Medium- or large-ring benzyl-substituted heterocyclic derivatives and related uses

Abstract

The present disclosure relates to a compound of formula (I') 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 disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or promoting emergence from anesthesia.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 315,438, filed March 1, 2022, and U.S. Provisional Application No. 63 / 439,477, filed January 17, 2023, the entire contents of each of which are incorporated herein by reference. [Background technology]

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

[0003] In narcolepsy type 1 (NT1), the immune system destroys the only neuronal populations that produce orexin A and B (also known as hypocretin-1 and -2) peptides, resulting in arousal boundary dysfunction. A mouse model of narcolepsy type 1 reproduces the loss of orexin neurons and two key symptoms observed in NT1 patients: excessive daytime sleepiness and cataplexy. Common symptoms of narcolepsy types 1 and 2 can 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 (REM atony) in response to emotional stimuli leading to wakefulness, is a hallmark of NT1.

[0004] Two hallmark symptoms of narcolepsy type 1, excessive daytime sleepiness and cataplexy, can be reduced by reactivating orexin neurotransmission at OX2R in mouse models. Reversal of cataplexy-like events and sleep / wake fragmentation has been achieved by genetically localizing OX2R signaling in the dorsal raphe nucleus of the pons and the tuberomammillary nucleus of the hypothalamus, respectively, in mice that otherwise lack orexin receptors in these regions. Intracerebroventricular (ICV) administration of orexin A (OXA) has been shown to increase awake time and reduce cataplexy-like behavior in orexin-neuron ablated mice. The selective OX2R agonist, YNT-185, administered intraperitoneally or ICV, modestly increases 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 slightly increased wakefulness in wild-type mice but not in OX2R knockout mice. A brain-penetrant, stable OX2R agonist that is bioavailable after alternative routes of administration (including, but not limited to, oral, intranasal, transmucosal, and transdermal) and binds with high affinity to potently excite wake-regulating neurons would offer an improvement over current treatments for patients with NT1. Indeed, initial clinical studies reported with TAK-925 demonstrated both significant levels of increased wakefulness and a tendency toward reduced cataplexy in individuals with NT1. OX1R activation is involved in the regulation of mood 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.Since OX2R stimulation promotes wakefulness in orexin-intact animals, orexin receptor agonists can treat excessive daytime sleepiness in patients with normal levels of orexin, including narcolepsy type 2, idiopathic hypersomnia, or sleep apnea.Similarly, orexin receptor agonists may provide wakefulness-promoting benefits in recurrent excessive sleepiness disorders such as Kleine-Levin syndrome, or inappropriately timed sleep (i.e., circadian rhythm sleep disorders) such as sleep phase delay or advance disorder, shift work disorder, and jet lag disorder. Abnormal daytime sleepiness, sleep-onset REM sleep, and cataplexy-like symptoms of rare genetic disorders (e.g., ADCA-DN, Coffin-Lowry syndrome, Moebius syndrome, Norrie disease, Niemann-Pick disease type C, and Prader-Willi syndrome) may be alleviated with orexin receptor agonists. Other indications for which orexin receptor agonists have been suggested to benefit 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 for modulation of orexin receptor activity in the brain, including activation of the orexin-2 receptor, with improved therapeutic potential. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical properties relative to existing compounds are desirable. Summary of the Invention [Means for solving the problem]

[0007] overview In some aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is —N(CH)— or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0008] In some aspects, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(CH3)- or C2-C6 alkyl; L is absent or C2-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and Rb together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0009] In some aspects, the present disclosure provides a compound of formula (I″): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is —N(CH)— or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0010] In some aspects, the present disclosure provides a compound of formula (I'''): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(CH3)- or C2-C6 alkyl; L is absent or C2-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0011] In some aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0012] In some aspects, the present disclosure provides a compound of formula (II'): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R btogether with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0013] In some aspects, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0014] In some aspects, the present disclosure provides a compound of formula (III'): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0015] 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 comprising one or more steps described in Schemes 1-9).

[0016] 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.

[0017] In some aspects, the present disclosure provides intermediates as described herein that are suitable for use in methods for preparing compounds as described herein (e.g., the intermediates are selected from the intermediates described in Examples 1-50).

[0018] In some aspects, the present disclosure provides a method 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.

[0019] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, the method 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.

[0020] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, the method 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.

[0021] 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).

[0022] 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.

[0023] 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.

[0024] 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).

[0025] 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 disease or disorder disclosed herein.

[0026] 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.

[0027] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0028] In some aspects, the disclosure provides methods of preparing compounds, the methods comprising one or more steps described herein.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular form includes the plural form unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can also 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 described 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 control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In case of conflict between the chemical structure and name of a compound disclosed herein, the chemical structure will control.

[0030] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0031] 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 processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in treating 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 emergence from anesthesia. definition

[0032] Unless otherwise stated, the following terms used in the specification and claims have the following meanings provided below.

[0033] While not wishing to be limited by this statement, it is understood that although various options for variables are described herein, the disclosure is intended to encompass workable embodiments having combinations of options. The disclosure may be interpreted to exclude inoperable embodiments resulting from certain combinations of options. For example, although various options for variables X, L, and Y are described herein, the disclosure may be interpreted to exclude structures in which the compounds are inoperable resulting from certain combinations of variables X, L, and Y (e.g., when each of X, L, and Y is -O-).

[0034] 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, but are not limited to, moieties having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-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.

[0035] 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 may 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.

[0036] 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 6 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.

[0037] 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 may 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.

[0038] 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 6 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) diunsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0039] 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 may 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.

[0040] Other optionally substituted moieties (such as 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.

[0041] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 30 carbon atoms (e.g., C3-C 12 , C3~C10 , or C3-C8). 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 cycloalkyls, only one of the rings in the cycloalkyl need be non-aromatic.

[0042] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic), or 11-14 membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms (such as O, N, S, P, or Se), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless otherwise specified.Examples of heterocycloalkyl groups include, but are not limited to, 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-diazepine ... nyl, 1,4-oxazepanyl, 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[cyclohexane-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 in the heterocycloalkyl need be non-aromatic (eg, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0043] When a variable has two bonds to the rest of the formula of the compound, it is understood that those two bonds can be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocycloalkyl and has two bonds to the rest of the formula of the compound, those two bonds can be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl.

[0044] As used herein, the term "aryl" includes groups with aromaticity, including "conjugated" or polycyclic systems containing one or more aromatic rings, and does not contain any heteroatoms within 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, etc.

[0045] 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 aromatic heterocyclic 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). Note that the total number of S and O atoms in the aromatic heterocycle is 1 or less. 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 may be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form a polycyclic system (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.

[0046] 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, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0047] 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, amino The aryl and heteroaryl groups may be substituted with arylcarbonyl, 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. The aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl, e.g., benzo[d][1,3]dioxol-5-yl).

[0048] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom have been replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded and 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 in 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). A "stable compound" and a "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent.

[0049] 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 a 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. However, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0050] 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 shown to be substituted with 0 to 2 R moieties, that group may optionally 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 only if such combinations result in stable compounds.

[0051] As used herein, the term "hydroxy" or "hydroxyl" includes -OH or -O -Groups containing:

[0052] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0053] The terms "haloalkyl" or "haloalkoxyl" refer to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0054] 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 may 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.

[0055] 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.

[0056] As used herein, the phrases "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, unless otherwise indicated, refer to a selection from the group consisting of all, A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0057] It should be understood that the present disclosure provides methods for the synthesis of any compound of the formula described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes, as well as those shown in the Examples.

[0058] Throughout the description, when a composition is described as having, including, or comprising specific components, it is understood that the composition also contemplates consisting essentially of or consisting of the recited components. Similarly, when a method or process is described as having, including, or comprising specific 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 for performing a particular act is immaterial so long as the invention remains operable. Moreover, two or more steps or acts can be performed simultaneously.

[0059] It should be understood that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups and, therefore, can employ a variety of substituted starting materials. While the processes generally provide the desired final compound at or near the end of the overall process, in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0060] 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. These methods and procedures can be found in any one or more sources, including, but not limited to, classic textbooks, 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 textbooks of organic synthesis known to those skilled in the art.

[0061] 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 require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. A list of protecting groups, as well as 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.

[0062] Unless otherwise stated, any description of a method of treatment or prevention should be understood to include the use of the compounds as described herein to provide such treatment or prevention. Furthermore, unless otherwise stated, any description of a method of treatment or prevention should be understood to include the use of the compounds to prepare 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.

[0063] Unless otherwise stated, any description of a method of treatment should be understood to include the use of the compounds as described herein to provide such treatment. Furthermore, unless otherwise stated, any description of a method of treatment should be understood to include the use of the compounds to prepare a medicament for treating such a condition. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0064] As used herein, the term "subject" includes humans 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.

[0065] As used herein, the term "subject in need thereof" refers to a subject having a disease or at increased risk of developing a disease. A subject in need thereof may be a subject who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be a subject at increased risk of 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 or has not yet responded to treatment). A subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need thereof has received and failed 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.

[0066] As used herein, the term "treating" or "treating" 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 "treating" can also include treatment of an in vitro cell or animal model. It should be recognized that reference to "treating" or "treatment" includes 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 that occur 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., preventing, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0067] 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.

[0068] As used herein, the terms "preventing," "prevent" or "protecting from" describe reducing or eliminating the occurrence of symptoms or complications of such diseases, conditions or disorders.

[0069] It should be understood that those skilled in the art may refer to general references for detailed descriptions of the known techniques discussed herein or equivalent techniques. 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 Edition (1990), which may, of course, be consulted when making or using aspects of the present disclosure.

[0070] 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.

[0071] 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 recognize that routine changes to the dosage may be necessary depending on the age and condition of the patient. The dosage also depends 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 preservatives, buffers, or propellants that are required.

[0072] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, 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.

[0073] As used herein, the term "pharmaceutically acceptable excipient" means 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 and more than one such excipient.

[0074] It should be understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of administration routes 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. The 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.

[0075] 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, taken orally, or applied through the skin with 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 condition of the disease state (for example, the disease or disorder disclosed herein) and the health of the patient should preferably be carefully monitored during and for a reasonable period after treatment.

[0076] 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, which is within the skill and judgment of the clinician.

[0077] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent to treat or improve 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 depends 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, which is within the skill and judgment of the clinician.

[0078] It should be understood that for any compound, the therapeutically effective amount can be estimated first, for example, in cell culture assays of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration range and administration route. Such information can then be used to determine the useful dose and route for administration in 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 (LD 50%) 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 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.

[0079] Dosage and administration are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, concurrent medications, reaction sensitivities, and tolerability / response to treatment. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0080] The pharmaceutical composition containing the active compound of the present disclosure can be prepared by generally known methods, for example, by conventional mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be prepared by conventional methods using one or more pharmaceutically acceptable carriers, including additives 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.

[0081] 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, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as 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, such as aluminum monostearate and gelatin in the composition.

[0082] Sterile injectable solution can be prepared by incorporating the required amount of active compound into suitable solvent, if necessary, with one or combination of above-listed components, and then sterilize by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains basic dispersion medium and other components that are required from above-listed.For the sterile powder that is used to prepare sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which produces the powder of active ingredient that adds any additional desired component from its solution that has been previously sterilized and filtered.

[0083] Oral compositions generally comprise inert diluents or edible pharmaceutically acceptable carriers.These can be enclosed in gelatin capsules or compressed into tablets.For the purpose of oral therapeutic administration, active compound can be incorporated with additives and used in the form of tablets, troches, capsules or sachets.Oral compositions can also be prepared using liquid carriers to be used as mouthwash, where the compound in the liquid carrier is orally applied, rinsed in the mouth, 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 additive 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.

[0084] 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.

[0085] Systemic administration can also be by 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 include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved by using nasal sprays, powders, or suppositories.For transdermal administration, active compound is formulated into ointments, liniments, gels, or creams as generally known in the art.

[0086] 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. Materials can also be commercially obtained from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeting 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.

[0087] 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 in association 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.

[0088] 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 that influence the selected dosage. Generally, the dosage should be sufficient to cause a slowing, preferably regression, of symptoms of the diseases or disorders disclosed herein, and preferably complete regression of the disease or disorder. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of a pharmaceutical agent is an amount that produces an objectively identifiable improvement, as noted by a clinician or other qualified 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.

[0089] It should be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0090] 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 present claimed disclosure.

[0091] 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 making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, 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, isethionine, These include those derived from inorganic and organic acids selected from the group consisting of lactic acid, lactobionic acid, laurylsulfonic acid, 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.

[0092] 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.

[0093] 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 by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion; or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. In the salt form, it is understood that the ratio of compound to cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0094] 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.

[0095] 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.

[0096] The dosage regimen that utilizes compound is selected according to various factors, including patient type, species, age, weight, sex and medical condition; the severity of the condition to be treated; administration route; patient's renal function and hepatic function; 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 drug that is required to prevent, counteract or stop the progression of condition.A doctor or veterinarian with ordinary skill can easily determine and prescribe the effective amount of drug that is required to counteract or stop the progression of condition.

[0097] Techniques for formulating and administering the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th Edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compounds described herein and their pharmaceutically acceptable salts are used in combination with pharmaceutically acceptable carriers or diluents in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0098] 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, those skilled in the art will be able to identify and use other components and methodologies useful for implementing the present disclosure.

[0099] In the synthetic 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, nor does it exclude the mixture of isomers, tautomers, positional isomers or stereoisomers;However, it will 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.

[0100] 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 herein. 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.

[0101] As used herein, the phrase "compounds of the present disclosure" refers to compounds disclosed herein both generically and specifically. Compounds of the Disclosure

[0102] In some aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is —N(CH)— or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0103] In some aspects, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(CH3)- or C2-C6 alkyl; L is absent or C2-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0104] In some aspects, the present disclosure provides a compound of formula (I″): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is —N(CH)— or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0105] In some aspects, the present disclosure provides a compound of formula (I'''): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(CH3)- or C2-C6 alkyl; L is absent or C2-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0106] In some aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0107] In some aspects, the present disclosure provides a compound of formula (II'): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens.10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0108] In some aspects, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0109] In some aspects, the present disclosure provides a compound of formula (III'): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0110] In some aspects, the present disclosure provides a compound of formula (III″): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0111] In some aspects, the present disclosure provides a compound of formula (III'''): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R btogether with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0112] In some aspects, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -O-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl or -OH; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0113] In some aspects, the present disclosure provides a compound of formula (IV'): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -O-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl or -OH; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0114] In some embodiments, the present disclosure provides a compound of formula (IV″): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -O-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl or -OH; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0115] In some embodiments, the present disclosure provides a compound of formula (IV'''): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X is -O-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl or -OH; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0116] For the compounds of the present disclosure, the variables X, L, Y, n, R a , R b , Z, R1, Ar1, and T may each be selected from groups described herein, where applicable, and the variables X, L, Y, n, R a , R b Any groups described herein for any of Z, R1, Ar1, and T, as well as the remaining variables X, L, Y, n, Ra , R b , Z, R1, Ar1, and T can be combined with any group described herein.

[0117] In some embodiments, X is -O-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl or -OH.

[0118] In some embodiments, X is —O—.

[0119] In some embodiments, X is -N(CH3)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl.

[0120] In some embodiments, X is —N(CH 3 )— or C 1 -C 6 alkyl.

[0121] In some embodiments, X is —N(CH 3 )—.

[0122] In some embodiments, X is C1-C6 alkyl.

[0123] In some embodiments, X is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl or -OH.

[0124] In some embodiments, X is one or more C1-C6 alkyl or C1-C6 alkyl substituted with -OH.

[0125] In some embodiments, X is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl.

[0126] In some embodiments, X is C1-C6 alkyl substituted with one or more C1-C6 alkyl.

[0127] In some embodiments, X is C1-C6 alkyl optionally substituted with one or more -OH.

[0128] In some embodiments, X is C1-C6 alkyl substituted with one or more -OH.

[0129] In some embodiments, X is methyl. In some embodiments, X is ethyl. In some embodiments, X is propyl. In some embodiments, X is butyl. In some embodiments, X is pentyl. In some embodiments, X is hexyl. In some embodiments, X is isopropyl. In some embodiments, X is isobutyl. In some embodiments, X is isopentyl. In some embodiments, X is isohexyl. In some embodiments, X is sec-butyl. In some embodiments, X is sec-pentyl. In some embodiments, X is sec-hexyl. In some embodiments, X is tert-butyl.

[0130] In some embodiments, X is -N(C1-C6 haloalkyl)-.

[0131] In some embodiments, X is -N(halomethyl)-. In some embodiments, X is -N(haloethyl)-. In some embodiments, X is -N(halopropyl)-. In some embodiments, X is -N(halobutyl)-. In some embodiments, X is -N(halopentyl)-. In some embodiments, X is -N(halohexyl)-.

[0132] In some embodiments, L is absent or is C1-C6 alkyl.

[0133] In some embodiments, L is absent or is C2-C6 alkyl.

[0134] In some embodiments, L is absent.

[0135] In some embodiments, L is C1-C6 alkyl.

[0136] In some embodiments, L is C2-C6 alkyl.

[0137] In some embodiments, L is methyl. In some embodiments, L is ethyl. In some embodiments, L is propyl. In some embodiments, L is butyl. In some embodiments, L is pentyl. In some embodiments, L is hexyl. In some embodiments, L is isopropyl. In some embodiments, L is isobutyl. In some embodiments, L is isopentyl. In some embodiments, L is isohexyl. In some embodiments, L is sec-butyl. In some embodiments, L is sec-pentyl. In some embodiments, L is sec-hexyl. In some embodiments, L is tert-butyl.

[0138] In some embodiments, Y is —O—.

[0139] In some embodiments, n is 1 or 2.

[0140] In some embodiments, n is 1. In some embodiments, n is 2.

[0141] In some embodiments, R a is H or a halogen.

[0142] In some embodiments, R a is H.

[0143] In some embodiments, R a is a halogen.

[0144] In some embodiments, R a is F, Cl, Br, or I. In some embodiments, R ais F, Cl, or Br. In some embodiments, R a is F or Cl.

[0145] In some embodiments, R a is F. In some embodiments, R a is Cl. In some embodiments, R a is Br. In some embodiments, R a is I.

[0146] In some embodiments, R b is H, halogen, or C1-C6 alkyl.

[0147] In some embodiments, R b is H.

[0148] In some embodiments, R b is a halogen.

[0149] In some embodiments, R b is F, Cl, Br, or I. In some embodiments, R b is F, Cl, or Br. In some embodiments, R b is F or Cl.

[0150] In some embodiments, R b is F. In some embodiments, R b is Cl. In some embodiments, R b is Br. In some embodiments, R b is I.

[0151] In some embodiments, R b is a C1-C6 alkyl.

[0152] In some embodiments, R b is methyl. In some embodiments, R b is ethyl. In some embodiments, R b is propyl. In some embodiments, Rb is butyl. In some embodiments, R b is pentyl. In some embodiments, R b is hexyl. In some embodiments, R b is isopropyl. In some embodiments, R b is isobutyl. In some embodiments, R b is isopentyl. In some embodiments, R b is isohexyl. In some embodiments, R b is sec butyl. In some embodiments, R b is sec pentyl. In some embodiments, R b is sec hexyl. In some embodiments, R b is tert butyl.

