Medium- or large-cyclic benzyl-substituted heterocyclic derivatives and their use as orexin-2 receptor agonists

Abstract

The present disclosure relates to compounds of formula (I') and their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating orexin-2 receptor activity and may be used in the treatment of disorders in which orexin-2 receptor activity is implicated, such as narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic diseases, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or promoting emergence from anesthesia. TIFF2023540350000454.tif45128

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 074,220, filed September 3, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background The present disclosure relates to small-molecule, potent orexin-2 receptor (OX2R) agonists designed for the treatment of narcolepsy and other disorders associated with orexin deficiency and / or excessive sleepiness. Narcolepsy affects 1 in 2,000 people worldwide. Onset occurs during adolescence and can have a lifelong, debilitating impact on quality of life. Narcolepsy type 1 (NT1) is caused by the loss of neurons in the brain that produce orexin neuropeptides. There is no known cure, and currently approved treatments are symptomatic. Therefore, the development of pharmacological therapies to restore lost orexin signaling is crucial to treating the underlying cause of NT1.

[0003] In narcolepsy type 1 (NT1), the sole neuronal population producing orexin A and B (also known as hypocretin-1 and -2) peptides is destroyed by immune mechanisms, leading to a disturbance in the boundary between wakefulness and wakefulness. A mouse model of narcolepsy type 1 reproduces the loss of orexin neurons and the two cardinal symptoms observed in NT1 patients: excessive daytime sleepiness and cataplexy. Common symptoms of narcolepsy types 1 and 2 include excessive daytime sleepiness, disrupted nocturnal sleep, and inappropriately timed rapid eye movement (REM) sleep, as well as sleep paralysis and hypnagogic hallucinations. Cataplexy, a sudden, reversible loss of muscle tone during wakefulness (atony of REM sleep) in response to emotional stimuli, is characteristic of NT1.

[0004] Two major symptoms of narcolepsy type 1, excessive daytime sleepiness and cataplexy, can be alleviated by reactivating orexin neurotransmission at OX2R in mouse models. Amelioration of cataplexy-like events and sleep / wake fragmentation was achieved by genetically localizing OX2R signaling in the dorsal raphe nucleus of the pons and the tuberomammillary nucleus of the hypothalamus, respectively, in mice lacking orexin receptors in these regions. Intracerebroventricular (ICV) administration of orexin A (OXA) has been shown to increase wake-up time and reduce cataplexy-like behavior in orexin neuron-depleted mice. The selective OX2R agonist YNT-185, administered intraperitoneally or ICV, modestly enhances wakefulness in wild-type (WT) and orexin ligand-deficient mice and reduces sleep-onset REM sleep and cataplexy-like events in the NT1 mouse model. Subcutaneous administration of the selective OX2R agonist TAK-925 moderately increased wakefulness in wild-type mice but not in OX2R knockout mice. A brain-penetrant, stable OX2R agonist that is bioavailable following alternative routes of administration (including, but not limited to, oral, intranasal, transmucosal, and transdermal) and binds with high affinity to highly excitable wake-state-controlling neurons would offer an improvement over current treatments for patients with NT1. Indeed, early clinical studies have reported that TAK-925 exhibits both significant levels of increased wakefulness and a tendency to reduce cataplexy in individuals with NT1. OX1R activation has been implicated in the regulation of emotion and reward behavior and may also contribute to wakefulness.

[0005] Orexin receptor agonists may also be useful in other indications characterized by some degree of orexin neurodegeneration and excessive daytime sleepiness, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and traumatic brain injury. Because orexin promotes wakefulness in intact animals, orexin receptor agonists may treat excessive daytime sleepiness in patients with normal orexin levels, including narcolepsy type 2, idiopathic hypersomnia, or sleep apnea. Similarly, orexin receptor agonists may confer wake-promoting effects in recurrent hypersomnia, such as Kleine-Levin syndrome, or in disorders of inappropriately timed sleep (i.e., circadian rhythm sleep disorders), such as sleep phase delay or sleep phase advance disorder, shift work disorder, and jet lag disorder. Orexin receptor agonists may reduce abnormal daytime sleepiness, sleep-onset REM sleep, and cataplexy-like symptoms in rare genetic disorders (e.g., ADCA-DN, Coffin-Lowry syndrome, Moebius syndrome, Norrie disease, Niemann-Pick disease type C, and Prader-Willi syndrome). Other indications suggested to benefit from orexin receptor agonists include attention-deficit hyperactivity disorder, age-related cognitive dysfunction, metabolic syndrome and obesity, osteoporosis, heart failure, coma, and emergence from anesthesia.

[0006] The present disclosure arises out of a need to provide additional compounds with improved therapeutic potential for modulating orexin receptor activity in the brain, including activation of the orexin-2 receptor. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical properties relative to existing compounds are desirable. Summary of the Invention

[0007] overview In some aspects, the present disclosure provides a compound of formula (I'): TIFF0007811578000001.tif45128, or a pharmaceutically acceptable salt thereof; During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl- is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; n is an integer ranging from 0 to 3; R a and R b are each independently H, halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S or R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from the group consisting of one or more R S may be substituted with; Each R S are independently halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; Z is -O- or -NR Z - where R Z is H or C1-C6 alkyl; R1 is -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with; Each R 1Sare independently oxo, halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), -S(C-C alkyl), -SO(C-C alkyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A1 may be substituted with; Each R A1 are independently Ar2, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; T is absent or Ar2; Each Ar2 is independently C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0008] In some aspects, the present disclosure provides compounds obtainable by or obtained by a method for preparing a compound as described herein (e.g., a method including one or more steps described in Schemes 1-5).

[0009] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0010] In some aspects, the present disclosure provides intermediates as described herein (e.g., the intermediates are selected from the intermediates described in Examples 1-37) suitable for use in methods for preparing compounds as described herein.

[0011] In some aspects, the present disclosure provides methods of modulating orexin-2 receptor activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0012] In some aspects, the present disclosure provides methods of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0013] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0014] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in modulating orexin-2 receptor activity (e.g., in vitro or in vivo).

[0015] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0016] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0017] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating orexin-2 receptor activity (e.g., in vitro or in vivo).

[0018] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0019] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0020] In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure.

[0021] In some aspects, the disclosure provides methods of preparing compounds comprising one or more of the steps described herein.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.In this specification, the singular form also includes the plural form unless the context clearly indicates otherwise.Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below.All publications, patent applications, patents and other references mentioned herein are incorporated by reference.References cited herein are not admitted to be prior art to the claimed invention.In case of conflict, the present specification, including definitions, will prevail.In addition, materials, methods and examples are illustrative only and are not intended to be limiting.In the event of a conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will prevail.

[0023] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed Description The present disclosure relates to macrocyclic ([1,1'-biphenyl]-3-ylmethyl)-substituted heterocyclic derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which can modulate orexin-2 receptor activity and are therefore useful in methods of treatment of the human or animal body. The disclosure also relates to methods for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of disorders in which the orexin-2 receptor is implicated, such as narcolepsy, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or anesthesia emergence.

[0025] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings indicated below.

[0026] Although not wishing to be limited by this description, it is understood that although various options for variables are described herein, the present disclosure is intended to encompass operable embodiments having combinations of options. The present disclosure may be interpreted as excluding inoperable embodiments caused by a particular combination of options. For example, although various options for variables X, L, and Y are described herein, the present disclosure may be interpreted as excluding structures for inoperable compounds caused by a particular combination of variables X, L, and Y (e.g., when X, L, and Y are each -O-).

[0027] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups, and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, l-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight-chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in other embodiments, a straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0028] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0029] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, a straight-chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0030] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0031] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched alkynyl groups. In certain embodiments, a straight-chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0032] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0033] Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties with one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0034] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10, or C3-C8), a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings of the cycloalkyl need be non-aromatic.

[0035] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic), having one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (e.g., O, N, S, P, or Se), e.g., 1, 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxa Zepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexyl San-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4 ,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of polycyclic heterocycloalkyls, only one of the rings of the heterocycloalkyl need be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0036] It is understood that when a variable has two bonds to the rest of the compound formula, the two bonds can be at the same atom or different atoms of the variable. For example, if a variable (e.g., variable X) is a cycloalkyl or heterocycloalkyl and has two bonds to the rest of the compound formula, the two bonds can be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl.

[0037] As used herein, the term "aryl" includes groups having aromaticity, including "conjugated" or polycyclic systems that have one or more aromatic rings and do not contain any heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, the aryl is phenyl.

[0038] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heteroaromatic ring consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)). p, where p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, heteroaryl is thiophenyl. In some embodiments, heteroaryl is benzothiophenyl.

[0039] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0040] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have at one or more ring positions (e.g., a ring carbon or a heteroatom such as N) a substituent as described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aryl The aryl and heteroaryl groups can be substituted with aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl, e.g., benzo[d][1,3]dioxol-5-yl).

[0041] As used herein, the term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced with one selected from the indicated group, provided that the normal valence of the specified atom is not exceeded and that the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents do not occur on aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

[0042] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When such substituent is listed without indicating the atom through which it is bonded to the remainder of the compound of a given formula, then such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0043] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is defined as substituted with 0 to 2 R moieties, that group may be substituted with up to 2 R moieties, and R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0044] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH or -O - The group includes a group having the formula:

[0045] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0046] The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl that is substituted with one or more halogen atoms.

[0047] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0048] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0049] As used herein, phrases such as "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," and the like are used interchangeably and all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

[0050] It should be understood that the present disclosure provides methods for synthesizing compounds of any of the formulas described herein. The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to the following schemes, as well as compounds shown in the Examples.

[0051] Throughout this description, when a composition is described as having, including, or comprising particular components, it should be understood that the composition is also envisioned as consisting essentially of, or consisting of, the recited components. Similarly, when a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of, or consists of, the recited process steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0052] It should be understood that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups and, therefore, can employ variously substituted starting materials. While the processes generally provide the desired final compound at or near the end of the overall process, in certain cases it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0053] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures that are known to those skilled in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules, and functional group transformations and manipulations, can be obtained from the relevant scientific literature or from standard textbooks in the field. Examples include, but are not limited to, any one or several sources, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5, incorporated herein by reference. th edition, John Wiley & Sons: New York, 2001;Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and recognized reference texts on organic synthesis known to those skilled in the art.

[0054] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may need to be protected from the reaction conditions using protecting groups. Protecting groups may also be used to distinguish between similar functional groups in a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0055] Unless otherwise specified, any reference to a method of treatment or prevention should be understood to include the use of a compound, as described herein, to provide such treatment or prevention. Furthermore, unless otherwise specified, any reference to a method of treatment or prevention should be understood to include the use of a compound for the preparation of a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention of humans or non-human animals, including rodents and other disease models.

[0056] Unless otherwise specified, any description of a method of treatment should be understood to include the use of a compound, as described herein, to provide such treatment. Furthermore, unless otherwise specified, any description of a method of treatment should be understood to include the use of a compound to prepare a medicament for treating such a condition. Treatment includes treatment of humans or non-human animals (including rodents and other disease models).

[0057] As used herein, the term "subject" includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject can also be a bird or poultry. In some embodiments, the subject is a human.

[0058] As used herein, the term "subject in need thereof" refers to a subject having a disease or a subject at high risk of developing a disease. A subject in need thereof can be a subject who has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be a subject who is at increased risk for developing such a disease or disorder compared to the general population (i.e., a subject who is more susceptible to developing such a disorder compared to the general population). A subject in need thereof may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond to or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need thereof is a subject who has unsuccessfully received all known effective treatments for a disease or disorder disclosed herein. In some embodiments, a subject in need thereof has received at least one prior treatment.

[0059] As used herein, the term "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" may also include the treatment of an in vitro cell or animal model. It should be understood that references to "treating" or "treatment" include the alleviation of established symptoms of the condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition in a person who may be afflicted with or susceptible to the condition, disorder, or condition but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0060] It is to be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, can or may be used to prevent the associated disease, condition or disorder, or to identify suitable candidates for such purposes.

[0061] As used herein, the terms "preventing," "prevent," or "protecting against" describe reducing or eliminating the occurrence of symptoms or complications of such disease, condition, or disorder.

[0062] It should be understood that those skilled in the art may refer to general references for detailed descriptions of known techniques or equivalent techniques discussed herein. These references include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000);Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY;Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY;Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 th These references may, of course, be consulted when making or using aspects of the present disclosure.

[0063] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0064] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk form or in unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump in an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that routine variations in dosage may sometimes be necessary depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrathoracic, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any required preservatives, buffers, or propellants.

[0065] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, substances, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0066] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one such excipient and multiple such excipients.

[0067] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent, e.g., water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent, e.g., benzyl alcohol or methylparaben; an antioxidant, e.g., ascorbic acid or sodium bisulfite; a chelating agent, e.g., ethylenediaminetetraacetic acid; a buffer, e.g., acetate, citrate, or phosphate, and a tonicity adjusting agent, e.g., sodium chloride or dextrose. pH can be adjusted with acids or bases, e.g., hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0068] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject by many of the well-known methods currently used for chemotherapeutic treatment.For example, the compound of the present disclosure can be injected into the bloodstream or body cavity, or taken orally, or applied through the skin by a patch.The selected dose should be sufficient to constitute effective treatment, but should not be so high as to cause unacceptable side effects.The state of disease condition (for example, the disease or disorder disclosed herein) and the health condition of the patient should preferably be carefully monitored during and for a reasonable period after treatment.

[0069] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent to treat, ameliorate, or prevent a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0070] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent to treat or ameliorate a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0071] It should be understood that for any compound, the therapeutically effective amount can be estimated initially in cell culture assays, for example, of tumor cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and administration routes. Such information can then be used to determine useful doses and routes for administration to humans. Therapeutic / prophylactic efficacy and toxicity, for example, ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 The dose lethal to 50% of the population (the dose lethal to 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the ratio LD 50 / ED 50Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0072] Dosage and administration are adjusted to provide a sufficient level of the active substance or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's overall health, the subject's age, weight, and sex, dietary habits, time and frequency of administration, concurrent medications, reaction sensitivity, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the specific formulation.

[0073] The pharmaceutical composition containing the active compound of the present disclosure can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee making, gelling (levigating), emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliary agents that facilitate the processing of active compound into pharmaceutically usable preparations.Of course, the appropriate formulation depends on the selected route of administration.

[0074] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), cyclodextrin, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption, for example, aluminum monostearate and gelatin in the composition.

[0075] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent, and if necessary, with one or a combination of the above-listed ingredients, and then sterilize by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains basic dispersion medium and other ingredients that are required from the above-listed ingredients.For the preparation of sterile powder for sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which produces the powder of active ingredient with any additional desired ingredients from the solution that has been previously sterilized and filtered.

[0076] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. These can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, capsules, or sachets. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, where the compound in the liquid carrier is applied orally, swished in the mouth, and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches, etc. can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavor.

[0077] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0078] Systemic administration can also be via transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and for example, for transmucosal administration, include surfactants, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved by using nasal sprays, powders, or suppositories.For transdermal administration, active compounds are formulated into ointments, salves, gels, or creams as are generally known in the art.

[0079] The active compounds can be prepared with pharmaceutically acceptable carriers that protect the compound from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0080] For ease of administration and uniformity of dosage, it is particularly advantageous to prepare oral or parenteral compositions in dosage unit form.Dosage unit form as used herein refers to the physically separate unit that is suitable for the single dosage of the subject to be treated; each unit contains a predetermined amount of active compound that is calculated to produce desired therapeutic effect together with required pharmaceutical carrier.The specification of dosage unit form of the present disclosure is determined and directly depends on the unique characteristics of active compound and the specific therapeutic effect that should be achieved.

[0081] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors influencing the selected dosage. Generally, dosages should be sufficient to cause a slowing, preferably regression, of symptoms of a disease or disorder disclosed herein, and preferably complete regression of the disease or disorder. Dosages can range from about 0.01 mg / kg / day to about 5000 mg / kg / day. An effective amount of a pharmaceutical agent is an amount that produces an objectively identifiable improvement, as noted by a clinician or other authorized observer. Improvements in survival and growth indicate regression. As used herein, the term "dosage effective manner" refers to the amount of an active compound to produce a desired biological effect in a subject or cell.

[0082] It should be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0083] It should be understood that the compounds of the present disclosure may further form salts, and all of these forms are also contemplated within the scope of the claimed disclosure.

[0084] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, in which the parent compound is modified by preparing its acid salts or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkalis, or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactate, and the like. These include, but are not limited to, salts derived from inorganic and organic acids selected from biotic acid, lauryl sulfate, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0085] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0086] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced either by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of compound to salt cation or anion can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0087] It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0088] The compound or its pharmaceutically acceptable salt can be administered orally, intranasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathoracically, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

[0089] The dosage regimen that utilizes the compound is selected according to various factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the specific compound or its salt that is used.A doctor or veterinarian with ordinary skill can easily determine and prescribe the effective amount of the drug that is required to prevent, counter or stop the progression of the disease state.A doctor or veterinarian with ordinary skill can easily determine and prescribe the effective amount of the drug that is required to counter or stop the progression of the disease state.

[0090] Techniques for formulation and administration of the disclosed compounds of this disclosure are found in Remington: The Science and Practice of Pharmacy, 1999. th ed., Mack Publishing Co., Easton, PA (1995). In some embodiments, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage in the range described herein.

[0091] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will be apparent from the examples. The examples provided illustrate various components and methodologies useful in implementing the present disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, one skilled in the art can identify and employ other components and methodologies useful in implementing the present disclosure.

[0092] In the synthesis schemes described herein, compounds may be depicted in one specific configuration for simplicity.This specific configuration should not be interpreted as limiting the present disclosure to any isomer, tautomer, positional isomer or stereoisomer, and does not exclude the mixture of isomer, tautomer, positional isomer or stereoisomer;However, it should be understood that a given isomer, tautomer, positional isomer or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer or stereoisomer.

[0093] All publications and patent documents cited herein are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated by reference. The citation of any publication or patent document is not intended as an admission that it is pertinent prior art, nor does it constitute any admission as to the contents or date thereof. While the present invention has been described above by written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative, not limiting, of the scope of the claims that follow.

[0094] As used herein, the phrase "compounds of the present disclosure" refers to compounds disclosed herein both generically and specifically.

[0095] Compounds of the Disclosure In some aspects, the present disclosure provides a compound of formula (I'): TIFF0007811578000002.tif45128, or a pharmaceutically acceptable salt thereof; During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; n is an integer ranging from 0 to 3; R a and R b are each independently H, halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S or R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from the group consisting of one or more R S may be substituted with; Each R S are independently halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; Z is -O- or -NR Z - where R Z is H or C1-C6 alkyl; R1 is -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -S(C6-C 10aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with; Each R 1S are independently oxo, halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), -S(C-C alkyl), -SO(C-C alkyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar1 is C6-C 10aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A1 may be substituted with; Each R A1 are independently Ar2, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; T is absent or Ar2; Each Ar2 is independently C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0096] In some aspects, the present disclosure provides a compound of formula (I): TIFF0007811578000003.tif45128, or a pharmaceutically acceptable salt thereof; During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; n is an integer ranging from 0 to 3; Z is -O- or -NR Z - where R Z is H or C1-C6 alkyl; R1 is -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10-cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with; Each R 1S are independently oxo, halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), -S(C-C alkyl), -SO(C-C alkyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A1 may be substituted with; Each R A1 are independently Ar2, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; T is absent or Ar2; Each Ar2 is independently C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0097] In some aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl-, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; n is an integer ranging from 0 to 3; Z is -O- or -NR Z - where R Z is H or C1-C6 alkyl; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with; Each R 1S are independently halogen, —CN, —OH, or C1-C6 alkoxy; Ar1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A1 may be substituted with; Each R A1are independently Ar2, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; T is absent or Ar2; Each Ar2 is independently C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0098] In some aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is —O— or C1-C6 alkyl; n is an integer ranging from 0 to 3; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more Ar2 groups. 10 is aryl; T is absent or Ar2; Each Ar2 is independently C6-C 10 It is aryl.

