Middle or macrocyclic benzyl substituted heterocyclic derivatives and related uses

Abstract

# imgabs0. The disclosure relates to compounds of Formula (I ') and prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation thereof. The compounds disclosed herein are useful for modulating orexin-2 receptor activity, and can be used to treat disorders in which orexin-2 receptor activity is involved, the pharmaceutical composition can be used for treating or preventing symptoms such as narcolepsy, hyperactivity disorder, neurodegenerative disorder, rare hereditary disorder, psychological health disorder, metabolic syndrome, osteoporosis, heart failure, coma or to promote waking from anesthesia.

Description

[0001] Related applications

[0002] 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 Art

[0003] The present disclosure relates to small molecule potent agonists of the orexin-2 receptor (OX2R) designed to treat narcolepsy and other disorders associated with orexin deficiency and / or excessive sleepiness. Narcolepsy afflicts 1 in 2,000 people worldwide. Onset can occur during adolescence, persist throughout life, and have a debilitating impact on quality of life. Narcolepsy type 1 (NT1) is caused by the loss of neurons in the brain that produce the orexin neuropeptide. There is no known cure, and currently approved treatments are symptomatic. Therefore, developing drug therapies to restore lost orexin signaling is crucial to treating the root cause of NT1.

[0004] In narcolepsy type 1 (NT1), the only population of neurons that produces orexin A and B (also known as hypocretin-1 and 2) peptides is destroyed by an immune mechanism that causes dysfunction at the boundary between wake states. Mouse models of narcolepsy type 1 reproduce the loss of orexin neurons and two major symptoms observed in NT1 patients, specifically, excessive daytime sleepiness and cataplexy. Common symptoms of narcolepsy type 1 and type 2 can include excessive daytime sleepiness, disrupted nocturnal sleep, and inappropriately timed rapid eye movement (REM) sleep, as well as sleep paralysis and half-awake / half-asleep hallucinations. Cataplexy is the sudden, reversible loss of muscle tone (atonia of REM sleep) that intrudes into the wakeful state in response to emotional stimuli and is a characteristic of NT1.

[0005] Two cardinal symptoms of narcolepsy type 1 (excessive daytime sleepiness and cataplexy) can be reduced by reactivating orexin neurotransmission at the OX2R in a mouse model. Reversal of cataplexy-like events and sleep / wake splitting has been achieved in mice by genetically focally restoring OX2R signaling in the dorsal raphe nucleus of the pons and the tuberomammillary nucleus of the hypothalamus, respectively (otherwise lacking orexin receptors in those regions). Intracerebroventricular (ICV) administration of orexin A (OXA) has been shown to increase wakefulness and reduce cataplexy-like behavior in orexin-neuron-ablated mice. The selective OX2R agonist YNT-185, administered intraperitoneally or ICV, modestly increased wakefulness in wild-type (WT) and orexin ligand-deficient mice and reduced sleep onset REM stage and cataplexy-like events in the NT1 mouse model. Subcutaneous administration of the selective OX2R agonist TAK-925 modestly increased wakefulness in WT mice, but not in OX2R-knockout mice. Brain-penetrant and stable OX2R agonists would provide improvements to current treatments for NT1 patients that are bioavailable after alternative routes of administration (including but not limited to oral, intranasal, transmucosal, and transdermal) and bind with high affinity to potently excite neurons that regulate arousal states. Indeed, preliminary clinical studies reported on TAK-925 showed a trend toward significantly increased arousal levels and reduced cataplexy in NT1 individuals. Activation of OX1R is associated with mood regulation and reward behavior and may also contribute to arousal.

[0006] Orexin receptor agonists can also be used for other indications marked by some degree of orexin neurodegeneration and excessive daytime sleepiness, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and traumatic brain injury. Because stimulation of OX2R promotes wakefulness in orexin-intact animals, orexin receptor agonists can treat excessive daytime sleepiness in patients with normal orexin levels, including narcolepsy type 2, idiopathic hypersomnia, or sleep apnea. Similarly, orexin receptor agonists can provide benefits in promoting wakefulness in disorders of recurrent hypersomnia (such as Klein-Levin syndrome) or inappropriately timed sleep (i.e., circadian rhythm sleep disorders) (such as delayed or advanced sleep phase disorders, shift work disorder, and jet lag disorder). Abnormal daytime sleepiness, REM sleep onset, and cataplexy-like symptoms in rare genetic disorders (e.g., ADCA-DN, Coffin-Lowry syndrome, Moebius syndrome, Norrie disease, Niemann-Pick disease type C, and Prader-Willi syndrome) can be alleviated with orexin receptor agonists. Other indications where orexin receptor agonists are thought to be of benefit include attention deficit hyperactivity disorder, age-related cognitive impairment, metabolic syndrome and obesity, osteoporosis, heart failure, coma, and emergence from anesthesia.

[0007] The present disclosure arises from the need to provide additional compounds with improved therapeutic potential for modulating orexin receptor activity in the brain, including activation of the orexin-2 receptor. In particular, compounds with improved physicochemical, pharmacological, and pharmaceutical properties compared to existing compounds are desired. Summary of the Invention

[0008] In some aspects, the present disclosure provides a compound of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] X is -N(CH3)- or C1-C6 alkyl;

[0012] L is absent or is a C1-C6 alkyl group;

[0013] Y is -O-;

[0014] n is 1 or 2;

[0015] R a is H or halogen;

[0016] R b is H, halogen or C1-C6 alkyl;

[0017] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0018] Z is -NH-;

[0019] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0020] Ar1 is C6-C 10 aryl; and

[0021] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0022] Provided that when X is alkyl, L is absent.

[0023] In some aspects, the present disclosure provides a compound of formula (I'):

[0024]

[0025] or a pharmaceutically acceptable salt thereof, wherein:

[0026] X is -N(CH3)- or C2-C6 alkyl;

[0027] L is absent or is a C2-C6 alkyl group;

[0028] Y is -O-;

[0029] n is 1 or 2;

[0030] R a is H or halogen;

[0031] R b is H, halogen or C1-C6 alkyl;

[0032] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0033] Z is -NH-;

[0034] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0035] Ar1 is C6-C 10 aryl; and

[0036] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0037] Provided that when X is alkyl, L is absent.

[0038] In some aspects, the present disclosure provides a compound of formula (I"):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein:

[0041] X is -N(CH3)- or C1-C6 alkyl;

[0042] L is absent or is a C1-C6 alkyl group;

[0043] Y is -O-;

[0044] n is 1 or 2;

[0045] R a is H or halogen;

[0046] R b is H, halogen or C1-C6 alkyl;

[0047] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0048] Z is -NH-;

[0049] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[0050] Ar1 is C6-C 10 aryl; and

[0051] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0052] Provided that when X is alkyl, L is absent.

[0053] In some aspects, the present disclosure provides a compound of formula (I'"):

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein:

[0056] X is -N(CH3)- or C2-C6 alkyl;

[0057] L is absent or is a C2-C6 alkyl group;

[0058] Y is -O-;

[0059] n is 1 or 2;

[0060] R a is H or halogen;

[0061] R b is H, halogen or C1-C6 alkyl;

[0062] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0063] Z is -NH-;

[0064] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[0065] Ar1 is C6-C 10 aryl; and

[0066] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0067] Provided that when X is alkyl, L is absent.

[0068] In some aspects, the present disclosure provides a compound of formula (II):

[0069]

[0070] or a pharmaceutically acceptable salt thereof, wherein:

[0071] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0072] L is absent or is a C1-C6 alkyl group;

[0073] Y is -O-;

[0074] n is 1 or 2;

[0075] R a is H or halogen;

[0076] R b is H, halogen or C1-C6 alkyl;

[0077] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0078] Z is -NH-;

[0079] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[0080] Ar1 is C6-C 10 aryl; and

[0081] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0082] Provided that when X is alkyl, L is absent.

[0083] In some aspects, the present disclosure provides a compound of formula (II'):

[0084]

[0085] or a pharmaceutically acceptable salt thereof, wherein:

[0086] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0087] L is absent or is a C1-C6 alkyl group;

[0088] Y is -O-;

[0089] n is 1 or 2;

[0090] R a is H or halogen;

[0091] R b is H, halogen or C1-C6 alkyl;

[0092] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0093] Z is -NH-;

[0094] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0095] Ar1 is C6-C 10 aryl; and

[0096] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0097] Provided that when X is alkyl, L is absent.

[0098] In some aspects, the present disclosure provides a compound of formula (III):

[0099]

[0100] or a pharmaceutically acceptable salt thereof, wherein:

[0101] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0102] L is absent or is a C1-C6 alkyl group;

[0103] Y is -O-;

[0104] n is 1 or 2;

[0105] R a is H or halogen;

[0106] R b is H, halogen or C1-C6 alkyl;

[0107] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0108] Z is -NH-;

[0109] R1 is C1-C6 haloalkyl, C1-C6 alkyl or C3 cycloalkyl substituted by halogen;

[0110] Ar1 is C6-C 10 aryl; and

[0111] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0112] Provided that when X is alkyl, L is absent.

[0113] In some aspects, the present disclosure provides a compound of formula (III'):

[0114]

[0115] or a pharmaceutically acceptable salt thereof, wherein:

[0116] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0117] L is absent or is a C1-C6 alkyl group;

[0118] Y is -O-;

[0119] n is 1 or 2;

[0120] R a is H or halogen;

[0121] R b is H, halogen or C1-C6 alkyl;

[0122] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0123] Z is -NH-;

[0124] R1 is C1-C6 haloalkyl, C2-C6 alkyl or C3 cycloalkyl substituted by halogen;

[0125] Ar1 is C6-C 10 aryl; and

[0126] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0127] Provided that when X is alkyl, L is absent.

[0128] In some aspects, the disclosure provides a compound obtainable or obtained by a method for preparing a compound as described herein (eg, a method comprising one or more steps described in Schemes 1-9).

[0129] 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.

[0130] In some aspects, the disclosure provides an intermediate as described herein, which is suitable for use in a method for preparing a compound as described herein (eg, the intermediate is selected from the intermediates described in Examples 1-50).

[0131] In some aspects, the present disclosure provides a method of modulating orexin-2 receptor activity (eg, 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.

[0132] 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, or a pharmaceutical composition of the present disclosure.

[0133] 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.

[0134] 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 (eg, in vitro or in vivo).

[0135] 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.

[0136] 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.

[0137] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for modulating orexin-2 receptor activity (eg, in vitro or in vivo).

[0138] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or disorder disclosed herein.

[0139] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or disorder disclosed herein.

[0140] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0141] In some aspects, the present disclosure provides a method of preparing a compound comprising one or more of the steps described herein.

[0142] Unless otherwise defined, all technical and scientific terms used in this article have the same meaning as those generally understood by those of ordinary skill in the art to which this disclosure belongs. In this specification, the singular also includes the plural, unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used for the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. It is not recognized that the references cited herein are prior art of the claimed invention. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are merely illustrative and are not intended to be restrictive. In the event of a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure shall prevail.

[0143] Other features and advantages of the disclosure will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0144] 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 treating the human or animal body. The present disclosure also relates to methods for preparing these compounds, pharmaceutical compositions containing them, and their use in treating disorders in which the orexin-2 receptor is involved, such as narcolepsy, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or emergence from anesthesia.

[0145] definition

[0146] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set forth below.

[0147] Without wishing to be limited by this statement, it should be understood that although various options for variables are described herein, the present disclosure is intended to encompass operable embodiments having combinations of options. The present disclosure can 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 present disclosure can be interpreted to exclude structures of inoperable compounds resulting from certain combinations of variables X, L, and Y (e.g., when each of X, L, and Y is -O-).

[0148] 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-chain 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 groups include moieties having 1-6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, a straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., C1-C6 for a straight chain, C3-C6 for a branched chain), and in another embodiment, a straight-chain or branched alkyl group has four or fewer carbon atoms.

[0149] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl group or an alkyl group 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, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0150] As used herein, the term "alkenyl" is included in terms of length and possible substitution similar to the above-mentioned alkyl, but contains an unsaturated aliphatic group of at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl. In certain embodiments, straight or branched alkenyl has six or less carbon atoms (e.g., C2-C6 for straight chain, C3-C6 for branched chain) in its backbone. The term "C2-C6" includes alkenyl containing 2-6 carbon atoms. The term "C3-C6" includes alkenyl containing 3-6 carbon atoms.

[0151] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or 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, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate ion, phosphinate ion, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate ion, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclic, alkylaryl or aromatic or heteroaromatic moieties.

[0152] As used herein, the term "alkynyl" is included in unsaturated aliphatic groups similar to the above-mentioned alkyl groups in terms of length and possible substitution, but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched chain alkynyl. In certain embodiments, straight or branched chain alkynyl has six or less 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 2-6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3-6 carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5 or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0153] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl groups or alkynyl groups 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, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl or an aromatic or heteroaromatic moiety.

[0154] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl groups include 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.

[0155] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 、C3-C 10The saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused ring, bridged ring, or spirocyclic) system of C-C (C or C-C). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cycloalkyls, only one ring in the cycloalkyl needs to be non-aromatic.

[0156] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms (such as O, N, S, P or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5 or 6 heteroatoms, unless otherwise specified, the heteroatoms being independently selected from nitrogen, oxygen and sulfur. Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa- 5-Azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1 ,5'-furo[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridinyl]-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]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thienyl, etc. In the case of polycyclic heterocycloalkyl groups, only one ring in the heterocycloalkyl group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0157] It should be understood that when a variable has two connections to the rest of the formula of a compound, the two connections can be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is a cycloalkyl or heterocycloalkyl group and has two connections to the rest of the formula of the compound, the two connections can be at the same atom or different atoms of the cycloalkyl or heterocycloalkyl group.

[0158] As used herein, the term "aryl" includes groups having aromatic properties, including "conjugated" or polycyclic ring systems having one or more aromatic rings and not containing any heteroatoms in the ring structure. The term aryl includes monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like.

[0159] As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles consisting of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)). p , wherein p = 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. The heteroaryl group can also be fused or bridged with a non-aromatic alicyclic or heterocyclic ring to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl group is thienyl or benzothienyl. In some embodiments, the heteroaryl group is thienyl. In some embodiments, the heteroaryl group is benzothienyl.

[0160] In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, for example, tricyclic, bicyclic, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0161] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring can be substituted at one or more ring positions (e.g., a ring-forming carbon or heteroatom such as N) with substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkyl The alkylthiocarbonyl group, phosphate ester, phosphonate ion group, phosphinate ion group, amino group (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino group (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino group, imino group, sulfhydryl group, alkylthio group, arylthio group, thiocarboxylate, sulfate ester, alkylsulfinyl group, sulfonate ion group, sulfamoyl group, sulfonamido group, nitro group, trifluoromethyl group, cyano group, azido group, heterocyclic group, alkylaryl group, or aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form a polycyclic system (for example, tetralin, methylenedioxyphenyl such as benzo [d] [1,3] dioxol-5-yl).

[0162] As used herein, the term "substituted" refers to any one or more hydrogen atoms on a designated atom being replaced by an option in a designated group, provided that the normal valence of the designated atom is not exceeded and that the substitution produces a stable compound. When the substituent is an oxo or keto group (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are intended to mean a compound that is robust enough to withstand isolation from a reaction mixture to a useful purity and to be formulated into an effective therapeutic agent.

[0163] 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 via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0164] When any variable (e.g., R) occurs more than one time in any component 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 0-2 R moieties, then that group can be optionally substituted with up to two R moieties, and R at each occurrence is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0165] As used herein, the term "hydroxy" or "hydroxyl" includes a group having -OH or -O - group.

[0166] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0167] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0168] As used herein, the term "optionally substituted haloalkyl" refers to unsubstituted haloalkyl or 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, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl or an aromatic or heteroaromatic moiety.

[0169] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently attached to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate ion, phosphinate ion, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate ion, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0170] As used herein, the expressions "one or more of A, B, or C," "one or more A, B, or C," "one or more of A, B, and C," "one or more A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," etc. are used interchangeably and all refer to options in the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

[0171] It should be understood that the present disclosure provides methods for synthesizing compounds of any formula described herein.The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to the following schemes and those shown in the examples.

[0172] It should be understood that throughout this specification, where a composition is described as having, including, or comprising a particular component, it is contemplated that the composition also consists essentially of, or consists of, the enumerated components. Similarly, where a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of, or consists of, the enumerated process steps. Further, it should be understood that the order of the steps, the order in which certain actions are performed, is unimportant as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0173] It should be understood that the synthetic methods disclosed herein can tolerate a variety of functional groups and therefore can use a variety of substituted starting materials. The methods generally provide the desired final compound at or near the end of the overall method, although it may be desirable to further convert the compound into a pharmaceutically acceptable salt thereof in some cases.

[0174] 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 available intermediates by employing standard synthetic methods and procedures that are known to those skilled in the art or that will become apparent to the skilled artisan based on the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd 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) (incorporated herein by reference) are useful and recognized reference textbooks on organic synthesis known to those skilled in the art.

[0175] Those of ordinary skill in the art will note that in reaction sequence as herein described and synthesis scheme, the order of some steps can be changed, such as the introduction and removal of blocking groups. Those of ordinary skill in the art will recognize that some groups may need to be protected from reaction conditions via the use of blocking groups. Blocking groups can also be used to distinguish similar functional groups in molecules. The list of blocking groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0176] It should be understood that, unless otherwise stated, any description of a method of treatment or prevention includes the use of a compound to provide such treatment or prevention, as described herein. It should be further understood that, unless otherwise stated, any description of a method of treatment or prevention includes the use of a compound to prepare a medicament to treat or prevent such a condition. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0177] It should be understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to provide such treatment, as described herein. It should be further understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to prepare a medicament to treat such a condition. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

[0178] 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.

[0179] As used herein, the term "subject in need" refers to an object suffering from a disease or an object with an increased risk of developing a disease. An object in need may be an object that has been diagnosed or identified as having a disease or disorder disclosed herein before. An object in need may also be an object suffering from a disease or disorder disclosed herein. Alternatively, an object in need may be an object with an increased risk of developing such a disease or disorder relative to the general population (i.e., an object that tends to develop such a disorder relative to the general population). An object in need may suffer from a disease or disorder disclosed herein that is refractory or resistant (i.e., a disease or disorder disclosed herein that has not responded or has not yet responded to treatment). An object may have resistance at the start of treatment, or may become resistant during treatment. In some embodiments, an object in need has received all known effective therapies for a disease or disorder disclosed herein and has failed. In some embodiments, an object in need has received at least one previous therapy.

[0180] As used herein, the term "treatment" describes the management and care of a patient in order to combat 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 a disease, condition, or disorder, or to eliminate a disease, condition, or disorder. The term "treatment" may also include the treatment of cells or animal models in vitro. It should be understood that references to "treatment" include the alleviation of existing symptoms of a condition. Thus, "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or condition in a person who may have or be susceptible to the condition, disorder, or condition but has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., preventing, reducing, or delaying the development of the disease, or its recurrence (in the case of maintenance therapy), or at least one of its clinical or subclinical symptoms, or (3) alleviating or relieving the disease, i.e., causing regression of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms.

[0181] It will be appreciated that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may or may also be used to prevent the relevant disease, condition or disorder, or to identify suitable candidates for such purpose.

[0182] As used herein, the terms "prevent," "suppress," or "protect against" describe the reduction or elimination of the onset of symptoms or complications of such a disease, condition, or disorder.

[0183] It should be understood that for detailed descriptions of known or equivalent techniques discussed herein, those skilled in the art can refer to general reference texts. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd 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, 18th Edition (1990). Of course, these texts can also be consulted when making or using an aspect of the present disclosure.

[0184] It will be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0185] As used herein, the term "pharmaceutical composition" is a preparation containing a compound of the present disclosure, which is in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a single pump or bottle on a capsule, IV bag, tablet, or aerosol inhaler. The amount of the active ingredient (e.g., a preparation of a disclosed compound or its salt, hydrate, solvate, or isomer) in the unit dose composition is an effective amount and varies according to the specific treatment involved. It will be understood by those skilled in the art that, depending on the age and condition of the patient, it is sometimes necessary to make conventional changes to the dosage. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of the present 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 desired preservatives, buffers, or propellants.

[0186] As used herein, the term "pharmaceutically acceptable" refers to those 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0187] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in this specification and claims, "pharmaceutically acceptable excipient" includes one and more than one such excipient.

[0188] It should be understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. The example of route of administration includes parenteral, for example, intravenous, intradermal, subcutaneous, oral (for example, ingestion), inhalation, transdermal (topical) and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous application can include the following components: sterile diluents such as water for injection, saline solutions, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and reagents for regulating tonicity such as sodium chloride or dextrose. pH can be adjusted with acid or alkali (such as hydrochloric acid or sodium hydroxide). Parenteral preparations can be placed in ampoules, disposable syringes or multiple dose bottles made of glass or plastic.

[0189] It should be understood that the compounds or pharmaceutical compositions of the present invention can be administered to a subject by many well-known methods currently used for chemotherapeutic treatments. For example, the compounds of the present invention can be injected into the bloodstream or body cavity or administered orally or applied through the skin with a patch. The selected dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The state of the condition (e.g., disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during treatment and within a reasonable period after treatment.