[0153] In some embodiments, R a and R b together with the atom to which they are attached form a C3 cycloalkyl.

[0154] In some embodiments, Z is —NH—.

[0155] In some embodiments, R1 is C1-C6 haloalkyl or C2-C6 alkyl.

[0156] In some embodiments, R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl substituted with halogen.

[0157] In some embodiments, R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl substituted with halogen.

[0158] In some embodiments, R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens.

[0159] In some embodiments, R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens.

[0160] In some embodiments, R1 is C1-C6 haloalkyl.

[0161] In some embodiments, R1 is C1-C6 haloalkyl.

[0162] In some embodiments, R1 is halomethyl. In some embodiments, R1 is haloethyl. In some embodiments, R1 is halopropyl. In some embodiments, R1 is halobutyl. In some embodiments, R1 is halopentyl. In some embodiments, R1 is halohexyl.

[0163] In some embodiments, R1 is C2-C6 alkyl.

[0164] In some embodiments, R1 is C1-C6 alkyl.

[0165] In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is propyl. In some embodiments, R1 is butyl. In some embodiments, R1 is pentyl. In some embodiments, R1 is hexyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is isobutyl. In some embodiments, R1 is isopentyl. In some embodiments, R1 is isohexyl. In some embodiments, R1 is secbutyl. In some embodiments, R1 is secpentyl. In some embodiments, R1 is sechexyl. In some embodiments, R1 is tertbutyl.

[0166] In some embodiments, R1 is C3 cycloalkyl.

[0167] In some embodiments, R1 is C3 cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl.

[0168] In some embodiments, R1 is C3 cycloalkyl optionally substituted with one or more halogens.

[0169] In some embodiments, R1 is C3 cycloalkyl substituted with halogen.

[0170] In some embodiments, R1 is a C3 cycloalkyl optionally substituted with one or more C1-C6 alkyl.

[0171] In some embodiments, R1 is a C3 cycloalkyl substituted with one or more C1-C6 alkyls.

[0172] In some embodiments, Ar is a C-C alkyl group optionally substituted with one or more halogens. 10 It is aryl.

[0173] In some embodiments, Ar1 is C6-C 10 It is aryl.

[0174] In some embodiments, Ar1 is a C6-C substituted with one or more halogens. 10 It is aryl.

[0175] In some embodiments, Ar1 is phenyl optionally substituted with one or more halogens.

[0176] In some embodiments, Ar1 is phenyl.

[0177] In some embodiments, Ar1 is phenyl substituted with one or more halogens.

[0178] In some embodiments, T is a C6-C alkyl optionally substituted with one or more halogen or C1-C6 alkyl. 10 It is aryl.

[0179] In some embodiments, T is a C-C optionally substituted with one or more halogens. 10 It is aryl.

[0180] In some embodiments, T is C-C 10 It is aryl.

[0181] In some embodiments, T is a C6-C alkyl group substituted with one or more halogens or C1-C6 alkyls. 10 It is aryl.

[0182] In some embodiments, T is a C-C substituted with one or more halogens. 10 It is aryl.

[0183] In some embodiments, T is phenyl optionally substituted with one or more halogen or C1-C6 alkyl.

[0184] In some embodiments, T is phenyl optionally substituted with one or more halogens.

[0185] In some embodiments, T is phenyl.

[0186] In some embodiments, T is phenyl substituted with one or more halogens or C1-C6 alkyl.

[0187] In some embodiments, T is phenyl substituted with one or more halogens.

[0188] In some embodiments, when X is alkyl, L is absent.

[0189] In some embodiments, the compound is of formula (I'-a) or (I'-b): [ka] or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the compound is of formula (II'-a), (II'-b), or (II'-c): [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4.

[0191] In some embodiments, the compound is of formula (IIIA'), (IIIA'-a), or (IIIA'-b): [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0192] In some embodiments, the compound is of formula (IVA'), (IVA'-a), or (IVA'-b): [ka] [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0193] In some embodiments, the compound is of formula (Ia) or (Ib): [ka] or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the compound is of formula (II-a), (II-b), or (II-c): [ka] [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4.

[0195] In some embodiments, the compound is of formula (IIIA), (IIIA-a), or (IIIA-b): [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0196] In some embodiments, the compound is of formula (IIIA'-1), (IIIA'-1a), or (IIIA'-1b): [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0197] In some embodiments, the compound is of formula (IIIA'-2), (IIIA'-2a), or (IIIA'-2b): [ka] [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4.

[0198] In some embodiments, the compound is selected from the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0199] In some embodiments, the compound is selected from the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0200] In some embodiments, the compound is selected from prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0201] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0202] In some embodiments, the compound is selected from the compounds set forth in Table 2, and prodrugs and pharmaceutically acceptable salts thereof.

[0203] In some embodiments, the compound is selected from the compounds set forth in Table 2 and pharmaceutically acceptable salts thereof.

[0204] In some embodiments, the compound is selected from the prodrugs of the compounds set forth in Table 2 and pharmaceutically acceptable salts thereof.

[0205] In some embodiments, the compound is selected from the compounds listed in Table 2.

[0206] In some embodiments, the compound is selected from the compounds set forth in Table 3, and prodrugs and pharmaceutically acceptable salts thereof.

[0207] In some embodiments, the compound is selected from the compounds set forth in Table 3 and pharmaceutically acceptable salts thereof.

[0208] In some embodiments, the compound is selected from the prodrugs of the compounds set forth in Table 3 and pharmaceutically acceptable salts thereof.

[0209] In some embodiments, the compound is selected from the compounds listed in Table 3.

[0210] In some embodiments, the compound is selected from the compounds set forth in Table 4, and prodrugs and pharmaceutically acceptable salts thereof.

[0211] In some embodiments, the compound is selected from the compounds set forth in Table 4 and pharmaceutically acceptable salts thereof.

[0212] In some embodiments, the compound is selected from the prodrugs of the compounds set forth in Table 4 and pharmaceutically acceptable salts thereof.

[0213] In some embodiments, the compound is selected from the compounds listed in Table 4.

[0214] In some embodiments, the compound is selected from the compounds set forth in Table 5, and prodrugs and pharmaceutically acceptable salts thereof.

[0215] In some embodiments, the compound is selected from the compounds set forth in Table 5 and pharmaceutically acceptable salts thereof.

[0216] In some embodiments, the compound is selected from the prodrugs of the compounds set forth in Table 5 and pharmaceutically acceptable salts thereof.

[0217] In some embodiments, the compound is selected from the compounds listed in Table 5. [Table 1]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 3-1

Table 3-2

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

[0218] In some embodiments, the compound is not described in PCT / US2021 / 049003.

[0219] In some embodiments, the compound is not selected from the compounds described in PCT / US2021 / 049003.

[0220] In some embodiments, the compound is not selected from the compounds listed in Table 6. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9]

[0221] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.

[0222] In some aspects, the present disclosure provides compounds that are isotopic derivatives (e.g., isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0223] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0224] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0225] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0226] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0227] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 2.

[0228] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2, and prodrugs and pharmaceutically acceptable salts thereof.

[0229] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2 and pharmaceutically acceptable salts thereof.

[0230] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 2 and pharmaceutically acceptable salts thereof.

[0231] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 2.

[0232] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 3.

[0233] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 3, and prodrugs and pharmaceutically acceptable salts thereof.

[0234] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 3 and pharmaceutically acceptable salts thereof.

[0235] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 3 and pharmaceutically acceptable salts thereof.

[0236] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3.

[0237] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 4.

[0238] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 4, and prodrugs and pharmaceutically acceptable salts thereof.

[0239] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 4 and pharmaceutically acceptable salts thereof.

[0240] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 4 and pharmaceutically acceptable salts thereof.

[0241] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 4.

[0242] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 5.

[0243] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 5, and prodrugs and pharmaceutically acceptable salts thereof.

[0244] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 5 and pharmaceutically acceptable salts thereof.

[0245] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds set forth in Table 5 and pharmaceutically acceptable salts thereof.

[0246] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 5.

[0247] 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 carrying out the procedures disclosed in the schemes and / or examples described herein.

[0248] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0249] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0250] The term "isotopic derivative," as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of Formula (I), Formula (I'), Formula (I"), Formula (I'"), Formula (II), Formula (II'), Formula (III), or Formula (III') is isotopically enriched with or labeled with one or more isotopes compared to the corresponding compound of Formula (I), Formula (I'), Formula (I"), Formula (I'"), Formula (II), Formula (II'), Formula (III), or Formula (III'). 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 or labeled with one or more atoms selected from S). 2In some embodiments, the compound is 18 In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compounds, or any combination thereof. In some embodiments, the compounds are: 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds, or any combination thereof.

[0251] 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 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 3S-labeled reagent.

[0252] The aforementioned 18 F, 123 I, 124 I, 125I, 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. 18 F, 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 advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0253] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that said group includes the broadest definition occurring first as well as each and every specific definition associated with that group.

[0254] The various functional groups and substituents that make up the compounds 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 is less than 900 daltons, e.g., less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons.

[0255] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as inorganic or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methane sulfonate, 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 pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0256] 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.

[0257] It will be understood that the compounds disclosed herein may be presented in one specific configuration. Such 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 a mixture 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; however, the presentation is further intended to refer to the specific configuration of the compound. For example, when a compound is [ka] When a product is presented as having a portion of [ka] The disclosure may be intended to encompass and refer to compounds having the moiety: [ka] may be intended to refer to a compound having a particular configuration of the moiety.

[0258] 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, a compound may be [ka] When a product is presented as having a portion of [ka] The disclosure may be intended to encompass and refer to compounds having the moiety, or any mixture thereof. Furthermore, the disclosure may include mixtures of cis isomers of the moiety, e.g., [ka] In another example, the compound may be intended to refer to a compound having a mixture of moieties: [ka] When a product is presented as having a portion of [ka] It may be intended to refer to a compound having the moiety

[0259] As used herein, the term "isomer" 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."

[0260] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0261] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center 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).

[0262] 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.

[0263] It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. 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 it should also be understood 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.

[0264] It should be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It should also be understood that not all atropisomers may have the same level of activity.

[0265] 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 a mixture, but recent advances in chromatography technology have made it possible to separate mixtures of two atropisomers in special cases.

[0266] 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 another. 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 the tautomers will be achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, the simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism, as exemplified by glucose, occurs as a result of the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxyl groups (-OH) in the same molecule to form a cyclic (annular) form.

[0267] It should be understood that the compounds of the present disclosure may be depicted as different tautomers. When a compound has tautomeric forms, it is intended that all tautomeric forms are included within the scope of the present disclosure, and it should also be understood that 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.

[0268] 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., as (+) or (-) isomers, 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."

[0269] 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 as mixtures thereof. Unless otherwise indicated, 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 isomerism 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.

[0270] The present disclosure also encompasses compounds of the present disclosure as defined herein that contain one or more isotopic substitutions.

[0271] It should be understood that the compounds of any formula described herein include the compounds themselves, and, if applicable, also their salts and solvates.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, maleate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0272] 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., carboxylate) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0273] It should be understood that compounds of the present disclosure, for example, salts of the 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.

[0274] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amount of solvent.Some compounds have the tendency to capture a certain molar ratio of solvent molecules in crystalline solid state, thus forming solvates.When the solvent is water, the solvate that forms is hydrate;When the solvent is alcohol, the solvate that forms is alcoholate.Hydrate is formed by the combination of one or more water molecules and one substance molecule, where water maintains its molecular state as H2O.

[0275] 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 comparable in function and appearance to the reference compound, but not in structural origin.

[0276] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0277] 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 exchange is to create a new compound with similar biological properties to the parent compound. The bioisostere exchange can be based on physicochemical or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0278] It should be understood that any particular compound of any one of the formulas disclosed herein can exist in solvated form as well as unsolvated form, such as hydrated form.Suitable pharmaceutically acceptable solvates are hydrates such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that retain inflammasome inhibitory activity.

[0279] It should also be understood that any one of the compounds of 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 X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance Fourier transform infrared (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.

[0280] Compounds of any one of the formulas disclosed herein may exist in several different tautomeric forms, and a reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, even if a compound may exist in one of several tautomeric forms and 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 (exemplified below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka]

[0281] A compound of 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., 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.

[0282] The compound of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is decomposed in the human or animal body to release the compound of the present disclosure.Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compound of the present disclosure.When the compound of the present disclosure contains a suitable group or substituent to which a group that modifies properties can be attached, a prodrug can be formed.Examples of prodrugs include derivatives that contain alkyl or acyl substituents that can be cleaved in vivo on the ester or amide group in any one of the formulas disclosed herein.

[0283] Therefore, the present disclosure includes the compounds of any one of the formulas disclosed herein as previously defined herein when they are available through organic synthesis and when they are available in the human or animal body through the cleavage of their prodrugs.Therefore, the present disclosure also includes the compounds of any one of the formulas disclosed herein that are produced by organic synthesis means, and the compounds that are produced in the human or animal body through the metabolism of precursor compounds, that is, the compounds of any one of the formulas disclosed herein can be synthetically produced compounds or metabolically produced compounds.

[0284] Suitable pharmaceutically acceptable prodrugs of compounds of any one of the formulae disclosed herein are those that, based on reasonable medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. 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.

[0285] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulas disclosed herein that possess a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. An in vivo cleavable ester or ether of a compound of any one of the formulas disclosed herein that contains a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is 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, C1-C 10 Alkoxycarbonyl groups include, for example, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl 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. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0286] 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, e.g., ammonia, C 1~4Alkylamines 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 amides formed with amino acids such as glycine or its esters.

[0287] Suitable pharmaceutically acceptable prodrugs of compounds 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.

[0288] The in vivo effect 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 effect of the compound of any one of the formulas disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug).

[0289] Preferably, the present disclosure excludes any individual compound that does not possess biological activity as defined herein. Synthesis method

[0290] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0291] In some aspects, the present disclosure provides a method of preparing a compound comprising one or more steps as described herein.

[0292] In some aspects, the present disclosure provides compounds that are obtainable by, obtained by, or obtained directly by, a method for preparing a compound as described herein.

[0293] In some aspects, the present disclosure provides intermediates as described herein that are suitable for use in methods for preparing compounds as described herein.

[0294] 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.

[0295] In the description 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 skilled in the art.

[0296] 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.

[0297] It will be appreciated that during the synthesis of 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. The skilled chemist will know when such protection is necessary and how to place and subsequently remove such protecting groups. For examples of protecting groups, see one of the many general texts on the 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 as suitable for the removal of the protecting group in question, or known to the skilled chemist, with such methods being selected so as to achieve removal of the protecting group with minimal disruption to groups elsewhere in the molecule. Thus, when reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0298] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, for example, acetyl; alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, for example, benzyloxycarbonyl; or aroyl groups, for example, benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the selection of protecting groups. 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, for example, lithium hydroxide 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.

[0299] Suitable protecting groups for hydroxy groups are, for example, acyl groups, e.g., 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 with the choice of protecting group. 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, e.g., lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation over a catalyst such as palladium on carbon.

[0300] Suitable protecting groups for carboxy groups are, for example, esterifying groups such as methyl or ethyl groups 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.

[0301] Once a compound of Formula (I), Formula (I'), Formula (I''), Formula (I'''), Formula (II), Formula (II'), Formula (III), or Formula (III') has been synthesized by any one of the processes defined herein, then the process may further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of Formula (I), Formula (I'), Formula (I''), Formula (I'''), Formula (II), Formula (II'), Formula (III), or Formula (III') to another compound of Formula (I), Formula (I'), Formula (I''), Formula (I'''), Formula (II), Formula (II'), Formula (III), or Formula (III'); (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof; and / or (iv) forming a prodrug thereof.

[0302] The resulting compound of Formula (I), Formula (I'), Formula (I''), Formula (I'''), Formula (II), Formula (II'), Formula (III), or Formula (III') can be isolated and purified using techniques well known in the art.

[0303] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, 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, such as 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.

[0304] The reaction temperature is preferably between about -100°C and 300°C, depending on the reaction step and conditions used.

[0305] Reaction times generally range from a fraction of a minute to several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times can be readily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally range from 10 minutes to 48 hours.

[0306] Moreover, by utilizing the procedures described herein, in combination 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.

[0307] 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 types of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how to apply and adapt them in any particular case (whenever 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; these methods are well known to those skilled in the art. Similarly, synthetic protecting (or protecting) groups will be applied (whenever necessary or useful) by those skilled in the art; suitable protecting groups, as well as methods for introducing and removing them, are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0308] General routes for the preparation of compounds of the present application are described herein in Schemes 1-9. [ka]

[0309] Compounds of formula (V) can be prepared from compounds of formula (I) by the method shown in Reaction Scheme 1. Compounds of formula (I) can be produced 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.

[0310] Examples of protecting groups for amino groups represented by P1 include carbamate-type protecting groups, such as tert-butyl carbamate. Compound (II), in which Y is oxygen, may be commercially available or may be prepared from commercially available materials by alkylation or Mitsunobu reaction. B represents a boronic acid, a boronic acid ester, or the like.

[0311] Examples of protecting groups represented by P2 when X is nitrogen include phthalimide-type protecting groups, etc. Examples of protecting groups represented by P2 when X is carbon or oxygen include carboxyl protecting groups, e.g., methyl, ethyl esters, etc.

[0312] Compound (III) can be produced by subjecting compound (I) and compound (II) to a palladium-mediated cross-coupling Suzuki-type reaction. When carrying out the coupling reaction, examples of metal catalysts to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 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.

[0313] Compound (IV) can be produced by removing the protecting groups represented by P1 and P2 according to a method known per se, for example, by using an acid, a base, or a nucleophilic reagent such as hydrazine, or by a reduction method.

[0314] Compound (V) can be produced by subjecting compound (IV) to a ring-closure reaction. When the ring-closure is carried out by amidation, urea, or carbamate formation, examples of the reagent 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 the base 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. [ka]

[0315] Alternatively, a compound of formula (V) can be produced from a compound of formula (I) according to the method shown in Reaction Scheme 2. Compound (VI) can be produced 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 carried out in each step, examples of metal catalysts to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 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 the "leaving group" represented by LG1 include a halogen atom, an optionally halogenated C 1~6 Alkyl sulfonyloxy groups (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy) and the like are included.

[0316] Compound (VII), where Y is carbon, can be produced by subjecting compound (VI) and an appropriate acetylene, either commercially available or available according to known methods, to a Sonogashira-type cross-coupling reaction using a metal catalyst. Examples of metal catalysts to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), 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. In addition, a base can be added to the reaction system, examples of which include inorganic bases.

[0317] Compound (VIII) can be produced by reducing compound (VII). When reducing a carbon-carbon double or triple bond, a method using a catalyst, such as palladium-carbon or Lindlar catalyst, may be used in combination with hydrogen gas.

