Compound, composition, and, method

Abstract

To provide a method of treating diseases.SOLUTION: The present disclosure relates generally to eukaryotic initiation factor 2B modulators, or pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and preparations thereof and use. In the present specification, treatment of neurodegenerative diseases (for example, neurodegenerative disease of prion disease), and / or compounds useful in prevention, or, pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit, pursuant to 35 U.S.C. § 119(e), of U.S. Provisional Application No. 62 / 543,307, filed August 9, 2017, U.S. Provisional Application No. 62 / 553,728, filed September 1, 2017, and U.S. Provisional Application No. 62 / 608,504, filed December 20, 2017, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates generally to small molecule modulators of eukaryotic initiation factor 2B and their use as therapeutics in the treatment of diseases such as Alzheimer's disease, Parkinson's disease, ALS, and frontotemporal dementia. [Background technology]

[0003] Neurodegenerative diseases such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and frontotemporal dementia (FTD) adversely affect the lives of millions of people.

[0004] The multisubunit protein complexes eukaryotic initiation factor 2B and eukaryotic initiation factor 2 are required for the initiation and regulation of protein synthesis in eukaryotic cells. Eukaryotic initiation factor 2B is composed of five subunits (α, β, γ, δ, and ε), and eukaryotic initiation factor 2 is composed of three subunits (α, β, and γ). Eukaryotic initiation factor 2B functions as a guanine nucleotide exchange factor (GEF) that catalyzes the exchange of guanosine-5'-diphosphate (GDP) with guanosine-5'-triphosphate (GTP) at eukaryotic initiation factor 2, thereby allowing GTP-bound eukaryotic initiation factor 2 to bind to initiator methionine-transfer RNA (ITR) and initiate protein synthesis.

[0005] Eukaryotic initiation factor 2B is active when it forms a complex as a dimer of 10 subunits. Eukaryotic initiation factor 2 is activated when bound to GTP but not GDP. Furthermore, phosphorylation of the α subunit of eukaryotic initiation factor 2 at serine 51 inhibits and regulates the guanine nucleotide exchange activity of eukaryotic initiation factor 2B. In the phosphorylated form, eukaryotic initiation factor 2 remains in an inactive GDP-bound state, blocking translation initiation.

[0006] The interaction between eukaryotic initiation factor 2B and eukaryotic initiation factor 2 plays a key role in the integrated stress response (ISR) pathway. Activation of this pathway leads, in part, to ATF4 (activated transcription factor 4) expression and stress granule formation. Aberrant ISR activation is observed in multiple neurodegenerative diseases, providing a strong functional link to pathologies characterized by the RNA-binding / stress granule protein TAR DNA-binding protein (TARDBP), also known as TDP43. Activation of eIF2B inhibits the ISR and ISR-dependent stress granule formation and has been shown to be neuroprotective in multiple disease models.

[0007] Impaired eukaryotic initiation factor 2B activity correlates with activation of the ISR pathway, which is involved in various neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and frontotemporal dementia. Mutations in TDP43 and other RNA-binding proteins / stress granule proteins alter stress granule dynamics and cause ALS. Inhibition of the ISR pathway can block and promote stress granule dissolution. Additionally, mutations in the human eukaryotic initiation factor 2B subunit have been identified as a cause of leukoencephalopathy with vanishing white matter (VWM) and childhood ataxia with central nervous system hypomyelination (CACH). Patients with VWM / CACH have significantly worsening white matter lesions and progressive worsening of neurological deficits after stress, and their eukaryotic initiation factor 2B guanine nucleotide exchange activity is weaker than normal. Summary of the Invention [Means for solving the problem]

[0008] Provided herein are compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, that are useful for the treatment and / or prevention of neurodegenerative diseases (e.g., prion disease neurodegeneration).

[0009] In some embodiments, compounds are provided that modulate the activity of eukaryotic initiation factor 2B. In some embodiments, the compounds modulate the regulation of eukaryotic initiation factor 2B. In some aspects, the compounds modulate the inhibition of eukaryotic initiation factor 2B by phosphorylated eukaryotic initiation factor 2. In some embodiments, the compounds interfere with the interaction between eukaryotic initiation factor 2B and phosphorylated eukaryotic initiation factor 2. In some embodiments, the phosphorylated eukaryotic initiation factor 2 is phosphorylated at its alpha subunit (eukaryotic initiation factor 2 alpha phosphate).

[0010] In some embodiments, compounds are provided that act as activators of eukaryotic initiation factor 2B by increasing its GDP / GTP nucleotide exchange activity. In some embodiments, the compounds promote eukaryotic initiation factor 2B dimerization. In other embodiments, the compounds enhance the guanine nucleotide exchange factor (GEF) activity of eukaryotic initiation factor 2B. In other embodiments, the compounds increase the guanine nucleotide exchange factor (GEF) activity of eukaryotic initiation factor 2B with its eukaryotic initiation factor 2 / GDP substrate.

[0011] In some embodiments, compounds are provided that desensitize cells to the deleterious effects of eukaryotic initiation factor 2B inhibition, which in some embodiments include ATF4 expression and stress granule formation.

[0012] In another embodiment, there is provided a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0013] In another embodiment, there is provided a method of treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B, the method comprising administering an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0014] In another embodiment, there is provided a method of treating a disease or condition mediated, at least in part, by modulation of eukaryotic initiation factor 2B, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0015] In another embodiment, there is provided a method of promoting or stabilizing eukaryotic initiation factor 2B dimer formation, the method comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof. The method comprises administering an effective amount of a pharmaceutical composition comprising the compound or prodrug and a pharmaceutically acceptable carrier.

[0016] In another embodiment, there is provided a method of promoting eukaryotic initiation factor 2B activity, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0017] In another embodiment, there is provided a method of desensitizing cells to eukaryotic initiation factor 2 phosphorylation, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0018] In another embodiment, there is provided a method of inhibiting the integrated stress response pathway, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0019] In another embodiment, there is provided a method of inhibiting stress granule formation, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0020] In another embodiment, there is provided a method of inhibiting ATF4 expression, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0021] The present disclosure also provides compositions, such as pharmaceutical compositions, kits containing the compounds, and methods of using (or administering) and manufacturing the compounds. The present disclosure also provides compounds or compositions thereof for use in methods of treating diseases, disorders, or conditions mediated at least in part by eukaryotic initiation factor 2B. Additionally, the present disclosure provides the use of compounds or compositions thereof for use in the manufacture of a medicament for the treatment of a disease, disorder, or condition mediated at least in part by eukaryotic initiation factor 2B. DETAILED DESCRIPTION OF THE INVENTION

[0022] The following description describes exemplary embodiments of the present technology, however, it should be understood that such description does not limit the scope of the disclosure, but is provided as a description of exemplary embodiments.

[0023] 1.Definition As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0024] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through this carbon atom. Dashes at the beginning or end of chemical groups are a matter of convenience; chemical groups are not intended to be attached according to their ordinary meaning. The symbols may be shown with or without one or more dashes without losing their meaning. Wavy or dashed lines drawn through lines in a structure indicate particular points of attachment for a group. No directionality or stereochemistry is implied by the order in which chemical groups are written or named unless chemically or structurally required.

[0025] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0026] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated value ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Also, the phrase "about X" includes the reference to "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plural of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0027] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbon atoms are included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0028] Certain commonly used alternative chemical names may be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., may be referred to as "alkylene" groups, or "alkylenyl" groups, or "arylene" groups, or "arylenyl" groups, respectively. Also, unless expressly indicated otherwise, when combinations of groups are referred to herein as a single moiety, e.g., arylalkyl or aralkyl, the last-mentioned group includes the atom at which the moiety is attached to the remainder of the molecule.

[0029] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0030] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbons atoms (i.e., C 2-4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0031] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0032] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl."

[0033] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0034] "Acyl" is the group -C(O)R y refers to R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0035] An "amide" is the group -C(O)NR y R z refers to the "C-amido" group, and the group -NR y C(O)R z "N-amide" refers to both R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z are joined together to form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0036] "Amino" is the group -NR y R z This refers to R y and R zis independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0037] "Aminoalkyl" refers to the group "-alkyl-NR y R z " refers to R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0038] "Amidino" is -C(NR y )(NR z 2) refers to R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0039] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, is defined below. The term "heteroaryl" encompasses and in no way overlaps with the term "heteroaryl." When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

[0040] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0041] "Carbamoyl" is the group -OC(O)NR y R z refers to the "O-carbamoyl" group and the group -NR y C(O)OR z The term "N-carbamoyl" refers to both the "N-carbamoyl" group and the "R" group. y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0042] "Carboxy ester" or "ester" refers to the -OC(O)R x , and -C(O)OR x It refers to both R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein.

[0043] "Cyanoalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 3) hydrogen atoms have been replaced with a cyano (-CN) group.

[0044] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0045] "Cycloalkoxy" refers to "-O-cycloalkyl".

[0046] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0047] "Cycloalkylalkoxy" refers to "-O-alkyl-cycloalkyl".

[0048] "Guanidino" is -NR y C(=NR z )(NR y R z ) and each R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hetero cyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0049] "Hydrazino" refers to -NHNH2.

[0050] "Imino" is the group -C(NR y )R z This refers to R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0051] "Imide" is the group -C(O)NR y C(O)R z This refers to R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0052] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, e.g., fluoro, chloro, bromo, or iodo.

[0053] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms have been replaced with halogen. For example, if a residue is substituted with multiple halogens, it can be referred to using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which are not necessarily the same, but may be the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0054] "Haloalkoxy" refers to an alkoxy group as defined above in which one or more (eg, 1 to 5, or 1 to 3) hydrogen atoms are replaced with halogen.

[0055] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 5, or 1 to 3) hydrogen atoms are replaced with a hydroxy group.

[0056] "Heteroalkyl" refers to an alkyl group in which one or more (e.g., 1-5, or 1-3) carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups, provided that the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Examples of heteroatom groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., but are not limited thereto; R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH 3. -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR yCH3, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. As used herein, heteroalkyl contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0057] "Heteroalkylene" refers to a divalent alkyl group (i.e., alkylene) in which one or more (e.g., 1 to 5 or 1 to 3) carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom groups. A "heteroalkylene" group must have at least one carbon and at least one heteroatom group in the chain. The term "heteroalkylene" includes unbranched or branched saturated chains containing carbon and heteroatoms. For example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Examples of heteroatom groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., but are not limited to these, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkylene groups include, for example, -CHOCH-, -CH(CH)OCH-, -CHCHOCH-, -CHCHOCHCHOCH-, -CHSCH-, -CH(CH)SCH-, -CHCHSCH-, -CHCHSCHCHSCH-, -CHS(O)CH-, -CH(CH)S(O)CH-, -CHCHS(O)CHCH-, -CHCHS(O)CHCHOCH-, -CHNR y CH2-, -CH(CH3)NR y CH2-, -CH2CH2NR y CH2-, -CH2CH2NRy CH2CH2NR y CH2-, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. As used herein, heteroalkylene contains 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. As used herein, the term "heteroalkylene" does not include groups such as amides or other functional groups with oxo present at one or more carbon atoms.

[0058] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a heteroaryl having 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8Heteroaryl) and contains 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain cases, heteroaryl includes 5- to 10-membered, 5- to 7-membered, or 5- to 6-membered ring systems, each having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, and oxazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and the heteroaryl can be attached via either ring of the fused system. Any aromatic ring, whether a single ring or multiple fused rings, containing at least one heteroatom is considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., through any one of the fused rings). Heteroaryl does not include or overlap with aryl, as defined above.

[0059] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0060] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl may be a single ring or multiple rings, which may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3, or 1 or 2) oxo (=O) or N-oxide (-O -) moiety. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl, regardless of attachment (i.e., it can be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, regardless of attachment to the rest of the molecule, and the ring may be fused to an aryl or heteroaryl ring. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclyl) has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, and octahydroisoinyl. Examples of heterocyclyl include hydroxyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when the two substitution positions are on the same carbon atom. Examples of spiroheterocyclyl rings include: Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl may be attached via either ring of the fused system.

[0061] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0062] "Oxime" is a group -CR y (=NOH), R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0063] "Sulfonyl" refers to the group -S(O)R y This refers to R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0064] "Sulfinyl" is the group -S(O)R y This refers to R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0065] "Sulfonamide" is a group -SO2NR y R z , and -NR y SO2R z This refers to R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0066] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes both cases where the event or circumstance occurs and cases where it does not occur. Also, the term "optionally substituted" refers to the fact that any one or more (e.g., 1-5, or 1-3) hydrogen atoms at a specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0067] In certain embodiments, R as used herein y and R z In certain embodiments, R as used herein is optionally substituted. y and R z Do not replace.

[0068] As used herein, the term "substituted" means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) where at least one hydrogen atom has been bonded to a non-hydrogen atom, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone, imino, imido, hydroxy, oxo, oxime. , nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y ) 3, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0069] In certain embodiments, "substituted" means that one or more (e.g., 1-5 or 1-3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g S(=O) 1-2 R h , -C(=O)R g , -C(=O)OR g , -OC(=O)OR g , -OC(=O)R g , -C(=O)NR g R h , -OC(=O)NR g R h , -OR g , -SR g , -S(=O)R g , -S(=O)2R g , -OS(=O) 1-2 R g , -S(=O) 1-2 R g , -NR g S(=O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(=O) 1-2 NR g R h

[0033] In certain embodiments, "substituted" refers to any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups substituted with -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" refers to any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups substituted with -C(=O)R. g , -C(=O)ORg , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also refers to the replacement of one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms with a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i means any of the above groups, where two of them, together with the atoms to which they are attached, are joined to form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0070] It is not intended herein to include polymers or similar indefinite structures arrived at by characterizing a substituent with an infinite number of additional substituents (e.g., a substituted aryl having a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein.

[0071] In certain embodiments, the phrase "one or more," as used herein, refers to 1 to 5. In certain embodiments, the phrase "one or more," as used herein, refers to 1 to 3.

[0072] Any compound or structure depicted herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of compounds are also referred to as "isotopically enriched analogs." Isotopically labeled compounds have structures depicted herein except that one or more (e.g., 1-5, or 1-3) atoms are replaced with atoms having selected atomic masses or mass numbers. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P,35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present disclosure include, for example: 3 H, 13 C, and 14 Certain compounds incorporate radioactive isotopes, such as C. Such isotopically labeled compounds may be useful in metabolism studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for radiation treatment of patients.

[0073] The term "isotopically enriched analog" includes "deuterated analogs" of compounds described herein in which one or more (e.g., 1 to 5, or 1 to 3) hydrogens, such as hydrogen at a carbon atom, are replaced with deuterium. Such compounds exhibit improved resistance to metabolism and are therefore useful for extending the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). The compounds are synthesized by methods well known in the art, for example, using starting materials in which one or more (e.g., 1 to 5, or 1 to 3) hydrogens have been replaced with deuterium.

[0074] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavy isotopes such as deuterium may confer certain therapeutic advantages due to increased metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, 11C-labeled compounds may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of the present disclosure, and their prodrugs, can generally be prepared by following the procedures disclosed in the schemes or examples, and the preparations described below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In this regard, it is understood that deuterium is considered a substituent in the compounds described herein.

[0075] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any element specifically designated as deuterium (D) is meant to represent deuterium.

[0076] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0077] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use. This refers to the following.

[0078] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise unsuitable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and organic acids. Furthermore, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), ), trialkenylamines (i.e., N(alkenyl)), substituted alkenylamines (i.e., NH(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)), mono-, di-, or tricycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, di-, or triarylamines (i.e., NH(aryl), HN(aryl), N(aryl)), or salts of mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0079] The term "hydrate" refers to a complex formed by mixing a compound described herein with water.

[0080] "Solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0081] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, one skilled in the art will understand the compound to include both the amide and imidic acid tautomers. Thus, the amide-containing compounds are understood to include their imidic acid tautomers. Similarly, It is understood that the imidic acid-containing compounds include their amide tautomers.

[0082] The compounds of the present invention, or pharmaceutically acceptable salts thereof, contain asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, with respect to amino acids, as (D)- or (L)-. The present invention is meant to include all such possible isotopes, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative), using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0083] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds, but having different, non-interchangeable three-dimensional structures. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0084] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0085] Relative centers of the compounds described herein are depicted using a "bold bond" style (bold or parallel lines), and absolute stereochemistry is indicated using a wedge bond (bold or parallel lines).

[0086] "Prodrug" refers to any compound that releases an active parent drug of the structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein in a way that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can also be prepared by modifying functional groups present in the compounds in a way that the modifications can be cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, and carbamates (e.g., N,N-dimethylaminocarbonyl) of the hydroxy functional groups in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire contents of each of which are incorporated herein by reference.

[0087] 2.Compound Provided herein are compounds that are modulators of eukaryotic initiation factor 2B.

[0088] In certain embodiments, the compound of formula I: [ka] I or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: L is 1 to 6 R 10 or L is an optionally substituted heteroalkylene, or an optionally substituted heterocyclyl, or an optionally substituted heteroaryl, with the proviso that when L is an optionally substituted heterocyclyl and is attached to the bridged cycloalkyl through a nitrogen ring atom, then the carbon atom in L adjacent to the point of attachment is not substituted with ═O or ═S; x is 1 or 2; z is 0 or 1, provided that z is 0 and X 1 is O and R 3 is not alkyl; X 1 , O, NR 9 , or is a bond; R 1 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl or heterocyclyl, each of which, other than hydrogen, is selected from one or more of halo, oxo, acetyl, amino, hydroxyl, or C 1-12 optionally substituted with alkyl, or R 1 and R 5 are joined together to form a heterocyclyl ring; R 2 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is selected from the group consisting of one or more R 11 wherein L is heteroalkylene and R 2 is C 3-10If cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of them may be separated by one or more R 11 with optional substitution; R 3 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is selected from the group consisting of one or more R 11 with optional substitution; R 4 , and R 5 each independently represents hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, or C 2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one or more halo, oxo, acetyl, amino, or hydroxyl; Or, R 3 , and R 4 are bonded together with the atoms to which they are attached to form C 3-10 cycloalkyl, heterocyclyl, or heteroaryl, each of which may be joined by one or more R 11 with optional substitution; Or, R 4 , and R 5 are bonded together with the atoms to which they are attached to form C 3-10 cycloalkyl or heterocyclyl, each of which may be joined by one or more R 11 with optional substitution; R 6 , R 7 , and R 8 each independently represents hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 2 0 R 21 , -S(O) 1-2 R 20 , or -S(O) 1-2 NR 20 where R 6 , R 7 , and R 8 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl in 12 optionally replacing with; or R 6 , R 7 , and R 8 are bonded to each other together with the atoms to which they are attached to form one or more halo, oxo, or C optionally substituted with one or more oxo, halo, hydroxyl, or amino. 1-12 alkyl independently forming an optionally substituted heterocyclyl; R 9 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl or heterocyclyl, each of which, other than hydrogen, is selected from one or more of halo, oxo, acetyl, amino, hydroxyl, or C 1-12 optionally substituted with alkyl; Each R 10 independently, halo, C 1-12 Alkyl or C 1-12 is haloalkyl; y is 1, 2, 3, 4, 5, 6, 7, or 8; Each R 11 are independently halo, cyano, nitro, oxo, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6, -C(O)OR 6 , -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -OC(O)NR 6 R 7 , -NR 6 C(O)R 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , or -NR 6 C(O)OR 7 where R 11 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl in 12 with optional substitution; Each R 12 are independently halo, cyano, nitro, oxo, -OR 30 , -SR 30 , -SF5, -NR 30 R 31 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 , -OC(O)R 30 , -C(O)NR 30 R 31 , -OC(O)NR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R30 , -S(O) 1-2 NR 30 , -NR 30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 , or -NR 30 C(=O)OR 31 where R 12 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino. 1-12 independently optionally substituted with alkyl; Each R 20 , and R 21 are independently hydrogen or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 is alkyl; or R 20 , and R 21 are joined together with the atoms to which they are attached to form one or more halo, or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 alkyl independently forming an optionally substituted heterocyclyl; and Each R 30 , and R 31 are independently hydrogen or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 is alkyl; or R 30 , and R 31 are joined together with the atoms to which they are attached to form one or more halo, or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 The alkyl independently forms an optionally substituted heterocyclyl.

[0089] In certain embodiments, the compound of formula IA: [ka] IA or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: L is 1 to 6 R 10 or L is an optionally substituted heteroalkylene, or an optionally substituted heterocyclyl, or an optionally substituted heteroaryl, with the proviso that when L is an optionally substituted heterocyclyl and is attached to the bridged cycloalkyl through a nitrogen ring atom, then the carbon atom in L adjacent to the point of attachment is not substituted with ═O or ═S; x is 1 or 2; X 1 , O, NR 9 , or is a bond; R 1 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl or heterocyclyl, each of which, other than hydrogen, is selected from one or more of halo, oxo, acetyl, amino, hydroxyl, or C 1-12 optionally substituted with alkyl, or R 1 and R 5 are joined together to form a heterocyclyl ring; R 2 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is selected from the group consisting of one or more R 11 wherein L is heteroalkylene and R 2 is C 3-10If cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of them may be separated by one or more R 11 with optional substitution; R 3 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is selected from the group consisting of one or more R 11 with optional substitution; R 4 , and R 5 each independently represents hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, or C 2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one or more halo, oxo, acetyl, amino, or hydroxyl; Or, R 3 , and R 4 are bonded together with the atoms to which they are attached to form C 3-10 cycloalkyl, heterocyclyl, or heteroaryl, each of which may be joined by one or more R 11 with optional substitution; Or, R 4 , and R 5 are bonded together with the atoms to which they are attached to form C 3-10 cycloalkyl or heterocyclyl, each of which may be joined by one or more R 11 with optional substitution; R 6 , R 7 , and R 8 each independently represents hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O)1-2 R 20 , or -S(O) 1-2 NR 20 where R 6 , R 7 , and R 8 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be replaced by one or more R 12 independently and optionally substituted with; or R 6 , R 7 , and R 8 are bonded to each other together with the atoms to which they are attached to form one or more halo, oxo, or C optionally substituted with one or more oxo, halo, hydroxyl, or amino. 1-12 heterocyclyl optionally substituted independently with alkyl form; R 9 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl or heterocyclyl, each of which, other than hydrogen, is selected from one or more of halo, oxo, acetyl, amino, hydroxyl, or C 1-12 optionally substituted with alkyl; Each R 10 independently, halo, C 1-12 Alkyl or C 1-12 is haloalkyl; y is 1, 2, 3, 4, 5, 6, 7, or 8; Each R 11 are independently halo, cyano, nitro, oxo, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6 , -C(O)OR 6, -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -OC(O)NR 6 R 7 , -NR 6 C(O)R 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , or -NR 6 C(O)OR 7 where R 11 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be replaced by one or more R 12 independently and arbitrarily substituted with; Each R 12 are independently halo, cyano, nitro, oxo, -OR 30 , -SR 30 , -SF5, -NR 30 R 31 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 , -OC(O)R 30 , -C(O)NR 30 R 31 , -OC(O)NR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R 30 , -S(O)1-2 NR 30 , -NR 30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 , or -NR 30 C(=O)OR 31 where R 12 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino. 1-12 independently optionally substituted with alkyl; Each R 20 , and R 21 are independently hydrogen or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 is alkyl; or R 20 , and R 21 are joined together with the atoms to which they are attached to form one or more halo, or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 alkyl independently forming an optionally substituted heterocyclyl; and Each R 30 , and R 31 are independently hydrogen or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 is alkyl; or R 30 , and R 31 are joined together with the atoms to which they are attached to form one or more halo, or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 The alkyl independently forms an optionally substituted heterocyclyl.

[0090] In certain embodiments, R3 is optionally substituted aryl or optionally substituted heteroaryl, then z is 1 and X 1 is O and L is an optionally substituted heteroaryl, L is -L 1 -R 14 is not substituted with, 1 is an optionally substituted alkylene, an optionally substituted heteroalkylene, or -O-; R 14 is hydrogen, optionally substituted aryl, or optionally substituted heteroaryl.

[0091] In some embodiments, if z is 1, then X 1 is O and R 3 is not optionally substituted aryl or optionally substituted heteroaryl.

[0092] In certain embodiments, z is 0 and X 1 If is a bond, then R 3 is not hydrogen or alkyl. In certain embodiments, z is 0 and X 1 If O, then R 3 is not hydrogen or alkyl. In certain embodiments, z is 0 and X 1 If O, then R 3 is hydrogen or is not hydrogen. In certain embodiments, z is 0 and X 1 If is a bond, then R 3 is not hydrogen.

[0093] In certain embodiments, R 3 is optionally substituted aryl or optionally substituted heteroaryl, then z is 1 and X 1 is O and L is an optionally substituted heteroaryl, and L is a group [ka] is not substituted with, wherein: L 1 is C 1-6alkylene, 2- to 7-membered heteroalkylene, or —O—, and each C 1-6 Alkylene or 2- to 7-membered heteroalkylene is 1 to 5 R x with optional substitutions; B is hydrogen, phenyl, or 5- to 6-membered heteroaryl, and each phenyl or 5- to 6-membered heteroaryl is selected from 1 to 5 R Y with optional substitutions; Each R x C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -SR E , -S(O)R D , and -S(O)R D independently selected from the group consisting of: Each R Y is selected from hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, amino-C1-C6 alkyl, cyano-C1-C6 alkyl, oxo, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , -S(R F ) m , -S(O)R D , -S(O)2R D , and G 1 independently selected from the group consisting of: Or, two R on adjacent atoms YThe groups, together with the atoms to which they are attached, are joined to one another by 1 to 5 R X forming a fused 3- to 7-membered cycloalkyl, a fused 3- to 7-membered heterocyclyl, an aryl, or a fused 5- to 6-membered heteroaryl, optionally substituted with; Each G 1 are independently 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl, and each 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl, aryl, or 5- to 6-membered heteroaryl is separated by 1 to 3 R z with optional substitution; Each R z C1-C6 alkyl, hydroxy-C1-C6 alkyl, halo-C1-C6 alkyl, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OH, -C(O)OR D , and -S(O)R D independently selected from the group consisting of: R A each occurrence independently represents hydrogen, C-C alkyl, halo-C-C alkyl, —C(O)NR B R C , -C(O)R D , -C(O)OH, or -C(O)OR D , and R B and R C are each independently hydrogen or C1-C6 alkyl; or R B and R C are bonded together with the atoms to which they are attached to form 1-3 R Z forming an optionally substituted 3- to 7-membered heterocyclyl ring; Each R D is independently C1-C6 alkyl or halo-C1-C6 alkyl; Each RE are independently hydrogen, C1-C6 alkyl, or halo-C1-C6 alkyl; Each R F are independently hydrogen, C1-C6 alkyl, or halo; and m is 1, 3, or 5.

[0094] In certain embodiments, L is an optionally substituted heteroaryl ring.

[0095] In certain embodiments, L is an optionally substituted 5-membered C 2-4 It is a heteroaryl ring.

[0096] In certain embodiments, L is an optionally substituted 5-membered C ring having 1-3 nitrogen ring atoms. 2-4 It is a heteroaryl ring.

[0097] In certain embodiments, L is an optionally substituted triazole, oxazole, imidazole, oxadiazole, or isoxazole.

[0098] In certain embodiments, L is an optionally substituted heterocyclyl ring.

[0099] In certain embodiments, L is an optionally substituted 5-membered C 2-4 It is a heterocyclyl.

[0100] In certain embodiments, L is an optionally substituted 5-membered C ring having 1-3 nitrogen ring atoms. 2-4 It is a heterocyclyl ring.

[0101] In certain embodiments, L is an optionally substituted dihydroisoxazole or an optionally substituted oxazolidine.

[0102] In certain embodiments, L is selected from 1 to 5 R 13 Further substitution is made with each R 13 Halo, cyano, oxo, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy.

[0103] In certain embodiments, L is selected from 1 to 6 R 10 is heteroalkylene optionally substituted with

[0104] In certain embodiments, L is a straight chain heteroalkylene of 2 to 4 atoms.

[0105] In certain embodiments, L is selected from 1 to 3 chain carbon atoms and O, NR y and one chain heteroatom selected from S.

[0106] In certain embodiments, L is -CH2O-, -CH2OCH2-, -CH2CH2O-, or -CF2CH2O-.

[0107] In certain embodiments, when L is heteroalkylene, the point of attachment of the heteroalkylene to the bridged cycloalkyl can be via a carbon atom. In certain embodiments, when L is heteroalkylene, the point of attachment of the heteroalkylene to the bridged cycloalkyl can be via a carbon atom or a heteroatom. In certain embodiments, when L is heteroalkylene, -R 2 The point of attachment of the heteroalkylene to the can be via a carbon atom or a heteroatom.

