

[0407] Example 51

[0408] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0409] Example 52

[0410] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0411] Example 53

[0412] The above mentioned compounds were synthesized using the method as 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 afford N-{4-[(2,2-difluorocyclopentyl)methoxy]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 25%).

[0413] Example 54

[0414] The above mentioned compounds were synthesized using the methods as 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%).

[0415] Example 55

[0416] The above mentioned compounds were synthesized using the method as 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 afford N-(4-((2,2-dimethylcyclopentyl)oxy)-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (12 mg, 14.2%).

[0417] Example 56

[0418] The above mentioned compounds were synthesized using the method as 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 afford N-[3-fluoro-4-(oxan-4-yloxy)phenyl]-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (47 mg, 37%).

[0419] Example 57

[0420] The above mentioned compounds were synthesized using the method as 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 afford N-(4-(cyclopentyloxy)-3-fluorophenyl)-2-(5-azaspiro[2.4]heptan-5-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 26%).

[0421] Example 58

[0422] The above mentioned compounds were synthesized using the method as 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 afford N-(3-fluoro-4-(3,3,3-trifluoropropoxy)phenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 31%).

[0423] Example 59

[0424] The above mentioned compounds were synthesized using the method as 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%).

[0425] Example 60

[0426] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0427] Example 61

[0428] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0429] Example 62

[0430] The above mentioned compounds were synthesized using the method as 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%).

[0431] Example 63

[0432] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0433] Example 64

[0434] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0435] Example 65

[0436] The above mentioned compounds were synthesized using the method as 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%).

[0437] Example 66

[0438] The above mentioned compounds were synthesized using the method as 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%).

[0439] Example 67

[0440] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0441] Example 68

[0442] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0443] Example 69

[0444] The above-mentioned compounds were synthesized using the methods 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 provide the racemic title compound. Chiral separations were performed on an Agilent 1200 series instrument. Column: CHIRALPAK IG (250 x 21 mm), 5 μm particle size. The separation was performed at ambient temperature with a flow rate of 21.0 mL / min. The mobile phase was a mixture of 70% hexane and 30% ethanol, maintained as an isocratic mixture at a wavelength of 280 nm for 40 minutes. 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%) was isolated.

[0445] Example 70

[0446] The above-mentioned compounds were synthesized using the method as 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 afford 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%).

[0447] Example 71

[0448] The above-mentioned compound was synthesized using the method as 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%).

[0449] Example 72

[0450] The above-mentioned compounds were synthesized using the method as 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 afford 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%).

[0451] Example 73

[0452] The above mentioned compounds were synthesized using the method as 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 afford N-(4-{cis-bicyclo[3.1.0]hexan-3-yloxy}-3-fluorophenyl)-2-{2-oxa-6-azaspiro[3.4]octane-6-yl}-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (40 mg, 30%).

[0453] Example 74

[0454] The above mentioned compounds were synthesized using the method as 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%).

[0455] Example 75

[0456] The above mentioned compounds were synthesized using the method as 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 afford 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%).

[0457] Example 76

[0458] The above mentioned compounds were synthesized using the method as 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 afford N-{4-[(2,2-difluorocyclohexyl)oxy]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 36%).

[0459] General procedure for the synthesis of Examples of general structure XXXV (Examples 77-83).

[0460]

[0461] Step 1: To a stirred solution of compound (XXX) (1.0 eq.) and potassium carbonate (2.0 eq.) in acetonitrile (3 mL / mmol) was added amine R a R b NH (1.1 equivalents). The reaction mass was heated at 80 ° C for 16 hours. 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. Using EtOAc / hexane as eluent, the crude material was purified by flash column chromatography to obtain intermediate compound XXXI.

[0462] Step 2: To a stirred solution of compound XXXI in 1,4-dioxane:water (5:1) at 0°C was added zinc powder (5.0 equivalents) followed by ammonium chloride (6.0 equivalents). The reaction mixture 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 Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography using EtOAc-hexane as eluent to afford intermediate compound XXXII.

[0463] Step 3: To a stirred solution of compound VII (1.0 eq.) in dioxane (3 mL / g) was added amine R c R d To the mixture of NH (1.1 equivalents) and DIPEA (3.0 equivalents) was added and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was concentrated under reduced pressure to remove dioxane. The crude product was purified by flash column chromatography using EtOAc-hexane as eluent to afford XXXIV.

[0464] Step 4: XXXII (0.8 equiv) was added to a stirred solution of XXXIV (1.0 equiv) in anhydrous toluene (30 mL / g), 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. After completion [monitored by TLC / LCMS], the reaction mixture was quenched with saturated ammonium chloride solution and distributed with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain XXXV.

[0465] All amines used as starting materials were purchased from commercial suppliers.

[0466] Example 77

[0467] The above mentioned compounds were synthesized using the method as described in the general scheme above, wherein compound XXX is 3,4-difluoronitrobenzene, 4,4-difluoropiperidine as amine in step 1 and 6,6-difluoro-2-azaspiro[3.3]heptane as amine in step 4 to give 2-{6,6-difluoro-2-azaspiro[3.3]heptane-2-yl}-N-[4-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (58 mg, 48%).

[0468] Example 78

[0469] The above mentioned compounds were synthesized using the method as described in the general scheme above, wherein compound XXX is 4-fluoro-3-trifluoromethylnitrobenzene, piperidine was used as amine in step 1 and 6,6-difluoro-2-azaspiro[3.3]heptane was used as amine in step 4 to give 2-{6,6-difluoro-2-azaspiro[3.3]heptane-2-yl}-N-[4-(piperidin-1-yl)-3-(trifluoromethyl)phenyl]-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (45 mg, 29%).

[0470] Example 79

[0471] The above mentioned compounds were synthesized using the method as described in the general scheme above, wherein compound XXX is 3,4-difluoronitrobenzene, N-methylcyclopentylamine was used as amine in step 1 and 6,6-difluoro-2-azaspiro[3.3]heptane was used as amine in step 4 to give 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%).

[0472] Example 80

[0473] The above mentioned compounds were synthesized using the method as described in the general scheme above, wherein compound XXX is 3,4-difluoronitrobenzene, N-methylbicyclo[3.1.0]hexan-3-amine as amine in step 1 and pyrrolidine as amine in step 4 to give 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%).

[0474] Example 81

[0475] The above-mentioned compounds were synthesized using the method as described in the general scheme above, wherein compound XXX is 3,4,5-trifluoronitrobenzene, 2,2-difluoro-N-methylcyclopentan-1-amine as amine in step 1 and pyrrolidine as amine in step 4 to give 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%).

[0476] Example 82

[0477] The above-mentioned compounds were synthesized using the method as described in the general scheme above, wherein compound XXX is 3,4-difluoronitrobenzene, 2,2-difluoro-N-methylcyclopentan-1-amine was used as the amine in step 1 and pyrrolidine was used as the amine in step 4 to give N-{4-[(2,2-difluorocyclopentyl)(methyl)amino]-3-fluorophenyl}-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 21%).

[0478] Example 83

[0479] The above mentioned compounds were synthesized using the method as described in the general scheme above, wherein compound XXX is 3,4-difluoronitrobenzene, 6-azabicyclo[3.1.1]heptane as amine in step 1 and pyrrolidine as amine in step 4 to afford N-(4-{6-azabicyclo[3.1.1]heptane-6-yl}-3-fluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (16 mg, 12%).

[0480] Example 84

[0481]

[0482] Step 1: synthesis of 5-nitro-2-(piperidin-1-yl)phenol: to a stirred suspension of 2-fluoro-5-nitrophenol (0.8g, 5.10mmol) and potassium carbonate (2.1g, 15.30mmol) in DMF (5mL) was added piperidine (0.86g, 10.2mmol) and the reaction was stirred at 80°C for 16 hours. After completion [monitored by TLC], the reaction mixture was diluted with ethyl acetate (20mL) and washed with water (2x 30mL). 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 obtain 5-nitro-2-(piperidin-1-yl)phenol (0.85g, 75%) as a yellow liquid.

[0483] 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) was added zinc powder (292 mg, 4.5 mmol) and ammonium chloride (287 mg, 5.4 mmol) at 0°C. The mixture was then stirred at room temperature for 3 hours. Upon completion [monitored by LC-MS], the reaction mixture was filtered through a sintered glass filter. The filtrate was dried over anhydrous Na2SO4, 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%).

[0484] 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 anhydrous toluene (5 mL) was added XXXIX (60 mg, 0.205 mmol), followed by dropwise addition of trimethylaluminum (2M in toluene, 0.4 mL, 0.80 mmol) at 0 ° C., and the resulting reaction mixture was stirred at room temperature for 2 hours. Upon 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 crude product 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%).

[0485] Example 85

[0486]

[0487] Step 1: add K to the stirred solution of 2-methoxy-5-nitrophenol (XL) (500mg, 2.95mmol) in DMF (10mL) CO (407mg, 2.95mmol) and benzyl bromide (505mg, 2.95mmol) and stir at room temperature for 16 hours.After completion [monitored by TLC], the reaction mixture was diluted with cold water [20mL] and extracted with EtOAc [20mL x 2]. The organic portion was separated, dried over sodium sulfate and concentrated under reduced pressure. Using 2-5% EtOAc-hexane as eluting solvent, the gained crude product was purified by flash column chromatography to obtain 2- (benzyloxy) -1- methoxy -4- nitrobenzene (XLII) (475mg, 62%) as a light yellow solid.

[0488] Step 2: add 10N NaOH solution (0.5mL) to the stirred solution of compound XLII (475mg, 1.83mmol) in DMSO (10mL) and stir 5 hours at 100 ℃.After completing [monitoring with TLC], use 1N HCl solution (about 2mL) acidification reaction mixture, extract with EtOAc [20mL x 2]. The organic part is separated, dried over sodium sulfate and concentrated under reduced pressure. Use 2-5% EtOAc-hexane as eluting solvent, the gained crude product is purified by flash column chromatography, to obtain 2-(benzyloxy)-4-nitrophenol (XLIII) (360mg, 80%).

[0489] Step 3: to a stirred solution of XLIII (360 mg, 1.46 mmol) in DMF (8 mL), bromocyclopentane (218.89 mg, 1.46 mmol), K CO , and stirred at 120° C. for 16 hours. After completion [monitored by TLC], the reaction mixture was diluted with cold water [20 mL] and extracted with EtOAc [20 mL x 2]. The organic portion was separated, dried over sodium sulfate and concentrated under reduced pressure. Using 15% EtOAc-hexane, the resulting crude product was purified by flash column chromatography to obtain 2-(benzyloxy)-1-(cyclopentyloxy)-4-nitrobenzene (XLIV) (300 mg, 65%).

[0490] Step 4: Pd / C (20%) (about 80 mg) was added to a stirred solution of XLIV (150 mg, 0.47 mmol) in ethanol (4 mL) and stirred for 1 hour under a hydrogen atmosphere. After completion [monitored by TLC], the reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was then purified by flash column chromatography using 50% EtOAc-hexane to obtain 5-amino-2-(cyclopentyloxy)phenol XLV (60 mg, 64%) as a brown solid.