[0318] 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 carried out at each step, azodicarboxylates (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0319] Compound (IV) can be produced by removing the protecting groups represented by P1 and P2 by a method known per se, for example, a method using an acid, a base, hydrazine, or the like, or a reduction method.

[0320] Compound (V) can be produced by a ring closure reaction as shown in Reaction Scheme 1.

[0321] Compounds of formula (V) can also be prepared by a ring-closing metathesis reaction approach as outlined in Reaction Schemes 3, 4, and 5. [ka]

[0322] Compound (IX) can be produced 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 a reduction method.

[0323] Compound (XI) can be produced 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) and triphosgene; 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 and organic bases. 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 a commercially available material according to a method known per se or a method similar thereto. L1 is C 1~5 Examples of leaving groups represented by LG2 include halogen atoms, optionally halogenated C 1~6Included are alkylsulfonyloxy groups (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), p-nitrophenol, and the like.

[0324] Compound (XII) may be commercially available or may be prepared from commercially available materials by a method known per se or a method analogous thereto. B represents a boronic acid, ester, etc. L1 represents C 1~3 Represents allyl, etc.

[0325] Compound (XIII) can be produced by subjecting a combination of compound (XI) and compound (XII) to the above-described palladium-mediated Suzuki-type cross-coupling, as shown in Reaction Scheme 1. [ka]

[0326] Compound (XIII) can be produced by subjecting the combination of compound (I) and compound (XII) to the above-described palladium-mediated Suzuki-type cross-coupling, as shown in Reaction Scheme 1.

[0327] Compound (XIV) can be produced by removing the protecting group represented by P1 according to known methods, for example, by using an acid, a base, hydrazine, or a reduction method.

[0328] Compound (XIII) can be produced by subjecting compound (XIV) and compound (X) to a condensation reaction, as described above in Reaction Scheme 3. [ka]

[0329] Compound (XIV) can be produced by subjecting compound (XIII) to a ring-closing reaction. When the ring-closing is carried out by a ring-closing metathesis reaction, examples of the catalyst to be used include ruthenium compounds, such as Grubbs I, Grubbs II, Hoveyda-Grubbs, etc.

[0330] Compound (V) can be produced by reducing 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 used together with hydrogen gas. [ka]

[0331] Compounds of formula (XV), R a =R b Formula V, where =H and n=2, can be prepared according to Reaction Scheme 6. Compound (XV) can be produced by deprotection and cyclization of compound (XVI). When the protecting group P is tert-butyloxycarbamate, deprotection can be carried out using an acid. Cyclization can be achieved by activating the carboxylic acid using a reagent such as imidazol-1-ium chloride or phosphorus oxychloride.

[0332] Compound (XVI) can be produced by subjecting compound (XVII) to palladium-mediated cross-coupling with a substituted bromophenyl compound, which can be prepared by known methods or methods analogous thereto. Suitable palladium catalysts include di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; and iron.

[0333] Compounds of type (XVII) can be prepared by palladium-mediated borylation of compound (XVIII) using a reagent such as bis-pinacolatodiborane and a catalyst such as palladium tricyclohexylphosphine complex.

[0334] Compound (XVIII) was produced by sulfonylation of compound (XIX), which can be accomplished in one step using an appropriate sulfonyl chloride, or in two steps by sulfinylation using a sulfinyl chloride followed by an oxidation step using an oxidant, such as mCPBA.

[0335] Compound (XIX) can be prepared as a single enantiomer by resolution of compound (XX) by chiral salt formation using a chiral acid, such as a tartaric acid derivative. Without this resolution, compound of formula (XV) can also be prepared as a single enantiomer by chiral chromatography of racemic compound (XV).

[0336] Compound (XX) can be prepared from compound (XXI) by reductive amination using a source of ammonia and a suitable catalyst. Ammonium formate is one such ammonia source, and catalysts such as those detailed in J. Org. Chem. 2019, 84, 10962-10977 are suitable for this transformation.

[0337] Compound (XXI) is prepared by alkylation of commercially available ketone (XXIII), which can be achieved via an enamine, such as compound (XXII), which is reacted with an appropriate benzyl halide, such as 2-fluoro-3-bromobenzyl bromide. The enamine can be prepared by treating (XXIII) with a suitable secondary amine and a Lewis acid, such as titanium tetraisopropoxide. [ka]

[0338] Compound (XXIV), R a or R bCompound (V) in which one of the N-protecting groups is fluorine can be prepared by similar macrocyclization of (XXV). Compound (XXV) can be prepared by sequential deprotection of compound (XXVI). When the N-protecting group is a benzyloxycarbamate, this deprotection can be achieved by hydrogenolysis using hydrogen and a suitable palladium catalyst, such as palladium on carbon. When the ester protecting group is a tert-butyl ester, deprotection can be achieved with an acid.

[0339] Compound (XXVI) can be prepared from compound (XXVII) in a manner similar to that carried out in Reaction Scheme 6.

[0340] Compound (XXVII) can be prepared from compound (XXVIII) by a boronation reaction similar to that in Reaction Scheme 6.

[0341] Compound (XXVIII) can be prepared from compound (XXIX) by sulfonylation with a sulfonyl chloride or a two-step sequence using sulfinyl chloride followed by oxidation with an oxidant, such as mCPBA. [ka]

[0342] Enantiomerically pure compound (XXIX) can be prepared by chiral chromatography or by resolution using a chiral salt of compound (XXX). When a chiral salt is used, a chiral acid, such as a tartaric acid derivative, can be used.

[0343] Compound (XXX) can be prepared by reduction of an azide such as (XXXI). Reduction can be accomplished with a phosphorous-based reducing agent, for example, 3-[bis(2-carboxythyl)phosphanyl]propanoic acid hydrochloride.

[0344] Compound (XXXI) can be prepared by azide displacement of sulfonate ester (XXXII), trifluoromethanesulfonate being preferred for this reaction. Sodium azide can be a suitable azide source for this purpose.

[0345] Sulfonate esters such as (XXXII) can be prepared by reaction of compound (XXXIII) with a sulfonylating agent, for example trifluoromethanesulfonic anhydride. [ka]

[0346] Compound (XXXIII) can be prepared by treating either an epoxide compound of formula (XXXIV) or a cyclic sulfonate of formula (XXXV) with fluoride. When an epoxide is used, a hydrogen fluoride salt, such as triethylamine hydrogen fluoride, is a suitable fluoride source. When a cyclic sulfonate is used, a tetra-alkylammonium salt, such as tetraethylammonium fluoride, is suitable.

[0347] The cyclic sulfonate (XXXV) can be prepared by oxidation of the cyclic sulfinate (XXXVI) with an oxidizing agent such as sodium periodate or ruthenium trichloride.

[0348] Compound (XXXVI) is prepared by sulfination of diol (XXXVII), which may be carried out with a sulfonyl chloride.

[0349] Diols (XXVII) are prepared by dihydroxylation of alkenes (XXXVIII). Dihydroxylation can be achieved using an oxidation system consisting of a catalytic osmium source and a reoxidant. Potassium osmate and N-methylmorpholine N-oxide are one such system.

[0350] Epoxides (XXXIV) can be prepared from alkenes (XXXVIII) using an oxidation reaction followed by chromatographic separation to isolate the desired relative stereochemistry. Suitable oxidizing agents include oxone and trifluoromethyl-methyl ketone.

[0351] Alkenes (XXXVIII) can be prepared by ring-closing metathesis of dienes such as (XXXIX). Ring-closing metathesis can be carried out with a ruthenium catalyst. Examples of catalysts that can be used include Grubbs I, Grubbs II, Hoveyda-Grubbs, etc.

[0352] Alkenes (XXXIX) can be prepared by alkylation of compounds (XL), which can be accomplished by reductive amination or treatment with an alkyl halide in the presence of a base.

[0353] Compound (XL) can be prepared by alkylation and deprotection of compound (XLI). The alkylation reaction may require the use of a strong base, such as an alkyllithium, to deprotonate (XLI). When used at low temperatures, n-butyllithium may be a suitable base. Deprotection can be achieved using an acid under aqueous conditions. Biological assays

[0354] 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.

[0355] Furthermore, high-throughput screening can be used to speed up the analysis using such assay.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 assay can use one or more different assay techniques, including but not limited to those described below.

[0356] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0357] 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, whereas 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.

[0358] In some embodiments, the biological assays are described in the Examples herein.

[0359] In some embodiments, the biological assay is an assay that measures the agonist activity of a compound on cells expressing the human orexin type 2 or human orexin type 1 receptor.

[0360] 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). Pharmaceutical Composition

[0361] 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 additives. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Tables A1, A2, B1, and B2.

[0362] 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.

[0363] 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.

[0364] The formulation of the present disclosure can be in the form of an aqueous solution containing an aqueous vehicle.The aqueous vehicle component can comprise water and at least one pharmaceutically acceptable additive.Suitable acceptable additives include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonicity agents, viscosity / suspending agents, buffering agents and pH adjusting agents, and mixtures thereof.

[0365] 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.

[0366] 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.

[0367] 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.

[0368] The aqueous vehicle may also contain a tonicity agent to adjust the tonicity (osmotic pressure), which may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0369] The aqueous vehicle 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.

[0370] 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 target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base; depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0371] The aqueous vehicle 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.

[0372] 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.

[0373] Oral compositions generally comprise inert diluents or edible pharmaceutically acceptable carriers.These can be enclosed in gelatin capsules or compressed into tablets.For the purpose of oral therapeutic administration, active compounds can be incorporated with additives and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using liquid carriers to be used as mouthwash, where the compound in the liquid carrier is orally applied, rinsed in the mouth, expectorated or swallowed.Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an additive 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.

[0374] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined hereinabove, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0375] 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), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), for administration by insufflation (e.g., as a finely divided powder), or for 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).

[0376] 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 may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0377] 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 the inflammasome-associated conditions referred to herein.

[0378] 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.

[0379] 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. How to use

[0380] In some aspects, the present disclosure provides a method of modulating orexin 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.

[0381] In some aspects, the present disclosure provides a method of modulating orexin receptor activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0382] In some aspects, the present disclosure provides a method 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.

[0383] In some aspects, the present disclosure provides a method of modulating orexin-2 receptor activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0384] In some aspects, the present disclosure provides a method 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.

[0385] 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.

[0386] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0387] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0388] 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.

[0389] 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.

[0390] In some embodiments, the disease or disorder is narcolepsy, hypersomnia, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or a complication upon emergence from anesthesia.

[0391] In some aspects, the present disclosure provides a method of treating or preventing narcolepsy, hypersomnia, a neurodegenerative disorder, symptoms of a rare genetic disorder, a 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.

[0392] In some aspects, the present disclosure provides a method of treating narcolepsy, hypersomnia, a neurodegenerative disorder, a symptom of a rare genetic disorder, a 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.

[0393] In some aspects, the present disclosure provides a method of treating or preventing narcolepsy, hypersomnia, a neurodegenerative disorder, symptoms of a rare genetic disorder, a 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0394] In some aspects, the present disclosure provides a method of treating narcolepsy, hypersomnia, a neurodegenerative disorder, a symptom of a rare genetic disorder, a 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0395] 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.

[0396] In some aspects, the present disclosure provides a method of treating or preventing an excessive sleep 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.

[0397] 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.

[0398] In some aspects, the present disclosure provides a method of treating or preventing a symptom of a rare genetic 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.

[0399] 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.

[0400] 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.

[0401] 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.

[0402] 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.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] In some aspects, the present disclosure provides a method of treating an excessive sleep 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.

[0407] 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.

[0408] In some aspects, the present disclosure provides a method of treating a symptom of a rare genetic 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.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0416] In some aspects, the present disclosure provides a method of treating or preventing an excessive sleep disorder in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0417] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0418] In some aspects, the present disclosure provides a method of treating or preventing a symptom of a rare genetic disorder in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0419] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0420] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0421] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0422] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0423] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0424] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0425] In some aspects, the present disclosure provides a method of treating narcolepsy in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0426] In some aspects, the present disclosure provides a method of treating an excessive sleep disorder in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0427] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0428] In some aspects, the present disclosure provides a method of treating a symptom of a rare genetic disorder in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0429] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0430] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0431] In some aspects, the present disclosure provides a method of treating osteoporosis in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0432] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0433] In some aspects, the present disclosure provides a method of treating coma in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0434] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0435] 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).

[0436] 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).

[0437] 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.

[0438] 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.

[0439] 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 disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0440] 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.

[0441] 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 an excessive sleep disorder in a subject in need thereof.

[0442] 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.

[0443] 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 disorder in a subject in need thereof.

[0444] 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.

[0445] 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.

[0446] 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.

[0447] 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.

[0448] 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.

[0449] 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.

[0450] 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, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0451] 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.

[0452] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating an excessive sleep disorder in a subject in need thereof.

[0453] 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.

[0454] 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 disorder in a subject in need thereof.

[0455] 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.

[0456] 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.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] 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.

[0461] 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).

[0462] 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).

[0463] 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 disease or disorder disclosed herein.

[0464] 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.

[0465] 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, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0466] 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.

[0467] 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 an excessive sleep disorder in a subject in need thereof.

[0468] 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.

[0469] 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 a symptom of a rare genetic disorder in a subject in need thereof.

[0470] 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 mental health disorder in a subject in need thereof.

[0471] 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.

[0472] 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.

[0473] 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.

[0474] 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.

[0475] 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.

[0476] 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, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or complications upon emergence from anesthesia in a subject in need thereof.

[0477] 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.

[0478] 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 an excessive sleep disorder in a subject in need thereof.

[0479] 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.

[0480] 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 symptom of a rare genetic disorder in a subject in need thereof.

[0481] 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.

[0482] 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.

[0483] 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.

[0484] 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.

[0485] 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.

[0486] 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.

[0487] The present disclosure provides compounds that function as modulators of orexin receptor activity.

[0488] In some embodiments, compounds of the present disclosure are agonists of orexin receptors.

[0489] The present disclosure provides compounds that function as modulators of orexin-2 receptor activity.

[0490] In some embodiments, compounds of the present disclosure are agonists of the orexin-2 receptor.

[0491] In some embodiments, modulation of the orexin receptor is activation of the orexin receptor.

[0492] 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.

[0493] The present disclosure also provides a method of treating a disease or disorder in which orexin receptor activity is implicated in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0494] The present disclosure also provides a method of treating a disease or disorder in which orexin-2 receptor activity is implicated in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0495] The present disclosure also provides a method of treating a disease or disorder in which orexin receptor activity is implicated in a patient in need of such treatment, comprising administering to said patient a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0496] The present disclosure also provides a method of treating a disease or disorder in which orexin-2 receptor activity is implicated in a patient in need of such treatment, comprising administering to said patient a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0497] In some embodiments, the present disclosure also provides methods for treating a disease or disorder by reducing excessive sleepiness and / or excessive daytime sleepiness.

[0498] In some embodiments, the present disclosure also provides methods for treating a disease or disorder by reducing excessive sleepiness.

[0499] In some embodiments, the present disclosure also provides methods for treating a disease or disorder by reducing excessive daytime sleepiness.

[0500] In some embodiments, the disease or disorder is associated with excessive sleepiness and / or excessive daytime sleepiness.

[0501] 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 disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or emergence from anesthesia.

[0502] 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 disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or a complication upon emergence from anesthesia.

[0503] In some embodiments, the excessive daytime sleepiness is associated with a neurodegenerative disorder.

[0504] In some embodiments, the neurodegenerative disorder associated with excessive daytime sleepiness is Parkinson's disease, Alzheimer's disease, Huntington's disease, or multiple sclerosis.

[0505] In some embodiments, the disease or disorder is recurrent hypersomnia.

[0506] In some embodiments, the recurrent hypersomnia is narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia.

[0507] In some embodiments, the disease or disorder is sleep apnea, traumatic brain injury, age-related cognitive dysfunction, or excessive daytime sleepiness.

[0508] In some embodiments, excessive daytime sleepiness is associated with sleep apnea, traumatic brain injury, or age-related cognitive dysfunction.

[0509] 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.

[0510] In some embodiments, excessive sleepiness is a symptom of narcolepsy.

[0511] In some embodiments, the disease or disorder is a symptom of narcolepsy.

[0512] In some embodiments, the symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, waking and hypnagogic hallucinations, disrupted nighttime sleep, or rapid eye movement (REM) sleep at inappropriate times.

[0513] In some embodiments, the symptom of narcolepsy is excessive daytime sleepiness.

[0514] In some embodiments, the symptom of narcolepsy is cataplexy. In some embodiments, cataplexy is a pathology of narcolepsy (e.g., narcolepsy type 1).

[0515] In some embodiments, the symptom of narcolepsy is sleep paralysis.

[0516] In some embodiments, the symptoms of narcolepsy are waking and hypnagogic hallucinations.

[0517] In some embodiments, the symptom of narcolepsy is disrupted nighttime sleep.

[0518] In some embodiments, the symptom of narcolepsy is inappropriately timed rapid eye movement (REM) sleep.

[0519] In some embodiments, the neurodegenerative disorder is characterized by cataplexy.

[0520] In some embodiments, the neurodegenerative disorder is characterized by excessive daytime sleepiness.

[0521] In some embodiments, the neurodegenerative disorder is Parkinson's disease.

[0522] In some embodiments, the neurodegenerative disorder is Alzheimer's disease.

[0523] In some embodiments, the neurodegenerative disorder is Huntington's disease.

[0524] In some embodiments, the neurodegenerative disorder is multiple sclerosis.

[0525] In some embodiments, the neurodegenerative disorder is traumatic brain injury.

[0526] In some embodiments, the neurodegenerative disorder is sleep apnea.

[0527] In some embodiments, the neurodegenerative disorder is age-related cognitive dysfunction.

[0528] In some embodiments, the neurodegenerative disorder is a disorder of recurrent excessive sleepiness.

[0529] In some embodiments, the recurrent excessive sleep disorder is Kleine-Levin syndrome, inappropriately timed sleep (eg, delayed or advanced sleep phase disorder), shift work disorder, or jet lag disorder.

[0530] In some embodiments, the disease or disorder is a symptom of a rare genetic disorder.

[0531] In some embodiments, the symptom of the rare genetic disorder is abnormal daytime sleepiness.

[0532] In some embodiments, the symptom of the rare genetic disorder is excessive daytime sleepiness.

[0533] In some embodiments, the symptom of the rare genetic disorder is sleep onset REM sleep.

[0534] In some embodiments, the symptoms of the rare genetic disorder are characterized by cataplexy-like symptoms.

[0535] In some embodiments, the rare genetic disorder is ADCA-DN, Coffin-Lowry syndrome, Moebius syndrome, Norrie disease, Niemann-Pick disease type C, or Prader-Willi syndrome.

[0536] In some embodiments, the disease or disorder is a mental health disorder.

[0537] In some embodiments, the mental health disorder is attention deficit hyperactivity disorder.

[0538] In some embodiments, the mental health disorder is attention deficit disorder.

[0539] In some embodiments, the disease or disorder is metabolic syndrome.