[0099] In some aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is —O— or C1-C6 alkyl; n is an integer ranging from 0 to 3; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is C1-C6 alkyl; Ar1 is C6-C 10 is aryl; T is C6-C 10 It is aryl.

[0100] In some aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is —O— or C1-C6 alkyl; n is an integer ranging from 0 to 3; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is C1-C6 alkyl; Ar1 is one or more C6-C 10 C6-C optionally substituted with aryl 10 is aryl; T does not exist.

[0101] In some aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is —O— or C1-C6 alkyl; n is 2; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S and the C1-C6 alkyl may be substituted with one or more R 1S is replaced by; Each R 1S are independently halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), -S(C-C alkyl), -SO(C-C alkyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar1 is one or more R A1 C6-C optionally substituted with 10 is aryl; Each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is Ar2; Ar2 is one or more R A2 C6-C optionally substituted with 10 is aryl; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0102] For the compounds of the present disclosure, the variables X, L, nl, Y, n, R a , R b , Z, R Z , R1, R 1S , Ar1, R A1 , T, Ar2, and R A2 can each be selected from the group described herein, where applicable, and the variables X, L, nl, Y, n, R a , R b , Z, R Z , R1, R 1S , Ar1, R A1 , T, Ar2, and R A2 Any group described herein for any of the variables X, L, nl, Y, n, R, if applicable, may be used. a , R b , Z, R Z , R1, R 1S , Ar1, R A1 , T, Ar2, and R A2 It is understood that one or more of the remaining groups may be combined with any group described herein.

[0103] Variable X In some embodiments, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0104] In some embodiments, X is —O—.

[0105] In some embodiments, X is -NH- or -N(C-C alkyl)-, where -N(C-C alkyl)- is optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0106] In some embodiments, X is —NH—.

[0107] In some embodiments, X is -N(C-C alkyl)- optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0108] In some embodiments, X is -N(C1-C6 alkyl)- optionally substituted with one or more halogens or -OH.

[0109] In some embodiments, X is -N(C1-C6 alkyl)- optionally substituted with one or more F or -OH.

[0110] In some embodiments, X is -N(C1-C6 alkyl)-.

[0111] In some embodiments, X is —N(CH 3 )—.

[0112] In some embodiments, X is -N(C1-C6 alkyl)- substituted with one or more halogens or -OH.

[0113] In some embodiments, X is -N(C1-C6 alkyl)- substituted with one or more F or -OH.

[0114] In some embodiments, X is -N(C1-C6 alkyl)- substituted with at least one F and at least one -OH.

[0115] In some embodiments, X is -N(C1-C6 alkyl)- substituted with 1-3 F and 1 -OH.

[0116] In some embodiments, X is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0117] In some embodiments, X is C-C alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0118] In some embodiments, X is C1-C6 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0119] In some embodiments, X is C1-C6 alkyl (eg, methyl, ethyl, or propyl) optionally substituted with one or more halogens (eg, F).

[0120] In some embodiments, X is C1-C6 alkyl (eg, methyl, ethyl, or propyl) optionally substituted with one or more C1-C6 haloalkyl.

[0121] In some embodiments, X is C1-C6 alkyl (eg, methyl, ethyl, or propyl) optionally substituted with one or more C1-C6 alkoxy.

[0122] In some embodiments, X is C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0123] In some embodiments, X is C-C alkyl (e.g., methyl, ethyl, or propyl) substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0124] In some embodiments, X is C1-C6 alkyl (e.g., methyl, ethyl, or propyl) substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0125] In some embodiments, X is C1-C6 alkyl (eg, methyl, ethyl, or propyl) substituted with one or more halogens (eg, F).

[0126] In some embodiments, X is C1-C6 alkyl (eg, methyl, ethyl, or propyl) substituted with one or more C1-C6 haloalkyl.

[0127] In some embodiments, X is C1-C6 alkyl (eg, methyl, ethyl, or propyl) substituted with one or more C1-C6 alkoxy.

[0128] In some embodiments, X is C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0129] In some embodiments, X is C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0130] In some embodiments, X is C3-C8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0131] In some embodiments, X is C3-C8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0132] In some embodiments, X is a C-C alkyl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy. 10 It is aryl.

[0133] In some embodiments, X is C6-C 10 It is aryl.

[0134] In some embodiments, X is a C-C alkyl substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy. 10 It is aryl.

[0135] In some embodiments, X is a 3-8 membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, or piperidinyl) optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0136] In some embodiments, X is a 3-8 membered heterocycloalkyl (eg, acetidinyl, pyrrolidinyl, or piperidinyl).

[0137] In some embodiments, X is a 3-8 membered heterocycloalkyl (e.g., acetidinyl, pyrrolidinyl, or piperidinyl) substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0138] In some embodiments, X is acetidinyl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy. The file is TIFF0007811578000004.tif24128.

[0139] In some embodiments, X is acetidinyl The file is TIFF0007811578000005.tif23128.

[0140] In some embodiments, X is acetidinyl substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy. The file is TIFF0007811578000006.tif21128.

[0141] In some embodiments, X is a 5-10 membered heteroaryl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0142] In some embodiments, X is a 5-10 membered heteroaryl.

[0143] In some embodiments, X is a 5-10 membered heteroaryl substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0144] Variables L and nl In some embodiments, L is absent.

[0145] In some embodiments, L is -O-, -NH-, -N(C-C alkyl)-, C-C alkyl, C-C alkenyl, -((C-C alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl-, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0146] In some embodiments, L is —O—.

[0147] In some embodiments, L is -NH- or -N(C1-C6 alkyl)-, where -N(C1-C6 alkyl)- is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0148] In some embodiments, L is —NH—.

[0149] In some embodiments, L is —N(C1-C6 alkyl)- optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0150] In some embodiments, L is -N(C1-C6 alkyl)-.

[0151] In some embodiments, L is —N(C1-C6 alkyl)- substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0152] In some embodiments, L is C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0153] In some embodiments, L is C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0154] In some embodiments, L is C1-C6 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one or more halogens, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0155] In some embodiments, L is C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0156] In some embodiments, L is C1-C6 alkyl (e.g., methyl, ethyl, or propyl) substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0157] In some embodiments, L is C2-C6 alkenyl optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0158] In some embodiments, L is C2-C6 alkenyl.

[0159] In some embodiments, L is C2-C6 alkenyl substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0160] In some embodiments, L is -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl-, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0161] In some embodiments, L is -((C1-C6 alkyl)-O) nl -or -(O-(C1-C6 alkyl)) nl -, where -((C1-C6 alkyl)-O) nl -or -(O-(C1-C6 alkyl)) nl - may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0162] In some embodiments, L is -((C-C alkyl)-O) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0163] In some embodiments, L is -((C1-C6 alkyl)-O) nl -It is.

[0164] In some embodiments, L is -((C-C alkyl)-O) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0165] In some embodiments, L is -(O-(C-C alkyl)) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0166] In some embodiments, L is -(O-(C1-C6 alkyl)) nl -It is.

[0167] In some embodiments, L is -(O-(C-C alkyl)) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl) nl -It is.

[0168] In some embodiments, L is -((C2-C6 alkenyl)-O) nl -or -(O-(C2-C6 alkenyl)) nl -, where -((C2-C6 alkenyl)-O) nl -or -(O-(C2-C6 alkenyl)) nl - may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0169] In some embodiments, L is -((C-C alkenyl)-O) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0170] In some embodiments, L is -((C2-C6 alkenyl)-O) nl -It is.

[0171] In some embodiments, L is -((C-C alkenyl)-O) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0172] In some embodiments, L is -(O-(C-C alkenyl)) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0173] In some embodiments, L is -(O-(C2-C6 alkenyl)) nl -It is.

[0174] In some embodiments, L is -(O-(C-C alkenyl)) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0175] In some embodiments, L is -((C1-C6 alkyl)-NH) nl -or -(NH-(C1-C6 alkyl)) nl -, where -((C1-C6 alkyl)-NH) nl -or -(NH-(C1-C6 alkyl)) nl - may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0176] In some embodiments, L is -((C-C alkyl)-NH) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl).nl -It is.

[0177] In some embodiments, L is -((C1-C6 alkyl)-NH) nl -It is.

[0178] In some embodiments, L is -((C-C alkyl)-NH) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0179] In some embodiments, L is -(NH-(C-C alkyl)) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0180] In some embodiments, L is -(NH-(C1-C6 alkyl)) nl -It is.

[0181] In some embodiments, L is -(NH-(C-C alkyl)) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl) nl -It is.

[0182] In some embodiments, L is -((C2-C6 alkenyl)-NH) nl -or -(NH-(C2-C6 alkenyl)) nl -, where -((C2-C6 alkenyl)-NH) nl -or -(NH-(C2-C6 alkenyl)) nl - may be substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0183] In some embodiments, L is -((C-C alkenyl)-NH) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0184] In some embodiments, L is -((C2-C6 alkenyl)-NH) nl -It is.

[0185] In some embodiments, L is -((C-C alkenyl)-NH) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0186] In some embodiments, L is -(NH-(C-C alkenyl)) optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0187] In some embodiments, L is -(NH-(C2-C6 alkenyl)) nl -It is.

[0188] In some embodiments, L is -(NH-(C-C alkenyl)) substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), or -N(C-C alkyl). nl -It is.

[0189] In some embodiments, nl is an integer ranging from 1-6.

[0190] In some embodiments, nl is 6.

[0191] In some embodiments, nl is an integer ranging from 1-5.

[0192] In some embodiments, nl is 5.

[0193] In some embodiments, nl is an integer ranging from 1 to 4.

[0194] In some embodiments, nl is 4.

[0195] In some embodiments, nl is an integer ranging from 1 to 3.

[0196] In some embodiments, nl is 1. In some embodiments, nl is 2. In some embodiments, nl is 3.

[0197] Variable factor Y In some embodiments, Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, wherein -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0198] In some embodiments, Y is —O—.

[0199] In some embodiments, Y is -NH- or -N(C1-C6 alkyl)-, where -N(C1-C6 alkyl)- is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0200] In some embodiments, Y is —NH—.

[0201] In some embodiments, -N(C-C alkyl)- optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0202] In some embodiments, -N(C1-C6 alkyl)-.

[0203] In some embodiments, -N(C1-C6 alkyl)- substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0204] In some embodiments, Y is C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0205] In some embodiments, Y is C-C alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0206] In some embodiments, Y is C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0207] In some embodiments, Y is C-C alkyl (e.g., methyl, ethyl, or propyl) substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0208] In some embodiments, Y is C2-C6 alkenyl optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0209] In some embodiments, Y is C2-C6 alkenyl.

[0210] In some embodiments, Y is C2-C6 alkenyl substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0211] Exemplary Embodiments of Variables X, L, and Y In some embodiments, at most one of X and L is -O-, -NH-, or an optionally substituted -N(C1-C6 alkyl)-.

[0212] In some embodiments, at most one of L and Y is -O-, -NH-, or an optionally substituted -N(C1-C6 alkyl)-.

[0213] In some embodiments, at most one of X and Y is -O-, -NH-, or an optionally substituted -N(C1-C6 alkyl)-.

[0214] In some embodiments, up to two of X, L, and Y are -O-, -NH-, or an optionally substituted -N(C1-C6 alkyl)-.

[0215] In some embodiments, at most one of X, L, and Y is -O-, -NH-, or an optionally substituted -N(C1-C6 alkyl)-.

[0216] In some embodiments, when X is -O-, -NH-, or optionally substituted -N(C-C alkyl)- and Y is -O-, -NH-, or optionally substituted -N(C-C alkyl)-, then L is not absent, -O-, -NH-, or optionally substituted -N(C-C alkyl)-.

[0217] In some embodiments, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl))nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is a C1-C6 alkyl or a C2-C6 alkenyl, where the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0218] In some embodiments, X is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl-, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is a C1-C6 alkyl or a C2-C6 alkenyl, where the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0219] In some embodiments, X is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl-, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0220] In some embodiments, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; and Y is -O- or C1-C6 alkyl.

[0221] In some embodiments, X is -O-, -NH-, or -N(C1-C6 alkyl)-; L is C1-C6 alkyl; and Y is -O-.

[0222] In some embodiments, X is C1-C6 alkyl; L is absent; and Y is C1-C6 alkyl.

[0223] Variable factor n In some embodiments, n is an integer ranging from 0-3.

[0224] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0225] Variable factor R a , R b , and R S In some embodiments, R a and R b are each independently H, halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S or R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from the group consisting of one or more R S may be substituted with.

[0226] In some embodiments, R a and R b One of them is H and R a and R bis halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S or R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from the group consisting of one or more R S may be substituted with.

[0227] In some embodiments, R a is H and R b is halogen, -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S or R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from the group consisting of one or more R S may be substituted with.

[0228] In some embodiments, R a and R b are each independently H or halogen; or R a and R btogether with the atoms to which they are attached, form one or more R S Forms an optionally substituted C3-C7 cycloalkyl.

[0229] In some embodiments, R a and R b are each independently H or halogen; or R a and R b together with the atoms to which they are attached form a C3-C7 cycloalkyl.

[0230] In some embodiments, R a and R b are each independently H or halogen; or R a and R b together with the atoms to which they are attached, form one or more R S to form an optionally substituted cyclopropyl group.

[0231] In some embodiments, R a and R b are each independently H or halogen; or R a and R b together with the atom to which they are attached form cyclopropyl.

[0232] In some embodiments, R a and R b are each independently H or halogen.

[0233] In some embodiments, R a and R b At least one of is H.

[0234] In some embodiments, R a and R b One of them is H.

[0235] In some embodiments, R a and R bare H, respectively.

[0236] In some embodiments, R a and R b are each independently a halogen.

[0237] In some embodiments, R a and R b are each independently F or Cl.

[0238] In some embodiments, R a and R b At least one of is a halogen.

[0239] In some embodiments, R a and R b At least one of is F or Cl.

[0240] In some embodiments, R a and R b One of them is H and R a and R b One of the is a halogen (eg, F or Cl).

[0241] In some embodiments, R a is H and R b is a halogen (e.g., F or Cl).

[0242] In some embodiments, R a and R b is -CN, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S may be substituted with.

[0243] In some embodiments, R a and R b At least one of is -CN.

[0244] In some embodiments, R a and R b at least one of is -OH or -O(C1-C6 alkyl), where -O(C1-C6 alkyl) is one or more R S may be substituted with.

[0245] In some embodiments, R a and R b is -NH, -NH(C-C alkyl), or -N(C-C alkyl), where -NH(C-C alkyl) or -N(C-C alkyl) is selected from one or more R S may be substituted with.

[0246] In some embodiments, R a and R b is a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S may be substituted with.

[0247] In some embodiments, R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from one or more R S may be substituted with.

[0248] In some embodiments, R a and R b together with the atoms to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl.

[0249] In some embodiments, R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from one or more R S is replaced by .

[0250] In some embodiments, R a and R b together with the atoms to which they are attached, form one or more R S Forms an optionally substituted C3-C7 cycloalkyl.

[0251] In some embodiments, R a and R b together with the atoms to which they are attached form a C3-C7 cycloalkyl.

[0252] In some embodiments, R a and R b together with the atoms to which they are attached, form one or more R S to form a C3-C7 cycloalkyl substituted with

[0253] In some embodiments, R a and R b together with the atoms to which they are attached, form one or more R S to form an optionally substituted cyclopropyl group.

[0254] In some embodiments, R a and R b together with the atom to which they are attached form cyclopropyl.

[0255] In some embodiments, R a and R b together with the atoms to which they are attached, form one or more R S to form a cyclopropyl substituted with

[0256] In some embodiments, R a and R b together with the atoms to which they are attached, form one or more R S and forming an optionally substituted 3- to 7-membered heterocycloalkyl.

[0257] In some embodiments, R a and R b together with the atom to which they are attached form a 3- to 7-membered heterocycloalkyl.

[0258] In some embodiments, R a and R b together with the atoms to which they are attached, form one or more R S Form a 3- to 7-membered heterocycloalkyl substituted with

[0259] In some embodiments, at least one R S is halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0260] In some embodiments, at least one R S is a halogen or —CN.

[0261] In some embodiments, at least one R S is —OH or —O(C1-C6 alkyl).

[0262] In some embodiments, at least one R S is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0263] In some embodiments, at least one R S is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl.

[0264] Variables Z and R Z In some embodiments, Z is —O— or —NR Z - where R Z is H or C1-C6 alkyl.

[0265] In some embodiments, Z is -O-. In some embodiments, Z is -NR Z In some embodiments, Z is -NH-. In some embodiments, Z is -N(C1-C6 alkyl)-. In some embodiments, R Z is H. In some embodiments, R Z is C1-C6 alkyl (e.g., methyl, ethyl, or propyl).

[0266] Variables R1 and R 1S In some embodiments, R1 is selected from the group consisting of -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with.

[0267] In some embodiments, R1 is selected from the group consisting of -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 -cycloalkyl), or -NH- (3- to 7-membered heterocycloalkyl), may be substituted with one or more halogen, -CN, -OH, or C1-C6 alkoxy.

[0268] In some embodiments, R1 is -OH.

[0269] In some embodiments, R1 is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, where -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 is selected from one or more R 1S may be substituted with.

[0270] In some embodiments, R1 is -NH2.

[0271] In some embodiments, R is one or more R 1S is —NH(C1-C6 alkyl) optionally substituted with

[0272] In some embodiments, R is one or more R 1S is —N(C1-C6 alkyl)2 optionally substituted with

[0273] In some embodiments, R1 is -SH, -S(C1-C6 alkyl), or -S(C6-C 10 aryl), where -S(C1-C6 alkyl) or -S(C6-C 10 aryl) can be one or more R 1S may be substituted with.

[0274] In some embodiments, R1 is -SH.

[0275] In some embodiments, R is -S(C-C alkyl) or -S(C-C 10 aryl), where -S(C1-C6 alkyl) or -S(C6-C 10 aryl) can be one or more R 1S may be substituted with.

[0276] In some embodiments, R is one or more R 1S is —S(C1-C6 alkyl) optionally substituted with

[0277] In some embodiments, R1 is -S(C1-C6 alkyl).

[0278] In some embodiments, R is one or more R 1S is —S(C1-C6 alkyl) substituted with

[0279] In some embodiments, R is one or more R 1S -S(C6-C 10 aryl).

[0280] In some embodiments, R is -S(C 10 aryl).

[0281] In some embodiments, R is one or more R 1S -S(C6-C 10 aryl).

[0282] In some embodiments, R is selected from the group consisting of C-C alkyl, C-C alkenyl, C-C alkynyl, C-C haloalkyl, C-C alkoxy, C-C 10 aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10An aryl, 5- to 10-membered heteroaryl, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl may be one or more R 1S may be substituted with.

[0283] In some embodiments, R is one or more R 1S and C1-C6 alkyl (for example, methyl, ethyl, or propyl) optionally substituted with

[0284] In some embodiments, R1 is C1-C6 alkyl (eg, methyl, ethyl, or propyl).

[0285] In some embodiments, R1 is methyl.

[0286] In some embodiments, R1 is ethyl.

[0287] In some embodiments, R1 is propyl.

[0288] In some embodiments, R is one or more R 1S and C1-C6 alkyl (e.g., methyl, ethyl, or propyl) substituted with

[0289] In some embodiments, R is one or more R 1S is a methyl substituted with

[0290] In some embodiments, R is one or more R 1S is ethyl substituted with

[0291] In some embodiments, R is one or more R 1S is a propyl substituted with

[0292] In some embodiments, R is one or more R 1S and C2-C6 alkenyl optionally substituted with

[0293] In some embodiments, R is one or more R 1S and C2-C6 alkynyl optionally substituted with.

[0294] In some embodiments, R is one or more R 1S and C1-C6 haloalkyl optionally substituted with.