[0108] In certain embodiments, R 3 , and R 4 are bonded together with the atoms to which they are attached, forming C 3-10 cycloalkyl or heterocyclyl, each of which may be one or more R 11 , and optionally replace with .

[0109] In certain embodiments, Formula II [ka] II or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: Ring A is an optionally substituted heterocyclyl or an optionally substituted heteroaryl, with the proviso that when Ring A is an optionally substituted heterocyclyl and is attached to the bridged cycloalkyl through a nitrogen ring atom, the carbon atom of Ring A adjacent to the point of attachment is not substituted with =0 or =S: x is 1 or 2; X 1 , O, NR 9 , or is a bond; R 1 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl or heterocyclyl, each of which, other than hydrogen, is selected from one or more of halo, oxo, acetyl, amino, hydroxyl, or C 1-12 optionally substituted with alkyl, or R 1 and R 5 are joined together to form a heterocyclyl ring; R 2 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is selected from the group consisting of one or more R 11 with optional substitution; R 3 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is selected from the group consisting of one or more R 11 with optional substitution; R4 , and R 5 each independently represents hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, or C 2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one or more halo, oxo, acetyl, amino, or hydroxyl; Or, R 3 , and R 4 are bonded together with the atoms to which they are attached to form C 3-10 cycloalkyl or heterocyclyl, each of which may be joined by one or more R 11 with optional substitution; Or, R 4 , and R 5 are bonded together with the atoms to which they are attached to form C 3-10 cycloalkyl or heterocyclyl, each of which may be joined by one or more R 11 with optional substitution; R 6 , R 7 , and R 8 each independently represents hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 , -C(O)OR 20 , -C(O)NR 20 R 21 , -S(O) 1-2 R 20 , or -S(O) 1-2 NR 20 where R 6 , R 7 , and R 8 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be replaced by one or more R 12 independently and optionally substituted with; or R 6 , R 7 , and R 8are bonded to each other together with the atoms to which they are attached to form one or more halo, oxo, or C optionally substituted with one or more oxo, halo, hydroxyl, or amino. 1-12 heterocyclyl optionally substituted independently with alkyl form; R 9 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl or heterocyclyl, each of which, other than hydrogen, is selected from one or more of halo, oxo, acetyl, amino, hydroxyl, or C 1-12 optionally substituted with alkyl; Each R 10 independently, halo, C 1-12 Alkyl or C 1-12 is haloalkyl; y is 1, 2, 3, 4, 5, 6, 7, or 8; Each R 11 are independently halo, cyano, nitro, oxo, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -OC(O)NR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , or -NR 6 C(O)OR 7 where R 11 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be replaced by one or more R 12 independently and arbitrarily substituted with; Each R 12 are independently halo, cyano, nitro, oxo, -OR 30 , -SR 30 , -SF5, -NR 30 R 31 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 30 , -C(O)OR 30 , -OC(O)OR 30 , -OC(O)R 30 , -C(O)NR 30 R 31 , -OC(O)NR 30 R 31 , -NR 30 C(O)NR 30 R 31 , -S(O) 1-2 R 30 , -S(O) 1-2 NR 30 , -NR 30 S(O) 1-2 R 31 , -NR 30 S(O) 1-2 NR 30 R 31 , -NR 30 C(O)R 31 , or -NR 30 C(=O)OR 31 where R 12wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino. 1-12 independently optionally substituted with alkyl; Each R 20 , and R 21 are independently hydrogen or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 is alkyl; or R 20 , and R 21 are joined together with the atoms to which they are attached to form one or more halo, or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 alkyl independently forming an optionally substituted heterocyclyl; and Each R 30 , and R 31 are independently hydrogen or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 is alkyl; or R 30 , and R 31 are joined together with the atoms to which they are attached to form one or more halo, or C optionally substituted independently with one or more oxo, halo, hydroxyl, or amino. 1-12 The alkyl independently forms an optionally substituted heterocyclyl.

[0110] In certain embodiments, R 3 is hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which, other than hydrogen, is selected from the group consisting of one or more R 11 with optional substitution; R 4 , and R 5 each independently represents hydrogen, C1-12 Alkyl, C 2-12 Alkenyl, or C 2-12 alkynyl, each of which, other than hydrogen, is independently optionally substituted with one or more halo, oxo, acetyl, amino, or hydroxyl; and y is 1, 2, 3, 4, 5, or 6.

[0111] In certain embodiments, the compound of formula IIA [ka] IIA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0112] In certain embodiments, the compound of formula IIB: [ka] IIB or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0113] In certain embodiments of Formula II, IIA, or IIB, R 2 is one or more R 11 C arbitrarily substituted with 3-10 In certain embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which may be selected from the group consisting of one or more R 11 In certain embodiments of Formula II, IIA, or IIB, each R 11 are independently halo, cyano, oxo, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C 1-12 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6, -C(O)OR 6 , -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -OC(O)NR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , or -NR 6 C(O)OR 7 and R 11 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 12 In certain embodiments of Formula II, IIA, or IIB, R 2 -OR 6 C arbitrarily substituted with 3-10 cycloalkyl, and R 6 is C optionally substituted with halo 1-12 It is alkyl.

[0114] In certain embodiments of Formula II, IIA, or IIB, R 3 are aryl or heteroaryl, each of which may be replaced by one or more R 11 In certain embodiments of Formula II, IIA, or IIB, R 3 is one or more of halo, cyano, nitro, oxo, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C 1-12 Alkyl, C 2-12 Alkenyl, C2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -OC(O)NR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , or -NR 6 C(O)OR 7 In certain embodiments of Formula II, IIA, or IIB, R 3 is phenyl optionally substituted with halo. In certain embodiments of IIB, R 2 -OR 6 C arbitrarily substituted with 3-10 is cycloalkyl, and R 6 is C optionally substituted with halo 1-12 alkyl, and R 3 is one or more R 11 It is a phenyl substituted with

[0115] In certain embodiments, ring A is an optionally substituted heteroaryl ring.

[0116] In certain embodiments, ring A is an optionally substituted 5-membered C 2-4 It is a heteroaryl ring.

[0117] In certain embodiments, ring A is an optionally substituted 5-membered C ring having 1-3 nitrogen ring atoms and, optionally, 1 or 2 oxygen and / or sulfur atoms. 2-4 In certain embodiments, Ring A is an optionally substituted 5-membered C heteroaryl ring having 1 to 3 nitrogen ring atoms. 2-4 It is a heteroaryl ring.

[0118] In certain embodiments, Ring A is an optionally substituted triazole, oxazole, imidazole, oxadiazole, benzoxazole, pyrazole, triazole, thiadiazole, tetrazole, or isoxazole. In certain embodiments, Ring A is an optionally substituted triazole, oxazole, imidazole, oxadiazole, or isoxazole.

[0119] In certain embodiments, ring A is an optionally substituted heterocyclyl ring.

[0120] In certain embodiments, ring A is an optionally substituted 5-membered C 2-4 It is a heterocyclyl.

[0121] In certain embodiments, ring A is an optionally substituted 5-membered C ring having 1-3 nitrogen ring atoms and, optionally, 1 or 2 oxygen and / or sulfur atoms. 2-4 In certain embodiments, Ring A is an optionally substituted 5-membered C heterocyclyl ring having 1 to 3 nitrogen ring atoms. 2-4 It is a heterocyclyl ring.

[0122] In certain embodiments, Ring A is an optionally substituted pyrrolidine, imidazolidine, dihydropyrrole, oxathiazolidine, dihydroisoxazole, or oxazolidine. In certain embodiments, Ring A is an optionally substituted dihydroisoxazole or an optionally substituted oxazolidine.

[0123] In certain embodiments, ring A contains 1 to 5 R 13 can be further substituted with each R13 Halo, cyano, oxo, thioxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 In certain embodiments, ring A is independently selected from 1 to 5 R 13 can be further substituted with each R 13 Halo, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, or C 1-6 haloalkoxy.

[0124] In certain embodiments, ring A is unsubstituted (i.e., R 2 In certain embodiments, ring A is not further substituted and is not further substituted with R 2 is one or more R 11 C arbitrarily substituted with 3-10 In certain embodiments, Ring A is an unsubstituted 5-membered C cycloalkyl having 1 to 3 nitrogen ring atoms and, optionally, 1 or 2 oxygen and / or sulfur atoms. 2-4 In certain embodiments, ring A is an unsubstituted 5-membered C heteroaryl ring having 1 to 3 nitrogen ring atoms. 2-4 In certain embodiments, ring A is an unsubstituted 5-membered C heteroaryl ring having 1 to 3 nitrogen ring atoms and, optionally, 1 or 2 oxygen and / or sulfur atoms. 2-4 In certain embodiments, ring A is a substituted heteroaryl ring having 1 to 3 nitrogen ring atoms. Not a 5-member C 2-4 It is a heteroaryl ring.

[0125] In certain embodiments, R 2 is hydrogen or halo. In certain embodiments, R 2 is hydrogen.

[0126] In certain embodiments, R 2 is C1-12 Alkyl, C 1-12 Alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, heterocyclyl, or aryl, each of which is selected from 1 to 6 R 11 , and optionally replace with .

[0127] In certain embodiments, R 2 is 1 to 6 R 11 C arbitrarily substituted with 3-10 It is cycloalkyl.

[0128] In certain embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, methyl, ethyl, propyl, methoxy, or cyclobutoxy, each of which is selected from 1 to 6 R 11 In certain embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, methyl, ethyl, propyl, methoxy, or cyclobutoxy, each of which is selected from 1 to 6 R 10 , and optionally replace with .

[0129] In certain embodiments, R 2 1 to 6 R 11 In certain embodiments, R 2 At least one R 11 Replace with .

[0130] In certain embodiments, R 2 is C 1-6 Haloalkoxy-substituted C 3-10 In certain embodiments, R 2 is cycloalkyl substituted with trifluoromethoxy. In certain embodiments, R 2 is 3-(trifluoromethoxy)cyclobutyl.

[0131] In certain embodiments, R2 is (C 1-6 Haloalkoxy)methyl-substituted C 3-10 In certain embodiments, R 2 is cycloalkyl substituted with (trifluoromethoxy)methyl. In certain embodiments, R 2 is 2-((trifluoromethoxy)methyl)cyclopropyl.

[0132] In certain embodiments, R 11 is hydroxyl, halo(C 1-6 alkoxy), halo, cycloalkyl, cycloalkoxy, phenyl, C 1-6 Alkoxycarbonyl, cyano, halo(C 1-6 alkyl), halo(C 1-6 alkoxy)cycloalkoxy, halo(C 1-6 alkoxy)alkyl, halo(heterocyclyl), or halophenoxy.

[0133] In certain embodiments, R 11 is 1,1,1-trifluoroethyl, 1,1-difluoroethyl, triazol-2-yl, trifluoromethylthio, trifluoromethoxy, (3,3-difluoropyrrolidin-1-yl)methyl, 2,2,2-trifluoro-1-methyl-ethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3-(trifluoromethyl)azetidin-1-yl, chloro, difluoromethoxy, difluoromethyl, fluoro, methyl, tert-butoxycarbonyl, trifluoromethoxymethyl, or cyclopropyl.

[0134] In certain embodiments, R 2 are (4-chloro-3-fluoro-phenoxy)methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3-(difluoromethoxy)cyclobutyl, 3 -(trifluoromethoxy)cyclobutoxymethyl, 3-(trifluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)propyl, 3-(trifluoromethyl)cyclobutyl, 3-cyanocyclobutyl, 3,3-difluoro-1-methyl-propyl, 4-chloro-3-fluoro-phenyl, 4-chlorophenyl, benzyl, cyanocyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopropyl, cyclopropylethyl, cyclopropylmethyl, hydroxycyclobutyl, methyl, N-tert-butoxy(carbonyl)azetidin-3-yl, N-tert-butoxy(carbonyl)pyrrolidin-3-yl, tetrahydrofuranyl, trifluoroethyl, trifluoromethoxy, (trifluoromethoxy)cyclobutoxy, trifluoromethoxyethyl, or trifluoromethoxymethyl.

[0135] In certain embodiments, R 2are (4-chloro-3-fluoro-phenoxy)methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3-(difluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)cyclobutoxymethyl, 3-(trifluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)propyl, 3-(trifluoromethyl)cyclobutyl, 3-cyanocyclobutyl, 3,3-difluoro-1-methyl-propyl, 4-chloro-3-fluoro-phenyl, 4-chlorophenyl, benzyl, cyanocyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl , cyclopropyl, cyclopropylethyl, cyclopropylmethyl, hydroxycyclobutyl, methyl, N-tert-butoxy(carbonyl)azetidin-3-yl, N-tert-butoxy(carbonyl)pyrrolidin-3-yl, tetrahydrofuranyl, trifluoroethyl, trifluoromethoxy, (trifluoromethoxy)cyclobutoxy, trifluoromethoxyethyl, trifluoromethoxymethyl, 3-(1,1-difluoroethyl)cyclobutyl, 3-(1,1,1-trifluoroethyl)azetidinyl, 3-(triazol-2-yl)cyclobutyl, 3-(trifluoromethylthio)cyclobutyl, or 3-(cyclopropyl)cyclobutyl.

[0136] In embodiments, R 2are (4-chloro-3-fluoro-phenoxy)methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3-(difluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)cyclobutoxymethyl, 3-(trifluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)propyl, 3-(trifluoromethyl)cyclobutyl, 3-cyanocyclobutyl, 3,3-difluoro-1-methyl-propyl, 4-chloro-3-fluoro-phenyl, 4-chlorophenyl, benzyl, cyanocyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopropyl, cyclopropylethyl, cyclopropylmethyl, hydroxycyclobutyl, methyl, N-tert-butoxy(carbonyl)azetidin-3-yl, N-tert-butoxy(carbonyl)pyrrolidin-3-yl, tetrahydrofuranyl, trifluoroethyl, trifluoromethyl acetoxin, (trifluoromethoxy)cyclobutoxy, trifluoromethoxyethyl, trifluoromethoxymethyl, 3-(1,1-difluoroethyl)cyclobutyl, 3-(1,1,1-trifluoroethyl)azetidinyl, 3-(triazol-2-yl)cyclobutyl, 3-(trifluoromethylthio)cyclobutyl, 3-(cyclopropyl)cyclobutyl, (3,3-difluoroazetidin-1-yl)methyl, (3,3-difluoropyrrolidin-1-yl)methyl, 1-(2 ,2,2-trifluoro-1-methyl-ethyl)azetidin-3-yl, 1-(2,2,2-trifluoroethyl)azetidin-3-yl, 1-(2,2,2-trifluoroethyl)pyrazol-3-yl, 1-(2,2,2-trifluoroethyl)pyrazol-4-yl, 1-(2,2-difluoroethyl)azetidin-3-yl, 1-tert-butoxycarbonyl-2-methylazetidin-3-yl, 2-(4-chloro-3-fluoro-phenyl, 2-(difluoromethyl)cyclohexyl) 2-(trifluoromethoxymethyl)cyclopropyl, 2,2-difluoro-1,1-dimethyl-ethyl, 2-methyl-1-(2,2,2-trifluoroethyl)azetidin-3-yl, 3-(trifluoromethoxymethyl)cyclobutyl, 3-(trifluoromethyl)azetidin-1-yl, 3-fluoro-1-(2,2,2-trifluoroethyl)azetidin-3-yl, 4-(2,2,2-trifluoroethyl)morpholin-2-yl, 4-tert-butoxycarbonyl-morpholin-2-yl, 5-(trifluoromethoxymethyl)tetrahydrofuran-2-yl, 2-((trifluoromethoxy)methyl)cyclopropyl, or 5-fluoro-3-pyridyl.

[0137] In certain embodiments, R 2are (4-chloro-3-fluoro-phenoxy)methyl, 1-fluorocyclopropyl, 1,1,1-trifluoroethyl, 2-methylcyclopropyl, 2,2-difluorocyclopropyl, 3-(difluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)cyclobutoxymethyl, 3-(trifluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)propyl, 3-(trifluoromethyl)cyclobutyl, 3-cyanocyclobutyl, 3,3-difluoro-1-methyl-propyl, 4-chloro-3-fluoro-phenyl, phenyl, 3-(trifluoromethyl)phenyl, 2-hydroxymethyl-4-(trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2,4-difluorophenyl, 4-chloro-2,6-difluorophenyl, 4-chloro-2,3-difluorophenyl phenyl, 4-chloro-2,5-difluorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-2-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-2-fluoro-phenyl, 5-(trifluoromethyl)-2-pyridyl, 6-(trifluoromethyl)-2-pyridyl, 2-(trifluoromethyl)pyrimidine-5- yl, 5-fluoropyridin-3-yl, 1,2,3-triazol-2-yl)cyclobut-3-yl, 1,2,3-triazol-2-yl)cyclobut-1-yl, 2-hydroxy-4-(trifluoromethyl)phenyl, 2-cyano-4-(trifluoromethyl)phenyl, 2,2-difluorobenzo[d][1,3]dioxol-5-yl, 3-((tert-butyldimethylsilyl)oxy)cyclobutyl, 5-(trifluoromethyl)-4,5-Dihydrooxazol-2-yl, 2-methoxycarbonyl-4-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)ethoxy, 4-chlorophenyl, benzyl, 2-cyanocyclobutyl, 2-hydroxycyclobutyl, cyclobutoxymethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopropyl, cyclopropylethyl, cyclopropylmethyl, hydroxycyclobutyl, methyl, N-tert-butoxy(carbonyl)azetidin-3-yl, N-tert-butoxy(carbonyl)pyrrolidin-3-yl, tetrahydrofuranyl, trifluoroethyl, trifluoromethoxy, (trifluoromethoxy)cyclobutoxy, trifluoromethoxyethyl, trifluoromethoxymethyl, 3-(1,1-difluoroethyl)cyclobutyl, 3-(1,1,1-trifluoroethyl)azetidinyl, 3-(triazol-2-yl)cyclobutyl, 3-( (trifluoromethylthio)cyclobutyl, 3-(cyclopropyl)cyclobutyl, (3,3-difluoroazetidin-1-yl)methyl, (33-difluoropyrrolidin-1-yl)methyl, 1-(2,2,2-trifluoro-1-methyl-ethyl)azetidin-3-yl, 1-(2,2,2-trifluoroethyl)azetidin-3-yl, 1-(2,2,2-trifluoroethyl)pyrazol-3-yl, 1-(2,2,2-trifluoroethyl)pyrazol-3-yl ) pyrazol-4-yl, 1-(2,2-difluoroethyl)azetidin-3-yl, 1-tert-butoxycarbonyl-2-methylazetidin-3-yl, 2-(4-chloro-3-fluoro-phenyl, 2-(difluoromethyl)cyclopropyl, 2-(trifluoromethoxymethyl)cyclopropyl, 2,2-difluoro-1,1-dimethyl-ethyl, 2-methyl-1-(2,2,2-trifluoroethyl)azetidin-3-yl, 3-(, trifluoromethoxymethyl)cyclobutyl, 3-(trifluoromethyl)azetidin-1-yl, 3-fluoro-1-(2,2,2-trifluoroethyl)azetidin-3-yl, 4-(2,2,2-trifluoroethyl)morpholin-2-yl, 4-tert-butoxycarbonyl-morpholin-2-yl, 5-(trifluoromethoxymethyl)tetrahydrofuran-2-yl, 2-((trifluoromethoxy)methyl)cyclopropyl, or 5-fluoro-3-pyridyl.

[0138] In certain embodiments, R 2 is 3-(1,1-difluoroethyl)cyclobutyl, 3-(1,1,1-trifluoroethyl)azetidinyl, 3-(triazol-2-yl)cyclobutyl, 3-(trifluoromethylthio)cyclobutyl, or 3-(cyclopropyl)cyclobutyl.

[0139] In certain embodiments, L or ring A is selected from the group consisting of (4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-oxadiazol-2-yl, 1-(3-cyanocyclobutyl)triazol-4-yl, 1-(3-hydroxycyclobutyl)triazol-4-yl, 1-(4-chlorophenyl)triazol-4-yl, 1-benzyltriazol-4-yl, 1-cyclobutyltriazol-4-yl, 1H-1,2,3-triazol-4-yl, 2-(3-cyanocyclobutyl)triazol-4-yl, 2-(trifluoromethoxy ... )ethyl]-1,3,4-oxadiazol-2-yl, 2-cyclobutyltriazol-4-yl, 3-[(trifluoromethoxy)cyclobutoxy]-imidazol-1-yl, 3-cyanocyclobutyl)triazol-4-yl, 3-cyclobutylisoxazol-5-yl, 4-(cyclobutylmethyl)imidazol-1-yl, 4-[3-(trifluoromethoxy)cyclobutyl]imidazol-1-yl, 4-cyclobutylimidazol-1-yl, 4-cyclobutyloxazol-2-yl, 5-((4-chloro-3-fluoromethyl)imidazol-1-yl (2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl, 5-(2,2,2-difluorocyclopropyl)-1,3,4-oxadiazol-2-yl, 5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl, 5-(3-cyanocyclobutyl)-1,3,4-oxadiazol-2-yl, 5-(3,3-difluoro-1-methyl)- 4-(4-chloro-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl, 5-(cyclobutoxymethyl)-1,3,4-oxadiazol-2-yl, 5-(cyclobutylmethyl)-1,3,4-oxadiazol-2-yl, 5-(cyclopropylmethyl)-1,3,4-oxadiazol-2-yl, 5-(trifluoromethoxymethyl)-1,3,4-oxadiazol-2-yl, 5-[(4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-Oxadiazol-2-yl, 5-[[3-(trifluoromethoxy)cyclobutoxy]methyl]-1,3,4-oxadiazol-2-yl, 5-[2-methylcyclopropyl]-1,3,4-oxadiazol-2-yl, 5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl, 5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazol-2-yl, 5-[3-(trifluoromethyl)cyclobutyl]-1,3,4-oxadiazol-2-yl, 5-[N-(1,1,1-trifluoroethyl)azetidin-3-yl]-1,3 ,4-oxadiazol-2-yl, 5-[N-(1,1,1-trifluoroethyl)pyrrolidin-3-yl]-1,3,4-oxadiazol-2-yl, 5-[N-tert-butoxy(carbonyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl, 5-[N-tert-butoxy(carbonyl)pyrrolidin-3-yl]-1,3,4-oxadiazol-2-yl, 5-cyclobutyl-1,3,4-oxadiazol-2-yl, 5-cyclobutyl-4,5-dihydroisoxazol-3-yl, 5-cyclobutylisoxazol-3-yl, 5-cyclobutyloxazole, -2-yl, 5-cyclopentyl-4,5-dihydroisoxazol-3-yl, or oxazolidin-2-one-5-yl.

[0140] In certain embodiments, R 2 is substituted with cyclobutyl, the substituent at the cyclobutyl is cis. In certain embodiments, the substituent at the cyclobutyl is trans.

[0141] In certain embodiments, X 1 is O. In certain embodiments, X 1 is a bond.

[0142] In certain embodiments, z is 0 and X 1 is a bond.

[0143] In certain embodiments, z is 0 and X1 is a bond and R 3 is C 1-12 Alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 11 , and optionally replace with .

[0144] In certain embodiments, R 3 is one or more R 11 C arbitrarily substituted with 1-12 It is alkyl.

[0145] In certain embodiments, z is 0. In certain embodiments, z is 1.

[0146] In certain embodiments, R 3 is C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 11 , and optionally replace with .

[0147] In certain embodiments, R 3 is C 3-10 cycloalkyl, aryl, or heteroaryl, each of which may be separated by one or more R 11 , and optionally replace with .

[0148] In certain embodiments, R 3 is cyclobutyl, triazolyl, or phenyl, each of which may be replaced by one or more R 11 , and optionally replace with .

[0149] In certain embodiments, R 3 is cyclobutyl. In certain embodiments, R 3 is cyclobutyl and R 11 is trifluoromethoxy.

[0150] In certain embodiments, R 3 is optionally substituted phenyl.

[0151] In certain embodiments, R 3 is halo, cyano, C optionally substituted with one or more halo 1-12 C optionally substituted with alkyl and one or more halo 1-12 and phenyl optionally substituted with one or more substituents independently selected from alkoxy.

[0152] In certain embodiments, R 3 is phenyl substituted with chloro, fluoro, or a combination thereof.

[0153] In certain embodiments, R 3 is 4-chlorophenyl, 4-chloro-3-fluorophenyl, or trifluoromethoxycyclobut-2-yl.

[0154] In certain embodiments, R 3 are 4-chlorophenyl, 4-chloro-3-fluorophenyl, trifluoromethoxycyclobut-2-yl(5-chloro-3-pyridyl)methyl, 1-(2,2,2-trifluoroethyl)azetidin-3-yl, 2-(trifluoromethoxy)ethyl, 2-spiro[2.3]hexan-5-yl, 3-(trifluoromethoxy)cyclobutyl, 3-(trifluoromethoxy)cyclobutyl]methyl, 3-(trifluoromethoxy)cyclopentyl, 3-(trifluoromethoxymethyl)cyclobutyl, 3-fluorophenyl, 4-cyclopropylphenoxy, 4-fluorophenyl, or 6,6-difluoro-3-bicyclo[3.1.0]hexanyl.

[0155] In certain embodiments, R 3are 3,4-difluorophenyl, 2-(trifluoromethyl)pyridin-5-yl, 4-(trifluoromethyl)phenyl, 2-(4-fluoro-1H-pyrazol-1-yl)ethyl, 2-(trifluoromethoxy)ethyl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 6-chlorochroman-2-yl, 6-fluorochroman-2-yl, 5-chlorobenzo[d] oxazol-2-yl, 6-(trifluoromethyl)quinolin-2-yl, 3-chloroquinolin-7-yl, 7-chloroquinolin-3-yl, 6-chloroquinolin-2-yl, 7-fluoroimidazo[1,2-a]pyridin-2-yl, 6-fluoropyrazolo[1,5-a]pyridin-2-yl, 3-(2H-1,2,3-triazol-2-yl)cyclobutyl, 3-(trifluoromethoxy)phenyl, 5-chlorobenzo[d]thiazol-2-yl, 7-Chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl, 7-chloroimidazo[1,2-b]pyridazin-2-yl, 5-fluorobenzo[d]oxazol-2-yl, 7-bromoimidazo[1,2-a]pyridin-2-yl, 6-fluoroimidazo[1,2-a]pyridin-2-yl, 7-chloropyrrolo[1,2-c]pyrimidin-3-yl, 7-chloroisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-bromoisoquinolin-3-yl Quinolin-3-yl, 7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl, 6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl, quinolin-2-yl, quinoxalin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, quinazolin-2-yl, 6-chlorobenzo[d]thiazol-2-yl, 5-bromobenzo[d]oxazol-2-yl, 7-chloro-6-fluoroimidazo[1,2-a]pyridin-2-yl, 6-chloroquinazolin-2-yl, 6-chloro-7-fluoroquinolin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazol-3-yl, 3-(trifluoromethoxy)cyclobutylmethyl, 3-(2-(trifluoromethoxy)ethoxy)cyclobutyl, 4-((trifluoromethoxy)methyl)cyclohexanyl, 1-(2,2,2-trifluoroethyl)azetidinyl, 3-ethoxycyclobutanyl, 3-cyanocyclobutyl, 2-(4-chloro 2-(4-chlorophenyl)-1-hydroxyethyl, 4-chloro-3-(hydroxymethyl)phenyl, 2-(4-chlorophenyl)-2-hydroxyethyl, 3-(4-fluoro-1H-pyrazol-1-yl)cyclobutyl, 1-(trifluoromethoxy)propan-2-yl, 6-chloro-3,4-dihydroisoquinolin-2(1H)-yl, 2-(trifluoromethoxy)propyl, 1-(2-(trifluoromethoxy)ethyl)-1H-imidazol-4-yl, 4-chloro-3-fluorophenyl, or trifluoromethoxycyclobut-2-yl.

[0156] In certain embodiments, R 4 , and R 5 is H. In certain embodiments, R 4 , and R 5 are each independently H, alkyl optionally substituted with hydroxy.

[0157] In certain embodiments, R 1 is H.

[0158] In certain embodiments, the compound of formula III: [ka] III wherein A, X 1 , y, z, R 1 , R 3 , R 4 , R 5 , R 10 , and R11 is as defined herein.

[0159] In certain embodiments, the compound of formula IV: [ka] IV wherein A, R 1 , R 3 , and R 11 is as defined herein.

[0160] In certain embodiments, the compound of formula V: [ka] V wherein A, R 1 , and R 11 is as defined herein and n is 0, 1, 2, or 3.

[0161] In certain embodiments, the compound of formula VI: [ka] VI wherein A, R 1 , and R 11 is as defined herein.