[0540] In some embodiments, the metabolic syndrome is obesity.

[0541] In some embodiments, the disease or disorder is osteoporosis.

[0542] In some embodiments, the disease or disorder is heart failure.

[0543] In some embodiments, the disease or disorder is coma.

[0544] In some embodiments, the disease or disorder is emergence from anesthesia.

[0545] In some embodiments, the disease or disorder is a complication upon emergence from anesthesia.

[0546] In some embodiments, the disease or disorder is narcolepsy, hypersomnia, 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 upon emergence from anesthesia.

[0547] In some embodiments, the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea. Route of administration

[0548] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as monotherapy or in addition to 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.

[0549] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e., alone, an adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering a compound of Formula (I), Formula (I'), Formula (I"), Formula (I'"), Formula (II), Formula (II'), Formula (III), or Formula (III') with another therapeutic agent (including treatment regimen) that also has therapeutic benefit.

[0550] 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 can be administered via different routes due to different physical and chemical properties.For example, the compound of the present disclosure can be administered orally to generate and maintain its good blood level, while the other therapeutic agents can be administered intravenously.Initial administration can be carried out according to established protocols known in the art, and then, based on the observed effect, skilled clinicians can change the dosage, administration mode and administration time.

[0551] The specific choice of other therapeutic agent will depend on the attending physician's diagnosis and 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, as defined hereinabove, or a pharmaceutically acceptable salt thereof, and another suitable agent, for use in treating a disease in which orexin activity is implicated.

[0552] 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, and in association with, a suitable pharmaceutically acceptable diluent or carrier.

[0553] In addition to their use in therapeutic agents, the compounds of Formula (I), Formula (I'), Formula (I"), Formula (I'"), Formula (II), Formula (II'), Formula (III), or Formula (III'), and pharmaceutically acceptable salts thereof, 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.

[0554] In any of the above-described pharmaceutical compositions, processes, methods, uses, medicaments and manufacturing features of the present disclosure, any of the alternative embodiments of the macromolecules of the present disclosure described herein also apply.

[0555] 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 (ie, at the desired site of action).

[0556] 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 powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via aerosol, e.g., via the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; and administration, e.g., by implantation of a depot or reservoir subcutaneously or intramuscularly. Illustrative Embodiments

[0557] First Exemplary Embodiment: A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is —N(CH)— or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0558] Second Exemplary Embodiment: A compound of formula (I'): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is -N(CH3)- or C2-C6 alkyl; L is absent or C2-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0559] A third exemplary embodiment. A compound of formula (I″): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is —N(CH)— or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0560] Fourth Exemplary Embodiment. A compound of Formula (I'''): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is -N(CH3)- or C2-C6 alkyl; L is absent or C2-C6 alkyl; Y is -O-; n is 1 or 2; Ra is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0561] Fifth Exemplary Embodiment: A compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0562] Sixth Exemplary Embodiment: A compound of formula (II'): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C optionally substituted with one or more halogens. 10 is aryl, provided that when X is alkyl, then L is absent.

[0563] Seventh Exemplary Embodiment. A compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0564] Eighth Exemplary Embodiment. A compound of formula (III'): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl; L is absent or C1-C6 alkyl; Y is -O-; n is 1 or 2; R a is H or a halogen; R b is H, halogen, or C1-C6 alkyl; or R a and R b together with the atom to which they are attached form a C3 cycloalkyl; Z is -NH-; R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl substituted with halogen; Ar1 is a C6-C alkyl group optionally substituted with one or more halogens. 10 is aryl; T is a C6-C alkyl optionally substituted with one or more halogens or C1-C6 alkyls. 10 is aryl, provided that when X is alkyl, then L is absent.

[0565] Ninth Exemplary Embodiment. The compound of any one of the preceding exemplary embodiments, wherein X is —N(CH 3 )—.

[0566] Tenth Exemplary Embodiment. The compound of any one of Exemplary Embodiments 1-8, wherein X is -N(C1-C6 haloalkyl)- or C1-C6 alkyl.

[0567] An eleventh exemplary embodiment. The compound of any one of the preceding exemplary embodiments, wherein L is absent.

[0568] Twelfth Exemplary Embodiment. The compound of any one of Exemplary Embodiments 1-10, wherein L is C1-C6 alkyl.

[0569] A thirteenth exemplary embodiment. The compound of any one of the preceding exemplary embodiments, wherein n is 1.

[0570] A fourteenth exemplary embodiment. The compound of any one of exemplary embodiments 1-12, wherein n is 2.

[0571] Fifteenth exemplary embodiment. a The compound of any one of the preceding exemplary embodiments, wherein

[0572] Sixteenth Exemplary Embodiment. R a The compound of any one of Exemplary Embodiments 1-14, wherein is halogen.

[0573] Seventeenth Exemplary Embodiment. b The compound of any one of the preceding exemplary embodiments, wherein

[0574] Eighteenth exemplary embodiment. R b The compound of any one of Exemplary Embodiments 1-16, wherein is halogen.

[0575] Nineteenth exemplary embodiment. a and R b together with the atom to which they are attached form a C3 cycloalkyl.

[0576] A twentieth exemplary embodiment. The compound of any one of the preceding exemplary embodiments, wherein R1 is C2-C6 alkyl.

[0577] A 21st exemplary embodiment. The compound of any one of exemplary embodiments 1-19, wherein R1 is C3 cycloalkyl substituted with halogen.

[0578] A 22nd exemplary embodiment. The compound of any one of the preceding exemplary embodiments, wherein Ar1 is phenyl optionally substituted with one or more halogens.

[0579] A 23rd exemplary embodiment. The compound of any one of the preceding exemplary embodiments, wherein T is phenyl optionally substituted with one or more halogens.

[0580] A twenty-fourth exemplary embodiment, wherein the compound is of formula (I'-a) or (I'-b): [ka] or a pharmaceutically acceptable salt thereof.

[0581] A twenty-fifth exemplary embodiment, wherein the compound is of formula (II'-a), (II'-b), or (II'-c): [ka] [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4], the compound of any one of the preceding exemplary embodiments.

[0582] A twenty-sixth exemplary embodiment, wherein the compound is of formula (IIIA'), (IIIA'-a), or (IIIA'-b): [ka] or a pharmaceutically acceptable salt thereof [In the formula, 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.

[0583] A twenty-seventh exemplary embodiment, wherein the compound is of formula (IVA'), (IVA'-a), or (IVA'-b): [ka] or a pharmaceutically acceptable salt thereof [In the formula, 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.

[0584] A twenty-eighth exemplary embodiment, wherein the compound is of formula (Ia) or (Ib): [ka] or a pharmaceutically acceptable salt thereof.

[0585] A 29th exemplary embodiment, wherein the compound is of formula (II-a), (II-b), or (II-c): [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4], the compound of any one of Exemplary Embodiments 1-24.

[0586] A 30th exemplary embodiment, wherein the compound is of formula (IIIA), (IIIA-a), or (IIIA-b): [ka] [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4], the compound of any one of Exemplary Embodiments 1-24.

[0587] A thirty-first exemplary embodiment, wherein the compound is of formula (IIIA'-1), (IIIA'-1a), or (IIIA'-1b): [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4], the compound of any one of Exemplary Embodiments 1-24.

[0588] A thirty-second exemplary embodiment, wherein the compound is of formula (IIIA'-2), (IIIA'-2a), or (IIIA'-2b): [ka] or a pharmaceutically acceptable salt thereof [In the formula, n1 is an integer ranging from 0 to 4; n2 is an integer ranging from 0 to 4], the compound of any one of Exemplary Embodiments 1-24.

[0589] A 33rd exemplary embodiment. The compound of any one of the preceding exemplary embodiments is selected from a compound set forth in Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

[0590] A 34th exemplary embodiment. A compound obtainable by or obtained by the methods described herein, optionally including one or more steps described in Schemes 1-9.

[0591] A 35th exemplary embodiment. A pharmaceutical composition comprising a compound of any one of the preceding exemplary embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0592] A thirty-sixth exemplary embodiment. The pharmaceutical composition of exemplary embodiment 35, wherein the compound is selected from the compounds set forth in Table 1, Table 2, Table 3, Table 4, or Table 5.

[0593] A 37th exemplary embodiment. A method of modulating orexin-2 receptor activity, comprising contacting a cell with an effective amount of a compound of any one of exemplary embodiments 1-34; optionally, the activity is in vitro or in vivo.

[0594] A 38th exemplary embodiment. A method of 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 of any one of exemplary embodiments 1-34, or the pharmaceutical composition of exemplary embodiment 35 or exemplary embodiment 36.

[0595] A thirty-ninth exemplary embodiment. The compound of any one of exemplary embodiments 1-34 or the pharmaceutical composition of exemplary embodiment 35 or exemplary embodiment 36, for use in modulating orexin-2 receptor activity; optionally, wherein the activity is in vitro or in vivo.

[0596] A fortieth exemplary embodiment. A compound of any one of exemplary embodiments 1-34 or the pharmaceutical composition of exemplary embodiment 35 or exemplary embodiment 36 for use in treating or preventing a disease or disorder.

[0597] A forty-first exemplary embodiment. Use of a compound of any one of exemplary embodiments 1-34 in the manufacture of a medicament for modulating orexin-2 receptor activity, where the activity is in vitro or in vivo, as appropriate.

[0598] Forty-second exemplary embodiment. Use of a compound of any one of exemplary embodiments 1-34 in the manufacture of a medicament for treating or preventing a disease or disorder.

[0599] Forty-third exemplary embodiment. The method, compound, pharmaceutical composition, or use of any one of exemplary embodiments 37-42, wherein the disease or disorder is associated with an implicated orexin-2 receptor.

[0600] Forty-fourth exemplary embodiment. The method, compound, pharmaceutical composition, or use of any one of exemplary embodiments 37-43, wherein the disease or disorder is narcolepsy, hypersomnia, 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 promoting emergence from anesthesia.

[0601] Forty-fifth exemplary embodiment. The method, compound, pharmaceutical composition, or use of any one of exemplary embodiments 37-44, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, sleep apnea, or insomnia. [Example]

[0602] For illustrative purposes, neutral compounds of Formula (I), Formula (I'), Formula (I"), Formula (I'"), Formula (II), Formula (II'), Formula (III), or Formula (III') are synthesized and tested in the Examples. It is understood that neutral compounds of Formula (I), Formula (I'), Formula (I"), Formula (I'"), Formula (II), Formula (II'), Formula (III), or Formula (III') can be converted to the corresponding pharmaceutically acceptable salt of the compound using techniques routine in the art (e.g., by saponification of an ester to a carboxylate salt or by hydrolyzing an amide to form the corresponding carboxylic acid and then converting the carboxylic acid to a carboxylate salt). [Table 7]

[0603] NMR spectra were recorded on a Bruker Avance III HD UltraShield 400 MHz spectrometer with a 5 mm PABBO probe, a Bruker DPX 300 MHz spectrometer with a 5 mm BBI probe, a Bruker AV 400 MHz spectrometer with a 5 mm PABBO probe, a Bruker DRX 500 MHz spectrometer 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. LCMS conditions

[0604] Method 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.

[0605] Method B: LC / MS (gradient: 5% B at 0.40 min, 5% B to 95% B from 0.40 to 3.00 min, hold at 95% B for 1.00 min, then 95% B to 5% B at 0.01 min, flow rate: 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). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization. MS range was 100–1000.

[0606] Method C: 5_95AB_6min-220-254-ELSD-MS2000: LC / MS (gradient: 5% B at 0.40 min, 5 to 95% B at 2.60 min, hold at 95% B at 1.00 min, then 95 to 5% B at 0.01 min; flow rate: 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 Kinetex C18 2.1 x 50 mm, 5 μm column. The detection method was diode array (DAD) and evaporative light scattering detection (ELSD). The MS mode was positive electrospray ionization. The MS range was 100-2000.

[0607] Method D: Hewlett Packard 1100 series with Masslynx software. Aqueous (C): 2.5 mL of 28% aqueous ammonia and 2.5 L of water. Organic (D): 125 mL of water, 2.5 mL of 28% aqueous ammonia, and 2.5 L of acetonitrile. The system was operated at a flow rate of 1.5 mL / min with a 1 μL injection volume using 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 with UV detection from 230 to 400 nm and a Waters micromass ZQ mass spectrometer were used. 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].

[0608] Method E: 5-95 AB_2 min: LC / MS (The column used for chromatography was a Kinetex 5 μm EVO C18 100 Å. 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 in 2.20 min, 0.5% B in 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80 min), 5% B in 1.81 min, and hold at 5% B for 0.39 min. The flow rate was 1.0 mL / min (0.01-1.80 min), 1.2 mL / min (1.81-2.20 min).

[0609] Method F: 5-95CD_4.5 min: LC / MS (The column used for chromatography was an Xbridge C18 2.1 x 50 mm, 5 μm). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000. Mobile phase A was 10 mM ammonium bicarbonate in water, and mobile phase B was HPLC-grade acetonitrile. The gradient was 5-95% B in 4.30 min, 5% B in 0.01 min, 5-95% B (0.01-3.00 min), hold at 95% B within 0.5 min, 95-5% B (3.50-3.51 min), hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01-4.30 min).

[0610] Method G: 10-80AB_10 min: LC / MS (Gradient: 10-80% B at 8:00 min, hold at 80% B for 2:00 min, hold at 80% B for 2:00 min, hold at 10% B for 2:99 min (flow rate 0.5 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 Halo C18 3.0 × 10 mm column (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000.

[0611] Method H: 5_95CD_6min-220-254: LC / MS. The gradient was 5% B at 0.40 min, 5-95% B from 0.40 to 3.40 min, hold at 95% B for 0.45 min, then 95-5% B at 0.01 min. The flow rate was 0.8 mL / min. Mobile phase A was HO + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was an Xbridge C18 2.1 x 50 mm column (5 μm particles). The detection method was diode array (DAD) detection. The MS mode was positive electrospray ionization. The MS range was 100-1000.

[0612] Method I: 5_95AB_6min-220-254: LC / MS gradient: 5% B at 0.40 min, 5 to 95% B at 2.60 min, hold at 95% B at 1.00 min, then 95 to 5% B at 0.01 min. The flow rate was 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 x 2.0 mm column (5 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000.

[0613] Method J: 5-95AB_2 min: LC / MS. The column used for chromatography was a Halo 5 μm C18 90A, 30 × 3.0 mm. The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 50–2000. 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 in 1.50 min, 5% B in 0.01 min, 5–95% B (0.01–0.70 min), 95% B over 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.

[0614] Method K: 10-100AB_2MIN: LC / MS. The column used for chromatography was a Halo C18 5 μm, 3.0 × 30 mm (5 μm particles). 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 10–100% B in 1.30 min, 10% B in 0.01 min, 10–100% B (0.01–0.70 min), and hold at 100% B for 0.60 min. The flow rate was 1.5 mL / min (0.00–1.30 min).

[0615] Method L: 10-80 AB_10 min: LC / MS (Gradient: 10-80% B at 8:00 min, hold at 80% B for 2:00 min, 80-10% B at 0.01 min, then hold at 10% B for 2:99 min (flow rate 0.5 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 Halo C18 3.0 × 100 mm column (2.7 μm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000.

[0616] Method M: Column: CSH C18 1.7 μm 2.1 × 50 mm; Run time: 1.40 min; Solvents: A) water, B) acetonitrile, D) 2% formic acid in water; Gradient run with 5% D throughout. Gradient: 0.8 mL / min at 40 °C, 2 to 95% B with 5% A and D over 1.20 min, hold at 95% B and 5% D to 1.40 min; Photodiode array detection at 215–350 nm.

[0617] Method N: Column: Agilent Poroshell SB-C18 3.0 x 30 mm, 2.7 μm. Detection method: Diode array. Mobile phase A: 0.04% TFA in water. Mobile phase B: 0.02% TFA in HPLC-grade acetonitrile. Gradient: 10% B over 0.01 min, then 10-100% B (0.01-0.70 min), hold at 100% B over 0.60 min. Flow rate was 1.5 mL / min.

[0618] Method O: LC / MS (The column used for chromatography was a Kinetex 5 μm EVO C18 100 Å 2.1 × 30 mm). 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% TFA in water, and mobile phase B was 0.02% TFA in HPLC-grade acetonitrile. The gradient was 5–95% B in 4.30 min, 5% B in 0.01 min, 5–95% B (0.01–3.00 min), hold at 95% B for 0.5 min, 95–5% B (3.50–3.51 min), hold at 5% B for 0.79 min. The flow rate was 1.0 mL / min. Synthesis of intermediates Synthesis of tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)piperidine-1-carboxylate [ka] Intermediate 1: tert-butyl 5-(diisobutylamino)-3,4-dihydropyridine-1(2H)-carboxylate [ka]

[0619] tert-Butyl 3-oxopiperidine-1-carboxylate (1.5 kg, 6.62 mol, 1 equiv.) was added to toluene (15 L) at 20-30°C under nitrogen and stirred at 25°C. Diisobutylamine (1.95 kg, 14.91 mol, 2.25 equiv.) was added, and the reaction mixture was heated to reflux (110-113°C) for 12 h with water removal (100 mL) via Dean Stark. The reaction was cooled to 20-30°C over 60 min (1.5°C / min) to give a brown solution, which was then concentrated under reduced pressure (55°C, 0.01 mPa) to give crude Intermediate 1 (2.25 kg, QNMR purity: 59%, yield: 65%) as a brown viscous oil, which was used directly for the next step without purification. 1 H NMR (400 MHz, CDCl3) δ ppm 0.50-1.00 (m, 14 H), 1.48 (s, 9 H), 1.75-1.85 (m, 2 H), 2.05-2.15 (m, 3 H), 2.50-2.60 (m, 4 H), 5.9-6.1 (m, 1H). Intermediate 2: tert-butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopiperidine-1-carboxylate [ka]

[0620] A 50 L reactor was charged with CHCN (4.6 L) and a solution of Intermediate 1 (2.25 kg, 4.28 mol, 1 equiv) in CHCN (3 L) was added at 20-30 °C. A solution of 1-bromo-3-(bromomethyl)-2-fluorobenzene (1.36 kg, 4.82 mol, 1.13 equiv) dissolved in CHCN (3 L) was added over 30 min at 20-30 °C, followed by the addition of a solution of TBAI (260.46 g, 684 mmol, 0.16 equiv) in CHCN (3 L) over 10 min at 20-30 °C. The reaction mixture was heated to 80 °C (internal temperature) over 30 min (1.84 °C / min), and the temperature was held at 80 °C under N for 12 h. The reaction was cooled to 20-30°C (internal) over 30 minutes (1.84°C / min) to give a brown solution.