[0295] In some embodiments, R is one or more R 1S and C1-C6 alkoxy optionally substituted with.

[0296] In some embodiments, R is one or more R 1S C6-C optionally substituted with 10 It is aryl.

[0297] In some embodiments, R is one or more R 1S and optionally substituted 5- to 10-membered heteroaryl.

[0298] In some embodiments, R is one or more R 1S and C3-C7 cycloalkyl optionally substituted with

[0299] In some embodiments, R is one or more R 1S and C3-C7 cycloalkyl optionally substituted with

[0300] In some embodiments, R is one or more R 1S and cyclopropyl, optionally substituted with

[0301] In some embodiments, R1 is cyclopropyl optionally substituted with one or more halogens.

[0302] In some embodiments, R 1 is cyclopropyl optionally substituted with one or more F.

[0303] In some embodiments, R is one or more R 1S and optionally substituted 3- to 7-membered heterocycloalkyl.

[0304] In some embodiments, R1 is -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 cycloalkyl), or -O-(3- to 7-membered heterocycloalkyl), where -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), or -O-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with.

[0305] In some embodiments, R is one or more R 1S -O-(C6-C 10 aryl).

[0306] In some embodiments, R is one or more R 1S is —O-(5- to 10-membered heteroaryl) optionally substituted with

[0307] In some embodiments, R is one or more R 1S -O-(C3-C 10 cycloalkyl).

[0308] In some embodiments, R is one or more R 1S and -O-(3- to 7-membered heterocycloalkyl) optionally substituted with

[0309] In some embodiments, R1 is -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where NH-(C6-C 10aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with.

[0310] In some embodiments, R is one or more R 1S -NH-(C6-C 10 aryl).

[0311] In some embodiments, R is one or more R 1S is —NH—(5- to 10-membered heteroaryl) optionally substituted with

[0312] In some embodiments, R is one or more R 1S -NH-(C3-C 10 cycloalkyl).

[0313] In some embodiments, R is one or more R 1S and -NH-(3- to 7-membered heterocycloalkyl) optionally substituted with

[0314] In some embodiments, at least one R 1S is halogen (e.g., F), —CN, —OH, or C1-C6 alkoxy.

[0315] In some embodiments, at least one R 1S is oxo.

[0316] In some embodiments, at least one R 1S is a halogen (e.g., F, Cl, or Br).

[0317] In some embodiments, at least one R 1S is F. In some embodiments, at least one R 1S is Cl. In some embodiments, at least one R 1Sis Br.

[0318] In some embodiments, at least one R 1S In some embodiments, at least one R 1S is -OH.

[0319] In some embodiments, at least one R 1S is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0320] In some embodiments, at least one R 1S is -S(C1-C6 alkyl). In some embodiments, at least one R 1S is -SO2(C1-C6 alkyl).

[0321] In some embodiments, at least one R 1S is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0322] In some embodiments, at least one R 1S is C1-C6 alkyl. In some embodiments, at least one R 1S is C2-C6 alkenyl. In some embodiments, at least one R 1S is C2-C6 alkynyl.

[0323] In some embodiments, at least one R 1S is C1-C6 alkoxy.

[0324] In some embodiments, at least one R 1S is a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl.

[0325] In some embodiments, at least one R 1S is a C3-C7 cycloalkyl.

[0326] In some embodiments, at least one R 1S is a 3- to 7-membered heterocycloalkyl.

[0327] Variables Ar1 and R A1 In some embodiments, Ar1 is selected from one or more R A1 C6-C optionally substituted with 10 It is aryl.

[0328] In some embodiments, Ar1 is C6-C 10 It is aryl.

[0329] In some embodiments, Ar1 is selected from one or more R A1 C6-C substituted with 10 It is aryl.

[0330] In some embodiments, Ar1 is selected from one or more R A1 and phenyl optionally substituted with .

[0331] In some embodiments, Ar1 is The file is TIFF0007811578000007.tif24128.

[0332] In some embodiments, Ar1 is TIFF0007811578000008.tif35128.

[0333] In some embodiments, Ar1 is phenyl.

[0334] In some embodiments, Ar1 is selected from one or more R A1 is a phenyl substituted with

[0335] In some embodiments, Ar1 is selected from one or more R A1 and optionally substituted 5- to 10-membered heteroaryl.

[0336] In some embodiments, Ar1 is a 5-10 membered heteroaryl.

[0337] In some embodiments, Ar1 is selected from one or more R A1 is a 5- to 10-membered heteroaryl substituted with

[0338] In some embodiments, Ar1 is selected from one or more R A1 and optionally substituted pyridyl or thiazolyl.

[0339] In some embodiments, Ar1 is pyridyl or thiazolyl.

[0340] In some embodiments, Ar1 is selected from one or more R A1 and pyridyl or thiazolyl substituted with

[0341] In some embodiments, Ar1 is selected from one or more R A1 and pyridyl optionally substituted with

[0342] In some embodiments, Ar1 is The file is TIFF0007811578000009.tif24128.

[0343] In some embodiments, Ar1 is pyridyl.

[0344] In some embodiments, Ar1 is selected from one or more R A1 and pyridyl substituted with

[0345] In some embodiments, Ar1 is selected from one or more R A1 and optionally substituted thiazolyl.

[0346] In some embodiments, Ar1 is thiazolyl.

[0347] In some embodiments, Ar1 is selected from one or more R A1 and thiazolyl substituted with

[0348] In some embodiments, at least one R A1 is Ar2.

[0349] In some embodiments, one R A1 is Ar2.

[0350] In some embodiments, at least one R A1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with.

[0351] In some embodiments, at least one R A1 is one or more R A2 C6-C optionally substituted with 10 It is aryl.

[0352] In some embodiments, at least one R A1 is C6-C 10 It is aryl.

[0353] In some embodiments, at least one R A1 is one or more R A2 C6-C substituted with 10 It is aryl.

[0354] In some embodiments, at least one R A1 is one or more R A2 and phenyl optionally substituted with .

[0355] In some embodiments, at least one R A1 is phenyl.

[0356] In some embodiments, at least one R A1 is one or more R A2 is a phenyl substituted with

[0357] In some embodiments, at least one R A1 is one or more R A2 and optionally substituted 5- to 10-membered heteroaryl.

[0358] In some embodiments, at least one R A1 is a 5- to 10-membered heteroaryl.

[0359] In some embodiments, at least one R A1 is one or more R A2 is a 5- to 10-membered heteroaryl substituted with

[0360] In some embodiments, at least one R A1 is one or more R A2 and optionally substituted pyridyl or thiazolyl.

[0361] In some embodiments, at least one R A1 is pyridyl or thiazolyl.

[0362] In some embodiments, at least one R A1 is one or more R A2 and pyridyl or thiazolyl substituted with

[0363] In some embodiments, at least one R A1 is one or more R A2 and pyridyl optionally substituted with

[0364] In some embodiments, at least one R A1 is pyridyl.

[0365] In some embodiments, at least one R A1 is one or more R A2 and pyridyl substituted with

[0366] In some embodiments, at least one R A1 is one or more RA2 and optionally substituted thiazolyl.

[0367] In some embodiments, at least one R A1 is thiazolyl.

[0368] In some embodiments, at least one R A1 is one or more R A2 and thiazolyl substituted with

[0369] In some embodiments, at least one R A1 is halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0370] In some embodiments, at least one R A1 is a halogen (e.g., F, Cl, or Br).

[0371] In some embodiments, at least one R A1 is F. In some embodiments, at least one R A1 is Cl. In some embodiments, at least one R A1 is Br.

[0372] In some embodiments, at least one R A1 In some embodiments, at least one R A1 is -OH.

[0373] In some embodiments, at least one R A1 is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0374] In some embodiments, at least one R A1is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0375] In some embodiments, at least one R A1 is C1-C6 alkyl.

[0376] In some embodiments, at least one R A1 is C1-C6 haloalkyl (e.g., -CH2F, -CHF2, or -CF3).

[0377] In some embodiments, at least one R A1 is C1-C6 alkoxy.

[0378] In some embodiments, at least one R A1 is C1-C6 haloalkoxy (e.g., -OCH2F, -OCHF2, or -OCF3).

[0379] In some embodiments, at least one R A1 is C2-C6 alkenyl. In some embodiments, at least one R A1 is C2-C6 alkynyl.

[0380] Variable factor T In some embodiments, T is absent.

[0381] In some embodiments, T is Ar2.

[0382] In some embodiments, T is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with.

[0383] In some embodiments, T is selected from one or more R A2 C6-C optionally substituted with10 It is aryl.

[0384] In some embodiments, T is The file is TIFF0007811578000010.tif19128.

[0385] In some embodiments, T is C6-C 10 It is aryl.

[0386] In some embodiments, T is selected from one or more R A2 C6-C substituted with 10 It is aryl.

[0387] In some embodiments, T is selected from one or more R A2 and phenyl optionally substituted with .

[0388] In some embodiments, T is phenyl.

[0389] In some embodiments, T is selected from one or more R A2 is a phenyl substituted with

[0390] In some embodiments, T is selected from one or more R A2 and optionally substituted 5- to 10-membered heteroaryl.

[0391] In some embodiments, T is a 5-10 membered heteroaryl.

[0392] In some embodiments, T is selected from one or more R A2 is a 5- to 10-membered heteroaryl substituted with

[0393] In some embodiments, T is selected from one or more R A2 and optionally substituted pyridyl or thiazolyl.

[0394] In some embodiments, T is pyridyl or thiazolyl.

[0395] In some embodiments, T is selected from one or more R A2 and pyridyl or thiazolyl substituted with

[0396] In some embodiments, T is selected from one or more R A2 and pyridyl optionally substituted with

[0397] In some embodiments, T is pyridyl.

[0398] In some embodiments, T is selected from one or more R A2 and pyridyl substituted with

[0399] In some embodiments, T is selected from one or more R A2 and optionally substituted thiazolyl.

[0400] In some embodiments, T is thiazolyl.

[0401] In some embodiments, T is selected from one or more R A2 and thiazolyl substituted with

[0402] Variable elements Ar1, R A1 , and exemplary embodiments of T In some embodiments, at least one R A1 is Ar2 and T is absent.

[0403] In some embodiments, at least one R A1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 and T is absent.

[0404] In some embodiments, at least one R A1 is one or more R A2 C6-C optionally substituted with10 It is aryl and T is absent.

[0405] In some embodiments, at least one R A1 is one or more R A2 and T is absent.

[0406] In some embodiments, at least one R A1 is one or more R A2 and T is absent.

[0407] In some embodiments, at least one R A1 is one or more R A2 and T is absent.

[0408] In some embodiments, Ar1 is TIFF0007811578000011.tif35128, where T does not exist.

[0409] In some embodiments, each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; and T is Ar.

[0410] In some embodiments, Ar1 is selected from one or more R A1 C6-C optionally substituted with 10 aryl and T is Ar2.

[0411] In some embodiments, Ar1 is selected from one or more R A1 and T is Ar2.

[0412] In some embodiments, Ar1 is TIFF0007811578000012.tif24128, where T is Ar2.

[0413] In some embodiments, Ar1 is TIFF0007811578000013.tif24128, and T is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with.

[0414] In some embodiments, Ar1 is TIFF0007811578000014.tif24128, where T is one or more R A2 C6-C optionally substituted with 10 It is aryl.

[0415] In some embodiments, Ar1 is TIFF0007811578000015.tif24128, where T is one or more R A2 and phenyl optionally substituted with .

[0416] In some embodiments, Ar1 is TIFF0007811578000016.tif23128, and T is The file is TIFF0007811578000017.tif21128.

[0417] In some embodiments, Ar1 is TIFF0007811578000018.tif24128, where T is one or more R A2 and optionally substituted 5- to 10-membered heteroaryl.

[0418] In some embodiments, Ar1 is TIFF0007811578000019.tif25128, where T is one or more RA2 and optionally substituted pyridyl or thiazolyl.

[0419] In some embodiments, Ar1 is TIFF0007811578000020.tif25128, where T is Ar2.

[0420] In some embodiments, each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; and T is Ar.

[0421] In some embodiments, each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is C-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with.

[0422] In some embodiments, each R A1 is independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is one or more R A2 C6-C optionally substituted with 10 It is aryl.

[0423] In some embodiments, each R A1is independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is one or more R A2 and phenyl optionally substituted with .

[0424] In some embodiments, each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is The file is TIFF0007811578000021.tif21128.

[0425] In some embodiments, each R A1 is independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is one or more R A2 and optionally substituted 5- to 10-membered heteroaryl.

[0426] In some embodiments, each R A1 is independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is one or more R A2 and optionally substituted pyridyl or thiazolyl.

[0427] Variables Ar2 and R A2 In some embodiments, at least one Ar2 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with.

[0428] In some embodiments, at least one Ar2 is selected from one or more R A2 C6-C optionally substituted with 10 It is aryl.

[0429] In some embodiments, at least one Ar2 is C6-C 10 It is aryl.

[0430] In some embodiments, at least one Ar2 is selected from one or more R A2 C6-C substituted with 10 It is aryl.

[0431] In some embodiments, at least one Ar2 is selected from one or more R A2 and phenyl optionally substituted with .

[0432] In some embodiments, at least one Ar2 is phenyl.

[0433] In some embodiments, at least one Ar2 is selected from one or more R A2 is a phenyl substituted with

[0434] In some embodiments, at least one Ar2 is selected from one or more R A2 and optionally substituted 5- to 10-membered heteroaryl.

[0435] In some embodiments, at least one Ar2 is a 5-10 membered heteroaryl.

[0436] In some embodiments, at least one Ar2 is selected from one or more R A2is a 5- to 10-membered heteroaryl substituted with

[0437] In some embodiments, at least one Ar2 is selected from one or more R A2 and optionally substituted pyridyl or thiazolyl.

[0438] In some embodiments, at least one Ar2 is pyridyl or thiazolyl.

[0439] In some embodiments, at least one Ar2 is selected from one or more R A2 and pyridyl or thiazolyl substituted with

[0440] In some embodiments, at least one Ar2 is selected from one or more R A2 and pyridyl optionally substituted with

[0441] In some embodiments, at least one Ar2 is pyridyl.

[0442] In some embodiments, at least one Ar2 is selected from one or more R A2 and pyridyl substituted with

[0443] In some embodiments, at least one Ar2 is selected from one or more R A2 and optionally substituted thiazolyl.

[0444] In some embodiments, at least one Ar2 is thiazolyl.

[0445] In some embodiments, at least one Ar2 is selected from one or more R A2 and thiazolyl substituted with

[0446] In some embodiments, at least one R A2 is a halogen (e.g., F, Cl, or Br).

[0447] In some embodiments, at least one R A2 is F. In some embodiments, at least one R A2 is Cl. In some embodiments, at least one R A2 is Br.

[0448] In some embodiments, at least one R A2 In some embodiments, at least one R A2 is -OH.

[0449] In some embodiments, at least one R A2 is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0450] In some embodiments, at least one R A2 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0451] In some embodiments, at least one R A2 is C1-C6 alkyl.

[0452] In some embodiments, at least one R A2 is C1-C6 alkoxy.

[0453] In some embodiments, at least one R A2 is C1-C6 haloalkyl (e.g., -CH2F, -CHF2, or -CF3).

[0454] In some embodiments, at least one R A2 is C2-C6 alkenyl. In some embodiments, at least one R A2 is C2-C6 alkynyl.

[0455] Exemplary Embodiments of Compounds In some embodiments, the compound has formula (I'-a) or (I'-b): TIFF0007811578000022.tif45128, or a pharmaceutically acceptable salt thereof.

[0456] In some embodiments, the compound has formula (IA'), (IA'-a), or (IA'-b): TIFF0007811578000023.tif99136, or a pharmaceutically acceptable salt thereof.

[0457] In some embodiments, the compound has formula (IB'), (IB'-a), or (IB'-b): TIFF0007811578000024.tif84134, or a pharmaceutically acceptable salt thereof.

[0458] In some embodiments, the compound has formula (II'), (II'-a), or (II'-b): TIFF0007811578000025.tif98128, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4.

[0459] In some embodiments, the compound has formula (IIA'), (IIA'-a), or (IIA'-b): TIFF0007811578000026.tif97133, or a pharmaceutically acceptable salt thereof.

[0460] In some embodiments, the compound has formula (IIB'), (IIB'-a), or (IIB'-b): TIFF0007811578000027.tif95135, or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the compound has formula (IIIA'), (IIIA'-a), or (IIIA'-b): TIFF0007811578000028.tif114152, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0462] In some embodiments, the compound has formula (IIIB'), (IIIB'-a), or (IIIB'-b): TIFF0007811578000029.tif116154, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 3; n2 is an integer ranging from 0 to 5.

[0463] In some embodiments, the compound has formula (IVA'), (IVA'-a), or (IVA'-b): TIFF0007811578000030.tif114152, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0464] In some embodiments, the compound has formula (VA'), (VA'-a), or (VA'-b): TIFF0007811578000031.tif114150, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0465] In some embodiments, the compound has formula (Ia) or (Ib): TIFF0007811578000032.tif46128, or a pharmaceutically acceptable salt thereof.

[0466] In some embodiments, the compound has formula (IA), (IA-a), or (IA-b): TIFF0007811578000033.tif100134, or a pharmaceutically acceptable salt thereof.

[0467] In some embodiments, the compound has formula (IB), (IB-a), or (IB-b): TIFF0007811578000034.tif84130, or a pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the compound has formula (II), (II-a), or (II-b): TIFF0007811578000035.tif98128, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4.

[0469] In some embodiments, the compound has formula (IIA), (IIA-a), or (IIA-b): TIFF0007811578000036.tif98131, or a pharmaceutically acceptable salt thereof.

[0470] In some embodiments, the compound has formula (IIB), (IIB-a), or (IIB-b): TIFF0007811578000037.tif94131, or a pharmaceutically acceptable salt thereof.

[0471] In some embodiments, the compound has formula (IIIA), (IIIA-a), or (IIIA-b): TIFF0007811578000038.tif119155, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0472] In some embodiments, the compound has formula (IIIB), (IIIB-a), or (IIIB-b): TIFF0007811578000039.tif118155, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 3; n2 is an integer ranging from 0 to 5.

[0473] In some embodiments, the compound has formula (IVA), (IVA-a), or (IVA-b): TIFF0007811578000040.tif114149, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0474] In some embodiments, the compound has formula (VA), (VA-a), or (VA-b): TIFF0007811578000041.tif116147, or a pharmaceutically acceptable salt thereof; During the ceremony, n1 is an integer ranging from 0 to 4, n2 is an integer ranging from 0 to 4.

[0475] In some embodiments, the compound is a compound of a formula described herein or a pharmaceutically acceptable salt thereof: During the ceremony, R1 is -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10-cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S and the C1-C6 alkyl may be substituted with one or more R 1S is replaced by; Each R 1S are independently halogen or C1-C6 alkyl; Each R A1 are independently halogen; Each R A2 are independently halogen; n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0476] In some embodiments, the compound is selected from the compounds set forth in Table A1 and pharmaceutically acceptable salts thereof.

[0477] In some embodiments, the compound is selected from Compound Nos. A1-6, A1-6, A1-10, A1-15, A1-42, A1-58, A1-59, A1-60, A1-61, A1-63 through A1-102, and pharmaceutically acceptable salts thereof.

[0478] In some embodiments, the compound is selected from the compounds set forth in Table A2 and pharmaceutically acceptable salts thereof.

[0479] In some embodiments, the compound is selected from the compounds set forth in Table B1 and pharmaceutically acceptable salts thereof.

[0480] In some embodiments, the compound is selected from the compounds set forth in Table B2 and pharmaceutically acceptable salts thereof.