[0491] Step 5: 5-amino-2-(cyclopentyloxy)phenol (66mg, 0.34mmol) is added to a stirred solution of XXXIX (100mg, 0.34mmol) in anhydrous toluene (4mL), then trimethylaluminum (2M in toluene, 0.68mL, 1.36mmol) is added dropwise at 0°C, and the resulting reaction mixture is stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture is quenched with saturated ammonium chloride solution (10mL) and distributed with EtOAc [30mL x 2]. The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure. Using 35% EtOAc-hexane as eluting solvent, the resulting crude product is purified by flash column chromatography to obtain N-(4-(cyclopentyloxy)-3-hydroxyphenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (20mg, 13%).

[0492] Example 86

[0493]

[0494] Step 1: To a stirred solution of 2-(benzyloxy)-4-nitrophenol (XLVI) (600 mg, 2.44 mmol) in acetone (8 mL) was added KCO (1 g, 7.34 mmol), chlorocyclopentanone (319 mg, 2.69 mmol) and stirred at 80°C for 16 hours. After completion [monitored by TLC], the reaction mixture was concentrated under reduced pressure to give the crude product XLVII. The crude material was purified by flash column chromatography using silica gel with a gradient of 0-50% EtOAc-hexane to give 2-[2-(benzyloxy)-4-nitrophenoxy]cyclopentan-1-one XLVII (293 mg, 37%).

[0495] Step 2: At 0 ° C, DAST (720 mg, 4.47 mmol) was added to a stirred solution of 2- [2- (benzyloxy) -4- nitrophenoxy] cyclopentan-1-one (XLVII) (293 mg, 0.89 mmol) in DCM (5 mL) and stirred at room temperature for 1 hour. After completion [monitored by TLC], the reaction mixture was quenched with saturated NH4Cl solution (about 20 mL) and extracted with EtOAc [20 mL x 2]. The organic portion was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product XLVIII. Under a gradient elution of 10% EtOAc-hexane, the resulting crude material was purified by flash column chromatography using silica gel to obtain 2- (benzyloxy) -1- [(2,2- difluorocyclopentyl) oxy] -4- nitrobenzene XLVIII (233 mg, 75%).

[0496] Step 3: Pd / C (about 80 mg) was added 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) and stirred for 16 hours under a hydrogen atmosphere. After completion [monitored by TLC], the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product XLIX. The crude material was purified by flash column chromatography using silica gel under 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.

[0497] Step 4: at 0 DEG C, trimethylaluminum (2M in toluene, 0.5mL, 1.0mmol) is added dropwise to a stirred solution of 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl) oxazole-4-ethyl formate XXXIX (70mg, 0.24mmol) and 5-amino-2-[(2,2-difluorocyclopentyl) oxy] phenol XLIX (55mg, 0.24mmol). The resulting reaction mixture is stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture is quenched with saturated ammonium chloride solution (10mL) and distributed with EtOAc [30mL x 2]. The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography using 35% EtOAc-hexanes as the eluting solvent 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%).

[0498] Example 87

[0499]

[0500] Step 1: to a stirred solution of 1,2-difluoro-4-nitrobenzene (500mg, 3.14mmol) in DMSO (5mL), NaHCO is added (924mg, 11.0mmol) and 2,2-difluorocyclopentyl-1-amine hydrochloride (495mg, 3.14mmol), the mixture is heated to 100°C (sealed tube) and stirred for 20 hours. After completion [monitored by TLC], the reaction mixture is concentrated and diluted with water [20mL] and extracted with EtOAc [2x 30mL]. The combined organic layers are separated, dried over sodium sulfate and concentrated under reduced pressure. Using 0-6% EtOAc in hexane as eluent, the obtained crude material is purified by flash column chromatography to obtain the desired product N-(2,2-difluorocyclopentyl)-2-fluoro-4-nitroaniline LII (500mg, 61%) as a yellow colloidal liquid.

[0501] Step 2: NaH (92mg, 2.3mmol) is added to the stirred solution of N-(2,2-difluorocyclopentyl)-2-fluoro-4-nitroaniline (300mg, 1.15mmol) in DMF (5mL), stirred at 0 DEG C for 30 minutes.Then ethyl iodide (0.186mL, 2.30mmol) is added, and the mixture is warmed to room temperature, stirred for 16 hours simultaneously. After completion [monitored by TLC], the reaction mixture is concentrated and diluted with water [20mL], and extracted with EtOAc [2x 30mL]. Using 10% EtOAc in hexane as eluent, gained crude material is passed through into flash column chromatography, to obtain the required product N-(2,2-difluorocyclopentyl)-N-ethyl-2-fluoro-4-nitroaniline LIII (160mg, 48%) as a yellow solid.

[0502] Step 3: NHCl.H2O (300 mg, 5.55 mmol) and zinc powder (361 mg, 5.55 mmol) were added 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) and stirred for 6 hours. After completion [monitored by TLC], the reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated and purified by flash column chromatography using 30% EtOAc in hexane as eluent to obtain the desired product N1-(2,2-difluorocyclopentyl)-N1-ethyl-2-fluorobenzene-1,4-diamine LIV (110 mg, 77%) as a brown liquid.

[0503] Step 4: To a stirred solution of ethyl 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-formate XXXIX (75 mg, 0.25 mmol) in anhydrous toluene (3 mL) was added N1-(2,2-difluorocyclopentyl)-N1-ethyl-2-fluorobenzene-1,4-diamine (53 mg, 0.20 mmol), then trimethylaluminum (2M in toluene, 0.5 mL, 1.0 mmol) was added dropwise 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 distributed with EtOAc [30 mL x 2]. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography using 20% ​​EtOAc-hexanes as the eluting solvent 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%).

[0504] Example 88

[0505]

[0506] 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 at room temperature for 3 hours under 1 atm of hydrogen. Upon completion [monitored by TLC], the reaction mixture was filtered through celite and concentrated to obtain 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%).

[0507] Preparation of intermediate ethyl 2-chloro-5-methyloxazole-4-carboxylate (LXI):

[0508]

[0509] Step 1: at room temperature, to a stirred solution of ethyl 2-oxobutanoate (16.0g, 123.07mmol) in EtOAc (1000mL) and DCM (600mL), CuBr (109.78g, 492.30mmol) is added. The mixture is then heated at 90°C for 16 hours. After completion [monitored by TLC], the reaction mixture is filtered through diatomaceous earth, and the filtrate is concentrated to obtain 3-bromo-2-oxobutanoic acid ethyl ester (LIX) (25.0g) in a brown colloidal liquid (crude product). It is used for the next step without further purification.

[0510] Step 2: at room temperature, to the solution of 3-bromo-2-oxobutanoic acid ethyl ester (25.0g, 120.19mmol) in ethanol (200mL), add urea (28.84g, 480.76mmol), and it is stirred at 80 ℃ for 24 hours.After completing [monitoring with TLC], concentrated reaction mixture is to remove ethanol.Then crude material is used saturated NaHCO The aqueous solution (200mL) is processed and extracted with EtOAc (2x 300mL).By organic part anhydrous Na SO Dry and concentrate under reduced pressure.By crude product and Et O grind together, gained precipitation is filtered by sintered glass filter and dried under vacuum, to obtain pure 2-amino-5-methyloxazole-4-ethyl formate (LX) (13.6g) in off-white solid.

[0511] Step 3: CuCl2 (6.51 g, 48.47 mmol) and tert-butyl nitrite (7.75 g, 75.29 mmol) were heated to 70°C in a suspension of acetonitrile (80 mL) and stirred for 15 minutes. 2-amino-5-methyloxazole-4-ethylcarboxylate (LX) (8.0 g, 47.05 mmol) was then added dropwise to a suspension of acetonitrile (120 mL) at 70°C, and stirred at room temperature for 16 hours. After completion [monitored by TLC], the reaction mixture was concentrated to remove volatiles, 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 Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel flash column using 5% EtOAc-hexanes as eluent to give ethyl 2-chloro-5-methyloxazole-4-carboxylate (LXI) (5.6 g, 62.77%).

[0512] General procedure for the synthesis of Examples of general structure LXIII (Examples 89-90).

[0513]

[0514] Step 1: To a stirred solution of amine / amine salt (1.2 eq) and CsCO (3.0 eq) in dioxane (30 mL / g) was added ethyl 2-chloro-5-methyloxazole-4-carboxylate (LXI) (1.0 eq) and the resulting reaction mixture was stirred at 80° C. for 16 hours. Upon completion [monitored by TLC], the reaction mixture was filtered through a sintered glass filter and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford LXII.

[0515] Step 2: To a stirred solution of LXII (1.0 equiv) in anhydrous 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 afford examples of general structure LXIII.

[0516] All amines used as starting materials were purchased from commercial suppliers.

[0517] Example 89

[0518] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein the amine in step 1 was 6,6-difluoro-2-azaspiro[3.3]heptane to give 2-(6,6-difluoro-2-azaspiro[3.3]heptane-2-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (25 mg, 19.39%).

[0519] Example 90

[0520] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein the amine in step 1 was 2-oxa-6-azaspiro[3.4]octane to give 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%).

[0521] Preparation of intermediate 2-chloro-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (LXVI):

[0522]

[0523] Step 1: At 0 ° C, to a solution of 2-chloro-5-methyloxazole-4-ethylcarboxylate (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) and then stirred at room temperature for 3 hours. After completion [monitored by LC-MS], the reaction mixture was acidified with HCl aqueous solution (1 N) and distributed between EtOAc (100 mL) and water (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2.4 g of 2-chloro-5-methyloxazole-4-carboxylic acid (LXIV) as an off-white solid (96%).

[0524] 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), HOBT (1.2 g, 9.6 mmol), and the resulting reaction mixture was stirred at room temperature for 16 hours. Upon 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 crude product was purified by flash column chromatography on silica gel using 10% EtOAc-hexanes as eluent to give 2-chloro-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (LXV) (0.47 g, 27.3%).

[0525] Preparation of Examples having the general structure LXVI:

[0526]

[0527] 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 equiv) in dioxane was added amine (2 equiv) followed by heating at 90°C for 16 hours. Upon completion (monitored by LC-MS), the reaction mixture was filtered through a glass frit. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with a gradient of EtOAc-hexanes or MeOH-DCM to afford examples of general structure LXVI.

[0528] Example 91

[0529] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein 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%).

[0530] Example 92

[0531] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein 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%).

[0532] Example 93

[0533] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein 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%).

[0534] Example 94

[0535] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein 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%).

[0536] Example 95

[0537] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein 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%).

[0538] Example 96

[0539]

[0540] Step 1: to 2- chloro- 5- methyloxazole -4- ethyl formate (200mg, 1.05mmol) and CsCO (687mg, 2.11mmol) suspension in dioxanes add pyrrolidin-3-ylmethanol (128mg, 1.26mmol), then heated at 90 DEG C for 16 hours.After completion [monitored by LC-MS], the reaction mixture is filtered through a sintered glass filter. The organic layer is separated and concentrated under reduced pressure. Using 30% EtOAc- hexane, the obtained crude material is purified by silica gel flash column chromatography, to obtain 2- (3- (hydroxymethyl) pyrrolidin-1-yl) -5- methyloxazole -4- ethyl formate LXVII as light yellow solid (90mg, 33%).

[0541] Step 2: At 0 ° C, 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 LiOH.HO (27 mg, 0.7 mmol) in water (1 mL) and then stirred at room temperature for 3 hours. After completion [monitored by LC-MS], the reaction mixture was acidified with HCl aqueous solution (1 N) and distributed 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%).