[0621] Water (6.5 L) was added to the reaction mixture. The mixture was then adjusted to pH 4-5 with AcOH (813 mL) at 20-30°C. The mixture was heated to 60°C (internal) for 30 minutes (1.16°C / min) and then held at 50-60°C (internal) for 1-2 hours. The mixture was concentrated under reduced pressure (45°C, 0.09 mPa) to remove CHCN (12 L) to give a brown solution. Ethyl acetate (6 L) was added, the mixture was stirred for 10 minutes, and the aqueous layer was separated. This extraction was repeated twice. The organic layer was adjusted to pH 2-3 by slowly adding aqueous HCl (0.5 N, 6 L). The mixture was stirred for 10 minutes, and the aqueous layer was separated. The organic layer was adjusted to pH 7-8 by slowly adding saturated NaHCO3 solution (9 L). The mixture was stirred for 10 minutes, and the aqueous layer was separated. The organic layer was washed with brine (3 L × 2), dried over anhydrous NaSO (1.5 kg), and filtered. Silica gel (2 kg) was added to the organic layer, and the mixture was stirred at 20-30 °C for 1 hour and then filtered. The filter cake was washed with ethyl acetate (3 L × 3). The filtrate was concentrated under reduced pressure (45 °C, 0.09 mPa) to give the crude product as a brown oil. The crude product was purified by recrystallization from n-heptane / MTBE (10 / 1, 1V) at 20-25 °C. A yellow solid gradually precipitated. The suspension was stirred at 20 °C for 2 hours. The suspension was filtered, and the filter cake was washed with n-heptane (500 mL × 4). The solid was dried under reduced pressure (45 °C, 0.01 mPa) to give Intermediate 2 (1.45 kg, purity: 99.4%, yield: 87.3%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 1.30-1.55 (m, 9 H), 1.80-2.10 (m, 2 H), 2.45-2.60 (m, 2 H), 2.90-3.25 (m, 3 H), 3.85-4.25 (m, 1 H), 4.70-4.90 (m, 1 H), 6.95 (t, 1 H), 7.05-7.35 (m, 1 H), 7.40-7.50 (m, 1 H). Intermediate 3: (rac)-tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)piperidine-1-carboxylate [ka]

[0622] HCO2NH4 (470.01 g, 7.30 mol, 3 equiv.) was added to a solution of Intermediate 2 (950 g, 2.43 mol, 1 equiv.) in MeOH (9.5 L) over 30 min at 20–30 °C (internal temperature). Catalyst A (prepared according to J. Org. Chem. 2019, 84, 10962–10977, 16.03 g, 24.35 mmol, 0.01 equiv.) was added over 10 min, and the reaction mixture was then heated to 60 °C (internal temperature) over 30 min (1.84 °C / min) and then held at 60 °C (internal) for 12 h under N2. The reaction mixture was cooled to 20 °C and adjusted to pH 7–8 by slow addition of aqueous NaHCO3 (5 L). The reaction mixture was concentrated under reduced pressure (40° C., 0.01 mPa) to one-third of the original volume and then extracted with ethyl acetate (2.5 L×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure (45° C., 0.01 mPa) to give crude Intermediate 3 (942 g). This batch was combined with another batch of Intermediate 3 (1.45 Kg from Intermediate 2) to give a total of 2.36 kg of Intermediate 3. The crude material was dissolved in ethyl acetate (5 L) and NH3 . HO (3 L, 7% w / w) was added to the reactor at 25 °C (pH = 10-11). The mixture was stirred at 25 °C for 1 h and then extracted with ethyl acetate (5 L × 3). The combined organic layers were washed with a saturated aqueous solution of sodium chloride (1 L), dried over NaSO, filtered, and concentrated under reduced pressure (45 °C, 0.09 mPa) to give intermediate 3 (2.17 Kg, QNMR: 91%, yield based on QNMR: 82.9%) as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ ppm 0.90-1.20 (m, 9 H), 1.25-1.50 (m, 3 H), 1.55-1.75 (m, 3 H), 2.75-2.95 (m, 3 H), 3.10 (d, 1 H), 3.65-3.95 (m, 1 H), 4.25-4.45 (m, 1 H), 7.00-7.10 (m, 1 H), 7.25 (t, 1 H), 7.50-7.60 (m, 1 H). Intermediate 3: Purification by salt formation [ka]

[0623] Racemic di-toluoyltartaric acid (149.64 g, 387.31 mmol, 1.5 equiv.) was dissolved as a suspension in ethyl acetate (1 L) and added to a solution of intermediate 3 (100 g, 258.21 mmol, 1 equiv.) in EtOAc (1 L) at 70 °C. The mixture was stirred at 70 °C for 16 h under N2 to give a yellow slurry. The reaction mixture was gradually cooled to 20 °C, and the solid was isolated by filtration, washed with ethyl acetate (0.5 L), and dried in vacuo (40 °C, 10 mbar) to give intermediate 3 salt (155 g, 85% yield) as a white solid. Intermediate 3 salt (155 g, 200.88 mmol) was dissolved in dichloromethane (775 mL) and NH3 . HO (7.0% w / w%, 650 mL, 5 equiv.) was added until pH = 9-10. The mixture was stirred at 25 °C for 1 h under N. The resulting mixture was extracted with dichloromethane (0.5 L × 3). The combined organic layers were washed with saturated brine (0.5 L), dried over NaSO, filtered, and concentrated under reduced pressure (45 °C, 0.01 mPa) to give racemic intermediate 3 (71 g, QNMR: 96.5%, yield: 76%) as a yellow solid. Synthesis of tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)piperidine-1-carboxylate [ka]

[0624] L-(-)-Di-toluoyltartaric acid (3.99 g, 10.33 mmol, 0.4 equiv.) was added to a solution of intermediate 3 (10 g, 25.82 mol, 1 equiv.) in ethyl acetate (98 mL) and MeOH (2 mL) at 95°C. The suspension was stirred at reflux for 10 minutes, then the temperature was gradually reduced by switching off the heating and stirred for 16 hours. Over the course of 2 hours, the temperature decreased from 75°C to 25°C (internal temperature). The solid was isolated by filtration, washed with ethyl acetate (300 mL), and dried in vacuo (40°C, 0.01 MPa) to give 5.7 g of intermediate 3 salt with ee% = 92.5%. This was suspended in ethyl acetate (71 mL), and the temperature was increased to reflux and maintained at this temperature for 15 minutes. The temperature was gradually reduced by switching off the heating and the suspension was stirred for 16 hours. The solid was isolated by filtration, washed with ethyl acetate (20 mL) and dried in vacuo to give intermediate 3 salt (5.2 g, purity: 98.5%, ee%=98.2%) as a white solid. The salt was suspended in dichloromethane (100 mL) and washed with 0.5 M aqueous NaHCO (150 mL). The organic phase was isolated, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over Na SO , filtered, and concentrated under reduced pressure to give tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)piperidine-1-carboxylate (3.4 g, 34% yield, 68% of theory) as a white solid. Synthesis of benzyl (2S,3R,4S)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate [ka]

[0625] The synthesis of benzyl (2S,3R,4S)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate is shown in Reaction Schemes 1-3. [ka]

[0626] Step a) N-allyl-1,1-diphenylmethanimine was prepared by the method of Li et al. (Organic Letters, 2017, 19, 4239) by heating a mixture of benzophenone imine with allylamine in dichloromethane under reflux for 18 hours. Yield: 95%.

[0627] UPLC-MS, Method M: (CSH-C18, 2~95%MeCN)R t =0.52 min, MS(ESI + ): m / z=[M+H] + 222. 1 H NMR (400 MHz, CDCl3): δ [ppm] = 4.03 (dt, 2H), 5.11 (dq, 1H), 5.17 (dq, 1H), 6.05 (ddt, 1H), 7.19-7.16 (m, 2H), 7.31-7.40 (m, 3H), 7.41-7.49 (m, 3H), 7.62-7.64 (m, 2H).

[0628] Step b) To a solution of N-allyl-1,1-diphenylmethanimine (2) (300 g, 1.36 mol) in tetrahydrofuran (2 L) was added n-butyllithium (2.5 M, 651 mL) dropwise over 30 minutes at −78° C. After the addition was complete, the mixture was stirred at −78° C. for 2 hours. Then, a solution of 3-bromo-2-fluorobenzyl bromide (399.53 g, 1.49 mol) in tetrahydrofuran (1 L) was added dropwise over 1 hour at −78° C. to the reaction. The resulting mixture was stirred at −78° C. for 2 hours. The reaction was quenched with ethanol (20 mL) to give a solution of the benzophenone imine of 1-(3-bromo-2-fluorophenyl)but-3-en-2-amine (3), which was used directly for step c). LCMS (ESI + ): m / z 407.9 (M+H) +

[0629] Step c) A solution of the benzophenone imine of 1-(3-bromo-2-fluorophenyl)but-3-en-2-amine (3) was added to a solution of potassium hydrogen sulfate (300.00 g, 2.20 mol) in water (1 L) at -30 °C, and the mixture was stirred at 25 °C for 12 h. The organic layer was separated, and the aqueous layer containing the product was washed with methyl tert-butyl ether (3.5 L) followed by dichloromethane (2 × 3.5 L). The aqueous layer was cooled to 0 °C and basified with 50% NaOH solution (400 mL) to pH = 9-10. The product was extracted into dichloromethane (1 L). The extract was washed with brine (2 × 500 mL), dried (NaSO), and concentrated under reduced pressure.

[0630] The products from five reactions (steps b) and c) starting with N-allyl-1,1-diphenylmethanimine 2 (300 g) were combined to give 1-(3-bromo-2-fluorophenyl)but-3-en-2-amine 3 (870 g, 52% over two steps) as a brown oil.

[0631] UPLC, Method M: (CSH-C18 2~95%MeCN)R t =0.46 min (99.2%), MS(ESI + ): m / z=244.0 / 246.0[M+H] + , Br isotopes. 1 H NMR (400 MHz, CDCl3) δ ppm 2.66-2.92 (m, 2H), 3.58-3.67 (m, 1H), 5.02-5.15 (m, 2H), 5.87 (ddd, 1H), 6.93-6.99 (m, 1H), 7.12-7.18 (m, 1H), 7.39-7.45 (m, 1H). 19 F NMR (376 MHz, CDCl3): δ [ppm] = -110.9 (t, 1F).

[0632] Step d) To a mixture of 1-(3-bromo-2-fluorophenyl)but-3-en-2-amine (3) (150 g, 614 mmol) and 4-bromobut-1-ene (124.4 g, 922 mmol) in N,N-dimethylformamide (1.5 L) was added potassium hydroxide (68.96 g, 1.23 mol) and potassium iodide (204 g, 1.23 mol) in one portion at 25 °C under nitrogen. The mixture was stirred at 80 °C for 12 hours, cooled to 25 °C, and concentrated under reduced pressure. The residue was poured into ice water (1 L) and stirred for 3 minutes. The aqueous phase was extracted with ethyl acetate (3 × 1 L). The combined organic phase was dried (NaSO), filtered, and concentrated under reduced pressure. N-(1-(3-bromo-2-fluorophenyl)but-3-en-2-yl)but-3-en-1-amine (4) (995 g, crude weight of yellow oil) was obtained from six reactions carried out in parallel and used in step e) without further purification. LCMS (ESI + ): m / z 298.0 [M+H] + .

[0633] Step e) Benzyl chloroformate (171.63 g, 1.01 mol) was added dropwise to a mixture of N-(1-(3-bromo-2-fluorophenyl)but-3-en-2-yl)but-3-en-1-amine (4) (200 g, 671 mmol) and sodium bicarbonate (112.69 g, 1.34 mol) in a mixture of tetrahydrofuran (1 L) and water (1 L) at 25 °C under nitrogen, and the mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (2 L) and extracted with ethyl acetate (3 × 1 L). The combined organic phases were dried (NaSO), filtered, and concentrated under reduced pressure. The products from five reactions at this scale were combined and purified by column chromatography on silica gel eluting with a gradient of petroleum ether:ethyl acetate = 1:0 to 5:1 to give benzyl (1-(3-bromo-2-fluorophenyl)but-3-en-2-yl)(but-3-en-1-yl)carbamate (5) (650 g, 41% yield over two steps) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.08-2.39 (m, 2H), 2.94-3.31 (m, 4H), 4.38-4.57 (m, 1H), 4.99 (br d, 2H), 5.06-5.14 (m, 2H), 5.15-5.22 (m, 2H), 5.57-5.80 (m, 1H), 5.88-6.15 (m, 1H), 6.82-6.90 (m, 1H), 6.91-7.13 (m, 1H), 7.29-7.45 (m, 6H).

[0634] Step f) Benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (Grubbs 2nd generation catalyst, 19.64 g, 23.13 mmol) was added to a solution of benzyl (1-(3-bromo-2-fluorophenyl)but-3-en-2-yl)(but-3-en-1-yl)carbamate (5) (100 g, 231 mmol) in dichloromethane (2 L) at 25° C. under nitrogen and protected from light. The mixture was heated at 40° C. for 12 hours and then concentrated under reduced pressure. The crude products from six reactions carried out at this scale were purified by column chromatography on silica gel eluting with a gradient of petroleum ether:ethyl acetate = 1:0 to 5:1 to give benzyl 6-(3-bromo-2-fluorobenzyl)-3,6-dihydropyridine-1(2H)-carboxylate (6) (477 g, 82% yield) as a yellow oil.

[0635] UPLC, Method M: (Column CSH-C18, 2-95% MeCN) t =3.17 minutes (100%), MS(ESI + ): m / z 404 / 406 [M+H] + , Br isotopes. 1H NMR (400 MHz, DMSO-d6, 80 °C): δ [ppm] = 1.95-1.99 (m, 1H), 2.06-2.14 (m, 1H), 2.86-3.02 (m, 3H), 4.04 (dd, 1H), 4.64-5.02 (m, 3H), 5.68 (d, 1H), 5.86-5.90 (m, 1H), 7.02 (t, 1H), 7.21-7.41 (m, 6H), 7.50 (t, J 7.3 Hz, 1H). 19 F NMR (376 MHz, DMSO-d6, 80 °C): δ [ppm] = -112.2 (1F). [ka]

[0636] Step g) To a mixture of benzyl 6-(3-bromo-2-fluorobenzyl)-3,6-dihydropyridine-1(2H)-carboxylate (6) (200 g, 498 mmol) and 1,1,1-trifluoropropan-2-one (355 mL, 3.96 mol) in a mixture of acetonitrile (1 L) and water (1 L) was added ethylenediaminetetraacetic acid (EDTA, 14.46 g, 49.5 mmol), Oxone® (CAS 70693-62-8, containing 3.26 mmol / g potassium persulfate, 912 g, 1.48 mol), and solid sodium bicarbonate (623 g, 7.42 mol) under nitrogen at 0° C. The mixture was stirred at 0° C. for 3 minutes, then heated to 25° C. and stirred for 12 hours. The mixture was poured into water (2 L) and stirred for 3 minutes. The aqueous phase was extracted with ethyl acetate (3 x 1 L). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure.

[0637] The crude product was combined with another reaction carried out using 177 g of compound 6.

[0638] Separation of the isomeric epoxides 7 and 8 was achieved by column chromatography on silica gel eluting with a gradient of petroleum ether:ethyl acetate = 1:0 to 3:1 to give (rac)-benzyl (1RS,2RS,6SR)-2-(3-bromo-2-fluorobenzyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (7) (150 g, 38%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 1.64-1.87 (m, 1H), 1.94-2.15 (m, 1H), 3.06 (br s, 4H), 3.21-3.42 (m, 1H), 3.56-3.96 (m, 1H), 4.71-4.89 (m, 1H), 4.91-5.16 (m, 2H), 6.82-7.07 (m, 1.5H), 7.27 (s, 2H), 7.28-7.47 (m, 4.5H).

[0639] Step h) A mixture of (rac)-benzyl (1RS,2RS,6SR)-2-(3-bromo-2-fluorobenzyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (7) (20.00 g, 47.59 mmol) and triethylamine trihydrofluoride (80 mL) was heated under nitrogen in a Teflon-lined autoclave at 120 °C for 12 h. The mixture was poured into water (2 L), stirred for 3 min, and extracted with ethyl acetate (3 × 1 L). The combined organic phases were dried (NaSO), filtered, and concentrated under reduced pressure.

[0640] The crude products from seven reactions were combined and purified by column chromatography on silica gel eluting with a gradient of petroleum ether:ethyl acetate = 1:0 to 2:1 to give (rac)-benzyl (2RS,3RS,4RS)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-hydroxypiperidine-1-carboxylate (9) (130 g, 89%) as a yellow oil.

[0641] UPLC, method M:R t= 2.55 minutes (96.0% according to UV-TAC), MS (ESI + ): m / z = 440.0 / 442.0, [M+H] + , Br isotope. 1 H NMR (396 MHz, DMSO-d6, 80 °C) δ [ppm] 1.76 - 1.83 (m, 1H), 1.91 - 2.11 (m, 1H), 2.97 (dd, 1H), 3.03 - 3.09 (m, 1H), 3.26 (dt, 1H), 3.77 (m, 1H), 3.92 (dd, 1H), 4.44 (dd, 1H), 4.68 (dq, 1H), 4.77 - 4.80 (m, 1H), 4.92 (d, 1H), 5.23 (d, 1H), 7.02 (t, 1H), 7.16 (d, 1H), 7.21 - 7.25 (m, 1H), 7.26 - 7.34 (m, 2H), 7.49 - 7.52 (m, 1H). 19 F NMR (373 MHz, DMSO-d6, 80 °C) δ [ppm] -112.3 (s, 1F), -185.8 (br t, 1F).

[0642] Step i) To a solution of (rac)-benzyl 6-(3-bromo-2-fluorobenzyl)-3,6-dihydropyridine-1(2H)-carboxylate (6) (30.0 g, 80% purity, 59.4 mmol) in a mixture of acetone (600 mL) and water (150 mL) was added potassium osmate dihydrate (547 mg, 1.49 mmol) and N-methylmorpholine-N-oxide (20.9 g, 178 mmol). The mixture was stirred at 25 °C for 3 hours. The acetone was removed under reduced pressure, and the residue was stirred with a mixture of ethyl acetate (200 mL) and a solution of sodium bisulfite (30.8 g, 297 mmol) in water (600 mL) for 30 minutes. After filtration, the aqueous phase was separated, and the organic phase was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether:ethyl acetate = 5:1 (1V) at 25 °C for 120 min to give benzyl (2RS,3RS,4SR)-2-(3-bromo-2-fluorobenzyl)-3,4-dihydroxypiperidine-1-carboxylate (10) (21 g, 75%) as an off-white solid.

[0643] UPLC method M:R t = 2.07 min (97.7% by UV-TAC), MS (ESI + ): m / z=438 / 440[M+H] + , Br isotope, MS(ESI): m / z=436 / 438[MH], Br isotope. 1 H NMR (396 MHz, DMSO-d6, 80 ℃) δ [ppm] 1.46-1.50 (m, 1H), 1.69 (qd, 1H), 2.86 (d, 2H), 2.98-3.11 (m, 1H), 3.59 (s, 1H), 3.83 (d, 1H), 3.96 (dd, 1H), 4.19-4.33 (m, 2H), 4.46 (t, 1H), 4.69-4.91 (m, 2H), 6.98 (t, 1H), 7.08-7.32 (m, 6H), 7.46 (td, 1H). 19 F NMR (373 MHz, DMSO-d6, 80℃) δ [ppm] -112.2 (s, 1F).