[0162] In certain embodiments, the compound of formula IIIA: [ka] IIIA wherein A, X 1 , y, z, R 1 , R 3 , R 4 , R 5 , R 10 , and R 11 is as defined herein.

[0163] In certain embodiments, the compound of formula IVA: [ka] IVA wherein A, R 1 , R 3 , and R 11 is as defined herein.

[0164] In certain embodiments, the compound of formula VA: [ka] VA wherein A, R 1 , and R 11 is as defined herein and n is 0, 1, 2, or 3.

[0165] In certain embodiments, the compound of formula VIA: [ka] VIA wherein A, R 1 , R 3 and R 11 is as defined herein.

[0166] In certain embodiments of formula III, IV, V, VI, IIIA, IVA, VA, or VIA, each R 11 are independently halo, cyano, oxo, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C 1-12 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -OC(O)NR6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , or -NR 6 C(O)OR 7 and R 11 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be replaced by one or more R 12 In certain embodiments of Formula III, IV, V, VI, IIIA, IVA, VA, or VIA, R 2 -OR 6 C arbitrarily substituted with 3-10 cycloalkyl, and R 6 is C optionally substituted with halo 1-12 It is alkyl.

[0167] In certain embodiments of formula III, IV, V, VI, IIIA, IVA, VA, or VIA, R 3 are aryl or heteroaryl, each of which may be replaced by one or more R 11 In certain embodiments of Formula III, IV, V, VI, IIIA, IVA, VA, or VIA, R 3 is one or more of halo, cyano, nitro, oxo, -OR 6 , -SR 6 , -SF5, -NR 6 R 7 , C 1-12 Alkyl, C 2-12 Alkenyl , C 2-12 Alkynyl, C 3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6 , -C(O)OR 6 , -OC(O)OR 6 , -OC(O)R 6 , -C(O)NR 6 R 7 , -OC(O)NR 6 R 7 , -NR 6 C(O)NR 7 R 8 , -S(O) 1-2 R 6 , -S(O) 1-2 NR 6 , -NR 6 S(O) 1-2 R 7 , -NR 6 S(O) 1-2 NR 7 R 8 , -NR 6 C(O)R 7 , or -NR 6 C(O)OR 7 In certain embodiments of Formula III, IV, V, VI, IIIA, IVA, VA, or VIA, R 3 is phenyl optionally substituted with halo.

[0168] In certain embodiments, L or ring A is [ka] , [ka] , [ka] ,or, [ka] is.

[0169] In certain embodiments of formula I, IA, or II, ring A is an optionally substituted heteroaryl and R 2 is an optionally substituted cycloalkyl.

[0170] In certain embodiments of formula I, IA, or II, ring A is an optionally substituted heteroaryl and R 2 is cyclopropyl, cyclobutyl, or cyclopentyl optionally substituted with halo, oxo, amino, hydroxyl, cyano, alkyl, alkenyl, alkynyl, or alkoxy, wherein the alkyl, alkenyl, alkynyl, and alkoxy are independently optionally substituted with oxo, halo, amino, or hydroxyl.

[0171] In certain embodiments, there is provided a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof: Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19]

[0172] In certain embodiments, there is provided a compound selected from Table 2, or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof: Table 2 [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0173] In certain embodiments, the structure [ka] or a salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof. In certain embodiments, the salt is an HCl salt.

[0174] In certain embodiments, the structure [ka] or a salt thereof. In certain embodiments, the salt is an HCl salt.

[0175] In certain embodiments, the structure [ka] or a salt thereof. In certain embodiments, the salt is an HCl salt.

[0176] 3. Method "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or lessening the severity of the disease or condition), b) slowing or halting the progression of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease state, causing partial or total relief of the disease or condition, enhancing the effectiveness of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0177] "Prevention" or "preventing" refers to any treatment of a disease or condition in which the clinical symptoms of that disease or condition do not develop. In some embodiments, the compounds may be administered to subjects (including humans) at risk of developing the disease or condition or who have a family history of the disease or condition.

[0178] "Subject" refers to an animal, such as a mammal (including a human), that is or will be the object of treatment, observation, or experimentation. The methods described herein may be useful for human treatment and / or veterinary applications. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0179] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, means an amount sufficient to effect treatment that provides a therapeutic benefit, such as amelioration of symptoms or delay of disease progression, when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or condition described herein. The therapeutically effective amount can vary depending on the subject and the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by one of ordinary skill in the art.

[0180] The methods described herein may be applied to cell populations in vivo or ex vivo. "In vivo" means within a living organism, such as within an animal or a human. In this context, the methods described herein may be used therapeutically on an individual. "Ex vivo" means outside of a living organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine optimal schedules and / or dosages for administration of the disclosed compounds for a given condition, cell type, individual, and other parameters. Information gathered from such use may be used experimentally or clinically to design in vivo treatment protocols. Other ex vivo uses for which the compounds and compositions described herein are suitable are described below or will be apparent to those skilled in the art. Selected compounds may be further characterized to determine safety or tolerated doses in human or non-human subjects. Such properties may be determined using methods known to those skilled in the art.

[0181] In certain embodiments, the compounds disclosed herein can be used to treat cell proliferative disorders, including both cancerous and non-cancerous cell proliferative disorders. Treatment of cell proliferative disorders can include, but is not limited to, inhibiting cell proliferation, such as rapid proliferation. It is believed that the compounds described herein can be used to treat all types of cancer, including, but not limited to, carcinomas, sarcomas, lymphomas, leukemias, and germ cell tumors. Exemplary cancers include adrenocortical carcinoma, anal cancer, appendix cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, or malignant fibrous histiocytoma, brain cancer (e.g., brain stem glioma, astrocytoma (e.g., cerebellar, cerebral, etc.), atypical teratoid / rhabdoid tumor, central nervous system embryonal tumor, malignant glioma, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, moderately differentiated pineal parenchymal tumor, supratentorial primitive neuroectodermal tumor, and / or pineoblastoma, visual pathway tumor, and / or , hypothalamic glioma, brain tumor, and spinal cord tumor, etc.), breast cancer, bronchial tumor, carcinoid tumor (e.g., gastrointestinal), cancer of unknown primary, cervical cancer, chordoma, chronic myeloproliferative disorder, colon cancer, colorectal cancer, embryonal tumor, cancer of the central nervous system, endometrial cancer, ependymoma, esophageal cancer, Ewing's tumor family, eye cancer (e.g., intraocular melanoma, retinoblastoma, etc.), gallbladder cancer, stomach cancer, gastrointestinal tumor (e.g., carcinoid tumor, stromal tumor (gastrointestinal stromal tumor), stromal cell tumor, etc.), germ cell tumors (e.g., extracranial, extragonadal, ovarian, etc.), gestational trophoblastic tumors, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, intraocular melanoma, pancreatic islet cell tumors, Kaposi's sarcoma, renal cancer, large cell tumors, laryngeal cancer (e.g., acute lymphoblastic, acute myeloid, etc.), leukemia (e.g., myeloid, acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myeloid, multiple myeloid, hairy cell, etc.), lip and / or oral cancer, liver cancer , lung cancer (e.g., non-small cell, small cell, etc.), lymphoma (e.g., AIDS-related, Burkitt, cutaneous T-cell, Hodgkin, non-Hodgkin, primary central nervous system, cutaneous T-cell, Waldenstrom's macroglobulinemia, etc.), malignant fibrous histiocytoma of bone and / or osteosarcoma, medulloblastoma, medulloepithelioma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell neck cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplasia syndrome,Myelodysplastic / myeloproliferative disorders (e.g., myeloproliferative disorders, chronic, etc.), nasal and / or paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cancer; oral cancer, oropharyngeal cancer; osteosarcoma and / or malignant fibrous histiocytoma of bone; ovarian cancer (e.g., ovarian epithelial carcinoma, ovarian germ cell tumor, ovarian low malignant tumor, etc.), pancreatic cancer (e.g., pancreatic islet cell tumor, etc.), papilloma, paranasal sinus and / or nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, moderately differentiated pineal parenchymal tumor, pineoblastoma, and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell carcinoma, transitional cell carcinoma, and chromosome 15-related nucleotide polyposis tumors. These include, but are not limited to, respiratory tract cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Ewing's family of tumors, Kaposi's, soft tissue, uterine, etc.), Sezary syndrome, skin cancer (e.g., non-melanoma, melanoma, Merkel cell, etc.), small intestine cancer, squamous cell carcinoma, squamous neck cancer with occult primary and metastatic gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma and / or thymic carcinoma, thyroid cancer, transitional cell carcinoma of the kidney, pelvic and / or urinary tract cancer (e.g., trophoblastic tumor, carcinoma of unknown primary site, urethral cancer, uterine cancer, endometrial, uterine sarcoma, etc.), vaginal cancer, visual pathway and / or hypothalamic glioma, vulvar cancer, Wilms' tumor, etc. Examples of non-cancerous cell proliferative disorders include, but are not limited to, fibroadenoma, adenoma, intraductal papilloma, breast adenoma, adenosis, fibrocystic disease or changes in the breast, plasma cell proliferative disorders (PCPD), restenosis, atherosclerosis, rheumatoid arthritis, myofibromatosis, fibrous hamartoma, granular lymphoproliferative disease, benign hyperplasia of the prostate, heavy chain disease (HCD), lymphoproliferative disorders, psoriasis, idiopathic pulmonary fibrosis, scleroderma, liver cirrhosis, IgA nephropathy, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, hemangioma, vascular and nonvascular intraocular proliferative disorders.

[0182] In certain embodiments, the compounds disclosed herein can be used to treat lung injury and / or pneumonia.

[0183] In certain embodiments, the compounds disclosed herein are useful for treating Alzheimer's disease, neuropathic pain, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson's disease, diabetes, metabolic syndrome, metabolic disorders, Huntington's disease, Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, and lipid metabolism disorders. It can be used to treat cancers, precancerous syndromes, and diseases / injuries associated with an activated unfolded protein response pathway, such as liver disease, hepatic steatosis, liver fibrosis, chronic and acute lung disease, pulmonary fibrosis, chronic and acute kidney disease, renal fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, frontotemporal dementia, tauopathy, Pick's disease, Neyman-Pick disease, amyloidosis, cognitive impairment, atherosclerosis, eye disease, cardiac arrhythmias, organ transplantation, and transplantation of organs for transplantation.

[0184] In embodiments, the compounds disclosed herein can be used to treat or alleviate cancer, Alzheimer's disease, stroke, type 1 diabetes, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, cardiac arrhythmia, or age-related macular degeneration.

[0185] In certain embodiments, the compounds disclosed herein can be used to treat neuropathic pain.

[0186] In certain embodiments, the compounds disclosed herein can be used to treat or reduce the severity of ocular diseases / angiogenesis. In certain embodiments, the ocular diseases include vascular leakage (e.g., edema or neovascularization of occlusive or inflammatory retinal vascular diseases, such as rubeosis iridis, neovascular glaucoma, pterygium, neovascular glaucoma blebs, conjunctival papillomas, etc.), choroidal neovascularization (e.g., neovascular age-related macular degeneration (AMD), myopia, anterior uveitis, trauma, or idiopathic edema), macular edema (e.g., postoperative macular edema, macular edema secondary to uveitis, including retinal and / or choroidal inflammation, Examples of neovascular age-related macular degeneration include macular edema secondary to diabetes and macular edema secondary to retinal vascular occlusive disease (i.e., branch and central retinal vein occlusion), retinal neovascularization due to diabetes (e.g., retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ocular or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eales disease), and genetic disorders (e.g., von Hippel-Lindau syndrome). In certain embodiments, the neovascular age-related macular degeneration is wet age-related macular degeneration. In certain embodiments, the neovascular age-related macular degeneration is dry age-related macular degeneration, and the patient is characterized as being at increased risk for developing wet age-related macular degeneration.

[0187] In certain embodiments, the compounds disclosed herein can be used to treat viral infections (eg, to prevent the initiation of viral protein synthesis). Exemplary viruses that can be treated using the compounds disclosed herein include Picornaviridae (e.g., poliovirus), Reoviridae (e.g., rotavirus), Togaviridae (e.g., encephalitis virus, yellow fever virus, rubella virus, etc.), Orthomyxoviridae (e.g., influenza virus), Paramyxoviridae (e.g., respiratory syncytial virus, measles virus, mumps virus, parainfluenza virus, etc.), Rhabdoviridae (e.g., rabies virus), Coronaviridae, Bunyaviridae, Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, and Retroviridae (e.g., human T-cell lymphotropic virus (HTLV), human immunodeficiency virus (HIV), etc.), Papovaviridae (e.g., papillomavirus), Adenoviridae (e.g., adenovirus), Herpesviridae (e.g., herpes simplex virus), and Poxviridae (e.g., smallpox virus). In certain embodiments, the viral infection is caused by hepatitis B virus, hepatitis C virus, and / or HIV.

[0188] In certain embodiments, the compounds disclosed herein can be used to treat disorders associated with viral infections, including neurological symptoms (e.g., encephalitis, meningoencephalitis, paralysis, spinal cord disorders, neuropathy, aseptic meningitis, hemiplegia, dementia, dysphagia, lack of muscle coordination, visual impairment, coma, etc.), wasting symptoms (e.g., inflammatory cell infiltration, perivascular cell infiltration of blood vessels, demyelination, necrosis, reactive gliosis, etc.), gastroenteritis symptoms (e.g., diarrhea, vomiting, convulsions, etc.), hepatitis symptoms (e.g., nausea, vomiting, right upper abdominal pain, elevated liver enzyme (e.g., AST, ALT, etc.) levels, jaundice, etc.), hemorrhagic fever symptoms (e.g., headache, fever, chills, body aches, diarrhea, vomiting, dizziness, confusion, abnormal behavior, pharyngitis, conjunctivitis, red face, red neck, bleeding, organ failure, etc.), carcinogenic symptoms (e.g., sarcoma, leukemia, etc.), as well as "rare" malignancies. These include, but are not limited to, cancers (e.g., Kaposi's sarcoma, oral hairy leukoplakia, lymphoma, etc.), immunodeficiency symptoms (e.g., opportunistic infections, wasting, rare malignancies, neurological disorders, fever, diarrhea, skin rash, etc.), lesions (e.g., warts (e.g., common warts, flat warts, deep hyperkeratotic palmoplantar warts, superficial mosaic palmoplantar warts, etc.)), epidermal dysplasia, mucosal lesions, ulcers, and systemic symptoms (e.g., fever, chills, headache, muscle pain, bone pain, joint pain, pharyngitis, tonsillitis, sinusitis, otitis media, bronchitis, pneumonia, bronchopneumonia, nausea, vomiting, increased salivation, rash, macules, lymphadenopathy, arthritis, ulcers, photosensitivity, weight loss, hypersensitivity, restlessness, anxiety, coma, death, etc.).

[0189] In certain embodiments, the compounds disclosed herein can be used to treat disorders characterized by the undesired synthesis and / or abnormal accumulation of one or more mutant and / or wild-type proteins. The compounds disclosed herein can inhibit translation initiation, thereby reducing the burden on the protein folding machinery and, therefore, the severity of the disorder. Disorders associated with the undesired synthesis and / or abnormal accumulation of one or more mutant and / or wild-type proteins include, but are not limited to, Tay-Sachs disease, cystic fibrosis, phenylketonuria, Fabry disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, frontotemporal dementia, congophilic vasculopathy, and prion-related disorders (i.e., Creutzfeldt-Jakob disease, kuru, fatal familial insomnia, scrapie, and transmissible spongiform encephalopathies such as bovine spongiform encephalopathy).

[0190] The compounds and compositions disclosed herein are believed to be capable of inhibiting neuronal cell death in diseases such as prion diseases. Generally, the method involves administering a therapeutically effective amount of a compound or composition described herein to a patient in need thereof.

[0191] In some embodiments, the disorder is a neurodegenerative disease. The term "neurodegenerative disease" refers to a disease or condition that impairs the function of a subject's nervous system. Examples of neurodegenerative diseases include, for example, Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spillmeyer-Vocht-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, Levitra, and others. dementia with cerebellar bodies, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined spinal degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, insulin resistance, or tabes dorsalis.

[0192] Other embodiments include therapeutic uses of the presently disclosed compounds, some embodiments include their use in the treatment of neurodegenerative diseases.

[0193] In other embodiments, there are provided compounds of the present disclosure for use in treating Alzheimer's disease, Parkinson's disease, dementia, or ALS.

[0194] In other embodiments, there is provided a use of a compound of the present disclosure for the manufacture of a medicament for treating a neurodegenerative disease.

[0195] In other embodiments, there is provided a use of a compound of the present disclosure for the manufacture of a medicament for treating Alzheimer's disease, Parkinson's disease, dementia, or ALS.

[0196] 4. Kit Also provided herein are kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and suitable packaging materials. In certain embodiments, the kit further comprises instructions for use. In some aspects, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a label and / or instructions for using the compound in treating a condition, including a disease or condition described herein.

[0197] Also provided herein are articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, in a suitable container, which may be a vial, jar, ampoule, preloaded syringe, or infusion bag.

[0198] 5. Pharmaceutical Compositions and Methods of Administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions are also provided herein that include one or more of the compounds described herein, their pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0199] The pharmaceutical compositions may be administered in either a single dose or multiple doses. The pharmaceutical compositions may be administered in a variety of ways, including, for example, rectally, orally, intranasally, and transdermally. In certain embodiments, the pharmaceutical compositions may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0200] One method of administration is parenteral, e.g., by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for injectable administration include, for example, aqueous or oily suspensions or emulsions in sesame, corn, cottonseed, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. .

[0201] Oral administration can be another route of administration for the compounds described herein. Administration can be, for example, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, the active ingredient is typically diluted with an excipient and / or enclosed in a carrier, which can be in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft or hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0202] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations may further include lubricating agents, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweetening agents, and flavoring agents.

[0203] Compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, can be formulated for immediate, sustained, or delayed release of the active ingredient after administration to a subject, using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems, including polymer-coated reservoirs and drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such transdermal patches can be constructed for continuous, pulsatile, or on-demand delivery of drugs.

[0204] For the preparation of solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof. When these preformulation compositions are homogenous, the active ingredient will be evenly dispersed throughout the composition so that the composition may be readily divided into unit dosage forms of equal potency, such as tablets, pills, and capsules.

[0205] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect from the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. These two components may be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for the enteric layer or coating, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0206] Compositions for inhalation or insufflation include solutions, suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized using inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0207] 6. Medication The specific dosage level of the compounds of the present application for a particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general condition, sex, diet, time of administration, route of administration, as well as the excretion rate, co-medications, and severity of the particular disease of the subject being treated. For example, dosages may be expressed in milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Dosages of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, dosages of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages of 0.5 to 60 mg / kg may be appropriate. In some embodiments, dosages of about 0.0001 to about 100 mg of compound per kg body weight per day, about 0.001 to about 50 mg of compound per kg body weight, or about 0.01 to about 10 mg of compound per kg body weight may be appropriate. Standardization according to subject weight is particularly useful when adjusting dosages among subjects of widely differing sizes, as occurs, for example, when using the drug in both human children and adults, or when converting an effective dosage in a non-human subject, such as a dog, to a dosage appropriate for a human subject.

[0208] 7. Compound Synthesis The compounds may be prepared using the methods disclosed herein and routine modifications thereof that become apparent given the disclosure herein and methods well known in the art. Conventional, well-known synthetic methods may be added to the disclosure herein. Synthesis of exemplary compounds described herein may be accomplished as described in the Examples below. Where possible, reagents and starting materials may be obtained commercially, for example, from Sigma Aldrich or other chemical manufacturers.

[0209] It will be understood that where conventional or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0210] In addition, conventional protecting groups may be required to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references cited therein, describe numerous protecting groups.

[0211] Additionally, compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds may be prepared as pure stereoisomers, i.e., individual enantiomers or diastereoisomers. Stereomers or stereoisomer-enriched mixtures can be prepared or isolated. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise specified. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0212] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are commercially available from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chem, or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0213] General Synthesis In certain embodiments, the compound of formula 1-A: [ka] 1-A with a compound of formula 2-A: [ka] 2-A and a compound of formula 3-A: [ka] 3-A and coupling a compound of formula 3-A under ring formation reaction conditions (if L is a ring) or coupling reaction conditions (if L is a heteroalkylene) optionally in combination with reduction to provide a compound of formula R 2 -C(O)H with a suitable reagent in combination with an acid to provide a compound of formula I, wherein R 1 , R 3 , R 4 , R 5 , R 10 ,x, y, z, and ,X 1 is as defined herein, and R 50 is H, -NHNH, or a leaving group, and LG is a leaving group (e.g., C 1-6 Additionally, compounds of formula I where L is heteroalkylene can be prepared by reacting a compound of formula 3A with a compound of formula R (e.g., if L contains O), optionally in combination with a reduction step. 2 Coupling of the -OH with an appropriately functionalized compound can provide:

[0214] The following reaction, shown in Scheme I, illustrates a general method that can be used to synthesize the compounds disclosed herein. In Scheme I, R 1 , R 3 , R 4 , R 5 , R 10 ,x, y, and ,X 1 is as defined herein, and R 50 is H or a leaving group, PG is a protecting group, and LG is a leaving group (C 1-6 alkoxy, or halo). Scheme I [ka]

[0215] Referring to Scheme I, compound 1-2 can be prepared by reacting R 50Compound 1-1, where L is -NHNH, can be prepared by reaction with an appropriately substituted carboxylic acid using a suitable reagent under ring-forming reaction conditions to give oxadiazole 1-2. Deprotection of compound 1-2 gives compound 1-3, which is subsequently coupled with an appropriately substituted compound of formula 1-4 to give compound 1-5. In certain embodiments, compound 1-3 is converted to a salt (e.g., an HCl salt) before coupling with an appropriately substituted compound of formula 1-4. Compounds of formula I, where L is triazole, can be prepared by reaction with R 50 It can be prepared from compound 1-1, where is hydrogen. Compound 1-1 can be deprotected and coupled with compound 1-4 under standard amide bond forming reaction conditions to give compound 1-6.This coupling is typically carried out using a carbodiimide (e.g., N,N'-dicyclohexylcarbodiimide (DCC), N,N'-dicyclopentylcarbodiimide, N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Nt-butyl-N-methylcarbodiimide (BMC), Nt-butyl-N-ethylcarbodiimide (BEC), 1,3-bis(2,2-dimethyl-1,3-diaminopropyl)carbodiimide ( ... oxolan-4-ylmethyl)carbodiimide (BDDC), etc.), anhydrides (e.g., symmetric, mixed, or cyclic anhydrides), activated esters (e.g., phenyl activated ester derivatives, p-hydroxamic acid activated esters, hexafluoroacetone (HFA), etc.), acyl azoles (e.g., acylimidazoles using CDI, acyl benzotriazoles, etc.), acyl azides, acid halides, phosphonium salts (e.g., HOBt, PyBOP, HOAt, etc.), aminium / uronium salts (e.g., tetramethylaminium salts, bispyrrolidinoaminium salts, bispiperidinoaminium salts, imidazolium uronium salts, pyrimidinium uronium salts, uronium salts derived from N,N,N'-trimethyl-N'-phenylurea, morpholino-based aminium / uronium coupling reagents, antimonate uronium salts, etc.), organophosphorus reagents (e.g., phosphinic acid derivatives and phosphoric acid derivatives, propylphosphonic acid derivatives, etc.), An appropriate reagent such as an acid anhydride, an organic sulfur reagent (e.g., a sulfonic acid derivative), a triazine coupling reagent (e.g., 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium chloride, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4 methylmorpholinium tetrafluoroborate, or the like is used. A pyridinium coupling reagent (e.g., Mukaiyama's reagent, pyridinium tetrafluoroborate coupling reagent, or the like) is used (e.g., El-Faham, et al., Chem. Rev., 2011, 111(11):6557-6602; Han, et al., Tetrahedron, 2004, 60:2447-2467).Conversion of compound 1-6 to the acetylene intermediate 1-7 allows for triazole formation using standard click chemistry reaction conditions. Triazole 1-8 can be converted to R under standard coupling reaction conditions. 2 Functionalization with a moiety can provide compounds 1-9.

[0216] The appropriate starting materials and reagents (ie, diamines, esters, and acids) can be purchased or prepared by methods known to those skilled in the art. [Example]

[0217] The following examples illustrate specific embodiments of the present disclosure. Those skilled in the art will understand that the techniques disclosed in the following examples represent fully functional techniques for implementing the present disclosure and can therefore be considered to constitute specific methods for its implementation. However, those skilled in the art will understand in light of the present disclosure that numerous changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0218] General Experimental Methods All solvents used were commercially available and were used without further purification. Reactions were typically carried out under an inert atmosphere of nitrogen using anhydrous solvents.

[0219] NMR spectroscopy: 1 H Nuclear Magnetic Resonance (NMR) spectroscopy was performed on a Bruker Avance III equipped with a BBFO 300 MHz probe operating at 300 MHz, or on the following instruments: a Bruker Avance 400 instrument equipped with the probe DUAL 400 MHz S1. , Probe 6 S1 400MHz 5mm 1 H- 13The NMR studies were carried out using one of the following instruments: a Bruker Avance 400 instrument equipped with a C ID, a Bruker Avance III 400 instrument with a nanobay equipped with a probe Broadband BBFO 5mm Direct, and a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBO probe, all operating at 400 MHz. All deuterated solvents typically contained 0.03%–0.05% v / v tetramethylsilane, which was used as a reference signal ( 1 H, and 13 (δ was set to 0.00 for both δ and C). Unless otherwise noted, measurements were performed at near room temperature with the specified solvent using a Bruker Avance 400 instrument operating at 400 MHz. 1 H nuclear magnetic resonance (NMR) spectroscopy was performed. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in million units using conventional abbreviations for identifying major peaks; e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0220] Thin layer chromatography: When thin-layer chromatography (TLC) was used, it refers to silica gel TLC using silica gel F254 (Merck) plates, and Rf is the distance traveled by the compound divided by the distance traveled by the solvent on the TLC plate. Automated flash chromatography systems were used with silica gel cartridges, or, in the case of reversed-phase chromatography with C18 cartridges, column chromatography was performed. Alternatively, thin-layer chromatography (TLC) was performed on Mancherey-Nagel Alugram® (silica gel 60 F254), and spots were typically visualized using UV. In some cases, additional visualization methods were also used. In these cases, the TLC plates were stained with iodine (approximately 1 g of I2 was added to 10 g of silica gel, followed by thorough mixing), ninhydrin (commercially available from Aldrich), or Magic Stain (25 g (NH4)6Mo7O 24 The compound is visualized by developing a color with 4H2O (prepared by thoroughly mixing 5 g of (NH4)2Ce(IV)(NO3)6 in 450 mL of water and 50 mL of concentrated H2SO4).

[0221] Liquid Chromatography Mass Spectrometry and HPLC Analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system, a photodiode array detector, and a Luna-C18(2) 2.0 × 50 mm, 5 μm column, with a flow rate of 1.2 mL / min. The gradient solvents were: mobile phase A (MPA, HO + 0.037% (v / v) TFA): mobile phase B (MPB, ACN + 0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS was performed at 220 and 254 nm, or with evaporative light scattering (ELSD) detection and positive electrospray ionization (MS). Semi-preparative HPLC was performed under either acidic or neutral conditions. Acidic: Luna C18 100 x 30 mm, 5 μm, MPA:HCl / H2O = 0.04% or formic acid / H2O = 0.2% (v / v), MPB:ACN. Neutral: Waters Xbridge 150 x 25, 5 μm, MPA:10 mM NH4HCO3H2O solution, MPB:ACN. Gradient for both conditions: 10% MPB to 80% MPB for 12 min, flow rate 20 mL / min, then 100% MPB for 2 min, 10% MPB for 2 min, UV detector. SFC analysis was performed on a Thar analytical SFC system with UV / visible detection and a series of chiral columns, including AD-3, AS-H, OJ-3, OD-3, AY-3, and IC-3. The columns were 4.6 × 100 mm, 3 μm columns, and the gradient solvent was: mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.05% (v / v) IPAm) at a flow rate of 4 mL / min (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56–5 min, 10% MPB). SFC preparative analysis was performed on a Thar 80 preparative SFC system with UV / visible detection. The analysis was performed on a 30 × 250 mm, 5 μm column with a series of chiral preparative columns, including AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, at a flow rate of 65 mL / min using a gradient solvent mobile phase A (MPA, CO2):mobile phase B (MPB, MeOH + 0.1% (v / v) NH3HO) (0.01 min: 10% MPB, 5 min: 40% MPB, 6 min: 40% MPB, 6.1–10 min: 10% MPB). LC-MS data were collected using a UPLC-MS Acquity™ system equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer operated in alternating positive and negative electrospray ionization mode. The column used was a Cortecs UPLC C18, 1.6 μm, 2.1 × 50 mm column. A linear gradient starting at 95% A (A: 0.1% formic acid in water) and ending at 95% B (B: MeCN with 0.1% formic acid) was applied over 2.0 min with a total run time of 2.5 min. The column temperature was 40°C and the flow rate was 0.8 mL / min.