[0190] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that is used to treat, ameliorate, or prevent an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0191] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that is used to treat or ameliorate an identified disease or condition or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0192] It will be appreciated that for any compound, the therapeutically effective amount can be initially assessed in cell culture assays (e.g., culture assays of neoplastic cells) or in animal models (typically rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity, for example, ED, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0193] Dosage and administration are adjusted to provide sufficient active agent levels or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, reaction sensitivity and tolerance / response to therapy. Depending on the half-life and clearance rate of the particular formulation, the long-acting pharmaceutical composition may be administered every 3 to 4 days, weekly or biweekly.

[0194] Pharmaceutical compositions containing the active compounds of the present disclosure can be prepared in a generally known manner (e.g., by conventional mixing, dissolving, granulating, preparing dragees, grinding, emulsifying, encapsulating, embedding, or lyophilizing processes). Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or adjuvants that facilitate processing of the active compounds into pharmaceutically acceptable products. Of course, appropriate formulations depend on the route of administration selected.

[0195] 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 TM(BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that it is easy to inject. It must be stable under preparation and storage conditions and must be preserved from the contaminating effects of microorganisms (such as bacteria and fungi). The carrier can be a solvent or dispersion medium, which contains, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.), cyclodextrin and a suitable mixture thereof. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size (in the case of a dispersion) and by using a surfactant. The prevention of the effect of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents in the composition, for example, sugars, polyols such as mannitol and sorbitol and sodium chloride. The absorption of the injectable composition can be prolonged by including an agent that delays absorption (for example, aluminum monostearate and gelatin) in the composition.

[0196] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound into an appropriate solvent together with one or a combination of ingredients listed above as needed, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof.

[0197] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with excipients and used in the form of tablets, lozenges, capsules, or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and gargled and expectorated or swallowed. Pharmaceutically compatible binders and / or excipients may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavor.

[0198] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0199] Systemic administration can also be through transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants suitable for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be accomplished by using nasal sprays, powders, or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams generally known in the art.

[0200] The active compound can be prepared together with a pharmaceutically acceptable carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, 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 preparations will be apparent to those skilled in the art. Materials can also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies directed 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. Patent No. 4,522,811.

[0201] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0202] In therapeutic applications, in addition to other factors that affect the selected dosage, the dosage of the pharmaceutical composition used according to the present disclosure varies with the age, weight and clinical condition of the patient receiving the treatment, and the experience and judgment of the clinician or practitioner administering the treatment. Generally, the dosage should be sufficient to cause a slowing down and preferably elimination of the symptoms of the disease or disorder disclosed herein, and also preferably to cause complete elimination of the disease or disorder. The dosage can be in the range of about 0.01 mg / kg / day to about 5000 mg / kg / day. The effective amount of the medicament is the amount of objectively identifiable improvement noted by a clinician or other qualified observer. Improved indications of survival and growth disappear. As used herein, the term "dosage effective manner" refers to the amount of the active compound that produces the desired biological effect in an object or cell.

[0203] It will be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0204] It is to be understood that for the compounds of the present disclosure that are capable of further forming salts, all such forms are also contemplated as being within the scope of the claimed disclosure.

[0205] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure wherein the parent compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic organic acid salts of basic residues such as amines, basic organic salts of acidic residues such as carboxylic acids, and the like. 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, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolylaminophenylarsanilic acid, hexylresorcinic ... ydrabamic), hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, hypoacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and common amino acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0206] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzylethylenediamine salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt.

[0207] 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, and the like. 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, an alkaline earth metal ion, or an aluminum ion); or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, it should be understood that the ratio of the compound to the 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.

[0208] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0209] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, inhaled, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

[0210] The dosage regimen using the compound is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and liver function; and the specific compound or salt thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug needed to prevent, counteract, or arrest the progression of the condition. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug needed to counteract or arrest the progression of the condition.

[0211] Techniques for preparing and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are combined with a pharmaceutically acceptable carrier or diluent for use in pharmaceutical preparations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compound will be present in such a pharmaceutical composition in an amount sufficient to provide the desired dosage within the range described herein.

[0212] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure will be apparent from the various examples. The examples provided illustrate the various components and methods for practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, a skilled artisan can identify and employ other components and methods for practicing the present disclosure.

[0213] In the synthetic schemes described herein, compounds may be drawn in a particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0214] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended to admit that any one of them is relevant prior art, nor does it constitute any admission as to their content or date. Having now described the invention by written description, those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and the foregoing description and the following examples are intended to illustrate rather than limit the claims that follow.

[0215] As used herein, the phrase "compounds of the present disclosure" refers to those compounds disclosed both generically and specifically herein.

[0216] Compounds of the present disclosure

[0217] In some aspects, the present disclosure provides compounds of formula (I):

[0218]

[0219] or a pharmaceutically acceptable salt thereof, wherein:

[0220] X is -N(CH3)- or C1-C6 alkyl;

[0221] L is absent or is a C1-C6 alkyl group;

[0222] Y is -O-;

[0223] n is 1 or 2;

[0224] R a is H or halogen;

[0225] R b is H, halogen or C1-C6 alkyl;

[0226] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0227] Z is -NH-;

[0228] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0229] Ar1 is C6-C 10 aryl; and

[0230] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0231] Provided that when X is alkyl, L is absent.

[0232] In some aspects, the present disclosure provides a compound of formula (I'):

[0233]

[0234] or a pharmaceutically acceptable salt thereof, wherein:

[0235] X is -N(CH3)- or C2-C6 alkyl;

[0236] L is absent or is a C2-C6 alkyl group;

[0237] Y is -O-;

[0238] n is 1 or 2;

[0239] R a is H or halogen;

[0240] R b is H, halogen or C1-C6 alkyl;

[0241] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0242] Z is -NH-;

[0243] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0244] Ar1 is C6-C 10 aryl; and

[0245] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0246] Provided that when X is alkyl, L is absent.

[0247] In some aspects, the present disclosure provides a compound of formula (I"):

[0248]

[0249] or a pharmaceutically acceptable salt thereof, wherein:

[0250] X is -N(CH3)- or C1-C6 alkyl;

[0251] L is absent or is a C1-C6 alkyl group;

[0252] Y is -O-;

[0253] n is 1 or 2;

[0254] R a is H or halogen;

[0255] R b is H, halogen or C1-C6 alkyl;

[0256] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0257] Z is -NH-;

[0258] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[0259] Ar1 is C6-C 10 aryl; and

[0260] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0261] Provided that when X is alkyl, L is absent.

[0262] In some aspects, the present disclosure provides a compound of formula (I'"):

[0263]

[0264] or a pharmaceutically acceptable salt thereof, wherein:

[0265] X is -N(CH3)- or C2-C6 alkyl;

[0266] L is absent or is a C2-C6 alkyl group;

[0267] Y is -O-;

[0268] n is 1 or 2;

[0269] R a is H or halogen;

[0270] R b is H, halogen or C1-C6 alkyl;

[0271] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0272] Z is -NH-;

[0273] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[0274] Ar1 is C6-C 10 aryl; and

[0275] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0276] Provided that when X is alkyl, L is absent.

[0277] In some aspects, the present disclosure provides a compound of formula (II):

[0278]

[0279] or a pharmaceutically acceptable salt thereof, wherein:

[0280] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0281] L is absent or is a C1-C6 alkyl group;

[0282] Y is -O-;

[0283] n is 1 or 2;

[0284] R a is H or halogen;

[0285] R b is H, halogen or C1-C6 alkyl;

[0286] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0287] Z is -NH-;

[0288] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[0289] Ar1 is C6-C 10 aryl; and

[0290] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0291] Provided that when X is alkyl, L is absent.

[0292] In some aspects, the present disclosure provides a compound of formula (II'):

[0293]

[0294] or a pharmaceutically acceptable salt thereof, wherein:

[0295] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0296] L is absent or is a C1-C6 alkyl group;

[0297] Y is -O-;

[0298] n is 1 or 2;

[0299] R a is H or halogen;

[0300] R b is H, halogen or C1-C6 alkyl;

[0301] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0302] Z is -NH-;

[0303] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0304] Ar1 is C6-C 10 aryl; and

[0305] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0306] Provided that when X is alkyl, L is absent.

[0307] In some aspects, the present disclosure provides a compound of formula (III):

[0308]

[0309] or a pharmaceutically acceptable salt thereof, wherein:

[0310] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0311] L is absent or is a C1-C6 alkyl group;

[0312] Y is -O-;

[0313] n is 1 or 2;

[0314] R a is H or halogen;

[0315] R b is H, halogen or C1-C6 alkyl;

[0316] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0317] Z is -NH-;

[0318] R1 is C1-C6 haloalkyl, C1-C6 alkyl or C3 cycloalkyl substituted by halogen;

[0319] Ar1 is C6-C 10 aryl; and

[0320] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0321] Provided that when X is alkyl, L is absent.

[0322] In some aspects, the present disclosure provides a compound of formula (III'):

[0323]

[0324] or a pharmaceutically acceptable salt thereof, wherein:

[0325] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0326] L is absent or is a C1-C6 alkyl group;

[0327] Y is -O-;

[0328] n is 1 or 2;

[0329] R a is H or halogen;

[0330] R b is H, halogen or C1-C6 alkyl;

[0331] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0332] Z is -NH-;

[0333] R1 is C1-C6 haloalkyl, C2-C6 alkyl or C3 cycloalkyl substituted by halogen;

[0334] Ar1 is C6-C 10 aryl; and

[0335] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0336] Provided that when X is alkyl, L is absent.

[0337] In some aspects, the present disclosure provides a compound of formula (III"):

[0338]

[0339] or a pharmaceutically acceptable salt thereof, wherein:

[0340] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0341] L is absent or is a C1-C6 alkyl group;

[0342] Y is -O-;

[0343] n is 1 or 2;

[0344] R a is H or halogen;

[0345] Rb is H, halogen or C1-C6 alkyl;

[0346] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0347] Z is -NH-;

[0348] R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl;

[0349] Ar1 is C6-C 10 aryl; and

[0350] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0351] Provided that when X is alkyl, L is absent.

[0352] In some aspects, the present disclosure provides a compound of formula (III'"):

[0353]

[0354] or a pharmaceutically acceptable salt thereof, wherein:

[0355] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[0356] L is absent or is a C1-C6 alkyl group;

[0357] Y is -O-;

[0358] n is 1 or 2;

[0359] R a is H or halogen;

[0360] R b is H, halogen or C1-C6 alkyl;

[0361] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0362] Z is -NH-;

[0363] R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl;

[0364] Ar1 is C6-C 10 aryl; and

[0365] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0366] Provided that when X is alkyl, L is absent.

[0367] In some aspects, the present disclosure provides a compound of formula (IV):

[0368]

[0369] or a pharmaceutically acceptable salt thereof, wherein:

[0370] 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;

[0371] L is absent or is a C1-C6 alkyl group;

[0372] Y is -O-;

[0373] n is 1 or 2;

[0374] R a is H or halogen;

[0375] R b is H, halogen or C1-C6 alkyl;

[0376] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0377] Z is -NH-;

[0378] R1 is C1-C6 haloalkyl, C1-C6 alkyl or C3 cycloalkyl substituted by halogen;

[0379] Ar1 is C6-C 10 aryl; and

[0380] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0381] Provided that when X is alkyl, L is absent.

[0382] In some aspects, the present disclosure provides a compound of formula (IV'):

[0383]

[0384] or a pharmaceutically acceptable salt thereof, wherein:

[0385] 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;

[0386] L is absent or is a C1-C6 alkyl group;

[0387] Y is -O-;

[0388] n is 1 or 2;

[0389] R a is H or halogen;

[0390] R b is H, halogen or C1-C6 alkyl;

[0391] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0392] Z is -NH-;

[0393] R1 is C1-C6 haloalkyl, C2-C6 alkyl or C3 cycloalkyl substituted by halogen;

[0394] Ar1 is C6-C 10 aryl; and

[0395] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0396] Provided that when X is alkyl, L is absent.

[0397] In some aspects, the present disclosure provides a compound of formula (IV"):

[0398]

[0399] or a pharmaceutically acceptable salt thereof, wherein:

[0400] 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;

[0401] L is absent or is a C1-C6 alkyl group;

[0402] Y is -O-;

[0403] n is 1 or 2;

[0404] R a is H or halogen;

[0405] R b is H, halogen or C1-C6 alkyl;

[0406] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0407] Z is -NH-;

[0408] R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl;

[0409] Ar1 is C6-C 10 aryl; and

[0410] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0411] Provided that when X is alkyl, L is absent.

[0412] In some aspects, the present disclosure provides a compound of formula (IV'"):

[0413]

[0414] or a pharmaceutically acceptable salt thereof, wherein:

[0415] 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;

[0416] L is absent or is a C1-C6 alkyl group;

[0417] Y is -O-;

[0418] n is 1 or 2;

[0419] R a is H or halogen;

[0420] R b is H, halogen or C1-C6 alkyl;

[0421] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0422] Z is -NH-;

[0423] R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl;

[0424] Ar1 is C6-C 10 aryl; and

[0425] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[0426] Provided that when X is alkyl, L is absent.

[0427] It is understood that for the compounds of the present disclosure, the variables X, L, Y, n, R a 、R b , Z, R1, Ar1 and T can each be selected from the groups described herein (where applicable), and the groups described herein for the variables X, L, Y, n, R a 、R b Any group described for any of the following: Z, R1, Ar1, and T may be combined (where applicable) with any of the groups described herein for the variables X, L, Y, n, R a 、R b , Z, R1, Ar1 and T are any combination of the remaining one or more described groups.

[0428] 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.

[0429] In some embodiments, X is -O-.

[0430] In some embodiments, X is -N(CH3)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl.

[0431] In some embodiments, X is -N(CH3)- or C1-C6 alkyl.

[0432] In some embodiments, X is -N(CH3)-.

[0433] In some embodiments, X is C1-C6 alkyl.

[0434] In some embodiments, X is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl or -OH.

[0435] In some embodiments, X is a C1-C6 alkyl group substituted with one or more C1-C6 alkyl groups or -OH.

[0436] In some embodiments, X is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl groups.

[0437] In some embodiments, X is a C1-C6 alkyl group substituted with one or more C1-C6 alkyl groups.

[0438] In some embodiments, X is C1-C6 alkyl optionally substituted with one or more -OH.

[0439] In some embodiments, X is C1-C6 alkyl substituted with one or more -OH groups.

[0440] 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.

[0441] In some embodiments, X is -N(C1-C6 haloalkyl)-.

[0442] 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)-.

[0443] In some embodiments, L is absent or is a C1-C6 alkyl.

[0444] In some embodiments, L is absent or is a C2-C6 alkyl.

[0445] In some embodiments, L is absent.

[0446] In some embodiments, L is C1-C6 alkyl.

[0447] In some embodiments, L is C2-C6 alkyl.

[0448] 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.

[0449] In some embodiments, Y is -O-.

[0450] In some embodiments, n is 1 or 2.

[0451] In some embodiments, n is 1. In some embodiments, n is 2.

[0452] In some embodiments, R a is H or halogen.

[0453] In some embodiments, R a It’s H.

[0454] In some embodiments, R a It's a halogen.

[0455] In some embodiments, R a is F, Cl, Br or I. In some embodiments, R a is F, Cl or Br. In some embodiments, R a It is F or Cl.

[0456] 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 It's I.

[0457] In some embodiments, R b is H, halogen or C1-C6 alkyl.

[0458] In some embodiments, R b It’s H.

[0459] In some embodiments, R b It's a halogen.

[0460] In some embodiments, R b is F, Cl, Br or I. In some embodiments, R bis F, Cl or Br. In some embodiments, R b It is F or Cl.

[0461] 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 It's I.

[0462] In some embodiments, R b It is a C1-C6 alkyl group.

[0463] In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b In some embodiments, R b It is tert-butyl.

[0464] In some embodiments, R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group.

[0465] In some embodiments, Z is -NH-.

[0466] In some embodiments, R1 is C1-C6 haloalkyl or C2-C6 alkyl.

[0467] In some embodiments, R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl substituted with halogen.

[0468] In some embodiments, R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl substituted with halogen.

[0469] In some embodiments, R1 is C1-C6 haloalkyl, C1-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens.

[0470] In some embodiments, R1 is C1-C6 haloalkyl, C2-C6 alkyl, or C3 cycloalkyl optionally substituted with one or more halogens.

[0471] In some embodiments, R1 is C1-C6 haloalkyl.

[0472] In some embodiments, R1 is C1-C6 haloalkyl.

[0473] In some embodiments, R1 is a halomethyl group. In some embodiments, R1 is a haloethyl group. In some embodiments, R1 is a halopropyl group. In some embodiments, R1 is a halobutyl group. In some embodiments, R1 is a halopentyl group. In some embodiments, R1 is a halohexyl group.

[0474] In some embodiments, R1 is C2-C6 alkyl.

[0475] In some embodiments, R1 is C1-C6 alkyl.

[0476] 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 sec-butyl. In some embodiments, R1 is sec-pentyl. In some embodiments, R1 is sec-hexyl. In some embodiments, R1 is tert-butyl.

[0477] In some embodiments, R1 is C3 cycloalkyl.

[0478] In some embodiments, R1 is C3 cycloalkyl optionally substituted with one or more halogen or C1-C6 alkyl.

[0479] In some embodiments, R1 is C3 cycloalkyl optionally substituted with one or more halogens.

[0480] In some embodiments, R1 is C3 cycloalkyl substituted with halogen.

[0481] In some embodiments, R1 is C3 cycloalkyl optionally substituted with one or more C1-C6 alkyl.

[0482] In some embodiments, R1 is a C3 cycloalkyl substituted with one or more C1-C6 alkyl groups.

[0483] In some embodiments, Ar1 is C6-C 10 Aryl.

[0484] In some embodiments, Ar1 is C6-C 10 Aryl.

[0485] In some embodiments, Ar1 is C6-C substituted with one or more halogens. 10 Aryl.

[0486] In some embodiments, Ar1 is phenyl optionally substituted with one or more halogens.

[0487] In some embodiments, Ar1 is phenyl.

[0488] In some embodiments, Ar1 is phenyl substituted with one or more halogens.

[0489] In some embodiments, T is C6-C6 optionally substituted with one or more halogen or C1-C6 alkyl. 10 Aryl.

[0490] In some embodiments, T is C6-C 10 Aryl.

[0491] In some embodiments, T is C6-C 10 Aryl.

[0492] In some embodiments, T is C6-C6 substituted with one or more halogen or C1-C6 alkyl. 10 Aryl.

[0493] In some embodiments, T is C6-C substituted with one or more halogens. 10 Aryl.

[0494] In some embodiments, T is phenyl optionally substituted with one or more halogen or C1-C6 alkyl.

[0495] In some embodiments, T is phenyl optionally substituted with one or more halogens.

[0496] In some embodiments, T is phenyl.

[0497] In some embodiments, T is phenyl substituted with one or more halogen or C1-C6 alkyl.

[0498] In some embodiments, T is phenyl substituted with one or more halogens.

[0499] In some embodiments, when X is alkyl, L is absent.

[0500] In some embodiments, the compound has formula (I'-a) or (I'-b):

[0501]

[0502] or a pharmaceutically acceptable salt thereof.

[0503] In some embodiments, the compound has formula (II'-a), (II'-b), or (II'-c):

[0504]

[0505] or a pharmaceutically acceptable salt thereof, wherein:

[0506] n1 is an integer ranging from 0 to 4.

[0507] In some embodiments, the compound has Formula (IIIA'), (IIIA'-a), or (IIIA'-b):

[0508]

[0509] or a pharmaceutically acceptable salt thereof, wherein:

[0510] n1 is an integer ranging from 0 to 4; and

[0511] n2 is an integer ranging from 0 to 4.

[0512] In some embodiments, the compound has Formula (IVA'), (IVA'-a), or (IVA'-b):

[0513] or a pharmaceutically acceptable salt thereof, wherein:

[0514] n1 is an integer ranging from 0 to 4; and

[0515] n2 is an integer ranging from 0 to 4.

[0516] In some embodiments, the compound has Formula (Ia) or (Ib):

[0517]

[0518] or a pharmaceutically acceptable salt thereof.

[0519] In some embodiments, the compound has formula (II-a), (II-b), or (II-c):

[0520]

[0521] or a pharmaceutically acceptable salt thereof, wherein:

[0522] n1 is an integer ranging from 0 to 4.

[0523] In some embodiments, the compound has Formula (IIIA), (IIIA-a), or (IIIA-b):

[0524] or a pharmaceutically acceptable salt thereof, wherein:

[0525] n1 is an integer ranging from 0 to 4; and

[0526] n2 is an integer ranging from 0 to 4.

[0527] In some embodiments, the compound has Formula (IIIA'-1), (IIIA'-1a), or (IIIA'-1b):

[0528]

[0529] or a pharmaceutically acceptable salt thereof, wherein:

[0530] n1 is an integer ranging from 0 to 4; and

[0531] n2 is an integer ranging from 0 to 4.

[0532] In some embodiments, the compound has Formula (IIIA'-2), (IIIA'-2a), or (IIIA'-2b):

[0533]

[0534]

[0535] or a pharmaceutically acceptable salt thereof, wherein:

[0536] n1 is an integer ranging from 0 to 4; and

[0537] n2 is an integer ranging from 0 to 4.

[0538] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0539] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0540] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0541] In some embodiments, the compound is selected from the compounds described in Table 1.

[0542] In some embodiments, the compound is selected from the compounds described in Table 2 and prodrugs and pharmaceutically acceptable salts thereof.