[0644] Step j) (rac)-Benzyl (2RS,3RS,4SR)-2-(3-bromo-2-fluorobenzyl)-3,4-dihydroxypiperidine-1-carboxylate (10) (21.0 g, 47.9 mmol) was suspended in dichloromethane (600 mL) under nitrogen. Anhydrous pyridine (15.16 g, 192 mmol) was added, and the resulting solution was cooled in an ice-water bath. Thionyl chloride (7.11 g, 71.9 mmol) was added dropwise, and the mixture was removed from the ice-water bath and stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO), filtered, and evaporated under reduced pressure to give (rac)-benzyl (3aR,4R,7aS)-4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]pyridine-5(4H)-carboxylate 2-oxide (11) (21 g, 88%, 4:1 mixture of epimers at sulfur) as a white solid, which was used in step k) without any purification.

[0645] UPLC method M:R t = 2.16 min (92% by UV-254 nM), MS (ESI + ): m / z=484 / 486.0[M+H] + , Br isotopes. 1 H NMR (396 MHz, DMSO-d6, 80℃) δ 1.62 (td, 0.8H), 2.08 (qd, 0.2H), 2.13-2.25 (m, 1H), 2.95-3.02 (m, 1H), 3.09-3.23 (m, 2H), 3.63-3.70 (dt, 0.8H), 3.87 (dt, 0.2H), 4.70-5.00 (m, 4H), 5.11-5.16 (m, 0.2H), 5.39 (dd, 0.8H), 7.00 (t, 1H), 7.05-7.17 (m, 2H), 7.21-7.32 (m, 4H), 7.48-7.52 (m, 1H). 19 F NMR (373 MHz, DMSO-d6, 80 ℃) δ [ppm] -112.0 (s, 1F).

[0646] Step k) To a solution of (rac)-benzyl (3aR,4R,7aS)-4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]pyridine-5(4H)-carboxylate 2-oxide (11) (21.0 g, 39.4 mmol) in acetonitrile (84 mL), dichloromethane (84 mL), and water (168 mL), sodium metaperiodate (9.26 g, 43.3 mmol) and ruthenium trichloride (81.7 mg, 0.394 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was filtered, and the solid was washed with ethyl acetate (50 mL). The filtrate was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was separated, dried (MgSO), filtered, and evaporated under reduced pressure to give benzyl (rac)-(3aR,4R,7aS)-4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]pyridine-5(4H)-carboxylate 2,2-dioxide (12) (19.3 g, 90% purity, 88% yield) as a white solid, which was used in the next step without further purification.

[0647] UPLC, method M:R t = 3.66 min (96.0% by UV-254 nm), MS (ESI -): m / z = 498 / 500 [M-H] - , Br isotope. 1 H NMR (396 MHz, DMSO-d6, 80 °C) δ [ppm] 1.95 - 2.06 (m, 1H), 2.27 - 2.34 (m, 1H), 2.94 - 3.12 (m, 1H), 3.17 - 3.24 (m, 1H), 3.87 (dt, 1H), 4.72 - 4.83 (m, 1H), 4.86 - 4.94 (m, 2H), 5.27 - 5.32 (m, 0.04H), 5.32 - 5.37 (m, 0.96H), 5.59 - 5.70 (m, 1H), 7.00 (t, 1H), 7.06 - 7.13 (m, 2H), 7.22 - 7.32 (m, 4H), 7.48 - 7.53 (m, 1H). 19 F NMR (373 MHz, DMSO-d6, 80 °C) δ [ppm] -111.9 (s, 1F).<00037​​Step l) To a solution of benzyl (rac)-(3aR,4R,7aS)-4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]pyridine-5(4H)-carboxylate 2,2-dioxide (12) (18 g, 36 mmol) in tert-butanol (360 mL) was added tetraethylammonium fluoride hydrate (12.0 g, 72 mmol). The mixture was stirred at 50 °C for 3 h. The mixture was filtered, and the solid was washed with ethyl acetate (50 mL). The filtrate was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (200 mL) and water (80 mL). The organic layer was separated, dried (MgSO), filtered, and evaporated under reduced pressure. The residue was dissolved in methyl tert-butyl ether (900 mL), and aqueous sulfuric acid (2 M, 900 mL) was added. The mixture was stirred at 25° C. for 1 hour. The mixture was diluted with water (500 mL) at 0° C. and extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (500 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate = 3:1. The product-containing fractions were combined and concentrated under reduced pressure, and the resulting solid was triturated with petroleum ether:methyl tert-butyl ether = 10:1 (3V) at 0° C. for 120 minutes to give (rac)-benzyl (2RS,3RS,4RS)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-hydroxypiperidine-1-carboxylate (9) (9.5 g, 73%) as a colorless solid. [ka]

[0649] Step m) To a mixture of (rac)-benzyl (2R,3R,4R)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-hydroxypiperidine-1-carboxylate (9) (130 g, 295 mmol) and pyridine (477 mL, 5.91 mol) in diisopropyl ether (1.9 L) was added triflic anhydride (244 mL, 1.48 mol) dropwise at 0 °C under nitrogen. The mixture was stirred at 0 °C for 3 minutes, then warmed to 25 °C and stirred for 12 hours. The mixture was poured into hydrochloric acid (0.25 M, 2 L). The aqueous phase was extracted with ethyl acetate (3 × 1 L). The combined organic phase was dried (Na SO ), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate = 1:0 to 3:1 to give (rac)-benzyl (2R,3R,4R)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)piperidine-1-carboxylate (13) (110 g, 60% yield) as a yellow oil.

[0650] UPLC, Method M: (CSH-C18 50~95%MeCN)R t =0.92 min(100%), MS(ESI + ): m / z = 572.1, 574.1 [M+H] + , Br isotopes. 1 H NMR (400 MHz, CDCl3): δ [ppm] 1.97-2.14 (m, 2H), 3.06-3.01 (m, 1H), 3.12-3.18 (m, 1H), 3.30 (m, 1H), 4.1 (br s, 1H minor rotamer), 4.24 (d, 1H major rotamer), 4.88-5.09 (m, 5H), 6.89 (t, J=7 Hz, 1H), 7.02 (t, 1H), 7.11-7.21 (m, 1H), 7.28-7.38 (m, 3H), 7.42 (t, 1H). 19F NMR (376 MHz, CDCl3): δ [ppm] -187.94 (s, 1F major rotamer), -187.85 (s, 1F minor rotamer), -111.6 (s, 1F major rotamer), -111.2 (s, 1F minor rotamer), -75.0 (s, 3F major rotamer), -74.8 (s, 3F minor rotamer).

[0651] Step m) Alternative procedure: A solution of (rac)-benzyl (2R,3R,4R)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-hydroxypiperidine-1-carboxylate (9) (0.5 g, 0.91 mmol) and pyridine (0.36 g, 4.54 mmol) in dichloromethane (10 mL) was degassed and purged with nitrogen three times. The mixture was cooled to 0 °C. A solution of triflic anhydride (0.77 g, 2.72 mmol) in dichloromethane (2 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hours and poured into aqueous copper sulfate (0.65 g in 30 mL of water) at 0 °C. The resulting mixture was partitioned between dichloromethane and water. The organic phase was washed twice with aqueous copper sulfate (0.65 g in 30 mL of water), saturated aqueous sodium bicarbonate (2.4 g in 25 mL of water), and finally with aqueous potassium dihydrogen phosphate (1 M, 20 mL) to remove any traces of alkali from the triflate. The organic phase was then dried (NaSO) and concentrated under reduced pressure. The crude triflate was coevaporated with tetrahydrofuran (2 × 10 mL) to give (rac)-benzyl (2R,3R,4R)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)piperidine-1-carboxylate (13) (510 g, 98%) as a nearly colorless oil.

[0652] Step n) To a mixture of (rac)-benzyl (2R,3R,4R)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)piperidine-1-carboxylate (13) (100 g, 174 mmol) in N,N-dimethylformamide (1.0 L) at 25 °C under nitrogen, sodium azide (34.1 g, 524 mmol) was added in one portion. The mixture was heated to 80 °C and stirred for 1 h. The mixture was cooled to 25 °C, poured into water (2 L), and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (3 × 1 L). The combined organic phases were washed with brine (3 × 800 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate = 1:0 to 3:1 to give (rac)-benzyl (2R,3S,4R)-3-azido-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (14) (56 g, 69% yield) as a pale yellow oil.

[0653] LCMS Method E (ESI + ):R t =0.775 min, m / z465.0(M+H) + . 1 H NMR (400 MHz, DMSO-d6) 1.73-1.86 (m, 1H), 2.02-2.08 (m, 1H), 2.97-3.11 (m, 2H), 3.30 (m, 1H), 3.91 (m, 1H), 4.17 (dd, 1H), 4.55-4.84 (br d, 3H), 5.13 (d, 1H), 7.00 (t, 2H), 7.35-7.25 (m, 5H), 7.53 (t, 1H).

[0654] Step o) To a mixture of (rac)-benzyl (2R,3S,4R)-3-azido-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (14) (56 g, 120 mmol) in tetrahydrofuran (560 mL) and water (560 mL) was added 3-[bis(2-carboxyethyl)phosphanyl]propanoic acid hydrochloride (69.0 g, 241 mmol) in one portion at 25° C. under nitrogen. The mixture was stirred at 25° C. for 3 minutes, then heated to 80° C. and stirred for 12 hours. The mixture was cooled to 25° C. The residue was poured into ice water (1 L) and stirred for 3 minutes. The aqueous phase was extracted with ethyl acetate (3×1 L). The combined organic phases were dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of petroleum ether:ethyl acetate = 1:0 to 0:1 to give (rac)-(2R,3S,4R)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (15) (35 g, 66% yield) as a colorless oil. LCMS (ESI + ): m / z 439.1 (M+H) + , R t =0.60 minutes

[0655] Step p) The enantiomers of (rac)-(2R,3S,4R)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (15) (35 g, 79.7 mmol) were separated by chiral supercritical fluid chromatography.

[0656] For analytical purposes, the enantiomers were separated using a Daicel Chiralpak IC-3 (50 mm x 4.6 mm, 3 μm); flow rate 3.4 mL / min at 35 °C. Mobile phase A = scCO2; mobile phase B = 0.1% isopropylamine in ethanol. Gradient: 0-0.2 min 5% B; 0.2-1.2 min 5-50% B, 1.2-2.2 min 50% B. The (+)-enantiomer eluted first (R t =1.11 min), the desired (-)-enantiomer (R t =1.28 min).

[0657] For the preparative separation, the enantiomers were separated using a Daicel Chiralpak IC (250 mm × 50 mm, 10 μm); mobile phase: 30% 0.1% aqueous ammonia in ethanol (isocratic) with 70% scCO 2 for 4.3 min. The (+)-enantiomer eluted first, followed by the desired (−)-enantiomer.

[0658] Benzyl (2S,3R,4S)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate was obtained as a colorless oil (14.7 g, 39% yield, 95.9% purity, ee=99.2%, [α] D = -2.11°, c = 1.04, MeOH, 20°C).

[0659] LCMS Method E:R t =2.14 minutes;(ESI + ): m / z 439.0 (M+H) + . 1 H NMR (400 MHz, CD3CN) δ ppm 1.65-1.88 (m, 1H + NH2), 1.98-2.06 (m, 1H), 2.87-3.01 (m, 2H), 3.14-3.31 (m, 2H), 3.95 (br d, 1H), 4.35-4.60 (m, 2 H), 4.81 (dq, 1H), 4.82 (br s, 1 H), 6.94 (t, 1H), 7.17 (br s, 2H), 7.18 (m, 1H), 7.24-7.35 (m, 3H), 7.41 (t, 1H). 19 F NMR (376 MHz, DMSO-d6) δ ppm -113.5 (s, 1 F), -198.3 (s, 1 F).

[0660] Step q) Alternative Method: A 100 mL round-bottom flask was charged with (rac)-(2R,3S,4R)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (15) (565.50 mg, 1.29 mmol), methanol (5.65 mL), and D-(+)-dibenzoyltartaric acid (461 mg, 1.29 mmol). The solution was stirred at room temperature for 16 hours, during which time a white precipitate formed. The solid was collected by filtration, washed with methanol (50 mL), and dried at 45 °C for 2 hours to give the D-(+)-dibenzoyltartaric acid salt of compound 1 (1:1 mol / mol ratio, 373 mg, 36%, 99% ee) as a colorless powder.

[0661] The salt (373 mg) was suspended in dichloromethane (50 mL) and washed with aqueous sodium bicarbonate (0.5 M, 50 mL). The organic phase was isolated and the aqueous phase was extracted with dichloromethane (2 × 10 mL). The combined organic phases were dried (NaSO), filtered, and concentrated in vacuo to give benzyl (2S,3R,4S)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (1) (191 mg, 34%, 98% ee) as a colorless oil. Example 1 Procedure for the preparation of Example 1 Step 1: tert-butyl-3-amino-2-(3-bromobenzyl)-4,4-difluoropyrrolidine-1-carboxylate, cis racemic [ka]

[0662] The compound was synthesized according to the procedure reported in WO2020 / 158958 A1 for tert-butyl-3-amino-2-(3-chloro-benzyl)-4,4-difluoropyrrolidine-1-carboxylate_cis racemate. Step 2: tert-Butyl 3-amino-2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-4,4-difluoro-pyrrolidine-1-carboxylate, cis racemic [ka]

[0663] To a solution of tert-butyl-3-amino-2-(3-bromobenzyl)-4,4-difluoropyrrolidine-1-carboxylate cis racemate (3 g, 7.7 mmol, 1 equiv.) in THF (60 mL) was added tert-butyl N-methyl-N-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (3.6 g, 9.2 mmol, 1.2 equiv.), KPO (3.27 g, 15.33 mmol, 2 equiv.), and XPhos-Pd-G (325 mg, 128 μmol, 0.05 equiv.). The mixture was stirred at 70 °C for 12 h under N. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 1:1) to give tert-butyl 3-amino-2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-4,4-difluoro-pyrrolidine-1-carboxylate_cis racemic (3 g, 68% yield) as a white solid. LCMS, Method E: (ESI+): m / z 580 (M+H) + , RT: 0.77 minutes. Step 3: tert-Butyl 2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-3-(difluoromethylsulfonylamino)-4,4-difluoro-pyrrolidine-1-carboxylate, cis racemic [ka]

[0664] To a solution of tert-butyl 3-amino-2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-4,4-difluoro-pyrrolidine-1-carboxylate cis racemate (1.3 g, 1.6 mmol, 1 equiv.) in acetonitrile (26 mL) was added pyridine (890 mg, 11.25 mmol, 910 μL, 5 equiv.). The reaction mixture was then cooled to 0° C., and difluoromethanesulfonyl chloride (1.69 g, 11.25 mmol, 5 equiv.) was added. The mixture was stirred at 20° C. for 12 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100:1 to 1:1) to give tert-butyl 2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-3-(difluoromethylsulfonylamino)-4,4-difluoro-pyrrolidine-1-carboxylate_cis racemic (850 mg, 55% yield) as a white solid. LCMS, Method E: (ESI+): m / z 594 (M+H-100). + , RT: 0.93 minutes. Step 4: N-[4,4-difluoro-2-[[3-[3-fluoro-2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]pyrrolidin-3-yl]-1,1-difluoro-methanesulfonamide, cis racemic [ka]

[0665] To a solution of tert-butyl 2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-3-(difluoromethylsulfonylamino)-4,4-difluoro-pyrrolidine-1-carboxylate cis racemate (850 mg, 1.23 mmol, 1 equiv.) in dioxane (10 mL), HCl / dioxane (4 M, 6.13 mL, 20 equiv.) was added. The mixture was stirred at 20° C. for 12 hours. The resulting mixture was concentrated under reduced pressure to give N-[4,4-difluoro-2-[[3-[3-fluoro-2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]pyrrolidin-3-yl]-1,1-difluoro-methanesulfonamide (500 mg, 83% yield) as a white solid. The crude product was used directly for the next step without purification. LCMS, Method E: (ESI+): m / z 494(M+H) + , RT: 0.57 minutes. Step 5: 1,1-difluoro-N-((4 2 S,4 3 R)-1 3 ,4 4 ,4 4 -Trifluoro-6-methyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide cis racemic [ka]

[0666] To a solution of N-[4,4-difluoro-2-[[3-[3-fluoro-2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]pyrrolidin-3-yl]-1,1-difluoro-methanesulfonamide cis racemate (500 mg, 1.0 mmol, 1 equiv.) in dichloromethane (2.5 L) was added triethylamine (510 mg, 5.1 mmol, 700 μL, 5 equiv.) and triphosgene (150 mg, 500 μmol, 0.5 equiv.). The mixture was stirred at 20° C. for 12 hours. The resulting mixture was then concentrated under reduced pressure to give a residue that was dissolved in acetonitrile (50 mL). To the solution was added KCO (420 mg, 3.0 mmol, 3 equiv.) at 20° C. The reaction was stirred at 20° C. for 12 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100:1 to 1:1) to give 1,1-difluoro-N-((4 2 S,4 3 R)-1 3 ,4 4 ,4 4 -Trifluoro-6-methyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 150 mg, 28.50% yield of (4-yl)methanesulfonamide cis racemate was obtained as a white solid. LCMS, Method E: (ESI+): m / z 520.2 (M+H) + , RT:2.441 minutes. Step 6: 1,1-difluoro-N-((4 2 S,4 3 R)-1 3 ,4 4 ,4 4 -Trifluoro-6-methyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide and 1,1-difluoro-N-((4 2 R,43 S)-1 3 ,4 4 ,4 4 -Trifluoro-6-methyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide [ka]

[0667] 1,1-difluoro-N-((4 2 S,4 3 R)-1 3 ,4 4 ,4 4 -Trifluoro-6-methyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 1,1-Difluoro-N-((4-yl)methanesulfonamide_cis racemate (150 mg) was subjected to superfluid CO2 chromatography separation to give 1,1-difluoro-N-((4-yl)methanesulfonamide_cis racemate (150 mg) 2 S,4 3 R)-1 3 ,4 4 ,4 4 -Trifluoro-6-methyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide (36 mg, 43% yield) and 1,1-difluoro-N-((4 2 R,4 3 S)-1 3 ,4 4 ,4 4 -Trifluoro-6-methyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide (36 mg, 43% yield) as a white solid. SFC separation method:

[0668] Equipment: Waters SFC150AP preparative SFC; Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); Mobile phase: A for CO2 and B for EtOH (0.1% NH3 in H2O); Gradient: B% from 10% to 35% in isocratic elution mode in 12 min; Flow rate: 35 g / min; Wavelength: 220 nm; Column temperature: 35 °C; System back pressure: 120 bar. Example 2 Procedure for the preparation of Example 2 Step 1: 2-(2-(3-bromo-2-fluorobenzyl)-2,5-dihydro-1H-pyrrol-1-yl)-1-phenyl-2λ2-ethan-1-one [ka]

[0669] The compound was synthesized according to the procedure reported in WO2020 / 158958 A1 for 2-(2-(3-chloro-2-fluorobenzyl)-2,5-dihydro-1H-pyrrol-1-yl)-1-phenyl-2 λ 2-ethan-1-one. Step 2: Benzyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka]

[0670] To a solution of 2-(2-(3-bromo-2-fluorobenzyl)-2,5-dihydro-1H-pyrrol-1-yl)-1-phenyl-2λ2-ethan-1-one (15 g, 38.45 mmol, 1 equiv.) in acetonitrile (90 mL) and water (60 mL), EDTA (225 mg, 770 μmol, 470 μL, 0.02 equiv.) and trifluoroacetone (34.45 g, 308 mmol, 27.55 mL, 8 equiv.) were added at 0° C. The mixture was stirred at 0° C. for 4 hours. Then, oxone (70.9 g, 115 mmol, 3 equiv.) and sodium carbonate (25.85 g, 308 mmol, 8 equiv.) were added at 0° C. The mixture was stirred at 25° C. for 12 hours. An aqueous solution of sodium sulfite (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 ml). The aqueous phase was extracted with ethyl acetate (3 x 150 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate = (71:29 to 0:100) to give benzyl 2-[(3-bromo-2-fluorophenyl)methyl]-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 g, 80% yield) as a yellow oil.