[0481] (Table A1) TIFF0007811578000042.tif176128TIFF0007811578000043.tif211104TIFF0007811578000044.tif212104TIFF0007811578000045.tif210104TIFF0007811578000046.tif209104TIFF0007811578000047.tif206104TIFF0007811578000048.tif189128TIFF0007811578000049.tif188128TIFF0007811578000050.tif191128TIFF0007811578000051.tif220104TIFF0007811578000052.tif197104TIFF0007811578000053.tif207104TIFF0007811578000054.tif208104TIFF0007811578000055.tif223104TIFF0007811578000056.tif181128TIFF0007811578000057.tif211104TIFF0007811578000058.tif179128TIFF0007811578000059.tif210104TIFF0007811578000060.tif188128TIFF0007811578000061.tif182128

[0482] (Table A2) TIFF0007811578000062.tif190128TIFF0007811578000063.tif21289TIFF0007811578000064.tif19389TIFF0007811578000065.tif19589TIFF0007811578000066.tif22189TIFF0007811578000067.tif20589TIFF0007811578000068.tif19689TIFF0007811578000069.tif20589TIFF0007811578000070.tif20589TIFF0007811578000071.tif21489TIFF0007811578000072.tif20589TIFF0007811578000073.tif19989TIFF0007811578000074.tif19689TIFF0007811578000075.tif19289TIFF0007811578000076.tif20289TIFF0007811578000077.tif21689TIFF0007811578000078.tif20389TIFF0007811578000079.tif20189TIFF0007811578000080.tif21989TIFF0007811578000081.tif21289TIFF0007811578000082.tif19789TIFF0007811578000083.tif21489TIFF0007811578000084.tif19389TIFF0007811578000085.tif19589TIFF0007811578000086.tif46128

[0483] (Table B1) TIFF0007811578000087.tif129128TIFF0007811578000088.tif21589TIFF0007811578000089.tif21089TIFF0007811578000090.tif182128

[0484] (Table B2) TIFF0007811578000091.tif20689TIFF0007811578000092.tif19489TIFF0007811578000093.tif22289TIFF00078115780 00094.tif21889TIFF0007811578000095.tif20989TIFF0007811578000096.tif20489TIFF0007811578000097.tif101128

[0485] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Tables A1, A2, B1, and B2.

[0486] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0487] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Tables A1, A2, B1, and B2, and prodrugs and pharmaceutically acceptable salts thereof.

[0488] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Tables A1, A2, B1, and B2, and pharmaceutically acceptable salts thereof.

[0489] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Tables A1, A2, B1, and B2, and pharmaceutically acceptable salts thereof.

[0490] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Tables A1, A2, B1, and B2.

[0491] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents by following the procedures disclosed in the schemes and / or examples described herein.

[0492] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0493] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds having the formulas disclosed herein.

[0494] The term "isotopic derivative" as used herein refers to a derivative of a compound in which one or more atoms are isotopically enriched or isotopically labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched with one or more isotopes or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched with or labeled with one or more atoms selected from S and S). 2 In some embodiments, the compound is 18 In some embodiments, the compound is a compound labeled with 123 Compounds labeled with I, 124 Compounds labeled with I, 125 Compounds labeled with I, 129 Compounds labeled with I, 131 Compounds labeled with I, 135I, or any combination thereof. In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds, or any combination thereof.

[0495] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any one of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein, instead of non-isotopically labeled reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 It can be prepared by using a reagent labeled with S.

[0496] The aforementioned 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 Compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing one or more S atoms are within the scope of the present invention. 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S, and / or 36 S) substitution may confer certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0497] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that said group encompasses the first occurring and broadest definition, and each and every specific definition associated with that group.

[0498] The various functional groups and substituents that make up the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More typically, the molecular weight of the compound will be less than 900 daltons, for example, less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons. More conveniently, the molecular weight is less than 600 daltons, for example, 550 daltons or less.

[0499] Suitable pharmaceutically acceptable salts of compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonate, or maleic acid. In addition, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that provide a pharmaceutically acceptable cation, for example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0500] It will be understood that a compound of any one of the formulas disclosed herein, and any pharmaceutically acceptable salt thereof, includes stereoisomers, mixtures of stereoisomers, and all isomeric polymorphic forms of said compound.

[0501] It will be understood that the compounds disclosed herein may be presented in one specific configuration.This specific configuration should not be interpreted as limiting the present disclosure to one or other isomer, tautomer, positional isomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers or stereoisomers.In some embodiments, the presentation herein of a compound in a specific configuration is intended to encompass and refer to each of the available isomers, tautomers, positional isomers and stereoisomers of the compound, or any mixture thereof, but the presentation is further intended to refer to the specific configuration of the compound.For example, when a compound is If it is presented as having a partial structure of TIFF0007811578000098.tif22128, the presentation would be The disclosure may be intended to encompass and refer to compounds having the partial structure of TIFF0007811578000099.tif24154, or any mixture thereof. It may be intended to refer to a compound having a particular configuration of the partial structure of TIFF0007811578000100.tif21128.

[0502] It will be understood that the compounds disclosed herein may be presented without specifying the configuration (e.g., without specifying the stereochemistry). Such presentation is intended to encompass all available isomers, tautomers, positional isomers, and stereoisomers of the compound. In some embodiments, presentation of a compound herein without specifying the configuration is intended to refer to each of the available isomers, tautomers, positional isomers, and stereoisomers of the compound, or any mixture thereof. For example, when a compound is If it is presented as having a partial structure of TIFF0007811578000101.tif23128, the presentation would be TIFF0007811578000102.tif24170, or any mixture thereof. Further, the disclosure may be intended to encompass and refer to mixtures of cis isomers of the substructure, e.g., In another example, the compound may be intended to refer to a compound having a mixture of the substructures: If it is presented as having a partial structure of TIFF0007811578000104.tif7128, the presentation would be It may be intended to refer to a compound having the partial structure of TIFF0007811578000105.tif13128, or a mixture thereof.

[0503] As used herein, the term "isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are mirror images of each other but are not superimposable are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0504] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0505] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having two or more chiral centers can exist either as individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the ranking rules of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0506] As used herein, the term "geometric isomer" refers to diastereomers that exist as a result of hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in designations by the prefixes cis and trans, or Z and E, which indicate whether the groups in the molecule are on the same or opposite sides of the double bond, according to the Cahn-Ingold-Prelog rules.

[0507] It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. It should also be understood that when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and that the naming of the compound does not exclude any isomeric form, and it is understood that not all isomers may have the same level of activity.

[0508] It should be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof, and it should also be understood that not all atropisomers may have the same level of activity.

[0509] As used herein, the term "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers exist as a result of restricted rotation caused by the hindrance of rotation of large groups around a central bond. Such atropisomers typically exist as mixtures, but recent advances in chromatography technology have made it possible to separate mixtures of two atropisomers in limited cases.

[0510] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric populations in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. This concept of tautomers that are interconvertible by tautomerization is called tautomerism. Among the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous electron and hydrogen atom shift occurs. Ring-chain tautomerism, as exemplified by glucose, occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to form a cyclic (ring-like) structure.

[0511] It should be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that if a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than others.

[0512] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the spatial arrangement of their atoms are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but are not superimposable are called "enantiomers." When a compound has an asymmetric center, e.g., is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., (+)-isomer or (-)-isomer, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0513] The compounds of the present disclosure may possess one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in this specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining the stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemates. Some of the compounds of the present disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, and mixtures thereof, that possess inflammasome inhibitory activity.

[0514] The present disclosure also encompasses compounds of the present disclosure as defined herein that contain one or more isotopic substitutions.

[0515] It should be understood that the compounds represented by any formula described herein include not only the compounds themselves, but also their salts and solvates, if applicable. Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0516] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt.Similarly, salts can also be formed between a cation and a negatively charged group (e.g., carboxylic acid) on the substituted compounds disclosed herein.Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cation, such as tetramethylammonium ion or diethylamine ion.The substituted compounds disclosed herein also include those salts containing a quaternary nitrogen atom.

[0517] It should be understood that compounds of the present disclosure, for example, salts of compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0518] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent.Some compounds tend to capture a certain molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate that is formed is a hydrate; when the solvent is alcohol, the solvate that is formed is an alcoholate.A hydrate is formed by combining one or more water molecules with one molecule of a substance, where water maintains its molecular state as HO.

[0519] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (such as the replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but not in structure or origin.

[0520] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0521] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of an atom or group of atoms with another generally similar atom or group of atoms. The purpose of bioisostere substitution is to create a new compound with similar biological properties to the parent compound. The bioisostere substitution can be based on physicochemical or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0522] It should also be understood that a particular compound represented by any one of the formulas disclosed herein can exist in solvated and unsolvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that the present disclosure encompasses all such solvated forms that retain inflammasome inhibitory activity.

[0523] It should also be understood that certain compounds represented by any one of the formulas disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that retain inflammasome inhibitory activity. It is generally known that crystalline materials can be analyzed using conventional techniques, such as powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0524] Compounds of any one of the formulas disclosed herein may exist in a number of different tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, a compound may exist in one of several tautomeric forms, and even if only one is specifically described or shown, all others are encompassed by formula (I). Examples of tautomeric forms include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. TIFF0007811578000106.tif20128

[0525] A compound represented by any one of the formulas disclosed herein containing an amine functional group may also form an N-oxide. Reference herein to a compound of formula (I) containing an amine functional group also includes the N-oxide. When a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514) by reacting an amine compound with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0526] The compounds of any one of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the human or animal body to release the compound of the present disclosure. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present disclosure. A prodrug can be formed when the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents on the ester or amide group in any one of the formulas disclosed herein.

[0527] Therefore, the present disclosure includes compounds of any one of the formulas disclosed herein, as defined herein above, when they are made available by organic synthesis and when they are made available in the human or animal body by cleavage of a prodrug thereof. Thus, in addition to compounds of any one of the formulas disclosed herein produced by organic synthetic means, the present disclosure also includes such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., compounds of any one of the formulas disclosed herein may be compounds produced by synthesis or compounds produced by metabolism.

[0528] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulas disclosed herein are those that, based on sound medical judgment, do not exhibit undesirable pharmacological activity and are not excessively toxic, and are suitable for administration to the human or animal body. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0529] Suitable pharmaceutically acceptable prodrugs of a compound having any one of the formulae disclosed herein that possesses a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of a compound having any one of the formulae disclosed herein that contain a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidate cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-C 10 Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C-C 10 Alkoxycarbonyl groups include, for example, ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0530] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein that possess a carboxy group include, for example, in vivo cleavable amides thereof, e.g., amines (such as ammonia), C 1-4 These are amides formed with alkylamines (such as methylamine), (C1-C4 alkyl)2 amines (such as dimethylamine, N-ethyl-N-methylamine or diethylamine), C1-C4 alkoxy-C2-C4 alkylamines (such as 2-methoxyethylamine), phenyl-C1-C4 alkylamines (such as benzylamine) and amino acids (such as glycine) or their esters.

[0531] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein that possess an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, C1-C 10 Alkanoyl groups include, for example, acetyl, benzoyl, phenylacetyl, and amides formed with substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0532] The in vivo effects of the compound of any one of the formulas disclosed herein may be exerted in part by one or more metabolic products formed in the human or animal body after administration of the compound of any one of the formulas disclosed herein.As mentioned hereinabove, the in vivo effects of the compound of any one of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug).

[0533] Advantageously, the present disclosure excludes any individual compound that does not possess biological activity as defined herein.

[0534] Synthesis method In some aspects, the present disclosure provides methods of preparing the compounds of the present disclosure.

[0535] In some aspects, the disclosure provides a method of preparing a compound comprising one or more steps as described herein.

[0536] In some aspects, the present disclosure provides compounds obtainable by, obtained by, or directly obtained by a method for preparing a compound as described herein.

[0537] In some aspects, the present disclosure provides intermediates, as described herein, suitable for use in methods for preparing compounds, as described herein.

[0538] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the accompanying Examples.

[0539] In the descriptions of synthetic methods described herein, and in any reference synthetic methods used to prepare starting materials, it should be understood that all suggested reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, can be selected by one of ordinary skill in the art.

[0540] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0541] It will be understood that during the synthesis of the compounds of the present disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent undesired reactions. A skilled chemist will understand when such protection is necessary and how to deploy and subsequently remove such protecting groups. For examples of protecting groups, see one of the many general texts on this subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to skilled chemists that is appropriate for the removal of the protecting group in question, and such methods will be selected so as to achieve removal of the protecting group with minimal interference to other groups in the molecule. Thus, if a reactant contains a group such as amino, carboxy, or hydroxy, it may be desirable to protect that group in some of the reactions listed herein.

[0542] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above protecting groups necessarily vary depending on the protecting group selected. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide (e.g., lithium or sodium hydroxide). Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon or by treatment with a Lewis acid, for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0543] Suitable protecting groups for hydroxy groups are, for example, acyl groups, such as alkanoyl groups (such as acetyl), aroyl groups (such as benzoyl), or arylmethyl groups (such as benzyl). The deprotection conditions for the above protecting groups will necessarily vary depending on the protecting group selected. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide (such as lithium or sodium hydroxide) or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation over a catalyst such as palladium on carbon.

[0544] A suitable protecting group for a carboxy group is, for example, an esterifying group, such as a methyl or ethyl group (which may be removed, for example, by hydrolysis with a base such as sodium hydroxide), or, for example, a tert-butyl group (which may be removed, for example, by treatment with an acid, for example an organic acid, such as trifluoroacetic acid), or, for example, a benzyl group (which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon).

[0545] Once a compound of formula (I) has been synthesized by any one of the processes defined herein, the process may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of formula (I) to another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0546] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0547] Conveniently, the reaction of compounds is preferably carried out in the presence of a suitable solvent that is inert under each reaction condition.Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, Examples include, but are not limited to, ethylene glycol monomethyl or monoethyl ether, or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of the above solvents or with water.

[0548] The reaction temperature is suitably between about -100°C and 300°C, depending on the reaction step and conditions used.

[0549] The reaction time generally ranges from just a few minutes to several days, depending on the reactivity of each compound and the respective reaction conditions. Suitable reaction times can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature given above, suitable reaction times generally range from 10 minutes to 48 hours.

[0550] Moreover, by utilizing the procedures described herein, together with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0551] As will be understood by those skilled in the art of organic synthesis, the compounds of the present disclosure can be easily accessed by a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will easily recognize what kinds of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how to apply and adapt them to any particular case (wherever necessary or useful). Furthermore, some of the compounds of the present disclosure can be easily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example, by converting one specific functional group present in the compounds of the present disclosure or their suitable precursor molecules into another by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions; such methods are well known to those skilled in the art. Likewise, those skilled in the art will be able to apply synthetic (or protective) groups (whenever necessary or useful); suitable protecting groups and methods for their introduction and removal are well known to those skilled in the art of chemical synthesis and are described in detail, for example, in PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0552] General routes for the preparation of compounds of the present application are described in Schemes 1-5 herein.

[0553] Scheme 1 TIFF0007811578000107.tif94128

[0554] Compound V can be prepared from compound I by the method shown in Scheme 1. Compound I can be prepared from commercially available materials by the route previously reported in WO2019 / 027058, or by methods analogous thereto. As used herein, Hal is a halogen atom.

[0555] Examples of protecting groups for amino groups represented by P1 include carbamate-type protecting groups, such as tert-butyl carbamate. Compound II, where Y is oxygen, may be commercially available or can be prepared from commercially available materials by alkylation or Mitsunobu reaction. B represents a boronic acid, a boronic acid ester, or the like.

[0556] Examples of protecting groups represented by P2 when X is nitrogen include phthalamide-type protecting groups, etc. Examples of protecting groups represented by P2 when X is carbon or oxygen include carboxyl protecting groups such as methyl and ethyl esters.

[0557] Compound III can be prepared by subjecting Compound I and Compound II to a palladium-mediated cross-coupling Suzuki-type reaction. When the coupling reaction is carried out, examples of metal catalysts to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)-palladium(II), tris(dibenzylideneacetone)dipalladium(O), 1,1'-bis(diphenylphosphino)-ferrocenepalladium(II) chloride, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, etc. Additionally, a base can be added to the reaction system, examples of which include inorganic bases.

[0558] Compound IV can be prepared by removing the protecting groups represented by P1 and P2 by methods known per se, for example, by employing methods using an acid, a base, or a nucleophile (e.g., hydrazine), reduction methods, etc.

[0559] Compound V can be prepared by subjecting compound IV to a ring-closure reaction. When ring-closure is carried out by amidation, urea, or carbamate formation, examples of reagents to be used include activated carboxylic acids, such as acid anhydrides, activated esters, activated carbamates, etc. Examples of activators for carboxylic acids include carbodiimide condensing agents, such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI); carbonate condensing agents, such as 1,1-carbonyldiimidazole (CDI), triphosgene, etc.; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); combinations thereof, etc. In addition, a base may be added to the reaction system. Examples of bases include inorganic bases, organic bases, etc. When a carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP), or the like may be further added to the reaction system.

[0560] Scheme 2 TIFF0007811578000108.tif85153

[0561] Alternatively, compound V can be prepared from compound I by the method shown in Reaction Scheme 2. Compound VI can be prepared by subjecting a combination of compound I, an arylboronic acid, or an arylboronic acid ester, etc., to a palladium-mediated cross-coupling Suzuki-type reaction. When a coupling reaction is performed in each step, examples of metal catalysts to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(O), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, etc. In addition, a base can be added to the reaction system, examples of which include inorganic bases. Examples of "leaving groups" represented by LG1 include halogen atoms, optionally halogenated C 1-6 Alkyl sulfonyloxy groups (for example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy) and the like are included.

[0562] Compound VII, where Y is carbon, can be prepared by subjecting compound VI and an appropriate acetylene, either commercially available or available by known methods, to a Sonogashira-type cross-coupling reaction using a metal catalyst. Examples of metal catalysts include palladium compounds, such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), and bis(acetonitrile)dichloropalladium(II). Phosphine ligands, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), can also be added to the reaction system. Additionally, a base, such as an inorganic base, can be added to the reaction system.

[0563] Compound VIII can be prepared by reduction of Compound VII. When a carbon-carbon double or triple bond is reduced, a method using a catalyst, such as palladium-carbon or Lindlar's catalyst, may be employed together with hydrogen gas.

[0564] Compound VIII, where Y is oxygen and LG1 is hydroxy, can be prepared directly from compound VI by the Mitsunobu reaction using commercially available materials. When the Mitsunobu reaction is performed at each stage, azodicarboxylates (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0565] Compound IV can be prepared by removing the protecting groups represented by P1 and P2 by methods known per se, for example, by employing a method using an acid, a base, hydrazine, or the like, a reduction method, or the like.

[0566] Compound V can be prepared by the ring closure reaction shown in Reaction Scheme 1.

[0567] Compound V can also be prepared by a ring-closing metathesis reaction approach as outlined in Schemes 3-5.

[0568] Scheme 3 TIFF0007811578000109.tif83134

[0569] Compound IX can be prepared by removing the protecting group represented by P1 from compound (I) by an appropriate known method, for example, by using an acid, a base, hydrazine, or the like, or a reduction method, or the like.

[0570] Compound XI can be prepared by subjecting compound IX and compound X to a condensation reaction. When LG2 is a suitable leaving group, examples of reagents to be used in the condensation reaction include activated carboxylic acids, such as acid anhydrides, activated esters, activated carbonates, activated carbamates, isocyanates, and the like. Examples of activators for carboxylic acids include carbodiimide condensing agents, such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI); carbonate condensing agents, such as 1,1-carbonyldiimidazole (CDI), triphosgene, and the like; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); and combinations thereof. In addition, a base may be added to the reaction system. Examples of bases include inorganic bases, organic bases, and the like. When a carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP) may be further added to the reaction system. Compound X may be commercially available or may be prepared from commercially available materials by a method known per se or a method analogous thereto. L1 is C 1-5 Examples of leaving groups represented by LG2 include halogen atoms, optionally halogenated C 1-6 Included are alkylsulfonyloxy groups (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), p-nitrophenol, and the like.

[0571] Compound XII may be commercially available or may be prepared from commercially available materials by methods known per se or analogous thereto. B represents a boronic acid, ester, etc. L1 represents C 1-3 Represents allyl, etc.