[0543] In some embodiments, the compound is selected from the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0544] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0545] In some embodiments, the compound is selected from the compounds described in Table 2.

[0546] In some embodiments, the compound is selected from the compounds described in Table 3 and prodrugs and pharmaceutically acceptable salts thereof.

[0547] In some embodiments, the compound is selected from the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0548] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0549] In some embodiments, the compound is selected from the compounds described in Table 3.

[0550] In some embodiments, the compound is selected from the compounds described in Table 4 and prodrugs and pharmaceutically acceptable salts thereof.

[0551] In some embodiments, the compound is selected from the compounds described in Table 4 and pharmaceutically acceptable salts thereof.

[0552] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 4 and pharmaceutically acceptable salts thereof.

[0553] In some embodiments, the compound is selected from the compounds described in Table 4.

[0554] In some embodiments, the compound is selected from the compounds described in Table 5 and prodrugs and pharmaceutically acceptable salts thereof.

[0555] In some embodiments, the compound is selected from the compounds described in Table 5 and pharmaceutically acceptable salts thereof.

[0556] In some embodiments, the compound is selected from prodrugs of the compounds described in Table 5 and pharmaceutically acceptable salts thereof.

[0557] In some embodiments, the compound is selected from the compounds described in Table 5.

[0558] Table 1

[0559]

[0560]

[0561] Table 2

[0562]

[0563]

[0564]

[0565]

[0566]

[0567] Table 3

[0568]

[0569]

[0570]

[0571] Table 4

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592] Table 5

[0593]

[0594]

[0595] In some embodiments, the compound is not described in PCT / US2021 / 049003.

[0596] In some embodiments, the compound is not selected from the compounds described in PCT / US2021 / 049003.

[0597] In some embodiments, the compound is not selected from the compounds described in Table 6.

[0598] Table 6

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0609] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0610] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, and prodrugs and pharmaceutically acceptable salts thereof.

[0611] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0612] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0613] In certain embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0614] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 2.

[0615] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2, and prodrugs and pharmaceutically acceptable salts thereof.

[0616] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0617] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 2 and pharmaceutically acceptable salts thereof.

[0618] In certain embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 2.

[0619] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 3.

[0620] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3, and prodrugs and pharmaceutically acceptable salts thereof.

[0621] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0622] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0623] In certain embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3.

[0624] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 4.

[0625] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 4, and prodrugs and pharmaceutically acceptable salts thereof.

[0626] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 4 and pharmaceutically acceptable salts thereof.

[0627] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 4 and pharmaceutically acceptable salts thereof.

[0628] In certain embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 4.

[0629] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 5.

[0630] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 5, and prodrugs and pharmaceutically acceptable salts thereof.

[0631] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 5 and pharmaceutically acceptable salts thereof.

[0632] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 5 and pharmaceutically acceptable salts thereof.

[0633] In certain embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 5.

[0634] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, by carrying out the procedures disclosed in the schemes and / or in the examples described herein, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0635] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0636] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0637] As used herein, the term "isotopic derivative" 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)-(II)-(III ... 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 In some embodiments, an isotopic derivative is a deuterium-labeled compound (i.e., one or more of its atoms is deuterated). 2 H enriched). In 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 compound or any combination thereof. In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compound or any combination thereof.

[0638] It will be appreciated that any of a variety of art-recognized techniques may be used to prepare 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36For example, by carrying out the procedures disclosed in the schemes and / or in the examples described herein, by using 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 3 S. 34 S. 35 S and / or 36 Deuterium-labeled compounds can usually be prepared by replacing non-isotopically labeled reagents with S-labeled reagents.

[0639] Containing the aforementioned 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and 36 The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing one or more of the following: S atoms are within the scope of the present invention. In addition, isotopes (e.g., 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 3 S. 34 S. 35 S and / or 36 S) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0640] For the avoidance of doubt, it should be understood that where "described herein" is used in this specification to define a group, the group encompasses the first occurring and broadest definition as well as each and every one of the specific definitions for that group.

[0641] The various functional groups and substituents constituting the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More typically, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons.

[0642] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of sufficiently basic compounds of the present invention, for example, acid addition salts with, for example, inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid). In addition, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., 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.

[0643] It is to be understood that the compounds of any of the formulae disclosed herein and any pharmaceutically acceptable salts thereof encompass stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of the compounds.

[0644] It should be understood that although the compounds disclosed herein can exist in one particular configuration. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers. In some embodiments, presentation of a compound herein in a particular 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; although such presentation is further intended to refer to a specific configuration of the compound. For example, when presenting a compound having When referring to a compound having a In addition, the present invention may be intended to refer to a compound having A compound having a specific configuration of a portion.

[0645] It should be understood that although the compounds disclosed herein may be presented without a specified configuration (e.g., without a specified stereochemistry), such presentation is intended to encompass all available isomers, tautomers, positional isomers, and stereoisomers of the compounds. In some embodiments, presentation of a compound herein without a specified configuration is intended to refer to each of the available isomers, tautomers, positional isomers, and stereoisomers of the compound, or any mixture thereof. For example, when presenting a compound having When referring to a compound having a In addition, the presentation may be intended to refer to a mixture of cis isomers having a portion thereof (e.g., For example, when the compound has When referring to a compound having a or a compound that is part of a mixture thereof.

[0646] As used herein, the term "isomerism" refers to compounds that have the same molecular formula 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 "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0647] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0648] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers, referred to as a "diastereomeric mixture." When there is one chiral center, the stereoisomers can be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center in question are sorted according to the sequence rule 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).

[0649] As used herein, the term "geometric isomers" refers to diastereomers that exist due to hindered rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans or Z and E, which indicate that the groups are located on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0650] It should be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form. It should be understood that not all isomers may have the same level of activity.

[0651] 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.

[0652] As used herein, the term "atropisomer" is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. Atropisomers exist due to restricted rotation of bulky groups around a central bond. Such atropisomers typically exist as a mixture, but recent advances in chromatographic techniques have made it possible to separate mixtures of two atropisomers in certain circumstances.

[0653] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium, and it is easy to convert from one isomeric form to another isomeric form. This conversion causes the form migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric combinations in solution. In a solution where tautomerization may occur, the chemical equilibrium of the tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that can be mutually converted by tautomerization is called tautomerism. Among the various possible types of tautomerism, two are usually observed. In keto-enol tautomerism, simultaneous displacement of electrons and hydrogen atoms occurs. The reason for the generation of ring-chain tautomerism is that the aldehyde group (-CHO) in the sugar chain molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to produce a cyclic (ring-shaped) form as shown by glucose.

[0654] It should be understood that the compounds of the present disclosure can be depicted as different tautomers. It should also be understood that when a compound has a tautomeric form, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It should be understood that certain tautomers can have a higher level of activity than other tautomers.

[0655] Compounds with the same molecular formula but different bonding properties or order of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers whose atoms are arranged differently in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S- ordering rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0656] The compounds of the present disclosure may have one or more asymmetric centers; therefore, such compounds may be generated as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include its individual enantiomers and racemic or other mixtures. The methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesizing from optically active starting materials or by splitting racemic forms. Some compounds of the present disclosure may have geometric isomerization centers (E- and Z-isomers). It should be understood that the present disclosure encompasses all optical diastereomers and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

[0657] The present disclosure also encompasses compounds of the present disclosure as defined herein containing one or more isotopic substitutions.

[0658] It should be understood that the compounds of any formula described herein include the compounds themselves, and, if applicable, their salts and their solvates. For example, salts can be formed between anions and positively charged groups (e.g., amino groups) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthenate, and acetate (e.g., trifluoroacetate).

[0659] 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 cations and negatively charged groups (e.g., carboxylates) on the substituted compounds disclosed herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions or diethylamine ions. Substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0660] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms 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.

[0661] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds tend to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with a molecule of a substance, where the water remains in its molecular form as HO.

[0662] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but has a slightly different composition (e.g., an atom is replaced by an atom of a different element, or a specific functional group is present, or a functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but differs from the reference compound in structural origin.

[0663] As used herein, the term "derivative" refers to compounds having a common core structure and substituted with various groups as described herein.

[0664] As used herein, the term "bioisostere" refers to a compound produced by the exchange of one atom or group of atoms with another substantially similar atom or group of atoms. The purpose of bioisosteric replacement is to create a new compound with similar biological properties as the parent compound. Bioisosteric replacement can be based on physical chemistry 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.

[0665] It will also be understood that certain compounds of any of the formulae disclosed herein may exist in solvated as well as unsolvated forms (such as, for example, hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It will be understood that the present disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0666] It will also be understood that certain compounds of any of the formulae disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof having 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, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0667] Any compound in the formula disclosed herein can exist with many different tautomeric forms, and the mentioning of the compound of formula (I) comprises all such forms.In order to avoid doubt, compound can exist with a kind of in several tautomeric forms and only specifically describe or show a kind of situation, every other form is still comprised by formula (I).The example of tautomeric form is included ketone-, enol-and enolate-form, as in for example following tautomerism pair: ketone / enol (exemplified below), imines / enamine, amides / imino alcohol, amidine / amidine, nitroso-group / oxime, thioketone / enethiol and nitro / acid nitro.

[0668]

[0669] Any compound of the formula disclosed herein containing an amine functional group can also form an N-oxide. The compounds of formula (I) containing an amine functional group mentioned herein also include N-oxides. In the case where the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. The specific example of an N-oxide is an N-oxide of a nitrogen atom of a tertiary amine or a nitrogen-containing heterocycle. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March's Advanced Organic Chemistry, 4th edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by LWDeady's procedure (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0670] Any of the compounds of the formula disclosed herein can be administered in the form of a prodrug that decomposes 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 compounds of the present disclosure. When the compounds of the present disclosure contain a suitable group or substituent (to which a modifying group can be connected), a prodrug can be formed. Examples of prodrugs include derivatives containing alkyl or acyl substituents that are cleavable in vivo at any of the esters or amide groups of the formula disclosed herein.

[0671] Thus, the present disclosure includes those compounds of any of the formulae disclosed herein as defined above when obtainable by organic synthesis and when obtained in a human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure includes those compounds of any of the formulae disclosed herein that are produced by organic synthesis, as well as such compounds produced in a human or animal body by metabolism of a precursor compound, i.e., the compounds of any of the formulae disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0672] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein are prodrugs that are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity, based on sound medical judgment. Various forms of prodrugs have been described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 309-396, K. Widder et al., eds. (Academic Press, 1985); b) Design of Pro-drugs, H. Bundgaard, ed., (Elsevier, 1985); c) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, eds., Chapter 5 "Design and Application of Pro-drugs", 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”, ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0673] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a hydroxyl group are, for example, esters or ethers thereof that can be cleaved in vivo. An in vivo cleavable ester or ether of a compound of any of the formulae disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include inorganic esters such as phosphates (including phosphoramidite cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include C1-C 10 Alkanoyl (such as acetyl), benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, C1-C 10Alkoxycarbonyl (such as ethoxycarbonyl), N, N- (C1-C6 alkyl) 2-carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl 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 of hydroxyl include α-acyloxyalkyl (such as acetoxymethyl and pivaloyloxymethyl).

[0674] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a carboxyl group are, for example, in vivo cleavable amides thereof, for example with amines (such as ammonia), C 1-4 Amides formed from alkylamines (such as methylamine), (C1-C4 alkyl)2amines (such as dimethylamine), N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines (such as 2-methoxyethylamine), phenyl-C1-C4 alkylamines (such as benzylamine) and amino acids (such as glycine) or their esters.

[0675] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having 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 Amides formed from alkanoyl (such as acetyl), benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0676] The in vivo effects of any of the compounds of the formulae disclosed herein can be exerted in part by one or more metabolites formed in the human or animal body after administration of any of the compounds of the formulae disclosed herein. As described above, the in vivo effects of any of the compounds of the formulae disclosed herein can also be exerted by the metabolism of a precursor compound (prodrug).

[0677] Suitably, the present disclosure excludes any individual compound that does not possess biological activity as defined herein.

[0678] Synthesis method

[0679] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0680] In some aspects, the present disclosure provides a method of producing a compound comprising one or more steps as described herein.

[0681] In some aspects, the present disclosure provides compounds obtainable or obtained by or directly obtained from a process for preparing a compound as described herein.

[0682] In some aspects, the present disclosure provides intermediates as described herein, which are suitable for use in methods of preparing compounds as described herein.

[0683] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[0684] In the descriptions of synthetic methods described herein and any referenced synthetic methods for preparing starting materials, it is 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.

[0685] Those skilled in the art of organic synthesis will understand that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0686] Should be understood that, in the process of synthesizing this disclosed compound in the method defined herein, or in the building-up process of some parent material, it may be desirable to protect some substituents to prevent their undesirable reaction. A skilled chemist will understand when such protection is needed, and how such blocking group can be placed and removed later. About the example of blocking group, referring to one of a plurality of general texts about this theme, for example " Protective Groups in Organic Synthesis " (publisher: John Wiley & Sons) by Theodora Green. Can remove blocking group by any method convenient for being suitable for removing the blocking group in question described in the document or known to a skilled chemist, select such method to realize the removal of blocking group, and the group elsewhere in the molecule is produced minimum interference. Therefore, if reactant comprises for example group such as amino, carboxyl or hydroxyl, it may be desirable to protect this group in some reactions mentioned herein.

[0687] For example, the suitable protecting group of amino or alkylamino is, for example, acyl (for example alkanoyl (such as acetyl)), alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl (for example benzyloxycarbonyl) or aroyl (for example benzoyl). The deprotection conditions of the above-mentioned protecting groups necessarily vary with the selection of the protecting group. Thus, for example, by, for example, hydrolysis with a suitable base (such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide), acyl (such as alkanoyl) or alkoxycarbonyl or aroyl can be removed. Alternatively, acyl such as tert-butoxycarbonyl can be removed, for example, by processing with a suitable acid (such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid), and, for example, by hydrogenation with a catalyst (such as palladium on carbon), or by processing with Lewis acid, for example tris (trifluoroacetic acid) boron, arylmethoxycarbonyl such as benzyloxycarbonyl can be removed. 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.

[0688] Suitable protecting groups for hydroxyl groups are, for example, acyl groups (e.g., alkanoyl groups (such as acetyl)), aroyl groups (e.g., benzoyl) or arylmethyl groups (e.g., 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, for example, 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, for example, over a catalyst (e.g., palladium on carbon).

[0689] A suitable protecting group for a carboxyl group is, for example, an esterifying group, for example a methyl or ethyl group, which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group, which can 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 can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0690] Once a compound of Formula (I)-(II)-(III) has been synthesized by any of the methods defined herein, the method may further comprise the following additional steps: (i) removing any protecting groups present; (ii) converting the compound of Formula (I)-(II)-(I"), (I')-(II"), (II')-(III") or (III') into another compound of Formula (I)-(I')-(I"), (I')-(II"), (II')-(III") or (III'); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0691] The resulting compounds of Formula (I), (I'), (I"), (I'"), (II), (II'), (III) or (III') can be isolated and purified using techniques well known in the art.

[0692] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is 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 ether 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-methylpyrrolidone (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 solvents or mixtures with water.

[0693] The reaction temperature is suitably between about -100°C and 300°C, depending on the reaction step and conditions used.

[0694] Reaction times normally is in the scope of less than one minute and several days, depends on the reactivity of various compounds and various reaction conditions.By methods known in the art such as reaction monitoring, easily determine suitable reaction times.Based on the temperature of reaction providing above, suitable reaction times is usually in the scope of between 10 minutes and 48 hours.

[0695] In addition, by utilizing the procedures described herein, combined with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily appreciate that known variations of the conditions and methods of the following preparative procedures can be used to prepare these compounds.

[0696] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure are readily obtained by a variety of synthetic routes, some of which are illustrated in the accompanying examples. The skilled person will readily recognize which reagents and reaction conditions to use and how to apply and adjust them in any particular case (whenever necessary or useful) to obtain the compounds of the present disclosure. In addition, some compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example, by converting a specific functional group present in a compound of the present disclosure or a suitable precursor molecule thereof 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, the skilled person will apply (whenever necessary or useful) the synthetic protecting (or protective) groups; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail in, for example, PGM Wuts, TW Greene, "Greene's Protective Groups in Organic Synthesis," 4th edition (2006) (John Wiley & Sons).

[0697] General routes for preparing compounds of the present application are described in Schemes 1-9 herein.

[0698] Reaction Scheme 1

[0699]

[0700] According to the method shown in Reaction Scheme 1, the compound of formula (V) can be prepared from the compound of formula (I). According to the approach previously reported in WO2019 / 027058 from commercially available materials, or according to a method similar thereto, the compound of formula (I) can be generated. As used herein, Hal is a halogen atom.

[0701] Examples of amino protecting groups represented by P1 include carbamate type protecting groups such as t-butyl carbamate, etc. When Y is oxygen, compound (II) can be commercially available or can be prepared from commercially available materials by alkylation or Mitsunobu reaction. B represents boric acid or boric acid ester, etc.

[0702] When X is nitrogen, examples of the protecting group represented by P2 include phthalimide type protecting groups, etc. When X is carbon or oxygen, examples of the protecting group represented by P2 include carboxyl protecting groups such as methyl ester, ethyl ester, etc.

[0703] Compound (I) and compound (II) are subjected to a palladium-mediated cross-coupling Suzuki-type reaction to generate compound (III). When the coupling reaction is performed, examples of the metal catalyst to be used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride(II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonatepalladium(II), etc. In addition, a base may be added to the reaction system, and examples thereof include inorganic bases, etc.

[0704] 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 employing a method using an acid, a base or a nucleophile (such as hydrazine, etc.), a reduction method, etc.

[0705] Compound (V) can be generated by subjecting compound (IV) to a ring-closing reaction. When the ring-closing is performed by amidation reaction, urea or carbamate formation, examples of the reagent to be used include activated carboxylic acids such as anhydrides, activated esters, activated carbamates, etc. Examples of carboxylic acid activators include carbodiimide condensation agents such as N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI), etc.; carbonate condensation 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 can be added to the reaction system. Examples of the base include inorganic bases, organic bases, etc. When a carbodiimide condensation agent is used, additives such as 1-hydroxybenzotriazole (HOBt), dimethylaminopyridine (DMAP), etc. can be further added to the reaction system.

[0706] Reaction Scheme 2

[0707]

[0708] Alternatively, according to the method shown in Reaction Scheme 2, a compound of formula (V) can be generated from a compound of formula (I). Compound (VI) can be generated 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 the coupling reaction is performed in each step, examples of the metal catalyst to be used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride (II), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II), etc. In addition, a base can be added to the reaction system, and examples thereof include inorganic bases, etc. Examples of the “leaving group” represented by LG1 include halogen atoms, optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy) and the like.

[0709] By using a metal catalyst to make compound (VI) and appropriate acetylene (commercially available or available according to known methods) carry out Sonogashira type cross coupling reaction, compound (VII) when Y is carbon can be generated. The example of the metal catalyst to be used includes palladium compounds such as palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), bis (acetonitrile) palladium dichloride (II) etc. It is also possible to add phosphine ligands such as 2-dicyclohexylphosphino-2', 4', 6' triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (SPhos) etc. to the reaction system. In addition, a base can be added to the reaction system, and its example includes inorganic bases etc.

[0710] Compound (VIII) can be produced by reducing compound (VII). When a carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar's catalyst, etc. can be employed in combination with hydrogen.

[0711] When Y is oxygen and LG1 represents a hydroxyl group, compound (VIII) can be directly prepared from compound (VI) by performing a Mitsunobu reaction from commercially available materials. When the Mitsunobu reaction is performed in each step, an azodicarboxylic acid ester (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0712] 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 employing a method using an acid, a base, hydrazine or the like, a reduction method or the like.

[0713] By a ring-closing reaction as shown in Reaction Scheme 1, compound (V) can be generated.

[0714] Compounds of formula (V) can also be prepared by ring-closing metathesis reaction methods as outlined in Reaction Schemes 3, 4, and 5.

[0715] Reaction Scheme 3

[0716]

[0717] Compound (IX) can be produced by removing the protecting group represented by P1 from compound (I) according to an appropriate known method, for example, by using an acid, a base, hydrazine or the like, or a reduction method or the like.

[0718] Compound (XI) can be generated by subjecting compound (IX) and compound (X) to a condensation reaction. Wherein LG2 is a suitable leaving group. When the condensation reaction is carried out, examples of reagents to be used include activated carboxylic acids such as anhydrides, activated esters, activated carbonates, activated carbamates, isocyanates, and the like. Examples of activators for carboxylic acids include carbodiimide condensation agents such as N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI); carbonate condensation agents such as 1,1-carbonyldiimidazole (CDI), triphosgene, and the like; O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU); combinations thereof, and the like. In addition, a base can be added to the reaction system. Examples of bases include inorganic bases, organic bases, and the like. When a carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP) may be further added to the reaction system. Compound (X) may be commercially available or may be produced from commercially available materials according to a method known per se or a method analogous thereto. L1 represents C 1-5 Allyl, allyloxy, etc. Examples of the leaving group represented by LG2 include halogen atoms, optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), p-nitrophenol, and the like.

[0719] Compound (XII) can be commercially available or produced from commercially available materials according to a method known per se or a method analogous thereto. B represents boronic acid, ester, etc. L1 represents C 1-3 Allyl, etc.