[0671] LCMS, Method E: (ESI+): m / z 406(M+H) + , RT: 0.84 minutes. 1 H NMR (400 MHz, methanol-d4) δ ppm 1.29 - 1.39 (m,1 H), 1.53 (br s, 2 H), 1.97 - 2.11 (m, 2 H), 2.13 - 2.24 (m, 1 H), 2.72 - 2.82 (m, 1 H), 3.36 - 3.63 (m, 2 H), 5.37 - 5.46 (m, 1 H), 5.52 - 5.64 (m, 1 H), 5.71 - 5.85 (m, 5 H), 5.92 (dddd, 1 H). Step 3: Benzyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-hydroxy-4-methyl-pyrrolidine-1-carboxylate [ka]

[0672] To a mixture of 2-[(3-bromo-2-fluoro-phenyl)methyl]-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10 g, 24.6 mmol, 1 equiv.), CuBr.Me2S (7.08 g, 34.5 mmol, 1.4 equiv.) in THF (140 mL) at −40° C. was added MeMgBr (3 M in THF, 45.9 mL, 5.6 equiv.). The mixture was then stirred at −20° C. for 2 hours. Saturated aqueous ammonium chloride solution (200 mL) was added to the mixture, and the mixture was allowed to warm to room temperature and then extracted with ethyl acetate (3×300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15:85 to 15:85) to give benzyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-hydroxy-4-methyl-pyrrolidine-1-carboxylate (6 g, 58% yield) as a yellow oil.

[0673] LCMS, Method E: (ESI+): m / z 422(M+H) + , RT: 0.83 minutes. 1H NMR (400 MHz, chloroform-d) δ ppm 0.92 - 0.92 (m, 1 H), 1.82 - 1.92 (m, 1 H), 2.66 (dd, 1 H), 2.70-2.81 (m, 1 H,), 2.85-2.96 (m, 1 H), 3.10-3.18 (m, 1 H), 3.27 - 3.34 (m, 1 H), 3.42-3.53 (m, 1 H), 3.69 - 3.76 (m, 2 H), 3.76 - 3.86 (m, 1 H), 4.99 - 5.10 (m, 2 H), 6.76 - 6.88 (2H, m), 7.01-7.09 (m, 1H), 7.15 (s, 1 H), 7.16 - 7.27 (m, 5 H), 7.28 - 7.34 (m, 1 H). Step 4: Benzyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-4-methyl-3-oxo-pyrrolidine-1-carboxylate, cis racemic [ka]

[0674] To a mixture of benzyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-hydroxy-4-methyl-pyrrolidine-1-carboxylate (6 g, 14.2 mmol, 1 equivalent) in dichloromethane (60 mL) was added Dess-Martin periodinane (12.06 g, 28.4 mmol, 2 equivalents) at 25° C. The mixture was then stirred at 45° C. for 12 hours. The reaction mixture was poured into water (70 mL) and extracted with ethyl acetate (75 mL). The aqueous phase was extracted with ethyl acetate (3×75 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give a residue. The combined residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (92:8 to 92:8) to give benzyl 2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-3-oxo-pyrrolidine-1-carboxylate cis racemate (4.63 g, 78% yield) as a pale yellow oil.

[0675] LCMS, Method E: (ESI+): m / z 420(M+H) + , RT: 1.09 minutes. 1 H NMR (400 MHz, acetonitrile-d3) δ ppm 0.76 - 0.90 (m, 3 H), 2.44 - 2.51 (m, 1 H), 2.54 - 2.69 (m, 1 H), 2.92 - 3.09 (m, 1 H), 3.21 - 3.33 (m, 1 H), 4.12 - 4.24 (m, 1 H), 4.30 - 4.43 (m, 1 H), 4.96 (br d, 1 H), 4.92 - 5.24 (m, 1 H), 6.94 - 7.05 (m, 2 H), 7.33 - 7.41 (m, 5 H), 7.43 - 7.53 (m, 1 H). Step 5: Benzyl 3-amino-2-[(3-bromo-2-fluoro-phenyl)methyl]-4-methyl-pyrrolidine-1-carboxylate, cis racemic [ka]

[0676] To a mixture of benzyl 2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-3-oxo-pyrrolidine-1-carboxylate cis racemate (1.5 g, 3.57 mmol, 1 equiv.) in MeOH (15 mL) was added ammonium formate (675 mg, 10.7 mmol, 3 equiv.). Nitrogen was bubbled through the reaction mixture for 2 minutes. Bis[2-(2-pyridyl)phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate (52 mg, 65 μmol, 0.01 equiv.) was added to the above mixture under nitrogen. The mixture was stirred at 80° C. for 12 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (40 mL). The aqueous phase was extracted with ethyl acetate (3×40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue. Three vials were set up as described above, and all four residues were combined together. The combined residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (45:65 to 5:95) to give benzyl 3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-pyrrolidine-1-carboxylate cis racemate (2.3 g, 44% yield) as a pale yellow oil.

[0677] LCMS, Method E: (ESI+): m / z 421(M+H) + , RT: 0.65 minutes. 1 H NMR (400 MHz, acetonitrile-d3) δ ppm 0.90 - 1.12 (m, 5 H), 2.06 - 2.22 (m, 2 H), 2.93 - 3.19 (m, 3 H), 3.63 - 3.73 (m, 1 H), 3.95 - 4.08 (m, 1 H), 4.80 - 5.13 (m, 2 H), 6.88 - 7.06 (m, 1 H), 7.13 - 7.60 (m, 7 H). Step 6: Benzyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylate, cis racemic [ka]

[0678] To a mixture of cis-racemic 3-amino-2-[(3-bromo-2-fluorophenyl)methyl]-4-methyl-pyrrolidine-1-carboxylate (1.4 g, 3.32 mmol, 1 equiv.) in acetonitrile (14 mL) was added pyridine (5.26 g, 66.5 mmol, 5.4 mL, 20 equiv.). Fluoromethanesulfonyl chloride (1.10 g, 4.98 mmol, 60% purity, 1.5 equiv.) was then added to the mixture at 0° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (35 mL). The aqueous phase was further extracted with ethyl acetate (3×35 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give a residue. Two vials were set up as described above, and all three residues were combined. The combined residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (93:7 to 85:15) to give benzyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylate cis racemate (1.3 g, 35.92% yield) as a pale yellow oil.

[0679] LCMS, Method E: (ESI+): m / z 519(M+H) + , RT: 0.82 minutes. 1H NMR (400 MHz, chloroform-d) δ ppm 1.14 - 1.22 (m, 3 H), 2.06 (s, 1 H), 2.43 - 2.57 (m, 1 H), 3.02 - 3.10 (m, 1 H), 3.74 - 3.90 (m, 1 H), 4.08 - 4.24 (m, 1 H), 4.15 - 4.23 (m, 1 H), 4.33 (q, 1 H), 4.64 - 5.02 (m, 2 H), 4.69 - 4.81 (m, 2 H), 5.05 - 5.12 (m, 1 H), 5.09 (br d, 1 H), 6.87 - 6.98 (m, 1 H), 7.26 - 7.28 (m, 3 H), 7.32 - 7.42 (m, 4 H). Step 7: Benzyl 2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylate, cis racemic [ka]

[0680] To a mixture of benzyl 2-[(3-bromo-2-fluorophenyl)methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylate cis racemate (1.15 g, 2.22 mmol, 1 equiv.) in THF (12 mL) was added tert-butyl N-methyl-N-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate (1.82 g, 3.33 mmol, 69% purity, 1.2 equiv.), KPO (1.42 g, 6.67 mmol, 3 equiv.), and Xphos-Pd-G (188 mg, 222 μmol, 0.1 equiv.) under nitrogen. The mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (25 mL). The aqueous phase was further extracted with ethyl acetate (3 × 25 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was dissolved in acetonitrile (4.5 mL). The filtrate was purified by preparative HPLC (column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 50%-70%, 8 min) to give benzyl 2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylate_cis racemic (460 mg, 30% yield) as a white solid. LCMS, Method E: (ESI+): m / z 588(M+H-100) + , RT: 0.92 minutes. Step 8: tert-Butyl N-[2-[2-[2-fluoro-3-[[3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidin-2-yl]methyl]phenyl]phenoxy]ethyl]-N-methyl-carbamate, cis racemic [ka]

[0681] To a mixture of benzyl 2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylate cis racemate (450 mg, 654 μmol, 1 equiv.) and triethylsilane (300 mg, 2.6 mmol, 420 μL, 4 equiv.) in dichloromethane (4.5 mL), PdCl (58 mg, 327 μmol, 0.5 equiv.) and triethylamine (200 mg, 1.96 mmol, 275 μL, 3 equiv.) were added at 25° C. N was bubbled through the reaction mixture for 2 minutes. The entire reaction mixture was then stirred at 25° C. for 12 hours. The reaction mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (25 mL). The aqueous phase was further extracted with ethyl acetate (3 x 25 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give tert-butyl N-[2-[2-[3-[[(2S,3R,4S)-3-(difluoromethylsulfonylamino)-4-fluoro-pyrrolidin-2-yl]methyl]-2-fluoro-phenyl]-4,6-difluoro-phenoxy]ethyl]-N-methyl-carbamate_cis racemic (300 mg, 83% yield) as a yellow oil. LCMS, Method E: (ESI+): m / z 611 (M+AcOH). + , RT: 1.00 minutes. Step 9: cis racemic 1-fluoro-N-[2-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-4-methyl-pyrrolidin-3-yl]methanesulfonamide [ka]

[0682] tert-Butyl-N-[2-[2-[3-[[(2S,3R,4S)-3-(difluoromethylsulfonylamino)-4-fluoro-pyrrolidin-2-yl]methyl]-2-fluoro-phenyl]-4,6-difluoro-phenoxy]ethyl]-N-methyl-carbamate cis racemate (300 mg, 540 μmol, 1 equiv.) was dissolved in HCl / dioxane (3 mL) and stirred at 25° C. for 1 h. The reaction mixture was concentrated to give 1-fluoro-N-[2-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-4-methyl-pyrrolidin-3-yl]methanesulfonamide cis racemate (240 mg, 98% yield) as an orange oil, which was used directly without any purification. LCMS, Method E: (ESI+): m / z 454 (M+H). + , RT: 0.54 minutes. Step 10: 1-Fluoro-N-((4 2 S,4 3 S,4 4 S)-2 2 -Fluoro-4 4 ,6-Dimethyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide and 1-fluoro-N-((4 2 R,4 3 R,4 4 R)-2 2 -Fluoro-4 4 ,6-Dimethyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide [ka]

[0683] To a solution of cis-racemic 1-fluoro-N-[2-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-4-methyl-pyrrolidin-3-yl]methanesulfonamide (145 mg, 320 μmol, 1 equiv.) in dichloromethane (1.45 L) was added triethylamine (97 mg, 960 μmol, 135 μL, 3 equiv.). The mixture was stirred at 25° C. for 1 minute. A solution of triphosgene (28 mg, 95.9 μmol, 0.3 equiv.) in dichloromethane (1 mL) was then added dropwise, and the entire reaction mixture was stirred at 25° C. for 36 hours. Three reactions were set up as described above, and all four reaction mixtures were combined. The reaction mixture was concentrated, the residue was dissolved in dimethylformamide (1.5 mL), and the solution was filtered. The filtrate was purified by preparative HPLC (column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (NH . H2O+NH4HCO3)-acetonitrile]; B%: 35%-65%, 8 min) to give the racemic desired compound (71 mg, 99% purity) as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 50%-50%, 10 min) to give 1-fluoro-N-((4 2 S,4 3 S,4 4 S)-2 2 -Fluoro-4 4 ,6-Dimethyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3 -yl)methanesulfonamide (26.9 mg, 37% yield) as a white solid and 1-fluoro-N-((4 2 R,4 3 R,4 4 R)-2 2 -Fluoro-4 4 ,6-Dimethyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane-4 3-yl)methanesulfonamide (21.3 mg, 30% yield) was obtained as a white solid. Example 3 Procedure for the preparation of Example 3 Step 1: tert-butyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-oxo-piperidine-1-carboxylate [ka]

[0684] To a solution of piperidin-3-one-N-tert-butyloxycarbamate (50 g, 250 mmol, 1 equiv.) in toluene (500 mL) was added pyrrolidine (71 g, 1.00 mol, 84 mL, 4 equiv.) at 25° C. The mixture was heated and stirred at 130° C. for 12 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (500 mL) and then cooled to 0° C. Tetrabutylammonium iodide (3.68 g, 9.95 mmol, 0.1 equiv.) and 1-bromo-3-(bromomethyl)-2-fluoro-benzene (40 g, 149.30 mmol, 1.5 equiv.) were added at 0° C., and the mixture was then heated to 95° C. and stirred for 12 hours under a nitrogen atmosphere. The mixture was poured into ice water (500 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-oxo-piperidine-1-carboxylate (25 g, 26.1% yield) as a white solid. LCMS, Method E: (ESI+): m / z 332 (M-tBu). + , RT: 0.88 minutes. Step 2: tert-Butyl 2-[[2-fluoro-3-(2-hydroxyphenyl)phenyl]methyl]-3-oxo-piperidine-1-carboxylate [ka]

[0685] To a solution of tert-butyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-oxo-piperidine-1-carboxylate (10 g, 25.9 mmol, 1 equiv.) and (2-hydroxyphenyl)boronic acid (7.14 g, 51.8 mmol, 2 equiv.) in THF (200 mL) was added Xphos-Pd-G3 (1.10 g, 1.29 mmol, 0.05 equiv.) and K3PO4 (10.99 g, 51.8 mmol, 2 equiv.) at 25 °C under N2. The reaction mixture was stirred at 70 °C for 8 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate=1 / 1) to give tert-butyl 2-[[2-fluoro-3-(2-hydroxyphenyl)phenyl]methyl]-3-oxo-piperidine-1-carboxylate (10 g, yield, 87%) as a white solid. LCMS, Method E: (ESI+): m / z 300 (M-100+H). + , RT: 0.82 minutes. Step 3: tert-Butyl 2-[[3-[2-[(E)-3-tert-butoxy-3-oxo-prop-1-enoxy]phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylate [ka]

[0686] To a solution of tert-butyl 2-[[2-fluoro-3-(2-hydroxyphenyl)phenyl]methyl]-3-oxo-piperidine-1-carboxylate (9.5 g, 20.2 mmol, 85% purity, 1 equiv.) and tert-butyl prop-2-ynoate (5.10 g, 40.4 mmol, 5.55 mL, 2 equiv.) in MeCN (95 mL) was added N-methyl-morpholine (1.02 g, 10.11 mmol, 1.11 mL, 0.5 equiv.) at 25° C. under N2. The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched by the addition of water (200 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl 2-[[3-[2-[(E)-3-tert-butoxy-3-oxo-prop-1-enoxy]phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylate (9 g, yield, 76%) as a white solid. LCMS, Method E: (ESI+): m / z 370 (M-155). + (M-Boc-tBu) + , RT: 0.95 minutes. Step 4: tert-Butyl 2-[[3-[2-(3-tert-butoxy-3-oxo-propoxy)phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylate [ka]

[0687] To a solution of tert-butyl 2-[[3-[2-[(E)-3-tert-butoxy-3-oxo-prop-1-enoxy]phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylate (2.25 g, 4.28 mmol, 1 equiv.) in MeOH (22.5 mL) was added Pd / C (560 mg, 10% on charcoal). The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. Three additional reactions were set up as detailed above. All four reaction mixtures were combined. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give tert-butyl 2-[[3-[2-(3-tert-butoxy-3-oxo-propoxy)phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylate (5.5 g, yield, 55%) as a white solid. LCMS, Method E: (ESI+): m / z 372 (M-Boc-t-Bu) + , RT: 0.88 minutes. Step 5: 3-[2-[2-fluoro-3-[(3-oxo-2-piperidyl)methyl]phenyl]phenoxy]propanoic acid [ka]

[0688] A solution of tert-butyl 2-[[3-[2-(3-tert-butoxy-3-oxo-propoxy)phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylate (5.5 g, 10.42 mmol, 1 equiv.) in 2N HCl / dioxane (55 mL) was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give 3-[2-[2-fluoro-3-[(3-oxo-2-piperidyl)methyl]phenyl]phenoxy]propanoic acid (5 g, yield, 100%) as a white solid, which was used in the next step without further purification. LCMS, Method E: (ESI+): m / z 404 (M+H). + , RT: 0.57 minutes. Step 6:2 2 -Fluoro-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 ,5-dione [ka]

[0689] To a solution of 3-[2-[2-fluoro-3-[(3-oxo-2-piperidyl)methyl]phenyl]phenoxy]propanoic acid (5 g, 13.5 mmol, 1 equiv.) in dichloromethane (5 L) was added 2-chloro-1,3-dimethyl-4,5-dihydroimidazol-1-ium chloride (3.41 g, 20.2 mmol, 1.5 equiv.) and DIEA (5.2 g, 40.4 mmol, 7.0 mL, 3 equiv.). The mixture was stirred at 25° C. for 12 hours. LCMS showed that all of the starting material had been consumed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give 2 2 -Fluoro-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 The 5-dione (2.8 g, yield, 53%) was obtained as a white solid. LCMS, Method E: (ESI+): m / z 354 (M+H) + , RT:0.70min Step 7: (4 2 S,4 3 S)-4 3 -amino-2 2 -Fluoro-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphan-5-one cis racemic [ka]