[0222] General Procedure A, T3P Coupling: To a flask containing an amine (1 equiv.) and a carboxylic acid (1.5 equiv.) in DMF or EtOAc (0.1 M–0.2 M) was added either N-methylimidazole, diisopropylethylamine, or triethylamine (3.0–5.0 equiv.), followed by T3P solution (1.5–3.0 equiv., 50% in EtOAc). The resulting reaction mixture was stirred at room temperature for 4 h, at which point 1 M NaOH solution was added, followed by EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using silica flash chromatography or reverse-phase HPLC to afford the desired product.

[0223] The following compounds were prepared using General Procedure A and used to prepare compounds disclosed herein: tert-butyl (3-(2-(3,4-difluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate and tert-butyl N-[1-[[2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetyl]amino]-3-bicyclo[1.1.1]pentanyl]carbamate.

[0224] General Procedure B, Hydrazide Formation: To a suspension of the methyl ester (1 equiv.) in EtOH (0.25-0.1 M) was added hydrazine hydrate (3-5 equiv.), and the reaction mixture was heated at 90°C overnight. Upon cooling to room temperature, the product often crystallized from solution. This solid was collected by removing the supernatant. If the product did not crystallize, the solution was concentrated to give the crude product, which was sufficiently pure for use in the next step.

[0225] General Procedure C, Oxadiazole Formation: To a solution of hydrazide (1 equiv.) and carboxylic acid (1.5 equiv.) in EtOAc or MeCN (0.1 M) was added NEt (5 equiv.), followed by T3P solution (3 equiv.). The resulting reaction mixture was heated in a sealed vial at 100 °C overnight. The reaction mixture was diluted with saturated NaHCO3 solution and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase HPLC.

[0226] General Procedure D, Acyl Chlorides: To a flask containing carboxylic acid (1 eq) and DCM (0.1 M-0.2 M) containing DMF (0.05 eq) at 0° C. was added oxalyl chloride (1.2 eq). The resulting reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was used directly.

[0227] Alternatively: A solution of acid (1 equiv.) in SOCl2 (0.5 M) was stirred for 3 h at 85° C. The reaction mixture was concentrated under reduced pressure to give the crude product, which was used directly.

[0228] General Procedure E, α-Bromoketones: To a solution of 1 equiv. of the acyl chloride in 0.1 M MeCN and 0.1 M THF was added 1.5 equiv. of TMSCHN2 in 0.1 M DCM at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. To the mixture was added aqueous HBr (1.1 equiv., 48% solution), at which point H2O was added, followed by EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was either used directly or purified using silica flash chromatography to give the desired product.

[0229] General Procedure F, Alkylation of Bromoketones: To a flask containing a primary amine (1 equiv.) and an α-bromoketone (1 equiv.) in MeCN (0.1 M–0.2 M) was added Na2CO3 (4 equiv.). The resulting reaction mixture was heated at 40 °C for 2 h. The reaction mixture was cooled to room temperature, and H2O was added, followed by EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was either used directly or purified using silica flash chromatography to give the desired product.

[0230] The following compounds were prepared using General Procedure F and used to prepare compounds disclosed herein: N-(3-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(2,4-difluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide acetamide, N-(3-((2-(4-fluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(3-fluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(3-fluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(3,4-difluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide N-(3-((2-(4-chlorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(3-fluoro-4-methylphenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(3-fluoro-4-methylphenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(( 2-(4-chlorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-trans-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(4-fluoro-2-methylphenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, 2-(3,4-difluorophenoxy)-N-(3-((2-oxo-2-(3-(trifluoromethoxy)cyclobutyl) N-(3-((2-(4-chloro-2-fluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclo N-(3-((2-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-((2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, and N-(3-((2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetamide.

[0231] General Procedure G, Formylation: To a solution of AcO (2 equiv.) in formic acid (0.1 M) was added a secondary amine (1 equiv.) in DCM (0.1 M) at 0° C., and the reaction mixture was stirred at 0° C. for 1 h, at which point saturated NaHCO, followed by EtOAc, was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was either used directly or purified using silica flash chromatography to give the desired product.

[0232] The following compounds were prepared using General Procedure G and used to prepare compounds disclosed herein: N-(3-(N-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(2,4-difluorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide cyclobutoxy)acetamide, N-(3-(N-(2-(4-fluorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(3-fluorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(3,4-difluorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide N-(3-(N-(2-(4-chlorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(3-fluoro-4-memylphenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis -(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(4-chlorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-trans-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(4-fluoro-2-methylphenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, 2-(3,4-difluoro tert-butyl (3-((2-(4-chlorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate, N-(3-(N-(2-(4-chloro-2-fluorophenyl)-2-oxoethyl)formamide) )bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(4-fluoro-3-methylphenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2- oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide, N-(3-(N-(2-oxo-2-( 4-(trifluoromethyl)phenyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis(trifluoromethoxy)cyclobutoxy)acetamide, and N-(3-(N-(2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)acetamide.

[0233] General Procedure H, Formic Acid Cyclization: To a solution of tertiary amine (1 equiv.) in AcOH (0.1 M) was added CH3COONH4 (5 equiv.) and the reaction mixture was heated at 110 °C for 15 h, at which point saturated NaHCO3, followed by EtOAc, was added. The layers were separated and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using p-HPLC.

[0234] The following compound was prepared using general procedure H and used to prepare compounds disclosed herein: tert-butyl (3-(4-(4-chlorophenyl)-1H-imidazol-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate.

[0235] Intermediate 1 Methyl 3-[[2-(4-chlorophenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate Prepared using general procedure A using methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid trifluoroacetate (255 mg, 1.0 mmol), 2-(4-chlorophenoxy)acetic acid (224 mg, 1.2 mmol), N-methylimidazole (246 mg, 3.0 mmol), and T3P (382 mg, 1.2 mmol) in DMF (2 mL). LC-MS m / z: = 310.1 [M+H] + . 1 H-NMR (400 MHz, CDCl3) : δ 7.24 - 7.30 (m, 2 H), 6.89 - 6.96 (m, 1 H), 6.81 - 6.88 (m, 2 H), 4.39 (s, 2 H), 3.66 - 3.74 (m, 3 H), 2.36 - 2.47 (m, 6 H).

[0236] Intermediate 2 Methyl 3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate Prepared using general procedure A using methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid trifluoroacetate (1.06 g, 4.14 mmol), 2-(4-chloro-3-fluoro-phenoxy)acetic acid (1.02 g, 4.97 mmol), DIPEA (1.61 g, 12.4 mmol), and T3P (1.58 g, 4.97 mmol) in 8.3 mL of DMF. 1 H-NMR (400 MHz, DMSO-d6): δ ppm 7.33 (t, J = 8.60 Hz, 1 H), 6.84 (br s, 1 H), 6.76 (dd, J = 10.14, 2.87 Hz, 1 H), 6.64 - 6.71 (m, 1 H), 4.40 (s, 2 H), 3.71 (s, 3 H), 2.44 (s, 6 H).

[0237] Intermediate 3 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure B using methyl 3-[[2-(4-chlorophenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (270 mg, 0.87 mmol), hydrazine hydrate (131 mg, 2.6 mmol) in EtOH (3.5 mL). LC-MS m / z: = 310.1 [M+H] + .

[0238] Intermediate 4 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure B using methyl 3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (1.46 g, 4.5 mmol), hydrazine hydrate (669 mg, 13.3 mmol) in EtOH (18 mL). LC-MS m / z: = 328.1 [M+H] + .

[0239] Intermediate 5 tert-Butyl 3-cis-hydroxycyclobutanecarboxylate To a mixture of tert-butyl 3-oxocyclobutanecarboxylate (70.0 g, 411 mmol) in MeOH (700 mL) was added NaBH (15.6 g, 411 mmol) over 2 h at −30 °C under N. The reaction mixture was stirred at −30 °C for 0.5 h. The reaction mixture was quenched by the slow addition of saturated NH Cl (700 mL) on ice over 30 min at 0 °C. The reaction mixture was concentrated under reduced pressure to leave the aqueous phase, which was extracted with EtOAc (3 × 300 mL). The combined organics were washed with saturated brine (300 mL), dried over anhydrous Na SO , filtered, and concentrated. The cis product was isolated as a mixture of diastereomers, with the cis product predominating. 1 H-NMR (400 MHz, CDCl3): δ 4.23-4.04 (m, 1H), 2.79 (br s, 1H), 2.60 -2.43 (m, 3H), 2.14-2.05 (m, 2H), 1.43 (s, 9H).

[0240] tert-Butyl 3-cis-(trifluoromethoxy)cyclobutanecarboxylate To a reaction flask equipped with a stir bar and covered with aluminum foil in a water bath under N2, AgOTf (134.3 g, 523 mmol), Selectfluor (92.6 g, 261 mmol), KF (40.5 g, 697 mmol), and tert-butyl 3-cis-hydroxycyclobutanecarboxylate (30.0 g, 174 mmol) were added. Next, EtOAc (1000 mL), 2-fluoropyridine (50.7 g, 523 mmol), and TMSCF3 (74.3 g, 523 mmol) were added dropwise in succession, while maintaining the internal temperature below 30 °C using a water bath. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered through a plug of silica, and The filtrate was concentrated under reduced pressure. The residue was washed with MTBE (800 mL) and filtered. The filtrate was washed with 1N CuSO (3 x 300 mL), and the organics were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H-NMR (400 MHz, CDCl3): δ 4.60-4.48 (m, 1H), 2.69-2.53 (m, 3H), 2.52-2.37 (m, 2H), 1.46 (s, 9H).

[0241] 3-cis-(trifluoromethoxy)cyclobutanecarboxylic acid To a solution of tert-butyl 3-cis-(trifluoromethoxy)cyclobutanecarboxylate (24.0 g, 100.0 mmol) in DCM (250 mL) was added TFA (77.0 g, 675 mmol). The reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL), washed with HO (3×30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. 1 H-NMR (400 MHz, DMSO-d6): δ 12.39 (s, 1H), 4.74 (quintet, J = 7.44 Hz, 1H), 2.76-2.64 (m, 1H), 2.63-2.53 (m, 2H), 2.33-2.21 (m, 2H).

[0242] Intermediate 6 3-cis-(benzyloxy)cyclobutanol To a mixture of 3-benzyloxycyclobutanone (100.0 g, 567 mmol) in MeOH (1000 mL) was added NaBH (21.5 g, 567 mmol) over 2 h at −30° C. under N. The reaction mixture was stirred at −30° C. for 0.5 h. The reaction mixture was quenched by the slow addition of saturated NH Cl (600 mL) and ice over 0.5 h at 0° C. The reaction mixture was concentrated under reduced pressure to leave the aqueous phase, which was extracted with EtOAc (3×200 mL). The combined organics were washed with saturated brine (200 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give a mixture of diastereomers with the cis product predominating. 1 H-NMR (400 MHz, CDCl3): δ 7.32-7.18 (m, 5H), 4.35 (s, 2H), 3.83 (quintet, J = 7.17 Hz, 1H), 3.56 (quintet, J = 6.95 Hz, 1H), 2.69-2.60 (m, 2H), 1.91-1.82 (m, 2H).

[0243] tert-Butyl 2-(3-cis-(benzyloxy)cyclobutoxy)acetate To a mixture of 3-cis-(benzyloxy)cyclobutanol (19.7 g, 110 mmol), tert-butyl 2-bromoacetate (32.3 g, 165 mmol), tetrabutylammonium hydrogen sulfate (1.9 g, 5.5 mmol), and water (10 mL) in toluene (400 mL) was added NaOH (66.3 g, 1.6 mol) in water (120 mL). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with ice water (120 mL) and extracted with MTBE (3 × 50 mL). The combined organics were washed with saturated brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was used directly. 1 H-NMR (400 MHz, CDCl3): δ 7.39-7.27 (m, 5H), 4.42 (s, 2H), 3.89 (s, 2H), 3.75-3.62 (m, 2H), 2.65 (dtd, J = 9.26, 6.28, 6.28, 3.31 Hz, 2H), 2.09-2.00 (m, 2H), 1.48 (s, 9H).

[0244] tert-Butyl 2-(3-cis-hydroxycyclobutoxy)acetate tert-Butyl 2-(3-cis-(benzyloxy)cyclobutoxy)acetate To a solution of (27.0 g, 92.4 mmol) in MeOH (350 mL) under N was added Pd / C (3.0 g, 10 wt% Pd on carbon). The reaction mixture was degassed under vacuum, purged with H three times, and stirred at 50 °C under H (50 psi) for 12 h. The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to give the crude product, which was used directly. 1 H-NMR (400 MHz, CDCl3): δ 3.94-3.89 (m, 1H), 3.88 (s, 2H), 3.67 (quintet, J = 6.89 Hz, 1H), 2.78-2.69 (m, 2H), 2.01-1.92 (m, 2H), 1.80 (br d, J = 6.39 Hz, 1H), 1.47 (s, 9H).

[0245] tert-Butyl 2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetate To a reaction flask equipped with a stir bar and covered with aluminum foil in a water bath under N2, add AgOTf (57.2 g, 222 mmol), Selectfluor (39.4 g, 111 mmol), KF (17.2 g, 297 mmol), and tert-butyl 2-(3-cis-hydroxycyclobutoxy)acetate (15.0 g, 74.2 mmol) was added. Next, EtOAc (600 mL), 2-fluoropyridine (21.6 g, 222 mmol), and TMSCF (31.6 g, 222 mmol) were added dropwise successively while maintaining the internal temperature below 30 °C using a water bath. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered through a plug of silica, and the filtrate was concentrated under reduced pressure. The residue was washed with MTBE (800 mL) and filtered. The residue was purified by silica gel column chromatography. 1 H-NMR (400 MHz, CDCl3): δ 4.35-4.22 (m, 1H), 3.90 (s, 2H), 3.81-3.69 (m, 1H), 2.86-2.72 (m, 2H), 2.40-2.23 (m, 2H), 1.49 (s, 9H).

[0246] 2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetic acid To a solution of tert-butyl 2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetate (11.5 g, 42.6 mmol) in DCM (100 mL) under N was added TFA (30.8 g, 270 mmol). The reaction mixture was stirred at 40 °C for 2 h and then concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), washed with HO (3 × 30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was used directly. 1 H-NMR (400 MHz, CDCl3): δ 4.26-4.19 (m, 1H), 4.00 (s, 2H), 3.73-3.70 (m, 1H), 2.77-2.74 (m, 2H), 2.27-2.24 (m, 2H).

[0247] Intermediate 7 N-Methoxy-N-methyl-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide To a solution of 2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetic acid (1.6 g, 7.7 mmol) in EtOAc (50 mL) was added N,N-diisopropylethylamine (4.47 mL, 25.7 mmol), followed by T3P (2.4 g, 7.7 mmol, 50% in EtOAc). The resulting reaction mixture was stirred for 10 minutes, and N,O-dimethylhydroxylamine hydrochloride (500 mg, 5.13 mmol) was added. The reaction mixture was stirred at 23 °C for 4 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was sufficiently pure to be used directly. 1 H-NMR (400 MHz; CD Cl3): δ 4.29 (t, J = 7.3 Hz, 1H), 4.21 (s, 2H), 3.83 (td, J = 7.0, 1.1 Hz, 1H), 3.71 (s, 3H), 3.21 (s, 3H), 2.83 (dtd, J = 9.8, 6.6, 3.2 Hz, 2H), 2.38-2.32 (m, 2H).

[0248] 2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetaldehyde To a cooled solution of N-methoxy-N-methyl-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide (100 mg, 0.39 mmol) in THF (3.9 mL) at −78 °C was added diisobutylaluminum hydride (0.78 mL, 0.78 mmol, 1 M in hexanes). The reaction mixture was stirred at −78 °C for 2 h. The reaction was quenched with anhydrous EtOAc (1.0 mL) and saturated NH Cl (3 mL), then removed from the cooling bath and stirred for 15 min. The reaction mixture was then diluted with water (20 mL) and extracted with Et O (3 × 15 mL). The combined organics were dried over Na SO , filtered, and concentrated under reduced pressure. The crude aldehyde was used immediately without further purification.

[0249] Intermediate 8 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine tert-butyl (3-(hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1.0 equiv.) in 2-propanol (1.0 M) at 0 °C was added NH2NH2·H2O (3.0 equiv.) in one portion. The mixture was stirred at 85 °C for 12 h. The reaction mixture was cooled to 25 °C and filtered. The filter cake was washed with 2-propanol and dried under reduced pressure to give the desired product. LC-MS: m / z: 242.1 [M+H] + .

[0250] tert-Butyl (3-(2-(3-cis-(trifluoromethoxy)cyclobutane-1-carbonyl)hydrazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a suspension of 3-cis-(trifluoromethoxy)cyclobutane-1-carboxylic acid (1.1 equiv; cis:trans ratio of 8:1 to 10:1) in anhydrous N,N-dimethylformamide (DMF) (1.1 M) was added dropwise TEA (4.0 equiv) and T3P (2.0 equiv, 50% in EtOAc) at 0°C. The reaction mixture was warmed to 20°C and stirred for 1 hour. The reaction mixture was then cooled to 0°C, and tert-butyl (3-(hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate (275 g, 1.14 mol, 1 equiv) was added portionwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction was quenched by the addition of saturated NaHCO3. The mixture was further stirred at 40° C. for 10 min and immediately filtered. The filter cake was washed with water and dried under reduced pressure at 45° C. The crude product was used directly. LC-MS: m / z: 408.1 [M+H]+ .

[0251] tert-Butyl (3-(5-(3-cis-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl (3-(2-(3-cis-(trifluoromethoxy)cyclobutane-1-carbonyl)hydrazine-1-carbonyl)bicyclo[1.1.1]pentane-1 To a suspension of (-yl)carbamate (1.0 equiv.) in MeCN (0.25 M) at 25 °C was added K2CO3 (powder, 325 mesh, 5.0 equiv.) [Note: CS2CO3 can be used instead of powdered K2CO3], 4 Å molecular sieves (1:1 w / w), and p-toluenesulfonyl chloride (TsCl) (2.5 equiv.). The resulting reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to 25 °C, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in MeCN (0.6 M) at 70 °C, and water (0.4 M) was added to the solution in one portion. The mixture was stirred at 20 °C for 15 min and filtered. The filter cake was washed with water and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in dichloromethane (1 M) at 20 °C, and hexane (0.3 M) was added to the solution in one portion. The mixture was stirred for 30 min and filtered. The filter cake was washed with hexane and dried under reduced pressure to give the desired product. LC-MS: m / z: 390.1 [M+H] + .

[0252] 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine HCl salt To tert-butyl (3-(5-(3-cis-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (1.0 equiv.) was added HCl (20 equiv., 4 M in EtOAc) in one portion at 0° C. The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a diastereomeric mixture of 1-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine, with an 8:1 to 10:1 predominance of 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine. The crude residue was used directly. LC-MS: m / z: 290.0 [M+H] + .

[0253] Intermediate 9 N-(3-ethynylbicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide N-(3-formylbicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide To a solution of N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide (430 mg, 1.39 mmol) in DCM (5.0 mL) at 0° C., DMP (649 mg, 1.53 mmol) was added portionwise. The mixture was warmed to 15° C. and stirred for 12 h. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. 1 H-NMR (400 MHz, CDCl3): δ 9.66 (s, 1H), 6.88 (br s, 1H), 4.37-4.25 (m, 1H), 3.80 (s, 2H), 3.73-3.70 (m, 1H), 2.83-2.80 (m, 2H), 2.40 (s, 6H), 2.30-2.20 (m, 2H).

[0254] N-(3-ethynylbicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide To a solution of N-(3-formylbicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide (240 mg, 0.78 mmol) in MeOH (5.0 mL) was added KCO (324 mg, 2.34 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate at 0 °C. (210 mg, 1.09 mmol) was added and the mixture was warmed to 15° C. and stirred for 4 h. The reaction mixture was diluted with water (10 mL) and concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted with EtOAc (3×5 mL) and the combined organics were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to deliver the title compound. 1 H-NMR (400 MHz, CDCl3): δ 6.80 (br s, 1H), 4.36-4.31 (m, 1H), 3.79 (s, 2H), 3.76-3.65 (m, 1H), 2.83-2.80 (m, 2H), 2.41 (s, 6H), 2.31-2.20 (m, 2H), 2.17 (s, 1H).

[0255] Example 1 2-(4-chlorophenoxy)-N-[3-(5-tetrahydrofuran-3-yl-1,3,4-oxadiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (20 mg, 0.06 mmol), tetrahydro-3-furoic acid (11 mg, 0.1 mmol), NEt (33 mg, 0.32 mmol), and T3P (62 mg, 0.19 mmol) in EtOAc (0.5 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.26-7.22 (m, 2H), 6.97-6.92 (m, 1H), 6.84-6.80 (m, 2H), 4.38-4.34 (m, 2H), 4.12-4.05 (m, 1H), 4.00-3.57 (m, 4H), 2.59-2.47 (m, 6H), 2.36-2.29 (m, 2H). LC-MS: m / z: 390.2 [M+H] + .

[0256] Example 2 2-(4-chlorophenoxy)-N-[3-(5-tetrahydrofuran-2-yl-1,3,4-oxadiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (20 mg, 0.06 mmol), tetrahydro-2-furoic acid (11 mg, 0.1 mmol), NEt (33 mg, 0.32 mmol), and T3P (62 mg, 0.19 mmol) in EtOAc (0.5 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.27-7.23 (m, 2H), 6.95 (s, 1H), 6.85-6.81 (m, 2H), 5.10-5.07 (m, 1H), 4.38 (s, 2H), 4.00-3.89 (m, 2H), 2.61 (s, 6H), 2.35-2.29 (m, 2H), 2.16-1.95 (m, 2H). LC-MS: m / z: 390.2 [M+H] + .

[0257] Example 3 2-(4-Chlorophenoxy)-N-[3-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (200 mg, 0.65 mmol), 3-cis-(trifluoromethoxy)cyclobutanecarboxylic acid (131 mg, 0.71 mmol; 8:1 to 10:1 cis:trans ratio), and triethylamine (NEt) (0.45 mL, 3.23 mmol) were dissolved in 2.6 mL of EtOAc, and To the resulting mixture was added T3P solution (0.58 mL, 1.94 mmol, 50% in EtOAc). The resulting reaction mixture was heated to 100° C. overnight, cooled to room temperature, and diluted with saturated aqueous NaHCO3 solution (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase preparative HPLC to deliver the desired product as a clear oil. 1 H-NMR (400 MHz;CDCl3): δ 7.33-7.29 (m, 2H), 7.03 (s, 1H), 6.91-6.87 (m, 2H), 4.76-4.69 (m, 1H), 4.44 (s, 2H), 3.39-3.30 (m, 1H), 2.92-2.84 (m, 2H), 2.74-2.68 (m, 2H), 2.67 (s, 6H). LC-MS m / z: = 458.20 [M+H] + .

[0258] Alternatively, 2-(4-chlorophenoxy)acetic acid (50 mg, 0.27 mmol), 2-(4-chlorophenoxy)acetic acid (50 mg, 0.27 mmol), NEt (123 mg, 1.21 mmol), and T3P (185 mg, 0.29 mmol, 50% purity) in DCM (1 mL) were stirred at 0 °C for 1 h. To this mixture was added 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine HCl salt (8:1 to 10:1, cis-diastereomer predominant) (70 mg, 0.24 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. Saturated aqueous NaHCO (4 mL) was added to the reaction. The aqueous phase was extracted with DCM (5 mL, 3 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound.

[0259] Example 4 2-(4-chlorophenoxy)-N-[3-[5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (25 mg, 0.08 mmol), 3,3,3-trifluoropropanoic acid (16 mg, 0.12 mmol), ΝEt (41 mg, 0.40 mmol), and T3P (77 mg, 0.24 mmol) in EtOAc (0.8 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.33-7.29 (m, 2H), 7.03 (s, 1H), 6.91-6.87 (m, 2H), 4.45 (s, 2H), 3.77 (q, J = 9.6 Hz, 2H), 2.69 (s, 6H). LC-MS m / z: = 402.11 [M+H] + .

[0260] Example 5 2-(4-chlorophenoxy)-N-[1-[5-(cyclobutoxymethyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chlorophenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (25 mg, 0.08 mmol), 2-(cyclobutoxy)acetic acid (16 mg, 0.12 mmol), NEt (41 mg, 0.40 mmol), and T3P (77 mg, 0.24 mmol) in EtOAc (0.8 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.34-7.30 (m, 2H), 7.01 (s, 1H), 6.91-6.87 (m, 2H), 4.60 (s, 2H), 4.44 (s, 2H), 4.12-4.05 (m, 1H), 2.68 (s, 6H), 2 .28-2.20 (m, 2H), 2.04-1.93 (m, 2H), 1.79-1.70 (m, 1H), 1.57-1.50 (m, 1H). LC-MS m / z: = 404.21 [M+H] + .

[0261] Example 6 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide 3-cis-(trifluoromethoxy)cyclobutanecarboxylic acid (138 mg, 0.75 mmol; 8:1 to 10:1 cis:trans ratio), 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (164 mg, 0.50 mmol), and NEt (0.35 mL, 2.5 mmol) were dissolved in MeCN (4.0 mL), and T3P solution (0.45 mL, 1.5 mmol) was added. The resulting reaction mixture was heated to 100 °C for 72 h. The reaction mixture was diluted with saturated NaHCO3 solution (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography followed by reverse phase HPLC to give the desired product. 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.99 (s, 1H), 6.79 (dd, J = 10.2, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.76-4.69 (m, 1H), 4.44 (s, 2H), 3.39-3.30 (m, 1H), 2.88 (dddt, J = 9.8, 7.3, 4.8, 2.5 Hz, 2H), 2.71-2.66 (m, 8H). LC-MS m / z: = 476.27 [M+H] + .

[0262] Example 7 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(3,3-difluoro-1-methyl-propyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), 4,4-difluoro-2-methyl-butanoic acid (26 mg, 0.18 mmol), NEt (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.79 (dd, J = 10.2, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 6.03 (tdd, J = 56.3, 5.3, 4.0 Hz, 1H), 4.46-4.42 (m, 2H), 3.39-3.30 (m, 1H), 2.67 (s, 6H), 2.50 (ddddd, J = 21.6, 14.6, 13.4, 8.1, 4.0 Hz, 1H), 2.26-2.12 (m, 1H), 1.48 (d, J = 7.1 Hz, 3H). LC-MS m / z: = 430.18 [M+H] + .

[0263] Example 8 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(1-cyclopropylethyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), 2-cyclopropylpropanoic acid (21 mg, 0.18 mmol), )NEt3 (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 mL). 1H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.99 (s, 1H), 6.79 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.44 (s, 2H), 2.66 (s, 6H), 2.34 (dq, J = 9.4, 7.1 Hz, 1H), 1.47 (d, J = 7.1 Hz, 3H), 1.11-1.02 (m, 1H), 0.67-0.53 (m, 2H), 0.40-0.34 (m, 1H), 0.29-0.23 (m, 1H). LC-MS m / z: = 406.27 [M+H] + .

[0264] Example 9 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-[(trans)-2-methylcyclopropyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), trans-2-methylcyclopropanecarboxylic acid (18 mg, 0.18 mmol), NEt (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.81-6.78 (m, 1H), 6.71 (ddd, J = 8.9, 2.8, 1.3 Hz, 1H), 4.44 (s, 2H), 2.63 (s, 6H), 1.85 (dd, J LC-MS m / z: = 392.15 [M+H] + .

[0265] Example 10 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(1-fluorocyclopropyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), 1-fluorocyclopropanecarboxylic acid (19 mg, 0.18 mmol), NEt (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.80 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.45 (s, 2H), 2.70 (s, 6H), 1.68-1.60 (m, 2H), 1.49-1.43 (m, 2H). LC-MS m / z: = 396.2 [M+H] + .

[0266] Example 11 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(cyclopropylmethyl) (ethyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), 2-cyclopropylacetic acid (18 mg, 0.18 mmol), NEt (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.0 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.80 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.44 (s, 2H), 2.76 (d, J = 7.1 Hz, 2H), 2.67 (s, 6H), 1.21-1.11 (m, 1H), 0.66-0.61 (m, 2H), 0.34-0.30 (m, 2H).LC-MS m / z: = 392.2 [M+H] + .