[0720] By subjecting the combination of compound (XI) and compound (XII) to the aforementioned palladium-mediated cross-coupling Suzuki type as shown in Reaction Scheme 1, compound (XIII) can be generated.

[0721] Reaction Scheme 4

[0722]

[0723] By subjecting the combination of compound (I) and compound (XII) to the aforementioned palladium-mediated cross-coupling Suzuki type as shown in Reaction Scheme 1, compound (XIII) can be generated.

[0724] By removing the protecting group represented by P1 according to a known method, for example, by using an acid, a base, hydrazine or the like, or a reduction method or the like, compound (XIV) can be produced.

[0725] Compound (XIII) can be produced by subjecting compound (XIV) and compound (X) to a condensation reaction as described above in Reaction Scheme 3.

[0726] Reaction Scheme 5

[0727]

[0728] Compound (XIV) can be produced by subjecting Compound (XIII) to a ring-closing reaction. When the ring-closing is performed by a ring-closing metathesis reaction, examples of the catalyst to be used include ruthenium compounds such as Grubbs I, Grubbs II, HoveydaGrubbs, and the like.

[0729] 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, Lindlar's catalyst, etc. can be employed together with hydrogen gas.

[0730] Reaction Scheme 6

[0731]

[0732] According to Reaction Scheme 6, the compound of formula (XV) can be prepared (when R a =R b =H and n=2). Compound (XV) can be generated 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 reagents such as imidazol-1-ium chloride or phosphorus oxychloride.

[0733] Compound (XVI) can be produced by palladium-mediated cross-coupling of compound (XVII) with a substituted bromophenyl compound which can be prepared by known methods or methods analogous thereto. Suitable palladium catalysts include di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; and iron.

[0734] Compounds of type (XVII) can be prepared by palladium-mediated borylation of compound (XVIII) using a reagent such as bispinacoldiborane and a catalyst such as palladium tricyclohexylphosphine complex.

[0735] Compound (XVIII) is generated by sulfonylation of compound (XIX).Sulfonylation can be achieved in one step using the appropriate sulfonyl chloride or in two steps by sulfenylation using sulfenyl chloride followed by an oxidation step using an oxidizing agent such as mCPBA.

[0736] Compound (XIX) can be prepared as a single enantiomer by using a chiral acid (e.g., a tartaric acid derivative) to form a chiral salt to resolve compound (XX). If this resolution is not performed, compounds of formula (XV) can still be prepared as a single enantiomer by chiral chromatography of the racemic compound (XV).

[0737] Compound (XX) can be prepared from compound (XXI) by reductive amination using an ammonia source and a suitable catalyst. Ammonium formate is one such ammonia source, and catalysts such as those described in detail in J. Org. Chem. 2019, 84, 10962-10977 are suitable for this transformation.

[0738] Compound (XXI) can be prepared by alkylation of commercially available ketone (XXIII), which can be achieved through an intermediate of an enamine such as compound (XXII), which will react with an appropriate benzyl halide (such as 2-fluoro-3-bromobenzyl bromide). Enamines can be prepared by treating (XXIII) with an appropriate secondary amine and a Lewis acid such as tetraisopropoxytitanium.

[0739] Reaction Scheme 7

[0740]

[0741] Compound (XXIV) (wherein R a or R b Compound (V) wherein one of the N protecting groups is fluorine can be prepared by a similar macrocyclization of (XXV). Compound (XXV) can be prepared by sequential deprotection of compound (XXVI) wherein the N protecting group is benzyloxycarbamate, which can be achieved by hydrogenolysis using hydrogen and an appropriate palladium catalyst such as palladium on carbon. If the ester protecting group is a tert-butyl ester, deprotection can be achieved by acid.

[0742] Compound (XXVI) can be prepared from compound (XXVII) in a similar manner to that performed in Reaction Scheme 6.

[0743] Compound (XXVII) can be prepared from compound (XXVIII) through a borylation reaction similar to that in Reaction Scheme 6.

[0744] Compound (XXVIII) can be prepared from compound (XXIX) by sulfonylation of a sulfonyl chloride, or a two-step sequence using a sulfenyl chloride followed by oxidation with an oxidizing agent such as mCPBA.

[0745] Reaction Scheme 8

[0746]

[0747] Enantiomerically pure compound (XXIX) can be prepared by chiral chromatography or resolution using a chiral salt of compound (XXX). In the case of using a chiral salt, a chiral acid such as a tartaric acid derivative can be employed.

[0748] Compound (XXX) can be prepared by reducing an azide such as (XXXI). The reduction can be achieved with a phosphorous-based reducing agent such as 3-[bis(2-carboxyethyl)phosphinyl]propionic acid hydrochloride.

[0749] Compound (XXXI) can be prepared by azide displacement of sulfonate (XXXII), and trifluoromethanesulfonate is suitable for this reaction. Sodium azide can be a suitable azide source.

[0750] Sulfonate esters such as (XXXII) can be prepared by reaction of compound (XXXIII) with a sulfonylating agent such as trifluoromethanesulfonic anhydride.

[0751] Reaction Scheme 9

[0752]

[0753] Compound (XXXIII) can be prepared by treating an epoxy compound of formula (XXXIV) or a cyclic sulfonate of formula (XXXV) with a fluoride. In the case of using an epoxy compound, a hydrogen fluoride salt (such as triethylamine.hydrogen fluoride) is a suitable fluoride source. In the case of using a cyclic sulfonate, a tetraalkylammonium salt such as tetraethylammonium fluoride is suitable.

[0754] Cyclic sulfonate (XXXV) can be prepared by oxidizing cyclic sulfinate (XXXVI) with an oxidizing agent such as sodium periodate, ruthenium trichloride.

[0755] Compound (XXXVI) can be prepared by sulfinating diol (XXXVII). Sulfinyl chloride can be used for the sulfinylation.

[0756] The diol (XXVII) is prepared by dihydroxylation of the olefin (XXXVIII). The 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.

[0757] Epoxides (XXXIV) can be prepared from alkenes (XXXVIII) using oxidation reactions and then chromatographic separation to separate the desired relative stereochemistry. Suitable oxidizing agents include oxone and trifluoromethyl-methyl ketone.

[0758] Olefins (XXXVIII) can be prepared by ring-closing metathesis of dienes such as (XXXIX). Ring-closing metathesis can be carried out using a ruthenium catalyst. Examples of catalysts to be used include Grubbs I, Grubbs II, Hoveyda Grubbs, and the like.

[0759] Olefin (XXXIX) can be prepared by alkylation of compound (XL). Alkylation can be achieved by reductive amination or treatment with an alkyl halide in the presence of a base.

[0760] 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 alkyl lithium to deprotonate (XLI). When used at low temperatures, n-butyl lithium may be a suitable base. Deprotection can be achieved using an acid under aqueous conditions.

[0761] Bioassay

[0762] Once the compounds designed, selected and / or optimized by the above methods are generated, they 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 to determine whether they have the predicted activity, binding activity and / or binding specificity using conventional assays, including but not limited to those described below.

[0763] In addition, high throughput screening can be used to accelerate the analysis using such assays. Therefore, the activity of the molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high throughput screening are described in, for example, Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0764] Various in vitro or in vivo bioassays can be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo bioassays can 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.

[0765] Despite the loss of orexin cells and decreased orexin in the cerebrospinal fluid in NT1, orexin receptors on postsynaptic neurons remain intact and represent suitable targets for pharmacological intervention. Orexins A and B (OXA and OXB) can be cleaved from a single precursor molecule (prepro-orexin) produced exclusively in the lateral hypothalamus. Both orexins bind to the OX2R with similar high affinity, but the orexin-1 receptor (OX1R) is preferentially bound by OXA. Postsynaptic excitation of these G protein-coupled orexin receptors can stimulate the release of monoaminergic and cholinergic neurotransmitters that promote wakefulness, as well as inhibitory neurotransmitters that suppress REM sleep atonia.

[0766] In some embodiments, the biological assays are described in the Examples herein.

[0767] In some embodiments, the bioassay 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.

[0768] In some embodiments, the assay involves preparing Chinese hamster ovary (CHO) cells that express human orexin type 2 receptor (hOX2R) or human orexin type 1 receptor (hOX1R).

[0769] Pharmaceutical composition

[0770] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Tables A1, A2, B1, and B2.

[0771] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0772] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. 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 using forms well known to those of ordinary skill in the pharmaceutical arts.

[0773] The formulations of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubilizers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH regulators, and mixtures thereof.

[0774] Any suitable solubilizing agent can be used. The example of a solubilizing agent includes cyclodextrins, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)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, random methylated-γ-cyclodextrin and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0775] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from ethylenediaminetetraacetic acid and its metal salts, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate and tetrasodium ethylenediaminetetraacetate and mixtures thereof.

[0776] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben, and sorbic acid, and mixtures thereof.

[0777] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent may be selected from glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride and sodium chloride and mixtures thereof.

[0778] 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 methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0779] In order 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, in particular a pH range of 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 an inorganic acid or a metal hydroxide base selected from potassium hydroxide, sodium hydroxide and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or alkaline pH adjusters are added to adjust the formulation to an acceptable target pH range. Therefore, it may not be necessary to use both an acid and a base simultaneously - depending on the formulation, adding one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0780] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer 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.

[0781] The formulation may further comprise a wetting agent. Suitable classes 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 glycerides, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0782] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be blended with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and gargled and expectorated or swallowed. Pharmaceutically compatible binders and / or excipients may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavor.

[0783] According to another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0784] The compositions of the present disclosure can be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[0785] 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, sweetening agents, flavoring agents and / or preservatives.

[0786] 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 alleviate the symptoms associated with an inflammasome-associated condition mentioned herein.

[0787] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an inflammasome-associated condition mentioned herein, slow its progression, and / or alleviate the symptoms associated with the condition.

[0788] The size of the dose of the compound of formula (I) for therapeutic or prophylactic purposes will naturally vary according to well-known medical principles depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0789] How to use

[0790] In some aspects, the present disclosure provides a method of modulating orexin receptor activity (eg, in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0791] In some aspects, the present disclosure provides a method of modulating orexin receptor activity (eg, in vitro or in vivo), the method comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0792] In some aspects, the present disclosure provides a method of modulating orexin-2 receptor activity (eg, in vitro or in vivo), the method comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0793] In some aspects, the present disclosure provides a method of modulating orexin-2 receptor activity (eg, in vitro or in vivo), the method comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0794] 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.

[0795] 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.

[0796] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0797] 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0798] In some embodiments, the disease or disorder is associated with orexin receptor activity. In some embodiments, the disease or disorder is one in which orexin receptor activity is involved.

[0799] In some embodiments, the disease or disorder is associated with orexin-2 receptor activity. In some embodiments, the disease or disorder is one in which orexin-2 receptor activity is implicated.

[0800] In some embodiments, the disease or disorder is narcolepsy, a hypersomnia disorder, a neurodegenerative disorder, a symptom of a rare genetic disorder, a mental health disorder, metabolic syndrome, osteoporosis, heart failure, coma, or a complication of emergence from anesthesia.

[0801] In some aspects, the present disclosure provides a method for treating or preventing narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications of emergence from anesthesia 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.

[0802] In some aspects, the present disclosure provides a method of treating narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications of emergence from anesthesia 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.

[0803] In some aspects, the present disclosure provides a method of treating or preventing narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications of emergence from anesthesia in a subject in need thereof, the method 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.

[0804] In some aspects, the present disclosure provides a method of treating narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications of emergence from anesthesia in a subject in need thereof, the method 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.

[0805] 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.

[0806] In some aspects, the present disclosure provides a method of treating or preventing hypersomnia 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.

[0807] 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.

[0808] In some aspects, the present disclosure provides a method of treating or preventing symptoms of a rare genetic disorder 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.

[0809] 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.

[0810] 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.

[0811] 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.

[0812] 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.

[0813] 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.

[0814] In some aspects, the present disclosure provides a method of treating or preventing complications of emergence from anesthesia 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.

[0815] 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.

[0816] In some aspects, the present disclosure provides a method of treating hypersomnia 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.

[0817] 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.

[0818] In some aspects, the present disclosure provides a method of treating a symptom of a rare genetic disorder 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.

[0819] 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.

[0820] 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.

[0821] 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.

[0822] 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.

[0823] 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.

[0824] In some aspects, the present disclosure provides a method of treating complications of emergence from anesthesia 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.

[0825] In some aspects, the present disclosure provides a method of treating or preventing narcolepsy in a subject in need thereof, the method 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.

[0826] In some aspects, the present disclosure provides a method of treating or preventing hypersomnia 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.

[0827] In some aspects, the present disclosure provides a method of treating or preventing a neurodegenerative disorder in a subject in need thereof, the method 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.

[0828] 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, the method 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.

[0829] In some aspects, the present disclosure provides a method of treating or preventing a mental health disorder in a subject in need thereof, the method 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.

[0830] In some aspects, the present disclosure provides a method of treating or preventing metabolic syndrome in a subject in need thereof, the method 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.

[0831] In some aspects, the present disclosure provides a method of treating or preventing osteoporosis in a subject in need thereof, the method 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.

[0832] In some aspects, the present disclosure provides a method of treating or preventing heart failure in a subject in need thereof, the method 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.

[0833] In some aspects, the present disclosure provides a method of treating or preventing coma in a subject in need thereof, the method 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.

[0834] In some aspects, the present disclosure provides a method of treating or preventing complications of emergence from anesthesia in a subject in need thereof, the method 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.

[0835] In some aspects, the present disclosure provides a method of treating narcolepsy in a subject in need thereof, the method 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.

[0836] In some aspects, the present disclosure provides a method of treating hypersomnia in a subject in need thereof, the method 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.

[0837] In some aspects, the present disclosure provides a method of treating a neurodegenerative disorder in a subject in need thereof, the method 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.

[0838] In some aspects, the present disclosure provides a method of treating a symptom of a rare genetic disorder in a subject in need thereof, the method 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.

[0839] In some aspects, the present disclosure provides a method of treating a mental health disorder in a subject in need thereof, the method 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.

[0840] In some aspects, the present disclosure provides a method of treating metabolic syndrome in a subject in need thereof, the method 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.

[0841] In some aspects, the present disclosure provides a method of treating osteoporosis in a subject in need thereof, the method 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.

[0842] In some aspects, the present disclosure provides a method of treating heart failure in a subject in need thereof, the method 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.

[0843] In some aspects, the present disclosure provides a method of treating coma in a subject in need thereof, the method 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.

[0844] In some aspects, the present disclosure provides a method of treating complications of emergence from anesthesia in a subject in need thereof, the method 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.

[0845] 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 (eg, in vitro or in vivo).

[0846] 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 (eg, in vitro or in vivo).

[0847] 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.

[0848] 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.

[0849] 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 a complication of emergence from anesthesia in a subject in need thereof.

[0850] 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.

[0851] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a hypersomnia disorder in a subject in need thereof.

[0852] 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.

[0853] 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.

[0854] 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.

[0855] 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.

[0856] 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.

[0857] 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.

[0858] 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.

[0859] 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 of emergence from anesthesia in a subject in need thereof.

[0860] 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 a complication of emergence from anesthesia in a subject in need thereof.

[0861] 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.

[0862] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a hypersomnia disorder in a subject in need thereof.

[0863] 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.

[0864] 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.

[0865] 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.

[0866] 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.

[0867] 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.

[0868] 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.

[0869] 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.

[0870] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating complications of emergence from anesthesia in a subject in need thereof.

[0871] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for modulating orexin activity (eg, in vitro or in vivo).

[0872] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for modulating orexin-2 activity (eg, in vitro or in vivo).

[0873] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a disease or disorder disclosed herein.

[0874] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or disorder disclosed herein.

[0875] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing narcolepsy, hypersomnia, neurodegenerative disorders, symptoms of rare genetic disorders, mental health disorders, metabolic syndrome, osteoporosis, heart failure, coma, or complications of emergence from anesthesia in a subject in need thereof.

[0876] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing narcolepsy in a subject in need thereof.

[0877] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a hypersomnia disorder in a subject in need thereof.

[0878] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a neurodegenerative disorder in a subject in need thereof.

[0879] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a symptom of a rare genetic disorder in a subject in need thereof.

[0880] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing a mental health disorder in a subject in need thereof.

[0881] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing metabolic syndrome in a subject in need thereof.

[0882] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing osteoporosis in a subject in need thereof.

[0883] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing heart failure in a subject in need thereof.

[0884] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing coma in a subject in need thereof.

[0885] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing complications of emergence from anesthesia in a subject in need thereof.

[0886] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation 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 of emergence from anesthesia in a subject in need thereof.

[0887] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating narcolepsy in a subject in need thereof.

[0888] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a hypersomnia disorder in a subject in need thereof.

[0889] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a neurodegenerative disorder in a subject in need thereof.

[0890] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a symptom of a rare genetic disorder in a subject in need thereof.

[0891] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a mental health disorder in a subject in need thereof.

[0892] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating metabolic syndrome in a subject in need thereof.

[0893] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating osteoporosis in a subject in need thereof.

[0894] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating heart failure in a subject in need thereof.

[0895] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating coma in a subject in need thereof.

[0896] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating complications of emergence from anesthesia in a subject in need thereof.

[0897] The present disclosure provides compounds that act as modulators of orexin receptor activity.

[0898] In some embodiments, the compounds of the present disclosure are agonists of the orexin receptor.

[0899] The present disclosure provides compounds that act as modulators of orexin-2 receptor activity.

[0900] In some embodiments, the compounds of the present disclosure are agonists of the orexin-2 receptor.

[0901] In some embodiments, modulation of an orexin receptor is activation of the orexin receptor.

[0902] The effectiveness of the compounds of the present disclosure can be determined by industry accepted assays / disease models according to standard practices for their elucidation as described in the art and found within the current general knowledge.

[0903] 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 the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0904] 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 the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0905] 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, said method comprising administering to said patient a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0906] 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, said method comprising administering to said patient a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0907] In some embodiments, the present disclosure also provides a method of treating a disease or disorder by reducing excessive sleepiness and / or excessive daytime sleepiness.

[0908] In some embodiments, the present disclosure also provides a method of treating a disease or disorder by reducing excessive sleepiness.

[0909] In some embodiments, the present disclosure also provides a method of treating a disease or disorder by reducing excessive daytime sleepiness.

[0910] In some embodiments, the disease or disorder is associated with excessive sleepiness and / or excessive daytime sleepiness.

[0911] In some embodiments, the disease or disorder is primary hypersomnia disorder, 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.

[0912] In some embodiments, the disease or disorder is primary hypersomnia disorder, 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 of emergence from anesthesia.

[0913] In some embodiments, the excessive daytime sleepiness is associated with a neurodegenerative disorder.

[0914] In some embodiments, the neurodegenerative disorder associated with excessive daytime sleepiness is Parkinson's disease, Alzheimer's disease, Huntington's disease, or multiple sclerosis.

[0915] In some embodiments, the disease or disorder is recurring hypersomnia.

[0916] In some embodiments, the recurrence of hypersomnia is narcolepsy type 1, narcolepsy type 2, or idiopathic hypersomnia.

[0917] In some embodiments, the disease or disorder is sleep apnea, traumatic brain injury, age-related cognitive dysfunction, or excessive daytime sleepiness.

[0918] In some embodiments, excessive daytime sleepiness is associated with sleep apnea, traumatic brain injury, or age-related cognitive impairment.

[0919] 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.

[0920] In some embodiments, the excessive sleep is a symptom of narcolepsy.

[0921] In some embodiments, the disease or disorder is a symptom of narcolepsy.

[0922] In some embodiments, the symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, half-awake and half-asleep hallucinations, disrupted nocturnal sleep, or inappropriately timed rapid eye movement (REM) sleep.

[0923] In some embodiments, the symptom of narcolepsy is excessive daytime sleepiness.

[0924] In some embodiments, the symptom of narcolepsy is cataplexy. In some embodiments, cataplexy is a diagnostic condition of narcolepsy (e.g., narcolepsy type 1).

[0925] In some embodiments, the symptom of narcolepsy is sleep paralysis.

[0926] In some embodiments, the symptoms of narcolepsy are semi-awake and semi-sleep hallucinations.

[0927] In some embodiments, the symptom of narcolepsy is disturbed nocturnal sleep.

[0928] In some embodiments, a symptom of narcolepsy is inappropriately timed rapid eye movement (REM) sleep.

[0929] In some embodiments, the neurodegenerative disorder is characterized by cataplexy.

[0930] In some embodiments, the neurodegenerative disorder is characterized by excessive daytime sleepiness.

[0931] In some embodiments, the neurodegenerative disorder is Parkinson's disease.

[0932] In some embodiments, the neurodegenerative disorder is Alzheimer's disease.

[0933] In some embodiments, the neurodegenerative disorder is Huntington's disease.

[0934] In some embodiments, the neurodegenerative disorder is multiple sclerosis.

[0935] In some embodiments, the neurodegenerative disorder is traumatic brain injury.

[0936] In some embodiments, the neurodegenerative disorder is sleep apnea.

[0937] In some embodiments, the neurodegenerative disorder is age-related cognitive dysfunction.

[0938] In some embodiments, the neurodegenerative disorder is recurrent hypersomnia disorder.