[0542] 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) was added DIPEA (0.13 mL, 1 mmol), EDC (98 mg, 0.51 mmol) and HOBT (68 mg, 0.51 mmol), and the resulting reaction mixture was stirred at room temperature for 16 hours. Upon 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 crude product was purified using flash column chromatography on silica gel using 30% EtOAc-hexanes as eluent to afford N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(3-(hydroxymethyl)pyrrolidin-1-yl)-5-methyloxazole-4-carboxamide (Example 96) (50 mg, 36%).

[0543] Amines were obtained from commercial suppliers.

[0544] Example 97

[0545] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein 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%).

[0546] Example 98

[0547] The above mentioned compound was synthesized using the method outlined in the above scheme, wherein 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%).

[0548] Preparation of Examples having the general formula LXXIV (Examples 99-104):

[0549]

[0550] Step 1: NBS (6.16 g, 34.82 mmol) and DBPO (1.12 g, 4.64 mmol) were added to a mixture of 2-chloro-5-methyloxazole-4-formic acid ethyl ester (LXI) (4.4 g, 23.21 mmol) in benzene, and then heated at 70 ° C for 9 hours. After the reaction was completed [monitored by TLC], the reaction mixture was filtered and the filtrate was concentrated to obtain a crude product. Using 5% ethyl acetate in hexane as eluent, the crude material was purified by silica flash column chromatography to obtain 5- (bromomethyl) -2-chlorooxazole -4-formic acid ethyl ester (LXVIII) (4.6 g, 73%) as a light yellow liquid.

[0551] 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 and 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 and washed with water, concentrated to obtain a crude material which was purified by flash column chromatography on silica gel using 10% EtOAc / hexanes as eluent to afford ethyl 5-(acetoxymethyl)-2-chlorooxazole-4-carboxylate (LXIX) (3.3 g, 64.94%) as a light yellow liquid.

[0552] 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) was added amine (7.29 mmol) 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 hexanes as eluent to give intermediate LXX (0.51 g, 37.19%) as a liquid.

[0553] Step 4: To a suspension of LXX in EtOH (15 mL) was added KCO (1.34 g, 9.71 mmol), followed by stirring 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 hexanes as eluent to afford intermediate LXXI (0.71 g, 60.83%) as an off-white solid.

[0554] Step 5: To a stirred solution of LXXI (1.0 eq) in DMF (5 mL / mmol) was added NaH (2.0 eq) portionwise under ice-cooling conditions. After 15 minutes, R c To the mixture of 1,1-dione (3,0 equivalents) and 1,1-dione (3,0 equivalents) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction [monitored by TLC], the reaction mixture was quenched with saturated ammonium chloride solution, and distributed with EtOAc. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Using EtOAc-hexanes as eluting solvents, the obtained crude material was purified by silica gel flash column chromatography to obtain LXXII as a pale solid.

[0555] 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 and stirred at room temperature for 3 hours. Upon 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 afford the acid product of structure LXXIII.

[0556] Step 7: to a stirred solution of LXXIII (0.18mmol) and appropriate fluoroaniline (1 equivalent) in DMF (3mL), DIPEA (0.057mL, 0.56mmol), EDC (54mg, 0.28mmol) and HOBT (38mg, 0.28mmol) was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by LC-MS), the reaction mixture was distributed between EtOAc (50mL) and water (100mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. Using 10% EtOAc-hexane as eluent, the crude product was purified by flash column chromatography on silica gel to obtain the pure final product of formula LXXIV.

[0557] All amines used as starting materials were purchased from commercial suppliers.

[0558] Example 99

[0559] 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 afford N-[3-fluoro-4-(piperidin-1-yl)phenyl]-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (15 mg, 15%).

[0560] Example 100

[0561] 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 give 5-(ethoxymethyl)-N-[3-fluoro-4-(piperidin-1-yl)phenyl]-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (19 mg, 24.3%).

[0562] Example 101

[0563] 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 give N-[4-(cyclopentyloxy)-3-fluorophenyl]-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (19 mg, 24.3%).

[0564] Example 102

[0565] 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 afford N-[3,5-difluoro-4-(piperidin-1-yl)phenyl]-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (32 mg, 19%).

[0566] Example 103

[0567] The above compound was synthesized by the general procedure outlined in the scheme above using 2-methylpyrrolidine as the amine in step 3, iodomethane in step 5, and 3-fluoro-4-(piperidin-1-yl)aniline in step 7 to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-(methoxymethyl)-2-(2-methylpyrrolidin-1-yl)oxazole-4-carboxamide (80 mg, 23%).

[0568] Example 104

[0569] The above compound was synthesized by the general method outlined in the scheme above using 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 give 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%).

[0570] Example 105

[0571] 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 give N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-(methoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (12 mg, 9.9%).

[0572] Example 106

[0573]

[0574] Step 1. Add 1 drop of acetic acid to a stirred solution of tert-butyl 3-formylpyrrolidine-1-formate (100 mg, 0.503 mmol) and azetidine (34 mg, 0.603 mmol) in methanol. The reaction was stirred at room temperature for 3 hours. Sodium cyanoborohydride (62 mg, 1.0 mmol) was then added to the reaction mixture at 0 ° C and stirred overnight. After the reaction was completed [GCMS monitoring], the reaction mass was concentrated to remove methanol. The crude material was diluted with DCM and washed with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by silica gel chromatography to obtain tert-butyl 3- (azetidine -1- ylmethyl) pyrrolidine -1-formate LXXVI (90 mg, 74.5%) as a viscous liquid.

[0575] Step 2: To a stirred solution of tert-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 afford crude 3-(azetidin-1-ylmethyl)pyrrolidine hydrochloride (LXXVII) (60 mg) as a gummy liquid, which was used as is in Step 3.

[0576] 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 addition of intermediate LXV (80 mg, 0.239 mol), and the mixture was heated at 90 ° C for 6 hours. After the reaction was completed [monitored by LC-MS], the reaction mass was filtered and the filtrate was evaporated to give a crude product. The crude material was purified by silica gel chromatography using 5% MeOH in DCM to give 2- (3- (azetidine -1- ylmethyl) pyrrolidin-1-yl) -N- (3- fluoro- 4- (piperidin-1-yl) phenyl) -5- methyloxazole -4- carboxamide (Example 106) (30 mg, 20%).

[0577] Example 107

[0578]

[0579] Step 1. to tert-butyl 3-(bromomethyl) pyrrolidine-1-formate (100mg, 0.38mmol) and 4,4-difluoropiperidine (46mg, 0.38mmol) in DMF (3mL) stirring solution, add cesium carbonate (365mg, 1.141mmol).Then the reaction is heated at 80 DEG C.After the completion of the reaction [monitored by TLC], the reaction mass is filtered. The filtrate is diluted with ethyl acetate (10mL) and washed with water (2x 20mL). The concentrated organic matter is to obtain a crude product, using 55% EtOAc-hexane as eluent, it is passed through silica gel column chromatography to obtain tert-butyl 3-((4,4-difluoropiperidin-1-yl) methyl) pyrrolidine-1-formate (LXXIX) (110mg, 95%).

[0580] 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 afford 4,4-difluoro-1-(pyrrolidin-3-ylmethyl)piperidine hydrochloride LXXX (68 mg) as a gummy liquid, which was used crude in the next step.

[0581] 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) was added 2-amino-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide LXV (80 mg, 0.24 mmol) 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 obtain the crude product. The crude product was purified by silica gel chromatography using 70% ethyl acetate in hexanes as 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%).

[0582] Examples 108 and 109

[0583]

[0584] Step 1: at room temperature, to a solution of 5-(hydroxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxylic acid ethyl ester (200 mg, 0.83 mmol) in isopropanol (2 mL) was added yttrium trifluoromethanesulfonate (45 mg, 0.083 mmol), and the mixture was stirred at 70 ° C for 2 hours. After completion [monitored by TLC], the reaction mixture was quenched with saturated NaHCO solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give a crude product. The crude product was purified by flash column chromatography on silica gel using ethyl acetate to give 5-(isopropoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-carboxylic acid ethyl ester LXXXI (22 mg, 9.3%) as a solid.

[0585] Step 2: at 0 ° C, to a stirred solution of 5-(isopropoxymethyl)-2-(pyrrolidin-1-yl)oxazole-4-formic acid ethyl ester LXXXI (60 mg, 0.19 mmol) and 3-fluoro-4-(piperidin-1-yl)aniline LXV (38 mg, 0.17 mmol) in anhydrous toluene (3 mL), trimethylaluminum (0.4 mL, 0.80 mmol) was added, 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 distributed with EtOAc [10 mL x 2]. 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-hexanes as the elution solvent to give 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.

[0586] Step 3: at 0 ° C, to a stirred solution of 5- (isopropoxymethyl) -2- (pyrrolidin-1-yl) oxazole -4- ethyl carboxylate LXXXI (50 mg, 0.177 mmol) and 4- ((2,2- difluorocyclopentyl) oxy) -3- fluoroaniline XII (31 mg, 0.16 mmol) in anhydrous toluene (3 mL), trimethylaluminum (0.35 mL, 0.70 mmol) was added, 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 distributed with EtOAc [10 mL x 2]. 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 elution solvent 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%).

[0587] General protocol for the synthesis of Examples 110 and 111

[0588]

[0589] Step 1. At room temperature, CuBr2 (3.5 equivalents) was added to a stirred solution of LXXXII (1 equivalent) in ethyl acetate and DCM (ratio 6:4). The mixture was then heated at 90 ° C for 16 hours. After the reaction was completed [monitored by TLC], the reaction mixture was filtered through celite and the filtrate was concentrated to give a crude LXXXIII as a brown colloidal liquid (in crude form). It was used directly in the next step without further purification.

[0590] Step 2: at room temperature, urea (4 equivalents) was added to a solution of LXXXIII (1 equivalent) in ethanol (200 mL), and the mixture was refluxed for 24 hours. After the reaction was completed [monitored by TLC], the reaction mixture was concentrated to remove ethanol. The crude material was then treated with a saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The organic matter was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude material was purified by grinding with ether. The solid was filtered and dried to obtain LXXXIV as an off-white solid.

[0591] Step 3: by CuCl (1.6 equivalents) and tert-butyl nitrite (1.05 equivalents) in acetonitrile (80mL) suspension is heated to 70 DEG C and stirred for 15 minutes, then LXXXIV (1 equivalent) in acetonitrile (120mL) suspension is added dropwise to above reaction mixture at 70 DEG C.The reaction is stirred at 70 DEG C for 16 hours.After the reaction is completed [monitored by TLC], the reaction mixture is concentrated to remove volatiles, then diluted with ethyl acetate (250mL) and water (250mL), and filtered through diatomaceous earth.Isolate the organic layer and use anhydrous Na2SO4 dry, concentrate to obtain crude product.Use 5% ethyl acetate in hexane, the crude material is purified by silica gel column chromatography, to obtain LXXXV (5.6g, 62.77%) as a colorless liquid.

[0592] Step 4: To a stirred solution of pyrrolidine (1.2 eq) and Cs2CO3 (3.0 eq) in dioxane (30 mL / g) was added LXXXV (1.0 eq) and the resulting reaction mixture was stirred at 80°C for 16 hours. 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 crude material was purified by silica gel column chromatography to afford LXXXVI.