[0267] Example 12 N-[3-[5-(4-chloro-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-2-[cis-3-(trifluoromethoxy)cyclobutoxy]acetamide Step 1: tert-Butyl N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]carbamate Prepared using general procedure B using methyl 3-(tert-butoxycarbonylamino)bicyclo[1.1.1]pentane-1-carboxylate (241 mg, 1.0 mmol), hydrazine hydrate (150 mg, 3.0 mmol) in EtOH (5.0 mL).

[0268] Step 2: tert-butyl N-[1-[5-(4-chloro-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]carbamate Prepared using general procedure C using tert-butyl N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]carbamate (30 mg, 0.12 mmol), 4-chloro-3-fluoro-benzoic acid (33 mg, 0.19 mmol), NEt (63 mg, 0.62 mmol), and T3P (119 mg, 0.37 mmol) in EtOAc (1.2 mL).

[0269] Step 3: 1-[5-(4-chloro-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine; 2,2,2-trifluoroacetic acid tert-Butyl N-[1-[5-(4-chloro-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]carbamate (35 mg, 0.09 mmol) was dissolved in CHCl (0.9 mL) at room temperature, and trifluoroacetic acid (105 mg, 0.92 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated. The crude material was used directly.

[0270] Step 4: N-[3-[5-(4-chloro-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-2-[cis-3-(trifluoromethoxy)cyclobutoxy]acetamide Methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid trifluoroacetate (35 mg, 0.09 mmol), 2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetic acid (23 mg, 0.11 mmol), NEt3 (27 mg, 0.27 mmol), ol) and T3P (34 mg, 0.27 mmol) in EtOAc (0.9 mL) using general procedure A. 1H-NMR (400 MHz; CDCl3): δ 7.86-7.80 (m, 2H), 7.58-7.55 (m, 1H), 6.98 (s, 1H), 4.36 (quintet, J = 7.1 Hz, 1H), 3.86 (s, 2H), 3.75 (quintet, J = 6.8 Hz, 1H), 2.89-2.82 (m, 2H), 2.70 (s, 6H), 2.34-2.26 (m, 2H). LC-MS m / z: = 476.4 [M+H] + .

[0271] Example 13 tert-Butyl 3-[5-[3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-1,3,4-oxadiazol-2-yl]azetidine-1-carboxylate Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), 1-tert-butoxycarbonylazetidine-3-carboxylic acid (37 mg, 0.18 mmol), ΝΕt (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.2 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.80 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.45 (s, 2H), 4.34 (t, J = 8.8 Hz, 2H), 4.27-4.23 (m, 2H), 4.03-3.96 (m, 1H), 2.68 (s, 6H), 1.48 (s, 9H). LC-MS m / z: = 437.2 [M+H -t-Bu]

[0272] Example 14 tert-Butyl 3-[5-[3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylic acid Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (39 mg, 0.18 mmol), ΝΕt (62 mg, 0.61 mmol), and T3P (117 mg, 0.37 mmol) in EtOAc (1.2 mL). 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.97 (s, 1H), 6.79 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.3 Hz, 1H), 4.44 (s, 2H), 3.86-3.80 (m, 1H), 3.67-3.61 (m, 3H), 3.51-3.46 (m, 1H), 2.66 (s, 6H), 2.40-2.25 (m, 2H), 1.49 (s, 9H). LC-MS m / z: = 451.2 [M+H -t-Bu]

[0273] Example 15 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide tert-Butyl 3-[5-[3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-1,3,4-oxo After dissolving 1-hydroxyazol-2-ylazetidine-1-carboxylate (34 mg, 0.07 mmol) in CHCl (0.7 mL) at ambient temperature, the reaction mixture was cooled to 0 °C. Subsequently, trifluoroacetic acid (118 mg, 1.03 mmol) was added dropwise. After 4 h, the reaction was quenched by the addition of saturated NaHCO, and the resulting biphasic reaction mixture was further diluted with saturated NaHCO and CHCl. ​​The layers were separated, and the aqueous layer was extracted with CHCl (3x). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude product was subjected to the next transformation without further purification.

[0274] The crude residue was dissolved in EtOAc (0.9 mL). HO (0.5 mL) and NaHCO (29 mg, 0.34 mmol) were then added sequentially, and the reaction was cooled to 0 °C. 2,2,2-trifluoroethyl trifluoromethanesulfonate (19 mg, 0.08 mmol) was then added dropwise. After 6 h, the reaction mixture was diluted with EtOAc and saturated NaHCO. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase HPLC. 1 H NMR (400 MHz;CDCl3): δ 7.37 (t, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.80 (dd, J = 10.2, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.45 (s, 2H), 4.06-3.94 (m, 3H), 3.65 (t, J = 6.7 Hz, 2H), 3.11 (q, J = 9.3 Hz, 2H), 2.67 (s, 6H). LC-MS m / z: = 475.30 [M+H] + .

[0275] Example 16 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-[1-(2-2,2-trifluoroethyl)pyrrolidin-3-yl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide tert-Butyl 3-[5-[3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate (38 mg, 0.07 mmol) was dissolved in CHCl (0.7 mL) at ambient temperature, and the reaction mixture was cooled to 0 °C. Subsequently, trifluoroacetic acid (128 mg, 1.12 mmol) was added dropwise. After 4 h, the reaction was quenched by the addition of saturated NaHCO, and the resulting biphasic reaction mixture was further diluted with saturated NaHCO and CHCl. ​​The layers were separated, and the aqueous layer was extracted with CHCl (3x). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude product was subjected to the next transformation without further purification.

[0276] The crude residue was dissolved in EtOAc (0.9 mL). HO (0.5 mL) and NaHCO (32 mg, 0.38 mmol) were then added sequentially, and the reaction was cooled to 0 °C. 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.08 mmol) was then added dropwise. After 6 h, the reaction mixture was diluted with EtOAc and saturated NaHCO. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase HPLC. 1 H-NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.80 (dd, J = 10.2, 2.9 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.44 (s, 2H), 3.65 (dq, J = 9.7, 7.2 Hz, 1H), 3.34 (t, J = 8.6 Hz, 1H), 3.18 (dtt, J = 14.3, 9.5, 4.8 Hz, 2H), 3.07 (td, J = 8.4, 5.4 Hz, 1H), 3.00 (dd, J = 9.3, 7.4 Hz, 1H), 2.86 (q, J = 7.7 Hz, 1H), 2.66 (s, 6H), 2.38 (dddd, J = 13.0, 9.7, 7.7, 6.8 Hz, 1H), 2.26 (dddd, J = 13.1, 8.0, 6.4, 5.3 Hz, 1H). LC-MS m / z: = 489.34 [M+H] + .

[0277] Example 17 2-(4-chloro-3-fluoro-phenoxy)-N-[3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-1-bicyclo[1.1.1]pentanyl]acetamide 2-(4-Chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol) was dissolved in EtOAc (1.2 mL) at ambient temperature, followed by the addition of NEt (62 mg, 0.61 mmol) and cyclopropanecarbonyl chloride (19 mg, 0.18 mmol). After 30 min, consumption of the starting material was complete by HPLC analysis, and T3P (233 mg, 0.37 mmol) was added. The resulting reaction mixture was heated in a sealed vial at 100 °C overnight. The reaction mixture was diluted with saturated NaHCO3 solution and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase HPLC. 1 H NMR (400 MHz; CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.95 (s, 1H), 6.79 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.44 (s, 2H), 2.64 (s, 6H), 2.18-2.11 (m, 1H), 1.16 (s, 4H). LC-MS m / z: = 378.24 [M+H] + .

[0278] Example 18 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[5-(2,2-difluorocyclopropyl)-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.12 mmol), 2,2-difluorocyclopropanecarboxylic acid (22 mg, 0.18 mmol), ΝΕt (62 mg, 0.61 mmol), and T3P (233 mg, 0.37 mmol) in EtOAc (1.2 mL). 1 H NMR (400 MHz;CDCl3): δ 7.36 (t, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.80 (dd, J = 10.2, 2.8 Hz, 1H), 6.71 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.45 (s, 2H), 2.95 (ddd, J = 11.5, 10.0, 7.9 Hz, 1H), 2.67 (s, 6H), 2.25 (dtd, J = 12.3, 8.1, 5.4 Hz, 1H), 2.13-2.05 (m, 1H). LC-MS m / z: = 414.12 [M+H] + .

[0279] Examples 19 and 20 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(2-cyclobutyltriazole] 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1-cyclobutyltriazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1-cyclobutyltriazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide Step 1: 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide (900 mg, 3.02 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (813 mg, 4.23 mmol) in MeOH (20 mL) was added KCO (1.25 g, 9.07 mmol) under N at 20 °C. The mixture was stirred at 20 °C for 16 h. The mixture was poured into ice water (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE = 1:0 to 3:1) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.33 (t, J = 8.60 Hz, 1 H), 6.82 (br s, 1 H), 6.75 (dd, J = 10.29, 2.89 Hz, 1 H), 6.67 (ddd, J = 8.88, 2.85, 1.19 Hz, 1 H), 4.38 (s, 2 H), 2.43 - 2.47 (m, 6 H), 2.19 (s, 1 H).

[0280] Step 2: 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1H-triazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide (80 mg, 0.27 mmol) and CuSO (0.4 mg, 0.003 mmol) in t-BuOH (3 mL) and HO (1 mL) was added TMSN (33 mg, 0.29 mmol), benzoic acid (3 mg, 0.027 mmol), and sodium ascorbate (1 mg, 0.005 mmol) under N at 20 °C. The mixture was stirred at 80 °C for 32 h. The mixture was cooled to 20 °C and poured into ice-water (5 mL) and extracted with EtOAc (3 × 2 mL). The combined organic phase was washed with saturated brine (2 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product, 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1H-triazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide, was carried to the next step without further purification. LC-MS m / z: = 337.1 [M+H] + .

[0281] Step 3: 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(2-cyclobutyltriazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1-cyclobutyltriazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1H-triazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide (71 mg, 211 μmol) and bromocyclobutane (43 mg, 316 μmol, 30 μL) in DMF (1 mL) was added CS2CO3 (206 mg, 633 μmol) at 20 °C under N2. The mixture was stirred at 80 °C for 6 h. The mixture was poured into ice water (3 mL) and extracted with EtOAc (3 × 1 mL). The combined organic phase was washed with saturated brine (3 × 1 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(2-cyclobutyltriazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide as the first eluting isomer. 1 H-NMR (400 MHz, CDCl3): δ 7.41 (s, 1 H ), 7.34 (t, J = 8.53 Hz, 1 H), 6.90 (br s, 1 H), 6.79 (dd, J = 10.29, 2.89 Hz, 1 H), 6.71 (br d, J = 9.16 Hz, 1 H), 5.06 (quintet, J = 8.28 Hz, 1 H), 4.42 (s, 2 H), 2.64 - 2.76 (m, 2 H), 2.45 - 2.55 (m, 8 H), 1.82 - 1.98 (m, 2 H). LC-MS m / z: = 391.3 [M+H] + .

[0282] The second eluting isomer is 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1-cyclobutyltriazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide. 1H-NMR (400 MHz, CDCl3): δ 7.42 (s, 1 H), 7.34 (t, J = 8.53 Hz, 1 H), 6.94 (br s, 1 H), 6.78 (dd, J = 10.29, 2.76 Hz, 1 H), 6.70 (br d, J = 8.91 Hz, 1 H), 5.03 (quintet, J = 8.47 Hz, 1 H), 4.43 (s, 2 H), 2.59 (br t, J = 8.66 Hz, 4 H), 2.53 (s, 6 H), 1.90 - 2.02 (m, 2 H). LC-MS m / z: = 391.3 [M+H] + .

[0283] Example 21 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-cyclopentyl-4,5-dihydroisoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)acetamide Step 1: 2-(4-chloro-3-fluoro-phenoxy)-N-[3-(hydroxymethyl)-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of methyl 3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (795 mg, 2.43 mmol) in THF (30 mL) was added LiBH (159 mg, 7.28 mmol) under N at 0 °C, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated NH Cl (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with saturated brine (10 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired product. 1 H-NMR (400 MHz; CDCl3): δ 7.33 (t, J = 8.60 Hz, 1 H), 6.84 (br s, 1 H), 6.77 (dd, J = 10.29, 2.89 Hz, 1 H), 6.68 (ddd, J = 8.88, 2.79, 1.13 Hz, 1 H), 4.39 (s, 2 H), 3.74 (br d, J = 3.76 Hz, 2 H), 2.10 (s, 6 H).

[0284] Step 2: 2-(4-chloro-3-fluorophenoxy)-N-(3-formylbicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanyl]acetamide (450 mg, 1.50 mmol) in anhydrous CHCl (20 mL) was added DMP (669 mg, 1.58 mmol) at 0 °C, and the mixture was stirred at 10 °C for 5 h. The reaction solution was quenched with saturated NaHCO and extracted with CHCl (3 × 10 mL). The organic layers were combined, washed with saturated brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz; CDCl3): δ 9.68 (s, 1 H), 7.32 - 7.36 (m, 1 H), 6.87 (br s, 1 H), 6.75 - 6. 78 (m, 1 H), 6.68 - 6.70 (m, 1 H), 4.40 (s, 2 H), 2.44 (s, 6 H).

[0285] Step 3: (E)-2-(4-chloro-3-fluorophenoxy)-N-(3-((hydroxyimino)methyl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide (500 mg, 1.68 mmol) in EtOH (3 mL) was added NHOH.HCl (210 mg, 3.02 mmol) and NaOAc (234 mg, 2.86 mmol). After the addition, the mixture was stirred at 85 °C for 3 h. The reaction mixture was quenched with saturated NaHCO at 0 °C and concentrated under reduced pressure. The residue was diluted with HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz; CDCl3): δ 7.50 (s, 1 H), 7.34 (t, J = 8.60 Hz, 1 H), 6.85 (br s, 1 H), 6.73 - 6.79 (m, 1 H), 6.64 - 6.71 (m, 1 H), 4.40 (s, 2 H), 2.50 (s, 1 H) 2.34 (s, 4 H). LC-MS m / z: = 313.3 [M+H] + .

[0286] Step 4: (Z)-3-(2-(4-chloro-3-fluorophenoxy)acetamido)-N-hydroxybicyclo[1.1.1]pentane-1-carbimidoyl chloride To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[(E)-hydroxyiminomethyl]-3-bicyclo[1.1.1]pentanyl]acetamide (50 mg, 0.16 mmol) in DMF (1 mL) was added NCS (23 mg, 0.18 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at 20° C. for 1 hour. The mixture was carried on to the next step without further purification.

[0287] Step 5: 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-cyclopentyl-4,5-dihydroisoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of (Z)-3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-N-hydroxy-bicyclo[1.1.1]pentane-1-carboximidoyl chloride (56 mg, 0.16 mmol) in DMF (1 mL) was added dropwise at 0 °C. After the addition, the mixture was stirred at 0 °C for 30 min and then at 20 °C for 30 min. The reaction mixture was quenched with HO (0.2 mL) at 0 °C and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz; CDCl3): δ 7.33 (t, J = 8.60 Hz, 1 H), 6.88 (br s, 1 H), 6.77 (dd, J = 10.25, 2.76 Hz, 1 H), 6.69 (br d, J = 8.82 Hz, 1 H), 4.41 - 4.49 (m, 1 H), 4.40 (s, 2 H), 2.94 (dd, J = 16.87, 10.25 Hz, 1 H), 2.58 (dd, J = 16.76, 8.60 Hz, 1 H), 2.39 (s, 6 H), 2.01 - 2.12 (m, 1 H), 1.76 - 1.90 (m, 1 H), 1.54 - 1.74 (m, 5H) 1.31 - 1.42 (m, 1 H), 1.14 - 1.29 (m, 1 H). LC-MS m / z: = 407.3 [M+H] + .

[0288] Example 22 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-cyclopentylisoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of (Z)-3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-N-hydroxy-bicyclo[1.1.1]pentane-1-carboximidoyl chloride (56 mg, 0.16 mmol) in DMF (1 mL) was added ethynylcyclopentane (18 mg, 0.19 mmol) and NEt (23 mg, 0.22 mmol) dropwise at 0 °C. After the addition, the mixture was stirred at 0 °C for 30 min and then at 20 °C for 30 min. The mixture was placed in a sealed tube and stirred at 70 °C for 11 h. The reaction mixture was quenched with HO (0.2 mL) at 0 °C and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz; CDCl3): δ 7.34 (t, J = 8.60 Hz, 1 H), 6.90 (s, 1 H), 6.78 (dd, J = 10.25, 2.76 Hz, 1 H), 6.66 - 6.73 (m, 1 H), 5.83 (s, 1 H), 4.42 (s, 2 H), 3.12 - 3.22 (m, 1 H), 2.50 (s, 6 H), 2.08 (br d, J = 8.60 Hz, 2 H), 1.64 - 1.83 (m, 6 H). LC-MS m / z: = 405.3 [M+H] + .

[0289] Example 23 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-cyclobutyl-4,5-dihydroisoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)acetamide A solution of (E)-2-(4-chloro-3-fluorophenoxy)-N-(3-((hydroxyimino)methyl)bicyclo[1.1.1]pentan-1-yl)acetamide (50 mg, 0.16 mmol) in dry 1,4-dioxane (5 mL) was added to vinylcyclobutane (131 mg, 1.60 mmol), t-BuOCl (35 mg, 0.32 mmol), NaI (48 mg, 0.32 mmol), and 2,6-lutidine at 20 °C. (0.037 mL, 0.32 mmol) was added and the mixture was stirred at 20° C. for 48 h. The mixture was quenched with saturated NH4Cl (5 mL) and extracted with EtOAc (3×5 mL). The organic layer was washed with saturated brine (5 mL), then dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC to give the desired product. LC-MS m / z: = 393.4 [M+H] + .

[0290] Example 24 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-cyclobutylisoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-cyclobutyl-4,5-dihydroisoxazol-3-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (20 mg, 0.05 mmol) in 1,4-dioxane (3 mL) was added DDQ (23.1 mg, 0.1 mmol) and the reaction was heated to reflux under O for 12 h. The reaction was cooled, filtered through a plug of Celite, and washed with EtOAc (2 x 5 mL). The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz; CDCl3): δ 7.34 (t, J = 8.60 Hz, 1 H), 6.91 (s, 1 H), 6.78 (dd, J = 10.29, 2.76 Hz, 1 H), 6.67 - 6.73 (m, 1 H), 5.88 (s, 1 H), 4.42 (s, 2 H), 3.61 (quintet, J = 8.56 Hz , 1 H), 2.51 (s, 6 H), 2.33 - 2.43 (m, 2 H), 2.20 - 2.32 (m, 2 H), 1.91 - 2.11 (m, 2 H). LC-MS m / z: = 391.3 [M+H] + .

[0291] Example 25 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(5-cyclobutyl-1,3,4-oxadiazol-2-yl)-3-bicyclo[1.1.1]pentanyl]acetamide Prepared using general procedure C using 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (45 mg, 0.14 mmol), cyclobutanecarboxylic acid (17 mg, 0.16 mmol), NEt (56 mg, 0.55), and T3P (87.5 mg, 0.27 mmol) in EtOAc (2 mL). 1 H-NMR (400 MHz, CDCl3): δ 7.34 (t, J = 8.60 Hz, 1 H), 6.98 (s, 1 H), 6.78 (dd, J = 10.23, 2.82 Hz, 1 H), 6.69 (ddd, J = 8.88, 2.79, 1.13 Hz, 1 LC-MS m / z: = 392.3 [M+H] + .

[0292] Example 26 2-(4-chloro-3-fluorophenoxy)-N-(3-(3-cyclobutylisoxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)acetamide Step 1: Cyclobutanecarbaldehyde oxime To a solution of cyclobutanecarbaldehyde (500 mg, 5.94 mmol) in EtOH (20 mL) was added NaOAc (829 mg, 10.1 mmol) and NHOH HCl (744 mg, 10.7 mmol). The mixture was stirred at 80 °C for 5 h. The reaction mixture was diluted with HO (40 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give cyclobutanecarbaldehyde oxime, which was used directly in the next step. 1 H-NMR (400 MHz, CDCl3): δ 1.82 - 1.93 (m, 4 H) 1.95 - 2.03 (m, 5 H) 2.06 - 2.12 (m, 9 H) 2.13 - 2.23 (m, 5 H) 2.24 - 2.33 (m, 2 H) 2.97 - 3.20 (m, 2 H) 3.72 (q, J=7.06 Hz, 1 H) 6.82 (d, J=6.39 Hz, 1 H) 7.50 (d, J=6.39 Hz, 3 H).

[0293] Step 2: N-Hydroxycyclobutanecarbimidoyl chloride To a solution of cyclobutanecarbaldehyde oxime (200 mg, 2.02 mmol) in DMF (8 mL) was added NCS (323 mg, 2.42 mmol) at 0° C. The mixture was stirred at 20° C. for 2 hours. The reaction solution was used directly in the next step.

[0294] Step 3: 2-(4-chloro-3-fluorophenoxy)-N-(3-(3-cyclobutylisoxazol-5-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of N-hydroxycyclobutanecarboximidoyl chloride (73 mg, 0.54 mmol) in DMF (3.5 mL), 2-(4-chloro-3-fluoro- (phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide (80 mg, 0.27 mmol) and ΝΕt (41 mg, 0.41 mmol) were added. The mixture was stirred at 60 °C for 5 hours. After the reaction was complete, the reaction mixture was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 1.83 - 2.06 (m, 2 H) 2.09 - 2.21 (m, 2 H) 2.23 - 2.35 (m, 2 H) 2.46 (s, 6 H) 3.51 (quintet, J=8.38 Hz, 1 H) 4.34 (s, 2 H) 5.89 (s, 1 H) 6.62 (dd, J=8.93, LC-MS m / z: = 391.3 [M+H] + .

[0295] Example 27 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(4-cyclobutyloxazol-2-yl)-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxamide (0.1 g, 0.32 mmol) in DMPU (5 mL) under N was added 2-bromo-1-cyclobutyl-ethanone (113 mg, 0.64 mmol) at 20 °C. The mixture was stirred at 150 °C for 5 h. The mixture was poured into ice water (10 mL). The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with saturated brine (5 × 5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1H-NMR (400 MHz; CDCl3): δ 7.30 - 7.40 (m, 2 H), 6.91 (s, 1 H), 6.78 (dd, J = 10.29, 2.89 Hz, 1 H), 6.66 - 6.72 (m, 1 H), 4.41 (s, 2 H), 3.41 (quintet, J = 8.41 Hz, 1 H), 2.59 (s, 6 H) 2.25 - 2.36 (m, 2 H), 2.08 - 2.20 (m, 2 H), 1.83 - 2.06 (m, 2 H). LC-MS m / z: = 391.3 [M+H] + .

[0296] Example 28 N-[1-[1-(4-chlorophenyl)triazol-4-yl]-3-bicyclo[1.1.1]pentanyl]-2-(cyclobutoxy)acetamide Step 1: Methyl 3-[[2-(cyclobutoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate To a mixture of 2-(cyclobutoxy)acetic acid (967 mg, 7.43 mmol) in CHCl (20 mL) under N was added Tp (6.45 g, 10.13 mmol, 50% in EtOAc) and NEt (3.42 g, 33.78 mmol) at 0 °C under N. After 1 h, methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate HCl salt (1.2 g, 6.76 mmol) was added to the solution at 0 °C, and the mixture was stirred at 20 °C for 15 h. The reaction mixture was adjusted to pH 7-8 with saturated NaHCO and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 6.89 (s, 1 H), 3.91 - 4.02 (m, 1 H), 3.77 (s, 2 H), 3.69 (s, 3 H), 2.47 - 2.48 (m, 1 H), 2.41 (s, 6 H), 2.17 - 2.27 (m, 2 H), 1.88 - 2.01 (m, 2 H), 1.68 - 1.79 (m , 1 H), 1.46 - 1.59 (m, 1 H).

[0297] Step 2: 2-(Cyclobutoxy)-N-[1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of methyl 3-[[2-(cyclobutoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (0.7 g, 2.76 mmol) in THF (20 mL) was added LiBH (120 mg, 5.53 mmol) under N at 0 °C, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated NH Cl (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (50 mL), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE = 100:1 to 0:1) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 6.88 (s, 1 H), 3.90 - 4.04 (m, 1 H), 3.78 (s, 2 H), 3.73 (s, 2 H), 3.22 (s, 1 H), 2.18 - 2.27 (m, 2 H), 2.05 - 2.09 (m, 6 H), 1.86 - 2.01 (m, 2 H), 1.67 - 1.80 (m, 1 H), 1.42 - 1.60 (m, 2 H).

[0298] Step 3: 2-(cyclobutoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide To a mixture of 2-(cyclobutoxy)-N-[1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanyl]acetamide (0.35 g, 1.55 mmol) in CHCl (10 mL) under N was added Dess-Martin reagent (692 mg, 1.63 mmol) at 0 °C, and the mixture was stirred at 20 °C for 4 h. The mixture was adjusted to pH 7-8 with saturated NaHCO. The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was slurried with MTBE, filtered, and the filtrate was concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 9.68 (s, 1 H), 3.87 - 4.13 (m, 1 H), 3.79 (s, 3 H), 2.41 (s, 6 H), 2.22 (s, 3 H), 1.97 (d, J = 7.78 Hz, 3 H), 1.66 - 1.82 (m, 2 H), 1.26 (s, 8 H), 1.20 (s, 5 H).

[0299] Step 4: 2-(cyclobutoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide To a mixture of 2-(cyclobutoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide (300 mg, 1.34 mmol) in MeOH (6 mL) under N was added KCO (557 mg, 4.03 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (361 mg, 1.88 mmol) at 20 °C, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 8 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 6.86 (s, 1 H), 3.96 (quintet, J = 7.22 Hz, 1 H), 3.76 (s, 2 H), 2.41 (s, 6 H), 2.18 - 2.27 (m, 2 H), 2.16 (s, 1 H), 1.88 - 2.00 (m, 2 H), 1.73 (q, J = 10.14 Hz, 1 H), 1.44 - 1.61 (m, 1 H).

[0300] Step 5: N-[1-[1-(4-chlorophenyl)triazol-4-yl]-3-bicyclo[1.1.1]pentanyl]-2-(cyclobutoxy)acetamide To a mixture of 2-(cyclobutoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide (50 mg, 0.23 mmol) and 1-azido-4-chloro-benzene (53 mg, 0.34 mmol) in t-BuOH (1 mL) and HO (2 mL) was added sodium ascorbate (0.9 mg, 0.0046 mmol), benzoic acid (3 mg, 0.023 mmol), and CuSO (364 mg, 0.0023 mmol) at 20 °C, and the mixture was stirred at 80 °C for 5 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.75 (s, 1 H), 7.62 - 7.70 (m, 2 H), 7.45 - 7.54 (m, 2 H), 6.99 (s, 1 H), 3.99 (quintet, J =7.18 Hz, 1 H), 3.81 (s, 2 H), 2.54 (s, 6 H), 2.17 - 2.31 (m, 2 H), 1.89 - 2.06 (m, 2 H), 1.75 (q, J = 10.04 Hz, 1 H), 1.48 - 1.63 (m, 1 H). LC-MS m / z: = 373.3 [M+H] + .

[0301] Example 29 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(3-cyanocyclobutyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (0.07 g, 0.21 mmol) and 3-cyanocyclobutanecarboxylic acid (32 mg, 0.26 mmol) in EtOAc (3 mL) was added T3P (272 mg, 0.43 mmol, 50% of EtOAc) and NEt3 (86 mg, 0.85 mmol) at 20 °C under N2. The mixture was stirred at 80 °C for 16 h. Then, NEt3 (108 mg, 1.07 mmol) and p-TsCl (81 mg, 0.43 mmol) were added to the solution at 20 °C, and the mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz, CDCl3): 7.35 (t, J = 8.60 Hz, 1 H), 7.04 (s, 1 H), 6.79 (dd, J = 10.25, 2.76 Hz, 1 H), 6.66 - 6.73 (m, 1 H), 4.47 (s, 2 H), 3.80 (quintet, J = 9.10 Hz, 1 H), 3.16 - 3.39 (m, 1 H), 2.82 - 2.91 (m, 4 H), 2.64 - 2.71 (m, 6 H). LC-MS m / z: = 417.3 [M+H] + .