[0572] Compound XIII can be prepared by subjecting a combination of compound XI and compound XII to the palladium-mediated Suzuki-type cross-coupling described above, as shown in Scheme 1.

[0573] Scheme 4 TIFF0007811578000110.tif88139

[0574] Compound XIII can be prepared by subjecting a combination of compound I and compound XII to the palladium-mediated Suzuki-type cross-coupling described above, as shown in Scheme 1.

[0575] Compound XIV can be prepared by removing the protecting group represented by P1 by a known method, for example, by employing an acid, a base, hydrazine, or the like, or a reduction method, or the like.

[0576] Compound XIII can be prepared by subjecting compound XIV and compound X to a condensation reaction, as described in Scheme 3 above.

[0577] Scheme 5 TIFF0007811578000111.tif47153

[0578] Compound XIV can be prepared by subjecting compound XIII to a ring-closing reaction. When the ring-closing reaction is carried out by a ring-closing metathesis reaction, examples of catalysts to be used include ruthenium compounds, such as Grubbs I, Grubbs II, Hoveyda-Grubbs, etc.

[0579] Compound V can be prepared by reduction of compound XIV. When the carbon-carbon double bond is reduced, a method using a catalyst, such as palladium-carbon or Lindlar's catalyst, may be employed along with hydrogen gas.

[0580] Biological assays Once produced, compounds designed, selected, and / or optimized by the methods described above can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to, the assays described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0581] Furthermore, high-throughput screening can be used to speed up the analysis using such assays.As a result, it may be possible to use techniques known in the art to rapidly screen the molecules described herein for activity.The general methodology for carrying out high-throughput screening is described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263.High-throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0582] Various in vitro or in vivo biological assays may be suitable for determining the effects of the compounds of the present disclosure, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0583] Despite the loss of orexin cells and reduced orexin peptides in the cerebrospinal fluid in NT1, orexin receptors on postsynaptic neurons remain intact and serve as suitable targets for pharmacotherapeutic intervention. Orexin peptides A and B (OXA and OXB) can be cleaved from a single precursor molecule (prepro-orexin) produced exclusively in the lateral hypothalamus. Both orexin peptides bind to the OX2R with similar high affinity, but OXA preferentially binds to the orexin-1 receptor (OX1R). Postsynaptic excitation of these G-protein-coupled orexin receptors can stimulate the release of monoaminergic and cholinergic neurotransmitters that promote wakefulness and inhibitory neurotransmitters that suppress REM sleep atony.

[0584] In some embodiments, biological assays are described in the Examples herein.

[0585] In some embodiments, the biological assay is an assay that measures the agonist activity of a compound on cells expressing human orexin type 2 or human orexin type 1 receptors.

[0586] In some embodiments, the assay involves preparing Chinese hamster ovary (CHO) cells expressing the human orexin type 2 receptor (hOX2R) or the human orexin type 1 receptor (hOX1R).

[0587] Pharmaceutical Compositions In some aspects, the present disclosure provides pharmaceutical compositions comprising the compounds of the present disclosure as active ingredients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Tables A1, A2, B1, and B2.

[0588] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0589] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each of which contains sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all in forms well known to those of ordinary skill in the pharmaceutical arts.

[0590] The formulation of the present disclosure can be in the form of an aqueous solution containing an aqueous medium.The aqueous medium component can include water and at least one pharmaceutically acceptable excipient.Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspending agents, buffers and pH adjusters, and mixtures thereof.

[0591] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0592] Any suitable chelating agent can be used, examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0593] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0594] The aqueous medium may also contain an isotonicity agent to adjust the isotonicity (osmotic pressure), which may be selected from the group consisting of glycols (propylene glycol, diethylene glycol, triethylene glycol, etc.), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0595] The aqueous medium may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycols (such as polyethylene glycol 300 and polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0596] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to a desired acceptable pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture into the desired pH range.

[0597] The aqueous medium may also contain a buffering agent to stabilize the pH. If used, the buffering agent is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or salts thereof, including disodium tetraborate), citrate buffers (such as citric acid or salts thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0598] The formulation may further comprise a wetting agent. Suitable types of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0599] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. These can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, where the compound in the liquid carrier is orally applied, swished in the mouth, and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches, etc. can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterot; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavor.

[0600] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined herein above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0601] Compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0602] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use can contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0603] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with an inflammasome-associated condition referred to herein.

[0604] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or reduce the symptoms associated with an inflammasome-associated condition referred to herein.

[0605] The size of a therapeutic or prophylactic dose of a compound of formula (I) will naturally vary according to well-known principles of medicine, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0606] How to use In some aspects, the present disclosure provides methods of modulating orexin-2 receptor activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0607] In some aspects, the present disclosure provides methods of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0608] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0609] In some embodiments, the disease or disorder is associated with implicated orexin receptor activity. In some embodiments, the disease or disorder is a disease or disorder in which orexin receptor activity is implicated.

[0610] In some embodiments, the disease or disorder is associated with implicated orexin-2 receptor activity. In some embodiments, the disease or disorder is a disease or disorder in which orexin-2 receptor activity is implicated.

[0611] In some embodiments, the disease or disorder is narcolepsy, hypersomnia, a neurodegenerative disorder, a symptom of a rare genetic disease, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or a complication upon emergence from anesthesia.

[0612] In some aspects, the present disclosure provides methods of treating or preventing narcolepsy, hypersomnia disorder, neurodegenerative disorders, symptoms of rare genetic diseases, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0613] In some aspects, the present disclosure provides a method of treating narcolepsy, hypersomnia disorder, neurodegenerative disorder, symptoms of a rare genetic disease, mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0614] In some aspects, the present disclosure provides a method of treating or preventing narcolepsy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0615] In some aspects, the present disclosure provides a method of treating or preventing a hypersomnia disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0616] In some aspects, the present disclosure provides a method of treating or preventing a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0617] In some aspects, the present disclosure provides a method of treating or preventing a symptom of a rare genetic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0618] In some aspects, the present disclosure provides a method of treating or preventing a mental health disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0619] In some aspects, the present disclosure provides a method of treating or preventing metabolic syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0620] In some aspects, the present disclosure provides a method of treating or preventing osteoporosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0621] In some aspects, the present disclosure provides a method of treating or preventing heart failure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0622] In some aspects, the present disclosure provides a method of treating or preventing coma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0623] In some aspects, the present disclosure provides a method of treating or preventing complications upon emergence from anesthesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0624] In some aspects, the present disclosure provides a method of treating narcolepsy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0625] In some aspects, the present disclosure provides a method of treating a hypersomnia disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0626] In some aspects, the present disclosure provides a method of treating a neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0627] In some aspects, the present disclosure provides a method of treating a symptom of a rare genetic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0628] In some aspects, the present disclosure provides a method of treating a mental health disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0629] In some aspects, the present disclosure provides a method of treating metabolic syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0630] In some aspects, the present disclosure provides a method of treating osteoporosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0631] In some aspects, the present disclosure provides a method of treating heart failure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0632] In some aspects, the present disclosure provides a method of treating coma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0633] In some aspects, the present disclosure provides a method of treating complications upon emergence from anesthesia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0634] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in modulating orexin receptor activity (e.g., in vitro or in vivo).

[0635] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in modulating orexin-2 receptor activity (e.g., in vitro or in vivo).

[0636] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease or disorder disclosed herein.

[0637] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0638] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing narcolepsy, hypersomnia, a neurodegenerative disorder, a symptom of a rare genetic disease, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0639] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing narcolepsy in a subject in need thereof.

[0640] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a hypersomnia disorder in a subject in need thereof.

[0641] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a neurodegenerative disorder in a subject in need thereof.

[0642] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a symptom of a rare genetic disease in a subject in need thereof.

[0643] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a mental health disorder in a subject in need thereof.

[0644] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing metabolic syndrome in a subject in need thereof.

[0645] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing osteoporosis in a subject in need thereof.

[0646] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing heart failure in a subject in need thereof.

[0647] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing coma in a subject in need thereof.

[0648] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing complications upon emergence from anesthesia in a subject in need thereof.

[0649] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating narcolepsy, hypersomnia disorder, neurodegenerative disorder, symptoms of a rare genetic disease, mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0650] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating narcolepsy in a subject in need thereof.

[0651] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a hypersomnia disorder in a subject in need thereof.

[0652] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a neurodegenerative disorder in a subject in need thereof.

[0653] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a symptom of a rare genetic disease in a subject in need thereof.

[0654] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a mental health disorder in a subject in need thereof.

[0655] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating metabolic syndrome in a subject in need thereof.

[0656] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating osteoporosis in a subject in need thereof.

[0657] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating heart failure in a subject in need thereof.

[0658] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating coma in a subject in need thereof.

[0659] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating complications upon emergence from anesthesia in a subject in need thereof.

[0660] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating orexin activity (e.g., in vitro or in vivo).

[0661] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating orexin-2 activity (e.g., in vitro or in vivo).

[0662] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0663] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0664] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing narcolepsy, hypersomnia disorder, neurodegenerative disorder, symptoms of a rare genetic disease, mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0665] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing narcolepsy in a subject in need thereof.

[0666] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a hypersomnia disorder in a subject in need thereof.

[0667] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a neurodegenerative disorder in a subject in need thereof.

[0668] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a symptom of a rare genetic disease in a subject in need thereof.

[0669] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a mental health disorder in a subject in need thereof.

[0670] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing metabolic syndrome in a subject in need thereof.

[0671] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing osteoporosis in a subject in need thereof.

[0672] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing heart failure in a subject in need thereof.

[0673] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing coma in a subject in need thereof.

[0674] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing complications upon emergence from anesthesia in a subject in need thereof.

[0675] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating narcolepsy, hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disease, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0676] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating narcolepsy in a subject in need thereof.

[0677] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a hypersomnia disorder in a subject in need thereof.

[0678] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a neurodegenerative disorder in a subject in need thereof.

[0679] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a symptom of a rare genetic disease in a subject in need thereof.

[0680] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a mental health disorder in a subject in need thereof.

[0681] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating metabolic syndrome in a subject in need thereof.

[0682] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating osteoporosis in a subject in need thereof.

[0683] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating heart failure in a subject in need thereof.

[0684] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating coma in a subject in need thereof.

[0685] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a complication upon emergence from anesthesia in a subject in need thereof.

[0686] The present disclosure provides compounds that function as modulators of orexin receptor activity.

[0687] In some aspects, the compounds of the present disclosure are agonists of orexin receptors.

[0688] The present disclosure provides compounds that function as modulators of orexin-2 receptor activity.

[0689] In some embodiments, the compounds of the present disclosure are agonists of the orexin-2 receptor.

[0690] In some embodiments, modulation of the orexin receptor is activation of the orexin receptor.

[0691] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models according to standard procedures for determining efficacy as described in the art and as found in current common general knowledge.

[0692] The present disclosure also provides a method of treating a disease or disorder implicated in orexin receptor activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0693] The present disclosure also provides a method of treating a disease or disorder implicated in orexin-2 receptor activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0694] In some embodiments, the present disclosure also provides methods for treating a disease or disorder by reducing excessive sleepiness and / or excessive daytime sleepiness.

[0695] In some aspects, the present disclosure also provides methods for treating a disease or disorder by reducing excessive sleepiness.

[0696] In some aspects, the present disclosure also provides methods for treating a disease or disorder by reducing excessive daytime sleepiness.

[0697] In some embodiments, the disease or disorder is associated with excessive sleepiness and / or excessive daytime sleepiness.

[0698] In some embodiments, the disease or disorder is primary hypersomnia disorder, a neurodegenerative disorder, a symptom of a hypersomnia disorder / neurodegenerative disorder, a symptom of a rare genetic disease, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or emergence from anesthesia.

[0699] In some embodiments, the disease or disorder is primary hypersomnia, a neurodegenerative disorder, a symptom of a hypersomnia / neurodegenerative disorder, a symptom of a rare genetic disease, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or a complication upon emergence from anesthesia.

[0700] In some aspects, excessive daytime sleepiness is associated with a neurodegenerative disorder.

[0701] In some embodiments, the neurodegenerative disorder associated with excessive daytime sleepiness is Parkinson's disease, Alzheimer's disease, Huntington's disease, or multiple sclerosis.

[0702] In some embodiments, the disease or disorder is recurrent hypersomnia.

[0703] In some embodiments, the recurrent hypersomnia is narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia.

[0704] In some embodiments, the disease or disorder is sleep apnea, traumatic brain injury, age-related cognitive impairment, or excessive daytime sleepiness.

[0705] In some embodiments, the excessive daytime sleepiness is associated with sleep apnea, traumatic brain injury, or age-related cognitive impairment.

[0706] In some embodiments, the disorder is narcolepsy. In some embodiments, the narcolepsy is narcolepsy type 1. In some embodiments, the narcolepsy is narcolepsy type 2.

[0707] In some embodiments, the hypersomnia is a symptom of narcolepsy.

[0708] In some embodiments, the disease or disorder is a symptom of narcolepsy.

[0709] In some embodiments, the symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, waking and hypnagogic hallucinations, disrupted nighttime sleep, or inappropriate rapid eye movement (REM) sleep.

[0710] In some embodiments, a symptom of narcolepsy is excessive daytime sleepiness.

[0711] In some embodiments, the symptom of narcolepsy is cataplexy. In some embodiments, cataplexy is characteristic of narcolepsy (e.g., narcolepsy type 1).

[0712] In some embodiments, the symptom of narcolepsy is sleep paralysis.

[0713] In some embodiments, the symptoms of narcolepsy are waking and hypnagogic hallucinations.

[0714] In some embodiments, the symptom of narcolepsy is disrupted nighttime sleep.

[0715] In some embodiments, a symptom of narcolepsy is inappropriately timed rapid eye movement (REM) sleep.

[0716] In some aspects, the neurodegenerative disorder is characterized by cataplexy.

[0717] In some aspects, the neurodegenerative disorder is characterized by excessive daytime sleepiness.

[0718] In some embodiments, the neurodegenerative disorder is Parkinson's disease.

[0719] In some embodiments, the neurodegenerative disorder is Alzheimer's disease.

[0720] In some embodiments, the neurodegenerative disorder is Huntington's disease.

[0721] In some embodiments, the neurodegenerative disorder is multiple sclerosis.

[0722] In some embodiments, the neurodegenerative disorder is traumatic brain injury.

[0723] In some aspects, the neurodegenerative disorder is sleep apnea.

[0724] In some aspects, the neurodegenerative disorder is age-related cognitive dysfunction.

[0725] In some embodiments, the neurodegenerative disorder is a recurrent hypersomnia disorder.

[0726] In some embodiments, the recurrent hypersomnia disorder is Kleine-Levin syndrome, inappropriately timed sleep (e.g., delayed sleep phase or advanced sleep phase disorder), shift work disorder, or jet lag disorder.

[0727] In some embodiments, the disease or disorder is a symptom of a rare genetic disease.

[0728] In some aspects, the symptom of the rare genetic disease is abnormal daytime sleepiness.

[0729] In some embodiments, the symptom of the rare genetic disease is excessive daytime sleepiness.

[0730] In some aspects, the symptom of the rare genetic disease is sleep onset REM sleep.

[0731] In some embodiments, the symptoms of the rare genetic disease are characterized by cataplexy-like symptoms.

[0732] In some embodiments, the rare genetic disease is ADCA-DN, Coffin-Lowry syndrome, Moebius syndrome, Norrie disease, Niemann-Pick disease type C, or Prader-Willi syndrome.

[0733] In some embodiments, the disease or disorder is a mental health disorder.

[0734] In some aspects, the mental health disorder is attention deficit hyperactivity disorder.

[0735] In some aspects, the mental health disorder is attention deficit disorder.

[0736] In some embodiments, the disease or disorder is metabolic syndrome.

[0737] In some embodiments, the metabolic syndrome is obesity.

[0738] In some embodiments, the disease or disorder is osteoporosis.

[0739] In some embodiments, the disease or disorder is heart failure.

[0740] In some embodiments, the disease or disorder is coma.

[0741] In some embodiments, the disease or disorder is emergence from anesthesia.

[0742] In some embodiments, the disease or disorder is a complication of emergence from anesthesia.

[0743] In some embodiments, the disease or disorder is narcolepsy, hypersomnia, a neurodegenerative disorder, a neurological disorder, a symptom of a rare genetic disease, a psychiatric disorder, a mental health disorder, a circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma, or a complication upon emergence from anesthesia.

[0744] In some embodiments, the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea.

[0745] Route of administration The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as monotherapy or in combination with one or more other substances and / or treatments. Such conjoint treatment may be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment.

[0746] For example, therapeutic efficacy may be enhanced by administration of an adjuvant (i.e., by itself, the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, and by way of example only, the benefit experienced by an individual may be increased by administering a compound of Formula (I) with another therapeutic agent (including a treatment regimen) that also has a therapeutic benefit.

[0747] When the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the present disclosure does not need to be administered via the same route as the other therapeutic agents, and may be administered via a different route due to different physical and chemical properties.For example, the compound of the present disclosure may be administered orally to generate and maintain a good blood level, while the other therapeutic agents may be administered intravenously.Initial administration may be carried out according to established protocols known in the art, and then, based on the observed effect, skilled clinicians can change the dosage, mode of administration and time of administration.

[0748] The specific selection of other therapeutic agents will depend on the diagnosis of the attending physician and their judgment regarding the individual's condition and the appropriate treatment protocol. According to this aspect of the disclosure, there is provided a combination comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, as defined herein above, and another suitable agent for use in treating a disease in which orexin activity is implicated.

[0749] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0750] In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of modulators of orexin-2 receptor activity in laboratory animals such as dogs, rabbits, monkeys, minipigs, rats and mice as part of the search for new therapeutic agents.

[0751] In any of the above-listed pharmaceutical compositions, processes, methods, uses, medicaments and manufacturing features of this disclosure, any of the alternative aspects of the macromolecules of this disclosure described herein also apply.

[0752] The compounds of the present disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0753] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., by nasal spray or nasal powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., by inhalation or insufflation therapy via the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal);

[0754] Exemplary Embodiments Exemplary Embodiment 1 A compound of formula (I'), or a pharmaceutically acceptable salt thereof: TIFF0007811578000112.tif45128In formula, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl- is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; n is an integer ranging from 0 to 3; R a and R b are each independently H, halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where —O(C1-C6 alkyl), —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is selected from the group consisting of one or more R S or R a and R b together with the atom to which they are attached form a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl, wherein the C3-C7 cycloalkyl or the 3- to 7-membered heterocycloalkyl is selected from the group consisting of one or more R S may be substituted with; Each R S are independently halogen, —CN, —OH, —O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 haloalkyl; Z is -O- or -NR Z - where R Z is H or C1-C6 alkyl; R1 is -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with; Each R 1Sare independently oxo, halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), -S(C-C alkyl), -SO(C-C alkyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A1 may be substituted with; Each R A1 are independently Ar2, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; T is absent or Ar2; Each Ar2 is independently C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0755] Exemplary Embodiment 2 A compound of formula (I), or a pharmaceutically acceptable salt thereof: TIFF0007811578000113.tif45128In formula, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; n is an integer ranging from 0 to 3; Z is -O- or -NR Z - where R Z is H or C1-C6 alkyl; R1 is -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -SH, -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl), -S(C1-C6 alkyl), -S(C6-C 10 aryl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, 3-7 membered heterocycloalkyl, -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10-cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) can be one or more R 1S may be substituted with; Each R 1S are independently oxo, halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), -S(C-C alkyl), -SO(C-C alkyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A1 may be substituted with; Each R A1 are independently Ar2, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; T is absent or Ar2; Each Ar2 is independently C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 may be substituted with; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0756] Exemplary Embodiment 3 During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl- is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; n is an integer ranging from 0 to 3; Z is -O- or -NR Z - where R Z is H or C1-C6 alkyl; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) is present in one or more R 1S may be substituted with; Each R 1S are independently halogen, —CN, —OH, or C1-C6 alkoxy; Ar1 is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 The aryl or 5- to 10-membered heteroaryl is selected from one or more R A1 may be substituted with; Each R A1are independently Ar2, halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; T is absent or Ar2; Each Ar2 is independently C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 The aryl or 5- to 10-membered heteroaryl is selected from one or more R A2 may be substituted with; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; The compound of any one of the preceding exemplary embodiments.