[0939] In some embodiments, the recurrent hypersomnia disorder is Klein-Levin syndrome, inappropriately timed sleep (eg, delayed or advanced sleep phase disorder), shift work disorder, and jet lag disorder.

[0940] In some embodiments, the disease or disorder is a symptom of a rare genetic disorder.

[0941] In some embodiments, the symptom of the rare genetic disorder is abnormal daytime sleepiness.

[0942] In some embodiments, the symptom of the rare genetic disorder is excessive daytime sleepiness.

[0943] In some embodiments, the symptom of the rare genetic disorder is REM stage sleep onset.

[0944] In some embodiments, the symptoms of the rare genetic disorder are characterized by cataplexy-like symptoms.

[0945] In some embodiments, the rare genetic disorder is ADCA-DN, Coffin-Lowry syndrome, Moebius syndrome, Norrie disease, Niemann-Pick disease type C, and Prader-Willi syndrome.

[0946] In some embodiments, the disease or disorder is a mental health disorder.

[0947] In some embodiments, the mental health disorder is attention deficit hyperactivity disorder.

[0948] In some embodiments, the mental health disorder is attention deficit disorder.

[0949] In some embodiments, the disease or disorder is metabolic syndrome.

[0950] In some embodiments, the metabolic syndrome is obesity.

[0951] In some embodiments, the disease or disorder is osteoporosis.

[0952] In some embodiments, the disease or disorder is heart failure.

[0953] In some embodiments, the disease or disorder is coma.

[0954] In some embodiments, the disease or disorder is emergence from anesthesia.

[0955] In some embodiments, the disease or disorder is a complication of emergence from anesthesia.

[0956] In some embodiments, the disease or disorder is narcolepsy, a hypersomnia disorder, 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 of emergence from anesthesia.

[0957] In some embodiments, the disease or disorder is narcolepsy, idiopathic hypersomnia, or sleep apnea.

[0958] Route of administration

[0959] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy, or may be administered together with one or more other substances and / or treatments. Such combined treatment may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment.

[0960] For example, the effectiveness of a treatment may be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only a small therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, by administering a compound of Formula (A)-(C), (I'), (I"), (I'"), (II), (II'), (III) or (III') with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit, the benefit experienced by the individual may be increased.

[0961] In the case where the compounds of the present invention are administered in combination with other therapeutic agents, the compounds of the present invention do not need to be administered via the same route as other therapeutic agents and can be administered by different routes due to different physical and chemical characteristics. For example, the compounds of the present invention can be administered orally to produce and maintain good blood levels, while other therapeutic agents can be administered intravenously. Initial administration can be performed according to established protocols known in the art, and then, based on the observed effects, skilled clinicians can modify the dosage, mode of administration, and number of administrations.

[0962] The specific choice of other therapeutic agents will depend on the diagnosis of the attending physician and their judgment of the individual condition and the appropriate treatment regimen. According to this aspect of the present disclosure, there is provided a combination for use in the treatment of a disease in which orexin activity is implicated, the combination comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0963] According to another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0964] In addition to their use in therapeutic drugs, compounds of Formula (I), (I'), (I"), (I'"), (II), (II'), (III) or (III') and pharmaceutically acceptable salts thereof can also be used as pharmacological tools in the development and standardization of in vitro and in vivo test systems to evaluate the effects of modulators of orexin-2 receptor activity in experimental animals (such as dogs, rabbits, monkeys, minipigs, rats and mice) as part of the search for new therapeutic agents.

[0965] In any of the above-mentioned 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.

[0966] The compounds of the present disclosure, or pharmaceutical compositions comprising these compounds, can be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0967] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal sprays or powders); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or reservoir, e.g., subcutaneous or intramuscular.

[0968] Exemplary embodiments

[0969] Exemplary embodiment No. 1. A compound of formula (I):

[0970]

[0971] or a pharmaceutically acceptable salt thereof, wherein:

[0972] X is -N(CH3)- or C1-C6 alkyl;

[0973] L is absent or is a C1-C6 alkyl group;

[0974] Y is -O-;

[0975] n is 1 or 2;

[0976] R a is H or halogen;

[0977] R b is H, halogen or C1-C6 alkyl;

[0978] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0979] Z is -NH-;

[0980] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0981] Ar1 is C6-C 10 aryl; and

[0982] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0983] Provided that when X is alkyl, L is absent.

[0984] Exemplary embodiment No. 2. A compound of formula (I'):

[0985]

[0986] or a pharmaceutically acceptable salt thereof, wherein:

[0987] X is -N(CH3)- or C2-C6 alkyl;

[0988] L is absent or is a C2-C6 alkyl group;

[0989] Y is -O-;

[0990] n is 1 or 2;

[0991] R a is H or halogen;

[0992] R b is H, halogen or C1-C6 alkyl;

[0993] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[0994] Z is -NH-;

[0995] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[0996] Ar1 is C6-C 10 aryl; and

[0997] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[0998] Provided that when X is alkyl, L is absent.

[0999] Exemplary embodiment No. 3. A compound of formula (I"):

[1000]

[1001] or a pharmaceutically acceptable salt thereof, wherein:

[1002] X is -N(CH3)- or C1-C6 alkyl;

[1003] L is absent or is a C1-C6 alkyl group;

[1004] Y is -O-;

[1005] n is 1 or 2;

[1006] R a is H or halogen;

[1007] R b is H, halogen or C1-C6 alkyl;

[1008] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[1009] Z is -NH-;

[1010] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[1011] Ar1 is C6-C 10 aryl; and

[1012] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[1013] Provided that when X is alkyl, L is absent.

[1014] Exemplary embodiment No. 4. A compound of formula (I''):

[1015]

[1016] or a pharmaceutically acceptable salt thereof, wherein:

[1017] X is -N(CH3)- or C2-C6 alkyl;

[1018] L is absent or is a C2-C6 alkyl group;

[1019] Y is -O-;

[1020] n is 1 or 2;

[1021] R a is H or halogen;

[1022] R b is H, halogen or C1-C6 alkyl;

[1023] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[1024] Z is -NH-;

[1025] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[1026] Ar1 is C6-C 10 aryl; and

[1027] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[1028] Provided that when X is alkyl, L is absent.

[1029] Exemplary embodiment No. 5. A compound of formula (II):

[1030]

[1031] or a pharmaceutically acceptable salt thereof, wherein:

[1032] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[1033] L is absent or is a C1-C6 alkyl group;

[1034] Y is -O-;

[1035] n is 1 or 2;

[1036] R a is H or halogen;

[1037] R b is H, halogen or C1-C6 alkyl;

[1038] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[1039] Z is -NH-;

[1040] R1 is C1-C6 haloalkyl or C1-C6 alkyl;

[1041] Ar1 is C6-C 10 aryl; and

[1042] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[1043] Provided that when X is alkyl, L is absent.

[1044] Exemplary embodiment No. 6. A compound of formula (II'):

[1045]

[1046] or a pharmaceutically acceptable salt thereof, wherein:

[1047] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[1048] L is absent or is a C1-C6 alkyl group;

[1049] Y is -O-;

[1050] n is 1 or 2;

[1051] R a is H or halogen;

[1052] R b is H, halogen or C1-C6 alkyl;

[1053] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[1054] Z is -NH-;

[1055] R1 is C1-C6 haloalkyl or C2-C6 alkyl;

[1056] Ar1 is C6-C 10 aryl; and

[1057] T is C6-C6 optionally substituted by one or more halogens 10 Aryl,

[1058] Provided that when X is alkyl, L is absent.

[1059] Exemplary embodiment No. 7. A compound of formula (III):

[1060]

[1061] or a pharmaceutically acceptable salt thereof, wherein:

[1062] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[1063] L is absent or is a C1-C6 alkyl group;

[1064] Y is -O-;

[1065] n is 1 or 2;

[1066] R a is H or halogen;

[1067] R b is H, halogen or C1-C6 alkyl;

[1068] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[1069] Z is -NH-;

[1070] R1 is C1-C6 haloalkyl, C1-C6 alkyl or C3 cycloalkyl substituted by halogen;

[1071] Ar1 is C6-C 10 aryl; and

[1072] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[1073] Provided that when X is alkyl, L is absent.

[1074] Exemplary embodiment No. 8. A compound of formula (III'):

[1075]

[1076] or a pharmaceutically acceptable salt thereof, wherein:

[1077] X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, or C1-C6 alkyl;

[1078] L is absent or is a C1-C6 alkyl group;

[1079] Y is -O-;

[1080] n is 1 or 2;

[1081] R a is H or halogen;

[1082] R b is H, halogen or C1-C6 alkyl;

[1083] or R a and R b Together with the atoms to which they are attached, they form a C3 cycloalkyl group;

[1084] Z is -NH-;

[1085] R1 is C1-C6 haloalkyl, C2-C6 alkyl or C3 cycloalkyl substituted by halogen;

[1086] Ar1 is C6-C 10 aryl; and

[1087] T is a C6-C6 alkyl group optionally substituted with one or more halogen or C1-C6 alkyl groups. 10 Aryl,

[1088] Provided that when X is alkyl, L is absent.

[1089] Exemplary Embodiment No. 9. The compound as described in any of the preceding exemplary embodiments, wherein X is -N(CH3)-.

[1090] Exemplary embodiment No. 10. The compound of any one of Exemplary embodiments 1-8, wherein X is -N(C1-C6 haloalkyl)- or C1-C6 alkyl.

[1091] Exemplary Embodiment No. 11. The compound as described in any of the preceding exemplary embodiments, wherein L is absent.

[1092] Exemplary embodiment No. 12. The compound of any one of Exemplary embodiments 1-10, wherein L is a C1-C6 alkyl group.

[1093] Exemplary Embodiment No. 13. The compound according to any one of the preceding exemplary embodiments, wherein n is 1.

[1094] Exemplary embodiment No. 14. The compound of any one of exemplary embodiments 1-12, wherein n is 2.

[1095] Exemplary embodiment No. 15. The compound as described in any one of the preceding exemplary embodiments, wherein R a It’s H.

[1096] Exemplary embodiment No. 16. The compound according to any one of exemplary embodiments 1-14, wherein R a It's a halogen.

[1097] Exemplary embodiment No. 17. The compound as described in any one of the preceding exemplary embodiments, wherein R b It’s H.

[1098] Exemplary embodiment No. 18. The compound according to any one of exemplary embodiments 1-16, wherein R b It's a halogen.

[1099] Exemplary embodiment No. 19. The compound according to any one of exemplary embodiments 1-14, wherein R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group.

[1100] Exemplary Embodiment No. 20. The compound as described in any of the preceding exemplary embodiments, wherein R1 is C2-C6 alkyl.

[1101] Exemplary embodiment No. 21. The compound of any one of Exemplary embodiments 1-19, wherein R1 is a C3 cycloalkyl substituted with halogen.

[1102] Exemplary Embodiment No. 22. The compound as described in any of the preceding exemplary embodiments, wherein Ar1 is phenyl optionally substituted with one or more halogens.

[1103] Exemplary Embodiment No. 23. The compound as described in any of the preceding exemplary embodiments, wherein T is phenyl optionally substituted with one or more halogens.

[1104] Exemplary embodiment No. 24. The compound according to any one of the preceding exemplary embodiments, wherein the compound has formula (I'-a) or (I'-b):

[1105]

[1106] or a pharmaceutically acceptable salt thereof.

[1107] Exemplary embodiment No. 25. The compound according to any one of the preceding exemplary embodiments, wherein the compound has formula (II'-a), (II'-b) or (II'-c):

[1108]

[1109] or a pharmaceutically acceptable salt thereof, wherein:

[1110] n1 is an integer ranging from 0 to 4.

[1111] Exemplary embodiment No. 26. The compound according to any one of the preceding exemplary embodiments, wherein the compound has formula (IIIA'), (IIIA'-a) or (IIIA'-b):

[1112]

[1113] or a pharmaceutically acceptable salt thereof, wherein:

[1114] n1 is an integer ranging from 0 to 4; and

[1115] n2 is an integer ranging from 0 to 4.

[1116] Exemplary Embodiment No. 27. The compound of any one of the preceding exemplary embodiments, wherein the compound has Formula (IVA'), (IVA'-a), or (IVA'-b):

[1117]

[1118] or a pharmaceutically acceptable salt thereof, wherein:

[1119] n1 is an integer ranging from 0 to 4; and

[1120] n2 is an integer ranging from 0 to 4.

[1121] Exemplary embodiment No. 28. The compound of any one of Exemplary embodiments 1-24, wherein the compound has formula (Ia) or (Ib):

[1122]

[1123] or a pharmaceutically acceptable salt thereof.

[1124] Exemplary embodiment No. 29. The compound of any one of Exemplary embodiments 1-24, wherein the compound has formula (II-a), (II-b) or (II-c):

[1125]

[1126] or a pharmaceutically acceptable salt thereof, wherein:

[1127] n1 is an integer ranging from 0 to 4.

[1128] Exemplary embodiment No. 30. The compound of any one of Exemplary embodiments 1-24, wherein the compound has formula (IIIA), (IIIA-a) or (IIIA-b):

[1129]

[1130]

[1131] or a pharmaceutically acceptable salt thereof, wherein:

[1132] n1 is an integer ranging from 0 to 4; and

[1133] n2 is an integer ranging from 0 to 4.

[1134] Exemplary embodiment No. 31. The compound of any one of Exemplary embodiments 1-24, wherein the compound has formula (IIIA'-1), (IIIA'-1a), or (IIIA'-1b):

[1135]

[1136] or a pharmaceutically acceptable salt thereof, wherein:

[1137] n1 is an integer ranging from 0 to 4; and

[1138] n2 is an integer ranging from 0 to 4.

[1139] Exemplary embodiment No. 32. The compound of any one of Exemplary embodiments 1-24, wherein the compound has formula (IIIA'-2), (IIIA'-2a), or (IIIA'-2b):

[1140] or a pharmaceutically acceptable salt thereof, wherein:

[1141] n1 is an integer ranging from 0 to 4; and

[1142] n2 is an integer ranging from 0 to 4.

[1143] Exemplary embodiment No. 33. The compound according to any one of the preceding exemplary embodiments, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 3, Table 4 or Table 5, or pharmaceutically acceptable salts thereof.

[1144] Exemplary Embodiment No. 34. A compound obtainable or obtained by the method described herein;

[1145] Optionally, the method comprises one or more steps described in Schemes 1-9.

[1146] Exemplary embodiment No. 35. A pharmaceutical composition comprising the compound according to any one of the preceding exemplary embodiments or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[1147] Exemplary embodiment No. 36. The pharmaceutical composition of Exemplary embodiment 35, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 3, Table 4, or Table 5.

[1148] Exemplary embodiment No. 37. 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 said activity is in vitro or in vivo.

[1149] Exemplary embodiment No. 38. 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 the compound of any one of Exemplary Embodiments 1-34 or the pharmaceutical composition of Exemplary Embodiment 35 or Exemplary Embodiment 36.

[1150] Exemplary embodiment number 39. A compound according to any one of exemplary embodiments 1-34 or a pharmaceutical composition according to exemplary embodiment 35 or exemplary embodiment 36 for use in modulating orexin-2 receptor activity; optionally the activity is in vitro or in vivo.

[1151] Exemplary Embodiment No. 40. 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 treating or preventing a disease or disorder.

[1152] Exemplary embodiment No. 41. Use of a compound of any one of Exemplary embodiments 1-34 for the preparation of a medicament for modulating orexin-2 receptor activity; optionally the activity is in vitro or in vivo.

[1153] Exemplary Embodiment No. 42. Use of a compound according to any one of Exemplary Embodiments 1-34 in the preparation of a medicament for treating or preventing a disease or disorder.

[1154] Exemplary embodiment No. 43. The method, compound, pharmaceutical composition or use of any one of exemplary embodiments 37-42, wherein the disease or disorder is associated with the orexin-2 receptor being involved.

[1155] Exemplary embodiment number 44. 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.

[1156] Exemplary embodiment No. 45. 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.

[1157] Example

[1158] For illustrative purposes, neutral compounds of Formula (I) (I'), (I"), (I'"), (II), (II'), (III), or (III') were synthesized and tested in the Examples. It should be understood that the neutral compounds of Formula (I), (I'), (I"), (I'"), (II), (II'), (III), or (III') can be converted to the corresponding pharmaceutically acceptable salts of the compounds using conventional techniques in the art (e.g., by saponification of the ester to a carboxylate, or by hydrolysis of the amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate).

[1159] abbreviation:

[1160]

[1161]

[1162] NMR spectra were recorded on a Bruker Avance III HD UltraShield 400 MHz with a 5 mm PABBO probe, a Bruker DPX 300 MHz equipped with a 5 mm BBI probe, a Bruker AV 400 MHz equipped with a 5 mm PABBO probe, a Bruker DRX500 MHz equipped with a 5 mm PABBI probe, and a Bruker Avance III 600 spectrometer equipped 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.

[1163] LCMS conditions

[1164] Method A: General UPLC method parameters: Gradient mobile phase of 0.1% formic acid in H2O and CH3CN or 0.05% NH3 in H2O and CH3CN. 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 / second, Filter count: 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, LM 1 resolution: 0.02, HM 1 resolution: 0.11.

[1165] Method B: LC / MS (gradient was 5% B in 0.40 min and 5-95% B in 0.40-3.00 min, held at 95% B for 1.00 min, and then 95-5% B in 0.01 min, flow rate was 1.0 mL / min. Mobile phase A was 0.04% trifluoroacetic acid in water, 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 with positive electrospray ionization. The MS range was 100-1000.)

[1166] Method C: 5_95AB_6min-220-254-ELSD-MS2000: LC / MS (gradient is 5% B in 0.40 min and 5-95% B in 2.60 min, keeps 1.00 min at 95% B, and then 95-5% B in 0.01 min, the flow rate is 1.0 mL / min. Mobile phase A is 0.04% trifluoroacetic acid in water, mobile phase B is 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography is Kinetex C18 2.1*50 mm, 5 μm. The detection method is diode array (DAD) and evaporative light scattering detection (ELSD). The MS mode is positive electrospray ionization. The MS range is 100-2000.

[1167] Method D: Hewlett Packard 1100 series with Masslynx software, aqueous phase (C): water (2.5 L) containing 2.5 mL of 28% aqueous ammonia, organic phase (D): acetonitrile (2.5 L) containing 125 mL of water and 2.5 mL of 28% aqueous ammonia. System operated at a flow rate of 1.5 mL / min, injection volume of 1 μL, Phenomenex Gemini-NX, 5 μm, C18, 30 x 2 mm. Column oven temperature of 45°C. Hewlett Packard G1315A diode array detector with UV detection from 230 to 400 nm and Waters micromass ZQ mass spectrometer. Gradients were 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].

[1168] Method E: 5-95AB_2min: LC / MS (column used for chromatography was Kinetex 5μm EVO C18 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 a 0.39 min hold at 5% B. The flow rate was 1.0 mL / min (0.01-1.80), 1.2 mL / min (1.81-2.20).

[1169] Method F: 5-95 CD_4.5 min: LC / MS (the column used for chromatography was an Xbridge C18 2.1*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) and held at 95% B in 0.5 min, 95-100% B (3.50-3.51 min), and held at 5% B for 0.79 min. The flow rate was 1.0 mL / min (0.01-4.30 min).

[1170] Method G: 10-80AB_10min: LC / MS (gradient was 10-80% B in 8.00 min, and held at 80% B for 2.00 min, 80-10% B in 0.01 min and then held at 10% for 2.99 min (0.5 mL / min flow rate). Mobile phase A was 0.04% trifluoroacetic acid in water, 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.

[1171] Method H: 5-95 CD-6 min-220-25 A: The LC / MS gradient was 5% B over 0.40 min and 5-95% B over 0.40-3.40 min, held at 95% B for 0.45 min, and then 95-5% B over 0.01 min, with a flow rate of 0.8 mL / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The column used for chromatography was an Xbridge C18 2.1*50 mm column (5 μm particles). The detection method was diode array (DAD) detection. The MS mode was positive electrospray ionization. The MS range was 100-1000.

[1172] Method I: 5-95AB-6 min-220-25A: The LC / MS gradient was 5% B over 0.40 min and 5-95% B over 2.60 min, holding 95% B over 1.00 min, and then 95-5% B over 0.01 min, with a flow rate of 1.0 mL / min. Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna C18 50*2.0 mm column (5 μm particles). The detection method was diode array (DAD) detection. The MS mode was positive electrospray ionization. The MS range was 100-1000.

[1173] Method J: 5-95AB_2 min: LC / MS: The column used for chromatography was a Halo 5μm C1890A, 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), and a hold of 0.46 min at 95% B. 95-5% B (1.61-1.50 min), and a hold of 0.11 min at 5% B. The flow rate was 1.5 mL / min.

[1174] Method K: 10-100AB_2MIN: LC / MS: The column used for chromatography was 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 a hold of 0.60 min at 100% B. The flow rate was 1.5 mL / min (0.00-1.30 min).

[1175] Method L: 10-80AB_10min: LC / MS (gradient was 10-80% B in 8.00 min, and held at 80% B for 2.00 min, 80-10% B in 0.01 min, and then held at 10% for 2.99 min (0.5 mL / min flow rate). Mobile phase A was 0.04% trifluoroacetic acid in water, 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.

[1176] 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 always run at 5% D. Gradient: 2-95% B and 5% D of A in 1.20 min, hold at 95% B 5% D until 1.40 min @ 0.8 mL / min, 40° C.; Photodiode array detection at 215-350 nm.