[0593] Step 5: To a stirred solution of LXXXVI (1.0 equiv) in anhydrous toluene (10 mL) was added 4-((2,2-difluorocyclopentyl)oxy)-3-fluoroaniline XII (0.8 equiv), then cooled to 0°C and trimethylaluminum (1 M in toluene, 4.0 equiv) was added dropwise, and the resulting reaction mixture was heated to 90°C for 16 hours. After completion of the reaction [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 crude product was purified by silica gel column chromatography to afford LXXXVII.

[0594] Example 110

[0595] The above mentioned compounds were synthesized using the general method outlined in the above scheme using ethyl 2-oxohexanoate as the ketoester in step 1 to give N-(4-((2,2-difluorocyclopentyl)oxy)-3-fluorophenyl)-5-propyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (20 mg, 17%).

[0596] Example 111

[0597] The above mentioned compounds were synthesized using the general method outlined in the above scheme using ethyl 5-methyl-2-oxohexanoate as the ketoester 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%).

[0598] General scheme for the synthesis of Examples 112 to 123.

[0599]

[0600] Step 1. To a mixture of commercially available ethyl 2-bromo-5-methyloxazole-4-formate (1 equivalent) in DMF was added KCO (1 equivalent) and a commercially available amine (1.2 equivalents). The resulting solution was heated to 90°C and stirred vigorously for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and treated with a 0.1M NaOH (2 equivalents) solution in EtOH. After the reaction was complete, HCl (2M in water) was added and the substance was extracted with EtOAc. The organic layers were combined, dried over NaSO, filtered, and evaporated under reduced pressure to obtain intermediate LXXVIII, which was used in the next step without purification.

[0601] Step 2. To a solution of 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, then 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, purification was performed as described below to provide examples of the general structure LXXXIX.

[0602] Amine derivatives were obtained from commercial suppliers.

[0603] Example 112

[0604] The title compound was prepared according to the general method 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 by HPLC (linear gradient, H2O 30% to 80% in CH3CN) gave N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (32%).

[0605] Example 113

[0606] The title compound was prepared according to 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 performed by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexanes to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(1H-pyrrol-1-yl)oxazole-4-carboxamide (50%).

[0607] Example 114

[0608] The title compound was prepared according to the general method shown in the scheme above using piperidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was carried out by HPLC (linear gradient, HO 30% to 95% in CHCN) to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(piperidin-1-yl)oxazole-4-carboxamide (41%).

[0609] Example 115

[0610] The title compound was prepared according to the general method 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 carried out by HPLC (linear gradient, H2O 30% to 95%) to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-2-(isopropyl(methyl)amino)-5-methyloxazole-4-carboxamide (37%).

[0611] Example 116

[0612] The title compound was prepared according to the general method 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 performed by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexanes to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-morpholinooxazole-4-carboxamide (Y=42%).

[0613] Example 117

[0614] The title compound was prepared according to the general method 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 performed by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexanes to give 2-(dimethylamino)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (52%).

[0615] Example 118

[0616] The title compound was prepared according to the general procedure shown in the scheme above, utilizing pyrazole as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was performed by silica gel column chromatography eluting with 0% to 30% EtOAc in n-hexanes to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(1H-pyrazol-1-yl)oxazole-4-carboxamide (48%).

[0617] Example 119

[0618] The title compound was prepared according to the general method shown in the above scheme using 2-methylpyrrolidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was carried out by HPLC (linear gradient, HO 30% to 95%) to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(2-methylpyrrolidin-1-yl)oxazole-4-carboxamide (38%).

[0619] Example 120

[0620] The title compound was prepared according to the general method 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 carried out by HPLC (linear gradient, H2O 30% to 80%) to give N-(4-(cyclopentyloxy)-3-fluorophenyl)-5-methyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (55%).

[0621] Example 121

[0622] The title compound was prepared according to the general method 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 carried out by HPLC (linear gradient, HO 30% to 95%) to give 2-(3,3-difluoropyrrolidin-1-yl)-N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyloxazole-4-carboxamide (67%).

[0623] Example 122

[0624] The title compound was prepared according to the general method shown in the above scheme using 3-methylpyrrolidine as the amine in step 1 and commercially available aniline CAS: 85983-56-8 in step 2. Purification was carried out by HPLC (linear gradient, H2O 30% to 95%) to give N-(3-fluoro-4-(piperidin-1-yl)phenyl)-5-methyl-2-(3-methylpyrrolidin-1-yl)oxazole-4-carboxamide (38%).

[0625] Example 123

[0626] The title compound was prepared according to the general procedure shown in the scheme above, 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 carried out by HPLC (linear gradient, HO 30% to 95%) to give 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%).

[0627] General conditions for preparing Examples of the general formula shown in Structure XCV (Examples 124-190):

[0628]

[0629] Step 1. add KOH (3.0 equivalents) to the stirred solution of XC (1.0 equivalents) and XCI (1.2 equivalents) in DMSO (3mL / mmol).The reaction was stirred at room temperature for 2 hours.After the reaction was completed [monitored by TLC], the resulting reaction mixture was distributed between EtOAc and water.The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.Use the EtOAc in the hexane as eluent, the crude product was purified by flash column chromatography, to obtain required product XCII.

[0630] Step 2: To a stirred solution of XCII (1.0 eq) in 1,4-dioxane:water (5:1) (3 mL / mmol) at 0°C was added zinc powder (5.0 eq) and ammonium chloride (6.0 eq). The mixture 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 sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to obtain pure XCIII.

[0631] Step 3: To a stirred solution of intermediate XVII (1.0 equiv.) and DIPEA (3.0 equiv.) in dioxane (3 mL / mmol) was added an amine of formula R2NH (1.1 equiv.) and the resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion [monitored by TLC], the reaction mixture was concentrated under reduced pressure to remove dioxane. The crude product was purified by flash column chromatography to obtain an intermediate of formula XCIV.

[0632] Step 4: to a stirred solution of XCIV (1.0 equivalent) in anhydrous toluene (30 mL / g), compound XCIII (0.8 equivalent) from step 2 was added, followed by dropwise addition of trimethylaluminum (2M in toluene, 4.0 equivalents) 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 distributed 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 obtain an embodiment with the general formula XCV.

[0633] All amines used as starting materials were purchased from commercial suppliers.

[0634] Synthesis of amine (R2NH)

[0635]

[0636] Step 1: At 0 ° C, NaH (221.19 mg, 5.52 mmol, 60% in oil) was added to a stirred solution of tert-butyl 3,3-bis(hydroxymethyl)azetidine-1-formate XCVI (300 mg, 1.38 mmol) in DMF (5 mL). After stirring for 20 minutes, CH3I (783 mg, 5.53 mmol) was added to the reaction mixture and stirred at room temperature for 16 hours. After completion [monitored by TLC], the resulting reaction mixture was quenched with saturated NH4Cl solution and distributed between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Using EtOAc in hexane as eluent, the crude product was purified by flash column chromatography to obtain the desired product tert-butyl 3,3-bis(methoxymethyl)azetidine-1-formate, XCVII (245 mg, 72%) as a colorless oil.

[0637] Step 2: tert-Butyl 3,3-bis(methoxymethyl)azetidine-1-carboxylate XCVII (490 mg, 1.99 mmol) was dissolved in 4N HCl in dioxane (5 mL) and stirred at room temperature for 1 hour. 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 gummy liquid.

[0638] All alcohols used as starting materials were purchased from commercial suppliers.

[0639] Synthesis of Spiro[3.5]nonan-6-ol

[0640]

[0641] Under ice-cold conditions, NaBH4 (82.4 mg, 2.17 mmol) was added to a stirred solution of spiro [3.5] nonyl -6- ketone XCIX (100 mg, 0.72 mmol) in CH3OH (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction was quenched with acetone and concentrated under vacuum to obtain a crude product. The crude product was then distributed between EtOAc and water. The organic layer was separated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the desired alcohol spiro [3.5] nonyl -6- alcohol, C (90 mg, 89%) as a light yellow solid.

[0642] Example 124

[0643] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC and 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 give 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%).

[0644] Example 125

[0645] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC and 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 give 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%).

[0646] Example 126

[0647] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1-chloro-2,3-difluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0648] Example 127

[0649] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1-chloro-2,3-difluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0650] Example 128

[0651] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC and 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 give 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%).

[0652] Example 129

[0653] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC and 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 give 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%).

[0654] Example 130

[0655] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1-chloro-2,3-difluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0656] Example 131

[0657] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC and 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 give 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%).

[0658] Example 132

[0659] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and spiro[2.5]octan-5-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-(3,5-difluoro-4-(spiro[2.5]octan-5-yloxy)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (70 mg, 46%).

[0660] Example 133

[0661] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0662] Example 134

[0663] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and spiro[3.5]nonan-6-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-(3,5-difluoro-4-(spiro[3.5]nonan-6-yloxy)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 41%).

[0664] Example 135

[0665] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0666] Example 136

[0667] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and bicyclo[1.1.1]pentan-1-ylmethanol as the alcohol in step 1 and pyrrolidine as the amine in step 3 to give 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%).

[0668] Example 137

[0669] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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-(3,5-difluoro-4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (50 mg, 37.97%).

[0670] Example 138

[0671] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and spiro[2.4]heptan-5-ol as the alcohol in step 1 and pyrrolidine as the amine in step 3 to give 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%).

[0672] Example 139

[0673] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and spiro[3.3]heptan-2-ol as the alcohol in step 1 and pyrrolidine as the amine in step 3 to give 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%).

[0674] Example 140

[0675] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0676] Example 141

[0677] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and bicyclo[2.2.1]heptan-2-ol as the alcohol in step 1 and pyrrolidine as the amine in step 3 to give 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%).

[0678] Example 142

[0679] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 2,3-difluoro-5-nitrobenzonitrile as compound XC and 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 give 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%).

[0680] Example 143

[0681] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 3 to give 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%).

[0682] Example 144

[0683] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0684] Example 145

[0685] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0686] Example 146

[0687] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 2-fluoro-5-nitrobenzonitrile as compound XC and 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 give 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%).

[0688] Example 147

[0689] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0690] Example 148

[0691] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0692] Example 149

[0693] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0694] Example 150

[0695] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0696] Example 151

[0697] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and (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 give 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%).

[0698] Example 152

[0699] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 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%).

[0700] Example 153

[0701] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0702] Example 154

[0703] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0704] Example 155

[0705] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0706] Example 156

[0707] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0708] Example 157

[0709] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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%).

[0710] Example 158

[0711] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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%).

[0712] Example 159

[0713] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0714] Example 160

[0715] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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%).

[0716] Example 161

[0717] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0718] Example 162

[0719] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3-fluorophenyl)-2-(hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (18 mg, 10%).

[0720] Example 163

[0721] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0722] Example 164

[0723] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-3-methyl-5-nitrobenzene as compound XC and 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 give 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%).

[0724] Example 165

[0725] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0726] Example 166

[0727] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0728] Example 167

[0729] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0730] Example 168

[0731] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0732] Example 169

[0733] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and bicyclo[3.1.1]heptan-3-ol as the alcohol in step 1 and pyrrolidine as the amine in step 3 to give 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%).

[0734] Example 170

[0735] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0736] Example 171

[0737] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0738] Example 172

[0739] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0740] Example 173

[0741] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0742] Example 174

[0743] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and azepane as the amine in step 3 to give 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%).