[0302] Example 31 2-(4-chloro-3-fluorophenoxy)-N-(3-ethynylbicyclo[1.1.1]pentan-1-yl)acetamide Step 1: 3-Cyanocyclobutyl methanesulfonate To a solution of 3-hydroxycyclobutanecarbonitrile (0.2 g, 2.06 mmol) in CHCl (2 mL) was added MsCl (283 mg, 2.47 mmol) and NEt (312 mg, 3.09 mmol) at 0 °C. The reaction mixture was diluted with CH2Cl2 (60 mL), washed with saturated NaHCO3 (3 x 20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 5.00 - 4.90 (m, 1H), 3.03 (s, 3H), 2.96 - 2.67 (m, 5H).

[0303] Step 2: 2-(4-chloro-3-fluorophenoxy)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of methyl 3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (500 mg, 1.53 mmol) in THF (10 mL) was added LiBH (99 mg, 4.58 mmol) at 0 °C. The mixture was stirred at 20 °C for 20 h. The reaction mixture was quenched with saturated NH Cl (60 mL) at 0 °C and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.33 (t, J = 8.6 Hz, 1H), 6.82 (s, 1H), 6.77 (dd, J = 2.9, 10.4 Hz, 1H), 6.72 - 6.65 (m, 1H), 4.39 (s, 2H), 3.74 (s, 2H), 2.10 (s, 6H). LC-MS m / z: = 300.1 [M+H] + .

[0304] Step 3: 2-(4-chloro-3-fluorophenoxy)-N-(3-formylbicyclo[1.1.1]pentan-1-yl)acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanyl]acetamide (370 mg, 1.23 mmol) in CHCl (10 mL) under N was added DMP (549 mg, 1.30 mmol) at 0 °C. The mixture was stirred at 20 °C for 4 h. The reaction mixture was quenched with saturated NaHCO (60 mL) at 0 °C and extracted with CHCl (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 9.68 (s, 1H), 7.34 (t, J = 8.6 Hz, 1H), 6.90 (br s, 1H), 6.77 (dd, J = 2.8, 10.2 Hz, 1H), 6.68 (ddd, J = 1.2, 2.8, 8.9 Hz, 1H), 4.41 (s, 2H), 2.49 - 2.41 (m, 6H).

[0305] Step 4: 2-(4-chloro-3-fluorophenoxy)-N-(3-ethynylbicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide (450 mg, 1.51 mmol) in MeOH (10 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (406 mg, 2.12 mmol) and K2CO3 (626, 4.53 mmol). The mixture was stirred at 20 °C for 15 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.33 (t, J = 8.7 Hz, 1H), 6.82 (br s, 1H), 6.75 (dd, J = 2.9, 10.3 Hz, 1H), 6.67 (ddd, J = 1.2, 2.8, 8.9 Hz, 1H), 4.38 (s, 2H), 2.49 - 2.39 (m, 6H), 2.19 (s, 1H). LC-MS m / z: = 294.3 [M+H] + .

[0306] Example 32 N-(3-(1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide A mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide (120 mg, 0.408 mmol), TMSN3 (70 mg, 0.612 mmol), sodium ascorbate (0.2 mg, 0.008 mmol), CuSO4 (1 mg, 0.008 mmol), and benzoic acid (5 mg, 0.041 mmol) in t-BuOH (0.5 mL) and HO (1 mL) was stirred at 80 °C under N2 in a pressure vessel for 40 h. HO (60 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz, CD3OD): δ 7.69 (s, 1H), 7.39 (t, J = 8.7 Hz, 1H), 6.95 (dd, J = 2.6, 11.0 Hz, 1H), 6.84 (dd, J = 2.8, 8.9 Hz, 1H), 4.50 (s, 2H), 2.47 (s, 6H). LC-MS m / z: = 337.3 [M+H] + .

[0307] Example 33 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-((trans)-3-cyanocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide A mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1H-triazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 0.118 mmol), cis-(3-cyanocyclobutyl)methanesulfonate (41 mg, 0.13 mmol), and KCO (32 mg, 0.23 mmol) in DMF (2 mL) was stirred in a pressure vessel at 100° C. for 13 h. The mixture was filtered through a pad of Celite and purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.37 - 7.31 (m, 1H), 6.91 (s, 1H), 6.78 (dd, J = 2.8, 10.2 Hz, 1H), 6.74 - 6.67 (m, 1H), 5.43 - 5.29 (m, 1H), 4.42 (s, 2H), 3.44 - 3.32 (m, 1H), 3.14 - 3.03 (m, 2H), 2.99 - 2.90 (m, 2H), 2.50 (s, 6H). LC-MS m / z: = 416.6 [M+H] + .

[0308] Example 34 2-(4-chloro-3-fluorophenoxy)-N-(3-(1-((trans)-3-cyanocyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide Step 1: 3-Azidocyclobutanecarbonitrile A solution of PPh3 (405 mg, 1.54 mmol) and DIAD (312 mg, 1.54 mmol) in THF (3 mL) was stirred at 0 °C for 0.5 h. A solution of 3-hydroxycyclobutanecarbonitrile (100 mg, 1.03 mmol) and DPPA (340 mg, 1.24 mmol) in THF (1 mL) was added dropwise to the solution. The mixture was warmed to 25 °C and then stirred at 25 °C for 15 h. HO (2 mL) was added to the reaction mixture, which was then extracted with EtOAc (2 mL). The combined organic layer was washed with saturated brine (2 mL) to give 3-azidocyclobutanecarbonitrile. A solution of bonitrile in THF (4 mL) and EtOAc (2 mL) was obtained.

[0309] Step 2: 2-(4-chloro-3-fluorophenoxy)-N-(3-(1-((trans)-3-cyanocyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide A mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide (40 mg, 0.13 mmol), sodium ascorbate (1 mg, 0.005 mmol), CuSO (1 mg, 0.002 mmol), benzoic acid (3 mg, 0.03 mmol), and 3-azidocyclobutanecarbonitrile (49 mg, 0.408 mmol, from the above solution in THF and EtOAc) in t-BuOH (0.5 mL) and HO (1 mL) was stirred in a sealed tube at 80 °C for 40 h. HO (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 1:2) to give the crude product, which was purified by preparative HPLC to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.39 - 7.31 (m, 2H), 6.92 (s, 1H), 6.78 (dd, J = 2.9, 10.3 Hz, 1H), 6.70 (td, J = 1.4, 8.9 Hz, 1H), 5.29 - 5.15 (m, 1H), 4.42 (s, 2H), 3.49 - 3.38 (m, 1H), 3.21 - 3.10 (m, 2H), 3.05 - 2.93 (m, 2H), 2.52 (s, 6H). LC-MS m / z: = 416.4 [M+H] + .

[0310] Example 35 2-(4-chloro-3-fluorophenoxy)-N-(3-(1-((cis)-3-cyanocyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide Step 1: 3-Iodocyclobutanecarbonitrile A mixture of (3-cyanocyclobutyl)methanesulfonate (300 mg, 1.71 mmol) and NaI (769 mg, 5.14 mmol) in DMF (2 mL) was stirred at 110° C. for 15 h. HO (60 mL) was added to the reaction mixture, which was then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 3-iodocyclobutanecarbonitrile. 1 H-NMR (400 MHz, CDCl3): δ 4.72 - 4.63 (m, 1H), 4.46 - 4.35 (m, 1H), 3.53 - 3.42 (m, 1H), 3.21 - 3.03 (m, 4H), 3.00 - 2.91 (m, 3H), 2.88 - 2.80 (m, 1H).

[0311] Step 2: 3-Azidocyclobutanecarbonitrile A mixture of 3-iodocyclobutanecarbonitrile (300 mg, 1.45 mmol) and NaN (188 mg, 2.90 mmol) in DMF (2 mL) was stirred under N at 80 °C for 15 h. HO (8 mL) was added to the reaction mixture, which was then extracted with EtOAc (2 × 4 mL). The combined organic layers were washed with saturated brine (2 × 4 mL) to give 3-azidocyclobutanecarbonitrile as a yellow liquid in EtOAc.

[0312] Step 3: 2-(4-chloro-3-fluorophenoxy)-N-(3-(1-((cis)-3-cyanocyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo [1.1.1]pentan-1-yl)acetamide A mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide (60 mg, 0.204 mmol), sodium ascorbate (2 mg, 0.008 mmol), CuSO (1 mg, 0.004 mmol), benzoic acid (5 mg, 0.041 mmol), and 3-azidocyclobutanecarbonitrile (74 mg, 0.612 mmol) in t-BuOH (0.5 mL) and HO (1 mL) was stirred at 80 °C for 40 h in a microwave tube. HO (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was separated by SFC to give the desired product. 1H-NMR (400 MHz, CD3OD): δ 8.80 (s, 1H), 7.97 (s, 1H), 7.38 (t, J = 8.7 Hz, 1H), 6.94 (dd, J = 2.9, 11.0 Hz, 1H), 6.83 (ddd, J = 1.2, 2.9, LC-MS m / z: = 416.4 [M+H] + .

[0313] Example 36 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-((cis)-3-cyanocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide A mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(1H-triazol-4-yl)-3-bicyclo[1.1.1]pentanyl]acetamide (120 mg, 0.35 mmol), 3-iodocyclobutanecarbonitrile (110 mg, 0.53 mmol), and CsCO (348 mg, 1.07 mmol) in DMF (2 mL) was stirred at 80 °C under N for 15 h. HO (30 mL) was added to the mixture, which was then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.35 (t, J = 8.6 Hz, 1H), 6.92 (s, 1H), 6.79 (dd, J = 2.9, 10.3 Hz, 1H), 6.71 (dd, J = 2.3, 8.4 Hz, 1H), 5.12 - 4.97 (m, 1H), 4.43 (s, 2H), 3.20 - 3.07 (m, 2H), 3.05 - 2.91 (m, 3H), 2.51 (s, 6H). LC-MS m / z: = 416.4 [M+H] + .

[0314] Example 37 N-(3-(5-((4-chloro-3-fluorophenoxy)methyl)-4H-1,2,4-triazol-3-yl)bicyclo[1.1.1]pentan-1-yl)-2-cyclobutoxyacetamide Step 1: tert-Butyl 2-cyclobutoxyacetate To a solution of cyclobutanol (20 g, 277 mmol) in THF (400 mL) was added NaH (12.20 g, 305 mmol, 60% purity) under N at 0 °C. The mixture was stirred at 0 °C for 1 h. To the mixture was added tert-butyl 2-bromoacetate (59.5 g, 305 mmol) under N at 0 °C. The mixture was stirred at 20 °C for 4 h. The reaction mixture was quenched with saturated NH Cl (600 mL) at 0 °C and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with saturated brine (300 mL), dried over Na SO , filtered, and It was then concentrated under reduced pressure to give tert-butyl 2-(cyclobutoxy)acetate.

[0315] Step 2: 2-Cyclobutoxyacetic acid To a solution of tert-butyl 2-(cyclobutoxy)acetate (20 g, 107 mmol) in CHCl (300 mL) was added TFA (48.98 g, 429 mmol). The mixture was stirred at 40 °C for 4 h. The reaction mixture was adjusted to pH = 9 with saturated NaHCO at 0 °C and extracted with MTBE (3 × 200 mL). The aqueous layer was adjusted to pH = 3 with 2 M HCl, extracted with EtOAc (3 × 200 mL), washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 2-(cyclobutoxy)acetic acid. 1 H-NMR (400 MHz, CDCl3): δ 4.11 - 4.00 (m, 3H), 2.30 - 2.19 (m, 2H), 2.07 - 1.95 (m, 2H), 1.79 - 1.67 (m, 1H), 1.59 - 1.46 (m, 1H).

[0316] Step 3: Methyl 3-(2-cyclobutoxyacetamido)bicyclo[1.1.1]pentane-1-carboxylate A mixture of 2-(cyclobutoxy)acetic acid (879 mg, 6.76 mmol), T3P (5.37 g, 8.44 mmol, 50% in EtOAc), and NEt3 (2.85 g, 28.2 mmol) in CHCl2 (20 mL) was stirred at 0 °C for 1 h. To the mixture was added methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate, HCl salt (1 g, 5.63 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated NaHCO3 (120 mL) and then extracted with CHCl2 (3 × 40 mL). The combined organic layers were washed with saturated brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:MTBE = 1:0 to 0:1) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 6.89 (s, 1H), 4.01 - 3.92 (m, 1H), 3.77 (s, 2H), 3.71 - 3.68 (m, 3H), 2.41 (s, 6H), 2.27 - 2.17 (m, 2H), 2.00 - 1.87 (m, 2H), 1.78 - 1.69 (m, 1H), 1.59 - 1.46 (m, 1H). LC-MS m / z: = 254.3 [M+H] + .

[0317] Step 4: 2-Cyclobutoxy-N-(3-(hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide To a mixture of methyl 3-[[2-(cyclobutoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (200 mg, 0.79 mmol) in EtOH (5 mL) was added NHNH·H0 (403 mg, 7.90 mmol) at 0 °C. The mixture was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz, CD3OD): δ 3.99 (quintet, J = 7.3 Hz, 1H), 3.77 (s, 2H), 2.31 (s, 6H), 2.25 - 2.17 (m, 2H), 2.01 - 1.90 (m, 2H), 1.71 (q, J = 10.3 Hz, 1H), 1.61 - 1.59 (m, 1H), 1.60 - 1.49 (m, 1H). LC-MS m / z: = 254.3 [M+H] + .

[0318] Step 5: 2-(4-chloro-3-fluorophenoxy)acetimidamide To a mixture of toluene (15 mL) containing NH4Cl (2.30 g, 43.0 mmol) To the resulting solution was added AlMe3 (2.5 M, 8.60 mL). The mixture was stirred at 25 °C for 1 hour. To the mixture was added ethyl 2-(4-chloro-3-fluoro-phenoxy)acetate (1.0 g, 4.30 mmol) in toluene (5 mL). The mixture was stirred at 90 °C for 14 hours. The reaction mixture was quenched with MeOH (60 mL) at 0 °C. After stirring at 20 °C for 2 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in CHCl:MeOH (60 mL, v:v=10:1) and stirred at 25 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz, CD3OD): δ 7.48 - 7.41 (m, 1H), 7.06 - 7.00 (m, 1H), 6.95 - 6.87 (m, 1H), 4.98 (s, 2H). LC-MS m / z: = 203.1 [M+H] + .

[0319] Step 6: N-(3-(5-((4-chloro-3-fluorophenoxy)methyl)-4H-1,2,4-triazol-3-yl)bicyclo[1.1.1]pentan-1-yl)-2-cyclobutoxyacetamide A mixture of 2-(cyclobutoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (50 mg, 0.197 mmol), 2-(4-chloro-3-fluoro-phenoxy)acetamidine (80 mg, 0.394 mmol), and KCO (54.56 mg, 0.394 mmol) in MeOH (3 mL) was stirred at 70 °C for 15 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.31 - 7.27 (m, 1H), 7.25 (d, J = 3.7 Hz, 1H), 6.84 (dd, J = 2.9, 10.6 Hz, 1H), 6.76 (ddd, J = 1.1, 2.8, 8.9 Hz, 1H), 5.17 (s, 2H), 4.05 - 3.98 (m, 1H), 3.92 (s, 2H), 2.70 (s, 6H), 2.29 - 2.22 (m, 2H), 2.03 - 1.94 (m, 2H), 1.77 (br d, J = 9.9 Hz, 1H), 1.62 - 1.53 (m, 1H). LC-MS m / z: = 421.4 [M+H] + .

[0320] Example 38 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(cyclobutylmethyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 0.31 mmol) and 2-cyclobutylacetic acid (42 mg, 0.37 mmol) in EtOAc (5 mL) was added T3P (388 mg, 0.62 mmol, 50% EtOAc) and NEt3 (124 mg, 1.22 mmol) at 20 °C. The mixture was stirred at 80 °C for 16 h. T3P (194 mg, 0.61 mmol, 50% EtOAc) was added and the mixture was stirred at 80 °C for 16 h. The mixture was adjusted to pH 7–8 with saturated NaHCO3. The aqueous phase was extracted with EtOAc (3 × 8 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CDCl3): 7.34 (t, J = 8.60 Hz, 1 H), 6.98 (s, 1 H), 6.77 (dd, J = 10.23, 2.82 Hz, 1 H), 6.69 (ddd, J = 8.85, 2.82, 1.25 Hz, 1 H), 4.43 (s, 2 H), 2.87 - 2.96 (m, 2 H), 2.76 (septet, J = 7.76 Hz, 1 H), 2.63 (s, 6 H), 2.09 - 2.22 (m, 2 H), 1.85 - 1.98 (m, 2 H), 1.74 - 1.84 (m, 2 H). LC-MS m / z: = 406.3 [M+H] + .

[0321] Example 39 2-(4-chloro-3-fluoro-phenoxy)-N-[3-(4-cyclobutylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]acetamide Step 1: 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[(2-cyclobutyl-2-oxo-ethyl)amino]-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of N-(1-amino-3-bicyclo[1.1.1]pentanyl)-2-(4-chloro-3-fluoro-phenoxy)acetamide·HCl (300 mg, 934.07 μmol) and 2-bromo-1-cyclobutyl-ethanone (330 mg, 1.87 mmol) in CH2CN (10 mL) was added Na2CO3 (396 mg, 3.74 mmol) under N2 at 20 °C. The mixture was heated to 40 °C and stirred for 7 h. Water (15 mL) was added to the mixture. The aqueous phase was extracted with EtOAc (3 × 8 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl2:MeOH = 100:0 to 10:1) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.30 - 7.35 (m, 1 H), 6.80 (br s, 1 H), 6.74 - 6.77 (m, 1 H), 6.67 (ddd, J = 8.93, 2.87, 1.21 Hz, 1 H), 4.39 (s, 2 LC-MS m / z: = 381.2 [M+H] + .

[0322] Step 2: 2-(4-chloro-3-fluoro-phenoxy)-N-[3-(4-cyclobutylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]acetamide 2-(4-Chloro-3-fluoro-phenoxy)-N-[1-[(2-cyclobutyl-2-oxo-ethyl)amino]-3-bicyclo[1.1.1]pentanyl]acetamide (40 mg, 105.03 μmol) and NEt (15 mg, 157.55 μmol, 21.93 μL) were placed in a microwave tube containing formamide (6.78 g, 150.53 mmol, 6.00 mL) under N. The sealed tube was heated in a microwave at 100 °C for 30 minutes. The reaction was purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 8.96 (d, J = 1.54 Hz, 1 H), 7.54 - 7.57 (m, 1 H), 7.39 (t, J = 8.71 Hz, 1 H), 6.95 (dd, J = 11.03, 2.87 Hz, 1 H), 6.84 (ddd, J = 8.99, 2.92, 1.32 Hz, 1 H), 4.54 (s, 2 H), 3.61 (quintet, J = 8.54 Hz, 1 H), 2.71 (s, 6 H), 2.38 - 2.47 (m, 2 H), 2.08 - 2.28 (m, 3 H), 1.92 - 2.02 (m, 1 H). LC-MS m / z: = 390.4 [M+H] + .

[0323] Example 40 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(5-methyl-1,3,4 -oxadiazol-2-yl)-3-bicyclo[1.1.1]pentanyl]acetamide Step 1: N-[1-(acetamidocarbamoyl)-3-bicyclo[1.1.1]pentanyl]-2-(4-chloro-3-fluoro-phenoxy)acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 0.31 mmol) and acetic acid (22 mg, 0.37 mmol) in EtOAc (3 mL) at 20 °C, T3P (388 mg, 0.62 mmol, 50% of EtOAc) and NEt3 (124 mg, 1.22 mmol) were added, and the mixture was stirred at 80 °C for 16 h. The mixture was adjusted to pH 7-8 with saturated NaHCO3. The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the desired product. LC-MS m / z: = 370.1 [M+H] + .

[0324] Step 2: 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(5-methyl-1,3,4-oxadiazol-2-yl)-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of N-[1-(acetamidocarbamoyl)-3-bicyclo[1.1.1]pentanyl]-2-(4-chloro-3-fluoro-phenoxy)acetamide (90 mg, 0.24 mmol) in CHCl (3 mL) was added ΝΕt (99 mg, 0.97 mmol) and p-TsCl (93 mg, 0.49 mmol) at 25 °C, and the mixture was stirred at 25 °C for 16 h. The mixture was adjusted to pH 7-8 with saturated NaHCO and concentrated. The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CDCl3): 7.34 (t, J = 8.60 Hz, 1 H), 7.01 (s, 1 H), 6.77 (dd, J = 10.14, 2.87 Hz, 1 H), 6.69 (dt, J = 8.93, 1.27 Hz, 1 H), 4.43 (s, 2 LC-MS m / z: = 352.3 [M+H] + .

[0325] Example 41 N-[1-[5-[(4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]-2-cis-[3-(trifluoromethoxy)cyclobutoxy]acetamide Step 1: 3-(tert-butoxycarbonylamino)bicyclo[1.1.1]pentane-1-carboxylic acid To a mixture of methyl 3-(tert-butoxycarbonylamino)bicyclo[1.1.1]pentane-1-carboxylate (500 mg, 2.07 mmol) in THF (10 mL) and water (2 mL) was added LiOH·HO (173 mg, 4.14 mmol) under N at 25 °C. The mixture was stirred at 25 °C for 12 h. Water (10 mL) was added to the mixture. The aqueous phase was extracted with MTBE (5 mL). The combined organic phase was adjusted to pH = 2 with HCl (2 M) and extracted with CHCl:MeOH (3 × 10 mL, v:v = 3:1), washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product. 1 H-NMR (400 MHz, DMSO-d6): δ 7.54 (s, 1 H), 2.05 (s, 6 H), 1.34 (s, 9 H).

[0326] Step 2: tert-Butyl N-[1-[[[2-(4-chloro-3-fluoro- (Phenoxy)acetyl]amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]carbamate To a mixture of 3-(tert-butoxycarbonylamino)bicyclo[1.1.1]pentane-1-carboxylic acid (50 mg, 0.22 mmol) and 2-(4-chloro-3-fluoro-phenoxy)acetohydrazide (48 mg, 0.22 mmol) in EtOAc (5 mL) under N was added T3P (420 mg, 0.66 mmol, 50% of EtOAc) and NEt3 (89 mg, 0.88 mmol) at 20 °C. The mixture was stirred at 80 °C for 12 h. The mixture was poured into aqueous NaHO3 (10 mL). The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product.

[0327] Step 3: tert-Butyl N-[1-[5-[(4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]carbamate To a mixture of tert-butyl N-[1-[[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]carbamate (94 mg, 0.22 mmol) and NEt (89 mg, 0.88 mmol) in CHCl (5 mL) was added p-TsCl (83 mg, 0.44 mmol) under N at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into aqueous NaHCO (10 mL). The aqueous phase was extracted with CHCl (3 × 5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE=100:1 to 0:1) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.32 (t, J = 8.60 Hz, 1 H), 6.85 (dd, J = 10.36, 2.87 Hz, 1 H), 6.75 - 6.81 (m, 1 H), 5.20 (s, 2 H), 5.05 (s, 1 H), 2.53 (s, 6 H), 1.47 (s, 9 H).

[0328] Step 5: 1-[5-[(4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine A mixture of tert-butyl N-[1-[5-[(4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]carbamate (64 mg, 0.16 mmol) in HCl / EtOAc (5 mL) was stirred for 3 h at 25° C. The mixture was concentrated under reduced pressure at 40° C. to give the desired product as the HCl salt.

[0329] Step 6: N-[1-[5-[(4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]-2-cis-[3-(trifluoromethoxy)cyclobutoxy]acetamide To a mixture of cis-2-[3-(trifluoromethoxy)cyclobutoxy]acetic acid (44 mg, 0.2 mmol) and 1-[5-[(4-chloro-3-fluoro-phenoxy)methyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine (53 mg, 0.15 mmol, HCl) in DMF (5 mL) was added HATU (117 mg, 0.31 mmol) and DIEA (132 mg, 1.03 mmol) under N at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into ice water (20 mL). The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with saturated brine (4 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3) Purification by HPLC gave the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.32 (t, J = 8.66 Hz, 1 H), 6.92 (s, 1 H), 6.86 (dd, J = 10.29, 2.51 Hz, 1 H), 6.79 (d, J = 8.66 Hz, 1 H), 5.21 (s, 2 H), 4.34 (t, J = 7.03 Hz, 1 H), 3.83 (s, 2 H), 3.65 - 3.77 (m, 1 H), 2.83 (dd, J = 6.84, 3.20 Hz, 2 H), 2.65 (s, 6 H), 2.28 (d, J = 6.53 Hz, 2 H). LC-MS m / z: = 506.4 [M+H] + .

[0330] Example 42 N-[1-[[(4-chloro-3-fluoro-benzoyl)amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]-2-(cyclobutoxy)acetamide To a solution of 4-chloro-3-fluorobenzoic acid (83 mg, 0.474 mmol) in EtOAc (3 mL) was added EtN (160 mg, 1.58 mmol), T3P (502 mg, 0.79 mmol, 50% of EtOAc), and 2-(cyclobutoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 0.395 mmol). After addition, the mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to give the desired product. LC-MS m / z: = 410.2 [M+H] + .

[0331] N-[1-[5-(4-chloro-3-fluoro-phenyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]-2-(cyclobutoxy)acetamide To N-[1-[[(4-chloro-3-fluoro-benzoyl)amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]-2-(cyclobutoxy)acetamide (130 mg, 0.317 mmol) in CHCl (2 mL) was added ETN (128.39 mg, 1.27 mmol) and TsCl (121 mg, 0.634 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was diluted with HO (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with 10 mL of brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.77 - 7.86 (m, 2 H), 7.55 (t, J = 7.78 Hz, 1 H), 7.05 (s, 1 H), 3.99 (quintet, J = 7.25 Hz, 1 H), 3.82 (s, 2 H), 2.68 (s, 6 H), 2.19 - 2.30 (m, 2 H), 1.90 - 2.05 (m, 4 H), 1.75 (q, J = 10.29 Hz, 1 H), 1.48 - 1.62 (m, 1 H). LC-MS m / z: = 392.3 [M+H] + .

[0332] Example 43 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-((cis)-3-(trifluoromethyl)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 0.31 mmol) and cis-3-(trifluoromethyl)cyclobutanecarboxylic acid (62 mg, 0.37 mmol) in EtOAc (3 mL) in a sealed tube was added T3P (388 mg, 0.61 mmol, 50% of EtOAc) and NEt (123 mg, 1.22 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was diluted with saturated NaHCO (10 mL) at 0 °C and then extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine (3 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-((cis)-3-(trifluoromethyl)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide. The crude product was used in the next step without further purification.

[0333] A mixture of 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-((cis)-3-(trifluoromethyl)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide (150 mg, 0.31 mmol), 4-methylbenzenesulfonyl chloride (120 mg, 0.63 mmol), and NEt (127 mg, 1.26 mmol) in CHCl (5 mL) was stirred at 25 °C for 16 h under a N atmosphere. The reaction mixture was quenched with HO (10 mL) at 0 °C and then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CD3OD): δ 7.38 (t, J = 8.71 Hz, 1 H), 6.94 (dd, J = 11.03, 2.87 Hz, 1 H), 6.83 (ddd, J = 8.93, 2.87, 1.21 Hz, 1 H), 4.50 (s, 2 H), 3.78 (quintet, J = 9.10 Hz, 1 H), 3.15 - 3.28 (m, 1 H), 2.46 - 2.70 (m, 10 H). LC-MS m / z: = 460.4 [M+H] + .

[0334] Example 44 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-trans]-[3-(trifluoromethyl)cyclobutyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 0.31 mmol) and tran-3-(trifluoromethyl)cyclobutanecarboxylic acid (62 mg, 0.37 mmol) in EtOAc (3 mL) was added T3P (388 mg, 0.61 mmol, 50% of EtOAc) and NEt3 (124 mg, 1.22 mmol) at 25 °C, and the mixture was stirred at 80 °C for 16 h. The mixture was adjusted to pH 7–8 with saturated NaHCO3. The aqueous phase was extracted with EtOAc (4 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[[[3-(trifluoromethyl)cyclobutanecarbonyl]amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]acetamide.

[0335] To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[[[trans-3-(trifluoromethyl)cyclobutanecarbonyl]amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]acetamide (130 mg, 0.27 mmol) in CHCl (5 mL) was added NEt (110 mg, 1.09 mmol) and p-TsCl (104 mg, 0.54 mmol) at 25 °C, and the mixture was stirred at 25 °C for 16 h. The mixture was adjusted to pH 7-8 with saturated NaHCO. The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CD3OD): δ 7.38 (t, J = 8.78 Hz, 1 H), 6.94 (dd, J = 10.92, 2.76 Hz, 1 H), 6.77 - 6.86 (m, 1 H), 4.50 (s, 2 H), 3.84 (quintet, J = 8.03 Hz, 1 H), 3.16 - 3.28 (m, 1 H), 2.67 (t, J = 7.91 Hz, 4 H), 2.59 (s, 6 H). LC-MS m / z: = 460.4 [M+H] + .