[0757] Exemplary Embodiment 4 During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O- or C1-C6 alkyl; n is an integer ranging from 0 to 3; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more Ar2 groups 10 is aryl; T is absent or Ar2; Each Ar2 is independently C6-C 10 is aryl, The compound of any one of the preceding exemplary embodiments.

[0758] Exemplary Embodiment 5 During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O- or C1-C6 alkyl; n is an integer ranging from 0 to 3; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is C1-C6 alkyl; Ar1 is C6-C 10 is aryl; T is C6-C 10 is aryl, The compound of any one of the preceding exemplary embodiments.

[0759] Exemplary Embodiment 6 During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O- or C1-C6 alkyl; n is an integer ranging from 0 to 3; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is C1-C6 alkyl; Ar1 is one or more C6-C 10 C6-C optionally substituted with aryl 10 is aryl; T does not exist, The compound of any one of the preceding exemplary embodiments.

[0760] Exemplary Embodiment 7 During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O- or C1-C6 alkyl; n is 2; Z is -NR Z - where R Z is H or C1-C6 alkyl; R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) is present in one or more R 1S is replaced by; Each R 1S are independently halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -SO2(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar1 is one or more R A1 C6-C optionally substituted with 10 is aryl; Each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; T is Ar2; Ar2 is one or more R A2 C6-C optionally substituted with 10 is aryl; Each R A2 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; The compound of exemplary embodiment 1.

[0761] Exemplary Embodiment 8 The compound of any one of the preceding exemplary embodiments, wherein X is —O—.

[0762] Illustrative Embodiment 9 The compound of any one of the preceding exemplary embodiments, wherein X is -NH- or -N(C-C alkyl)-, wherein -N(C-C alkyl)- is optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0763] Exemplary Embodiment 10 The compound of any one of the preceding exemplary embodiments, wherein X is —NH—.

[0764] Exemplary Embodiment 11 The compound of any one of the preceding exemplary embodiments, wherein X is -N(C1-C6 alkyl)-.

[0765] Exemplary Embodiment 12 The compound of any one of the preceding exemplary embodiments, wherein X is —N(CH 3 )—.

[0766] Exemplary Embodiment 13 The compound of any one of the preceding exemplary embodiments, wherein X is —N(C 1 -C 6 alkyl)- substituted with one or more halogens or —OH.

[0767] Exemplary Embodiment 14 The compound of any one of the preceding exemplary embodiments, wherein X is —N(C 1 -C 6 alkyl)- substituted with 1 to 3 F and 1 —OH.

[0768] Exemplary Embodiment 15 In the formula, X is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The compound of any one of the preceding exemplary embodiments, wherein the aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0769] Exemplary Embodiment 16 The compound of any one of the preceding exemplary embodiments, wherein X is C-C alkyl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0770] Exemplary Embodiment 17 The compound of any one of the preceding exemplary embodiments, wherein X is a 3-8 membered heterocycloalkyl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0771] Exemplary Embodiment 18 The compound of any one of the preceding exemplary embodiments, wherein X is azetidinyl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0772] Exemplary Embodiment 19 In the formula, X is TIFF0007811578000114.tif22128, where The compound of any one of the preceding exemplary embodiments, wherein TIFF0007811578000115.tif22128 is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0773] Exemplary Embodiment 20 The compound of any one of the preceding exemplary embodiments, wherein X is acetidinyl.

[0774] Exemplary Embodiment 21 In the formula, X is The compound of any one of the preceding exemplary embodiments, wherein the compound is TIFF0007811578000116.tif22128.

[0775] Exemplary Embodiment 22 The compound of any one of the preceding exemplary embodiments, wherein L is absent.

[0776] Exemplary Embodiment 23 In the formula, L is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl-, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl The compound of any one of the preceding exemplary embodiments, wherein - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0777] Exemplary Embodiment 24 The compound of any one of the preceding exemplary embodiments, wherein L is —O—.

[0778] Exemplary Embodiment 25 The compound of any one of the preceding exemplary embodiments, wherein L is -NH- or -N(C1-C6 alkyl)-, wherein -N(C1-C6 alkyl)- is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0779] Exemplary Embodiment 26 In the formula, L is C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O)nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl The compound of any one of the preceding exemplary embodiments, wherein - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0780] Exemplary Embodiment 27 The compound of any one of the preceding exemplary embodiments, wherein L is C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0781] Exemplary Embodiment 28 In the formula, L is -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl-, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl The compound of any one of the preceding exemplary embodiments, wherein - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0782] Exemplary Embodiment 29 In the formula, L is -((C1-C6 alkyl)-O) nl -or -(O-(C1-C6 alkyl)) nl -, where -((C1-C6 alkyl)-O) nl -or -(O-(C1-C6 alkyl)) nl The compound of any one of the preceding exemplary embodiments, wherein - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0783] Exemplary Embodiment 30 In the formula, L is -((C1-C6 alkyl)-NH) nl -or -(NH-(C1-C6 alkyl)) nl -, where -((C1-C6 alkyl)-NH) nl -or -(NH-(C1-C6 alkyl)) nl The compound of any one of the preceding exemplary embodiments, wherein - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0784] Exemplary Embodiment 31 The compound of any one of the preceding exemplary embodiments, wherein nl is an integer ranging from 1 to 3.

[0785] Exemplary Embodiment 32 The compound of any one of the preceding exemplary embodiments, wherein nl is 1.

[0786] Exemplary Embodiment 33 The compound of any one of the preceding exemplary embodiments, wherein nl is 2.

[0787] Exemplary Embodiment 34 The compound of any one of the preceding exemplary embodiments, wherein nl is 3.

[0788] Exemplary Embodiment 35 The compound of any one of the preceding exemplary embodiments, wherein Y is —O—.

[0789] Exemplary Embodiment 36 The compound of any one of the preceding exemplary embodiments, wherein Y is -NH- or -N(C-C alkyl)-, wherein -N(C-C alkyl)- is optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0790] Exemplary Embodiment 37 The compound of any one of the preceding exemplary embodiments, wherein Y is —NH—.

[0791] Exemplary Embodiment 38 The compound of any one of the preceding exemplary embodiments, wherein -N(C-C alkyl)- is optionally substituted with one or more halogen, -CN, -OH, -NH, -NH(C-C alkyl), -N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0792] Exemplary Embodiment 39 The compound of any one of the preceding exemplary embodiments, wherein Y is C-C alkyl or C-C alkenyl, wherein the C-C alkyl or C-C alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0793] Exemplary Embodiment 40 The compound of any one of the preceding exemplary embodiments, wherein Y is C-C alkyl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0794] Exemplary Embodiment 41 The compound of any one of the preceding exemplary embodiments, wherein Y is C-C alkenyl optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy.

[0795] Exemplary Embodiment 42 The compound of any one of the preceding exemplary embodiments, wherein at most one of X and L is -O-, -NH-, or optionally substituted -N(C1-C6 alkyl)-.

[0796] Exemplary Embodiment 43 The compound of any one of the preceding exemplary embodiments, wherein at most one of L and Y is -O-, -NH-, or optionally substituted -N(C1-C6 alkyl)-.

[0797] Exemplary Embodiment 44 The compound of any one of the preceding exemplary embodiments, wherein at most one of X and Y is -O-, -NH-, or optionally substituted -N(C1-C6 alkyl)-.

[0798] Exemplary Embodiment 45 The compound of any one of the preceding exemplary embodiments, wherein up to two of X, L, and Y are -O-, -NH-, or optionally substituted -N(C1-C6 alkyl)-.

[0799] Exemplary Embodiment 46 The compound of any one of the preceding exemplary embodiments, wherein at most one of X, L, and Y is -O-, -NH-, or optionally substituted -N(C1-C6 alkyl)-.

[0800] Exemplary Embodiment 47 wherein when X is -O-, -NH-, or optionally substituted -N(C-C alkyl)- and Y is -O-, -NH-, or optionally substituted -N(C-C alkyl)-, then L is not absent, -O-, -NH-, or optionally substituted -N(C-C alkyl)-.

[0801] Exemplary Embodiment 48 During the ceremony, X is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl-, where C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is C1-C6 alkyl or C2-C6 alkenyl, wherein the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; The compound of any one of the preceding exemplary embodiments.

[0802] Exemplary Embodiment 49 During the ceremony, X is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl-, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where -N(C1-C6 alkyl)-, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is a C1-C6 alkyl or a C2-C6 alkenyl, wherein the C1-C6 alkyl or C2-C6 alkenyl is optionally substituted with one or more halogen, —CN, —OH, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; The compound of any one of the preceding exemplary embodiments.

[0803] Exemplary Embodiment 50 During the ceremony, X is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be optionally substituted with one or more halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C haloalkyl, or C-C alkoxy; L is absent, C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl -, where C1-C6 alkyl, C2-C6 alkenyl, -((C1-C6 alkyl)-O) nl -, -(O-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-O) nl -, -(O-(C2-C6 alkenyl)) nl -, -((C1-C6 alkyl)-NH) nl -, -(NH-(C1-C6 alkyl)) nl -, -((C2-C6 alkenyl)-NH) nl -, or -(NH-(C2-C6 alkenyl)) nl - is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; n1 is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl, wherein -N(C1-C6 alkyl)-, C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogen, -CN, -OH, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 haloalkyl, or C1-C6 alkoxy; The compound of any one of the preceding exemplary embodiments.

[0804] Exemplary Embodiment 51 The compound of any one of the preceding exemplary embodiments, wherein X is -O-, -NH-, -N(C1-C6 alkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; and Y is -O- or C1-C6 alkyl.

[0805] Exemplary Embodiment 52 The compound of any one of the preceding exemplary embodiments, wherein X is -O-, -NH-, or -N(C1-C6 alkyl)-; L is C1-C6 alkyl; and Y is -O-.

[0806] Exemplary Embodiment 53 The compound of any one of the preceding exemplary embodiments, wherein X is C1-C6 alkyl; L is absent; and Y is C1-C6 alkyl.

[0807] Exemplary Embodiment 54 The compound of any one of the preceding exemplary embodiments, wherein n is 1.

[0808] Exemplary Embodiment 55 The compound of any one of the preceding exemplary embodiments, wherein n is 2.

[0809] Exemplary Embodiment 56 In the formula, R a and R b are each independently H or halogen; or R a and R btogether with the atoms to which they are attached, form one or more R S The compound of any one of the preceding exemplary embodiments, wherein the compound forms a C3-C7 cycloalkyl optionally substituted with

[0810] Exemplary Embodiment 57 In the formula, R a and R b One of the is H and R a and R b The compound of any one of the preceding exemplary embodiments, wherein one of is a halogen.

[0811] Exemplary Embodiment 58 In the formula, R a and R b

[0039] The compound of any one of the preceding exemplary embodiments, wherein, together with the atom to which they are attached, form a cyclopropyl.

[0812] Exemplary Embodiment 59 The compound of any one of the preceding exemplary embodiments, wherein Z is —O—.

[0813] Exemplary Embodiment 60 In the formula, Z is -NR Z The compound of any one of the preceding exemplary embodiments, wherein

[0814] Exemplary Embodiment 61 The compound of any one of the preceding exemplary embodiments, wherein Z is —NH—.

[0815] Exemplary Embodiment 62 In the formula, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10-cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) is present in one or more R 1S The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0816] Exemplary Embodiment 63 In the formula, R1 is -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 The compound of any one of the preceding exemplary embodiments, wherein —NH—(3- to 7-membered heterocycloalkyl), or —NH—(3- to 7-membered heterocycloalkyl) is optionally substituted with one or more halogen, —CN, —OH, or C1-C6 alkoxy.

[0817] Exemplary Embodiment 64 The compound of any one of the preceding exemplary embodiments, wherein R1 is -OH.

[0818] Exemplary Embodiment 65 wherein R1 is -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2, where -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2 is selected from one or more R 1S The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0819] Exemplary Embodiment 66 wherein R1 is -SH, -S(C1-C6 alkyl), or -S(C6-C 10 aryl), where -S(C1-C6 alkyl) or -S(C6-C 10 aryl) is one or more R 1S The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0820] Exemplary Embodiment 67 In the formula, R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 aryl, 5-10 membered heteroaryl, C3-C7 cycloalkyl, or 3-7 membered heterocycloalkyl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6-C 10 Aryl, 5- to 10-membered heteroaryl, C-C cycloalkyl, or 3- to 7-membered heterocycloalkyl may be present in one or more R 1S The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0821] Exemplary Embodiment 68 wherein R1 is one or more R 1S The compound of any one of the preceding exemplary embodiments, wherein R is C1-C6 alkyl optionally substituted with

[0822] Exemplary Embodiment 69 The compound of any one of the preceding exemplary embodiments, wherein R1 is C1-C6 alkyl.

[0823] Exemplary Embodiment 70 The compound of any one of the preceding exemplary embodiments, wherein R1 is methyl.

[0824] Exemplary Embodiment 71 The compound of any one of the preceding exemplary embodiments, wherein R1 is ethyl.

[0825] Exemplary Embodiment 72 wherein R1 is one or more R 1S The compound of any one of the preceding exemplary embodiments, wherein R is C3-C7 cycloalkyl optionally substituted with

[0826] Exemplary Embodiment 73 wherein R1 is one or more R 1SThe compound of any one of the preceding exemplary embodiments, wherein R is cyclopropyl, optionally substituted with R.

[0827] Exemplary Embodiment 74 The compound of any one of the preceding exemplary embodiments, wherein R1 is cyclopropyl optionally substituted with one or more F.

[0828] Exemplary Embodiment 75 In the formula, R1 is -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 cycloalkyl), or -O-(3- to 7-membered heterocycloalkyl), where -O-(C6-C 10 aryl), -O-(5-10 membered heteroaryl), -O-(C3-C 10 -cycloalkyl), or -O-(3- to 7-membered heterocycloalkyl) is present in one or more R 1S The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0829] Exemplary Embodiment 76 In the formula, R1 is -NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where NH-(C6-C 10 aryl), -NH-(5-10 membered heteroaryl), -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) is present in one or more R 1S The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0830] Exemplary Embodiment 77 wherein at least one R 1S The compound of any one of the preceding exemplary embodiments, wherein is halogen, —CN, —OH, or C1-C6 alkoxy.

[0831] Exemplary Embodiment 78 wherein at least one R 1S The compound of any one of the preceding exemplary embodiments, wherein is a halogen.

[0832] Exemplary Embodiment 79 wherein at least one R 1S

[0023] The compound of any one of the preceding exemplary embodiments, wherein is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0833] Exemplary Embodiment 80 wherein at least one R 1S is a C3-C7 cycloalkyl or a 3- to 7-membered heterocycloalkyl.

[0834] Exemplary Embodiment 81 wherein Ar1 is one or more R A1 C6-C optionally substituted with 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is aryl.

[0835] Exemplary Embodiment 82 wherein Ar1 is one or more R A1 The compound of any one of the preceding exemplary embodiments, wherein R is phenyl optionally substituted with R.

[0836] Exemplary Embodiment 83 In the formula, Ar1 is The compound of any one of the preceding exemplary embodiments, wherein the compound is TIFF0007811578000117.tif25128.

[0837] Exemplary Embodiment 84 In the formula, Ar1 is The compound of any one of the preceding exemplary embodiments, wherein the compound is TIFF0007811578000118.tif37128.

[0838] Exemplary Embodiment 85 wherein Ar1 is one or more R A1The compound of any one of the preceding exemplary embodiments, wherein the heteroaryl is a 5- to 10-membered heteroaryl optionally substituted with

[0839] Exemplary Embodiment 86 wherein Ar1 is one or more R A1 The compound of any one of the preceding exemplary embodiments, wherein the compound is pyridyl or thiazolyl optionally substituted with

[0840] Exemplary Embodiment 87 wherein Ar1 is one or more R A1 The compound of any one of the preceding exemplary embodiments, wherein the compound is pyridyl optionally substituted with

[0841] Exemplary Embodiment 88 In the formula, Ar1 is The compound of any one of the preceding exemplary embodiments, wherein the compound is TIFF0007811578000119.tif26128.

[0842] Exemplary Embodiment 89 wherein at least one R A1 The compound of any one of the preceding exemplary embodiments, wherein is Ar2.

[0843] Exemplary Embodiment 90 wherein at least one R A1 But C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 The aryl or 5- to 10-membered heteroaryl is selected from one or more R A2 The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0844] Exemplary Embodiment 91 wherein at least one R A1 but one or more R A2 C6-C optionally substituted with 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is aryl.

[0845] Exemplary Embodiment 92 wherein at least one R A1 but one or more R A2 The compound of any one of the preceding exemplary embodiments, wherein R is phenyl optionally substituted with R.

[0846] Exemplary Embodiment 93 wherein at least one R A1 is halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl.

[0847] Exemplary Embodiment 94 wherein at least one R A1 The compound of any one of the preceding exemplary embodiments, wherein is a halogen.

[0848] Exemplary Embodiment 95 wherein at least one R A1 The compound of any one of the preceding exemplary embodiments, wherein

[0849] Exemplary Embodiment 96 The compound of any one of the preceding exemplary embodiments, wherein T is absent.

[0850] Exemplary Embodiment 97 The compound of any one of the preceding exemplary embodiments, wherein T is Ar2.

[0851] Exemplary Embodiment 98 wherein T is C6-C 10 aryl or 5-10 membered heteroaryl, where C6-C 10 The aryl or 5- to 10-membered heteroaryl is selected from one or more R A2 The compound of any one of the preceding exemplary embodiments, optionally substituted with

[0852] Exemplary Embodiment 99 wherein T is one or more R A2C6-C optionally substituted with 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is aryl.

[0853] Exemplary Embodiment 100 wherein T is one or more R A2 The compound of any one of the preceding exemplary embodiments, wherein R is phenyl optionally substituted with R.

[0854] Exemplary Embodiment 101 In the formula, T is The compound of any one of the preceding exemplary embodiments, wherein the compound is TIFF0007811578000120.tif22128.

[0855] Exemplary Embodiment 102 wherein T is one or more R A2 The compound of any one of the preceding exemplary embodiments, wherein the heteroaryl is a 5- to 10-membered heteroaryl optionally substituted with

[0856] Exemplary Embodiment 103 wherein at least one R A1

[0023] The compound of any one of the preceding exemplary embodiments, wherein is Ar2 and T is absent.

[0857] Exemplary embodiment 104 In the formula, Ar1 is TIFF0007811578000121.tif35128, and T is absent.

[0858] Exemplary Embodiment 105 In the formula, each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; and T is Ar.

[0859] Exemplary Embodiment 106 In the formula, Ar1 is TIFF0007811578000122.tif24128 and T is Ar2.

[0860] Exemplary Embodiment 107 In the formula, Ar1 is TIFF0007811578000123.tif24128 and T is Ar2.

[0861] Exemplary Embodiment 108 In the formula, each R A1 are independently halogen, —CN, —OH, —NH, —NH(C-C alkyl), —N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, or C-C alkynyl; and T is Ar.

[0862] Exemplary Embodiment 109 wherein at least one Ar2 is selected from one or more R A2 C6-C optionally substituted with 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is aryl.

[0863] Exemplary Embodiment 110 wherein at least one Ar2 is selected from one or more R A2 The compound of any one of the preceding exemplary embodiments, wherein R is phenyl optionally substituted with R.

[0864] Exemplary Embodiment 111 wherein at least one Ar2 is selected from one or more R A2 The compound of any one of the preceding exemplary embodiments, wherein the heteroaryl is a 5- to 10-membered heteroaryl optionally substituted with

[0865] Exemplary Embodiment 112 wherein at least one R A2The compound of any one of the preceding exemplary embodiments, wherein is a halogen.