[0744] Example 175

[0745] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0746] Example 176

[0747] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0748] Example 177

[0749] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0750] Example 178

[0751] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0752] Example 179

[0753] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0754] Example 180

[0755] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0756] Example 181

[0757] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and cis-bicyclo[3.1.0]hexan-3-ol as the alcohol in step 1 and morpholine as the amine in step 3 to give 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%).

[0758] Example 182

[0759] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0760] Example 183

[0761] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0762] Example 184

[0763] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0764] Example 185

[0765] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(hexahydrocyclopenta[b]pyrrol-1(2H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 17%).

[0766] Example 186

[0767] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give N-(4-(cis-bicyclo[3.1.0]hexan-3-yloxy)-3,5-difluorophenyl)-2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (60 mg, 39%).

[0768] Example 187

[0769] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and 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 give 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%).

[0770] Example 188

[0771] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0772] Example 189

[0773] The above mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2,3-trifluoro-5-nitrobenzene as compound XC and 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 give 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%).

[0774] Example 190

[0775] The above-mentioned compounds were synthesized using the methods outlined in the above scheme using 1,2-difluoro-4-nitrobenzene as compound XC and bicyclo[3.1.0]hexan-3-ylmethanol as the alcohol in step 1 and pyrrolidine as the amine in step 3 to give 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%).

[0776] Example 191

[0777]

[0778] Step 1: under ice-cold conditions, 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), which was then stirred at 70 ° C for 3 hours. After completion [monitored by TLC], the reaction mixture was distributed between EtOAc and saturated NH4Cl aqueous solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Using 5% EtOAc in hexane as eluent, the resulting crude product was purified by flash column chromatography to obtain 2- (cis-bicyclo [3.1.0] hexane-3-yloxy) -3-fluoro-5-nitropyridine CII (295 mg, 39%) as a light yellow oily liquid.

[0779] Step 2: at 0 ° C, to 2- (cis -bicyclo [3.1.0] hexane -3- base oxygen base) -3- fluoro -5- nitropyridine CII (295 mg, 1.23 mmol) in 1,4 dioxane: water (6 mL, 5: 1) in a stirred solution of zinc powder (550 mg, 8.66 mmol) and ammonium chloride (463.7 mg, 8.66 mmol). Then stirred at room temperature for 3 hours. 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. Using 10% EtOAc in hexane as eluent, the resulting crude product was purified by flash column chromatography to obtain 6- (cis -bicyclo [3.1.0] hexane -3- base oxygen base) -5-fluoropyridine -3- amine CIII (180 mg, 69%) as a brown solid.

[0780] Step 3: To a stirred solution of 2-chloro-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylic acid ethyl ester VII (500 mg, 1.95 mmol) and DIPEA (1.77 mL, 9.72 mmol) in dioxane (6 mL) was added compound 6 (306 mg, 2.04 mmol), 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 crude product was purified by flash column chromatography using 20% ​​EtOAc in hexane as eluent to obtain 2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxylic acid ethyl ester CIV (480 mg, 74%).

[0781] Step 4: to a stirred solution of 2- (3,3- diethylazetidine -1- bases) -5- (2,2,2- trifluoroethyl) oxazole -4- carboxylic acid ethyl ester CIV (100 mg, 0.29 mmol) in anhydrous toluene (5 mL) add 6- (cis- bicyclo [3.1.0] hexane -3- bases oxygen base) -5- fluoropyridine -3- amine CIII (50 mg, 0.23 mmol), then trimethylaluminum oxide (0.6 mL, 1.2 mmol) was added dropwise 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 distributed with EtOAc. 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 15% EtOAc in hexanes as 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%).

[0782] General procedure for the synthesis of Examples of general structure CIX (Examples 192-216).

[0783]

[0784] Step 1: To a stirred suspension of fluoronitrobenzene CV (1.0 eq.) and K2CO3 (3.0 eq.) in CH3CN (3 mL / g CV) was added R a R b NH (1.2 equivalents) was added and the resulting reaction mixture was stirred in a sealed tube at 80° C. for 16 hours. After completion of the reaction [monitored by TLC], the reaction mixture was concentrated under reduced pressure to remove CH 3 CN. The crude product was purified by flash column chromatography to obtain an intermediate of structure CVI.

[0785] Step 2: At 0 ° C, zinc powder (5.0 equivalents) was added to a stirred solution of compound CVI in 1,4-dioxane: water (5:1), followed by ammonium chloride (6.0 equivalents). It was then stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was filtered through sintered glass. The filtrate was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography using EtOAc-hexane as eluent to obtain intermediate compound CVII.

[0786] Step 3: To a stirred solution of intermediate VII (1.0 eq.) and DIPEA (3.0 eq.) in dioxane (3 mL / mmol) was added R c Rd To the 4-nitro-2-oxo-1-oxo ...

[0787] Step 4: MeMgCl (3M in THF, 2.4 equivalents) was added dropwise to a stirred solution of CVIII (1.0 equivalents) and CVII (1.0 equivalents) in anhydrous THF (30 mL / g), and stirred at room temperature for 1 hour. The reaction was monitored by TLC. After 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 crude product was purified by combined flash column chromatography to obtain the desired compound CIX. Examples 192 to 195 were synthesized according to condition (ii): trimethylaluminum (2M in toluene, 4.0 equivalents) was added dropwise to a stirred solution of CVIII (1.0 equivalents) and amine CVII (0.8 equivalents) in anhydrous toluene (30 mL / g CVIII) 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 distributed 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 obtain the product of general structure CIX.

[0788] All amines used as starting materials were purchased from chemical suppliers.

[0789] Example 192

[0790] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]hept-3-amine was used as the amine in step 1 [reaction temperature and time were 120°C and 48 hours], and 3,3-diethylazetidine hydrochloride was used as the amine in step 3 to give N-(4-(bicyclo[3.1.1]hept-3-ylamino)-3-fluoro-5-methylphenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 13.3%).

[0791] Example 193

[0792] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]hept-3-amine was used as the amine in step 1 [reaction temperature and time were 120°C and 48 hours], and pyrrolidine was used as the amine in step 3 to give N-(4-(bicyclo[3.1.1]hept-3-ylamino)-3-fluoro-5-methylphenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (10 mg, 5.42%).

[0793] Example 194

[0794] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2-difluoro-3-methyl-5-nitrobenzene, 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 give 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%).

[0795] Example 195

[0796] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.2.1]octan-8-amine was used as the amine in step 1, and 3-methoxy-3-methylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0797] Example 196

[0798] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV is 2,3-difluoro-5-nitrobenzonitrile, 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 give 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%).

[0799] Example 197

[0800] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV is 2-fluoro-5-nitrobenzonitrile, 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 give 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%).

[0801] Example 198

[0802] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV is 1,2,3-trifluoro-5-nitrobenzene, 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 give 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%).

[0803] Example 199

[0804] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 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%).

[0805] Example 200

[0806] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV is 1,2,3-trifluoro-5-nitrobenzene, 8-azabicyclo[3.2.1]octane is used as the amine in step 1 and 3,3-dimethylazetidine hydrochloride is used as the amine in step 3 to give 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%).

[0807] Example 201

[0808] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 8-azabicyclo[3.2.1]octane was used as the amine in step 1, and hexahydro-1H-furo[3,4-c]pyrrole was used as the amine in step 3 to give 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%).

[0809] Example 202

[0810] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 3,4-difluoronitrobenzene, 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%).

[0811] Example 203

[0812] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane was used as the amine in step 1, and 3-ethyl-3-methoxyazetidine was used as the amine in step 3 to give N-(4-(3-azabicyclo[3.1.1]heptane-3-yl)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 11.66%).

[0813] Example 204

[0814] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[4.1.0]heptane was used as the amine in step 1, and 3-ethyl-3-methoxyazetidine was used as the amine in step 3 to give N-(4-(3-azabicyclo[4.1.0]heptane-3-yl)-3,5-difluorophenyl)-2-(3-ethyl-3-methoxyazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19.61%).

[0815] Example 205

[0816] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, octahydrocyclopenta[b]pyrrole was used as the amine in step 1, and 3-ethyl-3-methoxyazetidine was used as the amine in step 3 to give 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%).

[0817] Example 206

[0818] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 8-azabicyclo[3.2.1]octane was used as the amine in step 1, and 3-ethyl-3-methoxyazetidine was used as the amine in step 3 to give 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%).

[0819] Example 207

[0820] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 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 give 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%).

[0821] Example 208

[0822] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 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)-3,5-difluorophenyl)-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (30 mg, 19.56%).

[0823] Example 209

[0824] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 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 give N-(4-(3-azabicyclo[3.1.1]heptane-3-yl)-3,5-difluorophenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (25 mg, 22.17%).

[0825] Example 210

[0826] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 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 give 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%).

[0827] Example 211

[0828] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[4.1.0]heptane was used as the amine in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0829] Example 212

[0830] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 3,4-difluoronitrobenzene, 3-azabicyclo[4.1.0]heptane was used as the amine in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0831] Example 213

[0832] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, 3,3-dimethylpiperidine was used as the amine in step 1, and pyrrolidine was used as the amine in step 3 to give 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%).

[0833] Example 214

[0834] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, octahydrocyclopenta[b]pyrrole was used as the amine in step 1, and pyrrolidine was 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%).

[0835] Example 215

[0836] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 1,2,3-trifluoro-5-nitrobenzene, piperidine was used as the amine in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0837] Example 216

[0838] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CV was 3,4-difluoronitrobenzene, piperidine was used as the amine in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0839] Example 217

[0840]

[0841] Step 1: To a stirred suspension of 1,2-difluoro-3-methyl-5-nitrobenzene CX (281 mg, 1.62 mmol), K2CO3 (748 mg, 5.42 mmol) in CH3CN (10 mL) was added bicyclo [3.1.1] heptyl -3- amine (150 mg, 1.35 mmol), and the resulting reaction mixture was stirred in a sealed tube at 120 ° C for 48 hours. After completion of the reaction [monitored by TLC], the reaction mixture was concentrated under reduced pressure to remove CH3CN. The crude product was purified by combined flash column chromatography using 5% EtOAc in hexane as eluent to obtain the intermediate N- (2-fluoro-6-methyl-4-nitrophenyl) bicyclo [3.1.1] heptyl -3- amine CXI (250 mg, 69.8%) as a light yellow solid.

[0842] Step 2: under nitrogen atmosphere, NaH (45mg, 1.1mmol) is added to the stirred ice-cold solution of CXI (100mg, 0.378mmol) in DMF (3mL).MeI (107mg, 0.757mmol) is then added thereto at 0°C and stirred at room temperature for 1 hour.After completion [monitored by TLC], the reaction mixture is quenched with NHThe Cl aqueous solution (5mL) is extracted with EtOAc, and is concentrated under reduced pressure.Then, using 5% EtOAc in hexane as eluent, the gained crude product is purified by column chromatography, to obtain N- (2- fluoro- 6- methyl -4- nitrophenyl) -N- methyl bicyclo [3.1.1] hept- 3- amine CXII (80mg, 76%) as colorless oil.