[0336] Example 45 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(trifluoromethoxymethyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide Step 1: 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[[[2-(trifluoromethoxy)acetyl]amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 305.12 μmol) and 2-(trifluoromethoxy)acetic acid (52 mg, 366.15 μmol) in EtOAc (3 mL) under N was added T3P (388 mg, 610.24 μmol, 362.93 μL, 50% of EtOAc) and Et3N (123 mg, 1.22 mmol, 169.88 μL) at 25 °C under N2. The mixture was heated to 80 °C and stirred for 15 h. The mixture was quenched with saturated NaHCO3 (5 mL). The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 8.46 (br s, 2 H), 7.31 - 7.37 (m, 1 H), 6.91 (s, 1 H), 6.77 (dd, J = 10.16, 2.76 Hz, 1 H), 6.69 (dd, J = 9.03, 1.76 Hz, 1 H), 4.62 (s, 2 H), 4.58 (s, 2 H), 4.38 - 4.44 (m, 2 H), 2.45 - 2.53 (m, 6 H). LC-MS m / z: = 454.1 [M+H] + .

[0337] Step 2: 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[5-(trifluoromethoxymethyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide To a mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[[[2-(trifluoromethoxy)acetyl]amino]carbamoyl]-3-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 220.37 μmol) in CHCl (5 mL) under N was added NEt (89 mg, 882 μmol) and 4-methylbenzenesulfonyl chloride (84 mg, 441 μmol) at 25 °C, and the reaction was stirred for 15 h. The mixture was quenched with saturated NaHCO. The aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the desired product. 1 H-NMR (400 MHz, CDCl3): δ 7.35 (t, J = 8.53 Hz, 1 H), 6.97 (s, 1 H), 6.78 (dd, J = 10.23, 2.82 Hz, 1 H), 6.70 (dd, J = 8.85, 1.69 Hz, 1 H), 5.16 (s, 2 H), 4.43 (s, 2 H), 2.69 (s, 6 H). LC-MS m / z: = 436.3 [M+H] + .

[0338] Examples 46 to 48 The following examples shown in Table 1 were synthesized using procedures similar to those previously described. [Table 4]

[0339] Example 49 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-(3-(trifluoromethoxy)propyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)acetamide Benzyl 4-(trifluoromethoxy)butanoate To a solution of AgOTf (2.65 g, 10.30 mmol) in EtOAc (25 mL) under N2, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (2.74 g, 7.72 mmol), KF (897 mg, 15.5 mmol), and benzyl 4-hydroxybutanoate (1.0 g, 5.15 mmol) were placed in a foil-wrapped flask. 2-Fluoropyridine (1.00 g, 10.3 mmol) and trimethyl(trifluoromethyl)silane (1.46 g, 10.3 mmol) were added, and the reaction mixture was stirred at 25 °C for 12 h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography. 1 H NMR (400 MHz, MeOD): δ 7.47-7.29 (m, 5H), 5.15 (s, 2H), 4.03 (t, J = 6.1 Hz, 2H), 2.52 (t, J = 7.3 Hz, 2H), 2.05 (quintet, J = 6.7 Hz, 2H).

[0340] 4-(trifluoromethoxy)butanehydrazide To a solution of benzyl 4-(trifluoromethoxy)butanoate (200 mg, 0.76 mmol) in 1,4-dioxane (8 mL) was added hydrazine hydrate (0.38 mL, 7.63 mmol), and the solution was heated to 80° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue that was used directly. LC-MS: m / z: 187.1 [M+H] + .

[0341] 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(4-(trifluoromethoxy)butanoyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 4-(trifluoromethoxy)butanehydrazide (120 mg, 0.64 mmol) in THF (5 mL) was added 3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid (182 mg, 0.58 mmol), HATU (270 mg, 0.71 mmol), and DIEA (0.34 mL, 1.93 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative TLC. LC-MS: m / z: 482.3 [M+H] + .

[0342] 2-(4-chloro-3-fluorophenoxy)-N-(3-(5-(3-(trifluoromethoxy)propyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a mixture of 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(4-(trifluoromethoxy)butanoyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide (120 mg, 0.25 mmol) in DCM (6 mL) was added NEt (0.14 mL, 0.10 mmol) and TsCl (95 mg, 0.50 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into ice water (6 mL) and extracted with DCM (3 × 6 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC to give the title compound. LC-MS: m / z: 464.3 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.35 (t, J = 8.60 Hz, 1H), 6.94 (s, 1H), 6.78 (dd, J = 10.25, 2.76 Hz, 1H), 6.70 (dt, J = 8.88, 1.41 Hz, 1H), 4.43 (s, 2H), 4.11 (t, J = 5.95 Hz, 2H), 2.98 (t, J = 7.39 Hz, 2H), 2.65 (s, 6H), 2.23 (quintet, J = 6.73 Hz, 2H).

[0343] Examples 50 to 60 The following examples shown in Table 1 were synthesized using procedures similar to those previously described. [Table 5]

[0344] Examples 61 and 62 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[3-trans-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide cis-3-(trifluoromethoxy)cyclobutanecarbonyl chloride To a solution of 3-cis-(trifluoromethoxy)cyclobutanecarboxylic acid (2.0 g, 10.9 mmol, 8:1 to 10:1 cis:trans ratio) and DMF (79 mg, 1.1 mmol) in DCM (30 mL) was added (COCl) (4.14 g, 32.6 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The solution was concentrated under reduced pressure to give 3-cis-(trifluoromethoxy)cyclobutanecarbonyl chloride as a mixture of diastereomers with the cis-configuration predominating, which was carried on to the next step without further purification.

[0345] 2-Bromo-1-(3-cis-(trifluoromethoxy)cyclobutyl)ethanone To a solution of 3-cis-(trifluoromethoxy)cyclobutanecarbonyl chloride (2.5 g, 12.3 mmol) in CHCN (20 mL) and THF (20 mL) at 0° C., TMSCHN (2 M, 6.17 mL) was added dropwise over 10 min. The resulting reaction mixture was stirred at 0° C. for 20 min and then at 25° C. for 1 h. HBr (7.5 g, 37.0 mmol, 5.0 mL, 40% in water) was added dropwise at 0° C., and the mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with HO (50 mL) at 0° C. and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-bromo-1-(3-cis-(trifluoromethoxy)cyclobutyl)ethanone as a mixture of diastereomers with the cis configuration predominating, which was used directly without further purification. 1 H-NMR (400 MHz, CDCl3): δ 4.78 - 4.86 (m, 0.2 H), 4.57 - 4.70 (m, 1 H), 4.07 - 4.11 (m, 1 H), 3.86 - 3.94 (m, 1 H), 3.10 - 3.26 (m, 1 H), 2.59 - 2.71 (m, 2 H), 2.43 - 2.58 (m, 2 H).

[0346] 2-(4-chloro-3-fluorophenoxy)-N-(3-((2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of N-(1-amino-3-bicyclo[1.1.1]pentanyl)-2-(4-chloro-3-fluoro-phenoxy)acetamide HCl salt (1.2 g, 3.74 mmol) and 2-bromo-1-(3-cis-(trifluoromethoxy)cyclobutyl)ethanone (1.95 g, 7.47 mmol) in CHCN (20 mL) was added NaCO (1.58 g, 14.95 mmol). The mixture was stirred at 40 °C for 7 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with HO (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with saturated brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(4-chloro-3-fluorophenoxy)-N-(3-((2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)acetamide (as a mixture of diastereomers in a ratio of approximately 5:1, with the cis configuration predominating). The product was used directly in the next step. LC-MS m / z = 465.3 [M+H] + .

[0347] 2-(4-chloro-3-fluorophenoxy)-N-(3-(N-(2-oxo-2-(cis-3-(trifluoromethoxy)cyclobutyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of formic acid (4.88 g, 106 mmol, 4 mL) was added AcO (703 mg, 6.88 mmol) at 0 °C, followed by a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-((2-oxo-2-(cis-3-(trifluoromethoxy)cyclobutyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)acetamide (0.8 g, 1.72 mmol) in DCM (4 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and the pH was adjusted to 8-9 with saturated NaHCO3 (20 mL) at 0 °C, followed by HCl (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(4-chloro-3-fluorophenoxy)-N-(3-(N-(2-oxo-2-(cis-3-(trifluoromethoxy)cyclobutyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)acetamide as a mixture of diastereomers with the cis configuration predominating. This material was used in the next step without further purification. LC-MS m / z = 493.3 [M+H] + .

[0348] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[3-trans-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-(N-(2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)acetamide (0.78 g, 1.58 mmol) in CHCOOH (8 mL) was added CHCOONH (476 mg, 6.17 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with aqueous NaHCO (50 mL) at 0 °C and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Nano-micro Kromasil C18 100 mm × 30 mm, 5 μm; mobile phase: A: water with 0.1% TFA, B: MeCN, gradient: % B in A: 30% to 55% in 10 min) to provide a 3:1 mixture of diastereomers. This material was further purified by SFC. SFC conditions: Chiralcel OJ 250 mm × 30 mm, 10 μm; mobile phase: A: CO2, B: MeOH with 0.1% NH4OH, gradient: % B in A: 17% to 17% in 4 min).

[0349] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide: 1 H-NMR (400 MHz, MeOD): δ 7.99 (d, J = 0.88 Hz, 1 H), 7.39 (t, J = 8.71 Hz, 1 H), 7.18 (d, J = 0.66 Hz, 1 H), 6.95 (dd, J = 11.03, 2.87 Hz, 1 H), 6.84 (ddd, J = 8.99, 2.81, 1.21 Hz, 1 H), 4.73 (quintet, J = 7.50 Hz, 1 H), 4.52 (s, 2 H), 3.10 (tt, J = 10.12, 7.63 Hz, 1 LC-MS m / z: = 474.1 [M+H] +

[0350] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[3-trans-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide: 1 H-NMR (400 MHz, MeOD): δ 7.92 (d, J=0.88 Hz, 1 H), 7.39 (t, J = 8.71 Hz, 1 H), 7.19 (s, 1 H), 6.95 (dd, J = 10.80, 2.87 Hz, 1 H), 6.84 (ddd, J = 8.93, 2.87, 1.21 Hz, 1 H), 4.98 (quintet, J = 6.78 Hz, 1 H), 4.52 (s, 2 H), 3.48 - 3.58 (m, 1 H), 2.63 - 2.70 (m, 2 H), 2.62 (s, 6 H), 2.50 - 2.58 (m, 2 H). LC-MS m / z: = 474.1 [M+H] +

[0351] Example 63 2-[3-cis-(trifluoromethoxy)cyclobutoxy]-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide tert-Butyl (3-(2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of 2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetic acid (1.00 g, 4.67 mmol) in DMF (10 mL) was added tert-butyl 2-(2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetic acid at 20 °C. N-(1-amino-3-bicyclo[1.1.1]pentanyl)carbamate (926 mg, 4.67 mmol), HATU (1.95 g, 5.14 mmol), and DIEA (2.44 mL, 14.0 mmol) were added. The mixture was then stirred at 20 °C for 2 h. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography. 1 H-NMR (400 MHz, CDCl3): δ 6.81 (br s, 1H), 4.31 (quintet, J = 7.2 Hz, 1H), 3.79 (s, 2H), 3.70 (quintet, J = 6.9 Hz, 1H), 2.90 - 2.86 (m, 1H), 2.84 - 2.80 (m, 2H), 2.35 (br s, 6H), 2.30 - 2.19 (m, 2H), 1.44 (s, 9H).

[0352] N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide HCl salt To a solution of tert-butyl (3-(2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)carbamate (500 mg, 1.27 mmol) in EtOAc (10 mL) was added EtOAc / HCl (10 mL, 4 M) and the reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that was used directly. LC-MS: m / z = 295.1 [M+H] + .

[0353] N-(3-((2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide To a mixture of 2-bromo-1-(3-cis-(trifluoromethoxy)cyclobutyl)ethanone (1.04 g, 3.99 mmol; 8:1 to 10:1 cis:trans ratio), N-(3-aminobicyclo[1.1.1]pentan-1-yl)-2-(cis-3-(trifluoromethoxy)cyclobutoxy)acetamide HCl salt (1.2 g, 3.63 mmol) in CHCN (10 mL) was added NaCO (1.54 g, 14.51 mmol), and the mixture was stirred at 40 °C for 15 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography to deliver the desired compound. LC-MS: m / z = 475.2 [M+H] + .

[0354] N-(3-(N-(2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(cis-3-(trifluoromethoxy)cyclobutoxy)acetamide Formic acid (3.2 mL, 84 mmol) was dissolved in HCl (630 μL, 6.75 mmol) at 0 °C. ol) was added dropwise. After the addition, N-(3-((2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide (800 mg, 1.69 mmol) in DCM (2 mL) was added dropwise to the reaction mixture at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with aqueous NaHCO (10 mL) at 0 °C, adjusted to pH = 8-9, and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired compound. LC-MS: m / z = 503.2 [M+H] + .

[0355] 2-[3-cis-(trifluoromethoxy)cyclobutoxy]-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of N-(3-(N-(2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-3-cis-(trifluoromethoxy)cyclobutoxy)acetamide (800 mg, 1.59 mmol) in AcOH (8 mL) was added ammonium acetate (491 mg, 6.37 mmol), and the reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was diluted with aqueous NaHCO (20 mL) at 0 °C, adjusted to pH 8-9, and extracted with EtOAc (3 × 12 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC. 1 H-NMR (400 MHz, CDCl3): δ 7.40 (s, 1H), 6.93 (s, 1H), 6.70 (s, 1H), 4.62 (quintet, J = 7.6 Hz, 1H), 4.34 (quintet, J = 7.2 Hz, 1H), 3.84 (s, 2H), 3.73 (quintet, J = 6.9 Hz, 1H), 3.07 - 2.95 (m, 1H), 2.89 - 2.81 (m, 2H), 2.77 - 2.69 (m, 2H), 2.59 (s, 6H), 2.47 - 2.38 (m, 2H), 2.31 - 2.24 (m, 2H). LC-MS: m / z = 484.4 [M+H] + .

[0356] Examples 64 and 65 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[1-[3-trans-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[1-[3-cis-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide ((3-iodocyclobutoxy)methyl)benzene A mixture of (3-cis-benzyloxycyclobutyl)methanesulfonate (1.0 g, 3.90 mmol) and NaI (1.75 g, 11.7 mmol) in MeCN (10 mL) was stirred at 80° C. for 40 h. The reaction mixture was diluted with HO (150 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with HO (50 mL) and saturated brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (3-iodocyclobutoxy)methyl)benzene, which was used directly in the next step.

[0357] ((3-azidocyclobutoxy)methyl)benzene A mixture of ((3-iodocyclobutoxy)methyl)benzene (1.0 g, 3.47 mmol) and NaN (451 mg, 6.94 mmol) in DMF (10 mL) was stirred at 80 °C for 15 hours. To the reaction mixture, HO (60 mL) was added. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (2×20 mL) to give ((3-azidocyclobutoxy)methyl)benzene. The EtOAc and the solution were used directly.

[0358] N-(3-(1-(3-(benzyloxy)cyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide A mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide (0.4 g, 1.36 mmol), sodium ascorbate (5.0 mg, 0.027 mmol), CuSO (2 mg, 0.013 mmol), benzoic acid (16 mg, 0.136 mmol), and ((3-azidocyclobutoxy)methyl)benzene (414 mg, 2.04 mmol of EtOAc) in t-BuOH (2 mL) and HO (4 mL) was stirred at 80 °C for 15 h in a sealed tube. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE:MTBE = 1:0 to 0:1) to give N-(3-(1-(3-(benzyloxy)cyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide. LC-MS: m / z: = 497.7 [M+H] + .

[0359] 2-(4-chloro-3-fluorophenoxy)-N-(3-(1-(3-hydroxycyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of N-(3-(1-(3-(benzyloxy)cyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide (0.6 g, 1.21 mmol) in DCM (10 mL) at 0 °C was added BC13 (4.8 mL, 4.83 mmol, 1 M in DCM). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with HO (60 mL) and extracted with DCM:i-PrOH (3 × 60 mL, v:v = 3:1). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (MTBE:MeOH = 1:0 to 3:1) to give 2-(4-chloro-3-fluorophenoxy)-N-(3-(1-(3-hydroxycyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide. LC-MS: m / z: = 407.2 [M+H] + .

[0360] O-(3-(4-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)cyclobutyl)S-methylcarbonodithioate To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-(1-(3-hydroxycyclobutyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (180 mg, 0.44 mmol) in DMF (4.0 mL) was added DBU (80 mg, 0.53 mmol) at 0 °C. After 0.5 h, CS (134 mg, 1.77 mmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 0.5 h. To the mixture was added MeI (314 mg, 2.21 mmol) at 0 °C. The mixture was stirred at 25 °C for 15 h. The reaction mixture was diluted with HO (60 mL) and EtOAc (3 × 20 m The combined organic layers were washed with saturated brine (2×30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE:EtOAc=1:1) to give the title compound. LC-MS: m / z: = 497.2 [M+H] + .

[0361] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[1-[3-trans-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[1-[3-cis-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (103 mg, 0.362 mmol) in DCM (6 mL) was added pyridine hydrofluoride (683 mg, 4.83 mmol, 70%) at −78° C. The mixture was stirred at −78° C. for 0.5 hours. To the mixture was added O-(3-(4-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazol-1-yl)cyclobutyl)S-methylcarbonodithioate (60 mg, 0.172 mmol) in DCM (2 mL) at −78° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with HO (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated NaHCO (3 × 10 mL) and saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (neutral) to give the desired product as a mixture of diastereomers. These diastereomers were separated by SFC to give:

[0362] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[1-[3-trans-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide. 1 H-NMR (400 MHz, CDCl3) δ 7.44 - 7.29 (m, 2H), 6.93 (s, 1H), 6.82 - 6.64 (m, 2H), 5.20 - 5.03 (m, 2H), 4.42 (s, 2H), 3.13 - 2.99 (m, 2H), 2.96 - 2.84 (m, 2H), 2.52 (s, 6H). LCMS: m / z: = 475.3 [M+H] + .

[0363] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[1-[3-cis-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide. 1 H-NMR (400 MHz, CDCl3): δ 7.43 (s, 1H), 7.34 (t, J = 8.6 Hz, 1H), 6.92 (s, 1H), 6.78 (dd, J = 2.8, 10.2 Hz, 1H), 6.70 (dd, J = 1.8, 8.9 Hz, 1H), 4.73 (quintet, J = 8.3 Hz, 1H), 4.62 (quintet, LC-MS: m / z: = 475.3 [M+H] + .

[0364] Example 66 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[5-[3-cis-(difluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide Methyl 3-cis-(difluoromethoxy)cyclobutanecarboxylate Methyl 3-cis-hydroxycyclobutanecarboxylate (400 mg, 3.07 To a solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (657 mg, 3.69 mmol) in CHCN (5 mL) was added CuI (117 mg, 0.61 mmol), the mixture was heated to 50 °C, and a solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (657 mg, 3.69 mmol) in CHCN (5 mL) was added dropwise over 5 min. The reaction mixture was stirred at 50 °C for 2 h, diluted with HO (10 mL), and then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give methyl 3-(difluoromethoxy)cyclobutanecarboxylate, which was used directly in the next step.

[0365] 3-cis-(difluoromethoxy)cyclobutanecarboxylic acid To a solution of methyl 3-cis-(difluoromethoxy)cyclobutanecarboxylate (480 mg, 2.66 mmol) in THF (10 mL) was added LiOH·HO (447 mg, 10.66 mmol) and HO (2 mL), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with MTBE, and the layers were separated. The aqueous phase was extracted with MTBE (3 × 5 mL), and the pH of the aqueous layer was adjusted to 3 with HCl (2 N). The acidified mixture was extracted with EtOAc (3 × 5 mL), and the organic phase was washed with saturated brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 3-cis-(difluoromethoxy)cyclobutanecarboxylic acid, which was used directly in the next step.

[0366] 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-cis-(difluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-cis-bicyclo[1.1.1]pentanyl]acetamide (100 mg, 0.31 mmol) in THF (10 mL) was added 3-(difluoromethoxy)cyclobutanecarboxylic acid (61 mg, 0.37 mmol), HATU (139 mg, 0.37 mmol), and DIEA (0.16 mL, 0.92 mmol) at 0 °C, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (3 × 10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title product, which was used directly. LC-MS m / z: = 476.3 [M+H] + .

[0367] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[5-[3-cis-(difluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-cis-(difluoromethoxy)cyclobutanecarbonyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide (100 mg, 0.21 mmol) in DCM (6 mL) was added TEA (0.12 mL, 0.84 mmol) and p-TsCl (80 mg, 0.42 mmol) at 25° C., and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into ice water (10 mL) and extracted with DCM (3 × 10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (TFA) to give the desired compound, which was further separated by preparative TLC (DCM:MeOH = 10:1) to give the desired product. 1H-NMR (400 MHz, CDCl3): δ 7.35 (t, J = 8.60 Hz, 1 H), 6.97 (br s, 1 H), 6.78 (dd, J = 10.23, 2.82 Hz, 1 H), 6.70 (br d, J = 8.78 Hz, 1 H), 5.99 - 6.41 (m, 1 H), 4.70 (quintet, J = 7 .53 Hz, 1 H), 4.44 (s, 2 H), 3.25 - 3.39 (m, 1 H), 2.78 - 2.88 (m, 2 H), 2.66 (s, 6 H), 2.57 - 2.63 (m, 2 H). LC-MS m / z: = 458.3 [M+H] + .

[0368] Example 67 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide O1-Benzyl O3-ethyl azetidine-1,3-dicarboxylate To a mixture of ethyl azetidine-3-carboxylate hydrochloride (2.0 g, 12.1 mmol) in THF (20 mL) and HO (20 mL) was added aqueous NaOH (4 M, 3.0 mL) at 0 °C, followed by dropwise addition of CbzCl (2.06 g, 12.1 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (30 mL) and water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:MTBE = 100:1 to 1:1) to give O1-benzyl O3-ethyl azetidine-1,3-dicarboxylate. LC-MS m / z: = 264.1 [M + H] + .

[0369] 1-Benzyloxycarbonylazetidine-3-carboxylic acid To a mixture of O1-benzyl O3-ethyl azetidine-1,3-dicarboxylate (0.5 g, 1.90 mmol) in THF (2.5 mL) and HO (2.5 mL) was added LiOH.HO (159 mg, 3.80 mmol) at 0° C., and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with HO (10 mL) and extracted with MTBE (2×10 mL). The aqueous phase was adjusted to pH 2-3 with 2N HCl at 0° C. and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 1-benzyloxycarbonylazetidine-3-carboxylic acid.

[0370] Benzyl 3-chlorocarbonylazetidine-1-carboxylate To a mixture of 1-benzyloxycarbonylazetidine-3-carboxylic acid (0.5 g, 2.13 mmol) and DMF (16 mg, 0.21 mmol) in DCM (10 mL) was added (COCl) (809 mg, 6.38 mmol) at 0° C., and the mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give benzyl 3-chlorocarbonylazetidine-1-carboxylate.

[0371] Benzyl 3-(2-diazoacetyl)azetidine-1-carboxylate To a mixture of benzyl 3-chlorocarbonylazetidine-1-carboxylate (640 mg, 2.52 mmol) in THF (5 mL) and MeCN (5 mL) was added 2M TMSCHN (3.15 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with HO (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 100:1 to 0:1) to give benzyl 3-(2-diazoacetyl)azetidine-1-carboxylate. LC-MS m / z: = 260.0 [M + H] + .

[0372] Benzyl 3-(2-bromoacetyl)azetidine-1-carboxylate To a mixture of benzyl 3-(2-diazoacetyl)azetidine-1-carboxylate (450 mg, 1.74 mmol) in THF (10 mL) was added HBr (421 mg, 2.08 mmol, 40% HO) at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give benzyl 3-(2-bromoacetyl)azetidine-1-carboxylate. LC-MS m / z: = 312.0, 314.0 [M + H] + .

[0373] Benzyl 3-[2-[[3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]amino]acetyl]azetidine-1-carboxylate To a solution of N-(1-amino-3-bicyclo[1.1.1]pentanyl)-2-(4-chloro-3-fluoro-phenoxy)acetamide HCl salt (0.9 g, 2.80 mmol) and benzyl 3-(2-bromoacetyl)azetidine-1-carboxylate (1.05 g, 3.36 mmol) in MeCN (50 mL) was added NaCO (1.19 g, 11.21 mmol), and the mixture was stirred at 40° C. for 2 hours. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EtOAc = 100:1 to 0:1) to give benzyl 3-[2-[[3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]amino]acetyl]azetidine-1-carboxylate. LC-MS m / z: = 516.2, 518.2 [M + H] + .

[0374] Benzyl 3-[2-[[1-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-3-bicyclo[1.1.1]pentanyl]-formyl-amino]acetyl]azetidine-1-carboxylate To a solution of formic acid (102 mg, 2.13 mmol) was added AC0 (871 mg, 8.53 mmol) at 0° C. A solution of benzyl 3-[2-[[3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-1-bicyclo[1.1.1]pentanyl]amino]acetyl]azetidine-1-carboxylate (1.1 g, 2.13 mmol) in DCM (3 mL) was added dropwise, and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was adjusted to pH=7-8 with saturated NaHCO3, the aqueous phase was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give benzyl 3-[2-[[1-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-3-bicyclo[1.1.1]pentanyl]-formyl-amino]acetyl]azetidine-1-carboxylate.

[0375] Benzyl 3-[1-[1-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-3-bicyclo[1.1.1]pentanyl]imidazol-4-yl]azetidine-1-carboxylate To a solution of benzyl 3-[2-[[1-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-3-bicyclo[1.1.1]pentanyl]-formyl-amino]acetyl]azetidine-1-carboxylate (950 mg, 1.75 mmol) in AcOH (10 mL) was added ammonium acetate (673 mg, 8.73 mmol), and the mixture was stirred at 110° C. for 16 h. The reaction mixture was adjusted to pH 7-8 with saturated NaHCO3, and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give benzyl 3-[1-[1-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-3-bicyclo[1.1.1]pentanyl]imidazol-4-yl]azetidine-1-carboxylate. LC-MS m / z: = 525.2, 527.2 [M + H] + .

[0376] N-[3-[4-(azetidin-3-yl)imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]-2-(4-chloro-3-fluoro-phenoxy)acetamide To a solution of benzyl 3-[1-[1-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-3-bicyclo[1.1.1]pentanyl]imidazol-4-yl]azetidine-1-carboxylate (100 mg, 0.19 mmol) in EtOH (5 mL) was added Pd(OH) (10%). The suspension was degassed under vacuum and purged with H three times. The reaction mixture was stirred under H (30 psi) at 25 °C for 2.5 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to give N-[3-[4-(azetidin-3-yl)imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]-2-(4-chloro-3-fluoro-phenoxy)acetamide. LCMS m / z: = 391.1, 393.2 [M + H] + .

[0377] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of N-[3-[4-(azetidin-3-yl)imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]-2-(4-chloro-3-fluoro-phenoxy)acetamide (80 mg, 0.20 mmol) in THF (2 mL) was added DIEA (106 mg, 0.82 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (71 mg, 0.31 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 4 h and then diluted with HO (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (neutral) to give 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[4-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide. LCMS m / z: = 473.2 [M + H] + . 1 H-NMR (400 MHz, CDCl3): δ 7.42 (d, J = 1.13 Hz, 1 H), 7.35 (t, J = 8.60 Hz, 1 H), 6.96 (s, 1 H), 6.75 - 6.80 (m, 2 H), 6.69 (ddd, J = 8.88, 2.79, 1.25 Hz, 1 H), 4.41 - 4.49 (m, 2 H), 3.81 - 3.89 (m, 2 H), 3.69 - 3.81 (m, 1 H), 3.40 - 3.50 (m, 2 H), 3.08 (q, J = 9.49 Hz, 2 H), 2.59 - 2.65 (m, 6 H).

[0378] Examples 68 and 69 2-(4-chlorophenoxy)-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chlorophenoxy)-N-[3-[4-[3-trans -(Trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide 2-(4-chlorophenoxy)-N-(3-((2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)amino)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of N-(1-amino-3-bicyclo[1.1.1]pentanyl)-2-(4-chlorophenoxy)acetamide HCl salt (0.6 g, 1.98 mmol) and 2-bromo-1-[3-cis-(trifluoromethoxy)cyclobutyl]ethanone (1.03 g, 3.96 mmol; cis:trans ratio of 8:1 to 10:1) in CHCN (20 mL) was added NaCO (839 mg, 7.92 mmol). The reaction mixture was stirred at 40 °C for 6 h, then filtered and concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL) and HO (20 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic extracts were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography to give 2-(4-chlorophenoxy)-N-[1-[[2-oxo-2-[3-cis-(trifluoromethoxy)cyclobutyl]ethyl]amino]-3-bicyclo[1.1.1]pentanyl]acetamide (3:1 cis:trans ratio). LC-MS m / z: = 446.9 [M+H] + .