[0866] Exemplary Embodiment 113 wherein at least one R A2 The compound of any one of the preceding exemplary embodiments, wherein

[0867] Exemplary Embodiment 114 wherein at least one R A2 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0868] Exemplary Embodiment 115 wherein n1 is an integer ranging from 0 to 4, and n2 is an integer ranging from 0 to 4, the formulas (I'-a), (I'-b), (IA'), (IA'-a), (IA'-b), (IB'), (IB'-a), (IB'-b), (II'), (II'-a), (II'-b), (IIA'), (IIA'-a), (IIA'-b), (IIB'), (IIB'-a), (I The compound of any one of the preceding exemplary embodiments is a compound of Formula IB'-b), (IIIA'), (IIIA'-a), (IIIA'-b), (IIIB'), (IIIB'-a), or (IIIB'-b), (IVA'), (IVA'-a), (IVA'-b), (VA'), (VA'-a), or (VA'-b), or a pharmaceutically acceptable salt thereof.

[0869] Exemplary Embodiment 116 wherein n1 is an integer ranging from 0 to 4; and n2 is an integer ranging from 0 to 4. The compound of any one of the preceding exemplary embodiments is a compound of Formula (Ia), (Ib), (IA), (IA-a), (IA-b), (IB), (IB-a), (IB-b), (II), (II-a), (II-b), (IIA), (IIA-a), (IIA-b), (IIB), (IIB-a), (IIB-b), (IIIA), (IIIA-a), (IIIA-b), (IIIB), (IIIB-a), or (IIIB-b), (IVA), (IVA-a), (IVA-b), (VA), (VA-a), or (VA-b), or a pharmaceutically acceptable salt thereof.

[0870] Exemplary Embodiment 117 During the ceremony, R1 is -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, 5- to 10-membered heteroaryl, 3- to 7-membered heterocycloalkyl, -NH-(C3-C 10 cycloalkyl), or -NH-(3-7 membered heterocycloalkyl), where -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, 5-10 membered heteroaryl, 3-7 membered heterocycloalkyl, -NH-(C3-C 10 -cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) is present in one or more R 1S and the C1-C6 alkyl is optionally substituted with one or more R 1S is replaced by; Each R 1S are independently halogen or C1-C6 alkyl; Each R A1 are independently halogen; Each R A2 are independently halogen; n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4; The compound of any one of the preceding exemplary embodiments.

[0871] Exemplary Embodiment 118 The compound of any one of the preceding exemplary embodiments, wherein the compound is selected from the compounds set forth in Table A1 and pharmaceutically acceptable salts thereof.

[0872] Exemplary Embodiment 119 The compound of any one of the preceding exemplary embodiments, selected from compound numbers A1-6, A1-6, A1-10, A1-15, A1-42, A1-58, A1-59, A1-60, A1-61, A1-63 to A1-102, and pharmaceutically acceptable salts thereof.

[0873] Exemplary Embodiment 120 The compound of any one of the preceding exemplary embodiments, wherein the compound is selected from the compounds set forth in Table A2 and pharmaceutically acceptable salts thereof.

[0874] Exemplary Embodiment 121 The compound of any one of the preceding exemplary embodiments, wherein the compound is selected from the compounds set forth in Table B1 and pharmaceutically acceptable salts thereof.

[0875] Exemplary Embodiment 122 The compound of any one of the preceding exemplary embodiments, selected from the compounds set forth in Table B2 and pharmaceutically acceptable salts thereof.

[0876] Exemplary Embodiment 123 A compound obtainable or obtained by the method described herein; optionally the method comprising one or more steps described in Schemes 1-5.

[0877] Exemplary Embodiment 124 A pharmaceutical composition comprising a compound according to any one of the preceding exemplary embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0878] Exemplary Embodiment 125 The pharmaceutical composition of any one of the preceding exemplary embodiments, wherein the compound is selected from the compounds set forth in Tables A1, A2, B1, and B2.

[0879] Exemplary Embodiment 126 A method of modulating orexin-2 receptor activity, comprising contacting a cell with an effective amount of a compound of any one of the preceding exemplary embodiments, wherein optionally the activity is an in vitro or in vivo activity.

[0880] Exemplary Embodiment 127 A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of any one of the preceding exemplary embodiments.

[0881] Exemplary Embodiment 128 The compound or pharmaceutical composition of any one of the preceding exemplary embodiments for use in modulating orexin-2 receptor activity, optionally wherein the activity is in vitro or in vivo activity.

[0882] Exemplary Embodiment 129 The compound or pharmaceutical composition of any one of the preceding exemplary embodiments for use in treating or preventing a disease or disorder.

[0883] Exemplary Embodiment 130 Use of a compound of any one of the preceding exemplary embodiments in the manufacture of a medicament for modulating orexin-2 receptor activity, optionally wherein the activity is in vitro or in vivo activity.

[0884] Exemplary Embodiment 131 Use of a compound of any one of the preceding exemplary embodiments in the manufacture of a medicament for treating or preventing a disease or disorder.

[0885] Exemplary Embodiment 132 The method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments, wherein the disease or disorder is associated with the implicated orexin-2 receptor.

[0886] Exemplary Embodiment 133 The method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments, wherein the disease or disorder is a neurodegenerative disorder, a neurological disorder, a symptom of a rare genetic disorder, a psychiatric disorder, a mental health disorder, a circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma, or a complication in anesthesia emergence.

[0887] Exemplary Embodiment 134 The method, compound, pharmaceutical composition, or use of any one of the preceding exemplary embodiments, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, sleep apnea, or insomnia. [Example]

[0888] Abbreviation TIFF0007811578000124.tif183143

[0889] NMR NMR spectra were recorded on a Bruker Avance III HD UltraShield 400 MHz with a 5 mm PABBO probe, a Bruker DPX 300 MHz with a 5 mm BBI probe, a Bruker AV 400 MHz with a 5 mm PABBO probe, a Bruker DRX 500 MHz with a 5 mm PABBI probe, and a Bruker Avance III 600 spectrometer with a 5 mm RT BBI probe. Samples were recorded at 25 °C using DMSO-d6, CDCl3, or MeOH-d4 as solvents and TMS as an internal standard.

[0890] LCMS conditions Condition A. General UPLC method parameters: Gradient mobile phase of 0.1% formic acid and CH3CN in H2O or 0.05% NH3 and CH3CN in H2O. Columns: Acquity BEH 2.1 x 50 mm, 1.7 μm and Acquity BEH 2.1 x 100 mm, 1.7 μm. PDA detector settings: Wavelength: 210-400 nm, Resolution: 1.2 nm, Sampling Rate: 1.0 points / sec, Filter Response: 1. MS detector settings: MS scan: centroid, ionization mode: ES+ and ES-, mass range: 100-1250, scan time: 0.225 s, capillary: 1.30 kV (ES+) and 0.80 kV (ES-), cone: 15 V, extractor: 3.00 V, RF lens: 0.2 V, source temperature: 120 °C, desolvation temperature: 600 °C, LM1 resolution: 0.02, HM1 resolution: 0.11.

[0891] Condition B. LC / MS Agilent Technologies 1260 Infinity LC equipped with Chemstation software. Aqueous system (A2): 2.5 L of water with 2.5 mL of 28% aqueous ammonia; Organic system (B2): 2.5 L of acetonitrile with 125 mL of water and 2.5 mL of 28% aqueous ammonia. The system was operated at a flow rate of 1.5 mL / min, injection volume of 0.5 μL, and a Phenomenex Gemini-NX column, 5 μm C18, 30 × 2 mm. Column oven temperature was 40 °C. An Agilent 6120 single quadrupole mass spectrometer was equipped with a diode array detector for UV detection from 190 to 400 nm and an API-ES source. Gradient written in the following format: [time (min) / %A2:%B2], short runs: [0.00 / 95:5], [2.0 / 5:95], [2.5 / 5:95], [2.6 / 95:5], [3.0 / 95:5].

[0892] Condition C. LC / MS Agilent Technologies 1260 Infinity LC equipped with Chemstation software. Aqueous system (A2): 2.5 L of water with 2.5 mL of 28% aqueous ammonia; Organic system (B2): 2.5 L of acetonitrile with 125 mL of water and 2.5 mL of 28% aqueous ammonia. The system was operated at a flow rate of 1.5 mL / min, injection volume of 0.5 μL, and a Phenomenex Gemini-NX column, 5 μm C18, 30 x 2 mm. Column oven temperature was 40 °C. An Agilent 6120 single quadrupole mass spectrometer was equipped with a diode array detector for UV detection from 190 to 400 nm and an API-ES source. Gradient written in the following format: [time (min) / %A2:%B2], long runs: [0.00 / 98:2], [0.1 / 98:2], [8.4 / 5:95], [10.0 / 5:95], [10.1 / 98:2], [12.0 / 98:2].

[0893] Condition D. Hewlett Packard 1100 series with Masslynx software. Aqueous system (C): 2.5 L of water with 2.5 mL of 28% aqueous ammonia solution. Organic system (D): 2.5 L of acetonitrile with 125 mL of water and 2.5 mL of 28% aqueous ammonia solution. The system was operated at a flow rate of 1.5 mL / min with a 1 μL injection volume and a Phenomenex Gemini-NX column, 5 μm C18, 30 x 2 mm column. The column oven temperature was 45 °C. A Hewlett Packard G1315A diode array detector and a Waters micromass ZQ mass spectrometer were used, detecting UV from 230 to 400 nm. The gradient was written in the following format: [time (min) / %C:%D]. Short runs: [0.00 / 98:2], [0.1 / 98:2], [2.5 / 5:95], [3.5 / 5:95].

[0894] Condition E. Hewlett Packard 1100 series with Masslynx software. Aqueous system (C): 2.5 L of water with 2.5 mL of 28% aqueous ammonia; Organic system (D): 2.5 L of acetonitrile with 125 mL of water and 2.5 mL of 28% aqueous ammonia. The system was operated at a flow rate of 1.5 mL / min with a 1 μL injection volume and a Phenomenex Gemini-NX column, 5 μm C18, 30 x 2 mm column. The column oven temperature was 45 °C. A Hewlett Packard G1315A diode array detector and a Waters micromass ZQ mass spectrometer were used, detecting UV from 230 to 400 nm. The gradient was written in the following format: [time (min) / %C:%D]. Long runs: [0.00 / 98:2], [0.1 / 98:2], [8.4 / 5:95], [10.0 / 5:95].

[0895] Condition F. LC parameters TIFF0007811578000125.tif35152 Gradient TIFF0007811578000126.tif46128 Mass parameters TIFF0007811578000127.tif28128

[0896] Condition G. LC / MS (gradient: 5% B for 0.40 min, 5% B to 95% B from 0.40 to 3.00 min, 95% B for 1.00 min, then 95% B to 5% B for 0.01 min) with a flow rate of 1.0 mL / min. Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna C18 50*2.0 mm column (5 μm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization. The MS range was 100-1000.

[0897] Condition H. LC / MS (gradient: 5% B for 0.40 min, 5 to 95% B from 0.40 to 3.40 min, 95% B for 0.45 min, then 95 to 5% B for 0.01 min) with a flow rate of 0.8 mL / min. Mobile phase A was HO + 10 mM NHHCO, and mobile phase B was acetonitrile. The column used for chromatography was an Xbridge-C18 2.1*50 mm column (5 μm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization. The MS range was 100-1000.

[0898] Condition I. 5-95% B for 2 min: LC / MS (The column used for chromatography was a Kinetex 5 μm EVO C18 100A. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000. Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in HPLC-grade acetonitrile. The gradient was 5-95% B for 1.50 min, 5% B for 0.01 min, 5-95% B (0.01-0.70 min), 95% B for 0.46 min, 95-5% B (1.61-1.50 min), and hold at 5% B for 0.11 min. The flow rate was 1.5 mL / min.

[0899] Condition J. LC / MS (gradient: 5–95% B for 0.7 min, 95–95% B for 0.45 min, 95–5% B for 0.01 min, then hold at 0% B for 0.44 min (flow rate of 1.5 mL / min). Mobile phase A was 0.0375% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Chromolith Flash RP-18e25-2 mm column. The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and positive electrospray ionization (MS).

[0900] Synthesis of intermediate 1 Step 1: tert-butyl 2-(3-bromobenzyl)-3-oxopyrrolidine-1-carboxylate TIFF0007811578000128.tif32128

[0901] 2-Methyl-2-((3-oxopyrrolidine-1-carbonyl)oxy)propan-1-ylium (50.00 g, 270 mmol) was dissolved in toluene (500 mL) at room temperature. Pyrrolidine (33.25 mL, 405 mmol) was added at room temperature, and the reaction mixture was stirred at 120° C. for 5 hours using a Dean-Stark apparatus. The reaction mixture was concentrated in vacuo to give a red viscous residue. The residue was redissolved in acetonitrile (500 mL). 1-Bromo-3-(bromomethyl)benzene (66.9 g, 270 mmol) and tetrabutylammonium iodide (19.94 g, 54 mmol) were added at room temperature, and the reaction mixture was allowed to stir at 80° C. for 2 hours. The reaction mixture was diluted with water (1000 mL) and extracted with dichloromethane (250 mL). The aqueous layer was further extracted with dichloromethane (3×250 mL). The organic layers were combined and dried (NaSO). The solvent was removed in vacuo to give the crude compound, which was purified by normal phase gradient column chromatography (normal phase, silica) and the product was eluted with 0% to 2% EtOAc in hexane to give the title compound (24.00 g, 26% yield) as a yellow gum. LCMS (Method F) m / z 298 (ES+, M- t Bu), 2.43 min.

[0902] Step 2: tert-Butyl 3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate_cis racemic TIFF0007811578000129.tif31128

[0903] tert-Butyl 2-(3-bromobenzyl)-3-oxopyrrolidine-1-carboxylate (20.00 g, 56.67 mmol) was dissolved in methanol (100 mL). Ammonium formate (28.58 g, 453 mmol) and chloro[N-[4(dimethylamino)phenyl]-2-pyridinecarboxamidato](pentamethylcyclopentadienyl)iridium(III) (0.68 g, 1.13 mmol) were added at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (250 mL). The aqueous layer was further extracted with EtOAc (3 × 150 mL). The organic layers were combined, dried (NaSO), and the solvent removed in vacuo. The crude product was purified by reverse-phase gradient flash column chromatography (reverse-phase, C18 silica) eluting the product with 0% to 30% acetonitrile in water with 0.1% formic acid and 5 mmol ammonium acetate as modifiers to give a yellow solid. This solid was dissolved in saturated aqueous NaHCO3 (500 mL) and extracted with dichloromethane (3 x 250 mL). The organic layers were combined and dried (Na2SO4). The solvent was evaporated in vacuo to give the title compound (6.50 g, 26% yield) as an orange gum. LCMS (Method F) m / z 299 (ES+, M- t Bu), 1.38 min.

[0904] Step 3: tert-Butyl 2-(3-bromobenzyl)-3-(methylsulfonamido)pyrrolidine-1-carboxylate, cis racemic (Intermediate 1) TIFF0007811578000130.tif31128

[0905] To a solution of tert-butyl 3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate cis racemate (2.00 g, 5.63 mmol) in dichloromethane (25 mL) was added methanesulfonyl chloride (0.654 mL, 8.44 mmol) and N,N-diisopropylethylamine (2.45 mL, 14.1 mmol) at 0 °C, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO and brine, dried over MgSO, and evaporated. The residue was purified on an InterChim PuriFlash 520 plus purification system (25 g Si column, 15 μm, eluent: 0-100% ethyl acetate / cyclohexane) to yield the title compound (1.02 g). LCMS (Method A) (ESI-): 431.04 [1:1, MH]

[0906] Synthesis of intermediate 2 tert-Butyl 2-(3-bromobenzyl)-3-(ethylsulfonamido)pyrrolidine-1-carboxylate, cis racemic (Intermediate 2) TIFF0007811578000131.tif31128

[0907] To a cooled (<5°C) solution of tert-butyl 3-amino-2-(3-bromobenzyl)pyrrolidine-1-carboxylate cis racemic (5.7 g, 16 mmol) and EtN (4.52 mL, 32 mmol) in dichloromethane (80 mL) was added ethanesulfonyl chloride (2.09 mL, 24.07 mmol), and the reaction was stirred at RT for 1 h. The crude reaction was diluted with dichloromethane (50 mL), washed with 10% citric acid (50 mL), brine (50 mL), and the organic layer was separated, dried over MgSO, filtered, and concentrated in vacuo to afford the title compound (6.85 g, 15.31 mmol) as a light brown waxy solid. LCMS (Method D) m / z 447 (ES+, M+H), 2.22 min

[0908] Synthesis of intermediate 3 Step 1: tert-butyl 2-(3-bromobenzyl)-3-oxopiperidine-1-carboxylate TIFF0007811578000132.tif33136

[0909] tert-Butyl 3-oxopiperidine-1-carboxylate (50.00 g, 251 mmol) was dissolved in toluene (500 mL) at room temperature. Pyrrolidine (51.5 mL, 628 mmol) was added at 0° C., and the reaction mixture was allowed to stir at 120° C. for 5 hours. The reaction mixture was concentrated in vacuo to give an orange viscous residue. The residue was redissolved in acetonitrile (500 mL). 1-Bromo-3-(bromomethyl)benzene (37.36 g, 151 mmol) and tetrabutylammonium iodide (18.54 g, 50 mmol) were added at 0° C., and the reaction mixture was allowed to stir at 80° C. for 3 hours. The reaction mixture was concentrated under vacuum to afford the crude compound, which was purified by normal phase gradient column chromatography (normal phase, silica), eluting the product with 0% to 8% EtOAc in hexanes to afford the title compound (35.50 g, 38% yield) as a yellow sticky solid. LCMS (Method F) m / z 268 (ES+, M-Boc), 2.497 min

[0910] Step 2: tert-Butyl 3-amino-2-(3-bromobenzyl)piperidine-1-carboxylate_cis racemic TIFF0007811578000133.tif32128

[0911] tert-Butyl 2-(3-bromobenzyl)-3-oxopiperidine-1-carboxylate (33.3 g, 91 mmol) was dissolved in methanol (600 mL). Ammonium acetate (209.6 g, 2722 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (38.45 g, 181 mmol) was then added at 0° C., and the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo. The reaction mixture was then diluted with saturated aqueous NaHCO3 (600 mL) and extracted with EtOAc (300 mL). The aqueous layer was further extracted with EtOAc (3×100 mL). The organic layers were combined and dried (Na2SO4). The crude product was purified by normal phase gradient column chromatography (normal phase, silica gel) and the product was eluted with 0% to 10% MeOH in dichloromethane to afford the title compound (16.6 g, 50% yield) as a yellow sticky solid. LCMS (Method F) m / z 313 (ES+, M- t Bu), 1.59 min.

[0912] Step 3: tert-Butyl 2-(3-bromobenzyl)-3-(methylsulfonamido)piperidine-1-carboxylate, cis racemic (Intermediate 3) TIFF0007811578000134.tif32128

[0913] To a solution of tert-butyl 3-amino-2-(3-bromobenzyl)piperidine-1-carboxylate cis racemic (12.9 g, 35 mmol) and EtN (9.74 mL, 70 mmol) in dichloromethane (175 mL) cooled to <5 °C, methanesulfonyl chloride (3.24 mL, 42 mmol) was added, and the reaction was stirred at room temperature for 1 h. The reaction was washed with saturated NaHCO and brine, and the organic layer was separated, dried over MgSO, filtered, and concentrated in vacuo to provide the title compound (15 g, 95% yield) as a yellow solid. LCMS (Method B) m / z 347 (ES+, M-Boc), 1.46 min

[0914] Synthesis of intermediate 4 tert-Butyl 2-((2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)-piperidine-1-carboxylate, cis racemic (Intermediate 4) TIFF0007811578000135.tif41128

[0915] To a solution of tert-butyl 2-(3-bromobenzyl)-3-(methylsulfonamido)piperidine-1-carboxylate, cis racemic (Intermediate 3) (2.0 g, 4.47 mmol), 2-hydroxybenzeneboronic acid pinacol ester (1.08 g, 4.92 mmol), and XPhos-Pd-G3 (189 mg, 0.22 mmol) in THF (45 mL) was added 1 M potassium phosphate trihydrate solution (18 mL, 18 mmol), and the reaction was heated at 70 °C for 1 h. The reaction was washed with saturated NaHCO3 and brine, and the organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting oil was purified by flash column chromatography using a Biotage Isolera 50 g silica cartridge, eluting with 0% to 100% ethyl acetate / isohexane, to afford the title compound (2.4 g, 93% yield) as a light brown gum. LCMS (Method B) m / z 461 (ES+, M+H), 1.41 min.