[0843] Step 3: Under ice-cold conditions, zinc powder (190 mg, 2.84 mmol) was added to a stirred solution of CXII (80 mg, 0.287 mmol) in 1,4-dioxane (8 mL), followed by addition of ammonium chloride (153 mg, 2.84 mmol) dissolved in water (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture was filtered through a bed of celite. The filtrate was evaporated and the residue was distributed between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Using 30% EtOAc in hexane as eluent, the crude product was purified by flash column chromatography to obtain N1-(bicyclo[3.1.1]heptane-3-yl)-2-fluoro-N1,6-dimethylbenzene-1,4-diamine CXIII (60 mg, 84%) as a colorless oil.

[0844] Step 4: MeMgCl (0.26 mL, 3 M in THF) was added dropwise to a stirred solution of amine CXIII (60 mg, 0.256 mmol) and XCIV (90 mg, 0.307 mmol) in anhydrous THF (5 mL), and stirred at room temperature for 2 hours. The reaction was monitored by TLC. After 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. Using 20% ​​EtOAc in hexane as eluent, the resulting crude product was purified by combined flash column chromatography to obtain N-(4-(bicyclo[3.1.1]heptane-3-yl(methyl)amino)-3-fluoro-5-methylphenyl)-2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide, Example 217 (32 mg, 25.27%).

[0845] Example 218

[0846]

[0847] Step 1: Under ice-cold conditions, NaH (1.50 gm, 22.599 mmol, 60% in oil) was added in batches to a stirred solution of dimethyl malonate (2.5 mL, 22.599 mmol) in THF (20 mL). The resulting reaction mixture was stirred at 0 ° C for 1 hour. A solution of 3,4,5-trifluoronitrobenzene CXIV (2.0 g, 11.299 mmol) in THF (5 mL) was then added thereto, 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. Using 15% EtOAc in hexane as eluent, the crude product was purified by flash column chromatography to obtain dimethyl 2- (2,6-difluoro-4-nitrophenyl) malonate CXV (3.0 g, 91%) as a colorless liquid.

[0848] Step 2: To a stirred solution of dimethyl 2-(2,6-difluoro-4-nitrophenyl)malonate CXV (3.0 g, 10.381 mmol) in 0.5 N aqueous NaOH (84 mL) at 50° C., solid KMnO₄ (8.2 g, 51.903 mmol) was added portionwise. The resulting mixture was refluxed at 100° C. for 3 hours. It was then filtered through a celite bed at elevated temperature. The bed was washed with hot water. The aqueous layer was acidified with concentrated HCl to a pH of 1 and then extracted with ethyl acetate. The combined organic layers were then washed with water and brine solution, dried over anhydrous Na₂SO₄, and concentrated under vacuum to afford 2,6-difluoro-4-nitrobenzoic acid CXVI (1.3 gm) as a crude product.

[0849] Step 3: Under ice-cold conditions, borane-DMS complex (3.6 mL, 38.42 mmol) was added to a stirred solution of 2,6-difluoro-4-nitrobenzoic acid CXVI (1.3 g, 6.40 mmol) in THF (27 mL). After stirring at room temperature for 2 hours, borane-DMS complex (1.82 mL, 19.22 mmol) was added to the reaction mixture again and heated at 60 ° C for 3 hours. After completion [monitored by TLC], the resulting reaction mixture was quenched dropwise with MeOH at 0 ° C and stirred at room temperature for 30 minutes. The reaction mass was then concentrated, and 15% EtOAc in hexane was used as eluent, and the crude product was purified by flash column chromatography to obtain 2,6-difluoro-4-nitrophenyl) methanol CXVII (1.0 gm, 82%) as a colorless liquid.

[0850] Step 4: To an ice-cold solution of 2,6-difluoro-4-nitrophenyl)methanol CXVII (500 mg, 2.64 mmol) in DCM was added Dess-Martin periodinane (2.46 gm, 5.82 mmol) 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 another 13 hours. After completion [monitored by TLC], the resulting reaction mixture was quenched with saturated aqueous NaHCO3 solution and 10% aqueous sodium thiosulfate solution, and then extracted with DCM. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by flash column chromatography using 10% EtOAc in hexane as eluent to give 2,6-difluoro-4-nitrobenzaldehyde CXVIII (240 mg, 48%) as a semi-solid.

[0851] Step 5: DIPEA (864 mg, 6.68 mmol) was added to a solution of 3-azabicyclo [3.1.0] hexane (244 mg, 2.94 mmol) in methanol (20 mL) and stirred at room temperature for 15 minutes. 2,6-difluoro-4-nitrobenzaldehyde CXVIII (500 mg, 2.67 mmol) was then added, followed by acetic acid (513.36 mg, 8.556 mmol), 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 and dried over anhydrous sodium sulfate, concentrated to obtain the crude material, which was purified by combined flash column chromatography using 50% EtOAc in hexanes as eluent to afford 3-(2,6-difluoro-4-nitrobenzyl)-3-azabicyclo[3.1.0]hexane CXIX (260 mg, 38.5) as an off-white solid.

[0852] Step 6: To a solution of 3-[(2,6-difluoro-4-nitrophenyl)methyl]-3-azabicyclo[3.1.0]hexane CXIX (240 mg, 0.95 mmol) in dioxane was added an aqueous solution of NH4Cl (715 mg, 13.23 mmol) and zinc powder (860 mg, 13.29 mmol), which was then stirred at room temperature for 1.5 hours. After completion [monitored by TLC], the resulting reaction mixture was filtered through a bed of celite, and the filtrate was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and concentrated to obtain a crude material, which was purified by combined flash column chromatography using 60% EtOAc in hexane as eluent to afford 4-{3-azabicyclo[3.1.0]hexane-3-ylmethyl}-3,5-difluoroaniline CXX (150 mg, 70.5%) as an off-white solid.

[0853] Step 7: to an ice-cold solution of 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-ethyl formate XCIV (125.14 mg, 0.429 mmol) in toluene and an ice-cold solution of 4-{3-azabicyclo[3.1.0]hexane-3-ylmethyl}-3,5-difluoroaniline CXX (80 mg, 0.357 mmol) in toluene, trimethylaluminium oxide (2M in toluene, 0.80 mL, 1.60 mmol) was added and stirred at room temperature for 1.5 hours. After the reaction was completed [monitored by TLC / LCMS], the reaction mixture was quenched with saturated ammonium chloride solution and distributed with EtOAc. 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 40% EtOAc in hexanes as eluent to afford 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%). Preparation of intermediate ethyl 2-chloro-5-ethyloxazole-4-carboxylate (CXXV):

[0854]

[0855] Step 1: Under a nitrogen atmosphere, to a stirred suspension of Mg (25 g, 1033.05 mmol) in THF (20 mL) was slowly added 1,2-dibromoethane (1.5 mL), followed by the slow addition of 1-bromopropane (50 g, 413.22 mmol) dissolved in THF (600 mL) [the exotherm was neutralized by a common water bath] and stirred at room temperature for 1 hour. 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), maintaining the external temperature of the solution at -78°C and allowing it to gradually warm to 0°C. After stirring for 1.5 hours (monitored by TLC 10% EtOAc / hexane, Rf-0.2, (KMnO4 activity)), the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (2 x 500 mL). The organic layer was washed with brine solution (1 x 300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography using silica gel (100-200 mesh) with a gradient elution of 10% EtOAc / hexanes to afford ethyl 2-oxopentanoate CXXII (42 g, 70.5%) as a light brown liquid.

[0856] Step 2: CuBr (464.58 g, 2083.33 mmol) is added to a stirred solution of ethyl 2-oxopentanoate CXXII (150 g, 1041.67 mmol) in an EtOAc:DCM mixture (6000 mL, 3: 2), and the reaction mixture is heated to 80 ° C for 16 hours. After completion [monitored by TLC (20% EtOAc / hexanes), Rf-0.3 (KMnO4 activity)], reactant is filtered through a sinter funnel, and the filtrate is dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound. Under the gradient elution of 20% EtOAc / hexanes, using silica (100-200 mesh), the crude product is purified by column chromatography to obtain ethyl 3-bromo-2-oxopentanoate CXXIII (160 g, 68.86%) as a brown liquid.

[0857] Step 3: to the stirred solution of 3-bromo-2-oxopentanoic acid ethyl ester CXXIII (330g, 1479.82mmol) in ethanol (6600mL), urea (266.37g, 4439.46mmol) is added. The reaction is heated to 90 ℃, continues 16 hours. After completion [monitored by TLC 20% EtOAc / hexane, Rf-0.1], the reaction mixture is concentrated under reduced pressure. The gained crude product is diluted with ethyl acetate (1000mL), washed with saturated NaHCO solution (1x 500mL) and saline solution (1x 300mL). The organic portion is dried over sodium sulfate and concentrated under reduced pressure to obtain crude compound. The crude product was triturated three times with 70% n-pentane in diethyl ether [first with about 300 mL (70% pentane-diethyl ether), then twice with about 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%).

[0858] Step 4: to CuCl (111.42g, 831.52mmol) add tert-butyl nitrite (158.17mL, 1320.65mmol) in the stirred solution in acetonitrile (4000mL), be heated to 60 ℃ and continue 30 minutes.Then in this solution, add the 2-amino-5-ethyl oxazole-4-ethyl formate CXXIV (150g, 815.22mmol) that is dissolved in acetonitrile (2000mL), and reactant mixture is heated to 80 ℃ and stirred 2 hours.After completing, [monitor (40% EtOAc / hexane, Rf-0.7) by TLC], reactant mixture is under reduced pressure concentrated.Mixture is diluted in EtOAc (2000mL) and water (1000mL) and filtered by diatomite bed.Organic part is separated and washed with saline solution (1x 500mL), dried over sodium sulfate and under reduced pressure concentrated. The crude product was purified by column chromatography using silica (100-200 mesh) with a gradient elution of 0-10% EtOAc / hexanes to afford ethyl 2-chloro-5-ethyloxazole-4-carboxylate CXXV (115 g, 69.52%) as a colorless liquid.

[0859] General conditions for preparing Examples of the general formula shown in Structure CXXXI (Examples 219-247):

[0860]

[0861] Step 1. KOH (3.0 equivalents) was added to a stirred solution of CXXVI (1.0 equivalents) and CXXVII (1.2 equivalents) in DMSO (3 mL / mmol). The reaction was stirred at room temperature for 2 hours. After completion [monitored by TLC], the resulting reaction mixture was distributed between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Using EtOAc in hexane as eluent, the crude product was purified by flash column chromatography to obtain the desired product CXXVIII.

[0862] Step 2: To a stirred solution of CXXVIII (1 eq) in 20 mL / g CXXVIII 1,4-dioxane:water (5:1) was added zinc powder (7 eq) and ammonium chloride (7 eq) at 0°C. The mixture was then stirred at room temperature for 3 hours. Upon 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 crude product was purified by flash column chromatography using EtOAc in hexane to afford pure CXXIX.

[0863] Step 3: To a stirred solution of CXXV (1.0 eq) and DIPEA (3.0 eq) in dioxane (3 mL / mmol) was added R2NH (1.1 eq) 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 crude product was purified by flash column chromatography using EtOAc in hexane to afford pure CXXX.

[0864] Step 4: MeMgCl (3M in THF, 2.4 equivalents) was added dropwise to a stirred solution of CXXX (1.0 equivalent) and CXXIX (1.0 equivalent) in anhydrous THF (30 mL / g) and stirred at room temperature for 1 hour. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with 1N HCl and 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 combined flash column chromatography to obtain an embodiment of the general structure CXXXI.