[0379] 2-(4-chlorophenoxy)-N-(3-(N-(2-oxo-2-(3-cis-(trifluoromethoxy)cyclobutyl)ethyl)formamido)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of formic acid (3.17 g, 68.9 mmol) was added AC0 (457 mg, 4.48 mmol) at 0 °C, and then a solution of 2-(4-chlorophenoxy)-N-[1-[[2-oxo-2-[3-cis-(trifluoromethoxy)cyclobutyl]ethyl]amino]-3-bicyclo[1.1.1]pentanyl]acetamide (500 mg, 1.12 mmol) in DCM (2.5 mL) was added at 0 °C. The mixture was stirred at 0 °C for 2 h, and then the reaction mixture was diluted with HO (10 mL). Saturated NaHCO (20 mL) was added at 0 °C to adjust the pH to 8-9, and the layers were separated. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(4-chlorophenoxy)-N-[3-[formyl-[2-oxo-2-[3-cis-(trifluoromethoxy)cyclobutyl]ethyl]amino]-1-bicyclo[1.1.1]pentanyl]acetamide (3:1 cis:trans ratio), which was used without further purification. LC-MS m / z: = 475.3 [M+H] + .

[0380] 2-(4-chlorophenoxy)-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-chlorophenoxy)-N-[3-[4-[3-trans-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of 2-(4-chlorophenoxy)-N-[3-[formyl-[2-oxo-2-[3-cis-(trifluoromethoxy)cyclobutyl]ethyl]amino]-1-bicyclo[1.1.1]pentanyl]acetamide (360 mg, 0.76 mmol) in AcOH (4 mL) was added ammonium formate (228 mg, 2.96 mmol), and the reaction mixture was stirred at 110 °C for 12 h. The reaction was diluted with aqueous NaHCO (30 mL) at 0 °C and adjusted to pH 8-9. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was The crude reaction mixture was purified by preparative HPLC to give the desired product (3:1 cis:trans ratio). The individual diastereomers were separated by SFC to give:

[0381] 2-(4-chlorophenoxy)-N-[3-[4-[3-trans-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide: 1 H-NMR (400 MHz, MeOD): δ 8.48 (s, 1 H), 7.46 (s, 1 H), 7.26 - 7.33 (m, 2 H), 6.95 - 7.02 (m, 2 H), 4.93 - 5.01 (m, 1 H), 4.51 (s, 2 H), 3.54 - 3.67 (m, 1 H), 2.69 - 2.77 (m, 2 H), 2.67 (s, 6 H), 2.55 - 2.63 (m, 2 H). LC-MS m / z: = 456.3 [M+H] + .

[0382] 2-(4-chlorophenoxy)-N-[3-[4-[3-cis-(trifluoromethoxy)cyclobutyl]imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]acetamide: 1H-NMR (400 MHz, MeOD): δ 7.96 (d, J = 1.13 Hz, 1 H), 7.24 - 7.33 (m, 2 H), 7.17 (s, 1 H), 6.93 - 7.02 (m, 2 H), 4.66 - 4.78 (m, 1 H), 4.50 (s, 2 H), 2.99 - 3.15 (m, 1 H), 2.68 - 2.81 (m, 2 H), 2.62 (s, 6 H), 2.29 - 2.44 (m, 2 H). LC-MS m / z: = 456.3 [M+H] + .

[0383] Example 70 N-[3-[4-(4-chloro-3-fluoro-phenyl)imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide N-(3-((2-(4-chloro-3-fluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide To a mixture of 2-bromo-1-(4-chloro-3-fluorophenyl)ethanone (152 mg, 0.60 mmol) and N-(1-amino-3-bicyclo[1.1.1]pentanyl)-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide HCl salt (200 mg, 0.60 mmol) in GHCN (20 mL) was added NaCO (256 mg, 2.42 mmol), and the mixture was stirred at 40 °C for 1 h. The reaction mixture was diluted with water (5 mL) and EtOAc (5 mL) at 0 °C. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with saturated brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography to give the desired product, which was used directly. LC-MS m / z: = 465.1 [M+H] + .

[0384] N-(3-(N-(2-(4-chloro-3-fluorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide Formic acid (0.53 mL, 13.98 mmol) was added dropwise to AC0 (0.10 mL, 1.12 mmol) at 0 °C, followed by N-(3-((2-(4-chloro-3-fluorophenyl)-2-oxoethyl)amino)bicyclo[1.1.1] A solution of pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide (130 mg, 0.28 mmol) in DCM (5 mL) was added dropwise and the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with saturated NaHCO (10 mL) and EtOAc (10 mL) at 0° C. and the layers were separated. The aqueous layer was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with saturated brine (5 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the desired compound, which was used directly. LC-MS m / z: = 492.9 [M+H] + .

[0385] N-[3-[4-(4-chloro-3-fluoro-phenyl)imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide To a solution of N-(3-(N-(2-(4-chloro-3-fluorophenyl)-2-oxoethyl)formamido)bicyclo[1.1.1]pentan-1-yl)-2-(3-cis-(trifluoromethoxy)cyclobutoxy)acetamide (130 mg, 0.26 mmol) in AcOH (1.0 mL) was added ammonium formate (81 mg, 1.06 mmol) and the mixture was stirred at 120° C. for 8 h. The reaction mixture was diluted with saturated NaHCO (10 mL) and EtOAc (10 mL) at 0° C. The layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative TLC (EtOAc, 3 times) to deliver N-[3-[4-(4-chloro-3-fluoro-phenyl)imidazol-1-yl]-1-bicyclo[1.1.1]pentanyl]-2-[cis-3-(trifluoromethoxy)cyclobutoxy]acetamide. 1 H-NMR (400 MHz, , CDCl3): δ 7.62 - 7.43 (m, 3H), 7.41 - 7.33 (m, 1H), 7.21 (d, J = 1.3 Hz, 1H), 6.98 (s, 1H), 4.37 - 4.30 (m, 1H), 3.85 (s, 2H), 3.74 (quintet, J = 6.9 Hz, 1H), 2.87 - 2.81 (m, 2H), 2.69 - 2.58 (m, 6H), 2.28 (dtd, J = 3.5, 6.9, 10.1 Hz, 2H). LC-MS m / z: = 474.3.

[0386] Examples 71 and 72 2-(4-Fluorophenoxy)-N-[3-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide and 2-(4-Fluorophenoxy)-N-[3-[5-[3-trans-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of 2-(4-fluorophenoxy)acetic acid (60 mg, 0.35 mmol) in dry DMF (1 mL) was added HATU (161 mg, 0.42 mmol) at 25° C. After 15 min, 3-(5-(3-cis-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine HCl salt (115 mg, 0.35 mmol; cis:trans ratio of 8:1 to 10:1) and DIEA (0.25 mL, 1.41 mmol) were added, and the reaction mixture was stirred at 25° C. for 2 h. The reaction was diluted with ice water (5 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give 2-(4-fluorophenoxy)-N-[3-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazole-2 -yl]-1-bicyclo[1.1.1]pentanyl]acetamide was delivered: 1 H-NMR (400 MHz, CDCl3): δ 7.08 - 6.99 (m, 3H), 6.93 - 6.85 (m, 2H), 4.71 (quintet, J = 7.6 Hz, 1H), 4.42 (s, 2H), 3.33 (tt, J = 7.7, 10.2 Hz, 1H), 2.92 - 2.83 (m, 2H), 2.74 - 2.67 (m, 2H), 2.66 (s, 6H). LC-MS: m / z = 442.2 [M+H]+

[0387] 2-(4-fluorophenoxy)-N-[3-[5-[3-trans-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide: 1 H-NMR (400 MHz, CDCl3): δ 7.06 - 7.01 (m, 3H), 6.91 - 6.87 (m, 2H), 5.00 (quintet, J = 6.8 Hz, 1H), 4.75 - 4.68 (m, 1H), 4.42 (s, 2H), 3.77 - 3.66 (m, 1H), 3.38 - 3.28 (m, 1H), 2.91 - 2.74 (m, 4H), 2.65 (s, 5H), 2.67 - 2.64 (m, 1H). LC-MS: m / z = 442.2 [M+H] + .

[0388] Example 73 N-[1-[5-(5-fluoro-3-pyridyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide tert-Butyl N-[1-[5-(5-fluoro-3-pyridyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]carbamate tert-Butyl N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]carbamate (80.0 mg, 0.33 mmol), 5-fluoropyridine-3-carboxylic acid (70.2 mg, 0.50 mmol), and NEt (0.23 mL, 1.66 mmol) were dissolved in 2.5 mL of EtOAc, and T3P solution (300 μL, 0.99 mmol) was added. The resulting reaction mixture was heated to 100 °C overnight. The reaction mixture was diluted with saturated NaHCO3 solution (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase HPLC.

[0389] 1-[5-(5-fluoro-3-pyridyl)-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine TFA salt tert-Butyl N-[1-[5-(5-fluoro-3-pyridyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]carbamate (60.0 mg, 0.17 mmol) was dissolved in DCM (2.0 mL), cooled to 0 °C, and TFA (20 mg, 0.17 mmol) was added. The reaction mixture was allowed to warm to room temperature, stirred for 4 h, and concentrated under reduced pressure. The crude reaction mixture was used directly.

[0390] N-[1-[5-(5-fluoro-3-pyridyl)-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide 1-[5-(5-fluoro-3-pyridyl)-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine trifluoroacetate (60.0 mg, 0.17 mmol), 2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetic acid (42.8 mg, 0.20 mmol), and ΝΕt (70 μL, 0.50 mmol). was dissolved in EtOAc (1.0 mL) and T3P solution (63.6 mg, 0.20 mmol) was added. The resulting reaction mixture was heated to 100 °C overnight. The reaction mixture was diluted with saturated NaHCO3 solution (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse-phase HPLC. LC-MS, m / z = 443.6 [M+H] + .

[0391] Example 74 2-(4-chlorophenoxy)-N-prop-2-ynyl-N-[1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide To a solution of 2-(4-chlorophenoxy)-N-[1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-3-bicyclo[1.1.1]pentanyl]acetamide (4.2 mg, 0.01 mmol) in THF (0.5 mL) at room temperature was added NaH (0.2 mg, 0.01 mmol). The reaction was stirred for 10 minutes, and propargyl bromide (1.1 mg, 0.01 mmol) was added. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was treated with NH4Cl solution (5 mL) and EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using silica gel column chromatography to give the desired product. LC-MS, m / z = 496.3 [M+H] + .

[0392] Example 75 3-[3-cis-(trifluoromethoxy)cyclobutyl]-N-[3-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]propanamide 3-cis-(trifluoromethoxy)cyclobutanecarbaldehyde N-Methoxy-N-methyl-3-cis-(trifluoromethoxy)cyclobutanecarboxamide (2.46 g, 10.83 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. DIBAL-H (3.08 g, 21.6 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was treated with saturated sodium potassium tartrate solution (100 mL) and EtOAc (100 mL), and the resulting emulsion was stirred at room temperature for 8 h. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The crude reaction mixture was used directly.

[0393] Ethyl (E)-3-[3-cis-(trifluoromethoxy)cyclobutyl]prop-2-enoate NaH (534 mg, 13.4 mmol) was suspended in THF (45.0 mL) at 0° C. To this was added triethylphosphonoacetate (2.65 mL, 13.4 mmol) in 20 mL of THF. The reaction mixture was stirred until a clear solution formed, and 3-cis-(trifluoromethoxy)cyclobutanecarbaldehyde (1.87 g, 11.1 mmol) was added to 20 mL of THF. The reaction mixture was allowed to warm to room temperature, and TLC (20% EtOAc / hex, KMnO) showed no starting material and a new, less polar spot. The reaction mixture was treated with NH4Cl solution (25 mL) and EtOAc (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture is added to silica Purification using gel column chromatography (0-->15% EtOAc / hex) gave the desired product.

[0394] Ethyl 3-[3-cis-(trifluoromethoxy)cyclobutyl]propanoate Ethyl (E)-3-[3-cis-(trifluoromethoxy)cyclobutyl]prop-2-enoate (63.0 mg, 0.26 mmol) was dissolved in EtOH (2.6 mL) and palladium on carbon (6.3 mg, 10 wt%) was added. H2 gas was bubbled through the reaction mixture for 1 h. TLC (20% EtOAc / hex, KMnO4) showed no starting material and a new product spot. The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure. The crude reaction mixture was used directly.

[0395] 3-[3-cis-(trifluoromethoxy)cyclobutyl]propanoic acid Ethyl 3-[3-cis-(trifluoromethoxy)cyclobutyl]propanoate (57.0 mg, 0.24 mmol) was dissolved in MeOH (1.0 mL), 1 M NaOH (1.0 mL, 0.24 mmol) was added, and the reaction mixture was stirred at 65° C. overnight. The mixture was treated with 1 M HCl solution (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was used directly.

[0396] 3-[3-cis-(trifluoromethoxy)cyclobutyl]-N-[3-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]propanamide To a solution of 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine (45.0 mg, 0.16 mmol; 8:1 to 10:1 cis:trans ratio) in 1.0 mL of EtOAc was added N,N-diisopropylethylamine (80 μL, 0.47 mmol), followed by T3P solution (74.2 mg, 0.23 mmol). The reaction mixture was stirred for 10 minutes, and then cis-3-[3-(trifluoromethoxy)cyclobutyl]propanoic acid (49.5 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with NH4Cl solution (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified using reverse phase HPLC. LC-MS, m / z = 443.58 [M+H] + .

[0397] Example 76 5-chloro-N-[3-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-2,3-dihydrobenzofuran-2-carboxamide 5-chloro-2,3-dihydrobenzofuran-2-carboxylic acid: To a mixture of 2,3-dihydrobenzofuran-2-carboxylic acid (1.0 g, 6.09 mmol) in DMF (10 mL) at 25 °C, NCS (976 mg, 7.31 mmol) was added, and the mixture was heated to 60 °C for 3 hours. The reaction mixture was adjusted to pH 5-6 with 1 N HCl, and EtOAc (10 mL) was added. The layers were separated, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 5-chloro-2,3-dihydrobenzofuran-2-carboxylic acid.

[0398] 5-chloro-N-[3-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]-2,3-dihydrobenzofuran-2-carboxamide To a mixture of 1-[5-[3-cis-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pentan-3-amine HCl salt (120 mg, 0.368 mmol; 8:1 to 10:1 cis:trans ratio) and 5-chloro-2,3-dihydrobenzofuran-2-carboxylic acid (80 mg, 0.405 mmol) in DMF (5.0 mL) was added HATU (154 mg, 0.405 mmol) and DIEA (95 mg, 0.736 mmol) at 25° C., and the mixture was stirred for 2 hours at 25° C. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 5 mL), and the combined organic phases were washed with saturated brine (2 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA) to give the title compound. LC-MS m / z: = 470.1 [M + H] + .

[0399] 1 H-NMR (400 MHz, CDCl3) δ 7.17 (s, 1 H), 7.13 (br d, J = 8.41 Hz, 1 H), 7.06 (br s, 1 H), 6.79 (br d, J = 8.41 Hz, 1 H), 5.12 (br dd, J = 10.67, 6.78Hz, 1H), 4.70 (quintet, J = 7.50 Hz, 1 H), 3.52 - 3.63 (m, 1 H), 3.26 - 3.47 (m, 2 H), 2.81 - 2.90 (m, 2 H), 2.65 - 2.74 (m, 2 H), 2.61 (s, 6 H).

[0400] Example 77 N-[3-[1-(4-chloro-3-fluoro-phenyl)triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide Tert-butyl (3-(1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate A mixture of tert-butyl (3-ethynylbicyclo[1.1.1]pentan-1-yl)carbamate (1.0 g, 4.82 mmol), CuI (45 mg, 0.241 mmol), and TMSN3 (833 mg, 7.24 mmol) in DMF (10 mL) and MeOH (2 mL) was stirred at 100 °C for 15 h. The reaction mixture was diluted with HO (100 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified using silica gel column chromatography (PE:MTBE=1:0 to 0:1) to deliver tert-butyl (3-(1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate. 1 H-NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 5.15 (br s, 1H), 2.38 (s, 6H), 1.47 (s, 9H).

[0401] tert-Butyl (3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-Butyl (3-(1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (0.5 g, 2.0 mmol), (4-chloro- A mixture of (3-fluoro-phenyl)boronic acid (696 mg, 4.0 mmol), Cu(OAc) (72 mg, 0.39 mmol), and pyridine (316 mg, 4.0 mmol) in THF (10 mL) was stirred under O at 60 °C for 15 h. The reaction mixture was diluted with H O (60 mL) and EtOAc (60 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified using silica gel column chromatography (PE:MTBE = 1:0 to 0:1) to give tert-butyl (3-(2-(4-chloro-3-fluorophenyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate and tert-butyl (3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate. LCMS m / z: = 379.1, 381.1 [M+H] + .

[0402] 3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-amine A mixture of tert-butyl (3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (200 mg, 0.527 mmol) in HCl / EtOAc (20 mL) was stirred at 20° C. for 1 h. The mixture was concentrated under reduced pressure to give 3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-amine, HCl salt, which was used directly. LCMS m / z: = 279.1, 281.1 [M+H] + .

[0403] N-[3-[1-(4-chloro-3-fluoro-phenyl)triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide To a solution of 2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetic acid (119 mg, 0.558 mmol) in DMF (3 mL) was added HATU (212 mg, 0.558 mmol) and DIEA (196 mg, 1.52 mmol). The mixture was stirred at 20 °C for 30 min. To this mixture was added 3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-amine, HCl salt (160 mg, 0.507 mmol), and the mixture was stirred at 20 °C for 15 h. The reaction mixture was diluted with HO (30 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (NHHCO) to give N-[3-[1-(4-chloro-3-fluoro-phenyl)triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]-2-[cis-3-(trifluoromethoxy)cyclobutoxy]acetamide. 1 H-NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.63 (dd, J = 2.3, 9.3 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.53 - 7.44 (m, 1H), 6.92 (s, 1H), 4.34 (quintet, J = 7.2 Hz, 1H), 3.84 (s, 2H), 3.73 (quintet, J = 6.9 Hz, 1H), 2.91 - 2.76 (m, 2H), 2.56 (s, 6H), 2.35 - 2.21 (m, 2H). LC-MS m / z: = 475.3 [M+H] + .

[0404] Example 78 N-[3-[2-(4-chloro-3-fluoro-phenyl)triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide 3-(2-(4-chloro-3-fluorophenyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-amine HCl salt A mixture of tert-butyl (3-(2-(4-chloro-3-fluorophenyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (350 mg, 0.923 mmol) in HCl / EtOAc (4 M, 20 mL) was stirred at 20° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue that was used directly.

[0405] N-[3-[2-(4-chloro-3-fluoro-phenyl)triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]-2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetamide To a solution of 2-[3-cis-(trifluoromethoxy)cyclobutoxy]acetic acid (74 mg, 0.35 mmol) in DMF (5 mL) was added HATU (132 mg, 0.35 mmol) and DIEA (123 mg, 0.95 mmol). The mixture was stirred at 20 °C for 0.5 h. To this mixture was added 3-(2-(4-chloro-3-fluorophenyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-amine, HCl salt (100 mg, 0.317 mmol), and the mixture was stirred at 20 °C for 15 h. The reaction mixture was diluted with HO (30 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (neutral) to give N-[3-[2-(4-chloro-3-fluoro-phenyl)triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]-2-[cis-3-cis-(trifluoromethoxy)cyclobutoxy]acetamide. 1 H-NMR (400 MHz, CDCl3): δ 7.88 (dd, J = 2.4, 9.9 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.62 (s, 1H), 7.48 (t, J = 8.2 Hz, 1H), 6.91 (s, 1H), 4.34 (quintet, J = 7.2 Hz, 1H), 3.84 (s, 2H), 3.74 (quintet, J = 6.9 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.53 (s, 6H), 2.36 - 2.25 (m, 2H). LC-MS m / z: = 475.3 [M+H] + .

[0406] Example 79 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[2-[3-cis-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanyl]acetamide To a solution of methyl 3-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (4.0 g, 12.2 mmol) in THF (20 mL) at 0 °C, LiBH (2.66 g, 122 mmol) was added in three portions, and the reaction mixture was warmed to 20 °C and stirred for 16 h. The reaction mixture was poured onto ice, and DCM was added. The layers were separated, and the aqueous layer was extracted with DCM (3 × 100 mL). The combined organic layers were washed with saturated brine (3 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography ( Purification with PE: EtOAc (10:1 to 1:1) delivered 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanyl]acetamide. LC-MS m / z: = 300.1, 302.1 [M+H] + .

[0407] 2-(4-chloro-3-fluoro-phenoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide A mixture of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydroxymethyl)-3-bicyclo[1.1.1]pentanyl]acetamide (2.0 g, 6.67 mmol) and Dess-Martin (2.27 mL, 7.34 mmol) in DCM (50 mL) was stirred at 20 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO (50 mL) and DCM. The layers were separated, and the aqueous layer was extracted with DCM (3 × 50 mL). The combined organic extracts were washed with saturated brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(4-chloro-3-fluoro-phenoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide.

[0408] 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-(1-formyl-3-bicyclo[1.1.1]pentanyl)acetamide (1.70 g, 5.71 mmol) in MeOH (20 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (1.54 g, 7.99 mmol) and K2CO3 (2.37 g, 17.13 mmol), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (50 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-chloro-3-fluoro-phenoxy)-N-(1-ethynyl-3-bicyclo[1.1.1]pentanyl)acetamide.

[0409] N-(3-(2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide A mixture of 2-(4-chloro-3-fluorophenoxy)-N-(3-ethynylbicyclo[1.1.1]pentan-1-yl)acetamide (700 mg, 2.38 mmol), TMSN3 (824 mg, 7.15 mmol), sodium ascorbate (9.44 mg, 0.05 mmol), CuSO4 (7.61 mg, 0.05 mmol), and PhCOOH (58 mg, 0.48 mmol) in t-BuOH (3 mL) and HO (6 mL) was stirred at 80 °C in a sealed tube for 6 h. The reaction mixture was diluted with HO (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated NaHCO (5 mL), saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give N-(3-(2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide. LC-MS m / z: = 337.3, 339.3 [M+H] + .

[0410] 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-oxocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide N-(3-(2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]phenyl)- To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-oxocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (600 g, 1.78 mmol) in DMF (5 mL) was added CS2CO3 (581 mg, 1.78 mmol) and 3-bromocyclobutanone (400 mg, 2.67 mmol) at 0° C., and the mixture was stirred for 2 h at 0° C. The reaction mixture was poured into ice water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-oxocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide. LC-MS m / z: = 405.1, 407.1 [M+H] + .

[0411] 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-cis-hydroxycyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-oxocyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (500 mg, 1.24 mmol) in MeOH (5 mL) at −20° C. was added NaBH (42 mg, 1.11 mmol), and the mixture was stirred at −20° C. for 1 h. The reaction mixture was diluted with NH Cl (5 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue which was purified by preparative TLC (100% EtOAc) to give 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(3-cis-hydroxycyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide.

[0412] O-(3-cis-(4-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[1.1.1]pentan-1-yl)-2H-1,2,3-triazol-2-yl)cyclobutyl)S-methylcarbonodithioate To a solution of 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(cis-3-hydroxycyclobutyl)-2H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (180 mg, 0.44 mmol) in dry DMF (2 mL) was added DBU (81 mg, 0.53 mmol) at 0 °C. After 30 min, CS (135 mg, 1.77 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for an additional 30 min. At this point, MeI (314 mg, 2.21 mmol) was added at 0 °C, and the reaction was stirred at 20 °C for 15 h. The reaction mixture was poured into saturated NH Cl (5 mL), and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative TLC (PE: EtOAc = 2:1) to give the desired product. LC / MS m / z: = 497.1, 499.1 [M+H] + .

[0413] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[2-[3-cis-(trifluoromethoxy)cyclobutyl]triazol-4-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (86 mg, 0.30 mmol) in DCM (1 mL) was added pyridine·HF (0.52 mL, 4.02 mmol, 70%) at −78 °C. After 30 min, O-(3-cis-(4-(3-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[2.0.1.2 ...1.2.2.1.2.1.2.1.2.1.2.1.2.1.2.1.2.1.2.1.2.1.2.1. [1.1.1]pentan-1-yl)-2H-1,2,3-triazol-2-yl)cyclobutyl)S-methylcarbonodithioate (50 mg, 0.1 mmol) was added as a solution in DCM (1 mL) and the resulting reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice water (4 mL) and extracted with DCM (3×4 mL). The combined organic phases were washed with saturated brine (4 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (TFA) to give the title compound. 1 H-NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.35 (t, J = 8.6 Hz, 1H), 6.91 (s, 1H), 6.79 (dd, J = 2.9, 10.3 Hz, 1H), 6.71 (br d, J = 9.0 Hz, 1H), 4.74 (quintet, J = 8.2 Hz, 1H), 4.58 (quintet, J = 7.3 Hz, 1H), 4.43 (s, 2H), 3.06 - 2.98 (m, 4H), 2.52 - 2.48 (m, 1H), 2.50 (s, 5H). LC-MS m / z: = 475.2 [M+H] + .

[0414] Examples 80, 81, and 82 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[5-[2-[trans-(trifluoromethoxymethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide Ethyl 2-trans-((trifluoromethoxy)methyl)cyclopropanecarboxylate To a solution of AgOTf (11.23 g, 43.70 mmol) in EtOAc (80 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane; ditetrafluoroborate (7.74 g, 21.85 mmol), KF (3.39 g, 58.27 mmol), and ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (2.1 g, 14.57 mmol) at 25° C. After mixing, 2-fluoropyridine (4.24 g, 43.70 mmol) and trimethyl(trifluoromethyl)silane (6.21 g, 43.70 mmol) were added at 25° C., and the resulting mixture was stirred at 25° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 100:1 to 5:1) to give ethyl 2-(trifluoromethoxymethyl) cyclopropanecarboxylate (cis:trans ratio of 1:3).

[0415] 2-trans-((trifluoromethoxy)methyl)cyclopropanecarboxylic acid To a solution of ethyl 2-trans-(trifluoromethoxymethyl)cyclopropanecarboxylate (0.86 g, 4.05 mmol) in THF (10 mL) and HO (10 mL) was added LiOH.HO (510 mg, 12.16 mmol) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with HO (20 mL) and extracted with MTBE (3 × 10 mL). The aqueous phase was adjusted to pH 1-2 with 2 N HCl at 0 °C and extracted with DCM:MeOH (6 × 10 mL, v:v = 10:1). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give trans-2-(trifluoromethoxymethyl)cyclopropanecarboxylic acid (1:5 cis:trans ratio). The crude product was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 3.99 (dd, J = 10.80, 6.17 Hz, 1 H), 3.81 (dd, J = 10.80, 7.28 Hz, 1 H), 1.83 - 1.96 (m, 1 H), 1.68 (dt, J = 8.54, 4.44Hz, 1H), 1.34 - 1.42 (m, 1 H), 0.98 - 1.08 (m, 1 H).

[0416] 2-(4-chloro-3-fluorophenoxy)-N-(3-(2-(2-trans)-((trifluoromethoxy)methyl)cyclopropanecarbonyl)hydrazinecarbonyl)bicyclo[1.1.1]pentan-1-yl)acetamide To a solution of 2-trans-(trifluoromethoxymemyl)cyclopropanecarboxylic acid (0.2 g, 1.09 mmol), 2-(4-chloro-3-fluoro-phenoxy)-N-[1-(hydrazinecarbonyl)-3-bicyclo[1.1.1]pentanyl]acetamide (324 mg, 0.99 mmol), and TEA (400 mg, 3.95 mmol) in DMF (2 mL) in a sealed tube was added T3P (2.51 g, 3.95 mmol, 50% in EtOAc). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL), additional HO (5 mL), and EtOAc (10 mL) at 0 °C. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated brine (3×3 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound. LC-MS m / z: = 494.2 [M+H] + .

[0417] 2-(4-chloro-3-fluoro-phenoxy)-N-[3-[5-[2-trans-(trifluoromethoxymethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide To a solution of 2-(4-chloro-3-fluoro-phenoxy)-N-[1-[[[2-trans-(trifluoromethoxy...

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