[0690] 2 in MeOH (20 mL) 2-Fluoro-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 To a solution of 2,5-dione (200 mg, 570 μmol, 1 equiv.), ammonium formate (107 mg, 1.70 mmol, 3 equiv.) and bis[2-(2-pyridyl)phenyl]iridium(1+); 2-(2-pyridyl)pyridine hexafluorophosphate (7.15 mg, 8.5 μmol, 0.015 equiv.) were added. The mixture was stirred at 80 °C for 12 h under a N atmosphere. The reaction mixture was directly purified by preparative HPLC (Column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; Mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 25%-45%, 8 min) to give (4 2 S,4 3 S)-4 3 -amino-2 2 180 mg (63%) of racemic cis-fluoro-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphan-5-one was obtained as a white solid. LCMS, Method F: (ESI+): m / z 355 (M+H). + , RT: 1.54 minutes. Step 8: N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 -yl)propane-2-sulfonamide cis racemic [ka]

[0691] (4 in acetonitrile (1.8 mL) 2 S,4 3 S)-4 3 -amino-2 2To a solution of cis-fluoro-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphan-5-one racemic (180 mg, 510 μmol, 1 equiv.) and DBU (155 mg, 1.02 mmol, 153 μL, 2 equiv.) was added propane-2-sulfonyl chloride (130 mg, 914 μmol, 102 μL, 1.8 equiv.) at 0°C. The mixture was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; Mobile phase: [water(NH4HCO3)-acetonitrile]; B%: 20% to 50%, 8 min) to give N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 100 mg (43% yield) of cis-racemic (-yl)propane-2-sulfonamide was obtained as a white solid. LCMS, Method E: (ESI+): m / z 461 (M+H) + , RT: 0.71 minutes. Step 9: N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 -yl)propane-2-sulfonamide [ka]

[0692] N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3180 mg of N-((4-yl)propane-2-sulfonamide cis racemate) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3 / ETOH in H2O]; B%: 40% to 40%, 13 min) to obtain N-((4-yl)propane-2-sulfonamide cis racemate). 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 -yl)propane-2-sulfonamide (15 mg, yield, 6.4%) was obtained as a white solid. Example 4 Procedure for the preparation of Example 4 Step 1: tert-Butyl 6-(3-bromo-2-fluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate [ka]

[0693] Tetrahydrofuran (1.4 L) was charged to a reactor under nitrogen, and LiHMDS (4.0 L, 1 M in THF, 1.2 equiv.) was added. The reaction mixture was cooled to -70°C to -65°C. A solution of tert-butyl 7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (700 g, 1.0 equiv.) in THF (1.4 L) was added dropwise to the reactor at -70°C to -65°C and stirred for 3 hours. EtZn (3.3 L, 1 M in toluene, 1.0 equiv.) was then added dropwise to the reactor at -70°C to -65°C, followed by the dropwise addition of DMPU (552 g, 1.3 equiv.) to the reactor at -70°C to -65°C. A solution of 1-bromo-3-(bromomethyl)-2-fluorobenzene (977 g, 1.1 equiv.) in THF (1.4 L) was then added dropwise to the reactor and stirred at -70 to -65 °C for at least 3 hours. The reaction mixture was then poured into ice water (1.5 kg) at 0 °C and extracted twice with ethyl acetate (14 L). The organic phases were separated and combined, washed twice with brine (3.5 L), and then dried over Na SO (500 g) and filtered. The organic phase was concentrated under vacuum to give the crude product, which was purified by column chromatography (SiO, eluting with petroleum ether:ethyl acetate = 1:0 to 13:1) to give the title compound (969 g, 91.7% yield) as a white solid. LCMS (Method O) (ESI+): m / z 341.9 (M+H-55). + , RT: 1.97 minutes. Step 2: tert-Butyl (E / Z)-6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)imino)-5-azaspiro[2.4]heptane-5-carboxylate [ka]

[0694] To a solution of tert-butyl 6-(3-bromo-2-fluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate (100 g, 1.0 equiv.) in toluene (2.4 L) was added Ti(OEt)4 (171.8 g, 3 equiv.) and (R)-2-methylpropane-2-sulfinamide (70 g, 2.3 equiv.). The mixture was heated to 110 °C and refluxed for 3–4 h. A total of 10 batches were set up, combined, cooled to 15–25 °C, and poured into ice water (1.5 kg) at 0 °C. The resulting white solid precipitate was filtered. The filtrate was extracted with ethyl acetate (3 L) and washed twice with brine (1 L). The organic phase was dried over NaSO (500 g) and concentrated to give the crude product, which was purified by column chromatography (SiO, eluting with petroleum ether:ethyl acetate = 100:1 to 5:1) to give the title compound (954 g, 75.8% yield) as a yellow oil. LCMS (Method O) (ESI+): m / z 445.1 (M+H-56). + , RT=2.18 and 2.24. Step 3: tert-Butyl (6S,7S)-6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate [ka]

[0695] A solution of tert-butyl (E / Z)-6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)imino)-5-azaspiro[2.4]heptane-5-carboxylate (150 g, 1.0 equiv.) in THF (1.5 L, 10 V) and HO (30 mL, 0.2 V) was cooled to -50 °C. NaBH (17 g, 1.5 equiv.) was added to the reactor at -50 °C under nitrogen. The mixture was stirred at 25 ± 5 °C for at least 2 h. MeOH (0.9 L) was added to the reactor at 25-40 °C and stirred at 25 ± 5 °C for at least 3 h. Seven other reactions were set up as above, combined, and concentrated under vacuum at 45 °C. The residue was purified by column chromatography (SiO2, eluting with petroleum ether:ethyl acetate = 10:1 to 1:1) to give the crude product, which was triturated with petroleum ether / ethyl acetate = 8 / 1 (6V) for 8 hours to give the desired compound (318 g, 30.1% yield) as a white solid. LCMS (Method O) (ESI+): m / z 447.1 (M+H-56). + ,RT=2.03. Step 4: tert-Butyl (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylate [ka]

[0696] A solution of tert-butyl (6S,7S)-6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate (110 g, 1.0 equiv.) in MeOH (2.2 L) was cooled to 0 °C. Acetyl chloride (18.9 g, 1.1 equiv.) was then added dropwise and stirred under nitrogen at 25 + 5 °C for at least 18 h. A total of three batches were set up, combined, and transferred to saturated NaHCO3 solution (2.2 L) at 0-5 °C. The pH was maintained between 7 and 8, brine (1.1 L) was added, and the product was extracted twice with ethyl acetate (2.2 L). The organic phases were separated, combined, and dried over Na2SO4 (300 g). The organic phase was concentrated under vacuum below 45°C to give a residue which was triturated with 1 L of 10:1 petroleum ether:ethyl acetate for 8 hours. The precipitate was collected and dried under vacuum at <40°C for 8 hours to give the title compound (178 g, 68.2% yield) as a yellow solid.

[0697] 1 H NMR (400 MHz, methanol-d4) δ 0.39-0.68 (m, 3H), 0.88-1.02 (m, 1H), 1.07-1.33 (m, 9H), 2.96-3.09 (m, 1H), 3.13 (m, 2H), 3.44-3.72 (m, 2H), 4.26 (ddd, 1H), 6.94-7.06 (m, 1H), 7.17 (br t, 1H), 7.48 (br t, 1H). Step 5: tert-Butyl (6S,7S)-7-amino-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylate [ka]

[0698] To a solution of tert-butyl (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylate (900 mg, 2.25 mmol, 1 equiv.) in THF (8 mL) and HO (2 mL), KPO (960 mg, 4.51 mmol, 2 equiv.), Cpd 1A (1.28 g, 3.38 mmol, 1.5 equiv.), and cataCXium A-Pd-G (151 mg, 225 μmol, 0.1 equiv.) were added under N under N, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was then poured into water (20 mL), and the mixture was extracted with ethyl acetate (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue (2.5 g). The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give tert-butyl (6S,7S)-7-amino-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylate (1.2 g, 89% yield) as a yellow oil. LCMS, Method E. (ESI+): m / z 570.3 (M+H) + , RT:0.746 minutes. Step 6: tert-Butyl (6S,7S)-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-7-(difluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate [ka]

[0699] To a solution of tert-butyl (6S,7S)-7-amino-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylate (1.39 g, 2.44 mmol, 1 equiv.) in acetonitrile (14 mL) was added pyridine (3.87 g, 48.9 mmol, 3.94 mL, 20 equiv.), followed by difluoromethanesulfonyl chloride (551.75 mg, 3.67 mmol, 1.5 equiv.) at 0° C., and the mixture was then heated and stirred at 60° C. for 12 hours. The reaction mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (15 mL). The aqueous phase was extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue (3 g). The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give tert-butyl (6S,7S)-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-7-(difluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (700 mg, 41% yield) as a colorless oil. LCMS, Method E: (ESI+): m / z 584.3 (M-100). + , RT: 0.922 minutes. Step 7: 1,1-Difluoro-N-[(6S,7S)-6-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-5-azaspiro[2.4]heptan-7-yl]methanesulfonamide [ka]

[0700] A solution of tert-butyl (6S,7S)-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-7-(difluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate (558 mg, 816 μmol, 1 equiv.) in HCl / dioxane (30 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give 1,1-difluoro-N-[(6S,7S)-6-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-5-azaspiro[2.4]heptan-7-yl]methanesulfonamide (380 mg, 96% yield) as a white solid, which was used directly without any purification. LCMS, Method E: (ESI+): m / z 484.2(M+H) + , RT:0.590 minutes. Step 8: 1,1-Difluoro-N-((2'S,3'S)-2'-fluoro-6'-methyl-5'-oxospiro[cyclopropane-1,4'-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane]-3'-yl)methanesulfonamide [ka]

[0701] To a solution of 1,1-difluoro-N-[(6S,7S)-6-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-5-azaspiro[2.4]heptan-7-yl]methanesulfonamide (213 mg, 440 μmol, 1 eq.) in dichloromethane (2.2 L), TEA (223 mg, 2.20 mmol, 306 μL, 5 eq.) was added, and a solution of triphosgene (78 mg, 264 μmol, 0.6 eq.) in dichloromethane (1 mL) was added dropwise to the above mixture. The mixture was then stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Acetonitrile (2.2 mL) and K2CO3 (243 mg, 1.76 mmol, 4 eq.) were added to the mixture, and the mixture was then stirred at 60° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 35% to 65%, 8 min) to give 1,1-difluoro-N-((2'S,3'S)-2'-fluoro-6'-methyl-5'-oxospiro[cyclopropane-1,4'-9-oxa-6-aza-4(2,1)-pyrrolizina-1(1,2),2(1,3)-dibenzenacyclononaphane]-3'-yl)methanesulfonamide (66 mg, 16% yield) as a white solid. Table A: Experimental details for Examples 1-41

[0702] The compounds in Table A were synthesized according to the methods described above using the appropriate starting materials. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] [Table A-8] [Table A-9] [Table A-10] [Table A-11] [Table A-12] Example 41 Compound 125, 1-fluoro-N-((4 2 S,4 3 R,4 4 S)-1 3 ,1 5 ,2 2 ,4 4 -Tetrafluoro-5-oxo-8-oxa-4(2,1)-piperidina-1(1,2),2(1,3)-dibenzenacyclooctaphane-4 3 Synthesis of (-yl)methanesulfonamide. [ka] Synthesis of Intermediate 2, Benzyl (2S,3R,4S)-2-[(3-bromo-2-fluoro-phenyl)methyl]-4-fluoro-3-(fluoromethylsulfonylamino)piperidine-1-carboxylate [ka]

[0703] A solution of benzyl (2S,3R,4S)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (1) (5.2 g, 11.8 mmol, 1 equiv.) and 1-methylimidazole (2.92 g, 35.5 mmol, 2.83 mL, 3 equiv.) in tetrahydrofuran (20 mL) was degassed and purged with nitrogen at 20 °C. Fluoromethanesulfonyl chloride (2.35 g, 17.8 mmol, 1.5 equiv.) was dissolved in tetrahydrofuran (6 mL) and added dropwise at 0 °C, and the mixture was stirred at 0–25 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether: tert-butyl methyl ether (10:1, 20 mL). The resulting solid was collected by filtration, washed with petroleum ether: tert-butyl methyl ether (10:1, 5 mL), and dried under high vacuum to give benzyl (2S,3R,4S)-2-[(3-bromo-2-fluorophenyl)methyl]-4-fluoro-3-(fluoromethylsulfonylamino)piperidine-1-carboxylate (5.3 g, 84% yield) as a yellow solid. 1 H NMR: (400 MHz, DMSO-d6) δ ppm 1.75-2.05 (m, 2 H), 2.90-3.05 (br t, 1 H), 3.30 (m, 2 H), 3.65-4.00 (br m, 2 H), 4.40-4.06 (br m, 2 H), 4.80 - 5.05 (m, 2 H), 5.20-5.60 (m, 2 H), 6.80-7.15 (m, 3 H), 7.15-7.40 (m, 4 H), 7.50 (br t, 1 H), 8.65 (br s, 1 H) Synthesis of Intermediate 3, Benzyl (2S,3R,4S)-4-fluoro-3-(fluoromethylsulfonylamino)-2-[[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperidine-1-carboxylate [ka]

[0704] To a solution of intermediate 2 (5.3 g, 9.90 mmol, 1 equiv) in dioxane (53 mL) was added bispinacolatodiborane (7.54 g, 29.7 mmol, 3 equiv), potassium acetate (4.86 g, 49.5 mmol, 5 equiv), and Pd(dppf)Cl (362 mg, 495 μmol, 0.05 equiv) at 25 °C. The mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. The reaction was filtered, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate (100:1 to 1:100) to give benzyl (2S,3R,4S)-4-fluoro-3-(fluoromethylsulfonylamino)-2-[[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperidine-1-carboxylate (Intermediate 3, 5.1 g, 87% yield) as a yellow solid. LCMS, method G (ESI+): m / z 501 (M-81) + , RT: 6.436 min, m / z 583 (M + H) + , RT:8.821 minutes Synthesis of Intermediate 4, Benzyl (2S,3R,4S)-2-[[3-[2-(3-tert-butoxy-3-oxo-propoxy)-3,5-difluoro-phenyl]-2-fluoro-phenyl]methyl]-4-fluoro-3-(fluoromethylsulfonylamino)piperidine-1-carboxylate [ka]

[0705] A mixture of tert-butyl 3-(2-bromo-4,6-difluorophenoxy)propanoate (1.81 g, 5.37 mmol, 1.25 equiv.), Intermediate 3 (2.5 g, 4.29 mmol, 1 equiv.), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (140 mg, 215 μmol, 0.05 equiv.) and NaCO (2.27 g, 21.5 mmol, 5 equiv.) in dioxane (23 mL) and water (1.92 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 85° C. for 2 hours. The reaction mixture was quenched at 20° C. by the addition of water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (trifluoroacetic acid conditions, column: Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: B 40% to 70% over 8 min) to give benzyl (2S,3R,4S)-2-[[3-[2-(3-tert-butoxy-3-oxo-propoxy)-3,5-difluoro-phenyl]-2-fluoro-phenyl]methyl]-4-fluoro-3-(fluoromethylsulfonylamino)piperidine-1-carboxylate (Intermediate 4, 1.53 g, 50% yield) as a white solid. LCMS Method H: (ESI+): m / z 730 (M+18) + , RT:3.618 minutes Synthesis of Intermediate 5, 3-[2-[3-[[(2S,3R,4S)-1-benzyloxycarbonyl-4-fluoro-3-(fluoromethylsulfonylamino)-2-piperidyl]methyl]-2-fluoro-phenyl]-4,6-difluoro-phenoxy]propanoic acid [ka]

[0706] A solution of intermediate 4 (1.53 g, 2.15 mmol, 1 equiv) in hydrochloric acid (15 mL, 4 M solution in dioxane) was stirred for 2 hours at 25° C. The reaction was concen...

Claims

1. Compounds of formula (III): 【Chemistry 173】 or a pharmaceutically acceptable salt thereof [In the formula, X is -N(C １ ~C ６ alkyl)-, -N(C １ ~C ６ haloalkyl)-, or C １ ~C ６ is alkyl; L is absent or C １ ~C ６ is alkyl; Y is —O—; n is 1 or 2; R ａ is H or halogen; R ｂ is H, halogen, or C １ ~C ６ Is alkyl; or R ａ and R ｂ together with the atoms to which they are attached, C ３ forming a cycloalkyl; Z is —NH—; R １ is a halogen-substituted C ３ is cycloalkyl; Ar １ is a C optionally substituted with one or more halogens ６ ~C １０ is aryl; T is one or more halogens or C １ ~C ６ C optionally substituted with alkyl ６ ~C １０ is aryl, provided that when X is alkyl, then L is absent.

2. X is -N(C １ ~C ６ haloalkyl)- or C １ ~C ６ The compound of claim 1 , wherein the aryl group is alkyl.

3. The compound of claim 1 , wherein L is absent.

4. 2. The compound of claim 1, wherein n is 1.

5. 2. The compound of claim 1, wherein n is 2.

6. R ａ The compound of claim 1 , wherein is H.

7. R ａ The compound of claim 1 , wherein is a halogen.

8. R ｂ The compound of claim 1 , wherein is H or a halogen.

9. Ar １ 2. The compound of claim 1, wherein is phenyl optionally substituted with one or more halogens and T is phenyl optionally substituted with one or more halogens.

10. The compound is 【Chemistry 186】 10. The compound of claim 1, selected from:

11. The compound of claim 1 【Chemistry 187】 10. The compound of claim 1, which is:

12. The compound of claim 1, 【Chemical 188】 10. The compound of claim 1, which is:

13. The compound of claim 12, 【Chemical 189】 10. The compound of claim 1, which is:

14. The compound of claim 1, 【Chemistry 190】 10. The compound of claim 1, which is:

15. The compound of claim 1, 【Chemistry 191】 10. The compound of claim 1, which is:

16. The compound of claim 1, 【Chemistry 192】 10. The compound of claim 1, which is:

17. The compound of claim 1 【Chemistry 193】 10. The compound of claim 1, which is:

18. The compound of claim 17, 【Chemistry 194】 10. The compound of claim 1, which is:

19. The compound of claim 1 【Chemistry 195】 10. The compound of claim 1, which is:

20. The compound of claim 1, 【Chemistry 196】 10. The compound of claim 1, which is:

21. The compound of claim 1, 【Chemistry 197】 10. The compound of claim 1, which is:

22. The compound of claim 1, 【Chemistry 198】 10. The compound of claim 1, which is:

23. The compound of claim 1, 【Chemistry 199】 10. The compound of claim 1, which is:

24. The compound of claim 1, 【Chemistry 200】 10. The compound of claim 1, which is:

25. The compound of claim 1, 【Chemical Engineering 201】 10. The compound of claim 1, which is:

26. A pharmaceutical composition comprising the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

27. 27. The pharmaceutical composition of claim 26 for use in treating or preventing a disease or disorder.

28. 28. The pharmaceutical composition for use according to claim 27, wherein the disease or disorder is associated with the implicated orexin-2 receptor.

29. 28. The pharmaceutical composition for use according to claim 27, wherein the disease or disorder is narcolepsy, hypersomnia, 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 promoting emergence from anesthesia.

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