[0865] All alcohols and amines used as starting materials were purchased from commercial suppliers.

[0866] Example 219

[0867] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1-chloro-2,3-difluoro-5-nitrobenzene, 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 give 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%).

[0868] Example 220

[0869] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound CXXVI was 1-chloro-2,3-difluoro-5-nitrobenzene, 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 give 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%).

[0870] Example 221

[0871] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1-chloro-2,3-difluoro-5-nitrobenzene, 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 give 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%).

[0872] Example 222

[0873] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 1-chloro-2,3-difluoro-5-nitrobenzene, 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 give 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%).

[0874] Example 223

[0875] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1-chloro-2,3-difluoro-5-nitrobenzene, 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 give 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%).

[0876] Example 224

[0877] The above mentioned compounds were synthesized using the methods outlined in the above schemes, wherein compound CXXVI was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]heptan-3-ol was used as the alcohol in step 1, and (3-methylazetidin-3-yl)methanol was used as the amine in step 3 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%).

[0878] Example 225

[0879] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]heptan-3-ol was used as the alcohol in step 1, and pyrrolidine was used as the amine in step 3 to give 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%).

[0880] Example 226

[0881] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1,2-difluoro-3-methyl-5-nitrobenzene, 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 give 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%).

[0882] Example 227

[0883] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1,2-difluoro-3-methyl-5-nitrobenzene, 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 give 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%).

[0884] Example 228

[0885] The above mentioned compounds were synthesized using the methods outlined in the above schemes, wherein compound CXXVI was 1,2-difluoro-4-nitrobenzene, bicyclo[3.1.1]heptan-3-ol was used as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine was used as the amine in step 3 to give 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%).

[0886] Example 229

[0887] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound CXXVI was 3,4,5-trifluoronitrobenzene, bicyclo[3.1.1]heptan-3-ol was used as the alcohol in step 1, and pyrrolidine was used as the amine in step 3 to give 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%).

[0888] Example 230

[0889] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 3,4,5-trifluoronitrobenzene, bicyclo[3.1.1]heptan-3-ol was used as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine was used as the amine in step 3 to give 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%).

[0890] Example 231

[0891] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, 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%).

[0892] Example 232

[0893] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1, and 1H-pyrazole 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-(1H-pyrazol-1-yl)oxazole-4-carboxamide (60 mg, 30.96%).

[0894] Example 233

[0895] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1, and hexahydro-2H-furo[2,3-c]pyrrole 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-(hexahydro-5H-furo[2,3-c]pyrrol-5-yl)oxazole-4-carboxamide (30 mg, 18.3%).

[0896] Example 234

[0897] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, tetrahydrofuran-3-ol was used as the alcohol in step 1, and 3-ethyl-3-methoxyazetidine was used as the amine in step 3 to give 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%).

[0898] Example 235

[0899] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, 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 give 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%).

[0900] Example 236

[0901] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 3,4,5-trifluoronitrobenzene, tetrahydro-2H-pyran-3-ol was used as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0902] Example 237

[0903] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and hexahydro-1H-furo[3,4-c]pyrrole 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-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)oxazole-4-carboxamide (30 mg, 16.64%).

[0904] Example 238

[0905] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, 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 give 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%).

[0906] Example 239

[0907] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, 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 give 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%).

[0908] Example 240

[0909] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1, and octahydrocyclopenta[c]pyrrole 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-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)oxazole-4-carboxamide (18 mg, 10.95%).

[0910] Example 241

[0911] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound CXXVI was 3,4,5-trifluoronitrobenzene, 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 give 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%).

[0912] Example 242

[0913] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, cis-bicyclo[3.1.0]hexan-3-ol was used as the alcohol in step 1 and azepane was used as the amine in step 3 to give 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%).

[0914] Example 243

[0915] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, 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 give 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%).

[0916] Example 244

[0917] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 3,4,5-trifluoronitrobenzene, 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 give 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%).

[0918] Example 245

[0919] The above mentioned compounds were synthesized using the method outlined in the above scheme, where compound CXXVI was 1,2-difluoro-4-nitrobenzene, 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 give 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%).

[0920] Example 246

[0921] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1,2-difluoro-4-nitrobenzene, 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 give 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%).

[0922] Example 247

[0923] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1,2-difluoro-4-nitrobenzene, 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 give 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%).

[0924] Example 248

[0925]

[0926] 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 hours. After completion [monitored by TLC], the reaction mixture was distributed 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. Using 5% EtOAc in hexane as eluent, the resulting crude product was purified by flash column chromatography to obtain 3- (2- methyl -4- nitrophenoxy) bicyclo [3.1.0] hexane CXXXIII (300 mg, 66%) as a light yellow oily liquid.

[0927] Step 2: at 0 ° C, to 3- (2- methyl -4- nitrophenoxy) bicyclo [3.1.0] hexane CXXXIII (200 mg, 0.86 mmol) in 1,4 dioxane: a stirred solution of water (6 mL, 5: 1) was added zinc powder (280 mg, 4.23 mmol) and ammonium chloride (230 mg, 4.23 mmol). It 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. Using 10% EtOAc in hexane, the resulting crude product was purified by flash column chromatography to obtain 4- (cis-bicyclo [3.1.0] hexane -3- bases oxygen) -3- methylaniline CXXXIV (140 mg, 80%) as an off-white solid.

[0928] Step 3: To a stirred solution of 5-ethyl-2-(3-methoxy-3-methylazetidine-1-yl)oxazole-4-carboxylic acid ethyl ester CXXX (150 mg, 0.449 mmol) in anhydrous THF (5 mL) was added 4-(cis-bicyclo[3.1.0]hexane-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 distributed with EtOAc. 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% EtOAc in hexanes to afford 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%).

[0929] Example 249

[0930]

[0931] 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) was added CXXXV (200 mg, 1.143 mmol) and stirred at room temperature for 2 hours. 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. Using 5% EtOAc in hexane as eluent, the resulting crude product was purified by flash column chromatography to obtain 3- (2- chloro-4-nitrophenoxy) bicyclo [3.1.0] hexane CXXXVI (170 mg, 56%) as a light yellow oil.

[0932] Step 2: at 0 ° C, to 3- (2- chloro-4-nitrophenoxy) bicyclo [3.1.0] hexane CXXXVI (410 mg, 1.62 mmol) in 1,4 dioxane: a stirred solution of water (6 mL, 5: 1) was added zinc powder (737 mg, 11.34 mmol) and ammonium chloride (700 mg, 12.97 mmol). It 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. Using 10% EtOAc in hexane, the resulting crude product was purified by flash column chromatography to obtain 4- (cis-bicyclo [3.1.0] hexane -3- bases oxygen) -3- chloroaniline CXXXVII (350 mg, 96%) as an off-white solid.

[0933] Step 3: To a stirred solution of 5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxylic acid ethyl ester CXXX (150 mg, 0.559 mmol) in anhydrous THF (5 mL) was added 4-(cis-bicyclo[3.1.0]hexane-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 distributed with EtOAc. 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 5-10% EtOAc in hexanes to afford 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%).

[0934] Example 250

[0935]

[0936] Step 1: 1,2,3-trifluoro-4-nitrobenzene CXXXVIII (1000mg, 5.64mmol) is added to a stirred solution of bicyclo [3.1.0] hexan-3-ol XVIV (609mg, 6.21mmol), KOH powder (950mg, 16.94mmol) in DMSO (5mL) and stirred at room temperature for 2 hours. After completion [monitored by TLC], the reaction mixture is distributed between EtOAc (10mL) and water (2x 30mL). The organic layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Using 5% EtOAc in hexane as eluent, the resulting crude product is purified by flash column chromatography to obtain 3- (2,3-difluoro-4-nitrophenoxy) bicyclo [3.1.0] hexane CXXXIX (100mg, 28%) as a light yellow oily liquid.

[0937] Step 2: at 0 ° C, to 3- (2,3- difluoro -4- nitrophenoxy) bicyclo [3.1.0] hexane CXXXIX (200mg, 0.78mmol) in 1,4 dioxane: a stirred solution of water (6mL, 5: 1) was added zinc powder (410mg, 6.27mmol) and ammonium chloride (336mg, 6.27mmol). It 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. Using 10% EtOAc in hexane, the resulting crude product was purified by flash column chromatography to obtain 4- (cis-bicyclo [3.1.0] hexane -3- bases) -2,3- difluoroaniline CXL (120mg, 68%) as an off-white solid.

[0938] Step 3: To a stirred solution of 4-(cis-bicyclo[3.1.0]hexane-3-yloxy)-2,3-difluoroaniline CXL (7,60 mg, 0.21 mmol) in anhydrous toluene (3 mL) was added 5-ethyl-2-(3-methoxy-3-methylazetidin-1-yl)oxazole-4-carboxylic acid ethyl ester CXXX (72 mg, 0.32 mmol), followed by dropwise addition of Me3Al (2M in toluene, 0.42 mL, 0.84 mmol) 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 crude product was purified by flash column chromatography using 20% ​​EtOAc in hexanes to afford 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%).

[0939] Example 251

[0940]

[0941] 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) was added 1,2,4-trifluoro-5-nitrobenzene CXLI (500 mg, 2.82 mmol) and stirred at room temperature for 2 hours. 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. Using 5% EtOAc in hexane as eluent, the resulting crude product was purified by flash column chromatography to obtain 3- (2,5-difluoro-4-nitrophenoxy) bicyclo [3.1.0] hexane CXLII (255 mg, 41%) as a light yellow oily liquid.

[0942] Step 2: At 0 ° C, 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) was added zinc powder (535 mg, 8.23 ​​mmol) and ammonium chloride (508 mg, 9.41 mmol). 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 crude product was purified by flash column chromatography using 10% EtOAc in hexane to obtain 4- (cis-bicyclo [3.1.0] hexane -3- yloxy) -2,5-difluoroaniline CXLIII (220 mg, 83%) as a brown colloidal liquid.

[0943] Step 3: To a stirred solution of ethyl 5-ethyl-2-(3-ethyl-3-methoxyazetidine-1-yl)oxazole-4-carboxylate CXXX (100 mg, 0.354 mmol) in anhydrous toluene (5 mL) was added 4-(cis-bicyclo[3.1.0]hexane-3-yloxy)-2,5-difluoroaniline CXLIII (64 mg, 0.284 mmol), followed by dropwise addition of trimethylaluminum (2M in toluene, 0.7 mL, 1.418 mmol) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 1 hour. 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 crude product was purified by flash column chromatography using 5-10% EtOAc in hexanes to afford 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%).

[0944] General procedure for the synthesis of Examples of general structure CLVII (Examples 252-259).

[0945]

[0946] Step 1: To a stirred solution of fluoronitrobenzene XC (1.0 eq.) and K2CO3 (3.0 eq.) in CH3CN (3 mL / g VII) in a sealed tube was added R a R bNH (1.2 equiv.) was added and the resulting reaction mixture was stirred at 80° C. for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to remove CH 3 CN. The resulting crude product was purified by flash column chromatography to afford the intermediate of structure CXLIV.

[0947] Step 2: To a stirred solution of compound CXLIV in 1,4-dioxane:water (5:1) at 0°C was added zinc powder (7.0 equivalents) followed by ammonium chloride (7.0 equivalents). The mixture 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 Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography using EtOAc-hexane as eluent to afford the intermediate compound CXLV.