[1177] Method N: Column: Agilent Poroshell SB-C18 3.0 × 30 mm, 2.7 μm. Detection: Diode array. Mobile phase A: 0.04% TFA in water, mobile phase B: 0.02% TFA in HPLC-grade acetonitrile. Gradient: 10% B (hold 0.01 min), then 10-100% B (0.01-0.70 min), and 100% B (hold 0.60 min). Flow rate: 1.5 mL / min.

[1178] Method O: LC / MS (column used for chromatography was Kinetex 5 μm EVO C18 2.1*30mm. 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), and a 0.5 minute hold at 95% B, 95-5% B (3.50-3.51 min), and a 0.79 minute hold at 5% B. The flow rate was 1.0 mL / min.

[1179] Synthesis of intermediates Synthesis of tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)piperidine-1-carboxylate

[1180]

[1181] Intermediate 1: tert-Butyl 5-(diisobutylamino)-3,4-dihydropyridine-1(2H)-carboxylate

[1182]

[1183] Under nitrogen, at 20-30 ° C, tert-butyl 3-oxopiperidine-1-carboxylate (1.5 kg, 6.62 mol, 1 equivalent) was added to toluene (15 L) and stirred at 25 ° C. Diisobutylamine (1.95 kg, 14.91 mol, 2.25 equivalents) was added and the reaction mixture was heated to reflux (110-113 ° C) by Dean Stark for 12 hours while removing water (100 mL). The reaction was cooled to 20-30 ° C for 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 the crude intermediate 1 (2.25 kg, QNMR purity: 59%, yield: 65%) as a brown viscous oil, which was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) δppm 0.50-1.00(m,14H),1.48(s,9H),1.75-1.85(m,2H),2.05-2.15(m,3H),2.50-2.60(m,4H),5.9-6.1(m,1H).

[1184] Intermediate 2: tert-Butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopiperidine-1-carboxylate

[1185]

[1186] CH3CN (4.6 L) was injected into a 50 L reactor and a solution of intermediate 1 (2.25 kg, 4.28 mol, 1 eq) in CH3CN (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 eq) dissolved in CH3CN (3 L) was added at 20-30 ° C over 30 minutes, followed by a solution of TBAI (260.46 g, 684 mmol, 0.16 eq) in CH3CN (3 L) at 20-30 ° C over 10 minutes. The reaction mixture was heated to 80 ° C (internal temperature) for 30 min (1.84 ° C / min) and the temperature was maintained at 80 ° C under N2 for 12 h. The reaction was cooled to 20-30 ° C (internal) for 30 min (1.84 ° C / min) to give a brown solution.

[1187] Water (6.5L) is added to the reaction mixture. Then at 20-30°C, the mixture is adjusted to pH=4-5 by AcOH (813mL). The mixture is heated to 60°C (inside), continues for 30min (1.16°C / min) and then kept at 50-60°C (inside) for 1-2h. The mixture is concentrated under reduced pressure (45°C, 0.09mPa) to remove CH3CN (12L) to obtain a brown solution. Ethyl acetate (6L) is added and the mixture is stirred for 10 minutes, and the aqueous layer is separated. This extraction is repeated 2 times. By slowly adding HCl aqueous solution (0.5N, 6L), the organic layer is adjusted to pH=2-3. The mixture is stirred for 10 minutes, and the aqueous layer is separated. By slowly adding saturated NaHCO3 solution (9L), the organic layer is adjusted to pH=7-8. The mixture is stirred for 10 minutes, and the aqueous layer is separated. The organic layer is washed with brine (3L×2), dried over anhydrous Na2SO4 (1.5kg) and filtered. Silica gel (2kg) is added to the organic layer and the mixture is stirred at 20-30°C for 1h, then filtered. The filter cake is washed with ethyl acetate (3L×3). The filtrate is concentrated under reduced pressure (45°C, 0.09mPa) to obtain a crude product in the form of a brown oil. At 20-25°C, the crude product is purified by recrystallization from n-heptane / MTBE (10 / 1, 1V). There is a gradually precipitated yellow solid. The suspension is stirred at 20°C for 2h. The suspension is filtered and the filter cake is washed with n-heptane (500mL×4). The solid is dried under reduced pressure (45°C, 0.01mPa) to obtain intermediate 2 (1.45kg, purity: 99.4%, yield: 87.3%) as a yellow solid. 1H NMR (400MHz, CDCl3) δppm1.30-1.55(m,9H),1.80-2.10(m,2H),2.45-2.60(m,2H),2.90-3.25(m ,3H),3.85-4.25(m,1H),4.70-4.90(m,1H),6.95(t,1H),7.05-7.35(m,1H),7.40-7.50(m,1H).

[1188] Intermediate 3: (rac)-(2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)piperidine-1-carboxylic acid tert-butyl ester

[1189]

[1190] At 20-30 ° C (internal temperature), HCO2NH4 (470.01g, 7.30mol, 3 equivalents) was added to a solution of intermediate 2 (950g, 2.43mol, 1 equivalent) in MeOH (9.5L) over 30 minutes. Catalyst A (prepared according to J.Org.Chem.2019,84,10962-10977, 16.03g, 24.35mmol, 0.01 equivalent) was added over 10 minutes and the reaction mixture was then heated to 60 ° C (internal temperature) for 30min (1.84 ° C / min), then kept at 60 ° C (internal) for 12h under N2. The reaction mixture was cooled to 20 ° C and adjusted to pH = 7-8 by slowly adding NaHCO3 aqueous solution (5L). The reaction mixture was concentrated under reduced pressure (40 ° C, 0.01mPa) to 1 / 3 of the original volume and then extracted with ethyl acetate (2.5L×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure (45°C, 0.01mPa) to give crude intermediate 3 (942g). This batch was combined with another batch of intermediate 3 (1.45Kg from intermediate 2) to give 2.36kg of intermediate 3. At 25°C (pH = 10-11), the crude material was dissolved in ethyl acetate (5L) and NH3·H2O (3L, 7% w / w) was added to the reactor. The mixture was stirred at 25°C for 1h and then extracted with ethyl acetate (5L×3). The combined organic layers were washed with saturated aqueous sodium chloride solution (1L), dried over Na2SO4, filtered and concentrated under reduced pressure (45°C, 0.09mPa) to give intermediate 3 (2.17Kg, QNMR: 91%, yield: 82.9%, based on QNMR) as a yellow oil. 1H NMR(400MHz,d6-DMSO)δppm 0.90-1.20(m,9H),1.25-1.50(m,3H),1.55-1.75(m,3H),2.75-2.95(m,3H),3.10(d,1H), 3.65-3.95(m,1H),4.25-4.45(m,1H),7.00-7.10(m,1H),7.25(t,1H),7.50-7.60(m,1H).

[1191] Intermediate 3: Purification by salt formation

[1192]

[1193] At 70 ° C, racemic di-toluoyl tartaric acid (149.64g, 387.31mmol, 1.5 equivalents) is dissolved as a suspension in ethyl acetate (1L) and added to a solution of intermediate 3 (100g, 258.21mmol, 1 equivalent) in EtOAc (1L). Under N2, the mixture is stirred at 70 ° C for 16h to obtain a yellow slurry. The reaction mixture is gradually cooled to 20 ° C and the solid is separated by filtration, washed with ethyl acetate (0.5L) and vacuum dried (40 ° C, 10mbar) to obtain the intermediate 3 salt (155g, yield: 85%) as a white solid. Intermediate 3 salt (155g, 200.88mmol) is dissolved in dichloromethane (775mL) and NH3·H2O (7.0% w / w%, 650mL, 5 equivalents) is added until pH = 9-10. Under N2, the mixture was stirred at 25 ° C for 1 h. 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 Na2SO4, 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.

[1194] Synthesis of tert-butyl (2S,3S)-3-amino-2-(3-bromo-2-fluorobenzyl)piperidine-1-carboxylate

[1195]

[1196] At 95 ° C, L-(-)-di-toluoyltartaric acid (3.99g, 10.33mmol, 0.4 equivalents) was added to a solution of intermediate 3 (10g, 25.82mol, 1 equivalent) in ethyl acetate (98mL) and MeOH (2mL). The suspension was retained to stir at reflux temperature for 10 minutes, after which the temperature was gradually reduced by turning off the heating and retained to stir for 16 hours. Within 2 hours, the temperature was reduced from 75 ° C to 25 ° C (internal temperature). The solid was separated by filtration and washed with ethyl acetate (300mL), and vacuum dried (40 ° C, 0.01MPa) to produce 5.7g of intermediate 3 salt with ee%=92.5%. It was suspended in ethyl acetate (71mL), and the temperature was increased to reflux temperature and maintained at this temperature for 15 minutes. The temperature was gradually reduced by turning off the heating and the suspension was retained to stir for 16h. The solid was isolated via 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.

[1197] The salt is suspended in dichloromethane (100mL) and washed with 0.5M NaHCO the aqueous solution (150mL). The organic phase is separated and the aqueous phase is extracted with dichloromethane (50mL x 3). The organic phases merged are used Na sO dry, filtered and concentrated under reduced pressure to obtain (2S, 3S) -3- amino -2- (3- bromo -2- fluorobenzyl) piperidine -1- tert-butyl formate (3.4g, yield 34%, theoretically 68%) as a white solid.

[1198] Synthesis of Benzyl (2S,3R,4S)-3-Amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate

[1199]

[1200] 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.

[1201] Reaction Scheme 1

[1202]

[1203] Step a) N-allyl-1,1-diphenylmethaneimine was prepared by heating a mixture of benzophenone imine and allylamine in dichloromethane and reflux for 18 h according to the method of Li et al. (Organic Letters, 2017, 19, 4239). Yield: 95%.

[1204] UPLC-MS, Method M: (CSH-C18, 2 to 95% MeCN) R t =0.52min, MS (ESI + ):m / z=[M+H] + 222. 1 H NMR (400MHz, 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).

[1205] Step b) At -78 ° C, n-butyl lithium (2.5M, 651 mL) was added dropwise to a solution of N-allyl-1,1-diphenylmethaneimine (2) (300 g, 1.36 mol) in tetrahydrofuran (2 L) over 30 min. After the addition was complete, the mixture was stirred at -78 ° C for 2 h. Then, at -78 ° C, a solution of 3-bromo-2-fluorobenzyl bromide (399.53 g, 1.49 mol) in tetrahydrofuran (1 L) was added dropwise to the reaction over 1 h. The resulting mixture was stirred at -78 ° C for 2 h. The reaction was quenched with ethanol (20 mL) to obtain a benzophenone imine solution of 1-(3-bromo-2-fluorophenyl) but-3-ene-2-amine (3), which was used directly in step c). LCMS (ESI + ):m / z 407.9(M+H) +

[1206] Step c) A solution of 1-(3-bromo-2-fluorophenyl)but-3-en-2-amine (3) in benzophenone imine 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) and subsequently with dichloromethane (2 x 3.5 L). The aqueous layer was cooled to 0°C and basified to pH 9-10 with 50% NaOH solution (400 mL). The product was extracted into dichloromethane (1 L). The extract was washed with brine (2 x 500 mL), dried (Na2SO4) and concentrated under reduced pressure.

[1207] The products of five reactions (steps b) and c) starting from 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.

[1208] UPLC, Method M: (CSH-C18 2 to 95% MeCN) R t =0.46min (99.2%), MS (ESI + ):m / z=244.0 / 246.0[M+H] + , Br isotopes. 1 H NMR (400MHz, CDCl3) δppm 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 (376MHz, CDCl3): δ [ppm] = -110.9 (t, 1F).

[1209] Step d) Under nitrogen at 25 ° C, to a mixture of 1-(3-bromo-2-fluorophenyl)but-3-ene-2-amine (3) (150 g, 614 mmol) and 4-bromobut-1-ene (124.4 g, 922 mmol) in N,N-dimethylformamide (1.5 L) were added potassium hydroxide (68.96 g, 1.23 mol) and potassium iodide (204 g, 1.23 mol) in one portion. The mixture was stirred at 80 ° C for 12 h, cooled to 25 ° C and concentrated under reduced pressure. The residue was poured into ice water (1 L) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (3×1 L). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure.

[1210] 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 performed in parallel and used in step e) without further purification. LCMS (ESI + ):m / z298.0[M+H] + .

[1211] Step e) Under nitrogen, at 25 ° C, 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), and the mixture was stirred at 25 ° C for 12 h. The mixture was diluted with water (2 L) and extracted with ethyl acetate (3×1 L). The combined organic phases were dried (Na SO ), filtered and concentrated under reduced pressure. The products from five reactions of 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) as a yellow oil (650 g, 41% yield over two steps). 1 H NMR (400MHz, CDCl3) δppm 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).

[1212] Step f) Benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl]dichloro(tricyclohexylphosphine)ruthenium (Grubbs II 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 h and then concentrated under reduced pressure. The crude products of six reactions performed on 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 afford benzyl 6-(3-bromo-2-fluorobenzyl)-3,6-dihydropyridine-1(2H)-carboxylate (6) as a yellow oil (477 g, 82% yield).

[1213] UPLC, Method M: (column CSH-C18, 2 to 95% MeCN) R t =3.17 min (100%), MS (ESI + ):m / z404 / 406[M+H]+ , Br isotopes. 1 H NMR (400MHz, DMSO-d6, 80℃): 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 7.3Hz,1H). 19 F NMR (376MHz, DMSO-d6, 80°C): δ [ppm] = -112.2 (1F).

[1214] Reaction Scheme 2

[1215]

[1216] 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) at 0°C under nitrogen was added ethylenediaminetetraacetic acid (EDTA, 14.46 g, 49.5 mmol), (CAS 70693-62-8, containing potassium persulfate 3.26 mmol / g, 912 g, 1.48 mol) and solid sodium bicarbonate (623 g, 7.42 mol). 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.

[1217] The crude product was combined with another reaction performed using 177 g of compound 6.

[1218] 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). (rac)-(1RS,2RS,6SR)-2-(3-bromo-2-fluorobenzyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (7) was obtained as a yellow oil (150 g, 38%). 1H NMR (400MHz, CDCl3) δppm1.64-1.87(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).

[1219] Step h) A mixture of (rac)-(1RS,2RS,6SR)-2-(3-bromo-2-fluorobenzyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (7) (20.00 g, 47.59 mmol) and triethylamine trihydrofluoride (80 mL) was heated at 120° C. for 12 h in a Teflon-lined autoclave under nitrogen. 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 (Na 2 SO 4 ), filtered, and concentrated under reduced pressure.

[1220] The crude products from the seven reactions were combined and purified by column chromatography on silica gel using a gradient of petroleum ether:ethyl acetate = 1:0 to 2:1 to afford benzyl (rac)-(2RS,3RS,4RS)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-hydroxypiperidine-1-carboxylate (9) (130 g, 89%) as a yellow oil.

[1221] UPLC, Method M:R t = 2.55 min (96.0%, by UV-TAC), MS (ESI + ):m / z=440.0 / 442.0,[M+H] + ,Br isotope. 1 H NMR(396MHz,DMSO-d6,80℃)δ[ppm]1.76-1.83(m,1H),1.91-2.11(m,1H),2.9 7(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). 19F NMR (373MHz, DMSO-d6, 80℃) δ [ppm] -112.3 (s, 1F), -185.8 (br t, 1F).

[1222] Step i) To a solution of benzyl (rac)-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) were 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 h. 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 x 200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), 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.

[1223] 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 (396MHz, 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-d 6, 80℃)δ[ppm]-112.2(s,1F).

[1224] Step j) Under nitrogen, benzyl (rac)-(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). 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 h. 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 (MgSO4), filtered and evaporated under reduced pressure to give (rac)-(3aR,4R,7aS)-benzyl 4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]piperidine-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 further purification.

[1225] UPLC Method M:R t = 2.16 min (92%, by UV-254 nM), MS (ESI + ):m / z=484 / 486.0[M+H] + ,Br isotope. 1 H NMR (396MHz, DMSO-d6, 80℃) δ1.62(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 (373MHz, DMSO-d6, 80℃) δ [ppm]-112.0 (s, 1F).

[1226] Step k) To a solution of (rac)-(3aR,4R,7aS)-4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]piperidine-5(4H)-carboxylic acid benzyl ester 2-oxide (11) (21.0 g, 39.4 mmol) in acetonitrile (84 mL), dichloromethane (84 mL) and water (168 mL) was added sodium metaperiodate (9.26 g, 43.3 mmol) and ruthenium trichloride (81.7 mg, 0.394 mmol). The mixture was stirred at 25 ° C for 1 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 (150 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and evaporated under reduced pressure to give (rac)-(3aR,4R,7aS)-4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]piperidine-5(4H)-carboxylic acid benzyl ester 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.

[1227] UPLC, Method M:R t =3.66 min (96.0%, by UV-254 nm), MS (ESI - ):m / z=498 / 500[MH] - ,Br isotope. 1 H NMR(396MHz,DMSO-d6,80℃)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 (373MHz, DMSO-d6, 80℃) δ [ppm]-111.9 (s, 1F).

[1228] Step 1) To a solution of (rac)-(3aR,4R,7aS)-4-(3-bromo-2-fluorobenzyl)tetrahydro-[1,3,2]dioxathiolo[4,5-c]piperidine-5(4H)-carboxylic acid benzyl ester 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 (MgSO4), filtered and evaporated under reduced pressure. The residue was dissolved in methyl tert-butyl ether (900 mL) and aqueous sulfuric acid solution (2M, 900 mL) was added. The mixture was stirred at 25 ° C for 1 h. At 0 ° C, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic extracts were washed with brine (500 mL), dried (Na2SO4), 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 was combined, concentrated under reduced pressure and at 0 ° C, the resulting solid was ground with petroleum ether: methyl tert-butyl ether = 10: 1 (3V) for 120 min to obtain (rac) - (2RS, 3RS, 4RS) -2- (3-bromo-2-fluorobenzyl) -4-fluoro-3-hydroxypiperidine-1-carboxylic acid benzyl ester (9) (9.5 g, 73%) as a colorless solid.

[1229] Reaction Scheme 3

[1230]

[1231] Step m) At 0 ° C, under nitrogen, to a mixture of (rac)-(2R, 3R, 4R)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-hydroxypiperidine-1-carboxylic acid benzyl ester (9) (130 g, 295 mmol) and pyridine (477 mL, 5.91 mol) in diisopropyl ether (1.9 L) was added trifluoromethanesulfonic anhydride (244 mL, 1.48 mol) dropwise. The mixture was stirred at 0 ° C for 3 min, then allowed to warm to 25 ° C and stirred for 12 h. 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 phases were dried (Na SO ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 1:0 to 3:1) to give benzyl (rac)-(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.

[1232] UPLC, Method M: (CSH-C18 50 to 95% MeCN) R t =0.92min(100%),MS(ESI + ):m / z=572.1,574.1[M+H] + ,Br isotope. 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). 19 F NMR (376 MHz, CDCl-3): 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).

[1233] Step m) Alternative procedure: A solution of benzyl (rac)-(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 trifluoromethanesulfonic 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 h and poured into an aqueous solution of 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 alkalinity from the triflate. The organic phase was then dried (Na2SO4) and concentrated under reduced pressure. The crude triflate was co-evaporated with tetrahydrofuran (2 × 10 mL) to give (rac)-(2R,3R,4R)-2-(3-bromo-2-fluorobenzyl)-4-fluoro-3-(((trifluoromethyl)sulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (13) (510 g, 98%) as an almost colorless oil.

[1234] Step n) To a mixture of benzyl (rac)-(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) was added sodium azide (34.1 g, 524 mmol) in one portion at 25° C. under nitrogen. 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 (Na 2 SO 4 ), 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 benzyl (rac)-(2R,3S,4R)-3-azido-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (14) (56 g, 69% yield) as a light yellow oil.

[1235] LCMS method E(ESI + ):R t =0.775 min, m / z 465.0 (M+H) + . 1H NMR (400MHz, 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).

[1236] Step o) At 25 ° C, under nitrogen, to a mixture of (rac)-(2R, 3S, 4R)-3-azido-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylic acid benzyl ester (14) (56 g, 120 mmol) in tetrahydrofuran (560 mL) and water (560 mL) was added 3-[bis(2-carboxyethyl)phosphinyl] propionic acid hydrochloride (69.0 g, 241 mmol) in one portion. The mixture was stirred at 25 ° C for 3 min, then heated to 80 ° C and stirred for 12 h. The mixture was cooled to 25 ° C. The residue was poured into ice water (1 L) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (3×1 L). The combined organic phases were dried (Na2SO4), 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 =0.60min

[1237] 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.

[1238] For analytical purposes, the enantiomers were separated using the following: Daicel Chiralpak IC-3 (50 mm×4.6 mm, 3 μm); flow rate 3.4 mL / min, 35° C. Mobile phase A = scCO 2 ; 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 (R ) eluted first. t = 1.11 min), followed by the desired (-)-enantiomer (Rt =1.28min).

[1239] For preparative separation, the enantiomers were separated using the following: Daicel Chiralpak IC (250 mm×50 mm, 10 μm); mobile phase: 30% (isocratic) aqueous ammonia in ethanol containing 70% scCO 2 , 4.3 min). The (+)-enantiomer eluted first, followed by the desired (−)-enantiomer.