[0916] Synthesis of intermediate 5 tert-Butyl 3-(methylsulfonamido)-2-((2'-(((trifluoromethyl)sulfonyl)oxy)-[1,1'-biphenyl]-3-yl)methyl)piperidine-1-carboxylate, cis racemic (Intermediate 5) TIFF0007811578000136.tif39128

[0917] To a solution of tert-butyl 2-((2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)piperidine-1-carboxylate cis racemate (1.0 g, 2.17 mmol) in dichloromethane (43 mL) at 0 °C, EtN (920 μL, 6.5 mmol) and trifluoromethanesulfonic anhydride (560 μL, 3.3 mmol) were added, and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to afford the title compound (1.28 g, 99% yield) as a brown gum, which was used crude. LCMS (Method B) m / z 593 (ES+, M+H), 1.80 min

[0918] Example 1. Synthesis of Compound No. A1-13 Step 1: N-(2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide cis racemic (Intermediate 6) TIFF0007811578000137.tif30128

[0919] A solution of tert-butyl 2-(3-bromobenzyl)-3-(methylsulfonamido)pyrrolidine-1-carboxylate cis racemate (Intermediate 1) (130 mg, 0.30 mmol) in 4 M HCl / dioxane (1.12 mL, 4.50 mmol) was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was dissolved in dichloromethane (15 mL) / water (8 mL). The pH was adjusted to approximately 10 with 1 M NaOH, and the product was extracted with dichloromethane (3 × 10 mL). The organic layers were combined, dried over NaSO, and evaporated to give 100 mg of the title compound. LC-MS (Method A) (ESI+):333 [M+H].

[0920] Step 2: N-(2-(3-bromobenzyl)-1-(3-vinylazetidine-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide_cis racemic TIFF0007811578000138.tif41128

[0921] To a solution of triphosgene (33 mg, 0.111 mmol) in dichloromethane (2.0 mL) at 0° C. was added a mixture of 3-vinylazetidine×TFA (59 mg, 0.30 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in 1.0 mL of dichloromethane dropwise. After 20 min, a second mixture containing N-(2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide_cis racemic, Intermediate 6 (100 mg, 0.30 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in dichloromethane (2.0 mL) was added in one portion. The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was washed with saturated aqueous NaHCO (25 mL), and the organic layer was dried over NaSO and evaporated to yield 140 mg of the title compound. LC-MS (Method A) (ESI+):442 [M+H].

[0922] Step 3: N-(2-((2'-vinyl-[1,1'-biphenyl]-3-yl)methyl)-1-(3-vinylazetidine-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide_cis racemic TIFF0007811578000139.tif51128

[0923] To a solution of cis-racemic N-(2-(3-bromobenzyl)-1-(3-vinylazetidine-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide (133 mg, 0.30 mmol) in THF / water (2:1, 6 mL) was added (2-vinylphenyl)boronic acid (49 mg, 0.33 mmol), XPhos G3 (25 mg, 0.03 mmol), and KPO (191 mg, 0.9 mmol), and the reaction mixture was heated at 80° C. for 1 h. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (100 mL), dried over NaSO, and evaporated. The residue was purified using Interchim PuriFlash (4 g column, 15 μm, 15 mL / min, 0-100% dichloromethane / MeOH / NH3=90 / 9 / 1.5 in dichloromethane) to give 50 mg of the title compound. LC-MS (Method A) (ESI+): 466 [M+H].

[0924] Step 4: N-(5-oxo-4(2,1)-pyrrolizina-6(1,3)-azetidina-1(1,2),2(1,3)-dibenzenacyclo-octaphan-7-ene-4 3 -yl)methanesulfonamide cis racemic TIFF0007811578000140.tif41128

[0925] To a solution of cis-racemic N-(2-((2'-vinyl-[1,1'-biphenyl]-3-yl)methyl)-1-(3-vinylazetidine-1-carbonyl)pyrrolidin-3-yl)methanesulfonamide (50.0 mg, 0.11 mmol) in dichloromethane (50 ml), Grubbs 2nd generation catalyst (18 mg, 0.022 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. The solvent was evaporated, and the residue was purified using an Interchim PuriFlash (4 g column, 15 μm, 15 mL / min, 0-100% dichloromethane / MeOH / NH3 = 90 / 9 / 1.5 in dichloromethane) to afford 45 mg of the title compound. LC-MS (Method A) (ESI+): 438 [M+H].

[0926] Step 5: N-(5-oxo-4-(2,1)-pyrrolizina-6-(1,3)-azetidina-1-(1,2),2-(1,3)-dibenzena-cyclooctaphane-4 3 -yl)methanesulfonamide cis racemic (Compound No. A1-13) TIFF0007811578000141.tif41128

[0927] N-(5-oxo-4(2,1)-pyrrolizina-6-(1,3)-azetidina-1-(1,2),2-(1,3)-dibenzenacyclooctaphan-7-ene-4 3 To a suspension of (-yl)methanesulfonamide cis racemate (45.0 mg, 0.10 mmol) in MeOH (15 mL) was added ammonium formate (45 mg, 0.72 mmol) and Pd / C (10.0%, 55 mg, 0.051 mmol). The reaction mixture was heated in a microwave reactor at 70 °C for 10 min. The reaction mixture was filtered and the solvent evaporated. The residue was purified using Interchim PuriFlash (4 g column, 15 μm 10 mL / min, 0-100% dichloromethane / MeOH / NH3 = 90 / 5 / 0.5 in dichloromethane) to afford 12 mg of the title compound. TIFF0007811578000142.tif33161

[0928] Example 2. Synthesis of Compound No. A1-14 Step 1: N-(1-(3-allylazetidine-1-carbonyl)-2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide_cis racemic TIFF0007811578000143.tif45128

[0929] To a solution of triphosgene (25.0 mg, 0.084 mmol) in dichloromethane (2.0 mL) at 0° C. was added a mixture of 3-allylazetidine TFA salt (48 mg, 0.228 mmol) and N,N-diisopropylethylamine (88 mg, 0.684 mmol) in 1.0 mL of dichloromethane dropwise. After 20 min, a second mixture containing N-(2-(3-bromobenzyl)pyrrolidin-3-yl)methanesulfonamide_cis racemate, Intermediate 6 (76.0 mg, 0.228 mmol) and N,N-diisopropylethylamine (88 mg, 0.684 mmol) in dichloromethane (2.0 mL) was added in one portion. The reaction mixture was stirred at rt for 4 h. The reaction mixture was washed with sa...

Claims

1. A compound of formula (I'), or a pharmaceutically acceptable salt thereof: During the ceremony, X is -O-, -NH-, -N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 6 -C 10 aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, where —N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 6 -C 10 The aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be selected from the group consisting of one or more halogen, —CN, —OH, —NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Haloalkyl, or C 1 -C 6 optionally substituted with alkoxy; L is absent or is -O-, -NH-, -N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, -((C 1 -C 6 Alkyl)-O) nl -, -(O-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-O) nl -, -(O-(C 2 -C 6 alkenyl) nl -,-((C 1 -C 6 alkyl)-NH nl -, -(NH-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-NH nl - or -(NH-(C 2 -C 6 alkenyl) nl -, where -N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, -((C 1 -C 6 Alkyl)-O) nl -, -(O-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-O) nl -, -(O-(C 2 -C 6 alkenyl) nl -,-((C 1 -C 6 alkyl)-NH nl -, -(NH-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-NH nl - or -(NH-(C 2 -C 6 alkenyl) nl - is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 nl is an integer ranging from 1 to 6; Y is -O-, -NH-, -N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, or C 2 -C 6 alkenyl, where -N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, or C 2 -C 6 Alkenyl is a group consisting of one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Haloalkyl, or C 1 -C 6 optionally substituted with alkoxy; n is an integer ranging from 0 to 3; R a and R b are each independently H, halogen, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 alkynyl, where -O(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, or C 2 -C 6 Alkynyl is a group consisting of one or more R S or R a and R b together with the atoms to which they are bonded, C 3 -C 7 forming a cycloalkyl or 3- to 7-membered heterocycloalkyl, where C 3 -C 7 The cycloalkyl or 3- to 7-membered heterocycloalkyl may be one or more R S optionally substituted with; Each R S are independently halogen, -CN, -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, or C 1 -C 6 haloalkyl; Z is -O- or -NR Z - where R Z is H or C 1 -C 6 is alkyl; R 1 -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -SH, -S(C 1 -C 6 alkyl), -S(C 6 -C 10 aryl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, C 3 -C 7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C 3 -C 10 cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5- to 10-membered heteroaryl), -NH-(C 3 -C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl), where -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -S(C 1 -C 6 alkyl), -S(C 6 -C 10 aryl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 6 -C 10 Aryl, 5- to 10-membered heteroaryl, C 3 -C 7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, -O-(C 6 -C 10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C 3 -C 10 cycloalkyl), -O-(3- to 7-membered heterocycloalkyl), -NH-(C 6 -C 10 aryl), -NH-(5- to 10-membered heteroaryl), -NH-(C 3 -C 10 cycloalkyl), or -NH-(3- to 7-membered heterocycloalkyl) is one or more R 1S optionally substituted with; Each R 1S are independently oxo, halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -S(C 1 -C 6 alkyl), -SO 2 (C 1 -C 6 alkyl), C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 7 cycloalkyl, or 3- to 7-membered heterocycloalkyl; Ar 1 is C 6 -C 10 aryl or 5-10 membered heteroaryl, where C 6 -C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A1 optionally substituted with; Each R A1 are independently Ar 2 , halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 2 -C 6 Alkenyl, or C 2 -C 6 is alkynyl; T is absent or Ar 2 and Each Ar 2 independently C 6 -C 10 aryl or 5-10 membered heteroaryl, where C 6 -C 10 An aryl or 5- to 10-membered heteroaryl may be one or more R A2 optionally substituted with; Each R A2 are independently halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 2 -C 6 Alkenyl, or C 2 -C 6 It is alkynyl.

2. The compound of claim 1, which is a compound of formula (I), or a pharmaceutically acceptable salt thereof: 。

3. The compound according to any one of claims 1 to 2, wherein X is -O-.

4. X is -NH- or -N(C 1 -C 6 alkyl)-, where -N(C 1 -C 6 alkyl)- is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Haloalkyl, or C 1 -C 6 The compound according to any one of claims 1 to 2, which is optionally substituted with alkoxy.

5. X is -NH- or -N(CH 3 5. The compound of claim 1, 2, or 4, wherein:

6. X is one or more of halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Haloalkyl, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 The compound of any one of claims 1 to 2, which is alkyl.

7. X is one or more of halogen, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Haloalkyl, or C 1 -C 6 The compound according to any one of claims 1 to 2, which is azetidinyl optionally substituted with alkoxy.

8. The compound of any one of claims 1 to 7, wherein L is absent.

9. L is -O-, -NH-, -N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, -((C 1 -C 6 Alkyl)-O) nl -, -(O-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-O) nl -, -(O-(C 2 -C 6 alkenyl) nl -,-((C 1 -C 6 alkyl)-NH nl -, -(NH-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-NH nl - or -(NH-(C 2 -C 6 alkenyl) nl -, where -N(C 1 -C 6 alkyl)-, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, -((C 1 -C 6 Alkyl)-O) nl -, -(O-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-O) nl -, -(O-(C 2 -C 6 alkenyl) nl -,-((C 1 -C 6 alkyl)-NH nl -, -(NH-(C 1 -C 6 Alkyl)) nl -,-((C 2 -C 6 alkenyl)-NH nl - or -(NH-(C 2 -C 6 Al Kenil)) nl - is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 The compound according to any one of claims 1 to 7, optionally substituted with

10. The compound of any one of claims 1 to 7 and 9, wherein L is -O-.

11. L is -NH- or -N(C 1 -C 6 alkyl)-, where -N(C 1 -C 6 alkyl)- is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 The compound according to any one of claims 1 to 7 and 9, optionally substituted with

12. L is C 1 -C 6 Alkyl or C 2 -C 6 alkenyl, where C 1 -C 6 Alkyl or C 2 -C 6 Alkenyl may be one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 The compound according to any one of claims 1 to 7 and 9, optionally substituted with

13. L is -((C 1 -C 6 Alkyl)-O) nl - or -(O-(C 1 -C 6 Alkyl)) nl -, where -((C 1 -C 6 Alkyl)-O) nl - or -(O-(C 1 -C 6 Alkyl)) nl - is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 The compound according to any one of claims 1 to 7 and 9, optionally substituted with

14. L is -((C 1 -C 6 alkyl)-NH nl - or -(NH-(C 1 -C 6 Alkyl)) nl -, where -((C 1 -C 6 alkyl)-NH nl - or -(NH-(C 1 -C 6 Alkyl)) nl - is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 The compound according to any one of claims 1 to 7 and 9, optionally substituted with

15. 15. The compound of any one of claims 1 to 14, wherein nl is an integer ranging from 1 to 3.

16. The compound of any one of claims 1 to 15, wherein Y is -O-.

17. 16. The compound of any one of claims 1 to 15, wherein Y is -NH-.

18. Y is one or more halogens, -CN, -OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 Haloalkyl, or C 1 -C 6 C optionally substituted with alkoxy 1 -C 6 The compound of any one of claims 1 to 15, which is alkyl.

19. The compound of any one of claims 1 to 18, wherein n is 1.

20. The compound of any one of claims 1 to 18, wherein n is 2.

21. R a and R b are each independently H or halogen; or R a and R b together with the atoms to which they are attached, form one or more R S C optionally substituted with 3 -C 7 The compound of claim 1 which forms a cycloalkyl.

22. R a and R b One of the is H and R a and R b 10. The compound of claim 1, wherein one of is a halogen.

23. R a and R b The compound of claim 1 , wherein:

24. 24. The compound of any one of claims 1 to 23, wherein Z is -O-.

25. 24. The compound of any one of claims 1 to 23, wherein Z is -NH-.

26. R 1 but one or more R 1S C optionally substituted with 1 -C 6 The compound of any one of claims 1 to 25, which is alkyl.

27. R 1 The compound of any one of claims 1 to 26, wherein is methyl or ethyl.

28. R 1 but one or more R 1S C optionally substituted with 3 -C 7 The compound of any one of claims 1 to 25, which is cycloalkyl.

29. R 1 but one or more R 1S 29. The compound of any one of claims 1 to 25 and 28, wherein the cyclopropyl group is cyclopropyl, optionally substituted with .

30. At least one R 1S The compound of any one of claims 1 to 25, wherein is halogen.

31. Ar 1 but one or more R A1 C optionally substituted with 6 -C 10 The compound of any one of claims 1 to 30, which is aryl.

32. Ar 1 but one or more R A1 The compound of any one of claims 1 to 30, which is a 5- to 10-membered heteroaryl optionally substituted by:

33. At least one R A1 Ar 2 The compound according to any one of claims 1 to 32,

34. At least one R A1 but one or more R A2 C optionally substituted with 6 -C 10 The compound of any one of claims 1 to 32, which is aryl.

35. At least one R A1 The compound of any one of claims 1 to 32, wherein is halogen.

36. 36. The compound of any one of claims 1 to 35, wherein T is absent.

37. T is Ar 2 The compound according to any one of claims 1 to 35,

38. At least one R A1 Ar 2 and T is absent.

39. Ar 1 but and T is absent.

40. Ar 1 but and T is Ar 2 The compound according to any one of claims 1 to 30,

41. Ar 1 but and T is Ar 2 The compound according to any one of claims 1 to 30,

42. At least one Ar 2 but one or more R A2 C optionally substituted with 6 -C 10 The compound of any one of claims 1 to 41, which is aryl.

43. At least one Ar 2 but one or more R A2 The compound of any one of claims 1 to 41, which is a 5- to 10-membered heteroaryl optionally substituted by:

44. At least one R A2 The compound of any one of claims 1 to 43, wherein is halogen.

45. 2. The compound of claim 1, which is a compound of formula (I'-a), (I'-b), (IA'), (IA'-a), (IA'-b), (IB'), (IB'-a), (IB'-b), (II'), (II'-a), (II'-b), (IIA'), (IIA'-a), (IIA'-b), (IIB'), (IIB'-a), (IIB'-b), (IIIA'), (IIIA'-a), (IIIA'-b), (IIIB'), (IIIB'-a), or (IIIB'-b), (IVA'), (IVA'-a), (IVA'-b), (VA'), (VA'-a), or (VA'-b), or a pharmaceutically acceptable salt thereof: During the ceremony, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

46. 3. The compound of any one of claims 1 to 2, which is a compound of formula (Ia), (Ib), (IA), (IA-a), (IA-b), (IB), (IB-a), (IB-b), (II), (II-a), (II-b), (IIA), (IIA-a), (IIA-b), (IIB), (IIB-a), (IIB-b), (IIIA), (IIIA-a), (IIIA-b), (IIIB), (IIIB-a), or (IIIB-b), (IVA), (IVA-a), (IVA-b), (VA), (VA-a), or (VA-b), or a pharmaceutically acceptable salt thereof: During the ceremony, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

48. The compound is 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 48. The pharmaceutical composition of claim 47, wherein the compound is selected from the group consisting of:

49. A composition for use in a method for modulating orexin-2 receptor activity, comprising a compound according to any one of claims 1 to 46, the method comprising contacting a cell with the compound, and optionally, the activity being in vitro or in vivo.

50. A composition comprising a compound according to any one of claims 1 to 46 or a pharmaceutical composition according to any one of claims 47 to 48 for treating or preventing a disease or disorder in a subject in need thereof.

51. 49. A composition comprising a compound according to any one of claims 1 to 46 or a pharmaceutical composition according to any one of claims 47 to 48 for use in modulating orexin-2 receptor activity, optionally wherein the activity is in vitro or in vivo activity.

52. 50. Use of a compound according to any one of claims 1 to 46 in the manufacture of a medicament for modulating orexin-2 receptor activity, optionally wherein the activity is in vitro or in vivo activity.

53. 47. Use of a compound according to any one of claims 1 to 46 in the manufacture of a medicament for treating or preventing a disease or disorder.

54. 51. The composition or pharmaceutical composition of claim 50, wherein the disease or disorder is associated with an implicated orexin-2 receptor.

55. 51. The composition or pharmaceutical composition of claim 50, wherein the disease or disorder is narcolepsy, hypersomnia disorder, neurodegenerative disorder, neurological disorder, symptoms of a rare genetic disorder, psychiatric disorder, mental health disorder, circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma, or promoting emergence from anesthesia.

56. 51. The composition or pharmaceutical composition of claim 50, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, sleep apnea, or insomnia.

57. The use of claim 53, wherein the disease or disorder is associated with an implicated orexin-2 receptor.

58. The use of claim 53, wherein the disease or disorder is narcolepsy, hypersomnia disorder, neurodegenerative disorder, neurological disorder, symptoms of a rare genetic disorder, psychiatric disorder, mental health disorder, circadian rhythm disorder, metabolic syndrome, osteoporosis, heart failure, coma, or promoting emergence from anesthesia.

59. The use described in claim 53, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, sleep apnea, or insomnia.

60. The compound is selected from the group consisting of: 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 2. The compound of claim 1 selected from:

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