[0948] Step 3: To a stirred solution of CXXV (1.0 eq.) and DIPEA (3.0 eq.) in dioxane (3 mL / mmol) was added R c R d To the mixture was added 4-[ ...

[0949] Step 4, to a stirred solution of CXLVI (1.0 equivalent) and CXLV (1.0 equivalent) in anhydrous THF (30mL / g) was added MeMgCl (3M in THF, 2.4 equivalents) dropwise and stirred at room temperature for 1 hour. The reaction was monitored by TLC. After 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 product was purified by combined flash column chromatography to obtain the desired compound. Example 252 and Example 253 were synthesized according to the following condition (ii): at 0°C, to a stirred solution of CXLVI (1.0 equivalent) and amine CXLV (0.8 equivalent) in anhydrous toluene (30mL / g CXLVI) was added trimethylaluminum (2M in toluene, 4.0 equivalents) dropwise, 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 product was purified by flash column chromatography to obtain the product of general structure CXLVII.

[0950] All amines used as starting materials in Step 1 were purchased from chemical suppliers.

[0951] Example 252

[0952] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound XC was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]hept-3-amine was used as the amine in step 1, and pyrrolidine was used as the amine in step 3 to give N-(4-(bicyclo[3.1.1]hept-3-ylamino)-3-fluoro-5-methylphenyl)-5-ethyl-2-(pyrrolidin-1-yl)oxazole-4-carboxamide (25 mg, 13.89%).

[0953] Example 253

[0954] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound XC was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]hept-3-amine was used as the amine in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 3 to give N-(4-(bicyclo[3.1.1]hept-3-ylamino)-3-fluoro-5-methylphenyl)-2-(3,3-diethylazetidin-1-yl)-5-ethyloxazole-4-carboxamide (31 mg, 22%).

[0955] Example 254

[0956] The above mentioned compounds were synthesized using the methods outlined in the above schemes, wherein compound XC was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane as the amine in step 1, and 3-ethyl-3-methoxyazetidine as the amine in step 3 to give N-(4-(3-azabicyclo[3.1.1]heptane-3-yl)-3,5-difluorophenyl)-5-ethyl-2-(3-ethyl-3-methoxyazetidin-1-yl)oxazole-4-carboxamide (10 mg, 8.76%).

[0957] Example 255

[0958] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound XC was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane as the amine in step 1, and pyrrolidine as the amine in step 3 to give 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%).

[0959] Example 256

[0960] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound XC was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane was used as the amine in step 1, and 3,3-dimethylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0961] Example 257

[0962] The above mentioned compounds were synthesized using the methods outlined in the above schemes, wherein compound XC was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane as the amine in step 1 and hexahydro-1H-furo[3,4-c]pyrrole as the amine in step 3 to give 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%).

[0963] Example 258

[0964] The above mentioned compounds were synthesized using the methods outlined in the above schemes, where compound XC was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane was used as the amine in step 1, and 3-methoxy-3-methylazetidine hydrochloride was used as the amine in step 3 to give 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%).

[0965] Example 259

[0966] The above mentioned compounds were synthesized using the methods outlined in the above schemes, wherein compound XC was 1,2,3-trifluoro-5-nitrobenzene, 3-azabicyclo[3.1.1]heptane was used as the amine in step 1, and 6,6-difluoro-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetate was used 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%).

[0967] General procedure for the synthesis of Examples of general structure CLII (Examples 260-270).

[0968]

[0969] Step 1. KOH (3.0 equivalents) was added to a stirred solution of CXXVI (1.0 equivalents) and CXXVII (1.2 equivalents) in DMSO (3 mL / mmol). The reaction was stirred at room temperature for 2 hours. After completion [monitored by TLC], the resulting reaction mixture was distributed between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Using EtOAc in hexane as eluent, the crude product was purified by flash column chromatography to obtain the desired product CXLVIII.

[0970] Step 2: To a stirred solution of CXLVIII (1.0 equivalent) and KOH powder (3.0 equivalent) in DMSO (10 mL / g CXLVIII) was added BnOH (1.2 equivalents) and stirred at room temperature for 2 hours. 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 silica gel column chromatography to obtain a product of general structure CXLIX.

[0971] Step 3: To a stirred solution of CXLIX (1.0 equiv) in ethanol (20 mL / g CXLIX) was added 20% Pd / C (by weight %) and stirred at room temperature for 4 hours under a hydrogen atmosphere. 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 afford the amine CL.

[0972] Step 4: To a stirred solution of VII (1.0 equivalent) and DIPEA (3.0 equivalents) in dioxane (3 mL / mmol) was added R2NH (1.1 equivalents), 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 crude product was purified by combined flash column chromatography to obtain a product of general structure CLI.

[0973] Step 5: At 0 ° C, trimethylaluminum (2M in toluene, 4.0 equivalents) was added dropwise to a stirred solution of CLI (1.0 equivalents) and amine CL (0.8 equivalents) in anhydrous toluene (30 mL / g CLI), 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 crude product was purified by flash column chromatography to obtain a product of the general structure CLII.

[0974] All amines and alcohols used as starting materials were purchased from chemical suppliers.

[0975] Example 260

[0976] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1,2-difluoro-3-methyl-5-nitrobenzene, bicyclo[3.1.1]heptan-3-ol was used as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 4 to give N-(4-(bicyclo[3.1.1]heptan-3-yloxy)-3-hydroxy-5-methylphenyl)-2-(3,3-diethylazetidin-1-yl)-5-(2,2,2-trifluoroethyl)oxazole-4-carboxamide (115 mg, 64.2%).

[0977] Example 261

[0978] The above mentioned compounds were synthesized using the method outlined in the above scheme, wherein compound CXXVI was 1-chloro-2,3-difluoro-5-nitrobenzene, bicyclo[3.1.1]heptan-3-ol was used as the alcohol in step 1, and 3,3-diethylazetidine hydrochloride was used as the amine in step 4 to give N-(4-(bicyc...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: in: R 1 is a C1-C6 alkyl group optionally substituted by one or more R; R 2 is a C1-C6 alkyl group optionally substituted by one or more R; or R 1 and R 2 together to form a heterocycloalkyl or heteroaryl group; each optionally substituted by one or more R 1a replace; Each R 1a are 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 deuterated alkyl, 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted with one or more R; or two R on the same atom 1a Together they form an oxo group; R 3 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted with one or more R; Ring A is an aryl group or a heteroaryl group; Each R 4 are 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 deuterated alkyl, 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 each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted with one or more R; n is 0-4; Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and 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 deuterated alkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl or 3 to 6 membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogens; Or two R on the same atom form an oxo group.

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

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

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 are 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, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 are independently halogen, -CN, -OH, -OR a , -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d 、-NR b - Cycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl or heterocycloalkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 are independently halogen, -OH, -O-cycloalkyl, -O-heterocycloalkyl, -NR c R d 、-NR b - Cycloalkyl, C1-C6 alkyl or heterocycloalkyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 are independently halogen, -O-cycloalkyl, -O-heterocycloalkyl, -NR b - Cycloalkyl, C1-C6 alkyl or heterocycloalkyl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 are independently halogen, -O-cycloalkyl, C1-C6 alkyl or heterocycloalkyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 are independently halogen, -O-cycloalkyl or C1-C6 alkyl.

10. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ia): in: R 4a Hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; R 4b Deuterium, halogen, -CN, -NO2, -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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; and R 4c Deuterium, halogen, -CN, -NO2, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl.

11. The compound according to claim 10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl.

12. The compound according to claim 10 or 11, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a It is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

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

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

15. The compound according to any one of claims 10 to 12, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4a It is a C1-C6 alkyl group.

16. The compound according to any one of claims 10 to 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4b 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl.

17. The compound according to any one of claims 10 to 16, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4b 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.

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

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

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

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

22. The compound according to any one of claims 10 to 21, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4c It is halogen, -OH or C1-C6 haloalkyl.

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

24. The compound according to any one of claims 10 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 and R 2 together to form optionally one or more R 1a Substituted heterocycloalkyl.

25. The compound according to any one of claims 10 to 24, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 and R 2 together to form a monocyclic heterocycloalkyl or a bicyclic heterocycloalkyl; each optionally substituted by one or more R 1a replace.

26. The compound according to any one of claims 10-25, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 and R 2 together forming optionally one or more R 1a Substituted monocyclic heterocycloalkyl.

27. A compound according to any one of claims 10 to 26, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 and R 2 together to form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl; each optionally substituted by one or more R 1a replace.

28. The compound according to any one of claims 10-27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 and R 2 together to form pyrrolidinyl or piperidinyl; each optionally substituted by one or more R 1a replace.

29. The compound according to any one of claims 10-27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 and R 2 together forming optionally one or more R 1a Substituted azetidinyl groups.

30. The compound according to any one of claims 10-25, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 and R 2 together to form optionally one or more R 1a Substituted bicyclic heterocycloalkyl.

31. A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each 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 or C1-C6 heteroalkyl.

32. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1a Independently -OR a , C1-C6 alkyl, C1-C6 hydroxyalkyl or C1-C6 heteroalkyl.

33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1a Independently -OR a Or C1-C6 alkyl.

34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1a are independently C1-C6 alkyl.

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 It is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl.

36. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 It is C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 heteroalkyl.

37. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 It is a C1-C6 haloalkyl group.

38. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 It is -CH2CH3, -CH2CH2F or -CH2CF3.

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

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

41. A method of treating a TRPML1 mediated disorder or disease; the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-39, 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, cardiovascular disease, congenital developmental disorder, eye disease, blood and solid malignancies, 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 method of claim 41, wherein the TRPML1-mediated disorder or disease is Icardi-Gutiérrez syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, autism spectrum disorder, Batten disease, bipolar disorder, cerebral ataxia, Charcot-Marie-Tooth variant, chronic wasting disease, corticobasal degeneration, corticobasal syndrome, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Danon disease, Duchenne muscular dystrophy, exotic cloven-hoofed encephalopathy, Fabry disease, fatal familial insomnia, Friedreich's ataxia, feline spongiform encephalopathy, fragile X syndrome, frontotemporal dementia, Gaucher disease, Gerstmann-Straussler-Scheinker disease, giant axonal neuropathy, GM1 and GM2 gangliosidosis, Huntington disease, infantile Refsum disease, JUN Q and IPOD, Krabbe disease, Kuru disease, Leukoencephalopathy, Dementia with Lewy bodies, Ataxia with movement, Lyme disease, Machado-Joseph disease, Major depressive disorder, MPS-III, Mucolipidosis, Multiple sulfatase deficiency, Multiple system atrophy, Myofibrillar myopathy, Myotonic dystrophy, Niemann-Pick disease, Neuronal ceroid lipofuscinosis, Parkinson disease, Parkinson's syndrome, Pick disease, Polyglutamine disease, Pompe disease , pontocerebellar dysgenesis, prion disease, progressive nuclear palsy, progressive supranuclear palsy, pyruvate dehydrogenase deficiency, Sandhoff disease, schizophrenia, scrapie, Shy-Dregger syndrome, spinal muscular atrophy, spinocerebellar ataxia, sporadic familial insomnia, subacute degeneration of the spinal cord, subacute sclerosing panencephalitis, Tay-Sachs disease, transneuronal degeneration, tuberous sclerosis, spinocerebellar ataxia, or vascular dementia.

44. 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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