[1240] Benzyl (2S,3R,4S)-3-amino-2-(3-bromo-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (14.7 g, 39% yield, 95.9% purity, ee = 99.2%, [α] D =-2.11°, c=1.04, MeOH, 20°C).

[1241] LCMS Method E:R t =2.14min; (ESI + ):m / z 439.0(M+H) + . 1 H NMR (400MHz, CD3CN) δppm1.65-1.88(m,1H+NH2),1.98-2.06(m,1H),2.87-3.01(m ,2H),3.14-3.31(m,2H),3.95(brd,1H),4.35-4.60(m,2H),4.81(dq,1H),4.82(br s,1H),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 (376MHz, DMSO-d6) δppm-113.5(s,1F),-198.3(s,1F).

[1242] Step q) Alternative method: (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-(+)-di-benzoyltartaric acid (461 mg, 1.29 mmol) were charged into a 100 mL round-bottom flask. The solution was stirred at room temperature for 16 h, 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 h to yield D-(+)-di-benzoyltartaric acid salt of compound 1 (1:1 mol / mol ratio, 373 mg, 36%, 99% ee) as a colorless powder.

[1243] 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 separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were dried (Na 2 SO 4 ), filtered and concentrated in vacuo to yield 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.

[1244] Example 1. Procedure for preparing Example 1

[1245] Step 1: tert-Butyl 3-amino-2-(3-bromo-benzyl)-4,4-difluoropyrrolidine-1-carboxylate_cis racemic

[1246]

[1247] The compound was synthesized according to the cis-racemic procedure for tert-butyl 3-amino-2-(3-chloro-benzyl)-4,4-difluoropyrrolidine-1-carboxylate reported in WO2020 / 158958A1.

[1248] Step 2: 3-Amino-2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester_cis racemic

[1249]

[1250] To a solution of tert-butyl 3-amino-2-(3-bromo-benzyl)-4,4-difluoropyrrolidine-1-carboxylate cis-racemic (3 g, 7.7 mmol, 1 eq) 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 eq), K 3 PO 4 (3.27 g, 15.33 mmol, 2 eq) and XPhos-Pd-G 3 (325 mg, 128 μmol, 0.05 eq). The mixture was stirred at 70 ° C. under N 2 for 12 hours. 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) and dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100: 1 to 1: 1) to give 3-amino-2-[[3-[2-[2-[tert-butoxycarbonyl (methyl) amino] ethoxy] -3-fluoro-phenyl] phenyl] methyl] -4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester _ cis racemic (3 g, 68% yield) as a white solid. LCMS, method E: (ESI +): m / z 580 (M + H) + ,RT:0.77min.

[1251] Step 3: 2-[[3-[2-[2-[tert-Butoxycarbonyl(methyl)amino]ethoxy]-3-fluoro-phenyl]phenyl]methyl]-3-(difluoromethylsulfonylamino)-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester_cis racemic

[1252]

[1253] 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 racemic (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) and dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100: 1 to 1: 1) to give 2- [ [ 3 - [ 2 - [ 2 - [ tert - butoxycarbonyl (methyl) amino] ethoxy] -3-fluoro -phenyl] phenyl] methyl] -3- (difluoromethylsulfonylamino) -4,4-difluoro - pyrrolidine-1-carboxylic acid tert - butyl ester cis racemic (850 mg, 55% yield) as a white solid. LCMS, Method E: (ESI +): m / z 594 (M + H -100) + ,RT:0.93min.

[1254] 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

[1255]

[1256] 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 racemic (850 mg, 1.23 mmol, 1 eq) in dioxane (10 mL) was added HCl / dioxane (4 M, 6.13 mL, 20 eq). 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 in the next step without purification. LCMS, method E: (ESI+): m / z 494 (M+H) + ,RT:0.57min.

[1257] 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...4-oxa-6-aza-4-oxa-6-aza-4-oxa-6-methyl-5-ox 3 -yl)methanesulfonamide_cis racemic

[1258]

[1259] 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 racemic (500 mg, 1.0 mmol, 1 eq) in dichloromethane (2.5 L) was added triethylamine (510 mg, 5.1 mmol, 700 μL, 5 eq) and triphosgene (150 mg, 500 μmol, 0.5 eq). The mixture was stirred at 20 ° C for 12 hours. The resulting mixture was then concentrated under reduced pressure to give a residue, which was dissolved in acetonitrile (50 mL). To this solution was added K2CO3 (420 mg, 3.0 mmol, 3 eq) 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) and dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO 2 , 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...4-oxa-6-aza-4-oxa-6-aza-4-oxa-6-methyl-5-ox 3 -yl)methanesulfonamide-cis racemic (150 mg, 28.50% yield). LCMS, Method E: (ESI+): m / z 520.2 (M+H) + ,RT:2.441min.

[1260] 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...4-oxa-6-aza-4-oxa-6-aza-4-oxa-6-methyl-5-ox 3 -yl)methanesulfonamide 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...4-oxa-6-aza-4-oxa-6-aza-4-oxa-6-methyl-5-ox 3 -yl)methanesulfonamide

[1261]

[1262] 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...4-oxa-6-aza-4-oxa-6-aza-4-oxa-6-methyl-5-ox 3 -yl)methanesulfonamide-cis racemic (150 mg) was subjected to superfluid CO2 chromatography 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...4-oxa-6-aza-4-oxa-6-aza-4-oxa-6-methyl-5-ox 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...4-oxa-6-aza-4-oxa-6-aza-4-oxa-6-methyl-5-ox 3 -yl)methanesulfonamide (36 mg, 43% yield).

[1263] SFC separation method:

[1264] Instrument: Waters SFC150AP preparative SFC; column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A is CO2 and B is ethanol (0.1% NH3 in H2O); gradient: B% from 10% to 35% in 12 min isocratic elution mode; flow rate: 35 g / min; wavelength: 220 nm; column temperature: 35°C; system back pressure: 120 bar.

[1265] Example 2. Procedure for preparing Example 2

[1266] Step 1: 2-(2-(3-bromo-2-fluorobenzyl)-2,5-dihydro-1H-pyrrol-1-yl)-1-phenyl-2λ2-ethan-1-one

[1267]

[1268] The compound was synthesized according to the procedure reported in WO2020 / 158958A1 for 2-(2-(3-chloro-2-fluorobenzyl)-2,5-dihydro-1H-pyrrol-1-yl)-1-phenyl-2λ2-ethan-1-one.

[1269] Step 2: Benzyl 2-[(3-Bromo-2-fluoro-phenyl)methyl]-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

[1270]

[1271] 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 eq) in acetonitrile (90 mL) and water (60 mL) was added EDTA (225 mg, 770 μmol, 470 μL, 0.02 eq) and trifluoroacetone (34.45 g, 308 mmol, 27.55 mL, 8 eq) at 0°C. The mixture was stirred at 0°C for 4 h. Oxone (70.9 g, 115 mmol, 3 eq) and sodium carbonate (25.85 g, 308 mmol, 8 eq) were then added at 0°C. The mixture was stirred at 25°C for 12 h. 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 is extracted with ethyl acetate (3 × 150 mL). The combined organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue is purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = (71: 29 to 0: 100) to obtain 2- [(3- bromo-2- fluoro-phenyl) methyl] -6- oxa-3-azabicyclo [3.1.0] hexane -3- carboxylic acid benzyl ester (10 g, 80% yield) as a yellow oil.

[1272] LCMS, method E: (ESI+): m / z 406 (M+H) + ,RT:0.84min. 1 H NMR (400MHz, methanol-d4) δppm 1.29-1.39 (m, 1H), 1.53 (br s,2H),1.97-2.11(m,2H),2.13-2.24(m,1H),2.72-2.82(m,1H),3.36-3.63(m, 2H),5.37-5.46(m,1H),5.52-5.64(m,1H),5.71-5.85(m,5H),5.92(dddd,1H).

[1273] Step 3: 2-[(3-Bromo-2-fluoro-phenyl)methyl]-3-hydroxy-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester

[1274]

[1275] 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 eq), CuBr.MeS (7.08 g, 34.5 mmol, 1.4 eq) in THF (140 mL) was added MeMgBr (3 M in THF, 45.9 mL, 5.6 eq) at -40°C. 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, then extracted with ethyl acetate (3 x 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 (SiO 2 , 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.

[1276] LCMS, method E: (ESI+): m / z 422 (M+H) + ,RT:0.83min. 1 H NMR (400MHz, chloroform-d) δppm0.92-0.92(m,1H),1.82-1.92(m,1H),2.66(dd,1H),2.7 0-2.81(m,1H,),2.85-2.96(m,1H),3.10-3.18(m,1H),3.27-3.34(m,1H),3.42- 3.53(m,1H),3.69-3.76(m,2H),3.76-3.86(m,1H),4.99-5.10(m,2H),6.76-6.8 8(2H,m),7.01-7.09(m,1H),7.15(s,1H),7.16-7.27(m,5H),7.28-7.34(m,1H).

[1277] Step 4: 2-[(3-Bromo-2-fluoro-phenyl)methyl]-4-methyl-3-oxo-pyrrolidine-1-carboxylic acid benzyl ester_cis racemic

[1278]

[1279] To a mixture of 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-hydroxy-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester (6 g, 14.2 mmol, 1 eq) in dichloromethane (60 mL) at 25° C. was added Dess-Martin periodinane (12.06 g, 28.4 mmol, 2 eq). The mixture was then stirred at 45° C. for 12 h. 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 residues were purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = (92:8 to 92:8) to give 2- [(3-bromo-2-fluoro-phenyl) methyl] -4-methyl-3-oxo-pyrrolidine-1-carboxylic acid benzyl ester - cis racemic (4.63 g, yield 78%) as a light yellow oil.

[1280] LCMS, method E: (ESI+): m / z 420 (M+H) + ,RT:1.09min. 1 H NMR (400 MHz, acetonitrile-d3) δ ppm 0.76-0.90 (m, 3H), 2.44-2.51 (m, 1H), 2.54-2.69 (m, 1H), 2.92-3.09 (m, 1H), 3.21-3.33 (m, 1H), 4.12-4.24 (m, 1H), 4.30-4.43 (m, 1H), 4.96 (br d, 1H), 4.92-5.24 (m, 1H), 6.94-7.05 (m, 2H), 7.33-7.41 (m, 5H), 7.43-7.53 (m, 1H).

[1281] Step 5: 3-Amino-2-[(3-bromo-2-fluoro-phenyl)methyl]-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester_cis racemic

[1282]

[1283] To a mixture of 2-[(3-bromo-2-fluoro-phenyl)methyl]-4-methyl-3-oxo-pyrrolidine-1-carboxylic acid benzyl ester-cis racemic (1.5 g, 3.57 mmol, 1 eq) in MeOH (15 mL) was added ammonium formate (675 mg, 10.7 mmol, 3 eq). Nitrogen was bubbled into the reaction mixture for 2 min. Under nitrogen, bis[2-(2-pyridyl)phenyl]iridium(1+); 2-(2-pyridyl)piperidine; hexafluorophosphate (52 mg, 65 μmol, 0.01 eq) were added to the mixture. The mixture was stirred at 80 ° C for 12 h. 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. The combined residues were purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = (45:65 to 5:95) to give 3-amino-2-[(3-bromo-2-fluoro-phenyl)methyl]-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester-cis racemic (2.3 g, yield 44%) as a light yellow oil.

[1284] LCMS, method E: (ESI+): m / z 421 (M+H) + ,RT:0.65min. 1 H NMR (400 MHz, acetonitrile-d3) δ ppm 0.90-1.12 (m, 5H), 2.06-2.22 (m, 2H), 2.93-3.19 (m, 3H), 3.63-3.73 (m, 1H), 3.95-4.08 (m, 1H), 4.80-5.13 (m, 2H), 6.88-7.06 (m, 1H), 7.13-7.60 (m, 7H).

[1285] Step 6: 2-[(3-Bromo-2-fluoro-phenyl)methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester_cis racemic

[1286]

[1287] To a mixture of 3-amino-2-[(3-bromo-2-fluoro-phenyl)methyl]-4-methyl-pyrrolidine-1-carboxylate-cis racemic (1.4 g, 3.32 mmol, 1 eq) in acetonitrile (14 mL) was added pyridine (5.26 g, 66.5 mmol, 5.4 mL, 20 eq). Fluoromethanesulfonyl chloride (1.10 g, 4.98 mmol, 60% purity, 1.5 eq) was then added to the mixture at 0 ° C. The mixture was stirred at 25 ° C for 12 h. 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 residues were purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate = (93:7 to 85:15) to give 2- [(3-bromo-2-fluoro-phenyl) methyl] -3- (fluoromethylsulfonylamino) -4-methyl-pyrrolidine-1-carboxylic acid benzyl ester - cis racemic (1.3 g, 35.92% yield) as a light yellow oil.

[1288] LCMS, method E: (ESI+): m / z 519 (M+H) + ,RT:0.82min. 1 H NMR (400MHz, chloroform-d) δppm1.14-1.22(m,3H),2.06(s,1H),2.43-2.57(m,1H),3.02-3.10(m,1H),3.74-3.90(m,1H),4 .08-4.24(m,1H),4.15-4.23(m,1H),4.33(q,1H),4.64-5.02(m,2H),4.69-4.81(m,2H),5.05-5.12(m,1H),5.09(br d,1H),6.87-6.98(m,1H),7.26-7.28(m,3H),7.32-7.42(m,4H).

[1289] Step 7: 2-[[3-[2-[2-[tert-Butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester_cis racemic

[1290]

[1291] Under nitrogen, to the resulting mixture of 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester-cis racemic (1.15 g, 2.22 mmol, 1 equivalent) 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 equivalents), K 3 PO 4 (1.42 g, 6.67 mmol, 3 equivalents) and Xphos-Pd-G 3 (188 mg, 222 μmol, 0.1 equivalents). 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(NH 4 HCO 3 )-acetonitrile]; B%: 50%-70%, 8 min) to give 2-[[3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester-cis racemic (460 mg, 30% yield) as a white solid. LCMS, method E: (ESI+): m / z 588 (M+H-100) + ,RT:0.92min.

[1292] Step 8: N-[2-[2-[2-Fluoro-3-[[3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidin-2-yl]methyl]phenyl]phenoxy]ethyl]-N-methyl-carbamic acid tert-butyl ester_cis racemic

[1293]

[1294] At 25 ℃, to 2-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-3-(fluoromethylsulfonylamino)-4-methyl-pyrrolidine-1-carboxylic acid benzyl ester-cis racemic (450mg, 654μmol, 1 equivalent) and triethylsilane (300mg, 2.6mmol, 420μL, 4 equivalents) in dichloromethane (4.5mL) mixture, add PdCl2 (58mg, 327μmol, 0.5 equivalents) and triethylamine (200mg, 1.96mmol, 275μL, 3 equivalents). N2 is bubbled into the reaction mixture for 2 minutes. Then at 25 ℃, the entire reaction mixture is stirred for 12h. The reaction mixture is poured into water (20mL) and the mixture is extracted with ethyl acetate (25mL). The aqueous phase is further extracted with ethyl acetate (3×25mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give 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-carbamic acid tert-butyl ester-cis racemic as a yellow oil (300 mg, 83% yield). LCMS, Method E: (ESI+): m / z 611 (M+AcOH) + ,RT:1.00min.

[1295] Step 9: 1-Fluoro-N-[2-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-4-methyl-pyrrolidin-3-yl]methanesulfonamide_cis racemic

[1296]

[1297] 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-carbamic acid tert-butyl ester-cis-rac (300 mg, 540 μmol, 1 eq) 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-rac (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:0.54min. Step 10: 1-Fluoro-N-((4 2 S,43 S,4 4 S)-2 2 -Fluoro-4 4 ,6-dimethyl-5-oxo-9-oxa-6-aza-4(2,1)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ... 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ... 3 -yl)methanesulfonamide

[1298]

[1299] To a solution of 1-fluoro-N-[2-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-4-methyl-pyrrolidin-3-yl]methanesulfonamide-cis racemic (145 mg, 320 μmol, 1 eq) in dichloromethane (1.45 L) was added triethylamine (97 mg, 960 μmol, 135 μL, 3 eq). The mixture was stirred at 25 ° C for 1 min. A solution of triphosgene (28 mg, 95.9 μmol, 0.3 eq) in dichloromethane (1 mL) was then added dropwise and the entire reaction mixture was stirred at 25 ° C for 36 h. Three reactions were set up as described above and all four reaction mixtures were combined. The reaction mixture was concentrated and 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 3 ·H 2 O+NH 4 HCO 3 )-acetonitrile]; B%: 35%-65%, 8 min) to give the racemic desired compound (71 mg, purity 99%) as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm×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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ...3 -yl)methanesulfonamide (26.9 mg, 37% yield) 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclic ... 3 -yl)methanesulfonamide (21.3 mg, yield 30%).

[1300] Example 3. Procedure for preparing Example 3

[1301] Step 1: 2-[(3-Bromo-2-fluoro-phenyl)methyl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester

[1302]

[1303] At 25 ° C, pyrrolidine (71 g, 1.00 mol, 84 mL, 4 equivalents) was added to a solution of piperidin-3-one-N-tert-butoxycarbamate (50 g, 250 mmol, 1 equivalent) in toluene (500 mL). Under a nitrogen atmosphere, the mixture was heated and stirred at 130 ° C for 12 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (500 mL) and then cooled to 0 ° C. At 0 ° C, tetrabutylammonium iodide (3.68 g, 9.95 mmol, 0.1 equivalent) and 1-bromo-3-(bromomethyl)-2-fluoro-benzene (40 g, 149.30 mmol, 1.5 equivalents) were added and the mixture was then heated to 95 ° C and stirred under a nitrogen atmosphere for 12 hours. The mixture was poured into ice water (500 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was separated and washed with saturated aqueous NaHCO 3 solution (100 mL), dried over anhydrous Na 2 SO 4 , 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 2- [(3-bromo-2-fluoro-phenyl) methyl] -3-oxo-piperidine-1-carboxylic acid tert-butyl ester (25 g, 26.1% yield) as a white solid. LCMS, Method E: (ESI +): m / z 332 (M-tBu) + ,RT:0.88min.

[1304] Step 2: 2-[[2-Fluoro-3-(2-hydroxyphenyl)phenyl]methyl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester

[1305]

[1306] To a solution of tert-butyl 2-[(3-bromo-2-fluoro-phenyl)methyl]-3-oxo-piperidine-1-carboxylate (10 g, 25.9 mmol, 1 eq) and (2-hydroxyphenyl)boronic acid (7.14 g, 51.8 mmol, 2 eq) in THF (200 mL) at 25° C. under N 2 was added Xphos-Pd-G 3 (1.10 g, 1.29 mmol, 0.05 eq) and K 3 PO 4 (10.99 g, 51.8 mmol, 2 eq). The reaction mixture was stirred at 70° C. for 8 hours. 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 (eluted 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:0.82min.

[1307] Step 3: 2-[[3-[2-[(E)-3-tert-Butoxy-3-oxo-prop-1-enyloxy]phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester

[1308]

[1309] 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 eq) and tert-butyl prop-2-ynoate (5.10 g, 40.4 mmol, 5.55 mL, 2 eq) in MeCN (95 mL) was added N-methyl-morpholine (1.02 g, 10.11 mmol, 1.11 mL, 0.5 eq) at 25 ° C. under N 2 . 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 (eluted with petroleum ether / ethyl acetate=2 / 1) to give 2-[[3-[2-[(E)-3-tert-butoxy-3-oxo-prop-1-enyloxy]phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (9 g, yield, 76%) as a white solid. LCMS, Method E: (ESI+): m / z 370 (M-155) +(M-Boc-tBu) + ,RT:0.95min.

[1310] Step 4: 2-[[3-[2-(3-tert-Butoxy-3-oxo-propyloxy)phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester

[1311]

[1312] To a solution of tert-butyl 2-[[3-[2-[(E)-3-tert-butoxy-3-oxo-prop-1-enyloxy]phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylate (2.25 g, 4.28 mmol, 1 eq) 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 hours. Three additional reactions were set up as described 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 (with petroleum ether / ethyl acetate=30 / 1 to 10 / 1) to give 2-[[3-[2-(3-tert-butoxy-3-oxo-propyloxy)phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.5 g, yield, 55%) as a white solid. LCMS, Method E: (ESI+): m / z 372 (M-Boc-t-Bu) + ,RT:0.88min.

[1313] Step 5: 3-[2-[2-fluoro-3-[(3-oxo-2-piperidinyl)methyl]phenyl]phenoxy]propanoic acid

[1314]

[1315] A solution of 2-[[3-[2-(3-tert-butoxy-3-oxo-propoxy)phenyl]-2-fluoro-phenyl]methyl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.5 g, 10.42 mmol, 1 eq) 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-piperidinyl)methyl]phenyl]phenoxy]propanoic acid (5 g, 100% yield) as a white solid, which was used in the next step without further purification. LCMS, Method E: (ESI+): m / z 404 (M+H) + ,RT:0.57min.

[1316] Step 6:2 2-Fluoro-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 ,5-diketone

[1317]

[1318] To a solution of 3-[2-[2-fluoro-3-[(3-oxo-2-piperidinyl)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 the starting materials had been consumed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted with petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give 2 as a white solid 2 -Fluoro-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 ,5-dione (2.8 g, yield, 53%). LCMS, Method E: (ESI+): m / z 354 (M+H) + ,RT:0.70min

[1319] Step 7: (4 2 S,4 3 S)-4 3 -Amino-2 2 -Fluoro-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octa-5-one_cis racemic

[1320]

[1321] Towards 2 2 -Fluoro-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3To a solution of 5-dione (200 mg, 570 μmol, 1 eq) in MeOH (20 mL) was added ammonium formate (107 mg, 1.70 mmol, 3 eq) and bis[2-(2-pyridyl)phenyl]iridium(1+);2-(2-pyridyl)pyridinium hexafluorophosphate (7.15 mg, 8.5 μmol, 0.015 eq). Under N2 atmosphere, the mixture was stirred at 80 ° C for 12 hours. The reaction mixture was directly purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water(NH4HCO3)-acetonitrile]; B%: 25%-45%, 8 min) to give (4-dione) as a white solid. 2 S,4 3 S)-4 3 -Amino-2 2 -Fluoro-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclopenta ... + ,RT:1.54min.

[1322] Step 8: N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 -yl)propane-2-sulfonamide_cis racemic

[1323]

[1324] At 0℃, 2 S,4 3 S)-4 3 -Amino-2 2To a solution of -fluoro-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-5-one-cis racemic (180 mg, 510 μmol, 1 eq) and DBU (155 mg, 1.02 mmol, 153 μL, 2 eq) in acetonitrile (1.8 mL) was added propane-2-sulfonyl chloride (130 mg, 914 μmol, 102 μL, 1.8 eq). The mixture was stirred at 25 ° C. for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10 μm; mobile phase: [water (NH4HCO3)-acetonitrile]; B%: 20%-50%, 8 min) to give N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 -yl)propane-2-sulfonamide_cis racemic (100 mg, yield, 43%). LCMS, method E: (ESI+): m / z 461 (M+H) + ,RT:0.71min.

[1325] Step 9: N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 -yl)propane-2-sulfonamide

[1326]

[1327] 180 mg of N-((4 2 S,4 3 S)-2 2 -Fluoro-5-oxo-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 -yl) propane-2-sulfonamide_cis racemic to give N-((4 2 S,4 3 S)-2 2-Fluoro-5-oxo-8-oxa-4(2,1)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 -yl)propane-2-sulfonamide (15 mg, yield, 6.4%).

[1328] Example 4. Procedure for preparing Example 4

[1329] Step 1: tert-Butyl 6-(3-bromo-2-fluorobenzyl)-7-oxo-5-azaspiro[2.4]heptane-5-carboxylate

[1330]

[1331] Under nitrogen, tetrahydrofuran (1.4L) is injected into the reactor and LiHMDS (4.0L, 1M in THF, 1.2 equivalents) is added. The reaction mixture is cooled to -70°C to -65°C. At -70°C to -65°C, a solution of tert-butyl 7-oxo-5-azaspiro [2.4] heptane-5-formate (700g, 1.0 equivalents) in THF (1.4L) is added dropwise to the reactor and stirred for 3 hours. Then at -70°C to -65°C, Et2Zn (3.3L, 1M in toluene, 1.0 equivalents) is added dropwise to the reactor, followed by DMPU (552g, 1.3 equivalents) at -70°C to -65°C. Then a solution of 1- bromo-3- (bromomethyl) -2- fluorobenzene (977g, 1.1 equivalents) in THF (1.4L) was added dropwise to the reactor and stirred at -70°C to -65°C for at least 3h. Then at 0°C, the reaction mixture was poured into ice water (1.5kg) and extracted twice with ethyl acetate (14L). The organic phase was separated and combined and washed twice with brine (3.5L), and then dried with Na2SO4 (500g) and filtered. The organic phase was concentrated under vacuum to obtain a crude product, which was purified by column chromatography (SiO2, eluted with petroleum ether: ethyl acetate = 1:0 to 13:1) to obtain the subject compound (969g, 91.7% yield) as a white solid. LCMS (method O) (ESI+): m / z 341.9 (M+H-55) + ,RT:1.97min.

[1332] Step 2: (E / Z)-tert-Butyl 6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)imino)-5-azaspiro[2.4]heptane-5-carboxylate

[1333]

[1334] 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) (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 hours. 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. and 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 Na2SO4 (500 g) and concentrated to give the crude product, which was purified by column chromatography (SiO2, eluted 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.

[1335] Step 3: tert-Butyl (6S,7S)-6-(3-bromo-2-fluorobenzyl)-7-(((R)-tert-butylsulfinyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate

[1336]

[1337] 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 eq) in THF (1.5 L, 10 V) and H O (30 mL, 0.2 V) was cooled to -50°C. Under nitrogen, NaBH (17 g, 1.5 eq) was added to the reactor at -50°C. The mixture was stirred at 25±5°C for at least 2 h. At 25-40°C, MeOH (0.9 L) was added to the reactor and stirred at 25±5°C for at least 3 h. Seven additional reactions were set up as above, combined, and concentrated in vacuo at 45°C. The residue was purified by column chromatography (SiO 2 , eluted with petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give a crude product, which was triturated with petroleum ether / ethyl acetate = 8 / 1 (6 V) for 8 h 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.

[1338] Step 4: tert-Butyl (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylate

[1339]

[1340] 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 at 25+5 ° C under nitrogen for at least 18 h. A total of 3 batches were set up, combined and transferred to saturated NaHCO 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 in vacuo below 45 ° C to give a residue, which was triturated with petroleum ether:ethyl acetate = 10:1 (1 L) for 8 h. The precipitate was collected and dried in vacuo (<40° C.) for 8 h to afford the title compound as a yellow solid (178 g, 68.2% yield).

[1341] 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).

[1342] Step 5: (6S,7S)-7-amino-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester

[1343]

[1344] To a solution of (6S,7S)-7-amino-6-(3-bromo-2-fluorobenzyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (900 mg, 2.25 mmol, 1 eq) in THF (8 mL) and H2O (2 mL) was added K3PO4 (960 mg, 4.51 mmol, 2 eq), compound 1A (1.28 g, 3.38 mmol, 1.5 eq) and cataCXium A-Pd-G2 (151 mg, 225 μmol, 0.1 eq) under N2, 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 phases were 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 (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (6S, 7S) -7-amino-6- [ [3- [2- [tert-butoxycarbonyl (methyl) amino] ethoxy] phenyl] -2-fluoro-phenyl] methyl] -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (1.2 g, 89% yield) as a yellow oil. LCMS, Method E. (ESI +): m / z 570.3 (M + H) + ,RT:0.746min.

[1345] Step 6: (6S,7S)-tert-Butyl 6-[[3-[2-[2-[tert-Butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-7-(difluoromethylsulfonylamino)-5-azaspiro[2.4]heptane-5-carboxylate

[1346]

[1347] To a solution of (6S,7S)-7-amino-6-[[3-[2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]phenyl]-2-fluoro-phenyl]methyl]-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.39 g, 2.44 mmol, 1 eq) in acetonitrile (14 mL) was added pyridine (3.87 g, 48.9 mmol, 3.94 mL, 20 eq) followed by difluoromethanesulfonyl chloride (551.75 mg, 3.67 mmol, 1.5 eq) at 0 ° C. The mixture was then heated and stirred at 60 ° C. for 12 h. 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 phases were 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 2 , petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give (6S, 7S) -6- [ [3- [2- [tert-butoxycarbonyl (methyl) amino] ethoxy] phenyl] -2-fluoro-phenyl] methyl] -7- (difluoromethylsulfonylamino) -5- azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (700 mg, 41% yield) as a colorless oil. LCMS, Method E: (ESI +): m / z 584.3 (M-100) + ,RT:0.922min.

[1348] Step 7: 1,1-Difluoro-N-[(6S,7S)-6-[[2-fluoro-3-[2-[2-(methylamino)ethoxy]phenyl]phenyl]methyl]-5-azaspiro[2.4]hept-7-yl]methanesulfonamide

[1349]

[1350] 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 eq) in HCl / dioxane (30 mL) was stirred at 25° C. for 0.5 h. 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]heptane-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:0.590min.

[1351] 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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclopentaphenanthene]-3'-yl)methanesulfonamide

[1352]

[1353] 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]heptane-7-yl]methanesulfonamide (213 mg, 440 μmol, 1 eq) in dichloromethane (2.2 L) was added TEA (223 mg, 2.20 mmol, 306 μL, 5 eq) and a solution of triphosgene (78 mg, 264 μmol, 0.6 eq) in dichloromethane (1 mL) was added dropwise. The mixture was then stirred at 25 ° C for 12 h. 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 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water(NH4HCO3)-acetonitrile]; B%: 35%-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)-pyrrolidinyl-1(1,2),2(1,3)-diphenylheterocyclopentaphenanthene]-3'-yl)methanesulfonamide (66 mg, 16% yield) as a white solid.

[1354] Table A: Experimental details of Example Nos. 1-41

[1355] The compounds of Table A were synthesized using appropriate starting materials according to the above methods.

[1356]

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368] 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)-piperidin-1(1,2),2(1,3)-diphenylheterocyclic octahedral-4 3 -yl)methanesulfonamide synthesis.

[1369]

[1370] Intermediate 2, Synthesis of (2S,3R,4S)-2-[(3-bromo-2-fluoro-phenyl)methyl]-4-fluoro-3-(fluoromethylsulfonylamino)piperidine-1-carboxylic acid benzyl ester

[1371]

[1372] 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 eq) and 1-methylimidazole (2.92 g, 35.5 mmol, 2.83 mL, 3 eq) in tetrahydrofuran (20 mL) was degassed and purged with nitrogen at 20°C. Fluoromethanesulfonyl chloride (2.35 g, 17.8 mmol, 1.5 eq) was dissolved in tetrahydrofuran (6 mL) solution 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 phases were 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:methyl tert-butyl ether (10:1, 20 mL). The resulting solid was collected by filtration, washed with petroleum ether:methyl tert-butyl ether (10:1, 5 mL) and dried under high vacuum to give (2S,3R,4S)-2-[(3-bromo-2-fluoro-phenyl)methyl]-4-fluoro-3-(fluoromethylsulfonylamino)piperidine-1-carboxylic acid benzyl ester (5.3 g, 84% yield) as a yellow solid. 1 H NMR: (400MHz, DMSO-d6) δppm 1.75-2.05(m,2H),2.90-3.05(br t,1H),3.30(m,2H),3.65-4.00(br m,2H),4.40-4.06(br m,2H),4.80-5.05(m,2H),5.20-5.60(m,2H),6.80-7.15(m,3H),7.15-7.40(m,4H),7.50(brt,1H),8.65(br s,1H)

[1373] Intermediate 3, Synthesis of 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

[1374]

[1375] To a solution of intermediate 2 (5.3 g, 9.90 mmol, 1 eq) in dioxane (53 mL) was added bispinacolatodiborane (7.54 g, 29.7 mmol, 3 eq), potassium acetate (4.86 g, 49.5 mmol, 5 eq) and Pd(dppf)Cl (362 mg, 495 μmol, 0.05 eq) 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 eluted 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.

[1376] LCMS, Method G (ESI+): m / z 501 (M-81) + ,RT:6.436min,m / z 583(M+H) + ,RT:8.821min.

[1377] Intermediate 4, Synthesis of (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-carboxylic acid benzyl ester

[1378]

[1379] 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), di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (140 mg, 215 μmol, 0.05 equiv) and Na2CO3 (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 h. At 20 ° C, the reaction mixture was quenched by the addition of water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (trifluoroacetic acid conditions, column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: 40% -70% B, over 8 min) to give (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-carboxylic acid benzyl ester (Intermediate 4, 1.53 g, 50% yield) as a white solid. LCMS Method H: (ESI+): m / z 730 (M+18) + ,RT:3.618min

[1380] Synthesis of Intermediate 5, 3-[2-[3-[[(2S,3R,4S)-1-benzyloxycarbonyl-4-fluoro-3-(fluoromethylsulfonylamino)-2-piperidinyl]methyl]-2-fluoro-phenyl]-4,6-difluoro-phenoxy]propionic acid

[1381]

[1382] A solution of Intermediate 4 (1.53 g, 2.15 mmol, 1 eq) in hydrochloric acid (15 mL, 4 M solution in dioxane) was stirred for 2 h at 25° C. The reaction was concentrated under reduced pressure to give 3-[2-[3-[[(2S,3R,4S)-1-benzyloxycarbonyl-4-fluoro-3-(fluoromethylsulfonylamino)-2-piperidinyl]methyl]-2-fluoro-phenyl]-4,6-difluoro-phenoxy]propanoic acid (Intermediate 5, 1.62 g, 97.69% yield) as a white solid, which was used in the next step without purification. 1H NMR (400MHz, DMSO-d6) δppm 1.60-2.5(m,2H),2.35(t,1H),2.95-3.35(m,3H),3.70-3.95(br m,4H),4.40-5.00(m,4H),5.30-5.60(m,2H),6.80-7.50(m,10H),8.70(br s,1H),12.20(br s,1H).

[1383] Synthesis of the intermediate 6,3-[2,4-difluoro-6-[2-fluoro-3-[[(2S,3R,4S)-4-fluoro-3-(fluoromethylsulfonylamino)-2-piperidinyl]methyl]phenyl]phenoxy]propionic acid

[1384]

[1385] The mixture of intermediate 5 (1.62g, 2.47mmol, 1 equivalent), Pd / C (162mg, 10% purity) in ethyl acetate (16mL) is degassed and purged with H23 times, and then under H2 (15psi), at 25 DEG C, the mixture is stirred for 3h. The precipitate is filtered and the filter cake is washed with ethyl acetate (50mL), and the filtrate is concentrated under high vacuum to obtain a residue. The residue is ground with methyl tert-butyl ether (10mL). The gained solid is collected by filtration, washed with methyl tert-butyl ether (5mL) and dried under high vacuum to obtain 3- [2,4-difluoro-6- [2-fluoro-3- [[(2S, 3R, 4S) -4-fluoro-3- (fluoromethylsulfonylamino) -2-piperidinyl] methyl] phenyl] phenoxy] prop...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is -N(CH3)- or C1-C6 alkyl; L is absent or is a C1-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is C6-C 10 aryl; and T is C6-C 10 Aryl, Provided that when X is alkyl, L is absent.

2. A compound of formula (I'): or a pharmaceutically acceptable salt thereof, wherein: X is -N(CH3)- or C2-C6 alkyl; L is absent or is a C2-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is C6-C 10 aryl; and T is C6-C 10 Aryl, Provided that when X is alkyl, L is absent.

3. A compound of formula (I"): or a pharmaceutically acceptable salt thereof, wherein: X is -N(CH3)- or C1-C6 alkyl; L is absent or is a C1-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is C6-C 10 aryl; and T is C6-C 10 Aryl, Provided that when X is alkyl, L is absent.

4. A compound of formula (I''): or a pharmaceutically acceptable salt thereof, wherein: X is -N(CH3)- or C2-C6 alkyl; L is absent or is a C2-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is C6-C 10 aryl; and T is C6-C 10 Aryl, Provided that when X is alkyl, L is absent.

5. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)- or C1-C6 alkyl; L is absent or is a C1-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl or C1-C6 alkyl; Ar1 is C6-C 10 aryl; and T is C6-C 10 Aryl, Provided that when X is alkyl, L is absent.

6. A compound of formula (II'): or a pharmaceutically acceptable salt thereof, wherein: X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)- or C1-C6 alkyl; L is absent or is a C1-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl or C2-C6 alkyl; Ar1 is C6-C 10 aryl; and T is C6-C 10 Aryl, Provided that when X is alkyl, L is absent.

7. A compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)- or C1-C6 alkyl; L is absent or is a C1-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl, C1-C6 alkyl or C3 cycloalkyl substituted by halogen; Ar1 is C6-C 10 aryl; and T is C6-C6 optionally substituted by one or more halogen or C1-C6 alkyl. 10 Aryl, provided that when X is alkyl, L is absent.

8. A compound of formula (III'): or a pharmaceutically acceptable salt thereof, wherein: X is -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)- or C1-C6 alkyl; L is absent or is a C1-C6 alkyl group; Y is -O-; n is 1 or 2; R a is H or halogen; R b is H, halogen or C1-C6 alkyl; or R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl group; Z is -NH-; R1 is C1-C6 haloalkyl, C2-C6 alkyl or C3 cycloalkyl substituted by halogen; Ar1 is C6-C 10 aryl; and T is C6-C6 optionally substituted by one or more halogen or C1-C6 alkyl. 10 Aryl, Provided that when X is alkyl, L is absent.

9. A compound as claimed in any one of the preceding claims, wherein X is -N(CH3)-.

10. The compound of any one of claims 1-8, wherein X is -N(C1-C6 haloalkyl)- or C1-C6 alkyl.

11. A compound as claimed in any one of the preceding claims, wherein L is absent.

12. The compound of any one of claims 1-10, wherein L is a C1-C6 alkyl group.

13. A compound as claimed in any one of the preceding claims, wherein n is 1.

14. The compound of any one of claims 1-12, wherein n is 2.

15. A compound as claimed in any one of the preceding claims, wherein R a It's H.

16. A compound as described in any one of claims 1 to 14, wherein R a It's a halogen.

17. A compound as claimed in any one of the preceding claims, wherein R b It's H.

18. A compound as described in any one of claims 1 to 16, wherein R b It's a halogen.

19. A compound as described in any one of claims 1 to 14, wherein R a and R b Together with the atoms to which they are attached they form a C3 cycloalkyl.

20. A compound as claimed in any one of the preceding claims, wherein R1 is C2-C6 alkyl.

21. A compound as described in any one of claims 1 to 19, wherein R1 is a C3 cycloalkyl substituted by halogen.

22. A compound as claimed in any one of the preceding claims, wherein Ar1 is phenyl optionally substituted with one or more halogens.

23. A compound as claimed in any one of the preceding claims, wherein T is phenyl optionally substituted with one or more halogens.

24. A compound as claimed in any one of the preceding claims, wherein the compound has formula (I'-a) or (I'-b): or a pharmaceutically acceptable salt thereof.

25. A compound as claimed in any one of the preceding claims, wherein the compound has formula (II'-a), (II'-b) or (II'-c): or a pharmaceutically acceptable salt thereof, wherein: n1 is an integer ranging from 0 to 4.

26. The compound of any one of the preceding claims, wherein the compound has formula (IIIA'), (IIIA'-a) or (IIIA'-b): or a pharmaceutically acceptable salt thereof, wherein: n1 is an integer ranging from 0 to 4; and n2 is an integer ranging from 0 to 4.

27. The compound of any one of the preceding claims, wherein the compound has formula (IVA'), (IVA'-a) or (IVA'-b): or a pharmaceutically acceptable salt thereof, wherein: n1 is an integer ranging from 0 to 4; and n2 is an integer ranging from 0 to 4.

28. The compound of any one of claims 1 to 24, wherein the compound has formula (Ia) or (Ib): or a pharmaceutically acceptable salt thereof.

29. The compound of any one of claims 1 to 24, wherein the compound has formula (II-a), (II-b) or (II-c): or a pharmaceutically acceptable salt thereof, wherein: n1 is an integer ranging from 0 to 4.

30. The compound of any one of claims 1-24, wherein the compound has formula (IIIA), (IIIA-a) or (IIIA-b): or a pharmaceutically acceptable salt thereof, wherein: n1 is an integer ranging from 0 to 4; and n2 is an integer ranging from 0 to 4.

31. The compound of any one of claims 1-24, wherein the compound has formula (IIIA'-1), (IIIA'-1a) or (IIIA'-1b): or a pharmaceutically acceptable salt thereof, wherein: n1 is an integer ranging from 0 to 4; and n2 is an integer ranging from 0 to 4.

32. The compound of any one of claims 1-24, wherein the compound has formula (IIIA'-2), (IIIA'-2a) or (IIIA'-2b): or a pharmaceutically acceptable salt thereof, wherein: n1 is an integer ranging from 0 to 4; and n2 is an integer ranging from 0 to 4.

33. The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 3, Table 4 or Table 5, or a pharmaceutically acceptable salt thereof.

34. A compound obtainable or obtained by a method as described herein; Optionally, the method comprises one or more steps described in Schemes 1-9.

35. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

36. The pharmaceutical composition of claim 35, wherein the compound is selected from the compounds described in Table 1, Table 2, Table 3, Table 4 or Table 5.

37. A method of modulating orexin-2 receptor activity comprising contacting a cell with an effective amount of a compound of any one of claims 1-34.

38. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35 or claim 36.

39. A compound as claimed in any one of claims 1 to 34 or a pharmaceutical composition as claimed in claim 35 or claim 36 for use in modulating orexin-2 receptor activity.

40. A compound as claimed in any one of claims 1 to 34 or a pharmaceutical composition as claimed in claim 35 or claim 36 for use in treating or preventing a disease or disorder.

41. Use of a compound according to any one of claims 1 to 34 in the preparation of a medicament for modulating orexin-2 receptor activity.

42. Use of a compound as claimed in any one of claims 1 to 34 in the preparation of a medicament for the treatment or prevention of a disease or disorder.

43. The method, compound, pharmaceutical composition or use of any one of claims 37-42, wherein the disease or disorder is associated with the orexin-2 receptor being involved.

44. The method, compound, pharmaceutical composition or use of any one of claims 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.

45. The method, compound, pharmaceutical composition or use of any one of claims 37-44, wherein the disease or disorder is narcolepsy, idiopathic hypersomnia, sleep apnea or insomnia.

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